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Masashi Aoki
Section
Graduate School of Medicine
Job title
Professor
Degree
  • 博士(医学)(東北大学)

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私は筋萎縮性側索硬化症(ALS)をはじめとした神経変性疾患や筋疾患の病態解明を疾患特異的なiPS細胞やモデル動物を利用して進め、さらにその治療法の開発に取り組んでおります。東北大学神経内科では多発性硬化症、視神経脊髄炎などの神経免疫疾患やパーキンソン病などの神経変性疾患の病態解明進めると共に、ALSに対するHGFおよび遠位型ミオパチーに対するアセノイラミン酸の治療法開発を医師主導治験として進めてきました。遠位型ミオパチー(GNEミオパチー)に対するアセノイラミン酸は2024年に製造販売承認されました。
脳神経内科では現在は治療が困難と思われている疾患においても、次々に新しい治療法が実用化されています。脳神経内科医であれば、認知症や脳卒中などのcommon diseaseを診ることは当然ですが、それに加えて、ALSや筋ジストロフィーなどの希少疾患に自信を持って対応できる力量を持ちたいと考えています。神経学的診察等の技術がある限り、たとえ人工知能(AI)が診療に導入されたとしても私たちの立場は揺るがないと思います。その一方で、今後益々需要が増える脳神経内科医が不足していることは明らかです。特に東北地方における医師不足、中でも脳神経内科医の不足は顕著であり、一人でも多くの脳神経内科医を増やしたい、というのが私の一番の目標です。

Research History 8

  • 2023/04 - Present
    東北大学病院 臨床研究推進センター センター長(兼任)

  • 2011/02 - Present
    Tohoku University Graduate School of Medicine

  • 2012/04 - 2023/03
    東北大学病院 臨床研究推進センター 副センター長(兼任)

  • 2007/06 - 2011/01
    東北大学病院 神経内科 講師

  • 1998/09 - 2007/05
    東北大学医学部附属病院 神経内科 助手

  • 1998/07 - 1998/09
    Harvard Medical School Instructor in Neurology

  • 1996/04 - 1998/06
    Massachusetts General Hospital Research fellow

  • 1994/04 - 1996/03
    東北大学病院 医員

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Committee Memberships 10

  • 全国病院長会議 研究担当WG

    2022/04 - Present

  • 一般社団法人ARO協議会 理事

    2020/09 - Present

  • 日本神経学会 理事

    2018/05 - Present

  • 日本脊髄障害医学会 理事

    2017/11 - Present

  • 一般社団法人東北臨床研究審査機構(略称ACTIVATO) 理事長

    2017/06 - Present

  • 日本神経治療学会 理事(2024/11- 理事長)

    2015/11 - Present

  • 日本神経学会 筋萎縮性側索硬化症診療ガイドライン作成委員会 委員長

    2015/04 - Present

  • 臨床遺伝研究会 評議員

    2006/05 - Present

  • 日本人類遺伝学会 評議員

    2004/01 - Present

  • 日本神経学会 評議員

    2002/05 - Present

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Professional Memberships 10

  • 日本MGレジストリー

  • ARO協議会

  • 日本筋学会

  • 日本脳循環代謝学会

  • THE JAPANESE SOCIETY OF INTERNAL MEDICINE

  • 日本難病医療ネットワーク学会

  • 日本脊髄障害医学会

  • 日本神経治療学会

  • 日本人類遺伝学会(2004/01- 評議員)

  • 日本神経学会(2002/05- 評議員 2018/05-理事)

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Research Interests 48

  • 臨床開発

  • スタートアップ支援

  • 創薬

  • 希少性筋疾患

  • 多系統蛋白質症

  • ミオパチー

  • 抗MOG抗体関連疾患

  • Neurology

  • 脳神経内科

  • COVID-19

  • 災害医学

  • 神経内科

  • 災害医療

  • 分子イメージング

  • 幹細胞

  • 脊髄小脳変性症

  • 多系統萎縮症

  • 診断

  • 人工知能

  • ジスフェルリン

  • amyotrophic lateral sclerosis

  • SOD1

  • dysferlin

  • fus

  • 分子生物学

  • 臨床研究

  • 認知症

  • 生化学

  • 封入体筋炎

  • 神経内科学

  • 分子遺伝学

  • 神経科学

  • 脊髄損傷

  • プリオン病

  • 重症筋無力症

  • 希少疾患

  • 医師主導治験

  • 視神経脊髄炎

  • パーキンソン病

  • 多発性硬化症

  • iPS細胞

  • 再生医療

  • 神経変性疾患

  • 筋疾患

  • 臨床神経学

  • トランスレーショナルリサーチ

  • dysferlin

  • amyotrophic lateral sclerosis

Research Areas 3

  • Life sciences / Neuroscience - general /

  • Life sciences / Neurology /

  • Life sciences / Medical biochemistry /

Awards 6

  1. 平成21年度日本神経治療学会 学会賞

    2010/07/15 日本神経治療学会

  2. 平成21年度東北大学医学部奨学賞(金賞)、坂田賞

    2010/01 東北大学医学部

  3. 平成13年度研究奨励助成金

    2002/01 難病医学研究財団 変異Cu/Zn SOD遺伝子導入ラットの作製とALSに対する新しい治療法の開発

  4. 「生命の彩」ALS研究助成基金

    1999/04

  5. 平成6年度東北大学医学部奨学賞(銀賞)、坂田賞

    1995/01 東北大学医学部

  6. 第14回医学奨励賞(中村隆賞)銀賞

    1993/12 東北脳血管障害懇話会

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Papers 780

  1. An HTLV-1 carrier with sporadic late-onset nemaline myopathy accompanied by skin lesions indicating indolent adult T-cell leukemia/lymphoma and Sjögren's syndrome: a case report and literature review. International-journal Peer-reviewed

    Ako Miyata, Tomomi Shijo, Rumiko Izumi, Emi Yamazaki, Naoto Sugeno, Naoki Suzuki, Ichizo Nishino, Yoshihide Asano, Masashi Aoki

    Neuromuscular disorders : NMD 52 105417-105417 2025/06/13

    DOI: 10.1016/j.nmd.2025.105417  

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    Sporadic late-onset nemaline myopathy (SLONM) is a rare acquired myopathy. Herein, we report a rare case of co-occurring SLONM, indolent adult T-cell leukemia/lymphoma (ATL), and Sjögren's syndrome (SS) in a 60-year-old woman who was a human T-cell leukemia virus type 1 (HTLV-1) carrier. She presented with sub-acute proximal muscle weakness and chest erythema. Muscle biopsy revealed perivascular inflammation and accumulation of nemaline bodies in the atrophic fibers. Skin biopsy indicated indolent ATL. Analysis of specific antibodies and salivary gland biopsy led to a SS diagnosis. CD4-positive T cells expressing FoxP3 and CCR4, which constitute an HTLV-1-infected cell signature, were observed in all three tissues. Her muscular and cutaneous symptoms responded well to steroids. This case suggests a potential link between HTLV-1 latent infection and reactivation and SLONM development and progression. We review the clinicopathological features of SLONM across various etiologies, providing valuable insights into this rare condition.

  2. Safety Extension Study of Edaravone Oral Suspension in Patients With Amyotrophic Lateral Sclerosis for up to an Additional 96 Weeks of Treatment. International-journal Peer-reviewed

    Angela Genge, Gary L Pattee, Gen Sobue, Masashi Aoki, Hiide Yoshino, Philippe Couratier, Christian Lunetta, Susanne Petri, Daniel Selness, Vesna Todorovic, Nissim Sasson, Manabu Hirai, Fumihiro Takahashi, Alejandro Salah, Stephen Apple, Art Wamil, Alexander Kalin, Carlayne E Jackson

    Muscle & nerve 2025/06/09

    DOI: 10.1002/mus.28451  

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    INTRODUCTION/AIMS: Edaravone intravenous (IV) and oral suspension have been shown to have similar pharmacokinetics, safety, and slowing of functional decline in patients with amyotrophic lateral sclerosis (ALS). Study MT-1186-A01 indicated that edaravone oral suspension was well-tolerated over 48 weeks, with no new safety concerns identified relative to existing safety data of IV edaravone, including Study MCI186-19. The aim of this study was to assess the long-term safety and tolerability of edaravone oral suspension in patients with ALS. METHODS: Study MT-1186-A03 (NCT04577404) was a phase 3, open-label, multi-center, extension study that evaluated the long-term safety of edaravone oral suspension over an additional 96 weeks in patients with ALS who have completed the initial 48 weeks of Study MT-1186-A01, for a total of up to 144 weeks of treatment. Patients received a 105-mg dose of edaravone administered in treatment cycles identical to the approved edaravone on/off dosing schedule. Patients had definite, probable, probable-laboratory-supported, or possible ALS. RESULTS: In Study MT-1186-A03, edaravone oral suspension was well tolerated with no new safety concerns. The most common treatment-emergent adverse events (TEAEs) were fall, muscular weakness, dyspnea, constipation, and dysphagia. These TEAEs were consistent with the safety profile for edaravone from previous clinical trials. DISCUSSION: These results help establish the long-term safety and tolerability profile of edaravone oral suspension.

  3. Efficacy and Safety of Once Daily Dosing vs. Approved On/Off Dosing of Edaravone Oral Suspension Up to 48 Weeks in Patients With Amyotrophic Lateral Sclerosis (Study MT-1186-A02). International-journal Peer-reviewed

    Jeffrey Rothstein, Angela Genge, Shari De Silva, Lorne Zinman, Marvin Chum, Adriano Chio, Gen Sobue, Masashi Aoki, Hiide Yoshino, Manabu Doyu, Daniel Selness, Vesna Todorovic, Nissim Sasson, Manabu Hirai, Fumihiro Takahashi, Alejandro Salah, Art Wamil, Stephen Apple

    Muscle & nerve 2025/06/06

    DOI: 10.1002/mus.28448  

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    INTRODUCTION/AIMS: An On/Off dosing regimen of intravenous (IV) edaravone and edaravone oral suspension is approved in the US for the treatment of amyotrophic lateral sclerosis (ALS). Placebo-controlled clinical trials showed IV edaravone slows the rate of physical functional decline. This study evaluated whether investigational daily dosing displayed superior efficacy vs. approved on/off dosing of edaravone oral suspension, and assessed safety and tolerability, over 48 weeks in patients with ALS. METHODS: Study MT-1186-A02 (NCT04569084) was a multicenter, phase 3b, double-blind, parallel group, superiority study that randomized patients to edaravone oral suspension (105-mg dose) administered Once Daily or the same edaravone oral suspension dose administered according to the approved On/Off regimen including placebo to mimic daily drug dosing. Patients had definite or probable ALS, baseline forced vital capacity ≥ 70%, and baseline disease duration ≤ 2 years. The primary endpoint was a combined assessment of function and survival (CAFS) at week 48, which included change in ALS Functional Rating Scale-Revised (ALSFRS-R) and time to death. RESULTS: CAFS at week 48 indicated Once Daily dosing did not show a statistically significant difference vs. approved on/off dosing (p = 0.777). Both dosing regimens provided comparable change from baseline ALSFRS-R total score to week 48 (least squares mean difference: 0.27 [95% CI -1.43 to 1.97]). Edaravone oral suspension was well tolerated, and no new safety concerns were identified in either group. DISCUSSION: Daily edaravone oral suspension did not show superiority and had equivalent safety and tolerability vs. the approved On/Off regimen, reinforcing the appropriateness of the approved dosing regimen.

  4. Jacifusen for FUS-ALS: molecular effects and clinical outcomes in a case series. International-journal Invited Peer-reviewed

    Naoki Suzuki, Ayumi Nishiyama, Satoru Ebihara, Masashi Aoki

    Lancet (London, England) 2025/05/22

    DOI: 10.1016/S0140-6736(25)01038-4  

  5. Predictive value of the polygenic risk score for developing epilepsy: a systematic review and meta-analysis. International-journal Peer-reviewed

    Takafumi Kubota, Irma Wati Ngadimon, Hisashi Ohseto, Sindhu Viswanathan, Parthvi Ravat, Mrinal Kumar Acharya, Naoto Kuroda, Kazutoshi Konomatsu, Taku Obara, Kazutaka Jin, Masashi Aoki, Nobukazu Nakasato

    Epilepsy & behavior : E&B 169 110438-110438 2025/05/03

    DOI: 10.1016/j.yebeh.2025.110438  

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    PURPOSE: This study aimed to integrate the findings of previous studies to clarify the predictive value of the polygenic risk score (PRS) for epilepsy. METHODS: The MEDLINE, EMBASE, and CENTRAL databases were systematically searched for studies investigating PRS in epilepsy. Additionally, a meta-analysis was performed using random-effects models of studies that included PRS calculations using similar methodologies. The main outcome was the odds ratio (OR) for developing epilepsy based on the generalized or focal epilepsy PRS. The risk of bias (Q-Genie tool) and heterogeneity between the studies were also assessed. RESULTS: Overall, 585 records were retrieved on April 27, 2024. Eleven studies were included in this systematic review. Most studies were conducted on cohorts with European ancestry. The risk of developing epilepsy increased with a higher PRS, which was more pronounced in patients with generalized epilepsy. The total Q-Genie tool score of the included studies was 50.9 (good quality: >45). The meta-analysis included two studies and found that the ORs for generalized epilepsy were 2.18 (95 % confidence interval [CI] 1.91-2.48), 2.65 (95 % CI 2.07-3.39), and 4.62 (95 % CI 3.45-6.20) for the top 20 %, 5 %, and 0.5 % of the PRS distribution, respectively; the respective ORs for focal epilepsy were 1.19 (95 % CI 0.84-1.67), 1.40 (95 % CI 1.28-1.52), and 1.69 (95 % CI 1.27-2.24). Significant heterogeneity was found only in the top 20 % of PRS cases for focal epilepsy (I2 = 97.0 %; Q test p < 0.0001). CONCLUSION: The PRS could be an effective tool for predicting development of epilepsy.

  6. Adult‐onset epilepsy with startle‐induced seizure after febrile infection‐related epilepsy syndrome: A case report International-journal Peer-reviewed

    Kazutoshi Konomatsu, Yosuke Kakisaka, Kazutaka Jin, Yu Fujiwara, Takafumi Kubota, Maimi Ogawa, Makoto Ishida, Kazushi Ukishiro, Hirohiko Ono, Kimihiko Kaneko, Naoto Sugeno, Masashi Aoki, Nobukazu Nakasato

    Epileptic Disorders 2025/04/15

    Publisher: Wiley

    DOI: 10.1002/epd2.70026  

    ISSN: 1294-9361

    eISSN: 1950-6945

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    Abstract Startle‐induced seizure is a rare type of reflex seizure triggered by unexpected sensory stimuli that often occurs in children with early acquired cerebral lesions or brain malformations. We report a unique case of adult‐onset epilepsy with startle‐induced seizures. A 24‐year‐old woman had suffered high fever and focal to bilateral tonic–clonic seizures. A diagnosis of febrile infection‐related epilepsy syndrome (FIRES) was made based on the febrile infection occurring 7 days to 24 h before the onset of status epilepticus, which met all criteria for cryptogenic new‐onset refractory status epilepticus (NORSE) according to the cryptogenic NORSE score. Immunotherapy and several antiseizure medications resulted in transient resolution of the seizures. Four months later, she experienced startle‐induced seizures triggered by unexpected stimuli, such as auditory, visual, or unexpected events, and manifesting as initial tachycardia followed by right ear deafness, right hemifacial dysesthesia, eye deviation to the right, and tonic–clonic convulsions. Ictal electroencephalography revealed left temporal initial rhythmic delta activity, followed by rhythmic theta activity. The patient was diagnosed with startle epilepsy associated with FIRES and continued to receive anti‐seizure medications. Claustrum‐insular‐operculum lesions may have been the epileptic focus in this case, in contrast to previous cases of epilepsy with startle‐induced seizures originating in a frontoparietal network. This case indicates a new category of adult‐onset post‐FIRES epilepsy with startle‐induced seizures.

  7. CD4-Positive T-Cell Responses to MOG Peptides in MOG Antibody-Associated Disease. International-journal Peer-reviewed

    Hirohiko Ono, Tatsuro Misu, Chihiro Namatame, Yuki Matsumoto, Yoshiki Takai, Shuhei Nishiyama, Hiroshi Kuroda, Toshiyuki Takahashi, Ichiro Nakashima, Kazuo Fujihara, Masashi Aoki

    International journal of molecular sciences 26 (8) 2025/04/11

    DOI: 10.3390/ijms26083606  

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    To clarify T-cell responses in myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), we cultured the peripheral blood mononuclear cells of 24 patients with MOGAD and 20 with aquaporin-4 (AQP4) antibody-positive neuromyelitis optica spectrum disorders (NMOSD), and those of 17 healthy controls (HCs), in the presence of fourteen MOG peptides covering the full-length MOG, five AQP4 peptides, two myelin basic protein peptides, or two proteolipid protein peptides. Then, we measured T-cell activation markers, such as cell surface CD69 and the intracellular production of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon-γ in CD4-positive T-cells, with a flow cytometer. The expression of CD69 in response to MOG p16-40 and MOG p181-205 was significantly higher (Stimulation Index > 2) in MOGAD than in HCs. Also, CD69 for AQP4 p21-40, AQP4 p211-230, and MOG p166-190 were significantly increased in NMOSD than in HCs. Intracellular GM-CSF production responding to MOG p16-40 was significantly higher in MOGAD than in HCs (p < 0.05), although intracellular interferon-γ was not elevated. None of the responses to the other peptides were different between the groups. The present study showed subtle CD4-positive T-cell activation elicited by some MOG peptides alone in patients with MOGAD. Further studies of cytokines or other stimulation and alternative assay markers and metrics are needed to delineate the immunopathological roles of T-cells in MOGAD.

  8. Clinicopathological Features of Mixed Connective Tissue Disease-Related Myositis: A Case Series. International-journal Peer-reviewed

    Naohiro Sakamoto, Rumiko Izumi, Naoki Suzuki, Maki Tateyama, Masashi Aoki

    Muscle & nerve 71 (4) 583-592 2025/04

    DOI: 10.1002/mus.28360  

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    INTRODUCTION: Mixed connective tissue disease (MCTD) patients often have myositis, however, myopathological and clinical data for MCTD are limited. Recent reports have shown that the pathology of MCTD myositis resembles that of immune-mediated necrotizing myopathy (IMNM), whereas earlier reports described perifascicular atrophy or inflammatory infiltrates predominantly in the perivascular region in MCTD myositis. We aim to describe the clinical and myopathological features of MCTD myositis. METHODS: We analyzed the clinical and myopathological findings of nine myositis patients with U1-RNP antibodies who fulfilled the diagnostic criteria for MCTD. RESULTS: Eight patients had muscle weakness in the proximal extremities, and overall, six patients had atypical weakness in the face, neck, wrist, or fingers. Four of those patients required additional intensive treatment (intravenous immunoglobulin or methylprednisolone). Therapeutic responses were consistently favorable overall, and there were no deaths during the observation period. In biopsied muscle specimens, common findings were mild myogenic change, increased necrotic and regenerating fibers, and inflammatory infiltrates predominating in the perivascular region. Two specimens were classified into the spectrum of dermatomyositis (DM); the remaining seven specimens, which had a smaller number of necrotic fibers and nonspecific infiltration, were unclassifiable. DISCUSSION: Patients with MCTD myositis often exhibit an axial or atypical distribution of muscle weakness, which may require intensive therapy. Histological study demonstrates the heterogeneity of myopathology of MCTD myositis and suggests that DM and underlying vasculopathy might be present in these patients.

  9. Ultra-Orphan drug development for GNE Myopathy: A synthetic literature review and meta-analysis. International-journal Peer-reviewed

    Naoki Suzuki, Madoka Mori-Yoshimura, Ichizo Nishino, Masashi Aoki

    Journal of neuromuscular diseases 12 (2) 183-194 2025/03

    DOI: 10.1177/22143602241296226  

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    GNE myopathy is an autosomal recessive hereditary muscle disorder that has the following clinical characteristics: develops in early adulthood, gradually progresses from the distal muscles, and is relatively sparing of quadriceps until the advanced stages of the disease. With further progression, patients become non-ambulatory and need a wheelchair. There is growing concern about extra-muscular presentations such as thrombocytopenia, respiratory dysfunction, and sleep apnea syndrome. Pathologically, rimmed vacuoles and tubulofilamentous inclusions are observed in affected muscles. The cause of the disease is thought to be a sialic acid deficiency due to mutations of the GNE gene required for in vivo sialic acid biosynthesis. Sialic acid supplementation to a presymptomatic GNE myopathy mouse model was effective in preventing the development of the disease. Several clinical studies have been conducted to evaluate the safety and efficacy of sialic acid supplementation in humans. Based on the favorable results of these studies, an extended-release aceneuramic acid formulation was approved for treatment of GNE myopathy in Japan in March 2024. It is anticipated that it will be a significant step in the development of an effective treatment for GNE myopathy and other ultra-orphan diseases.

  10. Decoding Codon Bias: The Role of tRNA Modifications in Tissue-Specific Translation. International-journal Peer-reviewed

    Daisuke Ando, Sherif Rashad, Thomas J Begley, Hidenori Endo, Masashi Aoki, Peter C Dedon, Kuniyasu Niizuma

    International journal of molecular sciences 26 (2) 2025/01/15

    DOI: 10.3390/ijms26020706  

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    The tRNA epitranscriptome has been recognized as an important player in mRNA translation regulation. Our knowledge of the role of the tRNA epitranscriptome in fine-tuning translation via codon decoding at tissue or cell levels remains incomplete. We analyzed tRNA expression and modifications as well as codon optimality across seven mouse tissues. Our analysis revealed distinct enrichment patterns of tRNA modifications in different tissues. Queuosine (Q) tRNA modification was most enriched in the brain compared to other tissues, while mitochondrial tRNA modifications and tRNA expression were highest in the heart. Using this observation, we synthesized, and delivered in vivo, codon-mutated EGFP for Q-codons, where the C-ending Q-codons were replaced with U-ending codons. The protein levels of mutant EGFP were downregulated in liver, which is poor in Q, while in brain EGFP, levels did not change. These data show that understanding tRNA modification enrichments across tissues is not only essential for understanding codon decoding and bias but can also be utilized for optimizing gene and mRNA therapeutics to be more tissue-, cell-, or condition-specific.

  11. Swift induction of human spinal lower motor neurons and robust ALS cell screening via single-cell imaging. International-journal Peer-reviewed

    Selena Setsu, Satoru Morimoto, Shiho Nakamura, Fumiko Ozawa, Kagistia Hana Utami, Ayumi Nishiyama, Naoki Suzuki, Masashi Aoki, Yukio Takeshita, Yukihide Tomari, Hideyuki Okano

    Stem cell reports 20 (1) 102377-102377 2025/01/14

    DOI: 10.1016/j.stemcr.2024.11.007  

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    This study introduces a novel method for rapidly and efficiently inducing human spinal lower motor neurons (LMNs) from induced pluripotent stem cells (iPSCs) to eventually elucidate the pathomechanisms of amyotrophic lateral sclerosis (ALS) and facilitate drug screening. Previous methods were limited by low induction efficiency, poor LMN purity, or labor-intensive induction and evaluation processes. Our protocol overcomes these challenges, achieving around 80% induction efficiency within just two weeks by combining a small molecule-based approach with transcription factor transduction. Moreover, to exclude non-LMN cells from the analysis, we utilized time-lapse microscopy and machine learning to analyze the morphology and viability of iPSC-derived LMNs on a single-cell basis, establishing an effective pathophysiological evaluation system. This rapid, efficient, and streamlined protocol, along with our single-cell-based evaluation method, enables large-scale analysis and drug screening using iPSC-derived motor neurons.

  12. The real-world impact of biologics for NMOSD: A retrospective single-center study compared with natural course and conventional treatments in Japanese International-journal Peer-reviewed

    Naoya Yamazaki, Tatsuro Misu, Yuki Matsumoto, Yoshiki Takai, Chihiro Namatame, Hirohiko Ono, Kimihiko Kaneko, Shuhei Nishiyama, Hiroshi Kuroda, Toshiyuki Takahashi, Ichiro Nakashima, Kazuo Fujihara, Masashi Aoki

    Multiple Sclerosis and Related Disorders 92 106176-106176 2024/12

    Publisher: Elsevier BV

    DOI: 10.1016/j.msard.2024.106176  

    ISSN: 2211-0348

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    BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD), a central nervous system inflammatory disease associated with aquaporin-4 immunoglobulin G (AQP4-IgG), is conventionally treated with oral steroids and immunosuppressants (IS) in Japan. Several biologics which show great efficacy in the clinical trials have been developed recently. However, studies on their efficacy, especially those comparing them with conventional treatments in real-world situations are lacking. OBJECTIVE: Here, we conducted a single-center retrospective cohort study in Japan comparing the efficacy of biologics, over conventional drugs, in treating AQP4-IgG-positive NMOSD. METHODS: We extracted the medical history of patients with AQP4-IgG-positive NMOSD who visited the Tohoku University Hospital between 2000 and 2023, from the hospital patient database. All patients were diagnosed according to the international consensus diagnostic criteria for NMOSD 2015. We then classified the disease duration of each patient into four periods based on their prescription history as: no-treatment, prednisolone monotherapy (PSL-mono), immunosuppressants (IS) treatment, and biologics (Bio) treatment. Subsequently, the efficacy of Bio treatment, over the conventional treatment, in alleviating AQP4-IgG-positive NMOSD was estimated. We used univariate Poisson regression analysis to compare the annualized relapse rate (ARR), log-rank test for the first attack, and the hazard ratios (HR)-calculated using multivariate Andersen-Gill model for recurrent attacks-of the Bio and conventional treatment period groups. The safety of each treatment period group was assessed by comparing infection and mortality rates. RESULTS: A total of 109 patients (92 % females) met the eligibility criteria of the study. We could extract a total of 1,283 patient years with 289 NMOSD attacks from their medical history data. The mean ARR of no-treatment group was 0.60. Most of the Bio group initially received combined treatments with PSL or IS. The mean ARR of the Bio group was 0.01 [95 % confidence interval (CI): 0.002 to 0.08], which was significantly lower than the PSL-mono group (0.16, 95 % CI: 0.13 to 0.19, p = 0.03) and the IS group (0.17, 95 % CI: 0.13 to 0.22, p = 0.02). In the survival analysis, the Bio group showed a significantly prolonged attack-free period than the other groups, suggesting its potential in reducing 79 % of relapses in the no-treatment group, 33 % in the PSL-mono group, and 31 % in the IS group during the two years. The multivariate analysis using Andersen-Gill model showed that the Bio group had significantly lower HR (log HR -2.75, 95 % CI: -4.71 to -0.8, p = 0.006), relative to the PSL-mono group. Importantly, the patients needed significantly lower PSL (median 5 mg/day) during the Bio group treatment period than in the PSL-mono group treatment period (median 10 mg/day). Further, the concomitant use of IS could be stopped safely in all patients who were on Bio treatment. All treatment period groups showed similar safety profiles. CONCLUSION: In patients with AQP4-IgG-positive NMOSD, biologics demonstrated more efficacy than conventional PSL and/or IS treatment, without increasing infection and mortality rates.

  13. Updated Genetic Analysis of Japanese Familial ALS Patients Carrying SOD1 Variants Revealed Phenotypic Differences for Common Variants. International-journal Peer-reviewed

    Ayumi Nishiyama, Tetsuya Niihori, Naoki Suzuki, Rumiko Izumi, Tetsuya Akiyama, Masaaki Kato, Ryo Funayama, Keiko Nakayama, Hitoshi Warita, Yoko Aoki, Masashi Aoki

    Neurology. Genetics 10 (6) e200196 2024/12

    DOI: 10.1212/NXG.0000000000200196  

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    BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive neurodegenerative disease. Approximately 10% of ALS cases are familial, and more than 20 causative genes have been identified. As we have previously reported, SOD1 variants are the most common causes of familial ALS in Japan. Because antisense oligonucleotides for SOD1-linked ALS are being used in practical applications, the types of variants and the clinical features of patients need to be updated. METHODS: We consecutively recruited 160 families with familial ALS in Japan. We performed genetic analyses, focusing on SOD1-linked ALS as the most common in our cohort, updated their genotypes, and characterized clinical phenotypes. RESULTS: A total of 26 SOD1 variants in 56 patients and 49 families (30.6%) were collected, with the 3 most common (p.His47Arg [the conventional numbering; H46R], p.Leu127Ser [L126S], p.Asn87Ser [N86S]) accounting for 38.8% of all families. We also identified 2 novel variants (p.Ile36Phe [I35F] and p.Asn132Argfs*3 [N131Rfs*3]). The mean age at onset was 48.9 ± 12.2 (mean ± SD) years for all patients with SOD1-linked ALS. Lower limb onset comprised 70% of cases. The mean disease duration was 64.7 ± 82 months, and the median survival was 71.5 months. Some variants led to a relatively homogeneous phenotype, although clinical characteristics differed among types of variants and families. Patients with p.His47Arg (H46R) showed slower progression with lower limb onset and a predominance of lower motor neuron involvement. The p.Leu127Ser (L126S) variant led to varying degrees of progression in heterozygous or homozygous states and presented incomplete penetrance. Intrafamilial phenotypic differences were observed in families carrying p.Asn87Ser (N86S). Four variants (p.Cys7Gly [C6G], p.His44Arg [H43R], p.Leu85Val [L84V], and p.Cys147Arg [C146R]) were found to be associated with rapid disease progression. DISCUSSION: The genetic basis of familial ALS, at least for SOD1 variants, still differed by geographic and ethnic background. Understanding these clinical profiles will help optimize evaluation in targeted gene therapy worldwide and benefit efficient diagnosis, leading to precise application in clinical practice.

  14. SMN2 gene copy number affects the incidence and prognosis of motor neuron diseases in Japan. International-journal Peer-reviewed

    Tomohiko Ishihara, Akihide Koyama, Naoki Atsuta, Mari Tada, Saori Toyoda, Kenta Kashiwagi, Sachiko Hirokawa, Yuya Hatano, Akio Yokoseki, Ryoichi Nakamura, Genki Tohnai, Yuishin Izumi, Ryuji Kaji, Mitsuya Morita, Asako Tamura, Osamu Kano, Masashi Aoki, Satoshi Kuwabara, Akiyoshi Kakita, Gen Sobue, Osamu Onodera

    BMC medical genomics 17 (1) 263-263 2024/11/06

    DOI: 10.1186/s12920-024-02026-y  

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    BACKGROUND: The copy number status (CNS) of the survival motor neuron (SMN) gene may influence the risk and prognosis of amyotrophic lateral sclerosis (ALS) and lower motor neuron diseases (LMND) other than spinal muscular atrophy (SMA). However, previous studies of this association, mainly from Europe, have yielded controversial results, suggesting possible regional differences. Here, we investigated the effect of the SMN gene in Japanese patients with ALS and LMND. METHODS: We examined the SMN copy numbers and clinical histories of 487 Japanese patients with sporadic ALS (281 men; mean age at onset 61.5 years), 50 with adult LMND (50 men; mean age at onset 58.4 years) and 399 Japanese controls (171 men; mean age 62.2 years). Patients with pathogenic mutations in ALS-causing genes were excluded. SMN1 and SMN2 copy numbers were determined using the droplet digital polymerase chain reaction. RESULTS: The frequency of a copy number of one for the SMN2 gene was higher in patients with ALS (38.0%) than in healthy controls (30.8%) (odds ratio (OR) = 1.37, 95% confidence interval (CI) = 1.04-1.82, p < 0.05). The SMN2 copy number affected the survival time of patients with ALS (median time: 0 copies, 34 months; 1 copy, 39 months; 2 copies, 44 months; 3 copies, 54 months; log-rank test, p < 0.05). Cox regression analysis revealed that the SMN2 copy number was associated with increased mortality (hazard ratio = 0.84, 95% CI = 0.72-0.98, p < 0.05). Also, null SMN2 cases were significantly more frequent in the LMND group (12.0%) than in the control group (4.8%) (OR = 2.73, 95% CI = 1.06-6.98, p < 0.05). CONCLUSIONS: Our findings suggest that SMN2 copy number reduction may adversely affect the onset and prognosis of MND, including ALS and LMND, in Japanese.

  15. A Retrospective Cohort Study of a Newly Proposed Criteria for Sporadic Creutzfeldt-Jakob Disease. International-journal Peer-reviewed

    Toshiaki Nonaka, Ryusuke Ae, Koki Kosami, Hiroya Tange, Miho Kaneko, Takehiro Nakagaki, Tsuyoshi Hamaguchi, Nobuo Sanjo, Yoshikazu Nakamura, Tetsuyuki Kitamoto, Yoshiyuki Kuroiwa, Kensaku Kasuga, Manabu Doyu, Fumiaki Tanaka, Koji Abe, Shigeo Murayama, Ichiro Yabe, Hideki Mochizuki, Takuya Matsushita, Hiroyuki Murai, Masashi Aoki, Koji Fujita, Masafumi Harada, Masaki Takao, Tadashi Tsukamoto, Yasushi Iwasaki, Masahito Yamada, Hidehiro Mizusawa, Katsuya Satoh, Noriyuki Nishida

    Diagnostics (Basel, Switzerland) 14 (21) 2024/10/30

    DOI: 10.3390/diagnostics14212424  

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    BACKGROUND/OBJECTIVES: Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal neurodegenerative disorder traditionally diagnosed based on the World Health Organization (WHO) criteria in 1998. Recently, Hermann et al. proposed updated diagnostic criteria incorporating advanced biomarkers to enhance early detection of sCJD. This study aimed to evaluate the sensitivity and specificity of Hermann's criteria compared with those of the WHO criteria in a large cohort of patients suspected of prion disease in Japan. METHODS: In this retrospective cohort study, we examined the new criteria using data of 2004 patients with suspected prion disease registered with the Japanese Prion Disease Surveillance (JPDS) between January 2009 and May 2023. Patients with genetic or acquired prion diseases or incomplete data necessary for the diagnostic criteria were excluded, resulting in 786 eligible cases. The sensitivity and specificity of the WHO and Hermann's criteria were calculated by comparing diagnoses with those made by the JPDS Committee. RESULTS: Of the 786 included cases, Hermann's criteria helped identify 572 probable cases compared with 448 by the WHO criteria. The sensitivity and specificity of the WHO criteria were 96.4% and 96.6%, respectively. Hermann's criteria demonstrated a sensitivity of 99.3% and a specificity of 95.2%, indicating higher sensitivity but slightly lower specificity. Fifty-five cases were classified as "definite" by both criteria. CONCLUSIONS: The findings suggest that Hermann's criteria could offer improved sensitivity for detecting sCJD, potentially reducing diagnostic oversight. However, caution is advised in clinical practice to avoid misdiagnosis, particularly in treatable neurological diseases, by ensuring thorough exclusion of other potential conditions.

  16. Multiple lines of evidence for disruption of nuclear lamina and nucleoporins in FUS amyotrophic lateral sclerosis International-journal Peer-reviewed

    Kensuke Okada, Daisuke Ito, Satoru Morimoto, Chris Kato, Yuki Oguma, Hitoshi Warita, Naoki Suzuki, Masashi Aoki, Junko Kuramoto, Reona Kobayashi, Munehisa Shinozaki, Masahito Ikawa, Jin Nakahara, Shinichi Takahashi, Yoshinori Nishimoto, Shinsuke Shibata, Hideyuki Okano

    Brain 147 (11) 3933-3948 2024/09/23

    Publisher: Oxford University Press (OUP)

    DOI: 10.1093/brain/awae224  

    ISSN: 0006-8950

    eISSN: 1460-2156

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    Abstract Advanced pathological and genetic approaches have revealed that mutations in fused in sarcoma/translated in liposarcoma (FUS/TLS), which is pivotal for DNA repair, alternative splicing, translation and RNA transport, cause familial amyotrophic lateral sclerosis (ALS). The generation of suitable animal models for ALS is essential for understanding its pathogenesis and developing therapies. Therefore, we used CRISPR-Cas9 to generate FUS-ALS mutation in the non-classical nuclear localization signal (NLS), H517D (mouse position: H509D) and genome-edited mice. Fus WT/H509D mice showed progressive motor impairment (accelerating rotarod and DigiGait system) with age, which was associated with the loss of motor neurons and disruption of the nuclear lamina and nucleoporins and DNA damage in spinal cord motor neurons. We confirmed the validity of our model by showing that nuclear lamina and nucleoporin disruption were observed in lower motor neurons differentiated from patient-derived human induced pluripotent stem cells (hiPSC-LMNs) with FUS-H517D and in the post-mortem spinal cord of patients with ALS. RNA sequence analysis revealed that most nuclear lamina and nucleoporin-linking genes were significantly decreased in FUS-H517D hiPSC-LMNs. This evidence suggests that disruption of the nuclear lamina and nucleoporins is crucial for ALS pathomechanisms. Combined with patient-derived hiPSC-LMNs and autopsy samples, this mouse model might provide a more reliable understanding of ALS pathogenesis and might aid in the development of therapeutic strategies.

  17. Different Complement Activation Patterns Following C5 Cleavage in MOGAD and AQP4-IgG+NMOSD. International-journal Peer-reviewed

    Kimihiko Kaneko, Hiroshi Kuroda, Yuki Matsumoto, Naohiro Sakamoto, Naoya Yamazaki, Naoki Yamamoto, Shu Umezawa, Chihiro Namatame, Hirohiko Ono, Yoshiki Takai, Toshiyuki Takahashi, Juichi Fujimori, Ichiro Nakashima, Yasuo Harigaya, Hans Lassmann, Kazuo Fujihara, Tatsuro Misu, Masashi Aoki

    Neurology(R) neuroimmunology & neuroinflammation 11 (5) e200293 2024/09

    DOI: 10.1212/NXI.0000000000200293  

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    OBJECTIVES: In myelin oligodendrocyte glycoprotein IgG-associated disease (MOGAD) and aquaporin-4 IgG+ neuromyelitis optica spectrum disorder (AQP4+NMOSD), the autoantibodies are mainly composed of IgG1, and complement-dependent cytotoxicity is a primary pathomechanism in AQP4+NMOSD. We aimed to evaluate the CSF complement activation in MOGAD. METHODS: CSF-C3a, CSF-C4a, CSF-C5a, and CSF-C5b-9 levels during the acute phase before treatment in patients with MOGAD (n = 12), AQP4+NMOSD (n = 11), multiple sclerosis (MS) (n = 5), and noninflammatory neurologic disease (n = 2) were measured. RESULTS: CSF-C3a and CSF-C5a levels were significantly higher in MOGAD (mean ± SD, 5,629 ± 1,079 pg/mL and 2,930 ± 435.8 pg/mL) and AQP4+NMOSD (6,017 ± 3,937 pg/mL and 2,544 ± 1,231 pg/mL) than in MS (1,507 ± 1,286 pg/mL and 193.8 ± 0.53 pg/mL). CSF-C3a, CSF-C4a, and CSF-C5a did not differ between MOGAD and AQP4+NMOSD while CSF-C5b-9 (membrane attack complex, MAC) levels were significantly lower in MOGAD (17.4 ± 27.9 ng/mL) than in AQP4+NMOSD (62.5 ± 45.1 ng/mL, p = 0.0019). Patients with MOGAD with severer attacks (Expanded Disability Status Scale [EDSS] ≥ 3.5) had higher C5b-9 levels (34.0 ± 38.4 ng/m) than those with milder attacks (EDSS ≤3.0, 0.9 ± 0.7 ng/mL, p = 0.044). DISCUSSION: The complement pathway is activated in both MOGAD and AQP4+NMOSD, but MAC formation is lower in MOGAD, particularly in those with mild attacks, than in AQP4+NMOSD. These findings may have pathogenetic and therapeutic implications in MOGAD.

  18. Dopa-responsive Rest Tremor Preceding Tachyphemia in Progressive Supranuclear Palsy: A Case Report. Peer-reviewed

    Takuro Shiga, Shun Ishiyama, Naoto Sugeno, Kei Nozue, Kazuo Kakinuma, Masashi Aoki

    Internal medicine (Tokyo, Japan) 2024/08/10

    DOI: 10.2169/internalmedicine.4133-24  

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    Progressive supranuclear palsy (PSP) is characterized by progressive postural instability, falls, and supranuclear vertical gaze abnormalities. In this report, we present the case of a 71-year-old woman with dopa-responsive rest tremor followed by tachyphemia and postural instability. She initially presented with dopa-responsive slowness and tremor in the right hand. Two years later, she developed speech difficulties (tachyphemia) and a propensity for falls. Based on the diagnostic criteria for PSP, the patient was diagnosed with probable PSP-RS. The clinical manifestations observed in our patient are unique and are considered important for illustrating a broad spectrum of PSP syndrome.

  19. Impact of sex, age at onset, and anti-cN1A antibodies on sporadic inclusion body myositis. International-journal Peer-reviewed

    Satoshi Yamashita, Nozomu Tawara, Kazuma Sugie, Naoki Suzuki, Ichizo Nishino, Masashi Aoki

    Journal of the neurological sciences 464 123164-123164 2024/08/06

    DOI: 10.1016/j.jns.2024.123164  

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    BACKGROUND: Inclusion body myositis (IBM) is a progressive myopathy occurring in patients over 45 years of age, with heterogeneous and variable clinical features. This study aimed to determine the influence of autoantibodies, gender, and age of onset on the clinical features of IBM. METHODS: Medical records and muscle histology findings of 570 participants with suspected IBM were reviewed. Various characteristics of patients who met the 2011 ENMC IBM diagnostic criteria were compared based on the presence of anti-cytosolic 5'-nucleotidase 1 A (cN1A) autoantibodies, gender, age of onset, and disease duration. RESULTS: Of the 353 patients who met the criteria, 41.6% were female. The mean age at onset was 64.6 ± 9.3 years, and the mean duration from onset to diagnosis was 5.7 ± 4.7 years. 196 of the 353 patients (55.5%) were positive for anti-cN1A autoantibodies and 157 were negative. Logistic regression showed that patients with anti-cN1A autoantibodies had a higher frequency of finger flexion weakness. Multiple regression showed that patients with later age of onset had shorter disease duration, lower BMI, and lower serum CK levels. Male patients had a higher frequency of onset with finger weakness and female patients had a lower BMI. CONCLUSION: Autoantibodies, gender, age of onset, and disease duration may influence the clinical presentation of IBM, highlighting the need for a precision medicine approach that considers these factors along with the underlying mechanisms of the disease.

  20. Humanized-Aquaporin-4-Expressing Rat Created by Gene-Editing Technology and Its Use to Clarify the Pathology of Neuromyelitis Optica Spectrum Disorder. International-journal Peer-reviewed

    Chihiro Namatame, Yoichiro Abe, Yoshiki Miyasaka, Yoshiki Takai, Yuki Matsumoto, Toshiyuki Takahashi, Tomoji Mashimo, Tatsuro Misu, Kazuo Fujihara, Masato Yasui, Masashi Aoki

    International journal of molecular sciences 25 (15) 2024/07/26

    DOI: 10.3390/ijms25158169  

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    Conventional rodent neuromyelitis optica spectrum disorder (NMOSD) models using patient-derived immunoglobulin G (IgG) are potentially affected by the differences between the human and rodent aquaporin-4 (AQP4) extracellular domains (ECDs). We hypothesized that the humanization of AQP4 ECDs would make the rodent model lesions closer to human NMOSD pathology. Humanized-AQP4-expressing (hAQP4) rats were generated using genome-editing technology, and the human AQP4-specific monoclonal antibody (mAb) or six patient-derived IgGs were introduced intraperitoneally into hAQP4 rats and wild-type Lewis (WT) rats after immunization with myelin basic protein and complete Freund's adjuvant. Human AQP4-specific mAb induced astrocyte loss lesions specifically in hAQP4 rats. The patient-derived IgGs also induced NMOSD-like tissue-destructive lesions with AQP4 loss, demyelination, axonal swelling, complement deposition, and marked neutrophil and macrophage/microglia infiltration in hAQP4 rats; however, the difference in AQP4 loss lesion size and infiltrating cells was not significant between hAQP4 and WT rats. The patient-derived IgGs bound to both human and rat AQP4 M23, suggesting their binding to the shared region of human and rat AQP4 ECDs. Anti-AQP4 titers positively correlated with AQP4 loss lesion size and neutrophil and macrophage/microglia infiltration. Considering that patient-derived IgGs vary in binding sites and affinities and some of them may not bind to rodent AQP4, our hAQP4 rat is expected to reproduce NMOSD-like pathology more accurately than WT rats.

  21. Conventional magnetic resonance imaging key features for distinguishing pathologically confirmed corticobasal degeneration from its mimics: a retrospective analysis of the J-VAC study. International-journal Peer-reviewed

    Keita Sakurai, Aya M Tokumaru, Mari Yoshida, Yuko Saito, Koichi Wakabayashi, Takashi Komori, Masato Hasegawa, Takeshi Ikeuchi, Yuichi Hayashi, Takayoshi Shimohata, Shigeo Murayama, Yasushi Iwasaki, Toshiki Uchihara, Motoko Sakai, Ichiro Yabe, Satoshi Tanikawa, Hiroshi Takigawa, Tadashi Adachi, Ritsuko Hanajima, Harutoshi Fujimura, Kentaro Hayashi, Keizo Sugaya, Kazuko Hasegawa, Terunori Sano, Masaki Takao, Osamu Yokota, Tomoko Miki, Michio Kobayashi, Nobutaka Arai, Takuya Ohkubo, Takanori Yokota, Keiko Mori, Masumi Ito, Chiho Ishida, Jiro Idezuka, Yasuko Toyoshima, Masato Kanazawa, Masashi Aoki, Takafumi Hasegawa, Hirohisa Watanabe, Atsushi Hashizume, Hisayoshi Niwa, Keizo Yasui, Keita Ito, Yukihiko Washimi, Akatsuki Kubota, Tatsushi Toda, Kenji Nakashima, Ikuko Aiba

    Neuroradiology 2024/07/22

    DOI: 10.1007/s00234-024-03432-w  

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    PURPOSE: Due to the indistinguishable clinical features of corticobasal syndrome (CBS), the antemortem differentiation between corticobasal degeneration (CBD) and its mimics remains challenging. However, the utility of conventional magnetic resonance imaging (MRI) for the diagnosis of CBD has not been sufficiently evaluated. This study aimed to investigate the diagnostic performance of conventional MRI findings in differentiating pathologically confirmed CBD from its mimics. METHODS: Semiquantitative visual rating scales were employed to assess the degree and distribution of atrophy and asymmetry on conventional T1-weighted and T2-weighted images. Additionally, subcortical white matter hyperintensity (SWMH) on fluid-attenuated inversion recovery images were visually evaluated. RESULTS: In addition to 19 patients with CBD, 16 with CBD mimics (progressive supranuclear palsy (PSP): 9, Alzheimer's disease (AD): 4, dementia with Lewy bodies (DLB): 1, frontotemporal lobar degeneration with TAR DNA-binding protein of 43 kDa(FTLD-TDP): 1, and globular glial tauopathy (GGT): 1) were investigated. Compared with the CBD group, the PSP-CBS subgroup showed severe midbrain atrophy without SWMH. The non-PSP-CBS subgroup, comprising patients with AD, DLB, FTLD-TDP, and GGT, showed severe temporal atrophy with widespread asymmetry, especially in the temporal lobes. In addition to over half of the patients with CBD, two with FTLD-TDP and GGT showed SWMH, respectively. CONCLUSION: This study elucidates the distinct structural changes between the CBD and its mimics based on visual rating scales. The evaluation of atrophic distribution and SWMH may serve as imaging biomarkers of conventional MRI for detecting background pathologies.

  22. Dysregulation of SNX1-retromer axis in pharmacogenetic models of Parkinson's disease. International-journal Peer-reviewed

    Shun Yoshida, Takafumi Hasegawa, Takaaki Nakamura, Kazuki Sato, Naoto Sugeno, Shun Ishiyama, Kiyotoshi Sekiguchi, Muneshige Tobita, Atsushi Takeda, Masashi Aoki

    Cell death discovery 10 (1) 290-290 2024/06/17

    DOI: 10.1038/s41420-024-02062-8  

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    Since the identification of vacuolar protein sorting (VPS) 35, as a causative molecule for familial Parkinson's disease (PD), retromer-mediated endosomal machinery has been a rising factor in the pathogenesis of the disease. The retromer complex cooperates with sorting nexin (SNX) dimer and DNAJC13, another causal molecule in PD, to transport cargoes from endosomes to the trans-Golgi network, and is also involved in mitochondrial dynamics and autophagy. Retromer dysfunction may induce neuronal death leading to PD via several biological cascades, including misfolded, insoluble α-synuclein (aS) accumulation and mitochondrial dysfunction; however, the detailed mechanisms remain poorly understood. In this study, we showed that the stagnation of retromer-mediated retrograde transport consistently occurs in different PD-mimetic conditions, i.e., overexpression of PD-linked mutant DNAJC13, excess aS induction, or toxin-induced mitochondrial dysfunction. Mechanistically, DNAJC13 was found to be involved in clathrin-dependent retromer transport as a functional modulator of SNX1 together with heat shock cognate 70 kDa protein (Hsc70), which was controlled by the binding and dissociation of DNAJC13 and SNX1 in an Hsc70 activity-dependent manner. In addition, excess amount of aS decreased the interaction between SNX1 and VPS35, the core component of retromer. Furthermore, R33, a pharmacological retromer chaperone, reduced insoluble aS and mitigated rotenone-induced neuronal apoptosis. These findings suggest that retrograde transport regulated by SNX1-retromer may be profoundly involved in the pathogenesis of PD and is a potential target for disease-modifying therapy for the disease.

  23. Safety and efficacy of aceneuramic acid in GNE myopathy: open-label extension study. International-journal Peer-reviewed

    Naoki Suzuki, Madoka Mori-Yoshimura, Masahisa Katsuno, Masanori P Takahashi, Satoshi Yamashita, Yasushi Oya, Atsushi Hashizume, Shinichiro Yamada, Masayuki Nakamori, Rumiko Izumi, Masaaki Kato, Hitoshi Warita, Maki Tateyama, Hiroshi Kuroda, Ryuta Asada, Takuhiro Yamaguchi, Ichizo Nishino, Masashi Aoki

    Journal of neurology, neurosurgery, and psychiatry 2024/06/05

    DOI: 10.1136/jnnp-2024-333853  

  24. Reduced histone H3K4 trimethylation in oral mucosa of patients with DYT-KMT2B. International-journal Peer-reviewed

    Naoto Sugeno, Satoko Kumada, Hirofumi Kashii, Jun Ikezawa, Toshitaka Kawarai, Takaaki Nakamura, Ako Miyata, Shun Ishiyama, Kazuki Sato, Shun Yoshida, Hutoshi Sekiguchi, Kohei Hamanaka, Satoko Miyatake, Noriko Miyake, Naomichi Matsumoto, Hiroyuki Akagawa, Kenjiro Kosaki, Hiroshi Yoshihashi, Takafumi Hasegawa, Masashi Aoki

    Parkinsonism & related disorders 124 107018-107018 2024/05/27

    DOI: 10.1016/j.parkreldis.2024.107018  

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    BACKGROUND: DYT-KMT2B, also known as DYT28, is a childhood-onset hereditary dystonia caused by KMT2B mutation. The pathogenesis of DYT-KMT2B involves haploinsufficiency of KMT2B, an enzyme that catalyzes specific histone methylation (H3K4me3). Dysmorphic features in patients with DYT-KMT2B suggest that KMT2B dysfunction may extend beyond the neuronal system. Therefore, valuable diagnostic insights may be obtained from readily available tissue samples. OBJECTIVES: To explore the altered H3K4me3 levels in non-neural tissue of DYT-KMT2B patients. METHODS: A database analysis was performed to determine in which parts of the body and in which cells KMT2B is highly expressed. Twelve clinically and genetically diagnosed patients with DYT-KMT2B and 12 control subjects participated in this study. Oral mucosa-derived purified histone proteins were analyzed using Western blotting with anti-H3K4me3 and anti-H4 antibodies. RESULTS: Higher expression of KMT2B was observed in oral keratinocytes and gingival fibroblasts, constituting the oral mucosa. In oral mucosa analyses, DYT-KMT2B cases exhibited markedly reduced H3K4me3 levels compared with the controls. Using a cutoff window of 0.90-0.98, the H3K4me3/H4 expression ratio was able to distinguish patient groups. CONCLUSIONS: Oral mucosa H3K4me3 analysis is currently not sufficient as a diagnostic tool for DYT-KMT2B, but has the advantage for screening test since it is a non-invasive means.

  25. “Caterpillar sign” in corpus callosum associated with curvilinear pericallosal lipoma in MRI: A case report International-journal Peer-reviewed

    Kazutoshi Konomatsu, Yosuke Kakisaka, Shiho Sato, Takafumi Kubota, Temma Soga, Kazushi Ukishiro, Kazutaka Jin, Shunji Mugikura, Masashi Aoki, Nobukazu Nakasato

    Radiology Case Reports 19 (5) 2058-2061 2024/05

    DOI: 10.1016/j.radcr.2024.02.058  

    eISSN: 1930-0433

  26. Genetic generalized epilepsy with catecholaminergic polymorphic ventricular tachycardia complicated by ryanodine receptor 2 variant: A case report International-journal Peer-reviewed

    Kazutoshi Konomatsu, Yosuke Kakisaka, Kazutaka Jin, Takeshi Aiba, Shin Takahashi, Hironobu Ueda, Takafumi Kubota, Temma Soga, Kazushi Ukishiro, Masashi Aoki, Nobukazu Nakasato

    Seizure: European Journal of Epilepsy 117 284-287 2024/04

    Publisher: Elsevier BV

    DOI: 10.1016/j.seizure.2024.04.003  

    ISSN: 1059-1311

  27. The clinical practice guideline for the management of amyotrophic lateral sclerosis in Japan-update 2023. Peer-reviewed

    Makoto Urushitani, Hitoshi Warita, Naoki Atsuta, Yuishin Izumi, Osamu Kano, Toshio Shimizu, Yuki Nakayama, Yugo Narita, Hiroyuki Nodera, Takuji Fujita, Koichi Mizoguchi, Mitsuya Morita, Masashi Aoki

    Rinsho shinkeigaku = Clinical neurology 2024/03/23

    DOI: 10.5692/clinicalneurol.cn-001946  

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    Amyotrophic lateral sclerosis (ALS) is an adult-onset intractable motor neuron disease characterized by selective degeneration of cortical neurons in the frontotemporal lobe and motor neurons in the brainstem and spinal cord. Impairment of these neural networks causes progressive muscle atrophy and weakness that spreads throughout the body, resulting in life-threatening bulbar palsy and respiratory muscle paralysis. However, no therapeutic strategy has yet been established to halt ALS progression. Although evidence for clinical practice in ALS remains insufficient, novel research findings have steadily accumulated in recent years. To provide updated evidence-based or expert consensus recommendations for the diagnosis and management of ALS, the ALS Clinical Practice Guideline Development Committee, approved by the Japanese Society of Neurology, revised and published the Japanese clinical practice guidelines for the management of ALS in 2023. In this guideline, disease-modifying therapies that have accumulated evidence from randomized controlled trials were defined as "Clinical Questions," in which the level of evidence was determined by systematic reviews. In contrast, "Questions and Answers" were defined as issues of clinically important but insufficient evidence, according to reports of a small number of cases, observational studies, and expert opinions. Based on a literature search performed in February 2022, recommendations were reached by consensus, determined by an independent panel, reviewed by external reviewers, and submitted for public comments by Japanese Society of Neurology members before publication. In this article, we summarize the revised Japanese guidelines for ALS, highlighting the regional and cultural diversity of care processes and decision-making. The guidelines cover a broad range of essential topics such as etiology, diagnostic criteria, disease monitoring and treatments, management of symptoms, respiration, rehabilitation, nutrition, metabolism, patient instructions, and various types of care support. We believe that this summary will help improve the daily clinical practice for individuals living with ALS and their caregivers.

  28. Recurrent Ipsilateral C5 Nerve Palsy Associated With Hereditary Neuropathy With Liability to Pressure Palsy. International-journal Peer-reviewed

    Kei Nozue, Naoto Sugeno, Shun Ishiyama, Mikihiro Yoshida, Masashi Aoki

    Cureus 16 (3) e55948 2024/03

    DOI: 10.7759/cureus.55948  

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    Hereditary neuropathy with liability to pressure palsy (HNPP) is an autosomal dominant disorder caused by heteroplasmic deletion of the peripheral myelin protein 22 (PMP22) gene. HNPP typically presents with clinical features such as peroneal nerve palsy or cubital tunnel syndrome, which are caused by mechanical compression. Diagnosing cases where neuropathy is absent at the pressure site can be challenging. This is a case study of an 18-year-old man who underwent surgery on the left side of his neck over 10 years ago to remove lymphadenopathy. Following the surgery, he experienced recurrent weakness but only sought medical attention when muscle weakness persisted for longer than a week postoperatively. Upon admission, the patient exhibited neurological symptoms consistent with C5 neuropathy, mainly affecting the deltoid muscles. No serological abnormalities were found to be associated with neuropathy. Neither magnetic resonance imaging nor computed tomography scans detected any lesions around the C5 nerve root. The posture during sleep was believed to cause excessive extension of the C5 nerve root, leading to the assumption that there was some vulnerability in the nerve. A transient sensory loss in the area innervated by the ulnar nerve prompted us to examine the fluorescence in situ hybridization study on the blood sample, which revealed a deletion of the PMP22 gene. The patient was diagnosed with HNPP and was advised to avoid risky postures. Following the implementation of these lifestyle changes, he did not experience any further weakness in his shoulders.

  29. Case Report: An Adult Case of Poretti-Boltshauser Syndrome Diagnosed by Medical Checkup. International-journal Peer-reviewed

    Kensuke Ikeda, Ayane Tamagake, Takafumi Kubota, Rumiko Izumi, Tatsuo Yamaguchi, Kumiko Yanagi, Tatsuro Misu, Yoko Aoki, Tadashi Kaname, Masashi Aoki

    Cerebellum (London, England) 2024/02/29

    DOI: 10.1007/s12311-024-01673-2  

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    This report describes an adult case of Poretti-Boltshauser syndrome (PTBHS) and with novel variants of LAMA1. A 65-year-old Japanese woman with cerebellar malformation identified during a medical checkup was referred to our hospital. Subsequently, neurological examination, brain imaging, and genetic investigation via whole-exome sequencing were performed. The patient presented with mild cerebellar ataxia and intellectual disability. Magnetic resonance imaging revealed cerebellar dysplasia and cysts and an absence of molar tooth sign. Genetic analysis revealed a novel homozygous variant of c.1711_1712del in LAMA1 (NM_005559.4). Most cases with PTBHS are reported in pediatric patients; however, our patient expressed a mild phenotype and was undiagnosed until her 60 s. These findings suggest that PTBHS should be considered in not only pediatric cerebellar dysplasia but also adult cerebellar ataxia with mild presentation.

  30. Comprehensive Analysis of a Japanese Pedigree with Biallelic ACAGG Expansions in RFC1 Manifesting Motor Neuronopathy with Painful Muscle Cramps. International-journal Peer-reviewed

    Rumiko Izumi, Hitoshi Warita, Tetsuya Niihori, Yoshihiko Furusawa, Misa Nakano, Yasushi Oya, Kazuhiro Kato, Takuro Shiga, Kensuke Ikeda, Naoki Suzuki, Ichizo Nishino, Yoko Aoki, Masashi Aoki

    Cerebellum (London, England) 2024/02/07

    DOI: 10.1007/s12311-024-01666-1  

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    Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is an autosomal recessive multisystem neurologic disorder caused by biallelic intronic repeats in RFC1. Although the phenotype of CANVAS has been expanding via diagnostic case accumulation, there are scant pedigree analyses to reveal disease penetrance, intergenerational fluctuations in repeat length, or clinical phenomena (including heterozygous carriers). We identified biallelic RFC1 ACAGG expansions of 1000 ~ repeats in three affected siblings having sensorimotor neuronopathy with spinocerebellar atrophy initially presenting with painful muscle cramps and paroxysmal dry cough. They exhibit almost homogeneous clinical and histopathological features, indicating motor neuronopathy. Over 10 years of follow-up, painful intractable muscle cramps ascended from legs to trunks and hands, followed by amyotrophy and subsequent leg pyramidal signs. The disease course combined with the electrophysical and imagery data suggest initial and prolonged hyperexcitability and the ensuing spinal motor neuron loss, which may progress from the lumbar to the rostral anterior horns and later expand to the corticospinal tract. Genetically, heterozygous ACAGG expansions of similar length were transmitted in unaffected family members of three successive generations, and some of them experienced muscle cramps. Leukocyte telomere length assays revealed comparatively shorter telomeres in affected individuals. This comprehensive pedigree analysis demonstrated a non-anticipating ACAGG transmission and high penetrance of manifestations with a biallelic state, especially motor neuronopathy in which muscle cramps serve as a prodromal and disease progress marker. CANVAS and RFC1 spectrum disorder should be considered when diagnosing lower dominant motor neuron disease, idiopathic muscle cramps, or neuromuscular hyperexcitability syndromes.

  31. Anti-aquaporin-4 immune complex stimulates complement-dependent Th17 cytokine release in neuromyelitis optica spectrum disorders. International-journal Peer-reviewed

    Shuhei Nishiyama, Jin Myong Seok, Amy E Wright, Itay Lotan, Takahisa Mikami, Natalia C Drosu, Natasha Bobrowski-Khoury, Monique R Anderson, Philippe A Bilodeau, Patrick Schindler, Friedemann Paul, Masashi Aoki, Michael R Yeaman, Michael Levy

    Scientific reports 14 (1) 3146-3146 2024/02/07

    DOI: 10.1038/s41598-024-53661-5  

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    Proinflammatory cytokines, such as (IL: interleukin) IL-6 and IL-17A, and complement fixation are critical in the immunopathogenesis of neuromyelitis optica spectrum disorders (NMOSD). Blocking the IL-6 receptor or the C5 complement pathway reduces relapse risk. However, the role of interleukin (IL)-6 and complement in aquaporin-4 (AQP4) autoimmunity remains unclear. To investigate the role of the anti-AQP4 immunoglobulin (AQP4-IgG)/AQP4 immunocomplex on the induction and profile of ex vivo cytokine and surface marker expression in peripheral blood mononuclear cells (PBMC) culture. Isolated PBMCs obtained from 18 patients with AQP4-IgG-seropositive-NMOSD (8 treatment-naive, 10 rituximab-treated) or ten healthy controls were cultured with AQP4-immunocomplex with or without complement. Changes in PBMC surface markers and cytokine expression were profiled using flow cytometry and ELISA. PBMCs derived from treatment-naive NMOSD patients stimulated with a complex mixture of serum complement proteins produced significant elevations of IL-17A and IL-6. Rituximab-treated patients also exhibited higher IL-6 but not IL-17A release. IL-6 and IL-17A elevations are not observed without complement. Co-stimulation of PBMCs with AQP4-IgG/AQP4 immunocomplex and complement prompts a Th17-biased response consistent with the inflammatory paradigm observed in NMOSD. A possible inflammation model is proposed via antigen-specific autoreactive peripheral blood cells, including NK/NKT cells.

  32. Nationwide survey of patients with multisystem proteinopathy in Japan International-journal Peer-reviewed

    Satoshi Yamashita, Yuji Takahashi, Jun Hashimoto, Ayuka Murakami, Ryoichi Nakamura, Masahisa Katsuno, Rumiko Izumi, Naoki Suzuki, Hitoshi Warita, Masashi Aoki

    Annals of Clinical and Translational Neurology 2024/01/29

    DOI: 10.1002/acn3.52011  

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    OBJECTIVE: Multisystem proteinopathy (MSP) is an inherited disorder in which protein aggregates with TAR DNA-binding protein of 43 kDa form in multiple organs. Mutations in VCP, HNRNPA2B1, HNRNPA1, SQSTM1, MATR3, and ANXA11 are causative for MSP. This study aimed to conduct a nationwide epidemiological survey based on the diagnostic criteria established by the Japan MSP study group. METHODS: We conducted a nationwide epidemiological survey by administering primary and secondary questionnaires among 6235 specialists of the Japanese Society of Neurology. RESULTS: In the primary survey, 47 patients with MSP were identified. In the secondary survey of 27 patients, inclusion body myopathy was the most common initial symptom (74.1%), followed by motor neuron disease (11.1%), frontotemporal dementia (FTD, 7.4%), and Paget's disease of bone (PDB, 7.4%), with no cases of parkinsonism. Inclusion body myopathy occurred most frequently during the entire course of the disease (81.5%), followed by motor neuron disease (25.9%), PDB (18.5%), FTD (14.8%), and parkinsonism (3.7%). Laboratory findings showed a high frequency of elevated serum creatine kinase levels and abnormalities on needle electromyography, muscle histology, brain magnetic resonance imaging, and perfusion single-photon emission computed tomography. INTERPRETATION: The low frequency of FTD and PDB may suggest that FTD and PDB may be widely underdiagnosed and undertreated in clinical practice.

  33. Establishment of a novel amyotrophic lateral sclerosis patient (TARDBP N345K/+)-derived brain microvascular endothelial cell model reveals defective Wnt/β-catenin signaling: investigating diffusion barrier dysfunction and immune cell interaction. International-journal Peer-reviewed

    Kinya Matsuo, Jun Nagamatsu, Kazuhiro Nagata, Ryusei Umeda, Takaya Shiota, Satoru Morimoto, Naoki Suzuki, Masashi Aoki, Hideyuki Okano, Masayuki Nakamori, Hideaki Nishihara

    Frontiers in cell and developmental biology 12 1357204-1357204 2024

    DOI: 10.3389/fcell.2024.1357204  

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    Amyotrophic lateral sclerosis (ALS) is a major neurodegenerative disease for which there is currently no curative treatment. The blood-brain barrier (BBB), multiple physiological functions formed by mainly specialized brain microvascular endothelial cells (BMECs), serves as a gatekeeper to protect the central nervous system (CNS) from harmful molecules in the blood and aberrant immune cell infiltration. The accumulation of evidence indicating that alterations in the peripheral milieu can contribute to neurodegeneration within the CNS suggests that the BBB may be a previously overlooked factor in the pathogenesis of ALS. Animal models suggest BBB breakdown may precede neurodegeneration and link BBB alteration to the disease progression or even onset. However, the lack of a useful patient-derived model hampers understanding the pathomechanisms of BBB dysfunction and the development of BBB-targeted therapies. In this study, we differentiated BMEC-like cells from human induced pluripotent stem cells (hiPSCs) derived from ALS patients to investigate BMEC functions in ALS patients. TARDBP N345K/+ carrying patient-derived BMEC-like cells exhibited increased permeability to small molecules due to loss of tight junction in the absence of neurodegeneration or neuroinflammation, highlighting that BMEC abnormalities in ALS are not merely secondary consequences of disease progression. Furthermore, they exhibited increased expression of cell surface adhesion molecules like ICAM-1 and VCAM-1, leading to enhanced immune cell adhesion. BMEC-like cells derived from hiPSCs with other types of TARDBP gene mutations (TARDBP K263E/K263E and TARDBP G295S/G295S) introduced by genome editing technology did not show such BMEC dysfunction compared to the isogenic control. Interestingly, transactive response DNA-binding protein 43 (TDP-43) was mislocalized to cytoplasm in TARDBP N345K/+ carrying model. Wnt/β-catenin signaling was downregulated in the ALS patient (TARDBP N345K/+)-derived BMEC-like cells and its activation rescued the leaky barrier phenotype and settled down VCAM-1 expressions. These results indicate that TARDBP N345K/+ carrying model recapitulated BMEC abnormalities reported in brain samples of ALS patients. This novel patient-derived BMEC-like cell is useful for the further analysis of the involvement of vascular barrier dysfunctions in the pathogenesis of ALS and for promoting therapeutic drug discovery targeting BMEC.

  34. Sporadic inclusion body myositis-derived myotube culture revealed muscle cell-autonomous expression profiles. International-journal Peer-reviewed

    Naoki Suzuki, Makoto Kanzaki, Masashi Koide, Rumiko Izumi, Ryo Fujita, Tadahisa Takahashi, Kazumi Ogawa, Yutaka Yabe, Masahiro Tsuchiya, Masako Suzuki, Ryuhei Harada, Akiyuki Ohno, Hiroya Ono, Naoko Nakamura, Kensuke Ikeda, Hitoshi Warita, Shion Osana, Yoshitsugu Oikawa, Takafumi Toyohara, Takaaki Abe, Muliang Rui, Satoru Ebihara, Ryoichi Nagatomi, Yoshihiro Hagiwara, Masashi Aoki

    PloS one 19 (8) e0306021 2024

    DOI: 10.1371/journal.pone.0306021  

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    Sporadic inclusion body myositis (sIBM) is a muscle disease in older people and is characterized by inflammatory cell invasion into intact muscle fibers and rimmed vacuoles. The pathomechanism of sIBM is not fully elucidated yet, and controversy exists as to whether sIBM is a primary autoimmune disease or a degenerative muscle disease with secondary inflammation. Previously, we established a method of collecting CD56-positive myoblasts from human skeletal muscle biopsy samples. We hypothesized that the myoblasts derived from these patients are useful to see the cell-autonomous pathomechanism of sIBM. With these resources, myoblasts were differentiated into myotubes, and the expression profiles of cell-autonomous pathology of sIBM were analyzed. Myoblasts from three sIBM cases and six controls were differentiated into myotubes. In the RNA-sequencing analysis of these "myotube" samples, 104 differentially expressed genes (DEGs) were found to be significantly upregulated by more than twofold in sIBM, and 13 DEGs were downregulated by less than twofold. For muscle biopsy samples, a comparative analysis was conducted to determine the extent to which "biopsy" and "myotube" samples differed. Fifty-three DEGs were extracted of which 32 (60%) had opposite directions of expression change (e.g., increased in biopsy vs decreased in myotube). Apolipoprotein E (apoE) and transmembrane protein 8C (TMEM8C or MYMK) were commonly upregulated in muscle biopsies and myotubes from sIBM. ApoE and myogenin protein levels were upregulated in sIBM. Given that enrichment analysis also captured changes in muscle contraction and development, the triggering of muscle atrophy signaling and abnormal muscle differentiation via MYMK or myogenin may be involved in the pathogenesis of sIBM. The presence of DEGs in sIBM suggests that the myotubes formed from sIBM-derived myoblasts revealed the existence of muscle cell-autonomous degeneration in sIBM. The catalog of DEGs will be an important resource for future studies on the pathogenesis of sIBM focusing on primary muscle degeneration.

  35. Dynamic changes in patient admission and their disabilities in multiple sclerosis and neuromyelitis optica: A Japanese nationwide administrative data study International-journal Peer-reviewed

    Yuki Matsumoto, Kunio Tarasawa, Tatsuro Misu, Chihiro Namatame, Yoshiki Takai, Hiroshi Kuroda, Kazuo Fujihara, Kiyohide Fushimi, Kenji Fujimori, Masashi Aoki

    Multiple Sclerosis and Related Disorders 81 105349-105349 2024/01

    Publisher: Elsevier BV

    DOI: 10.1016/j.msard.2023.105349  

    ISSN: 2211-0348

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    BACKGROUND: The real-world data evidences how establishment of neuromyelitis optica (NMO) disease concept and development disease modifying therapy affect the patients with multiple sclerosis (MS) and NMO are lacking. The aim of this study is to clarify the diachronic trend of the severity and admissions of patients with MS and NMO. METHODS: We retrospectively investigated the trends in admissions, treatments, and disabilities in the patients with MS and NMO using the Japanese administrative data between 2012 and 2017. RESULTS: We analyzed acute stage 9545 and 2035 admissions in each 6100 MS and 1555 NMO patients. The annual number of admission in MS significantly decreased in 6 years; however, those in NMO consistently increased. The patient proportion with lower disability was significantly increased in MS and NMO. These trends were especially observed in patients admitted to centralized hospitals with more active treatments, such as second-line disease modifying therapy for MS and plasmapheresis for NMO. Patients with NMO using DMT for MS diminished in 6 years. CONCLUSION: A gradual improvement of disability in patients with MS and NMO was observed, probably due to advanced treatments, increased NMO awareness, and decreased misdiagnosis, which seems to be the key for better prognosis in MS and NMO.

  36. Nuclear pore pathology underlying multisystem proteinopathy type 3-related inclusion body myopathy. International-journal Peer-reviewed

    Rumiko Izumi, Kensuke Ikeda, Tetsuya Niihori, Naoki Suzuki, Matsuyuki Shirota, Ryo Funayama, Keiko Nakayama, Hitoshi Warita, Maki Tateyama, Yoko Aoki, Masashi Aoki

    Annals of clinical and translational neurology 2023/12/29

    DOI: 10.1002/acn3.51977  

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    OBJECTIVE: Multisystem proteinopathy type 3 (MSP3) is an inherited, pleiotropic degenerative disorder caused by a mutation in heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), which can affect the muscle, bone, and/or nervous system. This study aimed to determine detailed histopathological features and transcriptomic profile of HNRNPA1-mutated skeletal muscles to reveal the core pathomechanism of hereditary inclusion body myopathy (hIBM), a predominant phenotype of MSP3. METHODS: Histopathological analyses and RNA sequencing of HNRNPA1-mutated skeletal muscles harboring a c.940G > A (p.D314N) mutation (NM_031157) were performed, and the results were compared with those of HNRNPA1-unlinked hIBM and control muscle tissues. RESULTS: RNA sequencing revealed aberrant alternative splicing events that predominantly occurred in myofibril components and mitochondrial respiratory complex. Enrichment analyses identified the nuclear pore complex (NPC) and nucleocytoplasmic transport as suppressed pathways. These two pathways were linked by the hub genes NUP50, NUP98, NUP153, NUP205, and RanBP2. In immunohistochemistry, these nucleoporin proteins (NUPs) were mislocalized to the cytoplasm and aggregated mostly with TAR DNA-binding protein 43 kDa and, to a lesser extent, with hnRNPA1. Based on ultrastructural observation, irregularly shaped myonuclei with deep invaginations were frequently observed in atrophic fibers, consistent with the disorganization of NPCs. Additionally, regarding the expression profiles of overall NUPs, reduced expression of NUP98, NUP153, and RanBP2 was shared with HNRNPA1-unlinked hIBMs. INTERPRETATION: The shared subset of altered NUPs in amyotrophic lateral sclerosis (ALS), as demonstrated in prior research, HNRNPA1-mutated, and HNRNPA1-unlinked hIBM muscle tissues may provide evidence regarding the underlying common nuclear pore pathology of hIBM, ALS, and MSP.

  37. Myelin oligodendrocyte glycoprotein antibody‐associated disorders: An overview

    Tatsuro Misu, Yuki Matsumoto, Kimihiko Kaneko, Toshiyuki Takahashi, Yoshiki Takai, Hirohiko Ono, Chihiro Namatame, Shuhei Nishiyama, Juichi Fujimori, Hiroshi Kuroda, Ichiro Nakashima, Kazuo Fujihara, Masashi Aoki

    Clinical and Experimental Neuroimmunology 2023/12/19

    Publisher: Wiley

    DOI: 10.1111/cen3.12771  

    ISSN: 1759-1961

    eISSN: 1759-1961

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    Abstract In recent years, there is growing evidence of associations between antibodies against myelin oligodendrocyte glycoprotein (MOG) and several phenotypes of acute inflammatory demyelinating diseases such as acute disseminated encephalomyelitis (ADEM), optic neuritis, brainstem, and cerebral cortical encephalitis, called MOG antibody associated disorders (MOGAD). Monophasic course is known in about half of cases especially in pediatric onset ADEM and optic neuritis, mainly in cases with transient positivity of MOG antibody. Pathological features of MOGAD are considered as acute demyelinating lesions with CD4 dominant cell infiltrations, the deposition of humoral immunity, perivascular inflammation and perivenous demyelination, which is distinct from multiple sclerosis. Now the diagnosis of MOGAD is based on the international panel criteria of MOGAD launched in 2023, which the diagnostic frameworks are three parts, including MOGAD‐specific clinical features, MOG antibody positivity, and the exclusion of other diseases. The prognosis of MOGAD patients is considered relatively mild, but the problem is refractory relapsing cases. For its prevention, there are no approved drugs, but oral tapering corticosteroids, immunosuppressants such as azathioprine and mycophenolic mofetil, rituximab, and the maintenance intravenous immunoglobulin are recommended, and now there are a few clinical trials of promising biological drugs already approved in other neurological disorders.

  38. Alpha-synuclein promotes PRMT5-mediated H4R3me2s histone methylation by interacting with the BAF complex. International-journal Peer-reviewed

    Takaaki Nakamura, Naoto Sugeno, Takafumi Hasegawa, Kensho Ikeda, Shun Yoshida, Shun Ishiyama, Kazuki Sato, Atsushi Takeda, Masashi Aoki

    The FEBS journal 2023/12/17

    DOI: 10.1111/febs.17037  

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    α-Synuclein (αS) is a key molecule in the pathomechanism of Parkinson's disease. Most studies on αS to date have focused on its function in the neuronal cytosol, but its action in the nucleus has also been postulated. Indeed, several lines of evidence indicate that overexpressed αS leads to epigenomic alterations. To clarify the functional role of αS in the nucleus and its pathological significance, HEK293 cells constitutively expressing αS were used to screen for nuclear proteins that interact with αS by nanoscale liquid chromatography/tandem mass spectrometry. Interactome analysis of the 229 identified nuclear proteins revealed that αS interacts with the BRG1-associated factor (BAF) complex, a family of multi-subunit chromatin remodelers important for neurodevelopment, and protein arginine methyltransferase 5 (PRMT5). Subsequent transcriptomic analysis also suggested a functional link between αS and the BAF complex. Based on these results, we analyzed the effect of αS overexpression on the BAF complex in neuronally differentiated SH-SY5Y cells and found that induction of αS disturbed the BAF maturation process, leading to a global increase in symmetric demethylation of histone H4 on arginine 3 (H4R3me2s) via enhanced BAF-PRMT5 interaction. Chromatin immunoprecipitation sequencing confirmed accumulated H4R3me2s methylation near the transcription start site of the neuronal cell adhesion molecule (NRCAM) gene, which has roles during neuronal differentiation. Transcriptional analyses confirmed the negative regulation of NRCAM by αS and PRMT5, which was reconfirmed by multiple datasets in the Gene Expression Omnibus (GEO) database. Taken together, these findings suggest that the enhanced binding of αS to the BAF complex and PRMT5 may cooperatively affect the neuronal differentiation process.

  39. Referral odyssey plot to visualize causes of surgical delay in mesial temporal lobe epilepsy with hippocampal sclerosis. International-journal Peer-reviewed

    Kazutoshi Konomatsu, Yosuke Kakisaka, Makoto Ishida, Temma Soga, Kazushi Ukishiro, Shin-Ichiro Osawa, Kazutaka Jin, Masashi Aoki, Nobukazu Nakasato

    Epilepsy & behavior : E&B 147 109434-109434 2023/09/14

    DOI: 10.1016/j.yebeh.2023.109434  

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    The "odyssey plot" was used to visualize referral delays in epilepsy surgery. Participants were 36 patients (19 males; 13-67 years, median 27 years) with mesial temporal lobe epilepsy with hippocampal sclerosis (HS) who underwent resection surgery. The "referral odyssey plot" included five clinical episodes: seizure onset (T1), first visits to a non-epileptologist (T2) and to an epileptologist (T3), first admission to our epilepsy monitoring unit (EMU) (T4), and resection surgery (T5). For each patient, we identified the first seizure type: the physician who first diagnosed focal aware seizure (FAS), focal impaired awareness seizure (FIAS), focal to bilateral tonic-clonic seizure (FBTCS), and radiologically suspected HS. Within the overall delay (T1-T5, median 18 years; interquartile range [IQR] 14), non-epileptologist's delay (T2-T3, 11.5 years; IQR 12.25) was far (p < 0.0001) longer than patient's (T1-T2, 0 year; IQR 2.25), epileptologist's (T3-T4, 1 year; IQR 4), or after-EMU delay (T4-T5, 1 year; IQR 1). FAS onset cases had significantly longer T1-T2 (N = 5, median 7 years; IQR 6) than FIAS (N = 22, 0 year; IQR 1, p < 0.005) or FBTCS onset cases (N = 9, 0 year; IQR 0, p < 0.001). FAS was correctly diagnosed first by non-epileptologists in 17.9%, by out-patient epileptologists in 35.7%, and at the EMU in 46.4%. FIAS was correctly diagnosed first by non-epileptologists in 94.4% and by out-patient epileptologists in 5.6%. Non-epileptologists diagnosed FBTCS in all cases. HS was diagnosed by non-epileptologists in 13.9%, by out-patient epileptologists in 47.2%, and at the EMU in 38.9%. Early referral to epileptologists is most critical for early surgery. Early utilization of the EMU is highly recommended because FAS is often overlooked by outpatient epileptologists. The odyssey plot will be useful to improve the healthcare system for other types of epilepsy.

  40. Temporomandibular joint dislocation during epileptic seizures in the epilepsy monitoring unit: A case report International-journal Peer-reviewed

    Takafumi Kubota, Kazutaka Jin, Keigo Honoki, Temma Soga, Kazushi Ukishiro, Yosuke Kakisaka, Masashi Aoki, Nobukazu Nakasato

    Epileptic Disorders 25 (6) 904-906 2023/09

    Publisher: Wiley

    DOI: 10.1002/epd2.20158  

    ISSN: 1294-9361

    eISSN: 1950-6945

  41. The necessity to improve disaster preparedness among patients with amyotrophic lateral sclerosis and their families. International-journal Peer-reviewed

    Takehisa Hirayama, Mari Shibukawa, Harumi Morioka, Masamichi Hozumi, Hiroshi Tsuda, Naoki Atsuta, Yuishin Izumi, Yuki Nakayama, Toshio Shimizu, Haruhisa Inoue, Makoto Urushitani, Koji Yamanaka, Masashi Aoki, Satoru Ebihara, Atsushi Takeda, Osamu Kano

    Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 116 87-92 2023/08/31

    DOI: 10.1016/j.jocn.2023.08.002  

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    Disaster preparation is an important issue for patients with amyotrophic lateral sclerosis (ALS). However, to the best of our knowledge, no studies have investigated disaster preparedness among patients with ALS. In this study, we aimed to investigate disaster preparation in patients with ALS and their caregivers, including their families, in Japan. We conducted a nationwide webinar in September 2022 titled "ALS Café" and distributed a self-report questionnaire to participants with questions about awareness of disaster preparedness, social countermeasures, stockpiles, and electricity demand. Forty-eight patients with ALS (27 male; average age 60.0 ± 9.3 years) and 23 caregivers (8 male; 55.7 ± 9.9 years) responded. The median revised ALS Functional Rating Scale score was 30.5, and 25% of the patients with ALS were on a ventilator. More than 70% of the respondents answered that they were not prepared for disasters, increasing to 89% in patients not using ventilators. In the event of their phones being down, 86% of the respondents had no plans for alternative means of communication. <30% of the respondents, including ventilator users, had secured human resources for transportation. Twenty-five percent of the respondents did not stockpile food and beverages, and 12% of the ventilator users had no government-recommended ventilator preparation equipment. Thus, although patients with ALS and their families with ventilators have a high awareness of disaster preparedness, their awareness remains insufficient. Furthermore, patients with ALS and their families without ventilators have a low awareness of disaster preparedness. Therefore, better education regarding disaster preparedness is necessary for these groups.

  42. Oral edaravone - Introducing a Flexible Treatment Option for Amyotrophic lateral sclerosis. International-journal Peer-reviewed

    Gary L Pattee, Angela Genge, Philippe Couratier, Christian Lunetta, Gen Sobue, Masashi Aoki, Hiide Yoshino, Carlayne E Jackson, James Wymer, Alejandro Salah, Sally Nelson

    Expert review of neurotherapeutics 23 (10) 859-866 2023/08/30

    DOI: 10.1080/14737175.2023.2251687  

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    INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive and incurable neurodegenerative disease. While pharmacotherapy options remain limited, the Food and Drug Administration (FDA) approved intravenous (IV) and oral edaravone for the treatment of ALS in 2017 and 2022, respectively. With the addition of oral edaravone, patients with ALS may exclusively use oral medications. AREAS COVERED: The authors performed a review of the published literature using the United States (US) National Library of Medicine's PubMed.gov resource to describe the pharmacokinetics, pharmacodynamics, safety, and efficacy of oral edaravone, as well as pertinent completed and ongoing clinical trials, including the oral edaravone clinical trial development program. The clinical profile of oral edaravone is also discussed. EXPERT OPINION: Edaravone has been shown to slow the rate of motor function deterioration experienced by patients with ALS. As the oral formulation has been approved, patients with ALS may use it alone or in combination with other approved therapeutics. Additional clinical trials and real-world evidence are ongoing to gain further understanding of the clinical profile of oral edaravone.

  43. Dynamic electro‐clinical changes corresponding to immediate recovery after glucose administration from insulinoma‐induced hypoglycemia: report of two cases International-journal Peer-reviewed

    Kazutoshi Konomatsu, Yosuke Kakisaka, Kazutaka Jin, Kazushi Ukishiro, Ayumi Sakata, Takafumi Shimogawa, Takato Morioka, Takafumi Kubota, Temma Soga, Masashi Aoki, Nobukazu Nakasato

    Epileptic Disorders 2023/08/26

    Publisher: Wiley

    DOI: 10.1002/epd2.20155  

    ISSN: 1294-9361

    eISSN: 1950-6945

  44. Distal Chronic Inflammatory Demyelinating Polyneuropathy Following COVID-19 Vaccination in a Patient with Solitary Plasmacytoma: A Case Report and Literature Review Peer-reviewed

    Takafumi Kubota, Tomomi Shijo, Kensho Ikeda, Yoshihiko Mitobe, Shu Umezawa, Tatsuro Misu, Takafumi Hasegawa, Masashi Aoki

    Internal Medicine 62 (16) 2419-2425 2023/08/15

    Publisher: Japanese Society of Internal Medicine

    DOI: 10.2169/internalmedicine.1365-22  

    ISSN: 0918-2918

    eISSN: 1349-7235

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    We herein report a rare case of distal chronic inflammatory demyelinating polyneuropathy (CIDP) following coronavirus disease 2019 (COVID-19) vaccination. A 39-year-old woman with a solitary plasmacytoma developed general weakness 7 days after receiving the second dose of the Pfizer-BioNTech COVID-19 vaccine, which had progressed for 3 months. A neurological examination revealed limb weakness with areflexia. Serological tests identified the presence of IgG antibodies against anti-GM1 and anti-GM2 gangliosides. Comprehensive evaluations met the criteria of distal CIDP. Intravenous immunoglobulin, intravenous methylprednisolone, oral prednisolone, and plasma exchange were administered, and she gradually improved. Physicians should be aware of CIDP as a rare complication of COVID-19 vaccination.

  45. Efficacy confirmation study of aceneuramic acid administration for GNE myopathy in Japan International-journal Peer-reviewed

    Madoka Mori-Yoshimura, Naoki Suzuki, Masahisa Katsuno, Masanori P. Takahashi, Satoshi Yamashita, Yasushi Oya, Atsushi Hashizume, Shinichiro Yamada, Masayuki Nakamori, Rumiko Izumi, Masaaki Kato, Hitoshi Warita, Maki Tateyama, Hiroshi Kuroda, Ryuta Asada, Takuhiro Yamaguchi, Ichizo Nishino, Masashi Aoki

    Orphanet Journal of Rare Diseases 18 (1) 241-241 2023/08/11

    Publisher: Springer Science and Business Media {LLC}

    DOI: 10.1186/s13023-023-02850-y  

    ISSN: 1750-1172

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    <jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>A rare muscle disease, GNE myopathy is caused by mutations in the <jats:italic>GNE</jats:italic> gene involved in sialic acid biosynthesis. Our recent phase II/III study has indicated that oral administration of aceneuramic acid to patients slows disease progression.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>We conducted a phase III, randomized, placebo-controlled, double-blind, parallel-group, multicenter study. Participants were assigned to receive an extended-release formulation of aceneuramic acid (SA-ER) or placebo. Changes in muscle strength and function over 48 weeks were compared between treatment groups using change in the upper extremity composite (UEC) score from baseline to Week 48 as the primary endpoint and the investigator-assessed efficacy rate as the key secondary endpoint. For safety, adverse events, vital signs, body weight, electrocardiogram, and clinical laboratory results were monitored.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>A total of 14 patients were enrolled and given SA-ER (n = 10) or placebo (n = 4) tablets orally. Decrease in least square mean (LSM) change in UEC score at Week 48 with SA-ER (− 0.115 kg) was numerically smaller as compared with placebo (− 2.625 kg), with LSM difference (95% confidence interval) of 2.510 (− 1.720 to 6.740) kg. In addition, efficacy was higher with SA-ER as compared with placebo. No clinically significant adverse events or other safety concerns were observed.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>The present study reproducibly showed a trend towards slowing of loss of muscle strength and function with orally administered SA-ER, indicating supplementation with sialic acid might be a promising replacement therapy for GNE myopathy.</jats:p> <jats:p><jats:italic>Trial registration number</jats:italic>: ClinicalTrials.gov (NCT04671472).</jats:p> </jats:sec>

  46. LONRF2 is a protein quality control ubiquitin ligase whose deficiency causes late-onset neurological deficits. International-journal Peer-reviewed

    Dan Li, Yoshikazu Johmura, Satoru Morimoto, Miyuki Doi, Keiko Nakanishi, Manabu Ozawa, Yuji Tsunekawa, Akane Inoue-Yamauchi, Hiroya Naruse, Takashi Matsukawa, Yukio Takeshita, Naoki Suzuki, Masashi Aoki, Ayumi Nishiyama, Xin Zeng, Chieko Konishi, Narumi Suzuki, Atsuya Nishiyama, Alexander Stephen Harris, Mariko Morita, Kiyoshi Yamaguchi, Yoichi Furukawa, Kenta Nakai, Shoji Tsuji, Satoshi Yamazaki, Yuji Yamanashi, Shoichi Shimada, Takashi Okada, Hideyuki Okano, Tatsushi Toda, Makoto Nakanishi

    Nature aging 3 (8) 1001-1019 2023/07/20

    DOI: 10.1038/s43587-023-00464-4  

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    Protein misfolding is a major factor of neurodegenerative diseases. Post-mitotic neurons are highly susceptible to protein aggregates that are not diluted by mitosis. Therefore, post-mitotic cells may have a specific protein quality control system. Here, we show that LONRF2 is a bona fide protein quality control ubiquitin ligase induced in post-mitotic senescent cells. Under unperturbed conditions, LONRF2 is predominantly expressed in neurons. LONRF2 binds and ubiquitylates abnormally structured TDP-43 and hnRNP M1 and artificially misfolded proteins. Lonrf2-/- mice exhibit age-dependent TDP-43-mediated motor neuron (MN) degeneration and cerebellar ataxia. Mouse induced pluripotent stem cell-derived MNs lacking LONRF2 showed reduced survival, shortening of neurites and accumulation of pTDP-43 and G3BP1 after long-term culture. The shortening of neurites in MNs from patients with amyotrophic lateral sclerosis is rescued by ectopic expression of LONRF2. Our findings reveal that LONRF2 is a protein quality control ligase whose loss may contribute to MN degeneration and motor deficits.

  47. Pathogenic role of anti-cN1A autoantibodies in sporadic inclusion body myositis International-journal Peer-reviewed

    Satoshi Yamashita, Nozomu Tawara, Ziwei Zhang, Shunya Nakane, Kazuma Sugie, Naoki Suzuki, Ichizo Nishino, Masashi Aoki

    Journal of Neurology, Neurosurgery & Psychiatry 2023/07/14

    DOI: 10.1136/jnnp-2023-331474  

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    BACKGROUND: Sporadic inclusion body myositis (sIBM) is an intractable muscle disease that frequently affects elderly people. Autoantibodies recognising cytosolic 5'-nucleotidase 1A (cN1A) were found in the sera of patients with sIBM. However, the pathogenic role of the autoantibodies remained unknown. This study investigated the pathogenic properties of the autoantibodies using active cN1A peptides immunisation. METHODS: Wild-type C57BL6 mice were injected with three different mouse cN1A peptides corresponding to the previously reported epitope sequences of human cN1A. After confirming the production of autoantibodies to the corresponding cN1A peptides in each group, changes in body weight, exercise capacity by treadmill test and histological changes in mice injected with cN1A peptides or controls were investigated. RESULTS: Autoantibodies against cN1A were detected in serum samples from mice injected with cN1A peptide. Some groups of mice injected with cN1A peptide showed significant weight loss and decreased motor activity. The number of myofibres with internal nuclei increased in all the peptide-injected groups, with surrounding or invading CD8-positive T cells into myofibres, abnormal protein aggregates and overexpression of p62 and LC3. CONCLUSIONS: Active cN1A peptide immunisation partially reproduced the clinical and histological aspects of sIBM in wild-type mice. The murine model demonstrates the pathogenic properties of anti-cN1A autoantibodies to cause sIBM-like histological changes.

  48. Sortilin acts as an endocytic receptor for α-synuclein fibril. International-journal Peer-reviewed

    Shun Ishiyama, Takafumi Hasegawa, Naoto Sugeno, Junpei Kobayashi, Shun Yoshida, Yasuo Miki, Koichi Wakabayashi, Mitsunori Fukuda, Yasushi Kawata, Takaaki Nakamura, Kazuki Sato, Michinori Ezura, Akio Kikuchi, Atsushi Takeda, Masashi Aoki

    FASEB journal 37 (7) e23017 2023/07

    DOI: 10.1096/fj.202201605RR  

    eISSN: 1530-6860

  49. Detection of Modified Histones from Oral Mucosa of a Patient with DYT-KMT2B Dystonia International-journal Peer-reviewed

    Naoto Sugeno, Takafumi Hasegawa, Kazuhiro Haginoya, Takafumi Kubota, Kensuke Ikeda, Takaaki Nakamura, Shun Ishiyama, Kazuki Sato, Shun Yoshida, Eriko Koshimizu, Mitsugu Uematsu, Satoko Miyatake, Naomichi Matsumoto, Masashi Aoki

    Molecular Syndromology 14 (6) 461-468 2023/06/26

    DOI: 10.1159/000530625  

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    INTRODUCTION: DYT-KMT2B is a rare childhood-onset, hereditary movement disorder typically characterized by lower-limb dystonia and subsequently spreads into the craniocervical and laryngeal muscles. Recently, KMT2B-encoding lysine (K)-specific histone methyltransferase 2B was identified as the causative gene for DYT-KMT2B, also known as DYT28. In addition to the fact that many physicians do not have sufficient experience or knowledge of hereditary dystonia, the clinical features of DYT-KMT2B overlap with those of other hereditary dystonia, and limited clinical biomarkers make the diagnosis difficult. METHODS: Histone proteins were purified from the oral mucosa of patients with de novo KMT2B mutation causing premature stop codon, and then trimethylated fourth lysine residue of histone H3 (H3K4me3) which was catalyzed by KMT2B was analyzed by immunoblotting with specific antibody. We further analyzed the significance of H3K4me3 in patients with DYT-KMT2B using publicly available datasets. RESULTS: H3K4me3 histone mark was markedly lower in the patient than in the control group. Additionally, a reanalysis of publicly available datasets concerning DNA methylation also demonstrated that KMT2B remained inactive in DYT-KMT2B. DISCUSSION: Although only one case was studied due to the rarity of the disease, the reduction of H3K4me3 in the patient's biological sample supports the dysfunction of KMT2B in DYT-KMT2B. Together with informatics approaches, our results suggest that KMT2B haploinsufficiency contributes to the DYT-KMT2B pathogenic process.

  50. CGG repeat expansion in LRP12 in amyotrophic lateral sclerosis. International-journal Peer-reviewed

    Kodai Kume, Takashi Kurashige, Keiko Muguruma, Hiroyuki Morino, Yui Tada, Mai Kikumoto, Tatsuo Miyamoto, Silvia Natsuko Akutsu, Yukiko Matsuda, Shinya Matsuura, Masahiro Nakamori, Ayumi Nishiyama, Rumiko Izumi, Tetsuya Niihori, Masashi Ogasawara, Nobuyuki Eura, Tamaki Kato, Mamoru Yokomura, Yoshiaki Nakayama, Hidefumi Ito, Masataka Nakamura, Kayoko Saito, Yuichi Riku, Yasushi Iwasaki, Hirofumi Maruyama, Yoko Aoki, Ichizo Nishino, Yuishin Izumi, Masashi Aoki, Hideshi Kawakami

    American journal of human genetics 110 (7) 1086-1097 2023/06/20

    DOI: 10.1016/j.ajhg.2023.05.014  

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    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons. Although repeat expansion in C9orf72 is its most common cause, the pathogenesis of ALS isn't fully clear. In this study, we show that repeat expansion in LRP12, a causative variant of oculopharyngodistal myopathy type 1 (OPDM1), is a cause of ALS. We identify CGG repeat expansion in LRP12 in five families and two simplex individuals. These ALS individuals (LRP12-ALS) have 61-100 repeats, which contrasts with most OPDM individuals with repeat expansion in LRP12 (LRP12-OPDM), who have 100-200 repeats. Phosphorylated TDP-43 is present in the cytoplasm of iPS cell-derived motor neurons (iPSMNs) in LRP12-ALS, a finding that reproduces the pathological hallmark of ALS. RNA foci are more prominent in muscle and iPSMNs in LRP12-ALS than in LRP12-OPDM. Muscleblind-like 1 aggregates are observed only in OPDM muscle. In conclusion, CGG repeat expansions in LRP12 cause ALS and OPDM, depending on the length of the repeat. Our findings provide insight into the repeat length-dependent switching of phenotypes.

  51. Phase 1/2a clinical trial in ALS with ropinirole, a drug candidate identified by iPSC drug discovery. International-journal Peer-reviewed

    Satoru Morimoto, Shinichi Takahashi, Daisuke Ito, Yugaku Daté, Kensuke Okada, Chris Kato, Shiho Nakamura, Fumiko Ozawa, Chai Muh Chyi, Ayumi Nishiyama, Naoki Suzuki, Koki Fujimori, Tosho Kondo, Masaki Takao, Miwa Hirai, Yasuaki Kabe, Makoto Suematsu, Masahiro Jinzaki, Masashi Aoki, Yuto Fujiki, Yasunori Sato, Norihiro Suzuki, Jin Nakahara, Hideyuki Okano

    Cell stem cell 30 (6) 766-780 2023/06/01

    DOI: 10.1016/j.stem.2023.04.017  

    ISSN: 1934-5909

    eISSN: 1875-9777

  52. A Case of Amyotrophic Lateral Sclerosis with a Priority Request for a Postmortem Kidney Donation to a Relative. Peer-reviewed

    Masaya Toyoshima, Naoki Suzuki, Shio Mitsuzawa, Temma Soga, Rumiko Izumi, Kazuhiro Mitsui, Shigehito Miyagi, Masashi Aoki, Masaaki Kato

    Internal medicine (Tokyo, Japan) 2023/05/24

    DOI: 10.2169/internalmedicine.1574-23  

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    The patient was 57 years old when he was diagnosed with amyotrophic lateral sclerosis (ALS) at 1 year after developing bulbar symptoms. At 58 years old, he stated that he was considering donating his kidney to his son suffering from diabetic nephropathy. We confirmed the patient's intentions through repeated interviews before his death at 61 years old. Nephrectomy was performed 30 min after his cardiac death. Organ donation spontaneously proposed by an ALS patient should be considered in order to meet the requests of patients who want their families and other patients to live longer, thereby imparting a beneficial legacy through their deaths.

  53. Genetic factors affecting survival in Japanese patients with sporadic amyotrophic lateral sclerosis: a genome-wide association study and verification in iPSC-derived motor neurons from patients. International-journal Peer-reviewed

    Ryoichi Nakamura, Genki Tohnai, Masahiro Nakatochi, Naoki Atsuta, Hirohisa Watanabe, Daisuke Ito, Masahisa Katsuno, Akihiro Hirakawa, Yuishin Izumi, Mitsuya Morita, Takehisa Hirayama, Osamu Kano, Kazuaki Kanai, Nobutaka Hattori, Akira Taniguchi, Naoki Suzuki, Masashi Aoki, Ikuko Iwata, Ichiro Yabe, Kazumoto Shibuya, Satoshi Kuwabara, Masaya Oda, Rina Hashimoto, Ikuko Aiba, Tomohiko Ishihara, Osamu Onodera, Toru Yamashita, Koji Abe, Kouichi Mizoguchi, Toshio Shimizu, Yoshio Ikeda, Takanori Yokota, Kazuko Hasegawa, Fumiaki Tanaka, Kenji Nakashima, Ryuji Kaji, Jun-Ichi Niwa, Manabu Doyu, Chikashi Terao, Shiro Ikegawa, Koki Fujimori, Shiho Nakamura, Fumiko Ozawa, Satoru Morimoto, Kazunari Onodera, Takuji Ito, Yohei Okada, Hideyuki Okano, Gen Sobue

    Journal of neurology, neurosurgery, and psychiatry 94 (10) 816-824 2023/05/04

    DOI: 10.1136/jnnp-2022-330851  

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    BACKGROUND: Several genetic factors are associated with the pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) and its phenotypes, such as disease progression. Here, in this study, we aimed to identify the genes that affect the survival of patients with sporadic ALS. METHODS: We enrolled 1076 Japanese patients with sporadic ALS with imputed genotype data of 7 908 526 variants. We used Cox proportional hazards regression analysis with an additive model adjusted for sex, age at onset and the first two principal components calculated from genotyped data to conduct a genome-wide association study. We further analysed messenger RNA (mRNA) and phenotype expression in motor neurons derived from induced pluripotent stem cells (iPSC-MNs) of patients with ALS. RESULTS: Three novel loci were significantly associated with the survival of patients with sporadic ALS-FGF1 at 5q31.3 (rs11738209, HR=2.36 (95% CI, 1.77 to 3.15), p=4.85×10-9), THSD7A at 7p21.3 (rs2354952, 1.38 (95% CI, 1.24 to 1.55), p=1.61×10-8) and LRP1 at 12q13.3 (rs60565245, 2.18 (95% CI, 1.66 to 2.86), p=2.35×10-8). FGF1 and THSD7A variants were associated with decreased mRNA expression of each gene in iPSC-MNs and reduced in vitro survival of iPSC-MNs obtained from patients with ALS. The iPSC-MN in vitro survival was reduced when the expression of FGF1 and THSD7A was partially disrupted. The rs60565245 was not associated with LRP1 mRNA expression. CONCLUSIONS: We identified three loci associated with the survival of patients with sporadic ALS, decreased mRNA expression of FGF1 and THSD7A and the viability of iPSC-MNs from patients. The iPSC-MN model reflects the association between patient prognosis and genotype and can contribute to target screening and validation for therapeutic intervention.

  54. Genome-wide association study identifies a new susceptibility locus in PLA2G4C for Multiple System Atrophy. International-journal

    Yasuo Nakahara, Jun Mitsui, Hidetoshi Date, Kristine Joyce Porto, Yasuhiro Hayashi, Atsushi Yamashita, Yoshio Kusakabe, Takashi Matsukawa, Hiroyuki Ishiura, Tsutomu Yasuda, Atsushi Iwata, Jun Goto, Yaeko Ichikawa, Yoshio Momose, Yuji Takahashi, Tatsushi Toda, Rikifumi Ohta, Jun Yoshimura, Shinichi Morishita, Emil K Gustavsson, Darren Christy, Melissa Maczis, Matthew J Farrer, Han-Joon Kim, Sung-Sup Park, Beomseok Jeon, Jin Zhang, Weihong Gu, Sonja W Scholz, Andrew B Singleton, Henry Houlden, Ichiro Yabe, Hidenao Sasaki, Masaaki Matsushima, Hiroshi Takashima, Akio Kikuchi, Masashi Aoki, Kenju Hara, Akiyoshi Kakita, Mitsunori Yamada, Hitoshi Takahashi, Osamu Onodera, Masatoyo Nishizawa, Hirohisa Watanabe, Mizuki Ito, Gen Sobue, Kinya Ishikawa, Hidehiro Mizusawa, Kazuaki Kanai, Satoshi Kuwabara, Kimihito Arai, Shigeru Koyano, Yoshiyuki Kuroiwa, Kazuko Hasegawa, Tatsuhiko Yuasa, Kenichi Yasui, Kenji Nakashima, Hijiri Ito, Yuishin Izumi, Ryuji Kaji, Takeo Kato, Susumu Kusunoki, Yasushi Osaki, Masahiro Horiuchi, Ken Yamamoto, Mihoko Shimada, Taku Miyagawa, Yosuke Kawai, Nao Nishida, Katsushi Tokunaga, Alexandra Dürr, Alexis Brice, Alessandro Filla, Thomas Klockgether, Ullrich Wüllner, Caroline M Tanner, Walter A Kukull, Virginia M-Y Lee, Eliezer Masliah, Phillip A Low, Paola Sandroni, Laurie Ozelius, Tatiana Foroud, Shoji Tsuji

    medRxiv : the preprint server for health sciences 2023/05/02

    DOI: 10.1101/2023.05.02.23289328  

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    To elucidate the molecular basis of multiple system atrophy (MSA), a neurodegenerative disease, we conducted a genome-wide association study (GWAS) in a Japanese MSA case/control series followed by replication studies in Japanese, Korean, Chinese, European and North American samples. In the GWAS stage rs2303744 on chromosome 19 showed a suggestive association ( P = 6.5 × 10 -7 ) that was replicated in additional Japanese samples ( P = 2.9 × 10 -6 . OR = 1.58; 95% confidence interval, 1.30 to 1.91), and then confirmed as highly significant in a meta-analysis of East Asian population data ( P = 5.0 × 10 -15 . Odds ratio= 1.49; 95% CI 1.35 to 1.72). The association of rs2303744 with MSA remained significant in combined European/North American samples ( P =0.023. Odds ratio=1.14; 95% CI 1.02 to 1.28) despite allele frequencies being quite different between these populations. rs2303744 leads to an amino acid substitution in PLA2G4C that encodes the cPLA2γ lysophospholipase/transacylase. The cPLA2γ-Ile143 isoform encoded by the MSA risk allele has significantly decreased transacylase activity compared with the alternate cPLA2γ-Val143 isoform that may perturb membrane phospholipids and α-synuclein biology.

  55. Phase II/III Study of Aceneuramic Acid Administration for GNE Myopathy in Japan. International-journal Peer-reviewed

    Naoki Suzuki, Madoka Mori-Yoshimura, Masahisa Katsuno, Masanori P Takahashi, Satoshi Yamashita, Yasushi Oya, Atsushi Hashizume, Shinichiro Yamada, Masayuki Nakamori, Rumiko Izumi, Masaaki Kato, Hitoshi Warita, Maki Tateyama, Hiroshi Kuroda, Ryuta Asada, Takuhiro Yamaguchi, Ichizo Nishino, Masashi Aoki

    Journal of neuromuscular diseases 10 (4) 555-566 2023/04/25

    DOI: 10.3233/JND-230029  

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    BACKGROUND: GNE myopathy is an ultra-rare muscle disease characterized by a reduction in the synthesis of sialic acid derived from pathogenic variants in the GNE gene. No treatment has been established so far. OBJECTIVE: We evaluated the safety and efficacy of oral supplementation of aceneuramic acid in patients with GNE myopathy. METHODS: This multicenter, placebo-controlled, double-blind study comprised genetically confirmed GNE myopathy patients in Japan who were randomly assigned into treatment groups of sialic acid-extended release (SA-ER) tablets (6 g/day for 48 weeks) or placebo groups (4:1). The primary endpoint of effectiveness was set as the change in total upper limb muscle strength (upper extremity composite [UEC] score) from the start of administration to the final evaluation time point. RESULTS: Among the 20 enrolled patients (SA-ER group, 16; placebo group, 4), 19 completed this 48-week study. The mean value of change in UEC score (95% confidence interval [CI]) at 48 weeks was -0.1 kg (-2.1 to 2.0) in the SA-ER group and -5.1 kg (-10.4 to 0.3) in the placebo group. The least squares mean difference (95% CI) between the groups in the covariance analysis was 4.8 kg (-0.3 to 9.9; P = 0.0635). The change in UEC score at 48 weeks was significantly higher in the SA-ER group compared with the placebo group (P = 0.0013) in the generalized estimating equation test repeated measurement analysis. In one patient in the SA-ER group, who was found to be pregnant 2 weeks after drug administration fetal death with tangled umbilical cord occurred at 13 weeks after the discontinuation of treatment. No other serious adverse effects were observed. CONCLUSIONS: The present study indicates that oral administration of SA-ER tablets is effective and safe in patients with GNE myopathy in Japan.

  56. Reply to the Letter "Reversible Vasoconstriction Syndrome is a Complication of SARS-CoV-2 Infection/Vaccination Rather Than That of Leigh Syndrome". Peer-reviewed

    Ayane Ohyama-Tamagake, Kimihiko Kaneko, Ryo Itami, Masatsugu Nakano, Yasuhiro Namioka, Rumiko Izumi, Haruka Sato, Hideaki Suzuki, Atsuhito Takeda, Yukiko Yatsuka, Yasushi Okazaki, Takaaki Abe, Kei Murayama, Naoto Sugeno, Tatsuro Misu, Masashi Aoki

    Internal medicine (Tokyo, Japan) 2023/04/21

    DOI: 10.2169/internalmedicine.1962-23  

  57. Diagnostic implications of MOG-IgG detection in sera and cerebrospinal fluids. International-journal Peer-reviewed

    Yuki Matsumoto, Kimihiko Kaneko, Toshiyuki Takahashi, Yoshiki Takai, Chihiro Namatame, Hiroshi Kuroda, Tatsuro Misu, Kazuo Fujihara, Masashi Aoki

    Brain : a journal of neurology 146 (9) 3938-3948 2023/04/15

    DOI: 10.1093/brain/awad122  

    ISSN: 0006-8950

    eISSN: 1460-2156

  58. Dramatic Responses to Low-Dose Pramipexole in Painful Legs and Moving Toes Syndrome. International-journal Peer-reviewed

    Gakusuke Umezawa, Takafumi Hasegawa, Kensuke Ikeda, Genichi Saito, Masashi Aoki

    Cureus 15 (2) e34763 2023/02

    DOI: 10.7759/cureus.34763  

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    Painful legs and moving toes syndrome (PLMTS) is a rare movement disorder characterized by spontaneous abnormal, involuntary toe movements and unilateral or bilateral lower extremity pain that predominantly affects women in middle age or later. The background etiology of PLMTS includes peripheral neuropathy, a history of trauma, and nerve root damage, but the cause of the disease is often undetermined. The pain usually occurs first and is often more distressing to the patient than abnormal toe movement. Spontaneous resolution is rare, and symptomatic therapies include the oral administration of anticonvulsants, antidepressants, and various pain relievers, as well as other therapeutic interventions, including botulinum toxin injection and epidural block, but their effectiveness is uncertain. We report a case of PMLTS in which low doses of pramipexole, a non-ergot dopamine agonist, dramatically improved both abnormal toe movement and leg pain, which are documented by videography.

  59. Efficacy of oligodendrocyte precursor cells as delivery vehicles for single-chain variable fragment to misfolded SOD1 in ALS rat model International-journal Peer-reviewed

    Sumio Minamiyama, Madoka Sakai, Yuko Yamaguchi, Makiko Kusui, Hideki Wada, Ryota Hikiami, Yoshitaka Tamaki, Megumi Asada-Utsugi, Akemi Shodai, Akiko Makino, Noriko Fujiwara, Takashi Ayaki, Takakuni Maki, Hitoshi Warita, Masashi Aoki, Keizo Tomonaga, Ryosuke Takahashi, Makoto Urushitani

    Molecular Therapy - Methods &amp; Clinical Development 28 312-329 2023/02

    Publisher: Elsevier {BV}

    DOI: 10.1016/j.omtm.2023.01.008  

    ISSN: 2329-0501

    eISSN: 2329-0501

  60. Videofluoroscopic Dysphagia Scale as an Additional Indicator of Gastrostomy in Patients with Amyotrophic Lateral Sclerosis with Dysphagia. Peer-reviewed

    Tomomi Shijo, Ryoukichi Ikeda, Naoki Suzuki, Jun Ohta, Jun Suzuki, Ai Hirano-Kawamoto, Kengo Kato, Kensuke Ikeda, Rumiko Izumi, Shio Mitsuzawa, Hitoshi Warita, Masaaki Kato, Masashi Aoki, Yukio Katori

    The Tohoku journal of experimental medicine 259 (4) 293-300 2023/01/26

    DOI: 10.1620/tjem.2023.J005  

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    Pseudobulbar palsy and bulbar palsy cause dysphagia in patients with amyotrophic lateral sclerosis (ALS). Dysphagia in patients with ALS not only increases the risk of aspiration and pneumonia but also leads to malnutrition and weight loss, which are poor prognostic factors. Gastrostomy is the preferred route of feeding and nutritional support in patients with dysphagia. However, there are no established standards to determine the ideal timing of gastrostomy for patients with ALS. Therefore, we used the videofluoroscopic dysphagia scale (VDS), which objectively quantifies swallowing function, in videofluoroscopic swallowing study (VFSS) to investigate whether this scale at diagnosis can be a useful predictor for the timing of gastrostomy. We retrospectively evaluated 22 patients with ALS who were diagnosed at our hospital. We assessed the VDS scores in all patients within 3 months of diagnosis. A decline in the ALS functional rating scale revised (ALSFRS-R) scores was used as an indicator of disease progression. As a result, we found that the VDS score of the pharyngeal phase and the total VDS score were significantly correlated with the ΔALSFRS-R scores. These scores were also associated with the existing indicators for the timing of gastrostomy, i.e., decreased body weight and percent-predicted forced vital capacity. We demonstrated the noninferiority of the VDS scores relative to the existing indicators. In addition, the VDS score of the pharyngeal phase was significantly correlated with the time from diagnosis to gastrostomy. The VDS score could estimate the timing of gastrostomy in patients with ALS with dysphagia at diagnosis.

  61. Clinical course of pathologically confirmed corticobasal degeneration and corticobasal syndrome. International-journal Peer-reviewed

    Ikuko Aiba, Yuichi Hayashi, Takayoshi Shimohata, Mari Yoshida, Yuko Saito, Koichi Wakabayashi, Takashi Komori, Masato Hasegawa, Takeshi Ikeuchi, Aya M Tokumaru, Keita Sakurai, Shigeo Murayama, Kazuko Hasegawa, Toshiki Uchihara, Yasuko Toyoshima, Yufuko Saito, Ichiro Yabe, Satoshi Tanikawa, Keizo Sugaya, Kentaro Hayashi, Terunori Sano, Masaki Takao, Motoko Sakai, Harutoshi Fujimura, Hiroshi Takigawa, Tadashi Adachi, Ritsuko Hanajima, Osamu Yokota, Tomoko Miki, Yasushi Iwasaki, Michio Kobayashi, Nobutaka Arai, Takuya Ohkubo, Takanori Yokota, Keiko Mori, Masumi Ito, Chiho Ishida, Masaharu Tanaka, Jiro Idezuka, Masato Kanazawa, Kenju Aoki, Masashi Aoki, Takafumi Hasegawa, Hirohisa Watanabe, Atsushi Hashizume, Hisayoshi Niwa, Keizo Yasui, Keita Ito, Yukihiko Washimi, Eiichiro Mukai, Akatsuki Kubota, Tatsushi Toda, Kenji Nakashima

    Brain communications 5 (6) fcad296 2023

    DOI: 10.1093/braincomms/fcad296  

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    The clinical presentation of corticobasal degeneration is diverse, while the background pathology of corticobasal syndrome is also heterogeneous. Therefore, predicting the pathological background of corticobasal syndrome is extremely difficult. Herein, we investigated the clinical findings and course in patients with pathologically, genetically and biochemically verified corticobasal degeneration and corticobasal syndrome with background pathology to determine findings suggestive of background disorder. Thirty-two patients were identified as having corticobasal degeneration. The median intervals from the initial symptoms to the onset of key milestones were as follows: gait disturbance, 0.0 year; behavioural changes, 1.0 year; falls, 2.0 years; cognitive impairment, 2.0 years; speech impairment, 2.5 years; supranuclear gaze palsy, 3.0 years; urinary incontinence, 3.0 years; and dysphagia, 5.0 years. The median survival time was 7.0 years; 50% of corticobasal degeneration was diagnosed as corticobasal degeneration/corticobasal syndrome at the final presentation. Background pathologies of corticobasal syndrome (n = 48) included corticobasal degeneration (33.3%), progressive supranuclear palsy (29.2%) and Alzheimer's disease (12.5%). The common course of corticobasal syndrome was initial gait disturbance and early fall. In addition, corticobasal degeneration-corticobasal syndrome manifested behavioural change (2.5 years) and cognitive impairment (3.0 years), as the patient with progressive supranuclear palsy-corticobasal syndrome developed speech impairment (1.0 years) and supranuclear gaze palsy (6.0 years). The Alzheimer's disease-corticobasal syndrome patients showed cognitive impairment (1.0 years). The frequency of frozen gait at onset was higher in the corticobasal degeneration-corticobasal syndrome group than in the progressive supranuclear palsy-corticobasal syndrome group [P = 0.005, odds ratio (95% confidence interval): 31.67 (1.46-685.34)]. Dysarthria at presentation was higher in progressive supranuclear palsy-corticobasal syndrome than in corticobasal degeneration-corticobasal syndrome [P = 0.047, 6.75 (1.16-39.20)]. Pyramidal sign at presentation and personality change during the entire course were higher in Alzheimer's disease-corticobasal syndrome than in progressive supranuclear palsy-corticobasal syndrome [P = 0.011, 27.44 (1.25-601.61), and P = 0.013, 40.00 (1.98-807.14), respectively]. In corticobasal syndrome, decision tree analysis revealed that 'freezing at onset' or 'no dysarthria at presentation and age at onset under 66 years in the case without freezing at onset' predicted corticobasal degeneration pathology with a sensitivity of 81.3% and specificity of 84.4%. 'Dysarthria at presentation and age at onset over 61 years' suggested progressive supranuclear palsy pathology, and 'pyramidal sign at presentation and personality change during the entire course' implied Alzheimer's disease pathology. In conclusion, frozen gait at onset, dysarthria, personality change and pyramidal signs may be useful clinical signs for predicting background pathologies in corticobasal syndrome.

  62. Pathology of myelin oligodendrocyte glycoprotein antibody-associated disease: a comparison with multiple sclerosis and aquaporin 4 antibody-positive neuromyelitis optica spectrum disorders. International-journal Peer-reviewed

    Yoshiki Takai, Tatsuro Misu, Kazuo Fujihara, Masashi Aoki

    Frontiers in neurology 14 1209749-1209749 2023

    DOI: 10.3389/fneur.2023.1209749  

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    Myelin oligodendrocyte glycoprotein (MOG) is expressed on the outermost layer of the myelin sheath in the central nervous system. Recently, the clinical concept of MOG antibody-associated disease (MOGAD) was established based on the results of human MOG-transfected cell-based assays which can detect conformation-sensitive antibodies against MOG. In this review, we summarized the pathological findings of MOGAD and discussed the issues that remain unresolved. MOGAD pathology is principally inflammatory demyelination without astrocyte destruction, characterized by perivenous demyelination previously reported in acute disseminated encephalomyelitis and by its fusion pattern localized in both the white and gray matter, but not by radially expanding confluent demyelination typically seen in multiple sclerosis (MS). Some of demyelinating lesions in MOGAD show severe loss of MOG staining compared with those of other myelin proteins, suggesting a MOG-targeted pathology in the disease. Perivascular cuffings mainly consist of macrophages and T cells with CD4-dominancy, which is also different from CD8+ T-cell-dominant inflammation in MS. Compared to aquaporin 4 (AQP4) antibody-positive neuromyelitis optica spectrum disorders (NMOSD), perivenous complement deposition is less common, but can be seen on myelinated fibers and on myelin degradation products within macrophages, resembling MS Pattern II pathology. Thus, the pathogenetic contribution of complements in MOGAD is still debatable. Together, these pathological features in MOGAD are clearly different from those of MS and AQP4 antibody-positive NMOSD, suggesting that MOGAD is an independent autoimmune demyelinating disease entity. Further research is needed to clarify the exact pathomechanisms of demyelination and how the pathophysiology relates to the clinical phenotype and symptoms leading to disability in MOGAD patients.

  63. Adult-onset Leigh Syndrome with a m.9176 T>C Mutation Manifested as Reversible Cerebral Vasoconstriction Syndrome. Peer-reviewed

    Ayane Ohyama-Tamagake, Kimihiko Kaneko, Ryo Itami, Masatsugu Nakano, Yasuhiro Namioka, Rumiko Izumi, Haruka Sato, Hideaki Suzuki, Atsuhito Takeda, Yasushi Okazaki, Yukiko Yatsuka, Takaaki Abe, Kei Murayama, Naoto Sugeno, Tatsuro Misu, Masashi Aoki

    Internal medicine (Tokyo, Japan) 2022/12/21

    DOI: 10.2169/internalmedicine.0773-22  

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    A 26-year-old woman developed a sudden headache, ptosis, and diplopia. Magnetic resonance imaging and angiography demonstrated a symmetrical lesion from the midbrain to the brainstem, involving the solitary nucleus and multifocal cerebral artery narrowing. Reversible cerebral vasospasm syndrome (RCVS) was suspected, and the patient improved after vasodilatation. Leigh syndrome was suspected due to the elevated serum lactate levels, so mitochondrial DNA was analyzed, and an m.9176 T>C mutation was detected. The final diagnosis was adult-onset Leigh syndrome manifesting as RCVS. An uncontrolled baroreflex due to a solitary nuclear lesion or endothelial dysfunction may have contributed to her unique presentation.

  64. Upregulated complement receptors correlate with Fc gamma receptor 3A-positive natural killer and natural killer-T cells in neuromyelitis optica spectrum disorder. International-journal Peer-reviewed

    Shuhei Nishiyama, Amy E Wright, Itay Lotan, Takahisa Mikami, Friedemann Paul, Masashi Aoki, Michael Levy

    Journal of neuroinflammation 19 (1) 296-296 2022/12/12

    DOI: 10.1186/s12974-022-02661-1  

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    BACKGROUND AND OBJECTIVES: Inhibition of terminal complement in neuromyelitis optica spectrum disorder (NMOSD) using eculizumab helps prevent relapses, but the exact mechanism of action of the drug remains unclear. Similarly, genetic variants in the Fc Gamma receptor 3A (FCGR3A), also known as CD16, are correlated with outcomes in NMOSD, but the immune cells expressing those CD16 are unknown. We compared CD16 expression on immune cells modulated by complement activity in natural killer (NK) cells and natural killer-T (NKT) cells in NMOSD to disease and normal-healthy controls. METHODS: Peripheral blood cell (PBMC) samples from 45 patients with NMOSD with aquaporin 4 (AQP4)-IgG, 18 disease controls, and 19 normal controls were analyzed for CD16 expression and complement receptors in vitro. RESULTS: At baseline, the number of NKT cells was increased in NMOSD (p < 0.001), but the proportion that was CD16 positive was lower compared to normal and disease controls (p = 0.0012). NK cell count was normal, but the ratio that was CD16 positive was also significantly lower (p < 0.001). In both NK cells and NKT cells from NMOSD, C5 complement receptor expression was much higher than normal and disease controls (p < 0.001 for both). We also evaluated activation markers CD69 and CD83, which were also significantly higher in NK and NKT cells from NMOSD patients. FCGR3A p158 V/V genotype group in NMOSD patients showed decreased NK cell proportion with activation, and fewer CD16-expressing NKT cells than the F/F genotype group. DISCUSSION: Our results support an immunopathogenesis model in which complement pathway activation in NK/NKT cells upregulates CD16 expression that binds to antibody/antigen complexes. In the context of NMOSD, these complement-sensitive cells may be responsible for the escalating autoimmune activity.

  65. Patients with lower limb-onset ALS who have a longer duration from onset to diagnosis have a better prognosis Peer-reviewed

    Tomomi Shijo, Naoki Suzuki, Hitoshi Warita, Yuko Kawauchi, Shio Mitsuzawa, Kensuke Ikeda, Rumiko Izumi, Risako Ono, Akiyuki Ohno, Masaya Toyoshima, Ryuhei Harada, Hiroshi Kuroda, Masaaki Kato, Masashi Aoki

    NEUROLOGY AND CLINICAL NEUROSCIENCE 10 (5) 239-244 2022/09

    DOI: 10.1111/ncn3.12652  

    ISSN: 2049-4173

  66. Genetics of amyotrophic lateral sclerosis: seeking therapeutic targets in the era of gene therapy. International-journal Peer-reviewed

    Naoki Suzuki, Ayumi Nishiyama, Hitoshi Warita, Masashi Aoki

    Journal of human genetics 2022/06/13

    DOI: 10.1038/s10038-022-01055-8  

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    Amyotrophic lateral sclerosis (ALS) is an intractable disease that causes respiratory failure leading to mortality. The main locus of ALS is motor neurons. The success of antisense oligonucleotide (ASO) therapy in spinal muscular atrophy (SMA), a motor neuron disease, has triggered a paradigm shift in developing ALS therapies. The causative genes of ALS and disease-modifying genes, including those of sporadic ALS, have been identified one after another. Thus, the freedom of target choice for gene therapy has expanded by ASO strategy, leading to new avenues for therapeutic development. Tofersen for superoxide dismutase 1 (SOD1) was a pioneer in developing ASO for ALS. Improving protocols and devising early interventions for the disease are vital. In this review, we updated the knowledge of causative genes in ALS. We summarized the genetic mutations identified in familial ALS and their clinical features, focusing on SOD1, fused in sarcoma (FUS), and transacting response DNA-binding protein. The frequency of the C9ORF72 mutation is low in Japan, unlike in Europe and the United States, while SOD1 and FUS are more common, indicating that the target mutations for gene therapy vary by ethnicity. A genome-wide association study has revealed disease-modifying genes, which could be the novel target of gene therapy. The current status and prospects of gene therapy development were discussed, including ethical issues. Furthermore, we discussed the potential of axonal pathology as new therapeutic targets of ALS from the perspective of early intervention, including intra-axonal transcription factors, neuromuscular junction disconnection, dysregulated local translation, abnormal protein degradation, mitochondrial pathology, impaired axonal transport, aberrant cytoskeleton, and axon branching. We simultaneously discuss important pathological states of cell bodies: persistent stress granules, disrupted nucleocytoplasmic transport, and cryptic splicing. The development of gene therapy based on the elucidation of disease-modifying genes and early intervention in molecular pathology is expected to become an important therapeutic strategy in ALS.

  67. Anti-NXP2 antibody-positive dermatomyositis developed after COVID-19 manifesting as type I interferonopathy. International-journal Peer-reviewed

    Yuri Okada, Rumiko Izumi, Tatsuhiko Hosaka, Satoshi Watanabe, Tomomi Shijo, Naokazu Hatchome, Risa Konishi, Yuki Ichimura, Naoko Okiyama, Naoki Suzuki, Tatsuro Misu, Masashi Aoki

    Rheumatology (Oxford, England) 61 (4) e90-e92 2022/04/11

    DOI: 10.1093/rheumatology/keab872  

  68. MOG Antibody-Associated Disorders Following SARS-CoV-2 Vaccination: A Case Report and Literature Review. International-journal Peer-reviewed

    Yuki Matsumoto, Ayane Ohyama, Takafumi Kubota, Kensuke Ikeda, Kimihiko Kaneko, Yoshiki Takai, Hitoshi Warita, Toshiyuki Takahashi, Tatsuro Misu, Masashi Aoki

    Frontiers in neurology 13 845755-845755 2022/03/01

    DOI: 10.3389/fneur.2022.845755  

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    Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disorder (MOGAD) is a newly identified autoimmune demyelinating disorder that is often associated with acute disseminated encephalomyelitis and usually occurs postinfection or postvaccination. Here we report a case of MOGAD after mRNA severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. A previously healthy 68-year-old woman presented to our department with gradually worsening numbness on the right side of her face, which began 14 days after her second dose of an mRNA-1273 vaccination. The patient's brain MRI revealed a right cerebellar peduncle lesion with gadolinium enhancement, a typical finding of MOGAD. A neurological examination revealed paresthesia on her right V2 and V3 areas. Other neurological examinations were unremarkable. Laboratory workups were positive for serum MOG-IgG as assessed by live cell-based assays and the presence of oligoclonal bands in the cerebrospinal fluid (CSF). The patient's serum test results for cytoplasmic-antineutrophil cytoplasmic antibodies, perinuclear-cytoplasmic-antineutrophil cytoplasmic antibodies, GQ1b-antibodies, and aquaporin-4 antibodies (AQP4-IgG) were all negative. Tests for soluble interleukin (IL)-2 receptors in the serum, IL-6 in the CSF and skin pricks, and angiotensin converting enzyme tests were all unremarkable. The patient was diagnosed with MOGAD after receiving an mRNA SARS-CoV-2 vaccination. After two courses of intravenous methylprednisolone treatment, the patient's symptoms improved and her cerebellar peduncle lesion shrunk slightly without gadolinium enhancement. To date, there have only been two cases of monophasic MOGAD following SARS-CoV-2 vaccination, including both the ChAdOx1 nCOV-19 and mRNA-1273 vaccines, and the prognosis is generally similar to other typical MOGAD cases. Although the appearance of MOG antibodies is relatively rare in post-COVID-19-vaccine demyelinating diseases, MOGAD should be considered in patients with central nervous system (CNS) demyelinating diseases after receiving a SARS-CoV-2 vaccine.

  69. Cybernic treatment with wearable cyborg Hybrid Assistive Limb (HAL) improves ambulatory function in patients with slowly progressive rare neuromuscular diseases: a multicentre, randomised, controlled crossover trial for efficacy and safety (NCY-3001). International-journal Peer-reviewed

    Takashi Nakajima, Yoshiyuki Sankai, Shinjiro Takata, Yoko Kobayashi, Yoshihito Ando, Masanori Nakagawa, Toshio Saito, Kayoko Saito, Chiho Ishida, Akira Tamaoka, Takako Saotome, Tetsuo Ikai, Hisako Endo, Kazuhiro Ishii, Mitsuya Morita, Takashi Maeno, Kiyonobu Komai, Tetsuhiko Ikeda, Yuka Ishikawa, Shinichiro Maeshima, Masashi Aoki, Michiya Ito, Tatsuya Mima, Toshihiko Miura, Jun Matsuda, Yumiko Kawaguchi, Tomohiro Hayashi, Masahiro Shingu, Hiroaki Kawamoto

    Orphanet journal of rare diseases 16 (1) 304-304 2021/07/07

    DOI: 10.1186/s13023-021-01928-9  

    eISSN: 1750-1172

  70. Reduced PHOX2B stability causes axonal growth impairment in motor neurons with TARDBP mutations. International-journal Peer-reviewed

    Shio Mitsuzawa, Naoki Suzuki, Tetsuya Akiyama, Mitsuru Ishikawa, Takefumi Sone, Jiro Kawada, Ryo Funayama, Matsuyuki Shirota, Hiroaki Mitsuhashi, Satoru Morimoto, Kensuke Ikeda, Tomomi Shijo, Akiyuki Ohno, Naoko Nakamura, Hiroya Ono, Risako Ono, Shion Osana, Tadashi Nakagawa, Ayumi Nishiyama, Rumiko Izumi, Shohei Kaneda, Yoshiho Ikeuchi, Keiko Nakayama, Teruo Fujii, Hitoshi Warita, Hideyuki Okano, Masashi Aoki

    Stem cell reports 16 (6) 1527-1541 2021/06/08

    DOI: 10.1016/j.stemcr.2021.04.021  

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    Amyotrophic lateral sclerosis (ALS) is an adult-onset incurable motor neuron (MN) disease. The reasons for selective MN vulnerability in ALS are unknown. Axonal pathology is among the earliest signs of ALS. We searched for novel modulatory genes in human MN axon shortening affected by TARDBP mutations. In transcriptome analysis of RNA present in the axon compartment of human-derived induced pluripotent stem cell (iPSC)-derived MNs, PHOX2B (paired-like homeobox protein 2B) showed lower expression in TARDBP mutant axons, which was consistent with axon qPCR and in situ hybridization. PHOX2B mRNA stability was reduced in TARDBP mutant MNs. Furthermore, PHOX2B knockdown reduced neurite length in human MNs. Finally, phox2b knockdown in zebrafish induced short spinal axons and impaired escape response. PHOX2B is known to be highly express in other types of neurons maintained after ALS progression. Collectively, TARDBP mutations induced loss of axonal resilience, which is an important ALS-related phenotype mediated by PHOX2B downregulation.

  71. Difference in the Source of Anti-AQP4-IgG and Anti-MOG-IgG Antibodies in CSF in Patients With Neuromyelitis Optica Spectrum Disorder. International-journal Peer-reviewed

    Tetsuya Akaishi, Toshiyuki Takahashi, Tatsuro Misu, Kimihiko Kaneko, Yoshiki Takai, Shuhei Nishiyama, Ryo Ogawa, Juichi Fujimori, Tadashi Ishii, Masashi Aoki, Kazuo Fujihara, Ichiro Nakashima

    Neurology 97 (1) e1-e12 2021/05/12

    DOI: 10.1212/WNL.0000000000012175  

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    OBJECTIVE: To elucidate the differences in the source and in the level of intrathecal synthesis between anti-aquaporin-4 antibodies (AQP4-IgG) and anti-myelin oligodendrocyte glycoprotein antibodies (MOG-IgG). METHODS: Thirty-eight patients with MOG-IgG-associated disease and 36 with AQP4-IgG-positive neuromyelitis optica spectrum disorders (NMOSD) were studied for the antibody titers in the sera and cerebrospinal fluids (CSF) simultaneously collected in the acute attacks. The quotients between CSF and serum levels of albumin, total IgG, and each disease-specific antibody were calculated. Intrathecal production level in each disease-specific antibody was evaluated by calculating antibody index from these quotients. RESULTS: Eleven of the 38 patients with MOG-IgG were positive for the antibody only in the CSF, while no patient with AQP4-IgG showed CSF-restricted AQP4-IgG. Blood-brain barrier compromise as shown by raised albumin quotients was seen in 75.0% of MOG-IgG-positive cases and 43.8% of AQP4-IgG-positive cases. Moreover, MOG-IgG quotients were more than 10 times higher than AQP4-IgG quotients (effect size r = 0.659, p < 0.0001). Elevated antibody index (>4.0) was confirmed in 12 of 21 with MOG-IgG, whereas it was seen only in one of 16 with AQP4-IgG (φ = 0.528, p < 0.0001). The CSF MOG-IgG titers (rho = +0.519, p = 0.001) and antibody indexes for MOG-IgG (rho = +0.472, p = 0.036) correlated with the CSF cell counts but not with clinical disability. CONCLUSIONS: Intrathecal production of MOG-IgG may occur more frequently than that of AQP4-IgG. This finding implies the different properties of B-cell trafficking and antibody production between MOG-IgG-associated disease and AQP4-IgG-positive NMOSD.

  72. Optimal management of neuromyelitis optica spectrum disorder with aquaporin-4 antibody by oral prednisolone maintenance therapy. International-journal Peer-reviewed

    Yoshiki Takai, Hiroshi Kuroda, Tatsuro Misu, Tetsuya Akaishi, Ichiro Nakashima, Toshiyuki Takahashi, Shuhei Nishiyama, Kazuo Fujihara, Masashi Aoki

    Multiple sclerosis and related disorders 49 102750-102750 2021/04

    DOI: 10.1016/j.msard.2021.102750  

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    BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing neuroinflammatory disease associated with aquaporin-4 antibody. Since disabilities in patients with NMOSD accumulate with attacks, relapse prevention is crucially important for improving long-term outcomes. Corticosteroids are inexpensive and promising drugs for relapse prevention in NMOSD, but few studies have analysed the efficacy of corticosteroids in NMOSD, especially regarding the appropriate dosing and tapering regimens. METHODS: A single-center, retrospective analysis of corticosteroid therapy in aquaporin-4 antibody-positive NMOSD patients fulfilling the 2015 international consensus diagnostic criteria was conducted. RESULTS: Medical records of a total of 89 Japanese patients with aquaporin-4 antibody-positive NMOSD seen at Department of Neurology, Tohoku University Hospital (2000~2016) were reviewed. At the last follow-up, 66% of the patients were treated with prednisolone (PSL) monotherapy, and the percentage of those receiving PSL monotherapy or a combination of PSL and other immunosuppressants increased from 17.5% in 2000 to 94.1% in 2016. On the other hand, annualised relapse rate (ARR) decreased from 0.78 (13 attacks in 200 person-months) in 2000 to 0.07 (5 attacks in 819 person-months) in 2016. Under PSL treatment, the mean ARR significantly decreased, and disabilities stabilized (PSL treatment vs no-medication; ARR: 0.21 vs 0.98, P < 0.01, Expanded Disability Status Scale score change: +0.02 vs +0.89, P < 0.01, observation periods: 60.1 vs 68.2 months, P=0.26). Using Kaplan-Meier curves, the 10-year relapse-free rate was 46.5% with PSL monotherapy and 7.1% with no medication (hazard ratio: 0.069, 95% confidence interval [CI] 0.024-0.199, P < 0.01). Rapid tapering of PSL (10 mg or less in one year and/or 5 mg or less in two years after clinical attacks) was associated with frequent relapses compared to gradual tapering (more than 10 mg in one year and more than 5 mg in two years after clinical attacks) (rapid vs gradual, 36.7% vs 17.7%, odds ratio 2.69, 95% CI 1.12-6.44, P = 0.02). However, even with PSL of 5 mg/day or less, the relapse rate was low after two years of acute treatment (before vs after, 53.8% vs 13.6%, odds ratio 0.12, 95% CI 0.03-0.50, P < 0.01). Nine patients needed additional immunosuppressants due to insufficient relapse prevention by PSL monotherapy. PSL monotherapy was generally well tolerated, but seven patients had severe adverse events, mainly bone fractures (5 with bone fracture, 1 with femoral capital necrosis and 1 with cerebral infarction). CONCLUSION: Our study suggests that PSL monotherapy is effective to prevent relapses in about half of patients with aquaporin-4 antibody-positive NMOSD if the doses are gradually reduced. Although it is important to have a treatment strategy tailored to each patient, this study provides evidence that PSL monotherapy can be an option for relapse prevention in some patients with NMOSD.

  73. A novel deletion in the C-terminal region of HSPB8 in a family with rimmed vacuolar myopathy. International-journal Peer-reviewed

    Aya Inoue-Shibui, Tetsuya Niihori, Michio Kobayashi, Naoki Suzuki, Rumiko Izumi, Hitoshi Warita, Kenju Hara, Matsuyuki Shirota, Ryo Funayama, Keiko Nakayama, Ichizo Nishino, Masashi Aoki, Yoko Aoki

    Journal of human genetics 66 (10) 965-972 2021/03/20

    DOI: 10.1038/s10038-021-00916-y  

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    Heat shock protein family B member 8, encoded by HSPB8, is an essential component of the chaperone-assisted selective autophagy complex, which maintains muscle function by degrading damaged proteins in the cells. Mutations in HSPB8 have been reported to cause Charcot-Marie-Tooth type 2L, distal hereditary motor neuropathy IIa, and rimmed vacuolar myopathies (RVM). In this study, we identified a novel heterozygous frameshift variant c.525_529del in HSPB8 in a large Japanese family with RVM, using whole exome sequencing. Three affected individuals had severe respiratory failure, which has not been addressed by previous studies. Muscle atrophy in the paraspinal muscles was also a clinical feature of the individuals affected with RVM in this study. The frameshift mutation was located in the last coding exon, and the mutated protein was predicted to harbor an isoleucine-leucine-valine (ILV) sequence, which corresponds to the IXI/V (isoleucine, X amino acids, and isoleucine or valine) motif. The IXI/V motif is essential for assembly into larger oligomers in other small heat shock proteins and all frameshift mutants of HSPB8 were predicted to share the ILV sequence in the C-terminal extension. The in silico prediction tools showed low protein solubility and increased aggregation propensity for the region around the ILV sequence. The IXI/V motif might be associated with the pathogenesis of HSPB8-related RVM.

  74. Staging of astrocytopathy and complement activation in neuromyelitis optica spectrum disorders. International-journal Peer-reviewed

    Yoshiki Takai, Tatsuro Misu, Hiroyoshi Suzuki, Toshiyuki Takahashi, Hiromi Okada, Shinya Tanaka, Kenji Okita, Shunichi Sasou, Mika Watanabe, Chihiro Namatame, Yuki Matsumoto, Hirohiko Ono, Kimihiko Kaneko, Shuhei Nishiyama, Hiroshi Kuroda, Ichiro Nakashima, Hans Lassmann, Kazuo Fujihara, Yasuto Itoyama, Masashi Aoki

    Brain : a journal of neurology 144 (8) 2401-2415 2021/03/12

    DOI: 10.1093/brain/awab102  

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    Aquaporin 4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG+NMOSD) is an autoimmune astrocytopathic disease pathologically characterized by the massive destruction and regeneration of astrocytes with diverse types of tissue injury with or without complement deposition. However, it is unknown whether this diversity is derived from differences in pathological processes or temporal changes. Furthermore, unlike for the demyelinating lesions in multiple sclerosis, there has been no staging of astrocytopathy in AQP4-IgG+NMOSD based on astrocyte morphology. Therefore, we classified astrocytopathy of the disease by comparing the characteristic features, such as AQP4 loss, inflammatory cell infiltration, complement deposition and demyelination activity, with the clinical phase. We performed histopathological analyses in eight autopsied cases of AQP4-IgG+NMOSD. There were six women and two men, with a median age of 56.5 years (range, 46-71 years) and a median disease duration of 62.5 months (range, 0.6-252 months). Astrocytopathy in AQP4-IgG+NMOSD was classified into the following four stages defined by the astrocyte morphology and immunoreactivity for glial fibrillary acidic protein (GFAP): (a) astrocyte lysis: Extensive loss of astrocytes with fragmented and/or dust-like particles; (b) progenitor recruitment: Loss of astrocytes except small nucleated cells with GFAP-positive fibre-forming foot processes; (c) protoplasmic gliosis: Presence of star-shaped astrocytes with abundant GFAP-reactive cytoplasm; and (d) fibrous gliosis: Lesions composed of densely packed mature astrocytes. The astrocyte lysis and progenitor recruitment stages dominated in clinically acute cases (within 2 months after the last recurrence). Findings common to both stages were the loss of AQP4, a decreased number of oligodendrocytes, the selective loss of myelin-associated glycoprotein and active demyelination with phagocytic macrophages. The infiltration of polymorphonuclear cells and T cells (CD4-dominant) and the deposition of activated complement (C9neo), which reflects the membrane attack complex, a hallmark of acute NMOSD lesions, were selectively observed in the astrocyte lysis stage (98.4% in astrocyte lysis, 1.6% in progenitor recruitment, and 0% in protoplasmic gliosis and fibrous gliosis). Although most of the protoplasmic gliosis and fibrous gliosis lesions were accompanied by inactive demyelinated lesions with a low amount of inflammatory cell infiltration, the deposition of complement degradation product (C3d) was observed in all four stages, even in fibrous gliosis lesions, suggesting the past or chronic occurrence of complement activation, which is a useful finding to distinguish chronic lesions in NMOSD from those in multiple sclerosis. Our staging of astrocytopathy is expected to be useful for understanding the unique temporal pathology of AQP4-IgG+NMOSD.

  75. CH50 as a putative biomarker of eculizumab treatment in neuromyelitis optica spectrum disorder. International-journal Peer-reviewed

    Chihiro Namatame, Tatsuro Misu, Yoshiki Takai, Shuhei Nishiyama, Ichiro Nakashima, Kazuo Fujihara, Masashi Aoki

    Heliyon 7 (1) e05899 2021/01

    DOI: 10.1016/j.heliyon.2021.e05899  

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    Here we report 3 cases of neuromyelitis optica spectrum disorder (NMOSD), who were all treated with eculizumab and could be observed with monitoring serum C3, C4 and 50% hemolytic complement (CH50) before and after the treatment. Serum C3 and C4 were not dramatically changed during the treatment, in contrast serum CH50 level of each patient had diminished and kept under the detection limit after the treatment without clinical worsening, even in the situation of extending dosing. Serum CH50 level is useful to monitor the drug efficacy during eculizumab treatment.

  76. The genetic profile of dysferlinopathy in a cohort of 209 cases: Genotype-phenotype relationship and a hotspot on the inner DysF domain. International-journal Peer-reviewed

    Rumiko Izumi, Toshiaki Takahashi, Naoki Suzuki, Tetsuya Niihori, Hiroya Ono, Naoko Nakamura, Shinichi Katada, Masaaki Kato, Hitoshi Warita, Maki Tateyama, Yoko Aoki, Masashi Aoki

    Human mutation 41 (9) 1540-1554 2020/09

    DOI: 10.1002/humu.24036  

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    Dysferlinopathy is a group of autosomal recessive muscular dystrophies caused by variants in the dysferlin gene (DYSF), with variable proximal and distal muscle involvement. We performed DYSF gene analyses of 200 cases suspected of having dysferlinopathy (Cohort 1), and identified diagnostic variants in 129/200 cases, including 19 novel variants. To achieve a comprehensive genetic profile of dysferlinopathy, we analyzed the variant data from 209 affected cases from unrelated 209 families, including 80 previously diagnosed and 129 newly diagnosed cases (Cohort 2). Among the 90 types of variants identified in 209 cases, the NM_003494.3: c.2997G>T; p.Trp999Cys, was the most frequent (96/420; 22.9%), followed by c.1566C>G; p.Tyr522* (45/420; 10.7%) on an allele base. p.Trp999Cys was found in 70/209 cases (33.5%), including 20/104 cases (19.2%) with the Miyoshi muscular phenotype and 43/82 cases (52.4%) with the limb-girdle phenotype. In the analysis of missense variants, p.Trp992Arg, p.Trp999Arg, p.Trp999Cys, p.Ser1000Phe, p.Arg1040Trp, and p.Arg1046His were located in the inner DysF domain, representing in 113/160 missense variants (70.6%). This large cohort highlighted the frequent missense variants located in the inner DysF domain as a hotspot for missense variants among our cohort of 209 cases (>95%, Japanese) and hinted at their potential as targets for future therapeutic strategies.

  77. An Amyotrophic Lateral Sclerosis-Associated Mutant of C21ORF2 Is Stabilized by NEK1-Mediated Hyperphosphorylation and the Inability to Bind FBXO3. International-journal Peer-reviewed

    Yasuaki Watanabe, Tadashi Nakagawa, Tetsuya Akiyama, Makiko Nakagawa, Naoki Suzuki, Hitoshi Warita, Masashi Aoki, Keiko Nakayama

    iScience 23 (9) 101491-101491 2020/08/21

    DOI: 10.1016/j.isci.2020.101491  

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    C21ORF2 and NEK1 have been identified as amyotrophic lateral sclerosis (ALS)-associated genes. Both genes are also mutated in certain ciliopathies, suggesting that they might contribute to the same signaling pathways. Here we show that FBXO3, the substrate receptor of an SCF ubiquitin ligase complex, binds and ubiquitylates C21ORF2, thereby targeting it for proteasomal degradation. C21ORF2 stabilizes the kinase NEK1, with the result that loss of FBXO3 stabilizes not only C21ORF2 but also NEK1. Conversely, NEK1-mediated phosphorylation stabilizes C21ORF2 by attenuating its interaction with FBXO3. We found that the ALS-associated V58L mutant of C21ORF2 is more susceptible to phosphorylation by NEK1, with the result that it is not ubiquitylated by FBXO3 and therefore accumulates together with NEK1. Expression of C21ORF2(V58L) in motor neurons induced from mouse embryonic stem cells impaired neurite outgrowth. We suggest that inhibition of NEK1 activity is a potential therapeutic approach to ALS associated with C21ORF2 mutation.

  78. Myelin oligodendrocyte glycoprotein antibody-associated disease: an immunopathological study. International-journal Peer-reviewed

    Yoshiki Takai, Tatsuro Misu, Kimihiko Kaneko, Norio Chihara, Koichi Narikawa, Satoko Tsuchida, Hiroya Nishida, Takashi Komori, Morinobu Seki, Teppei Komatsu, Kiyotaka Nakamagoe, Toshimasa Ikeda, Mari Yoshida, Toshiyuki Takahashi, Hirohiko Ono, Shuhei Nishiyama, Hiroshi Kuroda, Ichiro Nakashima, Hiroyoshi Suzuki, Monika Bradl, Hans Lassmann, Kazuo Fujihara, Masashi Aoki

    Brain : a journal of neurology 143 (5) 1431-1446 2020/05/01

    DOI: 10.1093/brain/awaa102  

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    Conformation-sensitive antibodies against myelin oligodendrocyte glycoprotein (MOG) are detectable in patients with optic neuritis, myelitis, opticomyelitis, acute or multiphasic disseminated encephalomyelitis (ADEM/MDEM) and brainstem/cerebral cortical encephalitis, but are rarely detected in patients with prototypic multiple sclerosis. So far, there has been no systematic study on the pathological relationship between demyelinating lesions and cellular/humoral immunity in MOG antibody-associated disease. Furthermore, it is unclear whether the pathomechanisms of MOG antibody-mediated demyelination are similar to the demyelination patterns of multiple sclerosis, neuromyelitis optica spectrum disorders (NMOSD) with AQP4 antibody, or ADEM. In this study, we immunohistochemically analysed biopsied brain tissues from 11 patients with MOG antibody-associated disease and other inflammatory demyelinating diseases. Patient median onset age was 29 years (range 9-64), and the median interval from attack to biopsy was 1 month (range 0.5-96). The clinical diagnoses were ADEM (n = 2), MDEM (n = 1), multiple brain lesions without encephalopathy (n = 3), leukoencephalopathy (n = 3) and cortical encephalitis (n = 2). All these cases had multiple/extensive lesions on MRI and were oligoclonal IgG band-negative. Most demyelinating lesions in 10 of 11 cases showed a perivenous demyelinating pattern previously reported in ADEM (153/167 lesions) and a fusion pattern (11/167 lesions) mainly in the cortico-medullary junctions and white matter, and only three lesions in two cases showed confluent demyelinated plaques. In addition, 60 of 167 demyelinating lesions (mainly in the early phase) showed MOG-dominant myelin loss, but relatively preserved oligodendrocytes, which were distinct from those of AQP4 antibody-positive NMOSD exhibiting myelin-associated glycoprotein-dominant oligodendrogliopathy. In MOG antibody-associated diseases, MOG-laden macrophages were found in the perivascular spaces and demyelinating lesions, and infiltrated cells were abundant surrounding multiple blood vessels in and around the demyelinating lesions, mainly consisting of macrophages (CD68; 1814 ± 1188 cells/mm2), B cells (CD20; 468 ± 817 cells/mm2), and T cells (CD3; 2286 ± 1951 cells/mm2), with CD4-dominance (CD4+ versus CD8+; 1281 ± 1196 cells/mm2 versus 851 ± 762 cells/mm2, P < 0.01). Humoral immunity, evidenced by perivascular deposits of activated complements and immunoglobulins, was occasionally observed in some MOG antibody-associated demyelinating lesions, and the frequency was much lower than that in AQP4 antibody-positive NMOSD. Subpial lesions with perivenous demyelination were observed in both ADEM and cortical encephalitis. Our study suggests that ADEM-like perivenous inflammatory demyelination with MOG-dominant myelin loss is a characteristic finding of MOG antibody-associated disease regardless of whether the diagnostic criteria of ADEM are met. These pathological features are clearly different from those of multiple sclerosis and AQP4 antibody-positive NMOSD, suggesting an independent autoimmune demyelinating disease entity.

  79. AMPK Complex Activation Promotes Sarcolemmal Repair in Dysferlinopathy. International-journal Peer-reviewed

    Hiroya Ono, Naoki Suzuki, Shin-Ichiro Kanno, Genri Kawahara, Rumiko Izumi, Toshiaki Takahashi, Yasuo Kitajima, Shion Osana, Naoko Nakamura, Tetsuya Akiyama, Kensuke Ikeda, Tomomi Shijo, Shio Mitsuzawa, Ryoichi Nagatomi, Nobukazu Araki, Akira Yasui, Hitoshi Warita, Yukiko K Hayashi, Katsuya Miyake, Masashi Aoki

    Molecular therapy : the journal of the American Society of Gene Therapy 28 (4) 1133-1153 2020/04/08

    DOI: 10.1016/j.ymthe.2020.02.006  

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    Mutations in dysferlin are responsible for a group of progressive, recessively inherited muscular dystrophies known as dysferlinopathies. Using recombinant proteins and affinity purification methods combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS), we found that AMP-activated protein kinase (AMPK)γ1 was bound to a region of dysferlin located between the third and fourth C2 domains. Using ex vivo laser injury experiments, we demonstrated that the AMPK complex was vital for the sarcolemmal damage repair of skeletal muscle fibers. Injury-induced AMPK complex accumulation was dependent on the presence of Ca2+, and the rate of accumulation was regulated by dysferlin. Furthermore, it was found that the phosphorylation of AMPKα was essential for plasma membrane repair, and treatment with an AMPK activator rescued the membrane-repair impairment observed in immortalized human myotubes with reduced expression of dysferlin and dysferlin-null mouse fibers. Finally, it was determined that treatment with the AMPK activator metformin improved the muscle phenotype in zebrafish and mouse models of dysferlin deficiency. These findings indicate that the AMPK complex is essential for plasma membrane repair and is a potential therapeutic target for dysferlinopathy.

  80. Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial. International-journal Peer-reviewed

    Michael G Hanna, Umesh A Badrising, Olivier Benveniste, Thomas E Lloyd, Merrilee Needham, Hector Chinoy, Masashi Aoki, Pedro M Machado, Christina Liang, Katrina A Reardon, Marianne de Visser, Dana P Ascherman, Richard J Barohn, Mazen M Dimachkie, James A L Miller, John T Kissel, Björn Oskarsson, Nanette C Joyce, Peter Van den Bergh, Jonathan Baets, Jan L De Bleecker, Chafic Karam, William S David, Massimiliano Mirabella, Sharon P Nations, Hans H Jung, Elena Pegoraro, Lorenzo Maggi, Carmelo Rodolico, Massimiliano Filosto, Aziz I Shaibani, Kumaraswamy Sivakumar, Namita A Goyal, Madoka Mori-Yoshimura, Satoshi Yamashita, Naoki Suzuki, Masahisa Katsuno, Kenya Murata, Hiroyuki Nodera, Ichizo Nishino, Carla D Romano, Valerie S L Williams, John Vissing, Lixin Zhang Auberson, Min Wu, Ana de Vera, Dimitris A Papanicolaou, Anthony A Amato

    The Lancet. Neurology 18 (9) 834-844 2019/09

    DOI: 10.1016/S1474-4422(19)30200-5  

    ISSN: 1474-4422

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    BACKGROUND: Inclusion body myositis is an idiopathic inflammatory myopathy and the most common myopathy affecting people older than 50 years. To date, there are no effective drug treatments. We aimed to assess the safety, efficacy, and tolerability of bimagrumab-a fully human monoclonal antibody-in individuals with inclusion body myositis. METHODS: We did a multicentre, double-blind, placebo-controlled study (RESILIENT) at 38 academic clinical sites in Australia, Europe, Japan, and the USA. Individuals (aged 36-85 years) were eligible for the study if they met modified 2010 Medical Research Council criteria for inclusion body myositis. We randomly assigned participants (1:1:1:1) using a blocked randomisation schedule (block size of four) to either bimagrumab (10 mg/kg, 3 mg/kg, or 1 mg/kg) or placebo matched in appearance to bimagrumab, administered as intravenous infusions every 4 weeks for at least 48 weeks. All study participants, the funder, investigators, site personnel, and people doing assessments were masked to treatment assignment. The primary outcome measure was 6-min walking distance (6MWD), which was assessed at week 52 in the primary analysis population and analysed by intention-to-treat principles. We used a multivariate normal repeated measures model to analyse data for 6MWD. Safety was assessed by recording adverse events and by electrocardiography, echocardiography, haematological testing, urinalysis, and blood chemistry. This trial is registered with ClinicalTrials.gov, number NCT01925209; this report represents the final analysis. FINDINGS: Between Sept 26, 2013, and Jan 6, 2016, 251 participants were enrolled to the study, of whom 63 were assigned to each bimagrumab group and 62 were allocated to the placebo group. At week 52, 6MWD change from baseline did not differ between any bimagrumab dose and placebo (least squares mean treatment difference for bimagrumab 10 mg/kg group, 17·6 m, SE 14·3, 99% CI -19·6 to 54·8; p=0·22; for 3 mg/kg group, 18·6 m, 14·2, -18·2 to 55·4; p=0·19; and for 1 mg/kg group, -1·3 m, 14·1, -38·0 to 35·4; p=0·93). 63 (100%) participants in each bimagrumab group and 61 (98%) of 62 in the placebo group had at least one adverse event. Falls were the most frequent adverse event (48 [76%] in the bimagrumab 10 mg/kg group, 55 [87%] in the 3 mg/kg group, 54 [86%] in the 1 mg/kg group, and 52 [84%] in the placebo group). The most frequently reported adverse events with bimagrumab were muscle spasms (32 [51%] in the bimagrumab 10 mg/kg group, 43 [68%] in the 3 mg/kg group, 25 [40%] in the 1 mg/kg group, and 13 [21%] in the placebo group) and diarrhoea (33 [52%], 28 [44%], 20 [32%], and 11 [18%], respectively). Adverse events leading to discontinuation were reported in four (6%) participants in each bimagrumab group compared with one (2%) participant in the placebo group. At least one serious adverse event was reported by 21 (33%) participants in the 10 mg/kg group, 11 (17%) in the 3 mg/kg group, 20 (32%) in the 1 mg/kg group, and 20 (32%) in the placebo group. No significant adverse cardiac effects were recorded on electrocardiography or echocardiography. Two deaths were reported during the study, one attributable to subendocardial myocardial infarction (secondary to gastrointestinal bleeding after an intentional overdose of concomitant sedatives and antidepressants) and one attributable to lung adenocarcinoma. Neither death was considered by the investigator to be related to bimagrumab. INTERPRETATION: Bimagrumab showed a good safety profile, relative to placebo, in individuals with inclusion body myositis but did not improve 6MWD. The strengths of our study are that, to the best of our knowledge, it is the largest randomised controlled trial done in people with inclusion body myositis, and it provides important natural history data over 12 months. FUNDING: Novartis Pharma.

  81. Aberrant axon branching via Fos-B dysregulation in FUS-ALS motor neurons. International-journal Peer-reviewed

    Tetsuya Akiyama, Naoki Suzuki, Mitsuru Ishikawa, Koki Fujimori, Takefumi Sone, Jiro Kawada, Ryo Funayama, Fumiyoshi Fujishima, Shio Mitsuzawa, Kensuke Ikeda, Hiroya Ono, Tomomi Shijo, Shion Osana, Matsuyuki Shirota, Tadashi Nakagawa, Yasuo Kitajima, Ayumi Nishiyama, Rumiko Izumi, Satoru Morimoto, Yohei Okada, Takayuki Kamei, Mayumi Nishida, Masahiro Nogami, Shohei Kaneda, Yoshiho Ikeuchi, Hiroaki Mitsuhashi, Keiko Nakayama, Teruo Fujii, Hitoshi Warita, Hideyuki Okano, Masashi Aoki

    EBioMedicine 45 362-378 2019/07

    DOI: 10.1016/j.ebiom.2019.06.013  

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    BACKGROUND: The characteristic structure of motor neurons (MNs), particularly of the long axons, becomes damaged in the early stages of amyotrophic lateral sclerosis (ALS). However, the molecular pathophysiology of axonal degeneration remains to be fully elucidated. METHOD: Two sets of isogenic human-induced pluripotent stem cell (hiPSCs)-derived MNs possessing the single amino acid difference (p.H517D) in the fused in sarcoma (FUS) were constructed. By combining MN reporter lentivirus, MN specific phenotype was analyzed. Moreover, RNA profiling of isolated axons were conducted by applying the microfluidic devices that enable axon bundles to be produced for omics analysis. The relationship between the target gene, which was identified as a pathological candidate in ALS with RNA-sequencing, and the MN phenotype was confirmed by intervention with si-RNA or overexpression to hiPSCs-derived MNs and even in vivo. The commonality was further confirmed with other ALS-causative mutant hiPSCs-derived MNs and human pathology. FINDINGS: We identified aberrant increasing of axon branchings in FUS-mutant hiPSCs-derived MN axons compared with isogenic controls as a novel phenotype. We identified increased level of Fos-B mRNA, the binding target of FUS, in FUS-mutant MNs. While Fos-B reduction using si-RNA or an inhibitor ameliorated the observed aberrant axon branching, Fos-B overexpression resulted in aberrant axon branching even in vivo. The commonality of those phenotypes was further confirmed with other ALS causative mutation than FUS. INTERPRETATION: Analyzing the axonal fraction of hiPSC-derived MNs using microfluidic devices revealed that Fos-B is a key regulator of FUS-mutant axon branching. FUND: Japan Agency for Medical Research and development; Japanese Ministry of Education, Culture, Sports, Science and Technology Clinical Research, Innovation and Education Center, Tohoku University Hospital; Japan Intractable Diseases (Nanbyo) Research Foundation; the Kanae Foundation for the Promotion of Medical Science; and "Inochi-no-Iro" ALS research grant.

  82. Safety, Tolerability, and Pharmacodynamics of Intrathecal Injection of Recombinant Human HGF (KP-100) in Subjects With Amyotrophic Lateral Sclerosis: A Phase I Trial Peer-reviewed

    Hitoshi Warita, Masaaki Kato, Ryuta Asada, Atsuko Yamashita, Daichika Hayata, Kiichi Adachi, Masashi Aoki

    Journal of Clinical Pharmacology 59 (5) 677-687 2019/05

    DOI: 10.1002/jcph.1355  

    ISSN: 0091-2700

    eISSN: 1552-4604

  83. Modeling sporadic ALS in iPSC-derived motor neurons identifies a potential therapeutic agent. International-journal Peer-reviewed

    Koki Fujimori, Mitsuru Ishikawa, Asako Otomo, Naoki Atsuta, Ryoichi Nakamura, Tetsuya Akiyama, Shinji Hadano, Masashi Aoki, Hideyuki Saya, Gen Sobue, Hideyuki Okano

    Nature medicine 24 (10) 1579-1589 2018/10

    DOI: 10.1038/s41591-018-0140-5  

    ISSN: 1078-8956

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    Amyotrophic lateral sclerosis (ALS) is a heterogeneous motor neuron disease for which no effective treatment is available, despite decades of research into SOD1-mutant familial ALS (FALS). The majority of ALS patients have no familial history, making the modeling of sporadic ALS (SALS) essential to the development of ALS therapeutics. However, as mutations underlying ALS pathogenesis have not yet been identified, it remains difficult to establish useful models of SALS. Using induced pluripotent stem cell (iPSC) technology to generate stem and differentiated cells retaining the patients' full genetic information, we have established a large number of in vitro cellular models of SALS. These models showed phenotypic differences in their pattern of neuronal degeneration, types of abnormal protein aggregates, cell death mechanisms, and onset and progression of these phenotypes in vitro among cases. We therefore developed a system for case clustering capable of subdividing these heterogeneous SALS models by their in vitro characteristics. We further evaluated multiple-phenotype rescue of these subclassified SALS models using agents selected from non-SOD1 FALS models, and identified ropinirole as a potential therapeutic candidate. Integration of the datasets acquired in this study permitted the visualization of molecular pathologies shared across a wide range of SALS models.

  84. CSF cytokine profile in MOG-IgG+ neurological disease is similar to AQP4-IgG+ NMOSD but distinct from MS: A cross-sectional study and potential therapeutic implications Peer-reviewed

    Kimihiko Kaneko, Douglas Kazutoshi Sato, Ichiro Nakashima, Ryo Ogawa, Tetsuya Akaishi, Yoshiki Takai, Shuhei Nishiyama, Toshiyuki Takahashi, Tatsuro Misu, Hiroshi Kuroda, Satoru Tanaka, Kyoichi Nomura, Yuji Hashimoto, Dagoberto Callegaro, Lawrence Steinman, Kazuo Fujihara, Masashi Aoki

    Journal of Neurology, Neurosurgery and Psychiatry 89 (9) 927-936 2018/06/05

    Publisher: BMJ Publishing Group

    DOI: 10.1136/jnnp-2018-317969  

    ISSN: 1468-330X 0022-3050

  85. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial Peer-reviewed

    Koji Abe, Masashi Aoki, Shoji Tsuji, Yasuto Itoyama, Gen Sobue, Masanori Togo, Chikuma Hamada, Masahiko Tanaka, Makoto Akimoto, Kazue Nakamura, Fumihiro Takahashi, Kazuoki Kondo, Hiide Yoshino

    LANCET NEUROLOGY 16 (7) 505-512 2017/07

    DOI: 10.1016/S1474-4422(17)30115-1  

    ISSN: 1474-4422

    eISSN: 1474-4465

  86. MOG antibody-positive, benign, unilateral, cerebral cortical encephalitis with epilepsy Peer-reviewed

    Ryo Ogawa, Ichiro Nakashima, Toshiyuki Takahashi, Kimihiko Kaneko, Tetsuya Akaishi, Yoshiki Takai, Douglas Kazutoshi Sato, Shuhei Nishiyama, Tatsuro Misu, Hiroshi Kuroda, Masashi Aoki, Kazuo Fujihara

    Neurology: Neuroimmunology and NeuroInflammation 4 (2) e322 2017

    Publisher: Lippincott Williams and Wilkins

    DOI: 10.1212/NXI.0000000000000322  

    ISSN: 2332-7812

    eISSN: 2332-7812

  87. In vivo visualization of tau deposits in corticobasal syndrome by F-18-THK5351 PET Peer-reviewed

    Akio Kikuchi, Nobuyuki Okamura, Takafumi Hasegawa, Ryuichi Harada, Shoichi Watanuki, Yoshihito Funaki, Kotaro Hiraoka, Toru Baba, Naoto Sugeno, Ryuji Oshima, Shun Yoshida, Junpei Kobayashi, Michinori Ezura, Michiko Kobayashi, Ohito Tano, Shunji Mugikura, Ren Iwata, Aiko Ishiki, Katsutoshi Furukawa, Hiroyuki Arai, Shozo Furumoto, Manabu Tashiro, Kazuhiko Yanai, Yukitsuka Kudo, Atsushi Takeda, Masashi Aoki

    NEUROLOGY 87 (22) 2309-2316 2016/11

    DOI: 10.1212/WNL.0000000000003375  

    ISSN: 0028-3878

    eISSN: 1526-632X

  88. Corrigendum to "Predictive value of the polygenic risk score for developing epilepsy: a systematic review and meta-analysis" [Epilepsy Behav. 169 (2025) 110438]. International-journal

    Takafumi Kubota, Irma Wati Ngadimon, Hisashi Ohseto, Sindhu Viswanathan, Parthvi Ravat, Mrinal Kumar Acharya, Naoto Kuroda, Kazutoshi Konomatsu, Taku Obara, Kazutaka Jin, Masashi Aoki, Nobukazu Nakasato

    Epilepsy & behavior : E&B 170 110513-110513 2025/09

    DOI: 10.1016/j.yebeh.2025.110513  

  89. A Serial Assessment of T1 and T2 Mapping Cardiac Magnetic Resonance Before and After Heart Failure Onset in a Case of Cardiomyopathy in Anti-mitochondrial Antibody-positive Myositis.

    Mitsuru Ishizuka, Hideaki Suzuki, Satoshi Higuchi, Hidenobu Takagi, Naoki Suzuki, Rumiko Izumi, Hirofumi Watanabe, Haruka Sato, Taijyu Satoh, Saori Miyamichi-Yamamoto, Nobuhiro Yaoita, Kouki Takeuchi, Marina Arai, Hideka Hayashi, Kotaro Nochioka, Hiroyuki Takahama, Shunsuke Tatebe, Hiroshi Fujii, Masashi Aoki, Satoshi Yasuda

    Internal medicine (Tokyo, Japan) 2025/03/22

    DOI: 10.2169/internalmedicine.5007-24  

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    A 69-year-old woman presented with heart failure and progressive muscle weakness and was diagnosed as anti-mitochondrial antibody (AMA) myositis with cardiac involvement. Immunosuppressive therapy with prednisolone and intravenous cyclophosphamide significantly improved the symptoms, hemodynamics, and cardiac function. Cardiac magnetic resonance (CMR) T1 and T2 mapping showed elevated native T1, T2, and extracellular volume fractions during heart failure exacerbation (day 37) compared to pre-hospitalization values (10 months before admission) and follow-up conducted 6 and 12 months after admission. This case underscores the importance of comprehensive evaluation, such as serial CMR imaging and immunosuppressive therapy, in managing myocardial involvement in AMA-positive myositis.

  90. [Guidelines for presymptomatic genetic testing for adult-onset hereditary neuromuscular diseases in Japan].

    Yuka Shibata, Hyangri Chang, Katsuya Nakamura, Shinichiro Yamada, Masaaki Matsushima, Kazumasa Saigoh, Hiroyuki Ishiura, Yoshiki Sekijima, Hirofumi Maruyama, Takeshi Ikeuchi, Kazuko Hasegawa, Masashi Aoki, Masahisa Katsuno, Tatsushi Toda, Ichiro Yabe

    Rinsho shinkeigaku = Clinical neurology 65 (2) 101-107 2025/02/21

    Publisher: Societas Neurologica Japonica

    DOI: 10.5692/clinicalneurol.cn-002049  

    ISSN: 0009-918X

    eISSN: 1882-0654

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    In Japan, there are no nationwide guidelines for presymptomatic testing for hereditary neuromuscular diseases. Although each institution has been dealing with this situation by using their own procedures to date, it is necessary to develop a standardized guidelines based on the Japanese medical system, because the development of disease-modifying therapies has progressed, and we are entering an era in which early diagnosis and early treatment are necessary. The guidelines presented here were devised by the Committee on Medical Genetics of the Japan Neurological Society. During their development, Delphi surveys were conducted among individuals with extensive experience in presymptomatic testing throughout Japan, with 42 experts participating in all three surveys, and a consensus-building process was undertaken. Finally, the guidelines consist of 45 recommendations for performing presymptomatic testing for adult-onset inherited neurological and muscular diseases.

  91. ALS-associated RNA binding proteins converge onUNC13Atranscription through regulation of REST

    Yasuaki Watanabe, Naoki Suzuki, Tadashi Nakagawa, Masaki Hosogane, Tetsuya Akiyama, Hitoshi Warita, Masashi Aoki, Keiko Nakayama

    2024/10/23

    DOI: 10.1101/2024.10.22.619761  

  92. 深層学習を用いた単チャネル脳波のdensity spectral arrayによるてんかん発作と心因性非てんかん発作の鑑別

    此松 和俊, 柏田 祐樹, 久保田 隆文, 神 一敬, 高橋 健人, 黒田 直生人, 浮城 一司, 柿坂 庸介, 青木 正志, 中里 信和

    てんかん研究 42 (2) 584-584 2024/09

    Publisher: (一社)日本てんかん学会

    ISSN: 0912-0890

    eISSN: 1347-5509

  93. A Reduction in the Number of Hospitalized Cases of Acute Meningitis during the COVID-19 Pandemic in Japan. Peer-reviewed

    Tetsuya Akaishi, Kunio Tarasawa, Kiyohide Fushimi, Chiharu Ota, Sumireko Sekiguchi, Tetsuji Aoyagi, Nobuo Yaegashi, Masashi Aoki, Kenji Fujimori

    Internal medicine (Tokyo, Japan) 63 (10) 1353-1359 2024/05/15

    DOI: 10.2169/internalmedicine.3022-23  

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    Objective The changes in the prevalence of acute meningitis during the coronavirus disease 2019 (COVID-19) pandemic remain unclear. This study aimed to compare the prevalence of acute meningitis before and during the COVID-19 pandemic in Japan. Methods We retrospectively reviewed the Japanese nationwide administrative medical payment system database, Diagnosis Procedure Combination (DPC), from 2016 to 2022. A total of 547 hospitals consistently and seamlessly offered DPC data during this period. The study period was divided into the following three periods: April 2016 to March 2018 (fiscal years 2016-2017), April 2018-March 2020 (2018-2019), and April 2020-March 2022 (2020-2021). Results Among the 28,161,806 patients hospitalized during the study period, 28,399 were hospitalized for acute meningitis: 16,678 for viral/aseptic type, 6,189 for bacterial type, 655 for fungal type, 429 for tuberculous, 2,310 for carcinomatous type, and 2,138 for other or unknown types of meningitis. A significant decrease during the pandemic was confirmed in viral (n=7,032, n=5,775, and n=3,871 in each period; p<0.0001) and bacterial meningitis (n=2,291, n=2,239, and n=1,659; p<0.0001) cases. Meanwhile, no decrease was observed in fungal meningitis (n=212, n=246, and n=197; p=0.056) or carcinomatous meningitis (n=781, n=795, and n=734; p=0.27). The decrease in the number of tuberculous meningitis cases was equivocal (n=166, n=146, and n=117; p=0.014). The decrease during the pandemic was more remarkable in younger populations aged <50 years than in older populations, both for viral and bacterial meningitis. Conclusion The number of hospitalized cases of acute meningitis clearly decreased during the COVID-19 pandemic, especially for viral and bacterial meningitis in younger populations aged <50 years.

  94. 筋mounding現象で発症した特発性rippling muscle diseaseの1例

    吉田 幹裕, 石山 駿, 井泉 瑠美子, 割田 仁, 山口 慧, 菅野 直人, 青木 正志

    臨床神経学 64 (5) 367-367 2024/05

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  95. Stochastic models for the onset and disease course of multiple sclerosis. International-journal

    Tetsuya Akaishi, Tatsuro Misu, Toshiyuki Takahashi, Kazuo Fujihara, Juichi Fujimori, Ichiro Nakashima, Masashi Aoki

    Clinical neurology and neurosurgery 239 108224-108224 2024/03/02

    DOI: 10.1016/j.clineuro.2024.108224  

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    OBJECTIVE: Exact causes and mechanisms regulating the onset and progression in many chronic diseases, including multiple sclerosis (MS), remain uncertain. Until now, the potential role of random process based on stochastic models in the temporal course of chronic diseases remains largely unevaluated. Therefore, the present study investigated the applicability of stochastic models for the onset and disease course of MS. METHODS: Stochastic models with random temporal process in disease activity, underlying clinical relapse and/or subclinical brain atrophy, were developed. The models incorporated parameters regarding the distribution of temporal changes in disease activity and the drift constant. RESULTS: By adjusting the parameters (temporal change dispersion and drift constant) and the threshold for the onset of disease, the stochastic disease progression models could reproduce various types of subsequent disease course, such as clinically isolated syndrome (monophasic), relapsing-remitting MS, primary-progressive MS, and secondary-progressive MS. Furthermore, the disease prevalence and distribution of onset age could be also reproduced with stochastic models by adjusting the parameters. The models could further explain why approximately half of the patients with relapsing-remitting MS will eventually experience a transition to secondary-progressive MS. CONCLUSION: Stochastic models with random temporal changes in disease activity could reproduce the characteristic onset age distribution and disease course forms in MS. Further studies by using real-world data to underscore the significance of random process in the occurrence and progression of MS are warranted.

  96. Laser speckle flowgraphyを用いた視神経炎病態別の眼内血流評価について

    山口 知暁, 檜森 紀子, 清田 直樹, 大島 隆寛, 木村 暸, 津田 聡, 面高 宗子, 三須 建郎, 青木 正志, 中澤 徹

    日本眼科学会雑誌 128 (臨増) 193-193 2024/03

    Publisher: (公財)日本眼科学会

    ISSN: 0029-0203

  97. To evaluate ocular blood flow of optic neuritis using laser speckle flowgraphy

    山口知暁, 檜森紀子, 檜森紀子, 清田直樹, 大島隆寛, 木村瞭, 津田聡, 面高宗子, 三須建郎, 青木正志, 中澤徹

    日本眼科学会雑誌 128 (臨増) 193-193 2024/03

    Publisher:

    ISSN: 0029-0203

  98. Improved Activities of Daily Living With Adjunctive Intravenous Steroids in Bacterial Meningitis: A Nationwide, Population-Based Medical Database Study. International-journal

    Tetsuya Akaishi, Kunio Tarasawa, Kiyohide Fushimi, Nobuo Yaegashi, Masashi Aoki, Kenji Fujimori

    Cureus 16 (2) e54292 2024/02

    DOI: 10.7759/cureus.54292  

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    The benefit of using adjunctive intravenous steroids (IVS) to reduce the neurological sequelae in bacterial meningitis remains inconclusive. This study evaluated the effect of IVS on improving the subsequent Activities of Daily Living (ADL) in bacterial meningitis by analyzing data from a large nationwide administrative medical database in Japan. Data from 1,132 hospitals, covered by the administrative Diagnosis Procedure Combination (DPC) payment system from 2016 to 2022, were evaluated. The ADL levels at admission and discharge were measured using the Barthel Index (BI). Out of the cumulative 47,366,222 patients hospitalized, 8,736 were diagnosed with acute bacterial meningitis and had BI data available. The BI at discharge, adjusted for sex, age, and BI at admission, was significantly better among those treated with IVS (p<0.0001). Exploratory subgroup analyses suggested that this benefit is expected across a broad spectrum of bacterial species. In summary, the use of IVS for improving the subsequent ADL level in bacterial meningitis was suggested.

  99. Reliability study for the Japanese version of the Columbia Muscle Cramp Scale in amyotrophic lateral sclerosis

    Masahiro Sawada, Takehisa Hirayama, Masaru Yanagihashi, Koji Fukushima, Yuishin Izumi, Tameto Naoi, Mitsuya Morita, Hitoshi Warita, Masashi Aoki, Yohei Iguchi, Masahisa Katsuno, Nobuhiro Ogawa, Makoto Urusitani, Tomohiko Ishihara, Osamu Onodera, Yoshitaka Murakami, Hiroshi Mitsumoto, Osamu Kano

    Neurology and Clinical Neuroscience 2024

    DOI: 10.1111/ncn3.12838  

    eISSN: 2049-4173

  100. Demographic profiles and risk factors for mortality in acute meningitis: A nationwide population-based observational study. International-journal

    Tetsuya Akaishi, Kunio Tarasawa, Kiyohide Fushimi, Nobuo Yaegashi, Masashi Aoki, Kenji Fujimori

    Acute medicine & surgery 11 (1) e920 2024

    DOI: 10.1002/ams2.920  

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    AIM: Acute meningitis encompasses bacterial, viral (aseptic), fungal, tuberculous, and carcinomatous meningitis. The rate and risks of mortality in each type remain uncertain. This study aimed to elucidate these aspects in each type of meningitis. METHODS: This study utilized Japan's nationwide administrative Diagnosis Procedure Combination (DPC) database. Patients with acute meningitis, treated at 1132 DPC-covered hospitals from 2016 to 2022, were enrolled. RESULTS: Among 47,366,222 cumulative hospitalized patients, 48,758 (0.10%) were hospitalized with acute meningitis. The types of meningitis were as follows: 10,338 with bacterial, 29,486 with viral/aseptic, 965 with fungal, 678 with tuberculous, and 3790 with carcinomatous meningitis. Bacterial and viral meningitis exhibited bimodal age distributions, with the first peak occurring at 0-9 years. The median onset age was below 50 years only in viral meningitis. The mortality rate was the highest in carcinomatous meningitis (39%), followed by fungal meningitis (21%), and the lowest in viral meningitis (0.61%). Mortality rates increased with age across all meningitis types, but this trend was less prominent in carcinomatous meningitis. The duration from admission to mortality was longer in fungal and tuberculous meningitis compared with other types. Staphylococcus aureus in bacterial meningitis (adjusted odds ratio 1.71; p = 0.0016) and herpes simplex virus in viral meningitis (adjusted odds ratio 1.53; p = 0.0467) exhibited elevated mortality rates. CONCLUSION: Distinct demographic profiles and mortality rates were observed among different meningitis types. The high mortality rates in less common types of meningitis emphasize the necessity to further optimize the required diagnostic and treatment strategies.

  101. 運動ニューロン障害を合併した小脳性運動失調・感覚性ニューロパチー・前庭反射消失症候群(CANVAS)の一例

    志賀 太玖良, 吉田 幹裕, 鈴木 真紀, 池田 謙輔, 井泉 瑠美子, 鈴木 直輝, 割田 仁, 中島 一郎, 菅野 直人, 青木 正志

    臨床神経学 63 (12) 848-848 2023/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  102. 海綿静脈洞炎に合併した内頸動脈瘤の一例

    黒田 祐介, 石山 駿, 山口 慧, 小野 紘彦, 菅野 直人, 長谷川 隆文, 青木 正志

    臨床神経学 63 (12) 850-850 2023/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  103. 筋萎縮性側索硬化症患者とその家族の防災意識向上の必要性

    平山 剛久, 渋川 茉莉, 森岡 治美, 穗積 正迪, 津田 浩史, 熱田 直樹, 和泉 唯信, 中山 優季, 清水 俊夫, 井上 治久, 漆谷 真, 山中 宏二, 青木 正志, 海老原 覚, 武田 篤, 狩野 修

    日本難病医療ネットワーク学会機関誌 11 (1) 139-139 2023/11

    Publisher: 日本難病医療ネットワーク学会

    ISSN: 2188-1006

  104. [Efficacy of Aceneuramic Acid for Distal Myopathy with Rimmed Vacuoles].

    Masashi Aoki, Rumiko Izumi, Naoki Suzuki

    Brain and nerve = Shinkei kenkyu no shinpo 75 (10) 1149-1154 2023/10

    Publisher:

    DOI: 10.11477/mf.1416202492  

    ISSN: 1881-6096

    eISSN: 1344-8129

  105. 自己抗体から紐解く封入体筋炎の病態解明とバイオマーカー探索

    山下 賢, 杉江 和馬, 青木 正志, 村井 弘之

    国際医療福祉大学学会誌 28 (抄録号) 186-186 2023/09

    Publisher: 国際医療福祉大学学会

    ISSN: 2186-3652

  106. MOGAD急性期髄液における活性化補体の解析

    金子 仁彦, 黒田 宙, 小野 紘彦, 松本 勇貴, 阪本 直広, 山崎 直也, 山本 尚輝, 梅澤 周, 生田目 知尋, 高井 良樹, 高橋 利幸, 藤盛 寿一, 中島 一郎, 藤原 一男, 三須 建郎, 青木 正志

    神経免疫学 28 (1) 200-200 2023/09

    Publisher: (一社)日本神経免疫学会

    ISSN: 0918-936X

  107. 海馬硬化を伴う内側側頭葉てんかんの術後発作転帰予測因子

    曽我 天馬, 神 一敬, 柿坂 庸介, 此松 和俊, 大沢 伸一郎, 岩崎 真樹, 鈴木 博義, 青木 正志, 中里 信和

    臨床神経学 63 (Suppl.) S227-S227 2023/09

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  108. 片側扁桃体腫大を伴う側頭葉てんかん患者における発作時脳波の特徴

    此松 和俊, 神 一敬, 板橋 泉, 佐藤 志帆, 森下 陽平, 曽我 天馬, 柿坂 庸介, 麦倉 俊司, 青木 正志, 中里 信和

    てんかん研究 41 (2) 451-451 2023/09

    Publisher: (一社)日本てんかん学会

    ISSN: 0912-0890

    eISSN: 1347-5509

  109. 海馬硬化を伴う内側側頭葉てんかんの術後発作転帰予測因子

    曽我 天馬, 神 一敬, 柿坂 庸介, 此松 和俊, 大沢 伸一郎, 岩崎 真樹, 鈴木 博義, 青木 正志, 中里 信和

    臨床神経学 63 (Suppl.) S227-S227 2023/09

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  110. MRI陰性側頭葉てんかんの術後発作転帰と発作時心拍数上昇の関係

    曽我 天馬, 神 一敬, 柿坂 庸介, 浮城 一司, 此松 和俊, 久保田 隆文, 大沢 伸一郎, 岩崎 真樹, 鈴木 博義, 青木 正志, 中里 信和

    てんかん研究 41 (2) 449-449 2023/09

    Publisher: (一社)日本てんかん学会

    ISSN: 0912-0890

    eISSN: 1347-5509

  111. 片側扁桃体腫大を伴う側頭葉てんかん患者における発作時脳波の特徴

    此松 和俊, 神 一敬, 板橋 泉, 佐藤 志帆, 森下 陽平, 曽我 天馬, 柿坂 庸介, 麦倉 俊司, 青木 正志, 中里 信和

    てんかん研究 41 (2) 451-451 2023/09

    Publisher: (一社)日本てんかん学会

    ISSN: 0912-0890

    eISSN: 1347-5509

  112. MOGAD急性期髄液における活性化補体の解析

    金子 仁彦, 黒田 宙, 小野 紘彦, 松本 勇貴, 阪本 直広, 山崎 直也, 山本 尚輝, 梅澤 周, 生田目 知尋, 高井 良樹, 高橋 利幸, 藤盛 寿一, 中島 一郎, 藤原 一男, 三須 建郎, 青木 正志

    神経免疫学 28 (1) 200-200 2023/09

    Publisher: (一社)日本神経免疫学会

    ISSN: 0918-936X

  113. GNEミオパチーに対する経口アセノイラミン酸による治療開発

    鈴木 直輝, 森 まどか, 勝野 雅央, 高橋 正紀, 山下 賢, 井泉 瑠美子, 割田 仁, 浅田 隆太, 西野 一三, 青木 正志

    日本筋学会学術集会・筋ジストロフィー医療研究会合同学術集会プログラム・抄録集 9回・10回 63-63 2023/08

    Publisher: 日本筋学会・筋ジストロフィー医療研究会

  114. GNEミオパチーに対する経口アセノイラミン酸による治療開発

    鈴木 直輝, 森 まどか, 勝野 雅央, 高橋 正紀, 山下 賢, 井泉 瑠美子, 割田 仁, 浅田 隆太, 西野 一三, 青木 正志

    日本筋学会学術集会・筋ジストロフィー医療研究会合同学術集会プログラム・抄録集 9回・10回 63-63 2023/08

    Publisher: 日本筋学会・筋ジストロフィー医療研究会

  115. Associations between neuromyelitis optica spectrum disorder, Sjögren's syndrome, and conditions with electrolyte disturbances. International-journal Peer-reviewed

    Tetsuya Akaishi, Kunio Tarasawa, Yuki Matsumoto, Pulukool Sandhya, Tatsuro Misu, Kiyohide Fushimi, Toshiyuki Takahashi, Juichi Fujimori, Tadashi Ishii, Kenji Fujimori, Nobuo Yaegashi, Ichiro Nakashima, Kazuo Fujihara, Masashi Aoki

    Journal of the neurological sciences 452 120742-120742 2023/07/24

    DOI: 10.1016/j.jns.2023.120742  

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    OBJECTIVE: Electrolyte disorders are among the important conditions negatively affecting the disease course of neuromyelitis optica spectrum disorder (NMOSD). Possible mechanisms may include renal tubular acidosis (RTA) accompanying Sjögren's syndrome (SS), syndrome of inappropriate antidiuretic hormone secretion (SIADH), and central diabetes insipidus (DI). Currently, the overlap profiles between these conditions remain uncertain. METHODS: This cross-sectional study collected data from the nationwide administrative Diagnosis Procedure Combination (DPC) database and evaluated the overlap profiles. RESULTS: Among the 28,285,908 individuals from 1203 DPC-covered hospitals, 8477 had NMOSD, 174108 had SS, 4977 had RTA, 7640 had SIADH, and 24,789 had central DI. Of those with NMOSD, 986 (12%) had SS. The odds ratio (OR) for a diagnosis of NMOSD in those with SS compared with those without was 21 [95% confidence interval (CI), 20-23]. Overlap between NMOSD and SS was seen both in males (OR, 28 [95% CI, 23-33]) and females (OR, 16 [15-17]) and was more prominent in the younger population. Among patients with SS, the prevalence of RTA was lower in patients with NMOSD compared with those without NMOSD. Patients with NMOSD showed a higher prevalence of SIADH (OR, 11 [7.5-17]; p < 0.0001) and DI (OR, 3.7 [2.4-5.3]; p < 0.0001). Comorbid SS in NMOSD was associated with a higher prevalence of DI. CONCLUSIONS: Patients with NMOSD are likely to have SS, SIADH, and central DI. RTA in SS does not facilitate the overlap between NMOSD and SS. SS in NMOSD may predispose patients to DI.

  116. Rab40はDNAJC13のプロテアソーム分解を誘導する可能性がある

    佐藤 一輝, 長谷川 隆文, 石山 駿, 中村 貴彬, 吉田 隼, 管野 直人, 青木 正志

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集 17回 78-78 2023/07

    Publisher: Movement Disorder Society of Japan (MDSJ)

  117. SH-SY5Y細胞におけるαシヌクレイン過剰発現のトランスクリプトーム解析(Transcriptome analysis of alpha synuclein overexpression in SH-SY5Y cells)

    中村 貴彬, 菅野 直人, 石山 駿, 吉田 隼, 佐藤 一輝, 武田 篤, 長谷川 隆文, 青木 正志

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集 17回 78-78 2023/07

    Publisher: Movement Disorder Society of Japan (MDSJ)

  118. ヒト中脳オルガノイド由来のscRNA-seqの再解析(Re-analyses of scRNA-seq from human midbrain-like organoids)

    菅野 直人, 中村 貴彬, 石山 駿, 佐藤 一輝, 吉田 隼, 武田 篤, 長谷川 隆文, 青木 正志

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集 17回 104-104 2023/07

    Publisher: Movement Disorder Society of Japan (MDSJ)

  119. Time-Dependent Analysis of Sicca Symptoms and Anti-Ro/SSA and Anti-La/SSB Antibodies in Patients with AQP4-IgG-Positive Neuromyelitis Optica Spectrum Disorder. Peer-reviewed

    Tetsuya Akaishi, Toshiyuki Takahashi, Tatsuro Misu, Kazuo Fujihara, Ichiro Nakashima, Masashi Aoki

    The Tohoku journal of experimental medicine 2023/04/20

    DOI: 10.1620/tjem.2023.J034  

  120. White blood cell count profiles in anti-aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorder and anti-myelin oligodendrocyte glycoprotein antibody-associated disease. International-journal Peer-reviewed

    Tetsuya Akaishi, Tatsuro Misu, Kazuo Fujihara, Kumi Nakaya, Naoki Nakaya, Tomohiro Nakamura, Mana Kogure, Rieko Hatanaka, Fumi Itabashi, Ikumi Kanno, Kimihiko Kaneko, Toshiyuki Takahashi, Juichi Fujimori, Yoshiki Takai, Shuhei Nishiyama, Tadashi Ishii, Masashi Aoki, Ichiro Nakashima, Atsushi Hozawa

    Scientific reports 13 (1) 6481-6481 2023/04/20

    DOI: 10.1038/s41598-023-33827-3  

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    White blood cell (WBC) count profiles in anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) and anti-myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are still unknown. This study evaluated the total WBC count, differential WBC counts, monocyte-to-lymphocyte ratio (MLR), and neutrophil-to-lymphocyte ratio (NLR) in patients with these diseases within three months from an attack before acute treatment or relapse prevention and compared the profiles with those in matched volunteers or in multiple sclerosis (MS) patients. AQP4-NMOSD patients (n = 13) had a higher neutrophil count (p = 0.0247), monocyte count (p = 0.0359), MLR (p = 0.0004), and NLR (p = 0.0037) and lower eosinophil (p = 0.0111) and basophil (p = 0.0283) counts than those of AQP4-NMOSD-matched volunteers (n = 65). Moreover, patients with MOGAD (n = 26) had a higher overall WBC count (p = 0.0001), neutrophil count (p < 0.0001), monocyte count (p = 0.0191), MLR (p = 0.0320), and NLR (p = 0.0002) than those of MOGAD-matched volunteers (n = 130). The three demyelinating diseases showed similar levels of the total and differential WBC counts; however, MOGAD and MS showed different structures in the hierarchical clustering and distributions on a two-dimensional canonical plot using differential WBC counts from the other three groups. WBC count profiles were similar in patients with MOGAD and MS but differed from profiles in matched volunteers or patients with AQP4-NMOSD.

  121. 免疫療法が奏功した本邦2家系目の遺伝性神経痛性筋萎縮症の1例

    梅澤 岳助, 金子 仁彦, 石川 周, 井泉 瑠美子, 三須 建郎, 長谷川 隆文, 青木 正志

    臨床神経学 63 (4) 245-245 2023/04

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  122. 遠位優位の四肢筋力低下を呈した慢性肉芽腫性ミオパチーの78歳女性例

    石川 周, 池田 謙輔, 井泉 瑠美子, 長谷川 隆文, 菅野 直人, 青木 正志

    臨床神経学 63 (4) 248-248 2023/04

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  123. Olfactory Dysfunction, an Often Neglected Symptom of Hydrocephalus: Experience from a Case of Late-Onset Idiopathic Aqueductal Stenosis International-journal Peer-reviewed

    Naoya Yamazaki, Takafumi Hasegawa, Kensuke Ikeda, Ako Miyata, Shin-ichiro Osawa, Kuniyasu Niizuma, Shigenori Kanno, Teiji Tominaga, Masashi Aoki

    Case Reports in Neurology 15 (1) 41-47 2023/03/01

    Publisher: S. Karger AG

    DOI: 10.1159/000529532  

    eISSN: 1662-680X

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    Disturbance of smell is often accompanied with common neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases. In addition, patients with head trauma, intracranial tumors, and hydrocephalus can also develop olfactory dysfunction, and some of which can improve with treatment of the underlying disease. In clinical practice, few patients complain of smell disturbances, thus olfactory dysfunction is often overshadowed by visible motor symptoms. Herein, we report a case of late-onset idiopathic aqueductal stenosis, a rare form of adult-onset hydrocephalus in which olfactory dysfunction and gait disturbance was markedly improved after endoscopic ventriculostomy. This case report is expected to make more physicians aware that hydrocephalus can cause olfactory dysfunction and that it can be corrected postoperatively. Furthermore, in addition to motor and neuropsychological function, olfactory function test might be useful for functional assessment before and after surgical treatment of hydrocephalus.

  124. Effects of CX3CR1 and CXCR2 antagonists on running-dependent intramuscular neutrophil recruitments and myokine upregulation. International-journal Peer-reviewed

    Mazvita R Nyasha, Weijian Chen, Haopeng Wang, Fukie Yaoita, Masashi Aoki, Ryoichi Nagatomi, Makoto Kanzaki

    American journal of physiology. Endocrinology and metabolism 324 (5) E375-E389 2023/03/01

    DOI: 10.1152/ajpendo.00196.2022  

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    Muscle contractile activity stimulates intramuscular recruitment of immune cells including neutrophils emerging to serve as a prerequisite for exerting proper muscular performance, although the underlying mechanisms and their contributions to myokine upregulation remain ill-defined. We previously reported that pharmacological inhibition of CX3CR1, a fractalkine receptor, dampens gnawing-dependent neutrophil recruitment into masseter muscles along with compromising their masticatory activity. By employing a running exercise model, we herein demonstrated that hindlimb muscles require collaborative actions of both CX3CR1- and CXCR2-mediated signals for achieving neutrophil recruitment, upregulation of myokines including interleukin (IL)-6, enhanced GLUT4 translocation, and adequate endurance capability. Mechanistically, we revealed that a combination of CX3CR1 and CXCR2 antagonists, i.e., AZD8797 and SB2205002, inhibits exercise-inducible ICAM-1 and fractalkine upregulations in the area of the endothelium and muscle-derived CXCL1 upregulation, both of which apparently contribute to the intramuscular neutrophil accumulation in working muscles. Intriguingly, we also observed that 2 h of running results in intramuscular augmentation of innate lymphoid type 2 cells (ILC2s) markers, i.e., Bcl11b mRNA levels and anti-GATA-3-antibody-positive signals, and that these effects are completely abolished by administration of the combination of CX3CR1 and CXCR2 antagonists. Taken together, our findings strongly suggest that the exercise-evoked regional interplay among working myofibers, the adjacent endothelium and recruited immune cells including neutrophils and possibly ILC2s, mediated through these local factors, plays a key role in organization of the intramuscular microenvironment supporting the performance of hindlimb muscles during running.

  125. 扁桃体肥大を伴う側頭葉てんかん患者における発作間欠期の神経磁場スパイクのECD配向(ECD direction of interictal neuromagnetic spikes in patients with temporal lobe epilepsy with amygdala enlargement)

    Konomatsu Kazutoshi, Jin Kazutaka, Ishida Makoto, Sato Shiho, Morishita Yohei, Soga Temma, Ukishiro Kazushi, Kakisaka Yosuke, Kanno Akitake, Mugikura Shunji, Aoki Masashi, Nakasato Nobukazu

    日本生体磁気学会誌 36 (1) 158-159 2023

    Publisher: 日本生体磁気学会

    ISSN: 0915-0374

  126. Spinal Cord Infarction in an Adolescent with Protein S Deficiency: A Case Report and Literature Review

    Takafumi Kubota, Tatsuhiko Hosaka, Daisuke Ando, Kensuke Ikeda, Rumiko Izumi, Tatsuro Misu, Hitoshi Warita, Masashi Aoki

    Internal Medicine 2023

    Publisher: Japanese Society of Internal Medicine

    DOI: 10.2169/internalmedicine.0153-22  

    ISSN: 0918-2918

    eISSN: 1349-7235

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    Protein S deficiency causes spinal cord infarction in rare cases. We herein report the first case of severe cervicothoracic cord infarction in an adolescent with protein S deficiency. A 16-year-old boy presented with neck pain, four-limb paralysis, and numbness. Magnetic resonance imaging revealed spinal artery infarction in the C4 to Th4 area. Protein S antigen and activity were decreased. The patient was diagnosed with protein S deficiency-associated cervicothoracic cord infarction, which was treated with anticoagulation. Protein S deficiency should be considered as a potential cause of spinal cord infarction in young healthy patients and should be appropriately treated with anticoagulation.

  127. Mirror writing and cortical hypometabolism in Parkinson’s disease International-journal Peer-reviewed

    Mayumi Shinohara, Kayoko Yokoi, Kazumi Hirayama, Shigenori Kanno, Yoshiyuki Hosokai, Yoshiyuki Nishio, Toshiyuki Ishioka, Mika Otsuki, Atsushi Takeda, Toru Baba, Masashi Aoki, Takafumi Hasegawa, Akio Kikuchi, Wataru Narita, Etsuro Mori, Kyoko Suzuki

    PLOS ONE 17 (12) e0279007-e0279007 2022/12/14

    Publisher: Public Library of Science (PLoS)

    DOI: 10.1371/journal.pone.0279007  

    eISSN: 1932-6203

  128. Oral edaravone demonstrated a favorable safety profile in patients with amyotrophic lateral sclerosis after 48 weeks of treatment. International-journal

    Angela Genge, Gary L Pattee, Gen Sobue, Masashi Aoki, Hiide Yoshino, Philippe Couratier, Christian Lunetta, Susanne Petri, Daniel Selness, Sachin Bidani, Manabu Hirai, Takeshi Sakata, Alejandro Salah, Stephen Apple, Art Wamil, Alexander Kalin, Carlayne E Jackson

    Muscle & nerve 67 (2) 124-129 2022/12/11

    DOI: 10.1002/mus.27768  

    ISSN: 0148-639X

    eISSN: 1097-4598

  129. A novel association of osmotic demyelination in Sjögren's syndrome prompts revisiting role of aquaporins in CNS demyelinating diseases: A literature review. International-journal

    Pulukool Sandhya, Tetsuya Akaishi, Kazuo Fujihara, Masashi Aoki

    Multiple sclerosis and related disorders 69 104466-104466 2022/12/11

    DOI: 10.1016/j.msard.2022.104466  

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    BACKGROUND: Primary Sjögren's syndrome (SS) is a chronic systemic autoimmune disease with varied neurological manifestations. SS is associated with anti-aquaporin-4 antibody (AQP4-IgG)-positive neuromyelitis optica spectrum disorder (NMOSD), a demyelinating autoimmune disorder of the central nervous system (CNS). Intriguingly, there are reports of osmotic demyelinating syndrome (ODS), a supposedly non-inflammatory disorder, in the context of SS and renal tubular acidosis (RTA), both of which are not yet established risk factors for ODS. METHODS: A literature search was undertaken to identify case reports of ODS in patients with SS. Details of the clinical and laboratory features of these patients were compiled. Additionally, we searched for NMOSD in patients with SS. We looked for co-existing RTA in patients with SS-ODS as well as SS-NMOSD. We also screened for reports of ODS in RTA without underlying SS. RESULTS & DISCUSSION: We identified 15 patients (all women, median age 40 years) with ODS in SS, and all of these patients had comorbid RTA. There were only three reported cases of ODS in RTA without underlying SS. We identified a total of 67 patients with SS-NMOSD, of whom only 3 (4.5%) had RTA. Hence, unlike NMOSD, the development of ODS in SS requires a prolonged osmotic or electrolyte abnormality caused by the comorbid RTA. The 15 patients with ODS and SS -RTA, showed heterogeneous clinical manifestations and outcomes. The most common symptom was quadriparesis, seen in 14 of the 15 patients. Eleven of the 15 patients had one of the following features, either alone or in combination: worsening of the sensorium, extensor plantar response, dysphagia/dysarthria, and facial palsy. The latter four manifestations were present at the onset in 7 patients and later in the course of the illness in the remaining 4 patients. Ocular palsy was seen in only four of the 15 patients and was a late manifestation. One patient who had extensive long-segment myelitis and subsequent ODS died, but most patients recovered without significant sequelae. None had hyponatremia, while all patients had hypokalemia and/or hypernatremia. Hypokalemia causing nephrogenic diabetes insipidus (NDI) followed by rapid rise in sodium and the resultant osmotic stress could potentially explain the occurrence of ODS in SS-RTA. Aquaporin (AQP) in astrocytes is implicated in ODS, and renal AQP is downregulated in NDI. Antibodies against AQPs are present in some patients with SS. Defective AQP is therefore a common link underlying all the connected diseases, namely SS, NDI, and ODS, raising the possibility of immune-mediated AQP dysfunction in the pathogenesis. CONCLUSION: The hitherto unreported association between SS-RTA and ODS may implicate SS and/or RTA in the development of ODS. In the setting of SS-RTA, ODS must be suspected when a patient with flaccid quadriparesis does not respond to the correction of potassium or develops additional neurological features along with a rise in sodium. Defective functions of AQPs may be a possible mechanism linking demyelinating CNS lesions, SS, and RTA. Studies evaluating AQP functions and serum antibodies against AQPs in these conditions are warranted.

  130. フィーダーフリーの疾患特異的iPSCを使用したALSのより効率的な疾患モデルの確立

    Zohora Khatun, 小野寺 一成, 山口 真一, 岡田 梨奈, 伊藤 卓治, Rashid Muhammad Irfanur, 井上 治久, 青木 正志, 岡野 栄之, 道勇 学, 岡田 洋平

    末梢神経 33 (2) 376-376 2022/12

    Publisher: 日本末梢神経学会

    ISSN: 0917-6772

  131. Parkinson病との鑑別を要した晩発性中脳水道狭窄症の一例.

    山崎 直也, 池田 謙輔, 宮田 杏子, 三須 建郎, 長谷川 隆文, 青木 正志

    臨床神経学 62 (11) 904-904 2022/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  132. 東北大学病院難病医療連携センターについて

    関本 聖子, 遠藤 久美子, 遠藤 恵, 石橋 渚子, 山内 悦子, 松本 有史, 鈴木 直輝, 加藤 昌昭, 割田 仁, 青木 正志

    日本難病医療ネットワーク学会機関誌 10 (1) 106-106 2022/11

    Publisher: 日本難病医療ネットワーク学会

    ISSN: 2188-1006

  133. 抗MOG抗体関連疾患における皮質性脳炎は高率に頭痛症状を呈する

    小川 諒, 高橋 利幸, 中村 正史, 藤盛 寿一, 三須 建郎, 中島 一郎, 青木 正志

    日本頭痛学会誌 49 (2) 486-486 2022/11

    Publisher: (一社)日本頭痛学会

    ISSN: 1345-6547

    eISSN: 2436-1577

  134. 抗MOG抗体関連疾患における皮質性脳炎は高率に頭痛症状を呈する

    小川 諒, 高橋 利幸, 中村 正史, 藤盛 寿一, 三須 建郎, 中島 一郎, 青木 正志

    日本頭痛学会誌 49 (2) 486-486 2022/11

    Publisher: (一社)日本頭痛学会

    ISSN: 1345-6547

    eISSN: 2436-1577

  135. Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease With False-Positive Results in SARS-CoV-2 Antigen Tests: A Case Report. International-journal

    Naoki Yamamoto, Hajime Ikenouchi, Yoshiki Takai, Kaoru Endo, Masashi Aoki

    Cureus 14 (11) e31514 2022/11

    DOI: 10.7759/cureus.31514  

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    A 23-year-old man presented with headache, fever, and urinary retention. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen tests were positive, but SARS-CoV-2 polymerase chain reaction (PCR) results were negative. MRI showed long spinal cord lesions. Due to positive serum and cerebrospinal fluid myelin oligodendrocyte glycoprotein (MOG) antibodies, we made the diagnosis of MOG-associated disease. We concluded that the antigen tests were false positives because SARS-CoV-2 IgM and IgG were not elevated. Although the mechanism behind the false-positive results is unclear, physicians should consider the possibility of a false-positive result in the SARS-CoV-2 antigen test.

  136. 遺伝性ジストニアDYT28における非侵襲的ヒストン修飾検出法の検討

    菅野 直人, 長谷川 隆文, 中村 貴彬, 石山 駿, 吉田 隼, 佐藤 一輝, 青木 正志

    神経治療学 39 (6) S255-S255 2022/10

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  137. 病的バリアントと確定しがたいdysferlin遺伝子のc.3725G>A(p.R1242H)の検討

    高橋 俊明, 井泉 瑠美子, 鈴木 直輝, 八木沼 智香子, 島倉 奈緒子, 大矢 寧, 佐橋 功, 戸恒 智子, 杉村 容子, 谷口 さやか, 下瀬川 康子, 吉岡 勝, 馬場 徹, 大泉 英樹, 田中 洋康, 割田 仁, 新堀 哲也, 武田 篤, 青木 洋子, 青木 正志

    臨床神経学 62 (Suppl.) S221-S221 2022/10

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  138. ALS発症から診断までの期間は疾患進行の予測因子となりうる

    池田 謙輔, 四條 友望, 鈴木 直輝, 割田 仁, 川内 裕子, 光澤 志緒, 井泉 瑠美子, 黒田 宙, 加藤 昌昭, 青木 正志

    臨床神経学 62 (Suppl.) S328-S328 2022/10

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  139. 筋萎縮性側索硬化症では片側のみで正中神経刺激巨大体性感覚誘発電位を認めることがある

    板橋 泉, 浅黄 優, 四條 友望, 鈴木 直輝, 坂本 美佳, 佐藤 貴文, 小澤 鹿子, 青木 正志, 三木 俊, 中里 信和

    臨床神経生理学 50 (5) 400-400 2022/10

    Publisher: (一社)日本臨床神経生理学会

    ISSN: 1345-7101

    eISSN: 2188-031X

  140. 発作後心静止を呈したてんかん患者の臨床的特徴

    此松 和俊, 神 一敬, 曽我 天馬, 柿坂 庸介, 青木 正志, 中里 信和

    臨床神経生理学 50 (5) 393-393 2022/10

    Publisher: (一社)日本臨床神経生理学会

    ISSN: 1345-7101

    eISSN: 2188-031X

  141. 光突発反応を呈する焦点てんかん患者の臨床的特徴

    曽我 天馬, 神 一敬, 此松 和俊, 柿坂 庸介, 青木 正志, 中里 信和

    臨床神経生理学 50 (5) 442-442 2022/10

    Publisher: (一社)日本臨床神経生理学会

    ISSN: 1345-7101

    eISSN: 2188-031X

  142. SARS-CoV-2ワクチン後免疫性神経疾患の臨床的特徴と予後

    金子 仁彦, 松本 勇貴, 藤盛 寿一, 生田目 千尋, 高井 良樹, 中島 一郎, 三須 建郎, 青木 正志

    NEUROINFECTION 27 (2) 214-214 2022/10

    Publisher: 日本神経感染症学会

    ISSN: 1348-2718

    eISSN: 2435-2225

  143. SARS-CoV-2ワクチン後免疫性神経疾患の臨床的特徴と予後

    金子 仁彦, 松本 勇貴, 藤盛 寿一, 生田目 千尋, 高井 良樹, 中島 一郎, 三須 建郎, 青木 正志

    NEUROINFECTION 27 (2) 214-214 2022/10

    Publisher: 日本神経感染症学会

    ISSN: 1348-2718

    eISSN: 2435-2225

  144. 大規模レジストリデータベース(PRO-ACT)を活用したALSに対するロピニロール塩酸塩の有効性の検証

    森本 悟, 高橋 愼一, 伊東 大介, 伊達 悠岳, 岡田 健佑, Chai Muh Chy, 西山 亜由美, 鈴木 直輝, 平井 美和, 加部 泰明, 末松 誠, 陣崎 雅弘, 青木 正志, 佐藤 泰憲, 中原 仁, 鈴木 則宏, 岡野 栄之

    神経治療学 39 (6) S257-S257 2022/10

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  145. RSPO3 is a novel contraction-inducible factor identified in an "in vitro exercise model" using primary human myotubes. International-journal

    Tadahisa Takahashi, Yuqing Li, Weijian Chen, Mazvita R Nyasha, Kazumi Ogawa, Kazuaki Suzuki, Masashi Koide, Yoshihiro Hagiwara, Eiji Itoi, Toshimi Aizawa, Masahiro Tsuchiya, Naoki Suzuki, Masashi Aoki, Makoto Kanzaki

    Scientific reports 12 (1) 14291-14291 2022/08/22

    DOI: 10.1038/s41598-022-18190-z  

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    The physiological significance of skeletal muscle as a secretory organ is now well known but we can only speculate as to the existence of as-yet-unidentified myokines, especially those upregulated in response to muscle contractile activity. We first attempted to establish an "insert-chamber based in vitro exercise model" allowing the miniature but high cell-density culture state enabling highly developed contractile human myotubes to be readily obtained by applying electric pulse stimulation (EPS). By employing this in vitro exercise model, we identified R-spondin 3 (RSPO3) as a novel contraction-inducible myokine produced by cultured human myotubes. Contraction-dependent muscular RSPO3 mRNA upregulation was confirmed in skeletal muscles of mice subjected to sciatic nerve mediated in situ contraction as well as those of mice after 2 h of running. Pharmacological in vitro experiments demonstrated a relatively high concentration of metformin (millimolar range) to suppress the contraction-inducible mRNA upregulation of human myokines including RSPO3, interleukin (IL)-6, IL-8 and CXCL1. Our data also suggest human RSPO3 to be a paracrine factor that may positively participate in the myogenesis processes of myoblasts and satellite cells. Thus, the "insert chamber-based in vitro exercise model" is a potentially valuable research tool for investigating contraction-inducible biological responses of human myotubes usually exhibiting poorer contractility development even in the setting of EPS treatment.

  146. 海馬硬化を伴う内側側頭葉てんかんの臨床脳波的特徴

    曽我 天馬, 神 一敬, 大沢 伸一郎, 岩崎 真樹, 柿坂 庸介, 鈴木 博義, 青木 正志, 冨永 悌二, 中里 信和

    てんかん研究 40 (2) 397-397 2022/08

    Publisher: (一社)日本てんかん学会

    ISSN: 0912-0890

    eISSN: 1347-5509

  147. 扁桃体腫大を伴う側頭葉てんかん患者における発作時脳波所見の特徴

    此松 和俊, 神 一敬, 佐藤 志帆, 森下 陽平, 曽我 天馬, 柿坂 庸介, 麦倉 俊司, 青木 正志, 中里 信和

    てんかん研究 40 (2) 398-398 2022/08

    Publisher: (一社)日本てんかん学会

    ISSN: 0912-0890

    eISSN: 1347-5509

  148. αシヌクレインはBAF複合体と相互に作用することでトランスクリプトームに影響を及ぼす(Alpha-synuclein affects transcriptome through interacting with BAF complex)

    中村 貴彬, 菅野 直人, 池田 健祥, 長谷川 隆文, 石山 駿, 吉田 隼, 武田 篤, 青木 正志

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集 16回 84-84 2022/07

    Publisher: Movement Disorder Society of Japan (MDSJ)

  149. 遺伝性ジストニアDYT28の口腔粘膜由来ヒストン修飾

    菅野 直人, 長谷川 隆文, 中村 貴彬, 石山 駿, 吉田 隼, 武田 篤, 青木 正志

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集 16回 111-111 2022/07

    Publisher: Movement Disorder Society of Japan (MDSJ)

  150. 再発後早期にeculizumabを導入した抗アクアポリン4抗体陽性視神経脊髄炎の2例

    金子 仁彦, 浪岡 靖弘, 大山 綾音, 高井 良樹, 檜森 紀子, 中澤 徹, 三須 建郎, 青木 正志

    神経治療学 39 (4) 731-735 2022/07

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  151. [Recommendations (Proposal) for promoting research for overcoming neurological diseases 2020].

    Hideki Mochizuki, Masashi Aoki, Kensuke Ikenaka, Haruhisa Inoue, Takeshi Iwatsubo, Yoshikazu Ugawa, Hitoshi Okazawa, Kenjiro Ono, Osamu Onodera, Kazuo Kitagawa, Yuko Saito, Takayoshi Shimohata, Ryosuke Takahashi, Tatsushi Toda, Jin Nakahara, Riki Matsumoto, Hidehiro Mizusawa, Jun Mitsui, Shigeo Murayama, Masahisa Katsuno, Yoshitsugu Aoki, Hiroyuki Ishiura, Yuishin Izumi, Haruki Koike, Hitoshi Shimada, Yuji Takahashi, Takahiko Tokuda, Hideto Nakajima, Taku Hatano, Sonoko Misawa, Hirohisa Watanabe

    Rinsho shinkeigaku = Clinical neurology 62 (6) 429-442 2022/06/24

    DOI: 10.5692/clinicalneurol.cn-001695  

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    The Japanese Society of Neurology discusses research, education, and medical care in the field of neurology and makes recommendations to the national government. Dr. Mizusawa, the former representative director of the Japanese Society of Neurology, selected committee members and made "Recommendations for Promotion of Research for Overcoming Neurological Diseases" in 2013. After that, the Future Vision Committee was established in 2014, and these recommendations have been revised once every few years by the committee. This time, the Future Vision Committee made the latest recommendations from 2020 to 2021. In this section I, we will discuss clinical and research topics of neurology categorized by the methodology, including genetic research, translational research, nucleic acid therapies, iPS research, and nursing/welfare.

  152. [Recommendations (Proposal) for promoting research for overcoming neurological diseases 2020].

    Hideki Mochizuki, Masashi Aoki, Kensuke Ikenaka, Haruhisa Inoue, Takeshi Iwatsubo, Yoshikazu Ugawa, Hitoshi Okazawa, Kenjiro Ono, Osamu Onodera, Kazuo Kitagawa, Yuko Saito, Takayoshi Shimohata, Ryosuke Takahashi, Tatsushi Toda, Jin Nakahara, Riki Matsumoto, Hidehiro Mizusawa, Jun Mitsui, Shigeo Murayama, Masahisa Katsuno, Yoshitsugu Aoki, Hiroyuki Ishiura, Yuishin Izumi, Haruki Koike, Hitoshi Shimada, Yuji Takahashi, Takahiko Tokuda, Hideto Nakajima, Taku Hatano, Sonoko Misawa, Hirohisa Watanabe

    Rinsho shinkeigaku = Clinical neurology 62 (6) 443-457 2022/06/24

    DOI: 10.5692/clinicalneurol.cn-001696  

    More details Close

    The Japanese Society of Neurology discusses research, education, and medical care in the field of neurology and makes recommendations to the national government. Dr. Mizusawa, the former representative director of the Japanese Society of Neurology, selected committee members and made "Recommendations for Promotion of Research for Overcoming Neurological Diseases" in 2013. After that, the Future Vision Committee was established in 2014, and these recommendations have been revised once every few years by the committee. This time, the Future Vision Committee made the latest recommendations from 2020 to 2021. In this section II, we will discuss clinical and research topics of neurology categorized by the diseases. In each field, the hot topic of the disease was described by the expert.

  153. Follow-up of retinal thickness and optic MRI after optic neuritis in anti-MOG antibody-associated disease and anti-AQP4 antibody-positive NMOSD. International-journal

    Tetsuya Akaishi, Noriko Himori, Takayuki Takeshita, Tatsuro Misu, Toshiyuki Takahashi, Yoshiki Takai, Shuhei Nishiyama, Kimihiko Kaneko, Juichi Fujimori, Tadashi Ishii, Masashi Aoki, Kazuo Fujihara, Toru Nakazawa, Ichiro Nakashima

    Journal of the neurological sciences 437 120269-120269 2022/06/15

    DOI: 10.1016/j.jns.2022.120269  

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    BACKGROUND: Retinal atrophy in the chronic phase of optic neuritis (ON) in anti-aquaporin-4 antibody (AQP4-Ab)-positive neuromyelitis optica spectrum disorder (NMOSD) and anti-myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) remains unclear. METHODS: Patients with these diseases were repeatedly evaluated using optical coherence tomography (OCT) for the circumpapillary retinal nerve fiber layer (cpRNFL) and macular ganglion cell complex (mGCC) in the ON-involved eyes during relapse-free period after the first ON episode before relapse. Optic MRI with short tau inversion recovery (STIR) sequences was further evaluated retrospectively. RESULTS: Twelve patients with MOGAD (20 eyes with ON-involvement) and 14 with AQP4-Ab-positive NMOSD (16 eyes with ON-involvement) were enrolled. The progression of retinal atrophy ≥12 months after onset was observed in AQP4-Ab-positive NMOSD, but was not apparent in MOGAD. A decrease in retinal thickness by the same amount results in more severe visual impairment in AQP4-Ab-positive NMOSD. On optic MRI, the residual STIR hyperintensity in the optic nerves remained in the chronic phase in almost all eyes with ON in both diseases. Optic nerve atrophy occurred in all evaluated ON-involved eyes in AQP4-Ab-positive NMOSD, while it was observed in half of ON-involved eyes in MOGAD. CONCLUSIONS: Progression of retinal atrophy in the chronic phase has been observed in patients with AQP4-Ab-positive NMOSD, while it remains uncertain in patients with MOGAD. The visual impairments upon similar levels of retinal atrophy would be worse in AQP4-Ab-positive NMOSD, possibly attributable in part to a higher incidence of optic nerve atrophy in this disease.

  154. 脳神経疾患克服に向けた研究推進の提言2020、各論(疾患群別)

    望月 秀樹, 青木 正志, 池中 建介, 井上 治久, 岩坪 威, 宇川 義一, 岡澤 均, 小野 賢二郎, 小野寺 理, 北川 一夫, 齊藤 祐子, 下畑 享良, 高橋 良輔, 戸田 達史, 中原 仁, 松本 理器, 水澤 英洋, 三井 純, 村山 繁雄, 勝野 雅央, 日本神経学会将来構想委員会

    臨床神経学 62 (6) 443-457 2022/06

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  155. 脳神経疾患克服に向けた研究推進の提言2020、各論(方法論別)

    望月 秀樹, 青木 正志, 池中 建介, 井上 治久, 岩坪 威, 宇川 義一, 岡澤 均, 小野 賢二郎, 小野寺 理, 北川 一夫, 齊藤 祐子, 下畑 享良, 高橋 良輔, 戸田 達史, 中原 仁, 松本 理器, 水澤 英洋, 三井 純, 村山 繁雄, 勝野 雅央, 日本神経学会将来構想委員会

    臨床神経学 62 (6) 429-442 2022/06

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  156. SQSTM1, a protective factor of SOD1-linked motor neuron disease, regulates the accumulation and distribution of ubiquitinated protein aggregates in neuron. International-journal

    Shun Mitsui, Asako Otomo, Kai Sato, Masahito Ishiyama, Kento Shimakura, Chisa Okada-Yamaguchi, Eiji Warabi, Toru Yanagawa, Masashi Aoki, Hui-Fang Shang, Shinji Hadano

    Neurochemistry international 158 105364-105364 2022/05/28

    DOI: 10.1016/j.neuint.2022.105364  

    ISSN: 0197-0186

    eISSN: 1872-9754

  157. COVID-19後に皮膚筋炎を発症した一例

    岡田 友里, 保坂 龍彦, 渡部 聡, 四條 友望, 井泉 瑠美子, 三須 建郎, 青木 正志, 八丁目 直和, 小西 里沙, 市村 裕輝, 沖山 奈緒子

    臨床神経学 62 (5) 405-405 2022/05

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  158. Patulous Eustachian Tube Patients With Oculopharyngeal Muscular Dystrophy. International-journal Peer-reviewed

    Kento Ishigakii, Ryoukichi Ikeda, Jun Suzuki, Ai Hirano-Kawamoto, Jun Ohta, Kengo Kato, Rumiko Izumi, Naoki Suzuki, Masashi Aoki, Tetsuaki Kawase, Yukio Katori

    Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology 43 (4) e442-e445-E445 2022/04/01

    DOI: 10.1097/MAO.0000000000003494  

    ISSN: 1531-7129

    eISSN: 1537-4505

  159. Long-term outcomes after surgery to prevent aspiration for patients with amyotrophic lateral sclerosis. International-journal Peer-reviewed

    Temma Soga, Naoki Suzuki, Kengo Kato, Ai Kawamoto-Hirano, Yuko Kawauchi, Rumiko Izumi, Masaya Toyoshima, Shio Mitsuzawa, Tomomi Shijo, Kensuke Ikeda, Hitoshi Warita, Yukio Katori, Masashi Aoki, Masaaki Kato

    BMC neurology 22 (1) 94-94 2022/03/16

    DOI: 10.1186/s12883-022-02619-z  

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    BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons selectively. In particular, weakness in respiratory and swallowing muscles occasionally causes aspiration pneumonia and choking, which can be lethal. Surgery to prevent aspiration, which separates the trachea and esophagus, can reduce the associated risks. Central-part laryngectomy (CPL) is a relatively minimally invasive surgery to prevent aspiration. No studies have been conducted on the long-term outcomes of surgery to prevent aspiration in patients with ALS. This case series aimed to determine the long-term outcomes of surgery to prevent aspiration and the use of a continuous low-pressure aspirator in patients with ALS by evaluating the frequency of intratracheal sputum suctions performed per day, intra- and postoperative complications, oral intake data, and satisfaction of patients and their primary caregiver to predict improvement in patients' quality of life (QOL). METHODS: We report a case series of six patients with ALS who underwent CPL along with tracheostomy to prevent aspiration between January 2015 and November 2018. We evaluated their pre- and postoperative status and administered questionnaires at the time of last admission to the patients and their primary caregivers. RESULTS: The mean follow-up period after CPL was 33.5 months. Aerophagia was a common postoperative complication. The use of a continuous low-pressure aspirator resulted in reduced frequency of intratracheal sputum suctions. All cases avoided aspiration pneumonia. Oral intake was continued for 2-4 years after the tracheostomy and CPL. The satisfaction levels of the patient and primary caregiver were high. CONCLUSION: Our case series suggests that the use of a continuous low-pressure aspirator in patients undergoing CPL improves oral intake and reduces the frequency of intratracheal sputum suctions, which improves the QOL of patients with ALS and their families and caregivers. CPL and continuous low-pressure aspiration should be considered as a management option for ALS with significant bulbar and respiratory muscle weakness/dysfunction.

  160. Malignant otitis externa presenting cerebral infarction from pseudoaneurysm: A case report and a review of the literature. International-journal Peer-reviewed

    Yasutoshi Koshiba, Ryoukichi Ikeda, Jun Suzuki, Yohei Honkura, Yukino Funayama, Kensuke Ikeda, Hitoshi Warita, Masashi Aoki, Tetsuaki Kawase, Yukio Katori

    Clinical case reports 10 (2) e05276 2022/02

    DOI: 10.1002/ccr3.5276  

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    Chronic renal failure and diabetes mellitus could also be risk factors of pseudoaneurysm of the internal carotid artery (ICA) due to malignant otitis externa (MOE). Although pseudoaneurysm of the ICA is a rarely encountered disease, it should always be taken into consideration when treating patients of MOE.

  161. Feeder-supported in vitro exercise model using human satellite cells from patients with sporadic inclusion body myositis. International-journal Peer-reviewed

    Yuqing Li, Weijian Chen, Kazumi Ogawa, Masashi Koide, Tadahisa Takahashi, Yoshihiro Hagiwara, Eiji Itoi, Toshimi Aizawa, Masahiro Tsuchiya, Rumiko Izumi, Naoki Suzuki, Masashi Aoki, Makoto Kanzaki

    Scientific reports 12 (1) 1082-1082 2022/01/20

    DOI: 10.1038/s41598-022-05029-w  

    eISSN: 2045-2322

  162. White blood cell count profile in patients with physical complaints without known causes. International-journal

    Tetsuya Akaishi, Tadashi Ishii, Naoki Nakaya, Tomohiro Nakamura, Mana Kogure, Rieko Hatanaka, Fumi Itabashi, Ikumi Kanno, Masashi Aoki, Atsushi Hozawa

    SAGE open medicine 10 20503121221105328-20503121221105328 2022

    DOI: 10.1177/20503121221105328  

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    OBJECTIVES: The aim of this study was to search for routine blood test biomarkers in patients with physical symptoms but without a diagnosis after comprehensive routine screening diagnostic examinations. METHODS: A total of 228 adults aged < 65 years who presented with physical complaints without known causes after comprehensive screening diagnostic examinations and 228 age- and sex-matched healthy controls without physical complaints were enrolled. The blood cell count data at the first hospital visit were compared between these groups. RESULTS: Total white blood cell (p = 0.2143), red blood cell (p = 0.8954), and platelet (p = 0.7716) counts did not differ between the groups. The monocyte count (p = 0.0014) and resultant monocyte-to-lymphocyte ratio (p < 0.0001) were higher in the symptomatic group, while the other white blood cell subtypes did not differ significantly between the two groups. In the symptomatic group, patients with a monocyte-to-lymphocyte ratio > 0.25 were likely to have unexplained nonfocal physical symptoms (p < 0.0001). The characteristic findings included fatigability (p < 0.0001), prolonged slight fever (p = 0.0005), and widespread pain (p < 0.0001). The monocyte-to-lymphocyte ratio level was correlated with the proportion of patients with unexplained nonfocal symptoms. CONCLUSION: The blood cell count profile was largely the same between healthy individuals and patients with unexplained physical symptoms. However, patients with unexplained nonfocal physical complaints were likely to show an elevated monocyte-to-lymphocyte ratio, typically > 0.25.

  163. Calculating and Comparing the Annualized Relapse Rate and Estimating the Confidence Interval in Relapsing Neurological Diseases. International-journal

    Tetsuya Akaishi, Tadashi Ishii, Masashi Aoki, Ichiro Nakashima

    Frontiers in neurology 13 875456-875456 2022

    DOI: 10.3389/fneur.2022.875456  

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    Calculating the crude or adjusted annualized relapse rate (ARR) and its confidence interval (CI) is often required in clinical studies to evaluate chronic relapsing diseases, such as multiple sclerosis and neuromyelitis optica spectrum disorders. However, accurately calculating ARR and estimating the 95% CI requires careful application of statistical approaches and basic familiarity with the exponential family of distributions. When the relapse rate can be regarded as constant over time or by individuals, the crude ARR can be calculated using the person-years method, which divides the number of all observed relapses among all participants by the total follow-up period of the study cohort. If the number of relapses can be modeled by the Poisson distribution, the 95% CI of ARR can be obtained by finding the 2.5% upper and lower critical values of the parameter λ as the mean. Basic familiarity with F-statistics is also required when comparing the ARR between two disease groups. It is necessary to distinguish the observed relapse rate ratio (RR) between two sample groups (sample RR) from the unobserved RR between their originating populations (population RR). The ratio of population RR to sample RR roughly follows the F distribution, with degrees of freedom obtained by doubling the number of observed relapses in the two sample groups. Based on this, a 95% CI of the population RR can be estimated. When the count data of the response variable is overdispersed, the negative binomial distribution would be a better fit than the Poisson. Adjusted ARR and the 95% CI can be obtained by using the generalized linear regression models after selecting appropriate error structures (e.g., Poisson, negative binomial, zero-inflated Poisson, and zero-inflated negative binomial) according to the overdispersion and zero-inflation in the response variable.

  164. The Immediate Onset of Isolated and Unilateral Abducens Nerve Palsy Associated with COVID-19 Infection: A Case Report and Literature Review.

    Takafumi Kubota, Naoto Sugeno, Hirohito Sano, Koji Murakami, Kensuke Ikeda, Tatsuro Misu, Masashi Aoki

    Internal medicine (Tokyo, Japan) 61 (11) 1761-1765 2022

    DOI: 10.2169/internalmedicine.9308-22  

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    Cranial nerve palsy associated with coronavirus disease 2019 (COVID-19) is rare. We herein report the first Asian case of the immediate onset of isolated and unilateral abducens nerve palsy (ANP) accompanied with COVID-19 infection. A 25-year-old man developed diplopia one day after the COVID-19 symptom onset. Neurological examination revealed limitation of left eye abduction without ataxia and hyporeflexia. Negative anti-ganglioside antibody results and mild albuminocytological dissociation were noted. The patient was diagnosed with left ANP accompanied by COVID-19 infection. The ANP spontaneously recovered without treatment. ANP can develop during the early phase of COVID-19 infection and adversely affect patients' quality of life.

  165. Therapeutic effect of a novel curcumin derivative GT863 on a mouse model of amyotrophic lateral sclerosis. International-journal Peer-reviewed

    Hajime Kato, Hiroyasu Sato, Michiaki Okuda, Jun Wu, Shingo Koyama, Yasuhiko Izumi, Tomonori Waku, Mitsuyoshi Iino, Masashi Aoki, Shigeki Arawaka, Yasuyuki Ohta, Kenichi Ishizawa, Kanan Kawasaki, Yasuomi Urano, Tomohiro Miyasaka, Noriko Noguchi, Toshiaki Kume, Akinori Akaike, Hachiro Sugimoto, Takeo Kato

    Amyotrophic lateral sclerosis & frontotemporal degeneration 23 (7-8) 1-7 2021/12/11

    DOI: 10.1080/21678421.2021.2012699  

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    The present study investigated the therapeutic effects of the curcumin derivative 3-[(1E)-2-(1H-indol-6-yl)ethenyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]ethenyl]-1H-pyrazole (GT863) in amyotrophic lateral sclerosis (ALS). The inhibitory effect of GT863 on superoxide dismutase 1 (SOD1) aggregation was evaluated in cell-free assays. GT863 interfered with the conformational changes of the SOD1 protein and later, oligomeric aggregation. Furthermore, its antioxidant, anti-inflammatory, and neuroprotective effects were evaluated in cell-free and cultured cell assays. GT863 inhibited H2O2- and glutamate-induced cytotoxicity and activated an antioxidant responsive element pathway. Additionally, in vivo effects of GT863 in the ALS mice model were evaluated by its oral administration to H46R mutant SOD1 transgenic mice. Rotarod test showed that GT863 administration significantly slowed the progression of motor dysfunction in the mice. In addition, GT863 substantially reduced highly-aggregated SOD1, further preserving large neurons in the spinal cord of GT863-treated mice. Collectively, these results indicated that GT863 could be a viable therapeutic agent with multiple vital actions for the treatment of ALS.

  166. Mutation screening of the DNAJC7 gene in Japanese patients with sporadic amyotrophic lateral sclerosis. International-journal Peer-reviewed

    Genki Tohnai, Ryoichi Nakamura, Naoki Atsuta, Masahiro Nakatochi, Naoki Hayashi, Daisuke Ito, Hazuki Watanabe, Hirohisa Watanabe, Masahisa Katsuno, Yuishin Izumi, Akira Taniguchi, Kazuaki Kanai, Mitsuya Morita, Osamu Kano, Satoshi Kuwabara, Masaya Oda, Koji Abe, Masashi Aoki, Ikuko Aiba, Koichi Okamoto, Kouichi Mizoguchi, Tomohiko Ishihara, Akihiro Kawata, Takanori Yokota, Kazuko Hasegawa, Isao Nagano, Ichiro Yabe, Fumiaki Tanaka, Satoshi Kuru, Nobutaka Hattori, Kenji Nakashima, Ryuji Kaji, Gen Sobue

    Neurobiology of aging 113 131-136 2021/12/11

    DOI: 10.1016/j.neurobiolaging.2021.12.002  

    ISSN: 0197-4580

    eISSN: 1558-1497

  167. Relapse activity in the chronic phase of anti-myelin-oligodendrocyte glycoprotein antibody-associated disease. International-journal Peer-reviewed

    Tetsuya Akaishi, Tatsuro Misu, Kazuo Fujihara, Toshiyuki Takahashi, Yoshiki Takai, Shuhei Nishiyama, Kimihiko Kaneko, Juichi Fujimori, Tadashi Ishii, Masashi Aoki, Ichiro Nakashima

    Journal of neurology 269 (6) 3136-3146 2021/11/25

    DOI: 10.1007/s00415-021-10914-x  

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    OBJECTIVE: The patterns of relapse and relapse-prevention strategies for anti-myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are not completely investigated. We compared the patterns of relapse in later stages of MOGAD with those of anti-aquaporin-4 antibody (AQP4-Ab)-positive neuromyelitis optica spectrum disorder (NMOSD). METHODS: In this observational, comparative cohort study, 66 patients with MOGAD and 90 with AQP4-Ab-positive NMOSD were enrolled. We compared the patterns of relapse and annualized relapse rates (ARRs) in the first 10 years from disease onset, stratified by relapse-prevention treatments. RESULTS: Approximately 50% of the patients with MOGAD experienced relapses in the first 10 years. Among those not undergoing relapse-prevention treatments, ARRs in the first 5 years were slightly lower in MOGAD patients than in AQP4-Ab-positive NMOSD patients (MOGAD vs. AQP4-Ab NMOSD: 0.19 vs. 0.30; p = 0.0753). After 5 years, the ARR decreased in MOGAD patients (MOGAD vs. AQP4-Ab NMOSD: 0.05 vs. 0.34; p = 0.0001), with a 72% reduction from the first 5 years (p = 0.0090). Eight (61.5%) of the 13 MOGAD patients with more than 10-year follow-up from disease onset showed relapse 10 years after onset. Clustering in the timing and phenotype of attacks was observed in both disease patients. The effectiveness of long-term low-dose oral PSL for relapse prevention in patients with MOGAD has not been determined. CONCLUSIONS: The relapse risk in patients with MOGAD is generally lower than that in patients with AQP4-Ab-positive NMOSD, especially 5 years after onset. Meanwhile, relapses later than 10 years from onset are not rare in both diseases.

  168. [Recommendations (Proposal) for promoting research for overcoming neurological diseases 2020].

    Hideki Mochizuki, Masashi Aoki, Kensuke Ikenaka, Haruhisa Inoue, Takeshi Iwatsubo, Yoshikazu Ugawa, Hitoshi Okazawa, Kenjiro Ono, Osamu Onodera, Kazuo Kitagawa, Yuko Saito, Takayoshi Shimohata, Ryosuke Takahashi, Tatsushi Toda, Jin Nakahara, Riki Matsumoto, Hidehiro Mizusawa, Jun Mitsui, Shigeo Murayama, Masahisa Katsuno, Yoshitsugu Aoki, Hiroyuki Ishiura, Yuishin Izumi, Haruki Koike, Hitoshi Shimada, Yuji Takahashi, Takahiko Tokuda, Hideto Nakajima, Taku Hatano, Sonoko Misawa, Hirohisa Watanabe

    Rinsho shinkeigaku = Clinical neurology 61 (11) 709-721 2021/11/24

    DOI: 10.5692/clinicalneurol.cn-001639  

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    The Japanese Society of Neurology discusses research, education, and medical care in the field of neurology and makes recommendations to the national government. Dr. Mizusawa, the former representative director of the Japanese Society of Neurology, selected committee members and made "Recommendations for Promotion of Research for Overcoming Neurological Diseases" in 2013. After that, the Future Vision Committee was established in 2014, and these recommendations have been revised once every few years by the committee. This time, the Future Vision Committee made the latest recommendations from 2020 to 2021. In this document, the general part is 1) What is neurological disease? 2) Current status of neurological disease overcoming research, 3) Significance and necessity of neurological disease overcoming research, 4) Research promotion system for overcoming neurological disease, 5) the roadmap for overcoming neuromuscular diseases, 6) a summary version of these recommendations are explained using figures that are easy for the general public to understand.

  169. White blood cell count profiles in multiple sclerosis during attacks before the initiation of acute and chronic treatments. International-journal

    Tetsuya Akaishi, Tatsuro Misu, Kazuo Fujihara, Naoki Nakaya, Tomohiro Nakamura, Mana Kogure, Rieko Hatanaka, Fumi Itabashi, Ikumi Kanno, Toshiyuki Takahashi, Hiroshi Kuroda, Juichi Fujimori, Yoshiki Takai, Shuhei Nishiyama, Kimihiko Kaneko, Tadashi Ishii, Masashi Aoki, Ichiro Nakashima, Atsushi Hozawa

    Scientific reports 11 (1) 22357-22357 2021/11/16

    DOI: 10.1038/s41598-021-01942-8  

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    Multiple sclerosis (MS) is a major demyelinating disease of the central nervous system; however, its exact mechanism is unknown. This study aimed to elucidate the profile of white blood cells (WBCs) in the acute phase of an MS attack. Sixty-four patients with MS at the time of diagnosis and 2492 age- and sex-adjusted healthy controls (HCs) were enrolled. Data regarding the blood cell counts were compared between the groups. The total WBC (p < 0.0001), monocyte (p < 0.0001), basophil (p = 0.0027), and neutrophil (p < 0.0001) counts were higher in the MS group than in the HC group, whereas the lymphocyte and eosinophil counts did not differ. Adjustments for the smoking status and body mass index yielded the same results. The total and differential WBC counts of the patients with MS did not correlate with the counts of T2 hyperintense brain lesions or the levels of neurological disturbance. In summary, patients with MS showed elevated counts of total WBCs, monocytes, basophils, and neutrophils at the time of diagnosis. However, the clinical relevance of these biomarkers in the context of the development and progression of MS remains unclear.

  170. Development of Paraneoplastic Neuromyelitis Optica after Lung Resection in a Patient with Squamous Cell Carcinoma.

    Shunsuke Eba, Shuhei Nishiyama, Hirotsugu Notsuda, Hisashi Oishi, Masafumi Noda, Masashi Aoki, Yoshinori Okada

    Annals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia 29 (1) 49-52 2021/10/23

    DOI: 10.5761/atcs.cr.21-00144  

    ISSN: 1341-1098

    eISSN: 2186-1005

  171. リツキシマブが奏効した妊娠初期抗NMDA受容体脳炎の1例

    保坂 龍彦, 安藤 大祐, 松本 勇貴, 小野 紘彦, 金子 仁彦, 高井 良樹, 菅野 直人, 三須 建郎, 青木 正志

    神経治療学 38 (6) S277-S277 2021/10

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  172. 成人期に長時間ビデオ脳波モニタリング検査を行った環状20番染色体症候群の2例

    曽我 天馬, 神 一敬, 柿坂 庸介, 浮城 一司, 伊澤 理香子, 青木 正志, 中里 信和

    臨床神経生理学 49 (5) 420-420 2021/10

    Publisher: (一社)日本臨床神経生理学会

    ISSN: 1345-7101

    eISSN: 2188-031X

  173. iPS細胞創薬に基づいた筋萎縮性側索硬化症(ALS)に対するロピニロール塩酸塩の医師主導治験(ROPALS試験)

    森本 悟, 高橋 愼一, 伊東 大介, 伊達 悠岳, 岡田 健佑, Chai Muh Chyi, 西山 亜由美, 鈴木 直輝, 平井 美和, 加部 泰明, 末松 誠, 陣崎 雅弘, 青木 正志, 佐藤 泰憲, 中原 仁, 鈴木 則宏, 岡野 栄之

    神経治療学 38 (6) S261-S261 2021/10

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  174. C-NORSE後てんかん患者3例の脳波・脳磁図所見の特徴

    久保田 隆文, 神 一敬, 曽我 天馬, 浮城 一司, 石田 誠, 菅野 彰剛, 柿坂 庸介, 青木 正志, 中里 信和

    臨床神経生理学 49 (5) 419-419 2021/10

    Publisher: (一社)日本臨床神経生理学会

    ISSN: 1345-7101

    eISSN: 2188-031X

  175. 成人期に長時間ビデオ脳波モニタリング検査を行った環状20番染色体症候群の2例

    曽我 天馬, 神 一敬, 柿坂 庸介, 浮城 一司, 伊澤 理香子, 青木 正志, 中里 信和

    臨床神経生理学 49 (5) 420-420 2021/10

    Publisher: (一社)日本臨床神経生理学会

    ISSN: 1345-7101

    eISSN: 2188-031X

  176. 視神経脊髄炎におけるアストロサイトパチーに基づいた新たな病期分類の確立と経時変化の解析

    高井 良樹, 三須 建郎, 鈴木 博義, 高橋 利幸, 藤原 一男, 青木 正志

    神経免疫学 26 (1) 80-80 2021/10

    Publisher: (一社)日本神経免疫学会

    ISSN: 0918-936X

  177. 視神経脊髄炎急性期における抗補体療法の有用性

    金子 仁彦, 浪岡 靖弘, 大山 綾音, 高井 良樹, 三須 建郎, 青木 正志

    神経免疫学 26 (1) 149-149 2021/10

    Publisher: (一社)日本神経免疫学会

    ISSN: 0918-936X

  178. 【神経疾患を克服する-わが国の戦略(1)】研究手法の最新の話題 遺伝子・ゲノム医療

    青木 正志, 西山 亜由美

    Clinical Neuroscience 39 (9) 1103-1108 2021/09

    Publisher: (株)中外医学社

    ISSN: 0289-0585

  179. 臨床病型が大きく異なりFUS遺伝子変異のmosaicismが示唆された家族性ALS母子例

    久原 真, 西山 亜由美, 津田 笑子, 鈴木 秀一郎, 松村 晃寛, 石川 亜貴, 櫻井 晃洋, 元池 育子, 青木 正志, 青木 洋子, 下濱 俊

    臨床神経学 61 (Suppl.) S293-S293 2021/09

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  180. Five-year visual outcomes after optic neuritis in anti-MOG antibody-associated disease. International-journal

    Tetsuya Akaishi, Noriko Himori, Takayuki Takeshita, Tatsuro Misu, Toshiyuki Takahashi, Yoshiki Takai, Shuhei Nishiyama, Juichi Fujimori, Tadashi Ishii, Masashi Aoki, Kazuo Fujihara, Toru Nakazawa, Ichiro Nakashima

    Multiple sclerosis and related disorders 56 103222-103222 2021/08/24

    DOI: 10.1016/j.msard.2021.103222  

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    INTRODUCTION: Optic neuritis (ON) is a major phenotype of clinical attack related to demyelinating neurological diseases of the central nervous system, including multiple sclerosis (MS), anti-aquaporin-4 (AQP4) antibody-positive neuromyelitis optica spectrum disorder (NMOSD), and anti-myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). As the concept of MOGAD is relatively new, the long-term visual outcomes after ON in MOGAD remains unclear. METHODS: To elucidate the long-term visual prognosis after ON in MOGAD, patients with MOGAD whose visual acuity were regularly followed for more than 5 years from the onset of ON were enrolled. Best-corrected visual acuity (BCVA) at nadir in the acute phase and at 1 and 5 years from onset was evaluated. The data from patients with MOGAD were compared with those from patients with MS or anti-AQP4-positive NMOSD. RESULTS: Twenty-three patients (31 ON-involved eyes) with MOGAD, 20 patients (24 ON-involved eyes) with MS, and 22 patients (24 ON-involved eyes) with anti-AQP4-positive NMOSD were evaluated. All BCVA at nadir, 1 year, and 5 years from the onset of ON were much worse in anti-AQP4-positive NMOSD than in MS (p = 0.0024) and MOGAD (p = 0.0014) patients. In MOGAD and anti-AQP4-positive NMOSD, the serum disease-specific antibody titer was not associated with the subsequent visual prognosis. Visual acuity had almost fully recovered spontaneously or shortly after initiating acute treatment in 22 of the 23 patients with MOGAD-ON. The administration of high-dose intravenous steroid therapy further facilitated early recovery of visual acuity. Meanwhile, a small fraction of patients with extensive optic nerve lesions involving the chiasma irreversibly experienced severe visual impairment despite appropriate acute treatment. CONCLUSION: Although a small fraction of patients with MOGAD who presented with extensive optic nerve lesions experienced irreversible severe visual impairment, the long-term visual outcomes after 5 years from ON in patients with MOGAD were generally as good as that in patients with MS and much better than that in patients with anti-AQP4-positive NMOSD.

  181. A rare case of sporadic inclusion body myositis and rheumatoid arthritis exhibiting ectopic lymphoid follicle-like structures: a case report and literature review. International-journal

    Kazutoshi Konomatsu, Rumiko Izumi, Naoki Suzuki, Yoshiki Takai, Yuko Shirota, Ryoko Saito, Hiroshi Kuroda, Masashi Aoki

    Neuromuscular disorders : NMD 31 (9) 870-876 2021/07/08

    DOI: 10.1016/j.nmd.2021.07.002  

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    Sporadic inclusion body myositis (sIBM) is a degenerative, intractable, inflammatory myopathy with an immune pathomechanism. We report on a case of a 44-year-old Japanese man who began developing progressive muscle weakness at age 40. Rheumatoid arthritis symptoms manifested at 43 with strongly positive anti-cyclic citrullinated peptide antibodies. Along with typical sIBM pathology, a muscle biopsy revealed dramatic inflammation with prominent perivascular B-cell infiltration forming ectopic lymphoid follicle-like structures (ELFLSs). Exome sequencing identified no causative variants of hereditary myopathy or immune disorders. A combination of immunotherapy slowed the progression of the muscular symptoms. This unusual form of sIBM, including earlier age at onset, a partial response to immunotherapy, and a histopathology presenting B-cell infiltrate with ectopic lymphoid follicle-like structures, indicates a possible association of rheumatoid arthritis and heterogeneity with the autoimmune involvement of sIBM. We review the clinical and pathological features of patients with rheumatoid arthritis associated sIBM in the literature.

  182. 妊娠初期に急性精神症状で発症した自己免疫性脳炎の一例

    保坂 龍彦, 安藤 大祐, 高橋 幹弘, 松本 勇貴, 小野 紘彦, 高井 良樹, 菅野 直人, 三須 建郎, 青木 正志

    臨床神経学 61 (7) 507-507 2021/07

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  183. 両側小脳病変を呈し、MELASが疑われた兄妹例

    船山 由希乃, 原田 龍平, 鈴木 直輝, 三須 建郎, 青木 正志

    臨床神経学 61 (7) 509-509 2021/07

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  184. 一側上肢に限局する筋力低下を呈した抗GalNAc-GD1a IgG抗体陽性運動ニューロパチーの2例

    大友 瑞貴, 池田 謙輔, 四條 友望, 高井 良樹, 菅野 直人, 割田 仁, 三須 建郎, 青木 正志

    臨床神経学 61 (7) 509-509 2021/07

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  185. 【多系統蛋白質症に関する最近の進歩】RNP顆粒生成・分解からみた多系統蛋白質症

    割田 仁, 池田 謙輔, 青木 正志

    脳神経内科 95 (1) 112-120 2021/07

    Publisher: (有)科学評論社

    ISSN: 2434-3285

  186. MRI陰性・FDG-PET陽性側頭葉てんかんの前部側頭葉切除術後の発作転帰を頭皮脳波所見で予測できるか?

    曽我 天馬, 神 一敬, 大沢 伸一郎, 岩崎 真樹, 青木 正志, 中里 信和

    てんかん研究 39 (2) 317-317 2021/07

    Publisher: (一社)日本てんかん学会

    ISSN: 0912-0890

    eISSN: 1347-5509

  187. Identification of hub molecules of FUS-ALS by Bayesian gene regulatory network analysis of iPSC model: iBRN. International-journal

    Masahiro Nogami, Mitsuru Ishikawa, Atsushi Doi, Osamu Sano, Takefumi Sone, Tetsuya Akiyama, Masashi Aoki, Atsushi Nakanishi, Kazuhiro Ogi, Masato Yano, Hideyuki Okano

    Neurobiology of disease 155 105364-105364 2021/07

    DOI: 10.1016/j.nbd.2021.105364  

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    Fused in sarcoma/translated in liposarcoma (FUS) is a causative gene of amyotrophic lateral sclerosis (ALS). Mutated FUS causes accumulation of DNA damage and cytosolic stress granule (SG) formation, thereby motor neuron (MN) death. However, key molecular aetiology remains unclear. Here, we applied a novel platform technology, iBRN, "Non- biased" Bayesian gene regulatory network analysis based on induced pluripotent stem cell (iPSC)-derived cell model, to elucidate the molecular aetiology using transcriptome of iPSC-derived MNs harboring FUSH517D. iBRN revealed "hub molecules", which strongly influenced transcriptome network, such as miR-125b-5p-TIMELESS axis and PRKDC for the molecular aetiology. Next, we confirmed miR-125b-5p-TIMELESS axis in FUSH517D MNs such that miR-125b-5p regulated several DNA repair-related genes including TIMELESS. In addition, we validated both introduction of miR-125b-5p and knocking down of TIMELESS caused DNA damage in the cell culture model. Furthermore, PRKDC was strongly associated with FUS mis-localization into SGs by DNA damage under impaired DNA-PK activity. Collectively, our iBRN strategy provides the first compelling evidence to elucidate molecular aetiology in neurodegenerative diseases.

  188. Randomized phase 2 study of perampanel for sporadic amyotrophic lateral sclerosis. International-journal

    Hitoshi Aizawa, Haruhisa Kato, Koji Oba, Takuya Kawahara, Yoshihiko Okubo, Tomoko Saito, Makiko Naito, Makoto Urushitani, Akira Tamaoka, Kiyotaka Nakamagoe, Kazuhiro Ishii, Takashi Kanda, Masahisa Katsuno, Naoki Atsuta, Yasushi Maeda, Makiko Nagai, Kazutoshi Nishiyama, Hiroyuki Ishiura, Tatsushi Toda, Akihiro Kawata, Koji Abe, Ichiro Yabe, Ikuko Takahashi-Iwata, Hidenao Sasaki, Hitoshi Warita, Masashi Aoki, Gen Sobue, Hidehiro Mizusawa, Yutaka Matsuyama, Tomohiro Haga, Shin Kwak

    Journal of neurology 269 (2) 885-896 2021/06/30

    DOI: 10.1007/s00415-021-10670-y  

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    OBJECTIVE: To evaluate the efficacy and safety of perampanel in patients with sporadic amyotrophic lateral sclerosis (SALS). METHODS: This randomized, double-blind, placebo-controlled, multicenter, phase 2 clinical study was conducted at 12 sites. Patients with probable or definite ALS as defined by revised El Escorial criteria were enrolled. Sixty-six patients were randomly assigned (1:1:1) to receive placebo, 4 mg perampanel, or 8 mg perampanel daily for 48 weeks. Adverse events (AEs) were recorded throughout the trial period. The primary efficacy outcome was the change in Amyotrophic Lateral Sclerosis Rating Scale-Revised (ALSFRS-R) score after 48 weeks of treatment. RESULTS: One patient withdrew before starting the treatment. Of 65 patients included, 18 of 22 patients randomized to placebo (82%), 14 of 22 patients randomized to 4 mg perampanel (64%), and 7 of 21 patients randomized to 8 mg perampanel (33%) completed the trial. There was a significant difference in the change of ALSFRS-R scores [- 8.4 (95% CI - 13.9 to - 2.9); p = 0.015] between the placebo and the perampanel 8 mg group, primarily due to worsening of the bulbar subscore in the perampanel 8 mg group. Serious AEs were more frequent in the perampanel 8 mg group than in the placebo group (p = 0.0483). CONCLUSIONS: Perampanel was associated with a significant decline in ALSFRS-R score and was linked to worsening of the bulbar subscore in the 8 mg group.

  189. A web-based questionnaire survey on the influence of coronavirus disease-19 on the care of patients with muscular dystrophy. International-journal Peer-reviewed

    Tsuyoshi Matsumura, Hiroto Takada, Michio Kobayashi, Takashi Nakajima, Katsuhisa Ogata, Akinori Nakamura, Michinori Funato, Satoshi Kuru, Kiyonobu Komai, Naonobu Futamura, Yoshiki Adachi, Hajime Arahata, Takayasu Fukudome, Masatoshi Ishizaki, Shugo Suwazono, Masashi Aoki, Tohru Matsuura, Masanori P Takahashi, Yoshihide Sunada, Kouzou Hanayama, Hiroya Hashimoto, Harumasa Nakamura

    Neuromuscular disorders : NMD 31 (9) 839-846 2021/05/07

    DOI: 10.1016/j.nmd.2021.04.008  

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    To clarify the influence of coronavirus disease-19 (COVID-19) on the care of muscular dystrophy patients, we performed a questionnaire survey that was posted on the internet on May 11, 2020. By the end of July 2020, 542 responses had been collected. Approximately 30% of patients postponed regular consultations, and one-quarter of patients who received consultation more than once a month used telephone consultations. Two of 84 patients with Duchenne muscular dystrophy had reduced their steroid doses. A shortage of ventilator accessories and infection protection equipment occurred following the onset of COVID-19, and this shortage had a serious impact on medical care and infection prevention measures. Reductions in rehabilitation and other services, and avoidance of outings, led to a decrease in exercise and an increase in caregiver burden. Inpatients were restricted from going out and visiting family members. More than 20% of patients reported physical or mental complaints; however, few required treatment. COVID-19 has seriously affected the activities and quality of life of patients with muscular dystrophy. We will continue this survey and analyze the longitudinal changes.

  190. Optic neuritis after ocular trauma in anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder. International-journal Peer-reviewed

    Tetsuya Akaishi, Noriko Himori, Takayuki Takeshita, Kazuo Fujihara, Tatsuro Misu, Toshiyuki Takahashi, Juichi Fujimori, Tadashi Ishii, Masashi Aoki, Toru Nakazawa, Ichiro Nakashima

    Brain and behavior 11 (5) e02083 2021/05

    DOI: 10.1002/brb3.2083  

    eISSN: 2162-3279

  191. High prevalence of serum anti-NH2-terminal of α-enolase antibodies in patients with multiple system atrophy and corticobasal syndrome. International-journal

    Akio Kikuchi, Makoto Yoneda, Takafumi Hasegawa, Akiko Matsunaga, Masamichi Ikawa, Takaaki Nakamura, Michinori Ezura, Toru Baba, Naoto Sugeno, Shun Ishiyama, Yasunari Nakamoto, Atsushi Takeda, Masashi Aoki

    Journal of neurology 268 (11) 4291-4295 2021/04/15

    DOI: 10.1007/s00415-021-10553-2  

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    BACKGROUND: Hashimoto's encephalopathy with serum anti-NH2-terminal of α-enolase (NAE) antibodies occasionally displays clinical symptoms such as cerebellar ataxia and parkinsonism. We studied the frequency of anti-NAE antibodies in patients with Parkinson-plus syndrome. METHODS: We examined the positive rates of anti-NAE antibodies in 47 patients with multiple system atrophy (MSA), 29 patients with Parkinson's disease (PD), eight patients with corticobasal syndrome (CBS), and 18 patients with progressive supranuclear palsy (PSP) using conventional immunoblot analysis. RESULTS: Positive anti-NAE antibody rates of 31.9%, 10.3%, 50.0%, and 11.1% were reported in the MSA, PD, CBS, and PSP patients, respectively. The duration from onset to a wheelchair-bound state in seropositive MSA patients tended to be shorter than that in seronegative MSA patients. CONCLUSIONS: Anti-NAE antibodies are detected in some patients clinically diagnosed with MSA and CBS. Although its pathophysiological significance remains uncertain, serum anti-NAE antibodies might represent a prognostic marker in the clinical course of MSA.

  192. Efficacy and Safety of Bimagrumab in Sporadic Inclusion Body Myositis: Long-term Extension of RESILIENT. International-journal

    Anthony A Amato, Michael G Hanna, Pedro M Machado, Umesh A Badrising, Hector Chinoy, Olivier Benveniste, Ananda Krishna Karanam, Min Wu, László B Tankó, Agnes Annette Schubert-Tennigkeit, Dimitris A Papanicolaou, Thomas E Lloyd, Merrilee Needham, Christina Liang, Katrina A Reardon, Marianne de Visser, Dana P Ascherman, Richard J Barohn, Mazen M Dimachkie, James A L Miller, John T Kissel, Björn Oskarsson, Nanette C Joyce, Peter Van den Bergh, Jonathan Baets, Jan L De Bleecker, Chafic Karam, William S David, Massimiliano Mirabella, Sharon P Nations, Hans H Jung, Elena Pegoraro, Lorenzo Maggi, Carmelo Rodolico, Massimiliano Filosto, Aziz I Shaibani, Kumaraswamy Sivakumar, Namita A Goyal, Madoka Mori-Yoshimura, Satoshi Yamashita, Naoki Suzuki, Masashi Aoki, Masahisa Katsuno, Hirokazu Morihata, Kenya Murata, Hiroyuki Nodera, Ichizo Nishino, Carla D Romano, Valerie S L Williams, John Vissing, Lixin Zhang Auberson

    Neurology 96 (12) e1595-e1607 2021/03/23

    DOI: 10.1212/WNL.0000000000011626  

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    OBJECTIVE: To assess long-term (2 years) effects of bimagrumab in participants with sporadic inclusion body myositis (sIBM). METHODS: Participants (aged 36-85 years) who completed the core study (RESILIENT [Efficacy and Safety of Bimagrumab/BYM338 at 52 Weeks on Physical Function, Muscle Strength, Mobility in sIBM Patients]) were invited to join an extension study. Individuals continued on the same treatment as in the core study (10 mg/kg, 3 mg/kg, 1 mg/kg bimagrumab or matching placebo administered as IV infusions every 4 weeks). The co-primary outcome measures were 6-minute walk distance (6MWD) and safety. RESULTS: Between November 2015 and February 2017, 211 participants entered double-blind placebo-controlled period of the extension study. Mean change in 6MWD from baseline was highly variable across treatment groups, but indicated progressive deterioration from weeks 24-104 in all treatment groups. Overall, 91.0% (n = 142) of participants in the pooled bimagrumab group and 89.1% (n = 49) in the placebo group had ≥1 treatment-emergent adverse event (AE). Falls were slightly higher in the bimagrumab 3 mg/kg group vs 10 mg/kg, 1 mg/kg, and placebo groups (69.2% [n = 36 of 52] vs 56.6% [n = 30 of 53], 58.8% [n = 30 of 51], and 61.8% [n = 34 of 55], respectively). The most frequently reported AEs in the pooled bimagrumab group were diarrhea 14.7% (n = 23), involuntary muscle contractions 9.6% (n = 15), and rash 5.1% (n = 8). Incidence of serious AEs was comparable between the pooled bimagrumab and the placebo group (18.6% [n = 29] vs 14.5% [n = 8], respectively). CONCLUSION: Extended treatment with bimagrumab up to 2 years produced a good safety profile and was well-tolerated, but did not provide clinical benefits in terms of improvement in mobility. The extension study was terminated early due to core study not meeting its primary endpoint. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02573467. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with sIBM, long-term treatment with bimagrumab was safe, well-tolerated, and did not provide meaningful functional benefit. The study is rated Class IV because of the open-label design of extension treatment period 2.

  193. Progression pattern of neurological disability with respect to clinical attacks in anti-MOG antibody-associated disorders. International-journal

    Tetsuya Akaishi, Tatsuro Misu, Toshiyuki Takahashi, Yoshiki Takai, Shuhei Nishiyama, Juichi Fujimori, Tadashi Ishii, Masashi Aoki, Kazuo Fujihara, Ichiro Nakashima

    Journal of neuroimmunology 351 577467-577467 2021/02/15

    DOI: 10.1016/j.jneuroim.2020.577467  

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    The progression pattern of neurological disability among patients with anti-myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGAD) was evaluated. Neurological disability was evaluated annually for 408 person-years in 50 patients. More than 30% of the patients had clinical relapses in the first 5 years. Disability progression independent of relapse activity (PIRA) was not seen, whereas a stepwise disability progression was observed after clinical attacks in some instances. Disability worsening was more frequent after relapses than after the onset episode (p < 0.01). Similar to patients with anti-aquaporin-4 antibodies, attack-related stepwise disability progression without PIRA is typical in MOGAD, suggesting the importance of relapse prevention.

  194. タウオパチーの鑑別診断における18F-THK5351 PETの有用性の検討

    江面 道典, 菊池 昭夫, 岡村 信行, 吉田 隼, 小林 潤平, 菅野 直人, 長谷川 隆文, 石木 愛子, 原田 龍一, 荒井 啓行, 谷内 一彦, 古本 祥三, 田代 学, 工藤 幸司, 武田 篤, 青木 正志

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集 14回 78-78 2021/02

    Publisher: Movement Disorder Society of Japan (MDSJ)

  195. ニューロンでの取り込みとα-synuclein fibril伝播のための受容体の同定(Identification of receptor for neuronal uptake and propagation of alpha-synuclein fibril)

    石山 駿, 長谷川 隆文, 小林 潤平, 菅野 直人, 吉田 準, 中村 貴彬, 菊池 昭夫, 江面 道典, 武田 篤, 青木 正志

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集 14回 76-76 2021/02

    Publisher: Movement Disorder Society of Japan (MDSJ)

  196. タウオパチーの鑑別診断における18F-THK5351 PETの有用性の検討

    江面 道典, 菊池 昭夫, 岡村 信行, 吉田 隼, 小林 潤平, 菅野 直人, 長谷川 隆文, 石木 愛子, 原田 龍一, 荒井 啓行, 谷内 一彦, 古本 祥三, 田代 学, 工藤 幸司, 武田 篤, 青木 正志

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集 14回 78-78 2021/02

    Publisher: Movement Disorder Society of Japan (MDSJ)

  197. α-シヌクレインによるヒストン修飾を介した転写応答に関する分析(Analysis of the transcription responses through histone modifications triggered by alpha-synuclein)

    中村 貴彬, 菅野 直人, 長谷川 隆文, 石山 駿, 吉田 隼, 小林 潤平, 江面 道典, 菊池 昭夫, 武田 篤, 青木 正志

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集 14回 109-109 2021/02

    Publisher: Movement Disorder Society of Japan (MDSJ)

  198. Possible Somatic Mosaicism of Novel FUS Variant in Familial Amyotrophic Lateral Sclerosis. International-journal

    Shin Hisahara, Ayumi Nishiyama, Emiko Tsuda, Syuuichirou Suzuki, Akihiro Matsumura, Aki Ishikawa, Akihiro Sakurai, Ikuko N Motoike, Masashi Aoki, Yoko Aoki, Shun Shimohama

    Neurology. Genetics 7 (1) e552 2021/02

    DOI: 10.1212/NXG.0000000000000552  

  199. Impact of comorbid Sjögren syndrome in anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorders. International-journal

    Tetsuya Akaishi, Toshiyuki Takahashi, Kazuo Fujihara, Tatsuro Misu, Juichi Fujimori, Yoshiki Takai, Shuhei Nishiyama, Michiaki Abe, Tadashi Ishii, Masashi Aoki, Ichiro Nakashima

    Journal of neurology 268 (5) 1938-1944 2021/01/08

    DOI: 10.1007/s00415-020-10377-6  

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    BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) are autoimmune neurological diseases of the central nervous system, which are characterized by the presence of serum anti-aquaporin-4 autoantibodies (AQP4-IgG). An association between Sjögren syndrome (SjS) and AQP4-IgG-positive NMOSD has been proposed, but the rate of coexistence has not been determined. METHODS: In this study, 4,447 patients suspected of having NMOSD with acute neurological episodes were evaluated for the positivity of serum AQP4-IgG, serum SS-A/Ro antibody, and the presence of SjS-related symptoms (dry eye, dry mouth). RESULTS: Of the 4,447 patients, 1,651 were positive for serum AQP4-IgG, and the remaining 2,796 were negative. A significantly higher proportion of AQP4-IgG-positive patients were positive for serum anti-SSA/Ro antibody (26.3 vs. 4.5%; p < 0.0001) and anti-SSB/La antibody (7.2 vs. 1.2%; p < 0.0001) and had dry eye (9.1 vs .4.9%; p < 0.0001) and dry mouth symptoms (8.9 vs. 3.7%; p < 0.0001). More than 80% of the patients with SjS with acute neurological events such as myelitis or optic neuritis were AQP4-IgG positive. AQ4-IgG-positive patients with comorbid SjS showed a higher female rate (97.1 vs. 89.0%; p = 0.0062), a higher positivity rate for oligoclonal bands (15.4 vs. 7.5%; p = 0.029), and a higher relapse frequency (p = 0.027) than AQP4-IgG-positive patients without comorbid SjS. CONCLUSIONS: The prevalence of SjS is higher among AQP4-IgG-positive than AQP4-IgG-negative patients, with the potential prevalence of 10-20% at the diagnosis of AQP4-IgG-positive NMOSD. Comorbid SjS is more prevalent in females, and it has a higher relapse frequency among AQP4-IgG-positive patients.

  200. 神経変性疾患の動物モデルの実験的治療

    青木 正志, 望月 秀樹

    神経治療学 38 (4) 574-574 2021

    Publisher: 日本神経治療学会

    DOI: 10.15082/jsnt.38.4_574  

    ISSN: 0916-8443

    eISSN: 2189-7824

  201. Case Report: Isolated, unilateral oculomotor palsy with anti-GQ1b antibody following COVID-19 vaccination. International-journal

    Takafumi Kubota, Takafumi Hasegawa, Kensuke Ikeda, Masashi Aoki

    F1000Research 10 1142-1142 2021

    DOI: 10.12688/f1000research.74299.2  

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    Neurological complications following vaccinations are extremely rare, but cannot be eliminated. Here, we report the first case of unilateral oculomotor nerve palsy (ONP) with anti-GQ1b antibody after receiving the Pfizer-BioNTech COVID-19 (BNT162b2) mRNA vaccine. A 65-year-old man developed diplopia and ptosis in the right eye 17 days after vaccination, without preceding infection. Neurological examination revealed mild blepharoptosis, limitation of adduction, and vertical gaze on the right side. Increased levels of anti-GQ1b ganglioside antibody in the serum and albuminocytologic dissociation in the cerebrospinal fluid were detected. Cranial magnetic resonance imaging showed swelling and enhancement of the right oculomotor nerve. The patient was diagnosed with right ONP accompanied with anti-GQ1b antibody, and intravenous immunoglobulin (IVIG) therapy for 5 days was administered. The limitation of adduction and vertical gaze improved, and ptosis markedly resolved after IVIG treatment. Given the temporal sequence of disease progression, laboratory findings, and a favorable response to IVIG, a causal relationship cannot be ruled out between the occurrence of ONP and COVID-19 immunization. Since immunomodulatory treatments significantly hasten the recovery and minimize the residual symptoms in anti-GQ1b antibody syndrome, clinicians should be aware of this clinical condition following COVID-19 vaccination.

  202. 18F-THK5351 Positron Emission Tomography Imaging in Neurodegenerative Tauopathies. International-journal

    Michinori Ezura, Akio Kikuchi, Nobuyuki Okamura, Aiko Ishiki, Takafumi Hasegawa, Ryuichi Harada, Shoichi Watanuki, Yoshihito Funaki, Kotaro Hiraoka, Toru Baba, Naoto Sugeno, Shun Yoshida, Junpei Kobayashi, Michiko Kobayashi, Ohito Tano, Shun Ishiyama, Takaaki Nakamura, Ichiro Nakashima, Shunji Mugikura, Ren Iwata, Yasuyuki Taki, Katsutoshi Furukawa, Hiroyuki Arai, Shozo Furumoto, Manabu Tashiro, Kazuhiko Yanai, Yukitsuka Kudo, Atsushi Takeda, Masashi Aoki

    Frontiers in aging neuroscience 13 761010-761010 2021

    DOI: 10.3389/fnagi.2021.761010  

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    Introduction: We aimed to determine whether in vivo tau deposits and monoamine oxidase B (MAO-B) detection using 18F-THK5351 positron emission tomography (PET) can assist in the differential distribution in patients with corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and Alzheimer's disease (AD) and whether 18F-THK5351 retention of lesion sites in CBS and PSP can correlate with clinical parameters. Methods: 18F-THK5351 PET was performed in 35 participants, including 7, 9, and 10 patients with CBS, PSP, and AD, respectively, and 9 age-matched normal controls. In CBS and PSP, cognitive and motor functions were assessed using the Montreal Cognitive Assessment, Addenbrooke's Cognitive Examination-Revised, and Frontal Assessment Battery, Unified Parkinson's Disease Rating Scale Motor Score, and PSP Rating Scale. Results: 18F-THK5351 retention was observed in sites susceptible to disease-related pathologies in CBS, PSP, and AD. 18F-THK5351 uptake in the precentral gyrus clearly differentiated patients with CBS from those with PSP and AD. Furthermore, 18F-THK5351 uptake in the inferior temporal gyrus clearly differentiated patients with AD from those with CBS and PSP. Regional 18F-THK5351 retention was associated with the cognitive function in CBS and PSP. Conclusion: Measurement of the tau deposits and MAO-B density in the brain using 18F-THK5351 may be helpful for the differential diagnosis of tauopathies and for understanding disease stages.

  203. 異なる臨床病型を呈し母にFUS遺伝子変異のmosaicismが示唆された家族性ALSの親子例

    久原 真, 津田 笑子, 鈴木 秀一郎, 松村 晃寛, 石川 亜貴, 櫻井 晃洋, 西山 亜由美, 元池 育子, 青木 正志, 青木 洋子, 下濱 俊

    臨床神経学 61 (1) 55-55 2021/01

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  204. 日本人一般集団に高頻度で見出されるジスフェルリン遺伝子のc.3725G>A(p.R1242H)バリアントの臨床像の検討

    高橋 俊明, 井泉 瑠美子, 鈴木 直輝, 八木沼 智香子, 島倉 奈緒子, 大矢 寧, 佐橋 功, 小野 洋也, 戸恒 智子, 大城 咲, 谷口 さやか, 下瀬川 康子, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 割田 仁, 新堀 哲也, 武田 篤, 青木 洋子, 青木 正志

    筋ジストロフィー医療研究 7 65-65 2021/01

    Publisher: 筋ジストロフィー医療研究会

    ISSN: 2433-1708

  205. 日本人一般集団に高頻度で見出されるジスフェルリン遺伝子のc.3725G>A(p.R1242H)バリアントの臨床像の検討

    高橋 俊明, 井泉 瑠美子, 鈴木 直輝, 八木沼 智香子, 島倉 奈緒子, 大矢 寧, 佐橋 功, 小野 洋也, 戸恒 智子, 大城 咲, 谷口 さやか, 下瀬川 康子, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 割田 仁, 新堀 哲也, 武田 篤, 青木 洋子, 青木 正志

    筋ジストロフィー医療研究 7 65-65 2021/01

    Publisher: 筋ジストロフィー医療研究会

    ISSN: 2433-1708

  206. Case Report: Guitarist's cramp as the initial manifestation of dopa-responsive dystonia with a novel heterozygous GCH1 mutation. International-journal

    Takafumi Hasegawa, Tatsuhiko Hosaka, Ryuhei Harada, Ichiro Kawahata, Kyoko Hoshino, Naoto Sugeno, Akio Kikuchi, Masashi Aoki

    F1000Research 10 361-361 2021

    DOI: 10.12688/f1000research.51433.1  

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    Dopa-responsive dystonia (DRD), also known as Segawa syndrome, is a phenotypically and genetically heterogeneous group of neurological disorders that typically presents as early-onset lower limb dystonia with diurnal fluctuation, and exhibits a marked, persistent response to levodopa. Heterozygous loss-of-function mutations in the guanosine triphosphate cyclohydrolase 1 (GCH1) are the most common cause of DRD. In addition to the classic form of the disease, there have been a number of studies addressing atypical clinical features of GCH1 related DRD with variable age of onset. This report describes a 37-year-old Japanese male patient with a 10-year history of focal upper limb dystonia that initially emerged as task-specific, guitarist's cramp. The dystonic symptoms responded very well to levodopa treatment, and genetic analysis identified a novel heterozygous mutation in the C-terminal catalytic domain of GCH1. Insufficient recognition of this treatable condition often leads to misdiagnosis, which causes delays in the patient receiving adequate dopamine replenishing therapy. A diagnostic trial with levodopa should be considered in all patients with relatively young-onset dystonia, whether they have classic features of DRD or not.

  207. Early Treatment Initiation With Oral Prednisolone for Relapse Prevention Alleviates Depression and Fatigue in Aquaporin-4-Positive Neuromyelitis optica Spectrum Disorder. International-journal

    Tetsuya Akaishi, Toshiyuki Takahashi, Kazuo Fujihara, Tatsuro Misu, Juichi Fujimori, Yoshiki Takai, Shuhei Nishiyama, Michiaki Abe, Tadashi Ishii, Masashi Aoki, Ichiro Nakashima

    Frontiers in neurology 12 608149-608149 2021

    DOI: 10.3389/fneur.2021.608149  

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    Background:Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing autoimmune-related neurological disorder of the central nervous system. Most patients with NMOSD have serum anti-aquaporin-4 immunoglobulin G antibodies (AQP4-IgG). In addition to optic neuritis and myelitis, other insidious symptoms such as depressive state and chronic fatigue in NMOSD are gradually being recognized. Methods: To elucidate the impact of low- to medium-dose oral prednisolone (PSL) as a relapse prevention therapy for psychiatric disturbances and chronic fatigue in NMOSD, we evaluated clinical data from 39 patients with AQP4-IgG-positive NMOSD, along with the details of present and cumulative oral PSL dosage. Results: Thirty-six of the 39 patients were treated with low- to medium-dose oral PSL, and the mean and standard deviation of the present daily dose of oral PSL were 7.9 ± 4.0 mg/day. None of the patients were treated with a daily PSL dose of >15 mg. As a result, the disease duration and the untreated period before starting oral PSL showed weak to moderate correlations with the subsequent severities of psychiatric disturbance and fatigue level. Meanwhile, none of the other treatment-related variables evaluated, such as the present oral PSL daily dose, cumulative PSL dose, months of oral PSL administration, previous courses of steroid pulse therapy, and coadministered immunosuppressants, were correlated with these insidious symptoms. Conclusion: Our results suggest that the use of long-term low- to medium-dose oral PSL ≤15 mg daily for relapse prevention in AQP4-IgG-positive NMOSD would not aggravate the psychiatric and fatigue conditions. On the contrary, early initiation of oral PSL for relapse prevention, together with significantly decreased relapse rate, alleviated the subsequent depressive state and fatigue from the disease.

  208. Genetic and functional analysis of KIF5A variants in Japanese patients with sporadic amyotrophic lateral sclerosis. International-journal

    Ryoichi Nakamura, Genki Tohnai, Naoki Atsuta, Masahiro Nakatochi, Naoki Hayashi, Hazuki Watanabe, Daichi Yokoi, Hirohisa Watanabe, Masahisa Katsuno, Yuishin Izumi, Akira Taniguchi, Kazuaki Kanai, Mitsuya Morita, Osamu Kano, Satoshi Kuwabara, Masaya Oda, Koji Abe, Masashi Aoki, Ikuko Aiba, Koichi Okamoto, Kouichi Mizoguchi, Nobutaka Hattori, Kenji Nakashima, Ryuji Kaji, Gen Sobue

    Neurobiology of aging 97 147.e11-147.e17 2021/01

    DOI: 10.1016/j.neurobiolaging.2020.07.010  

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    Two recent genetic studies reported that loss-of-function mutation of the C-terminal cargo-binding tail domain of the KIF5A gene cause amyotrophic lateral sclerosis (ALS). The aim of this study is to investigate the frequency of KIF5A variants in Japanese patients with sporadic ALS. In total, 807 sporadic ALS patients and 191 normal controls from a multicenter ALS cohort in Japan were included. Whole exome sequencing on an Illumina HiSeq 2000/2500 sequencer was used to identify and select variants within the KIF5A gene. Thirteen patients harbored a nonsynonymous variant in the KIF5A gene; These were considered variants of uncertain significance. One patient harbored a novel splice-site variant (c.2993-3C>A) in the C-terminal cargo-binding tail domain of the KIF5A gene. Functional analysis of this variant revealed that it caused skipping of exon 27. The frequency of KIF5A mutations in Japanese patients with sporadic ALS was 0.12% (1/807). This study reports a novel loss-of-function variant in KIF5A, and indicates that loss-of-function variant in KIF5A is a rare cause of sporadic ALS in Japanese patients.

  209. Distinctive lesions of brain MRI between MOG-antibody-associated and AQP4-antibody-associated diseases. International-journal

    Yuki Matsumoto, Tatsuro Misu, Shunji Mugikura, Yoshiki Takai, Shuhei Nishiyama, Hiroshi Kuroda, Toshiyuki Takahashi, Juichi Fujimori, Ichiro Nakashima, Kazuo Fujihara, Masashi Aoki

    Journal of neurology, neurosurgery, and psychiatry 2020/12/30

    DOI: 10.1136/jnnp-2020-324818  

  210. Seasonal variation of onset in patients with anti-aquaporin-4 antibodies and anti-myelin oligodendrocyte glycoprotein antibody. International-journal

    Tetsuya Akaishi, Juichi Fujimori, Toshiyuki Takahashi, Tatsuro Misu, Yoshiki Takai, Shuhei Nishiyama, Kimihiko Kaneko, Ryo Ogawa, Michiaki Abe, Tadashi Ishii, Masashi Aoki, Kazuo Fujihara, Ichiro Nakashima

    Journal of neuroimmunology 349 577431-577431 2020/12/15

    DOI: 10.1016/j.jneuroim.2020.577431  

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    This study aimed to determine the seasonal impact on the clinical onset of inflammatory neurological diseases of the central nervous system by analyzing the onset month with information on clinical manifestations in Japanese patients. As a result, patients with anti-aquaporin-4 antibodies (AQP4-IgG)-positive neuromyelitis optica spectrum disorders (NMOSD) showed spring-summer predominance of the clinical onset. Conversely, patients with anti-myelin oligodendrocyte glycoprotein antibody (MOG-IgG)-associated disease showed autumn-winter predominance of the clinical onset. Both seasonal variations were irrespective of the clinical manifestation. Environmental factors with seasonal variation influence the development of neurological conditions related to AQP4-IgG and MOG-IgG.

  211. 封入体筋炎に対するHAL治療の有効性について

    鈴木 直輝, 曽我 天馬, 井泉 瑠美子, 豊嶋 昌弥, 芝崎 美和子, 佐藤 いつみ, 工藤 悠, 青木 正志, 加藤 昌昭

    日本筋学会学術集会プログラム・抄録集 6回 124-124 2020/12

    Publisher: 日本筋学会

    ISSN: 2433-975X

  212. 日本におけるSOD1遺伝子変異陽性筋萎縮性側索硬化症患者の臨床的特徴

    中村 亮一, 熱田 直樹, 藤内 玄規, 林 直毅, 勝野 雅央, 和泉 唯信, 金井 数明, 服部 信孝, 谷口 彰, 森田 光哉, 狩野 修, 澁谷 和幹, 桑原 聡, 鈴木 直輝, 青木 正志, 阿部 康二, 石原 智彦, 小野寺 理, 梶 龍兒, 祖父江 元

    臨床神経学 60 (Suppl.) S381-S381 2020/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  213. 臨床的に多発性硬化症と診断される抗MOG抗体陽性患者の検討

    生田目 知尋, 三須 建郎, 高橋 利幸, 小川 諒, 金子 仁彦, 高井 良樹, 西山 修平, 中島 一郎, 藤原 一男, 青木 正志

    臨床神経学 60 (Suppl.) S436-S436 2020/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  214. 多施設共同前向きコホートでみたALS患者の非侵襲的人工換気療法に関する予後の検討

    林 直毅, 熱田 直樹, 横井 大知, 中村 亮一, 勝野 雅央, 和泉 唯信, 金井 数明, 服部 信孝, 谷口 彰, 森田 光哉, 狩野 修, 澁谷 和幹, 桑原 聡, 鈴木 直輝, 青木 正志, 織田 雅也, 饗場 郁子, 梶 龍兒, 祖父江 元

    臨床神経学 60 (Suppl.) S381-S381 2020/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  215. 中国四国地域発で世界的に展開した学術業績 三好型遠位型筋ジストロフィー 原因遺伝子の発見後

    青木 正志, 井泉 瑠美子, 高橋 俊明

    臨床神経学 60 (Suppl.) S28-S28 2020/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  216. 知っておきたい!進化する難治性筋疾患の新展開 封入体筋炎の診断と新たな治療に向けて

    青木 正志, 鈴木 直輝, 井泉 瑠美子, 割田 仁, 森 まどか, 山下 賢, 橋口 昭大, 梶 龍兒, 村田 顕也, 杉江 和馬, 西野 一三

    臨床神経学 60 (Suppl.) S90-S90 2020/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  217. まるごと2時間封入体筋炎〜up to dateとpitfall〜 高齢化社会で重要性を増す封入体筋炎:疫学データを中心に

    青木 正志, 井泉 瑠美子, 鈴木 直輝

    臨床神経学 60 (Suppl.) S128-S128 2020/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  218. 入院終末期対応を行ったALSの現状と問題点について

    加藤 昌昭, 鈴木 直輝, 井泉 瑠美子, 曽我 天馬, 川内 裕子, 青木 正志

    臨床神経学 60 (Suppl.) S325-S325 2020/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  219. 日本人一般集団に高頻度で見出されるdysferlin遺伝子のc.3725G>A(p.R1242H)の検討

    高橋 俊明, 井泉 瑠美子, 鈴木 直輝, 八木沼 智香子, 島倉 奈緒子, 大矢 寧, 佐橋 功, 小野 洋也, 大城 咲, 谷口 さやか, 下瀬川 康子, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 割田 仁, 新堀 哲也, 武田 篤, 青木 洋子, 青木 正志

    臨床神経学 60 (Suppl.) S387-S387 2020/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  220. ジスフェルリン異常症209家系の臨床遺伝学的特徴

    井泉 瑠美子, 高橋 俊明, 鈴木 直輝, 新堀 哲也, 小野 洋也, 中村 尚子, 堅田 慎一, 加藤 昌昭, 割田 仁, 竪山 真規, 青木 洋子, 青木 正志

    臨床神経学 60 (Suppl.) S387-S387 2020/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  221. PNPLA2遺伝子関連中性脂肪蓄積病の臨床像

    寒川 真, 中村 尚子, 平野 牧人, 森川 みゆき, 坂田 花美, 西野 一三, 井泉 瑠美子, 鈴木 直輝, 黒田 宙, 滋賀 健介, 青木 正志, 楠 進

    臨床神経学 60 (Suppl.) S388-S388 2020/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  222. 封入体筋炎に対するHAL治療の有効性について

    鈴木 直輝, 芝崎 美和子, 佐藤 いつみ, 工藤 悠, 曽我 天馬, 井泉 瑠美子, 青木 正志, 加藤 昌昭

    臨床神経学 60 (Suppl.) S395-S395 2020/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  223. 在宅侵襲的人工呼吸器装着筋萎縮性側索硬化症患者の施設間情報共有の試み

    松本 有史, 石橋 渚子, 関本 聖子, 遠藤 久美子, 鈴木 直輝, 加藤 昌昭, 青木 正志, 永野 功

    臨床神経学 60 (Suppl.) S408-S408 2020/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  224. 当院におけるALS患者に対する誤嚥防止術5例の長期経過

    曽我 天馬, 井泉 瑠美子, 鈴木 直輝, 川内 裕子, 加藤 健吾, 香取 幸夫, 青木 正志, 加藤 昌昭

    臨床神経学 60 (Suppl.) S450-S450 2020/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  225. 著明な鉄欠乏性貧血を誘因とした中枢神経内多発血管症(Susac症候群)の一例

    保坂 龍彦, 原田 龍平, 高井 良樹, 菅野 直人, 割田 仁, 青木 正志

    臨床神経学 60 (11) 799-799 2020/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  226. 脳脊髄液糖減少をともなう無菌性髄膜炎で再発した抗MOG抗体関連疾患の一例

    大友 瑞貴, 安藤 大祐, 千葉 菜々絵, 高井 良樹, 三須 建郎, 菅野 直人, 割田 仁, 青木 正志

    臨床神経学 60 (11) 800-800 2020/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  227. 当院におけるALS患者に対する誤嚥防止術5例の長期経過

    曽我 天馬, 井泉 瑠美子, 鈴木 直輝, 川内 裕子, 加藤 健吾, 香取 幸夫, 青木 正志, 加藤 昌昭

    臨床神経学 60 (Suppl.) S450-S450 2020/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  228. 臨床的に多発性硬化症と診断される抗MOG抗体陽性患者の検討

    生田目 知尋, 三須 建郎, 高橋 利幸, 小川 諒, 金子 仁彦, 高井 良樹, 西山 修平, 中島 一郎, 藤原 一男, 青木 正志

    臨床神経学 60 (Suppl.) S436-S436 2020/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  229. 著明な鉄欠乏性貧血を誘因とした中枢神経内多発血管症(Susac症候群)の一例

    保坂 龍彦, 原田 龍平, 高井 良樹, 菅野 直人, 割田 仁, 青木 正志

    臨床神経学 60 (11) 799-799 2020/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  230. 脳脊髄液糖減少をともなう無菌性髄膜炎で再発した抗MOG抗体関連疾患の一例

    大友 瑞貴, 安藤 大祐, 千葉 菜々絵, 高井 良樹, 三須 建郎, 菅野 直人, 割田 仁, 青木 正志

    臨床神経学 60 (11) 800-800 2020/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  231. 知っておきたい!進化する難治性筋疾患の新展開 封入体筋炎の診断と新たな治療に向けて

    青木 正志, 鈴木 直輝, 井泉 瑠美子, 割田 仁, 森 まどか, 山下 賢, 橋口 昭大, 梶 龍兒, 村田 顕也, 杉江 和馬, 西野 一三

    臨床神経学 60 (Suppl.) S90-S90 2020/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  232. 日本人一般集団に高頻度で見出されるdysferlin遺伝子のc.3725G>A(p.R1242H)の検討

    高橋 俊明, 井泉 瑠美子, 鈴木 直輝, 八木沼 智香子, 島倉 奈緒子, 大矢 寧, 佐橋 功, 小野 洋也, 大城 咲, 谷口 さやか, 下瀬川 康子, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 割田 仁, 新堀 哲也, 武田 篤, 青木 洋子, 青木 正志

    臨床神経学 60 (Suppl.) S387-S387 2020/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  233. ジスフェルリン異常症209家系の臨床遺伝学的特徴

    井泉 瑠美子, 高橋 俊明, 鈴木 直輝, 新堀 哲也, 小野 洋也, 中村 尚子, 堅田 慎一, 加藤 昌昭, 割田 仁, 竪山 真規, 青木 洋子, 青木 正志

    臨床神経学 60 (Suppl.) S387-S387 2020/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  234. Hybrid Assistive Limb® for sporadic inclusion body myositis: A case series. International-journal

    Naoki Suzuki, Temma Soga, Rumiko Izumi, Masaya Toyoshima, Miwako Shibasaki, Itsumi Sato, Yu Kudo, Masashi Aoki, Masaaki Kato

    Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 81 92-94 2020/11

    DOI: 10.1016/j.jocn.2020.09.031  

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    We evaluated the efficacy of rehabilitation therapy with Hybrid Assistive Limb® (HAL; hereafter HAL therapy) in three patients diagnosed with sporadic inclusion body myositis (sIBM) who were hospitalized to undergo HAL therapy. Among them, one patient participated in eight courses and the other two in two courses of HAL therapy between 2017 and 2020. We determined the mean rate of improvement in two-minute walking distance and 6 m walking speed at the time of hospital discharge. After HAL therapy, we confirmed the patients' desire to continue the use of HAL. In one patient, we observed improvements of 146.0% and 120.0% in two-minute walk and 6 m walking speed, respectively, after the first course of HAL therapy; these values are 133.7% and 130% after the eighth course of HAL therapy. These values exceeded 90% in the other two patients after the second course of HAL therapy. HAL therapy maintained both quantity and quality of ambulation and showed positive psychological effects on patient conditions because it reduces exercise load and facilitates safety. While HAL therapy might be effective in maintaining and improving ambulation in patients with sIBM, we should consider to discontinue HAL therapy as it increased risk of falling.

  235. Unilateral loss of oculocephalic response in a patient with hemispheric cerebral hemorrhage International-journal

    Tetsuya Akaishi, Toshiki Endo, Makoto Hasebe, Tadashi Ishii, Masashi Aoki

    Clinical Neurology and Neurosurgery 198 106234-106234 2020/11

    DOI: 10.1016/j.clineuro.2020.106234  

    ISSN: 0303-8467

    eISSN: 1872-6968

  236. 中枢病変を伴わない末梢神経障害における抗MOG抗体 連続37例での検討

    金子 仁彦, 佐藤 ダグラス, 高橋 利幸, 高井 良樹, 西山 修平, 三須 建郎, 中島 一郎, 藤原 一男, 青木 正志

    神経免疫学 25 (1) 151-151 2020/10

    Publisher: (一社)日本神経免疫学会

    ISSN: 0918-936X

  237. 臨床的に多発性硬化症と診断される抗MOG抗体陽性患者の検討

    生田目 知尋, 三須 建郎, 高橋 利幸, 小川 諒, 金子 仁彦, 高井 良樹, 西山 修平, 中島 一郎, 藤原 一男, 青木 正志

    神経免疫学 25 (1) 152-152 2020/10

    Publisher: (一社)日本神経免疫学会

    ISSN: 0918-936X

  238. 骨格筋疾患の動物モデルの実験的治療 Dysferlinopathyに対する治療法の開発

    小野 洋也, 鈴木 直輝, 菅野 新一郎, 川原 玄理, 割田 仁, 林 由起子, 三宅 克也, 青木 正志

    神経治療学 37 (6) S101-S101 2020/10

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  239. 骨格筋疾患の動物モデルの実験的治療 Dysferlinopathyに対する治療法の開発

    小野 洋也, 鈴木 直輝, 菅野 新一郎, 川原 玄理, 割田 仁, 林 由起子, 三宅 克也, 青木 正志

    神経治療学 37 (6) S101-S101 2020/10

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  240. 抗MOG抗体及び抗AQP4抗体陽性疾患の頭部MRI画像における病変分布の比較検討

    松本 勇貴, 三須 建郎, 麦倉 俊司, 高井 良樹, 西山 修平, 黒田 宙, 高橋 利幸, 藤盛 寿一, 中島 一郎, 藤原 一男, 青木 正志

    神経免疫学 25 (1) 104-104 2020/10

    Publisher: 日本神経免疫学会

    ISSN: 0918-936X

  241. Impact of intrathecal IgG synthesis on neurological disability in patients with multiple sclerosis. International-journal Peer-reviewed

    Tetsuya Akaishi, Toshiyuki Takahashi, Kazuo Fujihara, Tatsuro Misu, Shuhei Nishiyama, Yoshiki Takai, Juichi Fujimori, Michiaki Abe, Tadashi Ishii, Masashi Aoki, Ichiro Nakashima

    Multiple sclerosis and related disorders 45 102382-102382 2020/10

    DOI: 10.1016/j.msard.2020.102382  

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    BACKGROUND: The association between routine laboratory findings, including cerebrospinal fluid biomarkers, and neurological outcomes in patients with multiple sclerosis (MS) has not been fully elucidated. In this study, we evaluated blood and cerebrospinal fluid (CSF) analysis results at diagnosis and before treatment in patients with MS and assessed their correlations with neurological outcomes. MATERIALS AND METHODS: In this study, 38 consecutive patients with MS (36 with relapsing-remitting MS and 2 with primary progressive MS) were recruited. Before treatment, all patients underwent routine CSF analysis at the time of diagnosis, including evaluation of albumin and immunoglobulin G (IgG) levels. The association between laboratory data and neurological outcomes was comprehensively evaluated. Subsequent neurological outcome was assessed by using the Expanded Disability Status Scale (EDSS) score at 1 year and 5 years after diagnosis and relapse frequency in the first year and in the first 5 years. RESULTS: The IgG level in the CSF (rho = 0.46, p = 0.004), oligoclonal band count (rho = 0.61, p = 0.006), ratio of IgG and total protein in CSF (rho = 0.59, p < 0.0001), and ratio of IgG and albumin in CSF (rho = 0.67, p < 0.0001) showed moderate to strong correlations with the subsequent EDSS score 1 year after diagnosis. These variables still showed significant correlations with EDSS 5 years later. Albumin and lactate dehydrogenase levels in CSF did not correlate with the subsequent EDSS score. Relapse frequency did not correlate with any of the studied serum and CSF biomarkers. CONCLUSION: IgG levels in CSF at MS diagnosis are significantly correlated with the level of neurological disability independent of the relapse frequency. Markers of intrathecal IgG synthesis, such as the IgG index, are useful in estimating the present and subsequent clinical severity in patients with MS.

  242. A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis. International-journal

    Ryoichi Nakamura, Kazuharu Misawa, Genki Tohnai, Masahiro Nakatochi, Sho Furuhashi, Naoki Atsuta, Naoki Hayashi, Daichi Yokoi, Hazuki Watanabe, Hirohisa Watanabe, Masahisa Katsuno, Yuishin Izumi, Kazuaki Kanai, Nobutaka Hattori, Mitsuya Morita, Akira Taniguchi, Osamu Kano, Masaya Oda, Kazumoto Shibuya, Satoshi Kuwabara, Naoki Suzuki, Masashi Aoki, Yasuyuki Ohta, Toru Yamashita, Koji Abe, Rina Hashimoto, Ikuko Aiba, Koichi Okamoto, Kouichi Mizoguchi, Kazuko Hasegawa, Yohei Okada, Tomohiko Ishihara, Osamu Onodera, Kenji Nakashima, Ryuji Kaji, Yoichiro Kamatani, Shiro Ikegawa, Yukihide Momozawa, Michiaki Kubo, Noriko Ishida, Naoko Minegishi, Masao Nagasaki, Gen Sobue

    Communications biology 3 (1) 526-526 2020/09/23

    DOI: 10.1038/s42003-020-01251-2  

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    Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10-8). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10-4). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10-11). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS.

  243. 【神経疾患治療の進歩2019】運動ニューロン疾患の治療の進歩

    秋山 徹也, 割田 仁, 鈴木 直輝, 青木 正志

    神経治療学 37 (5) 736-740 2020/09

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  244. 【神経疾患治療の進歩2019】運動ニューロン疾患の治療の進歩

    秋山 徹也, 割田 仁, 鈴木 直輝, 青木 正志

    神経治療学 37 (5) 736-740 2020/09

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  245. A case of inflammatory myopathy with anti-PM/Scl antibodies myopathologically presenting as polymyositis with mitochondrial pathology

    Arifumi Matsumoto, Rumiko Izumi, Naoto Sugeno, Naoki Suzuki, Chihiro Namatame, Temma Soga, Ayumi Nishiyama, Hiroshi Kuroda, Masashi Aoki, Isao Nagano

    NEUROLOGY AND CLINICAL NEUROSCIENCE 8 (5) 335-339 2020/09

    DOI: 10.1111/ncn3.12429  

    ISSN: 2049-4173

  246. Clinical characterization of patients with leucine-rich repeat kinase 2 genetic variants in Japan. International-journal Peer-reviewed

    Yuanzhe Li, Aya Ikeda, Hiroyo Yoshino, Genko Oyama, Mitsuhiro Kitani, Kensuke Daida, Arisa Hayashida, Kotaro Ogaki, Kousuke Yoshida, Takashi Kimura, Yoshiaki Nakayama, Hidefumi Ito, Naoto Sugeno, Masashi Aoki, Hiroaki Miyajima, Katsuo Kimura, Naohisa Ueda, Masao Watanabe, Takao Urabe, Masashi Takanashi, Manabu Funayama, Kenya Nishioka, Nobutaka Hattori

    Journal of human genetics 65 (9) 771-781 2020/09

    DOI: 10.1038/s10038-020-0772-4  

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    Variants of leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of familial Parkinson's disease (PD). We aimed to investigate the genetic and clinical features of patients with PD and LRRK2 variants in Japan by screening for LRRK2 variants in three exons (31, 41, and 48), which include the following pathogenic mutations: p.R1441C, p.R1441G, p.R1441H, p.G2019S, and p.I2020T. Herein, we obtained data containing LRRK2 variants derived from 1402 patients with PD (653 with sporadic PD and 749 with familial PD). As a result, we successfully detected pathogenic variants (four with p.R1441G, five with p.R1441H, seven with p.G2019S, and seven with p.I2020T) and other rare variants (two with p.V1447M, one with p.V1450I, one with p.T1491delT, and one with p.H2391Q). Two risk variants, p.P1446L and p.G2385R, were found in 10 and 146 patients, respectively. Most of the patients presented the symptoms resembling a common type of PD, such as middle-aged onset, tremor, akinesia, rigidity, and gait disturbance. Dysautonomia, cognitive decline, and psychosis were rarely observed. Each known pathogenic variant had a different founder in our cohort proven by haplotype analysis. The generation study revealed that the LRRK2 variants p.G2019S and p.I2020T were derived 3500 and 1300 years ago, respectively. Our findings present overviews of the prevalence and distribution of LRRK2 variants in Japanese cohorts.

  247. Progressive patterns of neurological disability in multiple sclerosis and neuromyelitis optica spectrum disorders. International-journal Peer-reviewed

    Tetsuya Akaishi, Toshiyuki Takahashi, Tatsuro Misu, Michiaki Abe, Tadashi Ishii, Juichi Fujimori, Masashi Aoki, Kazuo Fujihara, Ichiro Nakashima

    Scientific reports 10 (1) 13890-13890 2020/08/17

    DOI: 10.1038/s41598-020-70919-w  

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    The progressive patterns of neurological disability in multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) and the significance of clinical relapses to the progressions of neurological disability in these diseases have not been fully elucidated. In this study, to elucidate the impact of relapses to the progression of accumulated neurological disability and to identify the factors to affect the progression of neurological disability in MS and NMOSD, we followed 62 consecutive MS patients and 33 consecutive NMOSD patients for more than 5 years with the clinical symptoms, relapse occurrence, and Expanded Disability Status Scale (EDSS) in the chronic phase. All enrolled MS patients were confirmed to be negative for serum anti-myelin oligodendrocyte glycoprotein antibody. As a result, patients with NMOSD showed significantly severer neurological disability at 5 years from onset than MS patients. Progression in EDSS score was almost exclusively seen after clinical attacks in NMOSD, whereas progression could be observed apart from relapses in MS. Neurological disability did not change without attacks in NMOSD, whereas it sometimes spontaneously improved or deteriorated apart from relapses in MS (p < 0.001). In patients with MS, those with responsible lesions primarily in spinal cord were more likely to show such spontaneous improvement. In conclusion, clinical deterioration in NMOSD patients is irreversible and almost exclusively takes place at the timing of clinical attacks with stepwise accumulation of neurological disability. Meanwhile, changes in EDSS score can be seen apart from relapses in MS patients. Neurological disability in MS patients is partly reversible, and the patients with disease modifying drugs sometimes present spontaneous improvement of the neurological disability.

  248. Aberrant interaction between FUS and SFPQ in neurons in a wide range of FTLD spectrum diseases. International-journal Peer-reviewed

    Shinsuke Ishigaki, Yuichi Riku, Yusuke Fujioka, Kuniyuki Endo, Nobuyuki Iwade, Kaori Kawai, Minaka Ishibashi, Satoshi Yokoi, Masahisa Katsuno, Hirohisa Watanabe, Keiko Mori, Akio Akagi, Osamu Yokota, Seishi Terada, Ito Kawakami, Naoki Suzuki, Hitoshi Warita, Masashi Aoki, Mari Yoshida, Gen Sobue

    Brain : a journal of neurology 143 (8) 2398-2405 2020/08/01

    DOI: 10.1093/brain/awaa196  

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    Fused in sarcoma (FUS) is genetically and clinicopathologically linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). We have previously reported that intranuclear interactions of FUS and splicing factor, proline- and glutamine-rich (SFPQ) contribute to neuronal homeostasis. Disruption of the FUS-SFPQ interaction leads to an increase in the ratio of 4-repeat tau (4R-tau)/3-repeat tau (3R-tau), which manifests in FTLD-like phenotypes in mice. Here, we examined FUS-SFPQ interactions in 142 autopsied individuals with FUS-related ALS/FTLD (ALS/FTLD-FUS), TDP-43-related ALS/FTLD (ALS/FTLD-TDP), progressive supranuclear palsy, corticobasal degeneration, Alzheimer's disease, or Pick's disease as well as controls. Immunofluorescent imaging showed impaired intranuclear co-localization of FUS and SFPQ in neurons of ALS/FTLD-FUS, ALS/FTLD-TDP, progressive supranuclear palsy and corticobasal degeneration cases, but not in Alzheimer's disease or Pick's disease cases. Immunoprecipitation analyses of FUS and SFPQ revealed reduced interactions between the two proteins in ALS/FTLD-TDP and progressive supranuclear palsy cases, but not in those with Alzheimer disease. Furthermore, the ratio of 4R/3R-tau was elevated in cases with ALS/FTLD-TDP and progressive supranuclear palsy, but was largely unaffected in cases with Alzheimer disease. We concluded that impaired interactions between intranuclear FUS and SFPQ and the subsequent increase in the ratio of 4R/3R-tau constitute a common pathogenesis pathway in FTLD spectrum diseases.

  249. Facial onset amyotrophic lateral sclerosis with K3E variant in the Cu/Zn superoxide dismutase gene. International-journal Peer-reviewed

    Kazumoto Shibuya, Setsu Sawai, Atsuhiko Sugiyama, Mizuho Koide, Ayumi Nishiyama, Masashi Aoki, Satoshi Kuwabara

    Amyotrophic lateral sclerosis & frontotemporal degeneration 22 (1-2) 1-3 2020/07/30

    DOI: 10.1080/21678421.2020.1797092  

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    We describe a 48-year-old man, suffering from difficulties in closing his eyes. He subsequently experienced progressive weakness in the facial and bulbar regions and upper limbs. His father and paternal grandmother had limb weakness as initial manifestations and were diagnosed with amyotrophic lateral sclerosis (ALS). In the present case, neuroimaging and laboratory studies were unremarkable, and neurophysiological studies disclosed diffuse denervation. Genetic testing identified a heterozygous c.10A>G, p.K4E (K3E) variant in superoxide dismutase 1 (SOD1) gene, and he was diagnosed with familial ALS. In ALS, facial muscles are rarely involved as an initial symptom. The present patient is a first case of facial onset ALS with K3E variant in SOD1 gene. Two case reports identified facial palsy as an initial manifestation in familial ALS with C6G variant in SOD1 gene. Several ALS patients with variants in SOD1 gene may have facial onset history.

  250. Generation of an ALS human iPSC line KEIOi001-A from peripheral blood of a Charcot disease-affected patient carrying TARDBP p.N345K heterozygous SNP mutation. International-journal Peer-reviewed

    Nicolas Leventoux, Satoru Morimoto, Kenju Hara, Shiho Nakamura, Fumiko Ozawa, Shio Mitsuzawa, Tetsuya Akiyama, Ayumi Nishiyama, Naoki Suzuki, Hitoshi Warita, Masashi Aoki, Hideyuki Okano

    Stem cell research 47 101896-101896 2020/06/28

    DOI: 10.1016/j.scr.2020.101896  

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    Amyotrophic Lateral Sclerosis is the most common motor neuron degenerative disease in adults, and TARDBP gene mutations have been reported to be involved in the pathogenesis. We present here how we generated the human induced pluripotent stem cell (hiPSC) line KEIOi001-A/SM4-4-5 from the peripheral blood of a 63-year-old male patient presenting the c.1035C > G heterozygous SNP mutation in the TARDBP gene locus. The established hiPSC line does not express the exogenous reprogramming factors oriP nor EBNA1 and shows no karyotypic abnormalities, while it expresses pluripotent stem cell markers, presents the SNP mutation and is capable of three-germ layers differentiation in vitro.

  251. Risk factors of attacks in neuromyelitis optica spectrum disorders. International-journal Peer-reviewed

    Tetsuya Akaishi, Toshiyuki Takahashi, Kazuo Fujihara, Tatsuro Misu, Michiaki Abe, Tadashi Ishii, Masashi Aoki, Ichiro Nakashima

    Journal of neuroimmunology 343 577236-577236 2020/06/15

    DOI: 10.1016/j.jneuroim.2020.577236  

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    Predisposing factors before the onset of neuromyelitis optica spectrum disorders (NMOSD) have not been systematically evaluated by now. We investigated the detailed pre-onset history in consecutive NMOSD patients. Thirteen of the enrolled 53 NMOSD patients (24.5%) had accompanying autoimmune diseases, such as Sjögren's syndrome. History of malignancy was seen in 8 of the 53 patients (15.1%). Recent history of non-neurological clinical episodes, such as systemic allergic reaction, systemic infection, surgical operation, or traumatic injury, was seen in 23 of the 53 patients (43.4%). NMOSD patients are likely to have pre-onset history of other autoimmune diseases, malignancy, or recent non-neurological systemic conditions, which may predispose or trigger the onset of NMOSD.

  252. Logopenic aphasia due to Lewy body disease dramatically improved with donepezil. International-journal Peer-reviewed

    Kazuo Kakinuma, Toru Baba, Michinori Ezura, Keiko Endo, Yumiko Saito, Wataru Narita, Osamu Iizuka, Yoshiyuki Nishio, Akio Kikuchi, Takafumi Hasegawa, Masashi Aoki, Kyoko Suzuki

    eNeurologicalSci 19 100241-100241 2020/06

    DOI: 10.1016/j.ensci.2020.100241  

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    •Pathological basis of primary progressive aphasia is heterogeneous.•Logopenic primary progressive aphasia can precede dementia with Lewy bodies (DLB).•Cholinesterase inhibitor can improve logopenic aphasia with DLB.

  253. 神経難病におけるトランスレーショナル・リサーチ 筋萎縮性側索硬化症(ALS)に対する肝細胞増殖因子(HGF)治療

    青木 正志, 割田 仁, 加藤 昌昭, 長野 清一, 望月 秀樹

    神経治療学 37 (3) 401-405 2020/05

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  254. 神経難病におけるトランスレーショナル・リサーチ 筋萎縮性側索硬化症(ALS)に対する肝細胞増殖因子(HGF)治療

    青木 正志, 割田 仁, 加藤 昌昭, 長野 清一, 望月 秀樹

    神経治療学 37 (3) 401-405 2020/05

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  255. Clinical and Cerebral Metabolic Changes in Parkinson's Disease With Basal Forebrain Atrophy. International-journal Peer-reviewed

    Miyeong Gang, Toru Baba, Yoshiyuki Hosokai, Yoshiyuki Nishio, Akio Kikuchi, Kazumi Hirayama, Takafumi Hasegawa, Masashi Aoki, Atsushi Takeda, Etsuro Mori, Kyoko Suzuki

    Movement disorders : official journal of the Movement Disorder Society 35 (5) 825-832 2020/05

    DOI: 10.1002/mds.27988  

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    BACKGROUND: Cholinergic dysfunction plays a key role in cognitive dysfunction in Parkinson's disease (PD). Recent studies revealed that atrophy in the nucleus basalis of Meynert (NBM), the largest cholinergic nucleus in the basal forebrain, heralds cognitive decline in PD. Despite clinical importance of NBM atrophy in PD, clinical and radiological correlates of NBM atrophy remains to be elucidated. OBJECTIVE: We investigated the longitudinal changes in clinical and cerebral glucose metabolic characteristics in PD with atrophy in the NBM. METHODS: We analyzed the 3-year longitudinal data of 56 PD patients who underwent motor, nonmotor, and imaging evaluations at baseline. The patients were classified into PD with and without NBM atrophy based on the results of magnetic resonance imaging volumetry. We compared clinical characteristics and cerebral glucose metabolic changes between PD with and without NBM atrophy. RESULTS: At baseline, 20 patients and 36 patients were classified into PD with and without NBM atrophy groups, respectively. At follow-up, the data of the 14 PD patients in the NBM atrophy group and the 18 patients in the group without NBM atrophy completed full assessments and were available for the analysis. The PD with NBM atrophy group showed severe cognitive dysfunction and psychiatric symptoms both at baseline and follow-up. The NBM volume significantly correlated with motor and nonmotor functions. The PD with NBM atrophy showed significantly reduced metabolism in the parietal and occipital cortices both at baseline and follow-up. CONCLUSIONS: Basal forebrain atrophy is a simple and sensible marker of faster disease progression and cortical hypometabolism in PD. © 2020 International Parkinson and Movement Disorder Society.

  256. Osmotic pressure of serum and cerebrospinal fluid in patients with suspected neurological conditions. International-journal Peer-reviewed

    Tetsuya Akaishi, Toshiyuki Takahashi, Ichiro Nakashima, Michiaki Abe, Masashi Aoki, Tadashi Ishii

    Neural regeneration research 15 (5) 944-947 2020/05

    DOI: 10.4103/1673-5374.268906  

    ISSN: 1673-5374

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    Interstitial fluid movement in the brain parenchyma has been suggested to contribute to sustaining the metabolism in brain parenchyma and maintaining the function of neurons and glial cells. The pulsatile hydrostatic pressure gradient may be one of the driving forces of this bulk flow. However, osmotic pressure-related factors have not been studied until now. In this prospective observational study, to elucidate the relationship between osmolality (mOsm/kg) in the serum and that in the cerebrospinal fluid (CSF), we simultaneously measured the serum and CSF osmolality of 179 subjects with suspected neurological conditions. Serum osmolality was 283.6 ± 6.5 mOsm/kg and CSF osmolality was 289.5 ± 6.6 mOsm/kg. Because the specific gravity of serum and CSF is known to be 1.024-1.028 and 1.004-1.007, respectively, the estimated average of osmolarity (mOsm/L) in the serum and CSF covered exactly the same range (i.e., 290.5-291.5 mOsm/L). There was strong correlation between CSF osmolality and serum osmolality, but the difference in osmolality between serum and CSF was not correlated with serum osmolality, serum electrolyte levels, protein levels, or quotient of albumin. In conclusion, CSF osmolarity was suggested to be equal to serum osmolarity. Osmolarity is not one of the driving forces of this bulk flow. Other factors such as hydrostatic pressure gradient should be used to explain the mechanism of bulk flow in the brain parenchyma. This study was approved by the Institutional Review Board of the Tohoku University Hospital (approval No. IRB No. 2015-1-257) on July 29, 2015.

  257. Repeated follow-up of AQP4-IgG titer by cell-based assay in neuromyelitis optica spectrum disorders (NMOSD). International-journal Peer-reviewed

    Tetsuya Akaishi, Toshiyuki Takahashi, Ichiro Nakashima, Michiaki Abe, Tadashi Ishii, Masashi Aoki, Kazuo Fujihara

    Journal of the neurological sciences 410 116671-116671 2020/03/15

    DOI: 10.1016/j.jns.2020.116671  

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    INTRODUCTION: Neuromyelitis optica spectrum disorder (NMOSD) is characterized by the presence of serum anti-aquaporin 4 (AQP4) antibody. However, the significance of changes in the serum titer as a marker of disease severity or relapse prediction is unknown. METHODS: We collected clinical data and serum antibody titers by cell-based assay from 45 NMOSD patients for whom more than one titer measurement taken in 6-12 month interval periods was available. The AQP4-IgG titer was measured by a live cell-based assay method, and the serum titer levels between the acute phase and preceding chronic phase were compared. In addition, we evaluated the correlation between the serum titer and relapse frequency while following the clinical course of the enrolled NMOSD patients. RESULTS: Serum AQP4-IgG titer was not elevated in the acute phase, compared to that of the preceding chronic phase, irrespective of the clinical phenotypes. Moreover, there was no correlation between the titer at onset and relapse frequency in 10 years post-onset or neurological disability at 5 and 10 years after onset. The titer was slightly elevated several months before relapses in about half of the cases, but the change was trivial and may not be applicable for clinical use. CONCLUSION: Although evaluating the positivity of serum AQP4-IgG at the onset is necessary, the titer level does not reflect the ongoing disease activity or the following neurological prognosis. Repeated follow-up of titer levels may not be useful for the management of NMOSD patients.

  258. Serum AQP4-IgG level is associated with the phenotype of the first attack in neuromyelitis optica spectrum disorders. International-journal Peer-reviewed

    Tetsuya Akaishi, Toshiyuki Takahashi, Noriko Himori, Kazuo Fujihara, Tatsuro Misu, Michiaki Abe, Tadashi Ishii, Toru Nakazawa, Masashi Aoki, Ichiro Nakashima

    Journal of neuroimmunology 340 577168-577168 2020/03/15

    DOI: 10.1016/j.jneuroim.2020.577168  

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    We aimed in this study to elucidate the impact of serum AQP4-IgG titer before starting treatments to the clinical manifestation of neuromyelitis optica spectrum disorders (NMOSD). Serum titer at the onset, measured using live cell-based assay method, did not correlate to the subsequent relapse rate or neurological prognosis. Patients with optic neuritis as the first attack showed significantly higher serum titer than patients with acute myelitis or area postrema syndrome, although the titer did not correlate to the visual prognosis. The result implies that the pathological mechanism of optic neuritis and acute myelitis could be different in NMOSD.

  259. Perivenous demyelination: Association with anti-myelin oligodendrocyte glycoprotein antibody

    Tatsuro Misu, Yoshiki Takai, Toshiyuki Takahashi, Ichiro Nakashima, Kazuo Fujihara, Masashi Aoki

    Clinical and Experimental Neuroimmunology 11 (S1) 22-27 2020/03/01

    DOI: 10.1111/cen3.12569  

    eISSN: 1759-1961

  260. Prognosis of amyotrophic lateral sclerosis patients undergoing tracheostomy invasive ventilation therapy in Japan. International-journal Peer-reviewed

    Naoki Hayashi, Naoki Atsuta, Daichi Yokoi, Ryoichi Nakamura, Masahiro Nakatochi, Masahisa Katsuno, Yuishin Izumi, Kazuaki Kanai, Nobutaka Hattori, Akira Taniguchi, Mitsuya Morita, Osamu Kano, Kazumoto Shibuya, Satoshi Kuwabara, Naoki Suzuki, Masashi Aoki, Ikuko Aiba, Kouichi Mizoguchi, Masaya Oda, Ryuji Kaji, Gen Sobue

    Journal of neurology, neurosurgery, and psychiatry 91 (3) 285-290 2020/03

    DOI: 10.1136/jnnp-2019-322213  

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    OBJECTIVE: The aim of this study is to describe and clarify the factors affecting the prognosis of Japanese patients with amyotrophic lateral sclerosis (ALS) undergoing tracheostomy invasive ventilation (TIV) therapy. METHODS: We conducted a prospective longitudinal observational case-control study using a multicentre registry. ALS patients who started TIV therapy after registration (TIV group) and those who did not receive TIV (non-TIV group) were included. We compared the survival time between the TIV group and the non-TIV group using a propensity score matching analysis and evaluated the prognostic factors in the TIV group. RESULTS: From February 2006 to January 2018, 190 patients in the TIV group and 1093 patients in the non-TIV group were included in this study. The mean age of disease onset and usage rate of gastrostomy and non-invasive ventilation therapy differed between the groups. In the propensity score matching analysis using known prognostic factors, the median overall survival time of the TIV group was significantly greater than that of the non-TIV group (11.33 years vs 4.61 years; p<0.001). Analysis using the Cox proportional hazard model suggested that older age of onset and respiratory onset was an independent factor for poor prognosis after starting TIV therapy. CONCLUSION: We showed that there was a significant difference of approximately 7 years in life expectancy between Japanese ALS patients who did and did not receive TIV therapy.

  261. T-cell Lymphoma Presenting Neutrophilic Inflammation in the Cerebrospinal Fluid. Peer-reviewed

    Takaaki Nakamura, Yoshiki Takai, Kimihiko Kaneko, Hiroshi Kuroda, Tatsuro Misu, Kiyotaka Asanuma, Ryoko Saito, Masashi Aoki

    Internal medicine (Tokyo, Japan) 59 (4) 573-576 2020/02/15

    DOI: 10.2169/internalmedicine.3093-19  

    ISSN: 0918-2918

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    A 66-year-old woman presented with upper abdominal pain and weakness in the limbs. She had bilateral uveitis and gastric ulcers. A neurological examination revealed tetraparesis and sensory disturbance in the right arm. A cerebrospinal fluid (CSF) examination showed polymorphonuclear pleocytosis with elevated pro-inflammatory cytokine levels. Magnetic resonance imaging showed brain lesions and a long spinal cord lesion. She was initially diagnosed with neuro-Behçet's disease and was treated with corticosteroids, resulting in no improvement. A gastric mucosa biopsy indicated T-cell lymphoma colocalizing with neutrophils. The cytokine-mediated neutrophilic inflammation probably caused characteristic CSF and histopathological features. It is noteworthy that T-cell lymphoma may present with CSF neutrophilic inflammation.

  262. Radiological findings in siblings with dysferlin mutation with diverse phenotype. International-journal Peer-reviewed

    Ayako Shioya, Hiroshi Takuma, Toshiaki Takahashi, Akiko Ishii, Masashi Aoki, Akira Tamaoka

    Journal of the neurological sciences 409 116579-116579 2020/02/15

    DOI: 10.1016/j.jns.2019.116579  

    ISSN: 0022-510X

  263. Huntington病の診断、治療、療養の手引き

    中島 健二, 祖父江 元, 長谷川 一子, 饗場 郁子, 青木 正志, 阿部 康二, 池内 健, 小野寺 理, 梶 龍兒, 吉良 潤一, 桑原 聡, 小久保 康昌, 斎藤 加代子, 佐々木 秀直, 佐野 輝, 高橋 良輔, 辻 省次, 戸田 達史, 中川 正法, 野元 正弘, 服部 信孝, 村田 美穂, 村山 繁雄, 望月 秀樹, 森田 光哉, 横田 隆徳, 吉田 眞理, 渡辺 保裕, 保住 功, Huntington病の診断、治療、療養の手引きガイドライン作成委員会

    神経治療学 37 (1) 61-104 2020/01

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  264. Mitochondrial dysfunction underlying sporadic inclusion body myositis is ameliorated by the mitochondrial homing drug MA-5. International-journal

    Yoshitsugu Oikawa, Rumiko Izumi, Masashi Koide, Yoshihiro Hagiwara, Makoto Kanzaki, Naoki Suzuki, Koichi Kikuchi, Tetsuro Matsuhashi, Yukako Akiyama, Mariko Ichijo, Shun Watanabe, Takafumi Toyohara, Takehiro Suzuki, Eikan Mishima, Yasutoshi Akiyama, Yoshiaki Ogata, Chitose Suzuki, Hironori Hayashi, Eiichi N Kodama, Ken-Ichiro Hayashi, Eiji Itoi, Masashi Aoki, Shigeo Kure, Takaaki Abe

    PloS one 15 (12) e0231064 2020

    DOI: 10.1371/journal.pone.0231064  

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    Sporadic inclusion body myositis (sIBM) is the most common idiopathic inflammatory myopathy, and several reports have suggested that mitochondrial abnormalities are involved in its etiology. We recruited 9 sIBM patients and found significant histological changes and an elevation of growth differential factor 15 (GDF15), a marker of mitochondrial disease, strongly suggesting the involvement of mitochondrial dysfunction. Bioenergetic analysis of sIBM patient myoblasts revealed impaired mitochondrial function. Decreased ATP production, reduced mitochondrial size and reduced mitochondrial dynamics were also observed in sIBM myoblasts. Cell vulnerability to oxidative stress also suggested the existence of mitochondrial dysfunction. Mitochonic acid-5 (MA-5) increased the cellular ATP level, reduced mitochondrial ROS, and provided protection against sIBM myoblast death. MA-5 also improved the survival of sIBM skin fibroblasts as well as mitochondrial morphology and dynamics in these cells. The reduction in the gene expression levels of Opa1 and Drp1 was also reversed by MA-5, suggesting the modification of the fusion/fission process. These data suggest that MA-5 may provide an alternative therapeutic strategy for treating not only mitochondrial diseases but also sIBM.

  265. Inducible Rpt3, a Proteasome Component, Knockout in Adult Skeletal Muscle Results in Muscle Atrophy. International-journal

    Yasuo Kitajima, Naoki Suzuki, Kiyoshi Yoshioka, Rumiko Izumi, Maki Tateyama, Yoshitaka Tashiro, Ryosuke Takahashi, Masashi Aoki, Yusuke Ono

    Frontiers in cell and developmental biology 8 859-859 2020

    DOI: 10.3389/fcell.2020.00859  

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    The ubiquitin-proteasome system has the capacity to degrade polyubiquitinated proteins and plays an important role in many cellular processes. However, the role of Rpt3, a crucial proteasomal gene, has not been investigated in adult muscles in vivo. Herein, we generated skeletal-muscle-specific Rpt3 knockout mice, in which genetic inactivation of Rpt3 could be induced by doxycycline administration. The Rpt3-knockout mice showed a significant reduction by more than 90% in the expression of Rpt3 in adult muscles. Using this model, we found that proteasome dysfunction in adult muscles resulted in muscle wasting and a decrease in the myofiber size. Immunoblotting analysis showed that the amounts of ubiquitinated proteins were markedly higher in muscles of Rpt3-deficient mice than in those of the control mice. Analysis of the autophagy pathway in the Rpt3-deficient mice showed that the upregulation of LC3II, p62, Atg5, Atg7, and Beclin-1 in protein levels, which supposed to be compensatory proteolysis activation. Our results suggest that the proteasome inhibition in adult muscle severely deteriorates myofiber integrity and results in muscle atrophy.

  266. Rapid Administration of High-Dose Intravenous Methylprednisolone Improves Visual Outcomes After Optic Neuritis in Patients With AQP4-IgG-Positive NMOSD. International-journal

    Tetsuya Akaishi, Takayuki Takeshita, Noriko Himori, Toshiyuki Takahashi, Tatsuro Misu, Ryo Ogawa, Kimihiko Kaneko, Juichi Fujimori, Michiaki Abe, Tadashi Ishii, Kazuo Fujihara, Masashi Aoki, Toru Nakazawa, Ichiro Nakashima

    Frontiers in neurology 11 932-932 2020

    DOI: 10.3389/fneur.2020.00932  

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    Objective: The purpose of this study was to elucidate the rapid impact of high-dose intravenous methylprednisolone pulse therapy (1,000 mg/day for 3 days) on the eventual visual prognosis in patients with serum anti-aquaporin-4 immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica spectrum disorders (NMOSDs) who had an attack of optic neuritis (ON). Methods: Data from 32 consecutive NMOSD patients (1 male and 31 female) with at least one ON attack, involving a total of 36 ON-involved eyes, were evaluated. The following variables at ON onset were evaluated: sex, age at the first ON episode, visual acuity at nadir, visual acuity after 1 year, duration from ON onset to treatment for an acute ON attack, cycles of high-dose intravenous methylprednisolone pulse therapy for the ON attack, and cycles of plasmapheresis for the ON attack. Among the 36 ON-involved eyes, 27 eyes were studied using orbital MRI with a short-T1 inversion recovery sequence and gadolinium-enhanced fat-suppressed T1 imaging before starting treatment in the acute phase. Results: In univariate analyses, a shorter duration from ON onset to the initiation of high-dose intravenous methylprednisolone pulse therapy favorably affected the eventual visual prognosis 1 year later (Spearman's rho = 0.50, p = 0.0018). The lesion length on orbital MRI was also correlated with the eventual visual prognosis (rho = 0.68, p < 0.0001). Meanwhile, the days to steroid pulse therapy and lesion length on orbital MRI did not show a significant correlation. These findings suggest that the rapidness of steroid pulse therapy administration affects the eventual visual prognosis independent of the severity of ON. In multivariate analysis, a shorter time from ON onset to the start of acute treatment (p = 0.0004) and a younger age at onset (p = 0.0071) were significantly associated with better visual outcomes. Conclusions: Rapid initiation of high-dose intravenous methylprednisolone pulse therapy is essential to preserve the eventual visual acuity in patients with serum AQP4-IgG-positive NMOSD. Once clinicians suspect acute ON with serum AQP4-IgG, swift administration of steroid pulse therapy before confirming the positivity of serum AQP4-IgG would be beneficial for preserving visual function.

  267. Neutral Lipid Storage Disease Associated with the PNPLA2 Gene: Case Report and Literature Review. International-journal Peer-reviewed

    Makoto Samukawa, Naoko Nakamura, Makito Hirano, Miyuki Morikawa, Hanami Sakata, Ichizo Nishino, Rumiko Izumi, Naoki Suzuki, Hiroshi Kuroda, Kensuke Shiga, Kazumasa Saigoh, Masashi Aoki, Susumu Kusunoki

    European neurology 83 (3) 317-322 2020

    DOI: 10.1159/000508346  

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    Mutations in the PNPLA2 gene cause neutral lipid storage disease with myopathy (NLSDM) or triglyceride deposit cardiomyovasculopathy. We report a detailed case study of a 53-year-old man with NLSDM. The PNPLA2 gene was analyzed according to the reported method. We summarized the clinical, laboratory, and genetic information of 56 patients, including our patient and 55 other reported patients with homozygous or compound heterozygous mutations in the PNPLA2 gene. We found a novel homozygous mutation (c.194delC) in the PNPLA2 gene that resulted in frameshift. The patient suffered from normal-tension glaucoma and pulmonary cysts, symptoms that are relatively common in the elderly but were not previously reported for this disease. Our summary confirmed that Jordan's anomaly, polymorphonuclear leukocytes with lipid accumulation, was the most consistent finding of this disease. Because this disease is potentially treatable, our results may help rapid and correct diagnosis.

  268. Number of MRI T1-hypointensity corrected by T2/FLAIR lesion volume indicates clinical severity in patients with multiple sclerosis. International-journal Peer-reviewed

    Tetsuya Akaishi, Toshiyuki Takahashi, Kazuo Fujihara, Tatsuro Misu, Shunji Mugikura, Michiaki Abe, Tadashi Ishii, Masashi Aoki, Ichiro Nakashima

    PloS one 15 (4) e0231225 2020

    DOI: 10.1371/journal.pone.0231225  

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    INTRODUCTION: Progressive brain atrophy, development of T1-hypointense areas, and T2-fluid-attenuated inversion recovery (FLAIR)-hyperintense lesion formation in multiple sclerosis (MS) are popular volumetric data that are often utilized as clinical outcomes. However, the exact clinical interpretation of these volumetric data has not yet been fully established. METHODS: We enrolled 42 consecutive patients with MS who fulfilled the revised McDonald criteria of 2010. They were followed-up for more than 3 years from onset, and cross-sectional brain volumetry was performed. Patients with no brain lesions were excluded in advance from this study. For the brain volumetric data, we evaluated several parameters including age-adjusted gray-matter volume atrophy, age-adjusted white-matter volume atrophy, and T2-FLAIR lesion volume. The numbers of T1-hypointense and T2-FLAIR-hyperintense areas were also measured along the same timeline. The clinical data pertaining to disease duration, expanded disability status scale (EDSS), and MS severity score (MSSS) at the timing of volumetry were collected. RESULTS: Among the 42 patients with MS and brain lesions, the number of T1-hypointensity (rho = 0.51, p<0.001), gray-matter atrophy (rho = 0.40, p<0.01) and white-matter atrophy (rho = 0.49, p<0.001) correlated with the EDSS. T1-hypointensity count divided by FLAIR lesion volume correlated with the MSSS (rho = 0.60, p<0.001). Meanwhile, counts or volumes of FLAIR-hyperintense lesions were associated only with the times of past relapses, and did not correlate with present neurological disability level or ongoing disease activity. These findings were consistent regardless of the presence of spinal cord lesions. CONCLUSION: Numbers of T1-hypointensities and brain atrophy equally indicated the current neurological disability in MS. The number of T1-hypointensities divided by FLAIR lesion volume represented the clinical severity. The size or number of FLAIR lesions reflected earlier relapses but was not a good indicator of neurological disability or clinical severity.

  269. Omics Approach to Axonal Dysfunction of Motor Neurons in Amyotrophic Lateral Sclerosis (ALS). International-journal Peer-reviewed

    Naoki Suzuki, Tetsuya Akiyama, Hitoshi Warita, Masashi Aoki

    Frontiers in neuroscience 14 194-194 2020

    DOI: 10.3389/fnins.2020.00194  

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    Amyotrophic lateral sclerosis (ALS) is an intractable adult-onset neurodegenerative disease that leads to the loss of upper and lower motor neurons (MNs). The long axons of MNs become damaged during the early stages of ALS. Genetic and pathological analyses of ALS patients have revealed dysfunction in the MN axon homeostasis. However, the molecular pathomechanism for the degeneration of axons in ALS has not been fully elucidated. This review provides an overview of the proposed axonal pathomechanisms in ALS, including those involving the neuronal cytoskeleton, cargo transport within axons, axonal energy supply, clearance of junk protein, neuromuscular junctions (NMJs), and aberrant axonal branching. To improve understanding of the global changes in axons, the review summarizes omics analyses of the axonal compartments of neurons in vitro and in vivo, including a motor nerve organoid approach that utilizes microfluidic devices developed by this research group. The review also discusses the relevance of intra-axonal transcription factors frequently identified in these omics analyses. Local axonal translation and the relationship among these pathomechanisms should be pursued further. The development of novel strategies to analyze axon fractions provides a new approach to establishing a detailed understanding of resilience of long MN and MN pathology in ALS.

  270. Neuromyelitis optica spectrum disorders with unevenly clustered attack occurrence. International-journal Peer-reviewed

    Tetsuya Akaishi, Ichiro Nakashima, Toshiyuki Takahashi, Michiaki Abe, Tadashi Ishii, Masashi Aoki

    Neurology(R) neuroimmunology & neuroinflammation 7 (1) 2020/01

    DOI: 10.1212/NXI.0000000000000640  

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    OBJECTIVE: The aim of this study was to elucidate the characteristics of clinical attacks in neuromyelitis optica spectrum disorders (NMOSDs) with positive serum anti-aquaporin-4 antibody. Both the timing and sequential pattern of clinical types were analyzed. METHODS: A total of 69 patients with NMOSD were enrolled in this study, all of whom were treated at a single university hospital. All data regarding the clinical attacks (including types and date) together with other clinical information were collected. RESULTS: Analysis of clinical attacks from the enrolled patients showed that there were 2 distributional patterns of attack occurrence in each patient: (1) "clustered" occurrences, which occurred within 12 months from the previous attack, and (2) "nonclustered" intermittent occurrences, which occurred ≥12 months after the previous attack. These occurrences were regardless of the duration from the onset. During the "clustered" period, clinical attacks were more likely to show a similar clinical manifestation, such as optic neuritis or myelitis. After entering the "nonclustered" intermittent period, the relapses were of random clinical type, regardless of the previous clinical manifestation. CONCLUSIONS: Patients with NMOSD showed mixed periods of "clustered" occurrence with frequent attacks presenting with similar manifestations and "nonclustered" intermittent periods with sparse relapses. Approximately half of the relapses occurred during the "clustered" period within 12 months of the last clinical attack. Clinicians should pay special attention to whether the patients are presently in the "clustered" or "nonclustered" period to decide optimal relapse-preventive strategies.

  271. Preoperative risks of post-operative myasthenic crisis (POMC): A meta-analysis. International-journal Peer-reviewed

    Tetsuya Akaishi, Masakatsu Motomura, Hirokazu Shiraishi, Shunsuke Yoshimura, Michiaki Abe, Tadashi Ishii, Masashi Aoki

    Journal of the neurological sciences 407 116530-116530 2019/12/15

    DOI: 10.1016/j.jns.2019.116530  

    ISSN: 0022-510X

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    INTRODUCTION: Myasthenic crisis (MC) is a life-threatening condition in patients with myasthenia gravis (MG), for which thymectomy is known to be a predisposing factor. There are many preoperative factors that have been suggested to increase the occurrence of post-operative myasthenic crisis (POMC), but none have been unanimously concluded as definite risk factors. METHODS: We performed meta-analyses to assess preoperative risk factors for the occurrence of POMC in eligible case-control studies. RESULTS: A total of 10 articles were systematically reviewed and meta-analyses identified preoperative bulbar symptoms, a history of MC, and disease severity (p < .0001), as well as decreased vital capacity (p = .002), as risk factors for POMC. Among the identified risks, the presence of preoperative bulbar symptoms showed the least heterogeneity and was suggested to be the most reliable preoperative risks of POMC. CONCLUSION: Presence of preoperative bulbar symptoms is an easily discernable risk factor for the occurrence of POMC. A history of preoperative MC will further increase the risk of POMC. Patients with these risks require extra caution and should be closely monitored for POMC upon thymectomy.

  272. Ropinirole hydrochloride remedy for amyotrophic lateral sclerosis - Protocol for a randomized, double-blind, placebo-controlled, single-center, and open-label continuation phase I/IIa clinical trial (ROPALS trial). International-journal Peer-reviewed

    Satoru Morimoto, Shinichi Takahashi, Komei Fukushima, Hideyuki Saya, Norihiro Suzuki, Masashi Aoki, Hideyuki Okano, Jin Nakahara

    Regenerative therapy 11 143-166 2019/12

    DOI: 10.1016/j.reth.2019.07.002  

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    Introduction: Amyotrophic lateral sclerosis (ALS) is an intractable and incurable neurological disease. It is a progressive disease characterized by muscle atrophy and weakness caused by selective vulnerability of upper and lower motor neurons. In disease research, it has been common to use mouse models carrying mutations in responsible genes for familial ALS as pathological models of ALS. However, there is no model that has reproduced the actual conditions of human spinal cord pathology. Thus, we developed a method of producing human spinal motor neurons using human induced pluripotent stem cells (iPSCs) and an innovative experimental technique for drug screening. As a result, ropinirole hydrochloride was eventually discovered after considering such results as its preferable transitivity in the brain and tolerability, including possible adverse reactions. Therefore, we explore the safety, tolerability and efficacy of ropinirole hydrochloride as an ALS treatment in this clinical trial. Methods: The ROPALS trial is a single-center double-blind randomized parallel group-controlled trial of the safety, tolerability, and efficacy of the ropinirole hydrochloride extended-release tablet (Requip CR) at 2- to 16-mg doses in patients with ALS. Twenty patients will be recruited for the active drug group (fifteen patients) and placebo group (five patients). All patients will be able to receive the standard ALS treatment of riluzole if not changed the dosage during this trial. The primary outcome will be safety and tolerability at 24 weeks, defined from the date of randomization. Secondary outcome will be the efficacy, including any change in the ALS Functional Rating Scale-Revised (ALSFRS-R), change in the Combined Assessment of Function and Survival (CAFS), and the composite endpoint as a sum of Z-transformed scores on various clinical items. Notably, we will perform an explorative search for a drug effect evaluation using the patient-derived iPSCs to prove this trial concept. Eligible patients will have El Escorial Possible, clinically possible and laboratory-supported, clinically probable, or clinically definite amyotrophic lateral sclerosis with disease duration less than 60 months (inclusive), an ALSFRS-R score ≥2 points on all items and age from 20 to 80 years. Conclusion: Patient recruitment began in December 2018 and the last patient is expected to complete the trial protocol in November 2020. Trial registration: Current controlled trials UMIN000034954 and JMA-IIA00397. Protocol version: version 1.6 (Date; 5/Apr/2019).

  273. 同一遺伝子変異を有するdysferlinopathy同胞例の検討

    塩谷 彩子, 詫間 浩, 石井 亜紀子, 辻 浩史, 高橋 俊明, 青木 正志, 玉岡 晃

    臨床神経学 59 (Suppl.) S282-S282 2019/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  274. 侵襲的人工呼吸器装着ALS患者の定期的評価入院における身体機能評価表の作成および運用の試み

    石橋 渚子, 関本 聖子, 遠藤 久美子, 山内 悦子, 川内 裕子, 松本 有史, 鈴木 直輝, 加藤 昌昭, 割田 仁, 青木 正志

    日本難病医療ネットワーク学会機関誌 7 (1) 84-84 2019/11

    Publisher: 日本難病医療ネットワーク学会

    ISSN: 2188-1006

  275. 頭部外傷を契機に発症した抗MOG抗体関連脳脊髄炎の一例

    佐藤 一輝, 西山 亜由美, 鈴木 直輝, 張替 宗介, 齋藤 早紀, 池田 謙輔, 西山 修平, 三須 建郎, 割田 仁, 黒田 宙, 青木 正志

    臨床神経学 59 (11) 760-760 2019/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  276. 非典型的な画像所見を示し診断に難渋した脳原発悪性リンパ腫の1例

    齋藤 元一, 西山 修平, 阪本 直広, 四條 友望, 割田 仁, 青木 正志

    臨床神経学 59 (11) 761-761 2019/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  277. 日本人dysferlin遺伝子解析で見出されたバリアントの一般頻度による病的意義の推定

    高橋 俊明, 鈴木 直輝, 井泉 瑠美子, 八木沼 智香子, 小野 洋也, 島倉 奈緒子, 大城 咲, 杉村 容子, 谷口 さやか, 下瀬川 康子, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 割田 仁, 新堀 哲也, 武田 篤, 青木 洋子, 青木 正志

    臨床神経学 59 (Suppl.) S257-S257 2019/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  278. 18F-THK5351 PETによる進行性核上性麻痺とパーキンソン病の鑑別の検討

    菊池 昭夫, 江面 道典, 岡村 信行, 長谷川 隆文, 石木 愛子, 原田 龍一, 菅野 直人, 吉田 隼, 小林 潤平, 荒井 啓行, 谷内 一彦, 古本 祥三, 田代 学, 工藤 幸司, 武田 篤, 青木 正志

    臨床神経学 59 (Suppl.) S228-S228 2019/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  279. Consideration of gravity as a possible etiological factor in amyotrophic lateral sclerosis. International-journal Peer-reviewed

    Tetsuya Akaishi, Toshiyuki Takahashi, Michiaki Abe, Masashi Aoki, Tadashi Ishii

    Medical hypotheses 132 109369-109369 2019/11

    DOI: 10.1016/j.mehy.2019.109369  

    ISSN: 0306-9877

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    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with an unknown mechanism of onset that predominantly impairs the upper and lower motor neurons. Components of the sensory and autonomic nervous system were once thought to be spared in the disease, but more recently they have been identified to be impaired at various levels. However, some of the motor neurons such as oculomotor, abducens, or pudendal nerves are spared even in the later stages of ALS. The mechanism of such complex and heterogeneous neuronal loss in typical ALS is still unknown. In this study, the characteristics of the nervous system involved in the pathogenesis of ALS were comprehensively reviewed. As a result, the direction of the axon in the anatomical position, rather than the functional type or length of the axon, was suggested to contribute the most to the onset of ALS. This finding suggested that downward directed axons, represented by motor neurons, require extra energy to move waste or unnecessary substances from the synapse side to the neural cell body with retrograde fast axonal transport. Based on this theory, the extra energy that is required in vertically directed axons due to the effect of gravity was mathematically estimated. As a result, several percent more adenosine triphosphate molecules were suggested to be consumed in vertical axonal transport by gravity, compared to those consumed in transverse axonal transport. Because most of the motor neurons project downward in the anatomical position, unretrieved waste will gradually sediment in axon terminals by gravity, which could eventually result in motor neuron-dominant neuronal loss. Although the theory that gravity is one of the mechanisms responsible for ALS is still hypothetical, it is theoretically reasonable and compatible with the clinical manifestations of the disease. Further basic research studies with cultured neurons or animal models are necessary to confirm the association between gravity and the onset of ALS.

  280. Pathogenic mutations in the ALS gene CCNF cause cytoplasmic mislocalization of Cyclin F and elevated VCP ATPase activity. International-journal Peer-reviewed

    Yujiao Yu, Tadashi Nakagawa, Akane Morohoshi, Makiko Nakagawa, Noriko Ishida, Naoki Suzuki, Masashi Aoki, Keiko Nakayama

    Human molecular genetics 28 (20) 3486-3497 2019/10/15

    DOI: 10.1093/hmg/ddz119  

    ISSN: 0964-6906

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    Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease characterized by a progressive decline in motor function. Genetic analyses have identified several genes mutated in ALS patients, and one of them is Cyclin F gene (CCNF), the product of which (Cyclin F) serves as the substrate-binding module of a SKP1-CUL1-F-box protein (SCF) ubiquitin ligase complex. However, the role of Cyclin F in ALS pathogenesis has remained unclear. Here, we show that Cyclin F binds to valosin-containing protein (VCP), which is also reported to be mutated in ALS, and that the two proteins colocalize in the nucleus. VCP was found to bind to the NH2-terminal region of Cyclin F and was not ubiquitylated by SCFCyclin F in transfected cells. Instead, the ATPase activity of VCP was enhanced by Cyclin F in vitro. Furthermore, whereas ALS-associated mutations of CCNF did not affect the stability of Cyclin F or disrupt formation of the SCFCyclin F complex, amino acid substitutions in the VCP binding region increased the binding ability of Cyclin F to VCP and activity of VCP as well as mislocalization of the protein in the cytoplasm. We also provided evidence that the ATPase activity of VCP promotes cytoplasmic aggregation of transactivation responsive region (TAR) DNA-binding protein 43, which is commonly observed in degenerating neurons in ALS patients. Given that mutations of VCP identified in ALS patients also increase its ATPase activity, our results suggest that Cyclin F mutations may contribute to ALS pathogenesis by increasing the ATPase activity of VCP in the cytoplasm, which in turn increases TDP-43 aggregates.

  281. 治療抵抗性の重症抗MOG抗体関連疾患に対するリツキシマブの使用経験

    松本 勇貴, 三須 建郎, 高井 良樹, 西山 修平, 小野 紘彦, 黒田 宙, 割田 仁, 青木 正志, 黒澤 和大, 清水 洋, 藤原 一男

    神経治療学 36 (6) S288-S288 2019/10

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  282. 神経難病におけるトランスレーショナル・リサーチ ALSに対するHGF治療 Peer-reviewed

    青木 正志, 割田 仁, 加藤 昌昭, 長野 清一, 望月 秀樹

    神経治療学 36 (6) S132-S132 2019/10

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  283. FDG-PET detects extensive calcinosis cutis in anti-NXP2 antibody-positive dermatomyositis. International-journal Peer-reviewed

    Naoko Nakamura, Rumiko Izumi, Yosuke Hoshi, Yoshiki Takai, Risako Ono, Naoki Suzuki, Taichi Nagai, Yusho Ishii, Tomonori Ishii, Hideo Harigae, Shuko Okada, Setsuya Aiba, Naoko Okiyama, Manabu Fujimoto, Hiroshi Kuroda, Maki Tateyama, Masashi Aoki

    Rheumatology (Oxford, England) 58 (10) 1888-1888 2019/10/01

    DOI: 10.1093/rheumatology/kez083  

    ISSN: 1462-0324

  284. 自己免疫性脳炎 抗MOG抗体陽性患者におけるT細胞反応性に関する検討

    小野 紘彦, 三須 建郎, 高井 良樹, 西山 修平, 黒田 宙, 高橋 利幸, 中島 一郎, 藤原 一男, 青木 正志

    神経免疫学 24 (1) 96-96 2019/09

    Publisher: 日本神経免疫学会

    ISSN: 0918-936X

  285. MS/NMO 2 視神経脊髄炎中枢組織障害に対するIL-6の影響に関する病理学的検討

    高井 良樹, 三須 建郎, 松本 勇貴, 生田目 知尋, 小野 紘彦, 西山 修平, 黒田 宙, 藤原 一男, 青木 正志

    神経免疫学 24 (1) 118-118 2019/09

    Publisher: 日本神経免疫学会

    ISSN: 0918-936X

  286. 抗MOG抗体関連疾患急性期治療後の経時的障害度と予後の検討

    生田目 知尋, 三須 建郎, 西山 修平, 高井 良樹, 小野 紘彦, 松本 勇貴, 高橋 利幸, 中島 一郎, 藤原 一男, 青木 正志

    神経免疫学 24 (1) 153-153 2019/09

    Publisher: 日本神経免疫学会

    ISSN: 0918-936X

  287. Longitudinal changes in 18 F-THK5351 positron emission tomography in corticobasal syndrome. International-journal Peer-reviewed

    M Ezura, A Kikuchi, A Ishiki, N Okamura, T Hasegawa, R Harada, S Watanuki, Y Funaki, K Hiraoka, T Baba, N Sugeno, R Oshima, S Yoshida, J Kobayashi, M Kobayashi, O Tano, I Nakashima, S Mugikura, R Iwata, Y Taki, K Furukawa, H Arai, S Furumoto, M Tashiro, K Yanai, Y Kudo, A Takeda, M Aoki

    European journal of neurology 26 (9) 1205-1211 2019/09

    DOI: 10.1111/ene.13966  

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    BACKGROUND AND PURPOSE: Corticobasal syndrome (CBS) is pathologically characterized by tau deposits in neuronal and glial cells and by reactive astrogliosis. In several neurodegenerative disorders, 18 F-THK5351 has been observed to bind to reactive astrocytes expressing monoamine oxidase B. In this study, the aim was to investigate the progression of disease-related pathology in the brains of patients with CBS using positron emission tomography with 18 F-THK5351. METHODS: Baseline and 1-year follow-up imaging were acquired using magnetic resonance imaging and positron emission tomography with 18 F-THK5351 in 10 subjects: five patients with CBS and five age-matched normal controls (NCs). RESULTS: The 1-year follow-up scan images revealed that 18 F-THK5351 retention had significantly increased in the superior parietal gyrus of the patients with CBS compared with the NCs. The median increases in 18 F-THK5351 accumulation in the patients with CBS were 6.53% in the superior parietal gyrus, 4.34% in the precentral gyrus and 4.33% in the postcentral gyrus. In contrast, there was no significant increase in the regional 18 F-THK5351 retention in the NCs. CONCLUSIONS: Longitudinal increases in 18 F-THK5351 binding can be detected over a short interval in the cortical sites of patients with CBS. A monoamine oxidase B binding radiotracer could be useful in monitoring the progression of astrogliosis in CBS.

  288. Extracellular α-synuclein enters dopaminergic cells by modulating flotillin-1-assisted dopamine transporter endocytosis. International-journal Peer-reviewed

    Junpei Kobayashi, Takafumi Hasegawa, Naoto Sugeno, Shun Yoshida, Tetsuya Akiyama, Koki Fujimori, Hiroyasu Hatakeyama, Yasuo Miki, Arata Tomiyama, Yasushi Kawata, Mitsunori Fukuda, Ichiro Kawahata, Tohru Yamakuni, Michinori Ezura, Akio Kikuchi, Toru Baba, Atsushi Takeda, Makoto Kanzaki, Koichi Wakabayashi, Hideyuki Okano, Masashi Aoki

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33 (9) 10240-10256 2019/09

    DOI: 10.1096/fj.201802051R  

    ISSN: 0892-6638

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    The neuropathological hallmarks of Parkinson's disease (PD) include the appearance of α-synuclein (α-SYN)-positive Lewy bodies (LBs) and the loss of catecholaminergic neurons. Thus, a potential mechanism promoting the uptake of extracellular α-SYN may exist in susceptible neurons. Of the various differentially expressed proteins, we are interested in flotillin (FLOT)-1 because this protein is highly expressed in the brainstem catecholaminergic neurons and is strikingly up-regulated in PD brains. In this study, we found that extracellular monomeric and fibrillar α-SYN can potentiate FLOT1-dopamine transporter (DAT) binding and pre-endocytic clustering of DAT on the cell surface, thereby facilitating DAT endocytosis and down-regulating its transporter activity. Moreover, we demonstrated that α-SYN itself exploited the DAT endocytic process to enter dopaminergic neuron-like cells, and both FLOT1 and DAT were found to be the components of LBs. Altogether, these findings revealed a novel role of extracellular α-SYN on cellular trafficking of DAT and may provide a rationale for the cell type-specific, functional, and pathologic alterations in PD.-Kobayashi, J., Hasegawa, T., Sugeno, N., Yoshida, S., Akiyama, T., Fujimori, K., Hatakeyama, H., Miki, Y., Tomiyama, A., Kawata, Y., Fukuda, M., Kawahata, I., Yamakuni, T., Ezura, M., Kikuchi, A., Baba, T., Takeda, A., Kanzaki, M., Wakabayashi, K., Okano, H., Aoki, M. Extracellular α-synuclein enters dopaminergic cells by modulating flotillin-1-assisted dopamine transporter endocytosis.

  289. Sensitivity and specificity of meningeal signs in patients with meningitis. Peer-reviewed

    Tetsuya Akaishi, Junpei Kobayashi, Michiaki Abe, Kota Ishizawa, Ichiro Nakashima, Masashi Aoki, Tadashi Ishii

    Journal of general and family medicine 20 (5) 193-198 2019/09

    DOI: 10.1002/jgf2.268  

    ISSN: 2189-6577

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    Background: Several types of physical examinations are used in the diagnosis of meningitis, including nuchal rigidity, jolt accentuation, Kernig's sign, and Brudzinski's sign. Jolt accentuation was reported to have sensitivity of nearly 100% and to be highly efficient for excluding meningitis, but more recent studies showed that a number of patients with meningitis may present negative in this test. Methods: We systematically reviewed studies on the above-mentioned physical examination tests and performed meta-analysis of their diagnostic characteristics to evaluate the clinical usefulness. Nine studies, comprising a total of 599 patients with pleocytosis in the cerebrospinal fluid (CSF) and 1216 patients without CSF pleocytosis, were enrolled in the analysis. Results: Jolt accentuation showed a decent level of odds ratio (3.62; 99% confidence interval (CI): 1.13-11.60, P = 0.004) comparable to that in nuchal rigidity (2.52; 1.21-5.27, P = 0.001) for the correct prediction of CSF pleocytosis among subjects with suspected meningitis. The estimated sensitivity was relatively high (40%-60%) in nuchal rigidity or jolt accentuation tests. On the other hand, Kernig's and Brudzinski's signs exhibited relatively low sensitivity (20%-30%). The estimated specificity was higher in Kernig's and Brudzinski's signs (85%-95%) than in nuchal rigidity or jolt accentuation tests (65%-75%). Conclusion: Approximately half of the patients with meningitis may not present typical meningeal signs upon physical examination. Combining several examinations for the detection of meningeal signs may decrease the risk of misdiagnosis.

  290. MGTX extension study longitudinally favors early thymectomy in non-thymomatous young-adult patients with AChR antibody-positive myasthenia gravis. International-journal Peer-reviewed

    Akaishi T, Motomura M, Aoki M, Utsugisawa K

    Annals of translational medicine 7 (Suppl 6) S208 2019/09

    DOI: 10.21037/atm.2019.06.65  

    ISSN: 2305-5839

  291. In vitro exercise model using contractile human and mouse hybrid myotubes. International-journal Peer-reviewed

    Weijian Chen, Mazvita R Nyasha, Masashi Koide, Masahiro Tsuchiya, Naoki Suzuki, Yoshihiro Hagiwara, Masashi Aoki, Makoto Kanzaki

    Scientific reports 9 (1) 11914-11914 2019/08/15

    DOI: 10.1038/s41598-019-48316-9  

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    Contraction of cultured myotubes with application of electric pulse stimulation (EPS) has been utilized for investigating cellular responses associated with actual contractile activity. However, cultured myotubes derived from human subjects often exhibit relatively poor EPS-evoked contractile activity, resulting in minimal contraction-inducible responses (i.e. myokine secretion). We herein describe an "in vitro exercise model", using hybrid myotubes comprised of human myoblasts and murine C2C12 myoblasts, exhibiting vigorous contractile activity in response to EPS. Species-specific analyses including RT-PCR and the BioPlex assay allowed us to separately evaluate contraction-inducible gene expressions and myokine secretions from human and mouse constituents of hybrid myotubes. The hybrid myotubes, half of which had arisen from primary human satellite cells obtained from biopsy samples, exhibited remarkable increases in the secretions of human cytokines (myokines) including interleukins (IL-6, IL-8, IL-10, and IL16), CXC chemokines (CXCL1, CXCL2, CXCL5, CXCL6, CXCL10), CC chemokines (CCL1, CCL2, CCL7, CCL8, CCL11, CCL13, CCL16, CCL17, CCL19, CCL20, CCL21, CCL22, CCL25, CCL27), and IFN-γ in response to EPS-evoked contractile activity. Together, these results indicate that inadequacies arising from human muscle cells are effectively overcome by fusing them with murine C2C12 cells, thereby supporting the development of contractility and the resulting cellular responses of human-origin muscle cells. Our approach, using hybrid myotubes, further expands the usefulness of the "in vitro exercise model".

  292. ユビキチン-プロテアソーム系は筋幹細胞の恒常性維持に必須である

    北嶋 康雄, 鈴木 直輝, 布宮 亜樹, 長名 シオン, 吉岡 潔志, 田代 善崇, 高橋 良輔, 小野 悠介, 青木 正志, 永富 良一

    日本筋学会学術集会プログラム・抄録集 5回 131-131 2019/08

    Publisher: 日本筋学会

    ISSN: 2433-975X

  293. 日本人dysferlin遺伝子解析で見出されたバリアントのデータベースによる検討 Peer-reviewed

    高橋 俊明, 鈴木 直輝, 井泉 瑠美子, 八木沼 智香子, 小野 洋也, 島倉 奈緒子, 大城 咲, 谷口 さやか, 下瀬川 康子, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 割田 仁, 新堀 哲也, 武田 篤, 青木 洋子, 青木 正志

    日本筋学会学術集会プログラム・抄録集 5回 172-172 2019/08

    Publisher: 日本筋学会

    ISSN: 2433-975X

  294. p.N345K mutation in TARDBP in a patient with familial amyotrophic lateral sclerosis: An autopsy case. International-journal Peer-reviewed

    Takahiro Takeda, Mutsumi Iijima, Yuko Shimizu, Hiroshi Yoshizawa, Mayu Miyashiro, Hiromi Onizuka, Tomoko Yamamoto, Ayumi Nishiyama, Naoki Suzuki, Masashi Aoki, Noriyuki Shibata, Kazuo Kitagawa

    Neuropathology : official journal of the Japanese Society of Neuropathology 39 (4) 286-293 2019/08

    DOI: 10.1111/neup.12559  

    ISSN: 0919-6544

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    We report the neuropathology of a patient with a family history of amyotrophic lateral sclerosis (ALS) and a p.N345K mutation in the transactivation response DNA-binding protein 43 kDa (TDP-43) gene (TARDBP). A 62-year-old man had bulbar palsy with progressive weakness in the extremities. Neurological examination revealed evident upper motor neuron signs and lower motor neuron involvement corroborated by needle electromyography. The patient was diagnosed as having probable ALS according to the revised El Escorial diagnostic criteria and was eventually diagnosed with familial ALS. At 65 years of age, respiratory failure became critical, and artificial ventilation was initiated. At 70 years of age, the patient died from a urinary tract infection. Histopathological investigation showed Bunina bodies in the remaining motor neurons and anterolateral funicular myelin pallor in the spinal cord. TDP-43-positive cytoplasmic inclusions were quite rare in the spinal cord motor neurons, being predominantly present in the glial cells (especially astrocytes) of the spinal cord anterior horn. Although the reason for the preferential vulnerability of spinal glial cells to TARDBP mutations remains unclear, our findings indicate that TARDBP p.N345K mutation could have an influence on the topography of TDP-43 aggregation.

  295. MPL/BLOTCHP-MS法を用いた線維化αシヌクレイン受容体候補分子の網羅的探索

    小林 潤平, 長谷川 隆文, 菅野 直人, 吉田 隼, 石山 駿, 中村 貴彬, 菊地 昭夫, 江面 道典, 馬場 徹, 武田 篤, 青木 正志

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集 13回 103-103 2019/07

    Publisher: Movement Disorder Society of Japan (MDSJ)

  296. 肺癌術後に発症し、治療に難渋した傍腫瘍性NMOSDの1例

    松原 史歩, 西山 修平, 中屋 亮彦, 小野 理佐子, 西山 亜由美, 三須 建郎, 割田 仁, 黒田 宙, 青木 正志

    臨床神経学 59 (7) 477-477 2019/07

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  297. ALSに対する治験の最新情報-1 筋萎縮性側索硬化症に対する肝細胞増殖因子を用いた治験

    長野 清一, 割田 仁, 望月 秀樹, 青木 正志

    神経治療学 36 (4) 462-464 2019/07

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  298. ALSに対する治験の最新情報-1 筋萎縮性側索硬化症に対する肝細胞増殖因子を用いた治験 Peer-reviewed

    長野 清一, 割田 仁, 望月 秀樹, 青木 正志

    神経治療学 36 (4) 462-464 2019/07

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  299. The updated retrospective questionnaire study of sporadic inclusion body myositis in Japan. International-journal Peer-reviewed

    Naoki Suzuki, Madoka Mori-Yoshimura, Satoshi Yamashita, Satoshi Nakano, Ken-Ya Murata, Megumi Mori, Yukie Inamori, Naoko Matsui, En Kimura, Hirofumi Kusaka, Tomoyoshi Kondo, Hidefumi Ito, Itsuro Higuchi, Akihiro Hashiguchi, Hiroyuki Nodera, Ryuji Kaji, Maki Tateyama, Rumiko Izumi, Hiroya Ono, Masaaki Kato, Hitoshi Warita, Toshiaki Takahashi, Ichizo Nishino, Masashi Aoki

    Orphanet journal of rare diseases 14 (1) 155-155 2019/06/26

    DOI: 10.1186/s13023-019-1122-5  

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    BACKGROUND: Sporadic inclusion body myositis (sIBM) is the most prevalent muscle disease in elderly people, affecting the daily activities. sIBM is progressive with unknown cause and without effective treatment. In 2015, sIBM was classified as an intractable disease by the Japanese government, and the treatment cost was partly covered by the government. This study aimed to examine the changes in the number of patients with sIBM over the last 10 years and to elucidate the cross-sectional profile of Japanese patients with sIBM. METHODS: The number of sIBM patients was estimated through a reply-paid postcard questionnaire for attending physicians. Only patients diagnosed as "definite" or "probable" sIBM by clinical and biopsy sIBM criteria were included in this study (Lancet Neurol 6:620-631, 2007, Neuromuscul Disord 23:1044-1055, 2013). Additionally, a registered self-administered questionnaire was also sent to 106 patients who agreed to reply via their attending physician, between November 2016 and March 2017. RESULTS: The number of patients diagnosed with sIBM for each 5-year period was 286 and 384 in 2011 and 2016, respectively. Inability to stand-up, cane-dependent gait, inability to open a plastic bottle, choking on food ingestion, and being wheelchair-bound should be included as sIBM milestones. Eight patients were positive for anti-hepatitis C virus antibody; three of them were administered interferon before sIBM onset. Steroids were administered to 33 patients (31.1%) and intravenous immunoglobulin to 46 patients (43.4%). From 2016 to 2017, total of 70 patients applied for the designated incurable disease medical expenses subsidy program. Although the treatment cost was partly covered by the government, many patients expressed psychological/mental and financial anxieties. CONCLUSIONS: We determined the cross-sectional profile of Japanese patients with sIBM. Continuous support and prospective surveys are warranted.

  300. A case of neuralgic amyotrophy presented Vernet syndrome and suprascapular nerve palsy Peer-reviewed

    Iino Akira, Sugeno Naoto, Namatame Chihiro, Nishiyama Ayumi, Kuroda Hiroshi, Misu Tatsuro, Aoki Masashi

    NEUROLOGY AND CLINICAL NEUROSCIENCE 7 (3) 127-128 2019/05

    DOI: 10.1111/ncn3.12264  

    ISSN: 2049-4173

  301. Efficacy and safety of leuprorelin acetate for subjects with spinal and bulbar muscular atrophy: pooled analyses of two randomized-controlled trials International-journal

    Hashizume Atsushi, Katsuno Masahisa, Suzuki Keisuke, Banno Haruhiko, Takeuchi Yu, Kawashima Motoshi, Suga Noriaki, Mano Tomoo, Araki Amane, Hijikata Yasuhiro, Hirakawa Akihiro, Sobue Gen, Sasaki H, Aoki M, Nakano I, Ito S, Mizusawa H, Yamamoto To, Hasegawa K, Miyajima H, Kanda N, Nakajima K, Tsujino A, Uchino M, Morita M, Kanai K

    JOURNAL OF NEUROLOGY 266 (5) 1211-1221-1221 2019/05

    DOI: 10.1007/s00415-019-09251-x  

    ISSN: 0340-5354

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    BACKGROUND: Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, hereditary neuromuscular disease characterized by muscle atrophy, weakness, contraction fasciculation, and bulbar involvement. Although the causative gene, androgen receptor, has been identified, the development of novel therapeutics for SBMA is incomplete. In this study, the efficacy and safety of leuprorelin acetate administration for patients with SBMA, using the pooled data of two randomized-controlled trials, was studied. METHODS: Two randomized double-blinded studies (JASMITT-06DB and JASMITT-11DB) were done as multicentric, investigator-initiated clinical trials in Japan. In both studies, eligible patients were randomly assigned 1:1 to receive leuprorelin acetate administration once per 12 weeks for 48 weeks. The primary endpoint was the longitudinal change of pharyngeal barium residues from the baseline data measured with videofluorographic swallowing analyses. The pooled analysis plan was decided upon after the 06B study was finished and before the 11DB study began. RESULTS: The primary endpoint difference between the leuprorelin group and the placebo group was pharyngeal barium residue after initial swallowing, - 4.12% (95% CI, - 8.40-0.15; p = 0.058). The primary endpoint of this study does not reach significant results, although inter-group differences of pharyngeal barium residues after the initial swallowing indicated that leuprorelin acetate may be effective at each assessment point in both study groups. CONCLUSIONS: The efficacy of leuprorelin acetate for patients with SBMA was statistically similar in two randomized-controlled trials, and suggested that leuprorelin acetate may be effective and safe. Further investigations are needed to clarify the promising efficacy of the drug.

  302. Successful treatment of intractable menstrual migraine with the traditional herbal medicine tokishakuyakusan. Peer-reviewed

    Tetsuya Akaishi, Shin Takayama, Minoru Ohsawa, Akiko Kikuchi, Ryutaro Arita, Ichiro Nakashima, Masashi Aoki, Tadashi Ishii

    Journal of general and family medicine 20 (3) 118-121 2019/05

    DOI: 10.1002/jgf2.242  

    ISSN: 2189-6577

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    In this report, we present the successful treatment of five consecutive cases of premenopausal women suffering from severe menstrual migraine with tokishakuyakusan (TSS). Two patients were complicated by tension-type headache (TTH), and another patient was by medication overuse headache (MOH). The effects of triptans were limited in all of them. After starting TSS, they showed dramatic improvement in the severity and frequency of their attacks. The patients with TTH and MOH also showed dramatic improvement in their symptoms. TSS could be a promising alternative choice for patients with intractable menstruation-related headaches that are refractory to conventional treatments, including triptans.

  303. Interstitial pneumonia and other adverse events in riluzole-administered amyotrophic lateral sclerosis patients: a retrospective observational study. International-journal Peer-reviewed

    Aya Inoue-Shibui, Masaaki Kato, Naoki Suzuki, Junpei Kobayashi, Yoshiki Takai, Rumiko Izumi, Yuuko Kawauchi, Hiroshi Kuroda, Hitoshi Warita, Masashi Aoki

    BMC neurology 19 (1) 72-72 2019/04/27

    DOI: 10.1186/s12883-019-1299-1  

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    BACKGROUND: Riluzole is the only approved oral drug for amyotrophic lateral sclerosis (ALS). We performed a retrospective study including ALS patients treated with riluzole, focusing on adverse events. METHODS: Patients diagnosed with ALS according to the revised El Escorial criteria (World Federation of Neurology) in our center and who were administered 50 mg oral riluzole twice daily between January 2011 and September 2017 and followed up for at least 6 months from treatment initiation or until death were included. Data regarding sex, age, disease type, initial symptoms, biochemical analyses performed before and after riluzole administration, and medical history were collected. In case of withdrawal, cause of discontinuation and durations of disease and drug administration were recorded. RESULTS: A total of 92 cases were enrolled. Riluzole administration was discontinued in 20 cases (21.7%). The most frequent reason for discontinuation was elevated liver enzymes (n = 5, 5.4%), followed interstitial pneumonia (IP), nausea and appetite loss, dizziness, general malaise, tongue paresthesia, and urinary urgency. In two cases, administration was discontinued primarily because of progression of bulbar palsy. All adverse events occurred within 6 months from treatment initiation and improved soon after its discontinuation. Three IP cases developed severe respiratory failure and required steroid treatment. CONCLUSION: Riluzole administration was discontinued in 20 cases among total of 92 cases. Careful follow-up is important for the first six months after the initiation of riluzole administration, including through interviews, chemical analyses, and chest X-rays, as required.

  304. The human central nervous system discharges carbon dioxide and lactic acid into the cerebrospinal fluid. International-journal Peer-reviewed

    Tetsuya Akaishi, Eiko Onishi, Michiaki Abe, Hiroaki Toyama, Kota Ishizawa, Michio Kumagai, Ryosuke Kubo, Ichiro Nakashima, Masashi Aoki, Masanori Yamauchi, Tadashi Ishii

    Fluids and barriers of the CNS 16 (1) 8-8 2019/03/29

    DOI: 10.1186/s12987-019-0128-7  

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    BACKGROUND: The central nervous system was previously thought to draw oxygen and nutrition from the arteries and discharge carbon dioxide and other metabolic wastes into the venous system. At present, the functional role of cerebrospinal fluid in brain metabolism is not fully known. METHODS: In this prospective observational study, we performed gas analysis on venous blood and cerebrospinal fluid simultaneously acquired from 16 consecutive preoperative patients without any known neurological disorders. RESULTS: The carbon dioxide partial pressure (pCO2) (p < 0.0001) and lactic acid level (p < 0.001) in the cerebrospinal fluid were significantly higher than those in the peripheral venous blood, suggesting that a considerable proportion of metabolic carbon dioxide and lactic acid is discharged from the central nervous system into the cerebrospinal fluid. The oxygen partial pressure (pO2) was much higher in the cerebrospinal fluid than in the venous blood, corroborating the conventional theory of cerebrospinal fluid circulatory dynamics. The pCO2 of the cerebrospinal fluid showed a strong negative correlation with age (R = - 0.65, p = 0.0065), but the other studied variables did not show significant correlation with age. CONCLUSION: Carbon dioxide and lactic acid are discharged into the circulating cerebrospinal fluid, as well as into the venules. The level of carbon dioxide in the cerebrospinal fluid significantly decreased with age.

  305. A juvenile sporadic amyotrophic lateral sclerosis case with P525L mutation in the FUS gene: A rare co-occurrence of autism spectrum disorder and tremor. International-journal Peer-reviewed

    Nobuyuki Eura, Kazuma Sugie, Naoki Suzuki, Takao Kiriyama, Tesseki Izumi, Naoko Shimakura, Masaaki Kato, Masashi Aoki

    Journal of the neurological sciences 398 67-68 2019/03/15

    DOI: 10.1016/j.jns.2019.01.032  

    ISSN: 0022-510X

  306. Debate on the treatment of multiple sclerosis: Experience from an intractable multiple sclerosis case with rebound syndrome after fingolimod cessation

    Hiroshi Kuroda, Shuhei Nishiyama, Yuki Matsumoto, Tatsuro Misu, Kazuo Fujihara, Masashi Aoki

    Clinical and Experimental Neuroimmunology 10 (S1) 59-62 2019/03

    DOI: 10.1111/cen3.12504  

    eISSN: 1759-1961

  307. A novel homozygous mutation of the TFG gene in a patient with early onset spastic paraplegia and later onset sensorimotor polyneuropathy. International-journal Peer-reviewed

    Takuya Miyabayashi, Tatsuhiro Ochiai, Naoki Suzuki, Masashi Aoki, Takehiko Inui, Yukimune Okubo, Ryo Sato, Noriko Togashi, Hiroshi Takashima, Hiroyuki Ishiura, Shoji Tsuji, Kishin Koh, Yoshihisa Takiyama, Kazuhiro Haginoya

    Journal of human genetics 64 (2) 171-176 2019/02

    DOI: 10.1038/s10038-018-0538-4  

    ISSN: 1434-5161

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    The tropomyosin-receptor kinase fused gene (TFG) has recently been implicated in several distinct hereditary disorders, including the autosomal-recessive form of complicated hereditary spastic paraplegia called SPG57. Previously, three homozygous variants of the TFG gene were reported in five families with SPG57, in which early onset spastic paraplegia, optic atrophy, and peripheral neuropathy were variably identified. Here, we present the first Japanese patient with SPG57, and have added a homozygous p.Ile66Thr variant as the fourth SPG57 genotype.

  308. Macular degeneration as a common cause of visual loss in spinocerebellar ataxia type 1 (SCA1) patients. Peer-reviewed

    Nishiguchi KM, Aoki M, Nakazawa T, Abe T

    Ophthalmic genetics 40 (1) 49-53 2019/02

    DOI: 10.1080/13816810.2019.1571614  

    ISSN: 1381-6810

  309. Extranodal NK/T-cell Lymphoma Mimicking Granulomatous Myositis. Peer-reviewed

    Norihiko Kawaguchi, Rumiko Izumi, Masahiro Kobayashi, Maki Tateyama, Naoki Suzuki, Fumiyoshi Fujishima, Juichi Fujimori, Masashi Aoki, Ichiro Nakashima

    Internal medicine (Tokyo, Japan) 58 (2) 277-282 2019/01/15

    DOI: 10.2169/internalmedicine.0859-18  

    ISSN: 0918-2918

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    Extranodal NK/T-cell lymphoma (ENKTL) is an aggressive non-Hodgkin lymphoma that typically develops in the upper aerodigestive tract. We encountered an ENKTL patient who presented with generalized muscle weakness with eyelid swelling, diplopia, and facial edema. A muscle biopsy revealed lymphocytic infiltration without significant atypia; some lymphocytes formed granuloma-like structures. Although the initial response to steroids was encouraging, an ulcerative eruption appeared in the thigh, and a skin biopsy revealed lymphocytes with atypia. A re-analysis of the muscle biopsy with additional immunohistochemistry revealed neoplastic NK/T lymphocytes in the granulomatous structures. Our case highlights the significance of re-evaluating muscle biopsy specimens in cases of atypical myositis.

  310. Review/Advances in Neurological Therapeutics (2018). Motor neuron disease Peer-reviewed

    Akiyama Tetsuya, Suzuki Naoki, Warita Hitoshi, Aoki Masashi

    Neurological Therapeutics 36 (5) 584-587 2019

    Publisher: Japanese Society of Neurological Therapeutics

    DOI: 10.15082/jsnt.36.5_584  

    ISSN: 0916-8443

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    <p>Motor neuron diseases (MND) are devastating neurodegenerative disorder which primary affects motor neurons. Amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and spinal bulbar muscular atrophy (SBMA) are representative MND. Since the advent of novel drugs of SMA (Nusinersen) and SBMA (Leuprorelin) in 2017, the treatment of MND has changed dramatically and the door of new hope has opened. This review provides an overview of preclinical and clinical advances in MND research, future issues and prospects, and summarizes selected key literature on therapeutic approaches in 2018.</p>

  311. The Ubiquitin-Proteasome System Is Indispensable for the Maintenance of Muscle Stem Cells. International-journal Peer-reviewed

    Yasuo Kitajima, Naoki Suzuki, Aki Nunomiya, Shion Osana, Kiyoshi Yoshioka, Yoshitaka Tashiro, Ryosuke Takahashi, Yusuke Ono, Masashi Aoki, Ryoichi Nagatomi

    Stem cell reports 11 (6) 1523-1538 2018/12/11

    DOI: 10.1016/j.stemcr.2018.10.009  

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    Adult muscle stem cells (satellite cells) are required for adult skeletal muscle regeneration. A proper balance between quiescence, proliferation, and differentiation is essential for the maintenance of the satellite cell pool and their regenerative function. Although the ubiquitin-proteasome is required for most protein degradation in mammalian cells, how its dysfunction affects tissue stem cells remains unclear. Here, we investigated the function of the proteasome in satellite cells using mice lacking the crucial proteasomal component, Rpt3. Ablation of Rpt3 in satellite cells decreased proteasome activity. Proteasome dysfunction in Rpt3-deficient satellite cells impaired their ability to proliferate, survive and differentiate, resulting in defective muscle regeneration. We found that inactivation of proteasomal activity induced proliferation defects and apoptosis in satellite cells. Mechanistically, insufficient proteasomal activity upregulated the p53 pathway, which caused cell-cycle arrest. Our findings delineate a critical function of the proteasome system in maintaining satellite cells in adult muscle.

  312. 多施設共同前向きコホートでみたALS患者に対する気管切開下陽圧換気療法の予後

    林 直毅, 熱田 直樹, 横井 大知, 中村 亮一, 伊藤 瑞規, 渡辺 宏久, 勝野 雅央, 和泉 唯信, 饗場 郁子, 狩野 修, 谷口 彰, 森田 光哉, 阿部 康二, 金井 数明, 服部 信孝, 青木 正志, 桑原 聡, 梶 龍兒, 祖父江 元, JaCALS

    臨床神経学 58 (Suppl.) S347-S347 2018/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  313. ALSFRS-Rを用いた筋萎縮性側索硬化症患者の進行、予後予測と治験デザイン

    熱田 直樹, 中村 亮一, 林 直毅, 横井 大知, 伊藤 瑞規, 渡辺 宏久, 勝野 雅央, 和泉 唯信, 森田 光哉, 谷口 彰, 織田 雅也, 阿部 康二, 狩野 修, 桑原 聡, 青木 正志, 金井 数明, 服部 信孝, 梶 龍兒, 祖父江 元, JaCALS

    臨床神経学 58 (Suppl.) S205-S205 2018/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  314. 抗MOG抗体関連疾患に対する血漿交換療法add-onの有効性に関する検討

    生田目 知尋, 西山 修平, 三須 建郎, 高井 良樹, 黒田 宙, 中島 一郎, 藤原 一男, 青木 正志

    神経治療学 35 (6) S220-S220 2018/11

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  315. 再発寛解型多発性硬化症に対してNatalizumabを使用した11例の検討

    西山 修平, 三須 建郎, 高井 良樹, 黒田 宙, 中島 一郎, 藤原 一男, 青木 正志

    神経治療学 35 (6) S221-S221 2018/11

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  316. レボドパ/カルビドパ水和物配合経腸用液による加療中に生じたPEG-Jチューブ破損

    曽我 天馬, 菅野 直人, 馬場 徹, 金 笑奕, 小池 智幸, 長谷川 隆文, 青木 正志

    神経治療学 35 (6) S256-S256 2018/11

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  317. 筋萎縮性側索硬化症(ALS)に対する治験の最新情報-1 ALSに対するHGF治験 Peer-reviewed

    長野 清一, 割田 仁, 望月 秀樹, 青木 正志

    神経治療学 35 (6) S154-S154 2018/11

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  318. 異なる経過をたどり抗MOG抗体陽性であった中枢神経単純ヘルペス感染症の2例

    金子 仁彦, 佐藤 ダグラス, 高橋 利幸, 小川 諒, 高井 良樹, 西山 修平, 三須 建郎, 黒田 宙, 佐藤 亮介, 小林 修, 田中 覚, 田島 孝士, 中島 一郎, 藤原 一男, 青木 正志

    NEUROINFECTION 23 (2) 221-221 2018/10

    Publisher: 日本神経感染症学会

    ISSN: 1348-2718

    eISSN: 2435-2225

  319. Transient Pulmonary Interstitial Lesions in Aquaporin-4-positive Neuromyelitis Optica Spectrum Disorder. Peer-reviewed

    Asato Y, Kamitani T, Ootsuka K, Kuramochi M, Nakanishi K, Shimada T, Takahashi T, Misu T, Aoki M, Fujihara K, Kawabata Y

    Internal medicine (Tokyo, Japan) 57 (20) 2981-2986 2018/10

    DOI: 10.2169/internalmedicine.0580-17  

    ISSN: 0918-2918

  320. 再発寛解型多発性硬化症に対するNatalizumabの使用経験11例での検討

    西山 修平, 三須 建郎, 高井 良樹, 黒田 宙, 中島 一郎, 藤原 一男, 青木 正志

    神経免疫学 23 (1) 114-114 2018/09

    Publisher: 日本神経免疫学会

    ISSN: 0918-936X

  321. 炎症性中枢神経疾患における髄液多形核白血球増多例の検討

    黒田 宙, 金子 公彦, 小川 諒, 高井 良樹, 西山 修平, 三須 建郎, 中島 一郎, 藤原 一男, 青木 正志

    神経免疫学 23 (1) 126-126 2018/09

    Publisher: 日本神経免疫学会

    ISSN: 0918-936X

  322. 抗MOG抗体関連疾患に対する血漿交換療法add-onの有効性に関する検討

    生田目 知尋, 西山 修平, 三須 建郎, 高井 良樹, 黒田 宙, 中島 一郎, 藤原 一男, 青木 正志

    神経免疫学 23 (1) 131-131 2018/09

    Publisher: 日本神経免疫学会

    ISSN: 0918-936X

  323. 多発性硬化症におけるグラチラマー酢酸塩レスポンダー、ノンレスポンダーの末梢血T・B細胞の解析

    小野 紘彦, 佐藤 和貴郎, 三須 建郎, 中島 一郎, 藤原 一男, 青木 正志, 山村 隆

    神経免疫学 23 (1) 134-134 2018/09

    Publisher: 日本神経免疫学会

    ISSN: 0918-936X

  324. MS/NMO 抗MOG抗体関連性脱髄病巣の病理学的特徴 Peer-reviewed

    高井 良樹, 三須 建郎, 金子 仁彦, 高橋 利幸, 成川 孝一, 千原 典夫, 西田 裕哉, 土田 聡子, 青木 正志, 藤原 一男

    神経免疫学 23 (1) 108-108 2018/09

    Publisher: 日本神経免疫学会

    ISSN: 0918-936X

  325. Phase I clinical trial results of aceneuramic acid for GNE myopathy in Japan Peer-reviewed

    Naoki Suzuki, Masaaki Kato, Hitoshi Warita, Rumiko Izumi, Maki Tateyama, Hiroshi Kuroda, Ryuta Asada, Akifumi Suzuki, Takuhiro Yamaguchi, Ichizo Nishino, Masashi Aoki

    Translational Medicine Communications 3 (7) 2018/09

  326. Antagonizing bone morphogenetic protein 4 attenuates disease progression in a rat model of amyotrophic lateral sclerosis. International-journal Peer-reviewed

    Tomomi Shijo, Hitoshi Warita, Naoki Suzuki, Kensuke Ikeda, Shio Mitsuzawa, Tetsuya Akiyama, Hiroya Ono, Ayumi Nishiyama, Rumiko Izumi, Yasuo Kitajima, Masashi Aoki

    Experimental neurology 307 164-179 2018/09

    DOI: 10.1016/j.expneurol.2018.06.009  

    ISSN: 0014-4886

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    Amyotrophic lateral sclerosis (ALS) is an adult-onset, fatal neurodegenerative syndrome characterized by the systemic loss of motor neurons with prominent astrocytosis and microgliosis in the spinal cord and brain. Astrocytes play an essential role in maintaining extracellular microenvironments that surround motor neurons, and are activated by various insults. Growing evidence points to a non-cell autonomous neurotoxicity caused by chronic and sustained astrocytic activation in patients with neurodegenerative diseases, including ALS. However, the mechanisms that underlie the harmful effects of astrocytosis in patients with ALS remain unresolved. We focused on bone morphogenetic proteins as a major soluble factor that promotes astrocytogenesis and its activation in the adult spinal cord. In a transgenic rat model with ALS-linked mutant Cu/Zn superoxide dismutase gene, BMP4 was progressively up-regulated in reactive astrocytes of the spinal ventral horns, whereas the BMP-antagonist noggin was decreased in association with neuronal degeneration. Continuous intrathecal noggin supplementation after disease onset significantly ameliorated motor dysfunction symptoms, neurogenic muscle atrophy, and extended survival of symptomatic ALS model rats, despite lack of deterrence against neuronal death itself. The exogenous noggin inhibited astrocytic hypertrophy, astrocytogenesis, and neuroinflammation by inactivating both Smad1/5/8 and p38 mitogen-activated protein kinase pathways. Moreover, intrathecal infusion of a Bmp4-targeted antisense oligonucleotides and provided selective Bmp4 knockdown in vivo, which suppressed astrocyte and microglia activation, reproducing the aforementioned results by noggin treatment. Collectively, we clarified the involvement of BMP4 in the processes of excessive gliosis that exacerbate the disease progression of the ALS model rats. Our study demonstrated that BMP4, with its downstream signaling, might be a novel therapeutic target for disease-modifying therapies in ALS.

  327. Abnormal Osmolality Gap Exists in Distal Symmetric Polyneuropathy. Peer-reviewed

    Tetsuya Akaishi, Toshiyuki Takahashi, Ichiro Nakashima, Masashi Aoki

    The Tohoku journal of experimental medicine 246 (1) 59-64 2018/09

    DOI: 10.1620/tjem.246.59  

    ISSN: 0040-8727

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    Distal symmetric polyneuropathy, represented by chronic inflammatory demyelinating polyneuropathy, is a popular neurological condition. Some cases are known to be associated with genetic mutations or serum auto-antibodies, but the exact mechanisms in most cases are unknown. Recently, osmotic factors have been suggested to trigger some neurological disorders, such as neuromyelitis optica. The aim of the present study was to assess the possible association of osmotic factors in the pathogenesis of distal polyneuropathy. We prospectively measured the serum levels of osmolality, electrolytes, total protein, albumin, blood urea nitrogen, glucose, and osmolality gap in the patients with acute distal polyneuropathy before treatments (n = 12) and those with other comprehensive neurological disorders such as multiple sclerosis and neurodegenerative diseases (n = 176). Then, we compared each osmotic fraction between the two groups. As a result, all of the 12 patients with acute distal polyneuropathy, including 4 patients with chronic inflammatory demyelinating polyneuropathy, showed abnormally high or low values of osmolality gap, compared to the others (p < 0.0001, F-test). In the patients with other diseases, there were 2 patients with abnormally high osmolality gap values, which were attributable to their hyperlipidemia or high titer of serum autoantibody unrelated to polyneuropathy. In conclusion, serum osmolality gap would be elevated or decreased in the acute phase of distal symmetric polyneuropathy. Osmotic imbalance between the serum and nerve cells, based on abnormal excess or deficit of some unidentified serum osmolytes, may be one of the mechanisms in symmetric polyneuropathy with unknown causes.

  328. 下位脳神経障害を伴った神経痛性筋萎縮症の1例

    生田目 知尋, 西山 亜由美, 菅野 直人, 黒田 宙, 三須 建郎, 青木 正志

    臨床神経学 58 (8) 536-536 2018/08

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  329. Chloride imbalance is involved in the pathogenesis of optic neuritis in neuromyelitis optica Peer-reviewed

    Tetsuya Akaishi, Toshiyuki Takahashi, Noriko Himori, Takayuki Takeshita, Toru Nakazawa, Masashi Aoki, Ichiro Nakashima

    Journal of Neuroimmunology 320 98-100 2018/07/15

    Publisher: Elsevier B.V.

    DOI: 10.1016/j.jneuroim.2018.03.010  

    ISSN: 1872-8421 0165-5728

  330. The Clinical Findings Useful for Driving Safety Advice for Parkinson's Disease Patients. Peer-reviewed

    Ando R, Iwaki H, Tsujii T, Nagai M, Nishikawa N, Yabe H, Aiba I, Hasegawa K, Tsuboi Y, Aoki M, Nakashima K, Nomoto M, Parkinson's, Disease Safe, Driving Study, Group of Japan

    Internal medicine (Tokyo, Japan) 57 (14) 1977-1982 2018/07

    DOI: 10.2169/internalmedicine.9653-17  

    ISSN: 0918-2918

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    Objective We conducted a study to obtain information that could be used to provide Parkinson's disease (PD) patients with appropriate advice on safe driving. Methods Consecutive PD patients who visited our office were studied. Among these patients, those who had experienced driving after being diagnosed with PD were interviewed by neurologists and a trained nurse to investigate their previous car accidents, motor function, cognitive function, sleepiness, levodopa equivalent dose (LED), and emotional dysregulation. The rates of major car accidents before and after the onset of PD were compared. Results Fifteen patients had experienced a major car accident resulting in human injury or serious property damage since the onset of PD. When the rates of major car accidents before and after the onset of PD were compared, the ratio was 4.3 [95% confidence interval (CI) 1.9-9.7]. The incidence of accidents after the onset of PD was correlated with age, disease duration, LED, the cognitive function Mini-Mental Scale Examination (MMSE), Japanese translation of the Montreal Cognitive Assessment (MoCA-J), but not the motor symptom score [Unified Pankinson's disease rating scale (UPDRS) part III at the time of the study]. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP) score was also higher in patients with major car accidents. Conclusion The severity of symptoms (Hoehn-Yahr classification), cognitive function, and disease duration were expected to be risk factors for car accidents. However, the motor symptom score (UPDRS part III) was not associated with the incidence of major car accidents. In addition to a low cognitive function and the severity of symptoms, the QUIP score might be an independent factor that can be referenced when advising PD patients to refrain from driving.

  331. Paradoxical Cerebral Embolism after Gastrointestinal Endoscopy in a Patient with Crohn's Disease Peer-reviewed

    Hajime Ikenouchi, Naoto Sugeno, Takaaki Nakamura, Junpei Kobayashi, Ryuji Oshima, Hiroshi Kuroda, Masashi Aoki

    Journal of Stroke and Cerebrovascular Diseases 27 (7) e117-e118 2018/07/01

    Publisher: W.B. Saunders

    DOI: 10.1016/j.jstrokecerebrovasdis.2018.01.022  

    ISSN: 1532-8511 1052-3057

  332. TARDBP p.G376D mutation, found in rapid progressive familial ALS, induces mislocalization of TDP-43. International-journal Peer-reviewed

    Shio Mitsuzawa, Tetsuya Akiyama, Ayumi Nishiyama, Naoki Suzuki, Masaaki Kato, Hitoshi Warita, Rumiko Izumi, Shion Osana, Shingo Koyama, Takeo Kato, Yoshihiro Suzuki, Masashi Aoki

    eNeurologicalSci 11 20-22 2018/06

    DOI: 10.1016/j.ensci.2018.04.001  

  333. Systemic overexpression of SQSTM1/p62 accelerates disease onset in a SOD1H46R-expressing ALS mouse model. International-journal Peer-reviewed

    Shun Mitsui, Asako Otomo, Masahisa Nozaki, Suzuka Ono, Kai Sato, Ryohei Shirakawa, Hiroaki Adachi, Masashi Aoki, Gen Sobue, Hui-Fang Shang, Shinji Hadano

    Molecular brain 11 (1) 30-30 2018/05/29

    DOI: 10.1186/s13041-018-0373-8  

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    Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by a selective loss of upper and lower motor neurons. Recent studies have shown that mutations in SQSTM1 are linked to ALS. SQSTM1 encodes SQSTM1/p62 that regulates not only autophagy via the association with MAP1LC3/LC3 and ubiquitinated proteins but also the KEAP1-NFE2L2/Nrf2 anti-oxidative stress pathway by interacting with KEAP1. Previously, we have demonstrated that loss of SQSTM1 exacerbates disease phenotypes in a SOD1H46R-expressing ALS mouse model. To clarify the effects of SQSTM1 overexpression in this model, we generated SQSTM1 and SOD1 H46R double-transgenic (SQSTM1;SOD1 H46R ) mice. SQSTM1;SOD1 H46R mice exhibited earlier disease onset and shorter lifespan than did SOD1 H46R mice. Conversely, disease progression after the onset rather slightly but significantly slowed in SQSTM1;SOD1 H46R mice. However, there were observable differences neither in the number of Nissl positive neurons nor in the distribution of ubiquitin-positive and/or SQSTM1-positive aggregates between SOD1 H46R and SQSTM1;SOD1 H46R mice. It was noted that these protein aggregates were mainly observed in neuropil, and partly localized to astrocytes and/or microglia, but not to MAP2-positive neuronal cell bodies and dendrites at the end-stage of disease. Nonetheless, the biochemically-detectable insoluble SQSTM1 and poly-ubiquitinated proteins were significantly and progressively increased in the spinal cord of SQSTM1;SOD1 H46R mice compared to SOD1 H46R mice. These results suggest that overexpression of SQSTM1 in SOD1 H46R mice accelerates disease onset by compromising the protein degradation pathways.

  334. Oral corticosteroid dosing regimen and long-term prognosis in generalised myasthenia gravis: a multicentre cross-sectional study in Japan. International-journal Peer-reviewed

    Imai T, Utsugisawa K, Murai H, Tsuda E, Nagane Y, Suzuki Y, Minami N, Uzawa A, Kawaguchi N, Masuda M, Konno S, Suzuki H, Akaishi T, Aoki M

    Journal of neurology, neurosurgery, and psychiatry 89 (5) 513-517 2018/05

    DOI: 10.1136/jnnp-2017-316625  

    ISSN: 0022-3050

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    OBJECTIVE: We examined the correlation between the dosing regimen of oral prednisolone (PSL) and the achievement of minimal manifestation status or better on PSL ≤5 mg/day lasting >6 months (the treatment target) in patients with generalised myasthenia gravis (MG). METHODS: We classified 590 patients with generalised MG into high-dose (n=237), intermediate-dose (n=187) and low-dose (n=166) groups based on the oral PSL dosing regimen, and compared the clinical characteristics, previous treatments other than PSL and prognosis between three groups. The effect of oral PSL dosing regimen on the achievement of the treatment target was followed for 3 years of treatment. RESULTS: To achieve the treatment target, ORs for low-dose versus high-dose regimen were 10.4 (P<0.0001) after 1 year of treatment, 2.75 (P=0.007) after 2 years and 1.86 (P=0.15) after 3 years; and those for low-dose versus intermediate-dose regimen were 13.4 (P<0.0001) after 1 year, 3.99 (P=0.0003) after 2 years and 4.92 (P=0.0004) after 3 years. Early combined use of fast-acting treatment (OR: 2.19 after 2 years, P=0.02; OR: 2.11 after 3 years, P=0.04) or calcineurin inhibitors (OR: 2.09 after 2 years, P=0.03; OR: 2.36 after 3 years, P=0.02) was associated positively with achievement of treatment target. CONCLUSION: A low-dose PSL regimen with early combination of other treatment options may ensure earlier achievement of the treatment target in generalised MG.

  335. 長期経過中に敗血症で死亡した家族性広汎型筋萎縮性側索硬化症の一剖検例

    宮代 麻由, 鬼塚 裕美, 武田 貴裕, 山本 智子, 鈴木 直輝, 西山 亜由美, 青木 正志, 北川 一夫, 柴田 亮行

    日本病理学会会誌 107 (1) 532-532 2018/04

    Publisher: (一社)日本病理学会

    ISSN: 0300-9181

  336. Frequency and characteristics of the TBK1 gene variants in Japanese patients with sporadic amyotrophic lateral sclerosis. International-journal Peer-reviewed

    Genki Tohnai, Ryoichi Nakamura, Jun Sone, Masahiro Nakatochi, Daichi Yokoi, Masahisa Katsuno, Hazuki Watanabe, Hirohisa Watanabe, Mizuki Ito, Yuanzhe Li, Yuishin Izumi, Mitsuya Morita, Akira Taniguchi, Osamu Kano, Masaya Oda, Satoshi Kuwabara, Koji Abe, Ikuko Aiba, Koichi Okamoto, Kouichi Mizoguchi, Kazuko Hasegawa, Masashi Aoki, Nobutaka Hattori, Osamu Onodera, Hiroya Naruse, Jun Mitsui, Yuji Takahashi, Jun Goto, Hiroyuki Ishiura, Shinichi Morishita, Jun Yoshimura, Koichiro Doi, Shoji Tsuji, Kenji Nakashima, Ryuji Kaji, Naoki Atsuta, Gen Sobue

    Neurobiology of aging 64 158.e15-158.e19-158.e19 2018/04

    DOI: 10.1016/j.neurobiolaging.2017.12.005  

    ISSN: 0197-4580

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    Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease, and the etiology of sporadic ALS is generally unknown. The TANK-binding kinase 1 (TBK1) gene was identified as an ALS gene contributing to a predisposition toward ALS. To reveal the frequency and characteristics of variants of the TBK1 gene in sporadic ALS patients in Japan, we analyzed the TBK1 gene by exome sequencing in a large Japanese cohort of 713 sporadic ALS patients and 800 controls. We identified known or potentially toxic rare variants of TBK1 gene in 9 patients (1.26%) with sporadic ALS, including 4 novel missense variants (p.V23I, p.H322R, p.R358C, and p.T478I) and 3 loss-of-function variants (p.R357X, p.P378_I379del, and p.T419_G420del). The odds ratio between sporadic ALS patients and controls was 10.2 (p = 0.008, 95% confidence interval = 1.67-62.47). These findings support the contribution of TBK1 to the etiology of sporadic ALS in Japanese patients.

  337. Myelin oligodendrocyte glycoprotein immunoglobulin G-associated disease: An overview

    Kazuo Fujihara, Douglas K. Sato, Ichiro Nakashima, Toshiyuki Takahashi, Kimihiko Kaneko, Ryo Ogawa, Tetsuya Akaishi, Yuki Matsumoto, Yoshiki Takai, Shuhei Nishiyama, Hiroshi Kuroda, Tatsuro Misu, Masashi Aoki

    Clinical and Experimental Neuroimmunology 9 48-55 2018/03

    Publisher: Wiley-Blackwell

    DOI: 10.1111/cen3.12434  

    ISSN: 1759-1961

    eISSN: 1759-1961

  338. Parkinson's disease-linked DNAJC13 mutation aggravates alpha-synuclein-induced neurotoxicity through perturbation of endosomal trafficking. International-journal Peer-reviewed

    Shun Yoshida, Takafumi Hasegawa, Mari Suzuki, Naoto Sugeno, Junpei Kobayashi, Morio Ueyama, Mitsunori Fukuda, Akemi Ido-Fujibayashi, Kiyotoshi Sekiguchi, Michinori Ezura, Akio Kikuchi, Toru Baba, Atsushi Takeda, Hideki Mochizuki, Yoshitaka Nagai, Masashi Aoki

    Human molecular genetics 27 (5) 823-836 2018/03/01

    DOI: 10.1093/hmg/ddy003  

    ISSN: 0964-6906

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    Mutations in DNAJC13 gene have been linked to familial form of Parkinson's disease (PD) with Lewy pathology. DNAJC13 is an endosome-related protein and believed to regulate endosomal membrane trafficking. However, the mechanistic link between DNAJC13 mutation and α-synuclein (αSYN) pathology toward neurodegeneration remains poorly understood. In this study, we showed that PD-linked N855S-mutant DNAJC13 caused αSYN accumulation in the endosomal compartment, presumably due to defective cargo trafficking from the early endosome to the late and/or recycling endosome. In vivo experiments using human αSYN transgenic flies showed that mutant DNAJC13 not only increased the amount of insoluble αSYN in fly head but also induced dopaminergic neurodegeneration, rough eye phenotype and age-dependent locomotor impairment. Together, these findings suggest that DNAJC13 mutation perturbs multi-directional endosomal trafficking, resulting in the aberrant endosomal retention of αSYN, which might predispose to the neurodegenerative process that leads to PD.

  339. Rostrocaudal areal patterning of human PSC-derived cortical neurons by FGF8 signaling Peer-reviewed

    Kent Imaizumi, Koki Fujimori, Seiji Ishii, Asako Otomo, Yasushi Hosoi, Hiroaki Miyajima, Hitoshi Warita, Masashi Aoki, Shinji Hadano, Wado Akamatsu, Hideyuki Okano

    eNeuro 5 (2) 2018/03/01

    Publisher: Society for Neuroscience

    DOI: 10.1523/ENEURO.0368-17.2018  

    ISSN: 2373-2822

  340. Aberrant astrocytic expression of chondroitin sulfate proteoglycan receptors in a rat model of amyotrophic lateral sclerosis Peer-reviewed

    Tomomi Shijo, Hitoshi Warita, Naoki Suzuki, Yasuo Kitajima, Kensuke Ikeda, Tetsuya Akiyama, Hiroya Ono, Shio Mitsuzawa, Ayumi Nishiyama, Rumiko Izumi, Masashi Aoki

    JOURNAL OF NEUROSCIENCE RESEARCH 96 (2) 222-233 2018/02

    DOI: 10.1002/jnr.24127  

    ISSN: 0360-4012

    eISSN: 1097-4547

  341. DnaJ/Hsp40 family and Parkinson's disease Peer-reviewed

    Takafumi Hasegawa, Shun Yoshida, Naoto Sugeno, Junpei Kobayashi, Masashi Aoki

    Frontiers in Neuroscience 11 (JAN) 743 2018/01/10

    Publisher: Frontiers Media S.A.

    DOI: 10.3389/fnins.2017.00743  

    ISSN: 1662-4548

    eISSN: 1662-453X

  342. PEG‐J tube breakage in a patient with Parkinson's disease receiving levodopa‐carbidopa intestinal gel therapy Peer-reviewed

    Temma Soga, Naoto Sugeno, Toru Baba, Xiaoyi Jin, Tomoyuki Koike, Takafumi Hasegawa, Masashi Aoki

    Neurology and Clinical Neuroscience 6 (6) 197-198 2018

    DOI: 10.1111/ncn3.12220  

    ISSN: 2049-4173

  343. Fingolimod-associated PML with mild IRIS in MS International-journal Peer-reviewed

    Shuhei Nishiyama, Tatsuro Misu, Yukiko Shishido-Hara, Kazuo Nakamichi, Masayuki Saijo, Yoshiki Takai, Kentarou Takei, Naoki Yamamoto, Hiroshi Kuroda, Ryuta Saito, Mika Watanabe, Teiji Tominaga, Ichiro Nakashima, Kazuo Fujihara, Masashi Aoki

    Neurology: Neuroimmunology and NeuroInflammation 5 (1) e415 2018/01/01

    DOI: 10.1212/NXI.0000000000000415  

    ISSN: 2332-7812

    eISSN: 2332-7812

  344. Subclinical retinal atrophy in the unaffected fellow eyes of multiple sclerosis and neuromyelitis optica Peer-reviewed

    Tetsuya Akaishi, Kimihiko Kaneko, Noriko Himori, Takayuki Takeshita, Toshiyuki Takahashi, Toru Nakazawa, Masashi Aoki, Ichiro Nakashima

    Journal of Neuroimmunology 313 10-15 2017/12/15

    Publisher: Elsevier B.V.

    DOI: 10.1016/j.jneuroim.2017.10.001  

    ISSN: 1872-8421 0165-5728

  345. 視神経脊髄炎関連疾患に対する経口ステロイド維持療法の最適化

    高井 良樹, 中島 一郎, 三須 建郎, 黒田 宙, 西山 修平, 高橋 利幸, 藤原 一男, 青木 正志

    神経治療学 34 (6) S221-S221 2017/11

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  346. Open-label 24-week extension study of edaravone (MCI-186) in amyotrophic lateral sclerosis

    Koji Abe, Masashi Aoki, Shoji Tsuji, Yasuto Itoyama, Gen Sobue, Masanori Togo, Chikuma Hamada, Hidenao Sasaki, Ichiro Yabe, Shizuki Doi, Hitoshi Warita, Takashi Imai, Hiroaki Ito, Mitsumasa Fukuchi, Etsuko Osumi, Manabu Wada, Imaharu Nakanoy, Mitsuya Morita, Katsuhisa Ogata, Yuichi Maruki, Kimiko Ito, Osamu Kano, Mineo Yamazaki, Yuji Takahashi, Hiroyuki Ishiura, Mieko Ogino, Ryoko Koike, Chiho Ishida, Tsuyoshi Uchiyama, Koichi Mizoguchi, Tomokazu Obi, Hirohisa Watanabe, Naoki Atsuta, Ikuko Aiba, Akira Taniguchi, Hideyuki Sawada, Takanori Hazama, Harutoshi Fujimura, Hirofumi Kusaka, Takenobu Kunieda, Hitoshi Kikuchi, Hidenori Matsuo, Hidetsugu Ueyama, Kazutoshi Uekawa, Masahiko Tanaka, Makoto Akimoto, Kazue Nakamura, Masaki Ueda, Kuniko Kotani, Hiroshi Matsui, Takatomo Yoneoka, Kazunori Morimoto, Kouichi Sasaki, Manabu Hirai, Aiko Murakami, Tomoko Natori, Rie Sumii, Hidetomo Terai, Takuya Kudou, Fumihiro Takahashi, Tomohisa Iwasaki, Kazuoki Kondo, Hiide Yoshino

    Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 18 55-63 2017/10/31

    DOI: 10.1080/21678421.2017.1364269  

    ISSN: 2167-8421

    eISSN: 2167-9223

  347. Exploratory double-blind, parallel-group, placebo-controlled extension study of edaravone (MCI-186) in amyotrophic lateral sclerosis

    Koji Abe, Yasuto Itoyama, Shoji Tsuji, Gen Sobue, Masashi Aoki, Manabu Doyu, Chikuma Hamada, Hidenao Sasaki, Asako Takei, Isao Yamashita, Takashi Imai, Imaharu Nakanoyy, Koichi Okamoto, Yuichi Maruki, Shuichi Mishima, Jin Nishimiya, Yasuo Iwasaki, Mineo Yamazaki, Yuji Takahashi, Mieko Ogino, Yutaka Ogino, Masafumi Ogawa, Tetsumasa Kamei, Tsuyoshi Uchiyama, Hirohisa Watanabe, Yasumasa Kokubo, Hideyuki Sawada, Takanori Hazama, Fumiharu Kimura, Harutoshi Fujimura, Hirofumi Kusaka, Tsukasa Hashimoto, Takeshi Yamada, Yuji Kanamori, Kenji Yamasaki, Shizuma Kaku, Hitoshi Kikuchi, Shigehiro Imamura, Seiichiro Sugimoto, Masahiko Kishi, Masahiko Tanaka, Makoto Akimoto, Kazue Nakamura, Hiroshi Naito, Aiko Murakami, Hajime Sakamoto, Takatomo Yoneoka, Katsuyuki Enjoji, Junko Ogawa, Kiyoe Yano, Makiko Yashiro, Manabu Hirai, Keiko Furuta, Kouichi Sasaki, Youichi Shiide, Gen Takayanagi, Fumihiro Takahashi, Tomohisa Iwasaki, Kazuoki Kondo, Hiide Yoshino

    Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 18 20-31 2017/10/31

    DOI: 10.1080/21678421.2017.1362000  

    ISSN: 2167-8421

    eISSN: 2167-9223

  348. Five-year history of dysphagia as a sole initial symptom in inclusion body myositis Peer-reviewed

    Saori Shibata, Rumiko Izumi, Tomonori Hara, Ryuji Ohshima, Naoko Nakamura, Naoki Suzuki, Hiroshi Kuroda, Masashi Aoki, Kengo Kato, Yukio Katori, Maki Tateyama

    JOURNAL OF THE NEUROLOGICAL SCIENCES 381 325-327 2017/10

    DOI: 10.1016/j.jns.2017.09.014  

    ISSN: 0022-510X

    eISSN: 1878-5883

  349. EARLY FAST-ACTING TREATMENT STRATEGY AGAINST GENERALIZED MYASTHENIA GRAVIS

    Kimiaki Utsugisawa, Yuriko Nagane, Tetsuya Akaishi, Yasushi Suzuki, Tomihiro Imai, Emiko Tsuda, Naoya Minami, Akiyuki Uzawa, Naoki Kawaguchi, Masayuki Masuda, Shingo Konno, Hidekazu Suzuki, Hiroyuki Murai, Masashi Aoki

    MUSCLE & NERVE 55 (6) 794-801 2017/06

    DOI: 10.1002/mus.25397  

    ISSN: 0148-639X

    eISSN: 1097-4598

  350. Bilateral frontal cortex encephalitis and paraparesis in a patient with anti-MOG antibodies Peer-reviewed

    Fujimori, Juichi, Takai, Yoshiki, Nakashima, Ichiro, Sato, Douglas Kazutoshi, Takahashi, Toshiyuki, Kaneko, Kimihiko, Nishiyama, Shuhei, Watanabe, Mika, Tanji, Hiroaki, Kobayashi, Michiko, Misu, Tatsuro, Aoki, Masashi, Fujihara, Kazuo

    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 88 (6) 534-536 2017/06

    DOI: 10.1136/jnnp-2016-315094  

    ISSN: 0022-3050

    eISSN: 1468-330X

  351. Comprehensive targeted next-generation sequencing in Japanese familial amyotrophic lateral sclerosis. International-journal Peer-reviewed

    Ayumi Nishiyama, Tetsuya Niihori, Hitoshi Warita, Rumiko Izumi, Tetsuya Akiyama, Masaaki Kato, Naoki Suzuki, Yoko Aoki, Masashi Aoki

    Neurobiology of aging 53 194.e1-194.e8-194.e8 2017/05

    DOI: 10.1016/j.neurobiolaging.2017.01.004  

    ISSN: 0197-4580

    More details Close

    Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by loss of motor neurons. We have recently identified SOD1 and FUS mutations as the most common causes in a consecutive series of 111 familial ALS pedigrees in Japan. To reveal possible genetic causes for the remaining 51 patients with familial ALS (45 pedigrees), we performed targeted next-generation sequencing of 35 known ALS/motor neuron diseases-related genes. Known variants in ANG, OPTN, SETX, and TARDBP were identified in 6 patients. A novel likely pathogenic homozygous variant in ALS2 was identified in 1 patient. In addition, 18 patients harbored 1-3 novel variants of uncertain significance, whereas hexanucleotide repeat expansions in C9ORF72 were not detected using repeat-primed polymerase chain reaction. Collectively, in our Japanese cohort, the frequencies of SOD1, FUS, SETX, TARDBP, ANG, and OPTN variants were 32%, 11%, 2%, 2%, 1%, and 1%, respectively. These findings indicate considerable differences in the genetic variations associated with familial ALS across populations. Further genetic analyses and functional studies of novel variants are warranted.

  352. Whole brain and grey matter volume of Japanese patients with multiple sclerosis Peer-reviewed

    Tetsuya Akaishi, Ichiro Nakashima, Shunji Mugikura, Masashi Aoki, Kazuo Fujihara

    JOURNAL OF NEUROIMMUNOLOGY 306 68-75 2017/05

    DOI: 10.1016/j.jneuroim.2017.03.009  

    ISSN: 0165-5728

    eISSN: 1872-8421

  353. Membrane Trafficking Illuminates a Path to Parkinson's Disease Peer-reviewed

    Takafumi Hasegawa, Naoto Sugeno, Akio Kikuchi, Toru Baba, Masashi Aoki

    TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE 242 (1) 63-76 2017/05

    DOI: 10.1620/tjem.242.63  

    ISSN: 0040-8727

    eISSN: 1349-3329

  354. Impact of the Great East Japan Earthquake in 2011 on MS and NMOSD: a study in Sendai, Japan Peer-reviewed

    Kanamori, Yoko, Nakashima, Ichiro, Takai, Yoshiki, Misu, Tatsuro, Kuroda, Hiroshi, Nishiyama, Shuhei, Takahashi, Toshiyuki, Sato, Shigeru, Fujimori, Juichi, Higuchi, Jun, Itoyama, Yasuto, Aoki, Masashi, Fujihara, Kazuo

    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 88 (4) 362-+ 2017/04

    DOI: 10.1136/jnnp-2016-313890  

    ISSN: 0022-3050

    eISSN: 1468-330X

  355. Pathomechanisms of Anti-Cytosolic 5 '-Nucleotidase 1A Autoantibodies in Sporadic Inclusion Body Myositis Peer-reviewed

    Nozomu Tawara, Satoshi Yamashita, Xiao Zhang, Mai Korogi, Ziwei Zhang, Tsukasa Doki, Yoshimasa Matsuo, Shunya Nakane, Yasushi Maeda, Kazuma Sugie, Naoki Suzuki, Masashi Aoki, Yukio Ando

    ANNALS OF NEUROLOGY 81 (4) 512-525 2017/04

    DOI: 10.1002/ana.24919  

    ISSN: 0364-5134

    eISSN: 1531-8249

  356. Disseminated cerebral amyloid angiopathy-related inflammation manifesting as non-convulsive status epilepticus

    Yasuaki Watanabe, Hiroshi Kuroda, Shuhei Nishiyama, Junpei Kobayashi, Kazutaka Jin, Masashi Aoki

    Neurology and Clinical Neuroscience 5 (2) 65-67 2017/03

    Publisher: Wiley

    DOI: 10.1111/ncn3.12104  

    ISSN: 2049-4173

  357. 神経変性疾患における自動車運転事故のリスクファクター パーキンソン病における検討

    安藤 利奈, 矢部 勇人, 西川 典子, 永井 将弘, 饗場 郁子, 長谷川 一子, 青木 正志, 深江 治郎, 坪井 義夫, 野元 正弘

    日本内科学会雑誌 106 (Suppl.) 259-259 2017/02

    Publisher: (一社)日本内科学会

    ISSN: 0021-5384

    eISSN: 1883-2083

  358. Adult MOG-Igg-Positive, Benign, Unilateral, Cerebral Cortical Encephalitis with Epileptic Seizure Peer-reviewed

    Ryo Ogawa, Ichiro Nakashima, Toshiyuki Takahashi, Hirohiko Ono, Kimihiko Kaneko, Tetsuya Akaishi, Kazuhiro Kurosawa, Yoshiki Takai, Douglas Kazutoshi Sato, Shuhei Nishiyama, Tatsuro Misu, Hiroshi Kuroda, Kazuo Fujihara, Masashi Aoki

    MULTIPLE SCLEROSIS JOURNAL 23 (2) 352-352 2017/02

    ISSN: 1352-4585

    eISSN: 1477-0970

  359. Elevated Cerebrospinal Fluid-CRMP5 As A Biomarker of Damage to Astrocyte Foot Process and Growth Corn in AQP4-Igg-Seropositve NMOSD Peer-reviewed

    Shuhei Nishiyama, Tatsuro Misu, Ichiro Nakashima, Toshiyuki Takahashi, Kazuo Fujihara, Masashi Aoki

    MULTIPLE SCLEROSIS JOURNAL 23 (2) 319-320 2017/02

    ISSN: 1352-4585

    eISSN: 1477-0970

  360. Social disadvantages associated with myasthenia gravis and its treatment: a multicentre cross-sectional study Peer-reviewed

    Yuriko Nagane, Hiroyuki Murai, Tomihiro Imai, Daisuke Yamamoto, Emiko Tsuda, Naoya Minami, Yasushi Suzuki, Tetsuya Kanai, Akiyuki Uzawa, Naoki Kawaguchi, Masayuki Masuda, Shingo Konno, Hidekazu Suzuki, Masashi Aoki, Kimiaki Utsugisawa

    BMJ OPEN 7 (2) e013278 2017/02

    DOI: 10.1136/bmjopen-2016-013278  

    ISSN: 2044-6055

  361. [Therapeutic development for GNE myopathy.] Peer-reviewed

    Suzuki N, Izumi R, Kato M, Warita H, Aoki M

    Clinical calcium 27 (3) 429-434 2017

    ISSN: 0917-5857

  362. Clinical trial networks for rare diseases

    Aoki Masashi

    Neurological Therapeutics 33 (6) 619-620 2017

    Publisher: Japanese Society of Neurological Therapeutics

    DOI: 10.15082/jsnt.33.6_619  

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    <p>Therapeutic development in rare diseases shares many challenges, such as incomplete understanding of natural history to design clinical trials, and difficulties of recruiting patients to participation. To secure clinical studies and clinical research at national university hospitals in Japan, National University Hospital Clinical Research Promotion Initiative (NUH–CRPI) founded in October 2012. The topic group (TG2) promotes information sharing, standardization and coordination, and discusses the network of national university hospitals. They set up the web system of feasibility study assessing capacity in university hospitals for clinical trials in rare diseases. The support and training program for translational research that was initiated by the Ministry of Education, Culture, Sports, Science and Technology was launched in 2007. The second term of Translational Research Network Program started in 2012. In this program, they are setting up the patient registry system for screening for eligibility and enrollment in clinical trials.</p>

  363. Exploratory double-blind, parallel-group, placebo-controlled study of edaravone(MCI-186) in amyotrophic lateral sclerosis (Japan ALS severity classification: Grade 3, requiring assistance for eating, excretion or ambulation)

    Koji Abe, Yasuto Itoyama, Shoji Tsuji, Gen Sobue, Masashi Aoki, Manabu Doyu, Chikuma Hamada, Shizuki Doi, Katsuhisa Ogata, Kouichi Mizoguchi, Ikuko Aiba, Hidenori Matsu, Masahiko Tanaka, Makoto Akimoto, Kazue Nakamura, Ric Sumii, Takatomo Yoneoka, Katsuyuki Enjoji, Makiko Yashiro, Fumihiro Takahashi, Tomohisa Iwasaki, Kazuoki Kondo, Hiide Yoshino

    AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION 18 40-48 2017

    DOI: 10.1080/21678421.2017.1361441  

    ISSN: 2167-8421

    eISSN: 2167-9223

  364. A post-hoc subgroup analysis of outcomes in the first phase III clinical study of edaravone (MCI-186) in amyotrophic lateral sclerosis

    Koji Abe, Yasuto Itoyarna, Shoji Tsuji, Gen Sobue, Masashi Aoki, Manabu Doyu, Chikuma Hamada, Masanori Togo, Takatomo Yoneoka, Masahiko Tanaka, Makoto Akimotot, Kazue Nakamura, Fumihiro Takahashi, Kazuoki Kondo, Hiide Yoshino

    AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION 18 11-19 2017

    DOI: 10.1080/21678421.2017.1363780  

    ISSN: 2167-8421

    eISSN: 2167-9223

  365. Longitudinal study of cognitive and cerebral metabolic changes in Parkinson's disease Peer-reviewed

    Toru Baba, Yoshiyuki Hosokai, Yoshiyuki Nishio, Akio Kikuchi, Kazumi Hirayama, Kyoko Suzuki, Takafumi Hasegawa, Masashi Aoki, Atsushi Takeda, Etsuro Mori

    JOURNAL OF THE NEUROLOGICAL SCIENCES 372 288-293 2017/01

    DOI: 10.1016/j.jns.2016.11.068  

    ISSN: 0022-510X

    eISSN: 1878-5883

  366. Altered Tau Isoform Ratio Caused by Loss of FUS and SFPQ Function Leads to FTLD-like Phenotypes Peer-reviewed

    Shinsuke Ishigaki, Yusuke Fujioka, Yohei Okada, Yuichi Riku, Tsuyoshi Udagawa, Daiyu Honda, Satoshi Yokoi, Kuniyuki Endo, Kensuke Ikenaka, Shinnosuke Takagi, Yohei Iguchi, Naruhiko Sahara, Akihiko Takashima, Hideyuki Okano, Mari Yoshida, Hitoshi Warita, Masashi Aoki, Hirohisa Watanabe, Haruo Okado, Masahisa Katsuno, Gen Sobue

    CELL REPORTS 18 (5) 1118-1131 2017/01

    DOI: 10.1016/j.celrep.2017.01.013  

    ISSN: 2211-1247

  367. Questionnaire survey on the process of specialty training in neurology in Japan Peer-reviewed

    Masahiro Sonoo, Kazutoshi Nishiyama, Tetsuo Ando, Katsuro Shindo, Takashi Kanda, Masashi Aoki, Satoshi Kamei, Seiji Kikuchi, Susumu Kusunoki, Norihiro Suzuki, Gen Sobue, Kenji Nakashima, Hideo Hara, Koichi Hirata, Hidehiro Mizusawa, Hiroyuki Murai, Miho Murata, Hideki Mochizuki, Ryosuke Takahashi, Jun-Ichi Kira

    Clinical Neurology 57 (7) 402-410 2017

    Publisher: Societas Neurologica Japonica

    DOI: 10.5692/clinicalneurol.cn-001061  

    ISSN: 0009-918X

  368. パーキンソン病患者の自動車運転の調査と、安全運転へのアドバイス方法の研究

    安藤 利奈, 山崎 知恵子, 岩城 寛尚, 西川 典子, 永井 将弘, 饗場 郁子, 青木 正志, 坪井 義夫, 中島 健二, 野元 正弘

    臨床神経学 56 (Suppl.) S406-S406 2016/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  369. Tardily accelerated neurologic deterioration in two-step thallium intoxication Peer-reviewed

    Hiroshi Kuroda, Yoshiyuki Mukai, Shuhei Nishiyama, Takayuki Takeshita, Maki Tateyama, Atsushi Takeda, Masashi Aoki

    JOURNAL OF CLINICAL NEUROSCIENCE 34 234-236 2016/12

    DOI: 10.1016/j.jocn.2016.09.003  

    ISSN: 0967-5868

    eISSN: 1532-2653

  370. Multiple sclerosis lesion in the medulla oblongata in a patient with takotsubo cardiomyopathy. Peer-reviewed

    Kozu K, Suzuki H, Nishiyama S, Yaoita N, Yamamoto S, Tatebe S, Miura M, Aoki T, Hao K, Matsumoto Y, Sugimura K, Aoki M, Shimokawa H

    International journal of cardiology 222 980-981 2016/11

    DOI: 10.1016/j.ijcard.2016.08.128  

    ISSN: 0167-5273

  371. Myelin injury without astrocytopathy in neuroinflammatory disorders with MOG antibodies Peer-reviewed

    Kimihiko Kaneko, Douglas Kazutoshi Sato, Ichiro Nakashima, Shuhei Nishiyama, Satoru Tanaka, Romain Marignier, Jae-Won Hyun, Luana Michelli de Oliveira, Markus Reindl, Thomas Seifert-Held, Maria Sepulveda, Sasitorn Siritho, Patrick Joseph Waters, Kazuhiro Kurosawa, Tetsuya Akaishi, Hiroshi Kuroda, Tatsuro Misu, Naraporn Prayoonwiwat, Thomas Berger, Albert Saiz, Ho Jin Kim, Kyoichi Nomura, Dagoberto Callegaro, Kazuo Fujihara, Masashi Aoki

    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 87 (11) 1257-U128 2016/11

    DOI: 10.1136/jnnp-2015-312676  

    ISSN: 0022-3050

    eISSN: 1468-330X

  372. Hypoxia-like tissue injury and glial response contribute to Balo concentric lesion development Peer-reviewed

    Yoshiki Takai, Tatsuro Misu, Shuhei Nishiyama, Hirohiko Ono, Hiroshi Kuroda, Ichiro Nakashima, Ryuta Saito, Masayuki Kanamori, Yukihiko Sonoda, Toshihiro Kumabe, Shunji Mugikura, Mika Watanabe, Masashi Aoki, Kazuo Fujihara

    NEUROLOGY 87 (19) 2000-2005 2016/11

    DOI: 10.1212/WNL.0000000000003308  

    ISSN: 0028-3878

    eISSN: 1526-632X

  373. Multicenter questionnaire survey for sporadic inclusion body myositis in Japan Peer-reviewed

    Naoki Suzuki, Madoka Mori-Yoshimura, Satoshi Yamashita, Satoshi Nakano, Ken-ya Murata, Yukie Inamori, Naoko Matsui, En Kimura, Hirofumi Kusaka, Tomoyoshi Kondo, Itsuro Higuchi, Ryuji Kaji, Maki Tateyama, Rumiko Izumi, Hiroya Ono, Masaaki Kato, Hitoshi Warita, Toshiaki Takahashi, Ichizo Nishino, Masashi Aoki

    ORPHANET JOURNAL OF RARE DISEASES 11 (1) 146 2016/11

    DOI: 10.1186/s13023-016-0524-x  

    ISSN: 1750-1172

  374. Response to treatment of myasthenia gravis according to clinical subtype Peer-reviewed

    Tetsuya Akaishi, Yasushi Suzuki, Tomihiro Imai, Emiko Tsuda, Naoya Minami, Yuriko Nagane, Akiyuki Uzawa, Naoki Kawaguchi, Masayuki Masuda, Shingo Konno, Hidekazu Suzuki, Hiroyuki Murai, Masashi Aoki, Kimiaki Utsugisawa

    BMC NEUROLOGY 16 (1) 225 2016/11

    DOI: 10.1186/s12883-016-0756-3  

    ISSN: 1471-2377

  375. 筋強直性ジストロフィー患者の夜間経皮的PCO2の測定に関する検討 Peer-reviewed

    杉村 容子, 高橋 俊明, 太田 卓志, 滝口 尚子, 下瀬川 康子, 谷口 さやか, 大泉 英樹, 田中 洋康, 吉岡 勝, 武田 篤, 青木 正志

    筋ジストロフィー医療研究 3 62-62 2016/10

    Publisher: 筋ジストロフィー医療研究会

    ISSN: 2433-1708

  376. 遺伝子治療可能な日本人dysferlinopathyの割合 Peer-reviewed

    高橋 俊明, 八木沼 智香子, 鈴木 直輝, 井泉 瑠美子, 小野 洋也, 杉村 容子, 島倉 奈緒子, 谷口 さやか, 下瀬川 康子, 大泉 英樹, 田中 洋康, 吉岡 勝, 武田 篤, 青木 正志

    筋ジストロフィー医療研究 3 91-91 2016/10

    Publisher: 筋ジストロフィー医療研究会

    ISSN: 2433-1708

  377. Deficient RNA-editing enzyme ADAR2 in an amyotrophic lateral sclerosis patient with a FUS(P525L) mutation. International-journal Peer-reviewed

    Hitoshi Aizawa, Takuto Hideyama, Takenari Yamashita, Takashi Kimura, Naoki Suzuki, Masashi Aoki, Shin Kwak

    Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 32 128-9 2016/10

    DOI: 10.1016/j.jocn.2015.12.039  

    ISSN: 0967-5868

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    Mutations in the fused in sarcoma (FUS) gene can cause amyotrophic lateral sclerosis (ALS), and FUS gene mutations have been reported in sporadic ALS patients with basophilic cytoplasmic inclusions. Deficiency of adenosine deaminase acting on RNA 2 (ADAR2), an enzyme that specifically catalyzes GluA2 Q/R site-editing, has been reported in considerable proportions of spinal motor neurons of the majority of sporadic ALS patients. We describe the relationship between GluA2 Q/R site-editing efficiency and FUS-positive inclusions in a patient with FUS(P525L). A 24-year-old woman with ALS presented with basophilic cytoplasmic inclusions, significantly reduced GluA2 Q/R site-editing efficiency in the spinal motor neurons, and markedly decreased ADAR2 mRNA levels. Neuropathologic examination showed that not all spinal motor neurons expressed ADAR2 and revealed FUS-positive cytoplasmic inclusions in motor neurons irrespective of ADAR2 immunoreactivity. There were no phosphorylated transactive response (TAR) DNA-binding protein 43 kDa (TDP-43)-positive inclusions, indicating that there was no tight correlation between ADAR2 deficiency and TDP-43 deposition. ADAR2 deficiency can occur in ALS patients with a FUS(P525L) mutation and is unrelated to the presence of FUS-positive inclusions. FUS-associated ALS may share neurodegenerative characteristics with classical sporadic ALS.

  378. Pregnancy-related relapse risk factors in women with anti-AQP4 antibody positivity and neuromyelitis optica spectrum disorder Peer-reviewed

    Yuko Shimizu, Kazuo Fujihara, Takashi Ohashi, Ichiro Nakashima, Kazumasa Yokoyama, Ryotaro Ikeguch, Toshiyuki Takahashi, Tatsuro Misu, Satoru Shimizu, Masashi Aoki, Kazuo Kitagawa

    MULTIPLE SCLEROSIS JOURNAL 22 (11) 1413-1420 2016/10

    DOI: 10.1177/1352458515583376  

    ISSN: 1352-4585

    eISSN: 1477-0970

  379. Different etiologies and prognoses of optic neuritis in demyelinating diseases Peer-reviewed

    Tetsuya Akaishi, Ichiro Nakashima, Takayuki Takeshita, Kimihiko Kaneko, Shunji Mugikura, Douglas Kazutoshi Sato, Toshiyuki Takahashi, Toru Nakazawa, Masashi Aoki, Kazuo Fujihara

    JOURNAL OF NEUROIMMUNOLOGY 299 152-157 2016/10

    DOI: 10.1016/j.jneuroim.2016.09.007  

    ISSN: 0165-5728

    eISSN: 1872-8421

  380. Genotype-phenotype relationships in familial amyotrophic lateral sclerosis with FUS/TLS mutations in Japan. International-journal Peer-reviewed

    Tetsuya Akiyama, Hitoshi Warita, Masaaki Kato, Ayumi Nishiyama, Rumiko Izumi, Chikako Ikeda, Masaki Kamada, Naoki Suzuki, Masashi Aoki

    Muscle & nerve 54 (3) 398-404 2016/09

    DOI: 10.1002/mus.25061  

    ISSN: 0148-639X

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    INTRODUCTION: We investigated possible genotype-phenotype correlations in Japanese patients with familial amyotrophic lateral sclerosis (FALS) carrying fused in sarcoma/translated in liposarcoma (FUS/TLS) gene mutations. METHODS: A consecutive series of 111 Japanese FALS pedigrees were screened for copper/zinc superoxide dismutase 1 (SOD1) and FUS/TLS gene mutations. Clinical data, including onset age, onset site, disease duration, and extramotor symptoms, were collected. RESULTS: Nine different FUS/TLS mutations were found in 12 pedigrees. Most of the patients with FUS/TLS-linked FALS demonstrated early onset in the brainstem/upper cervical region, and relatively short disease duration. A few mutations exhibited phenotypes that were distinct from typical cases. Frontotemporal dementia was present in 1 patient. CONCLUSIONS: This study revealed a characteristic phenotype in FUS/TLS-linked FALS patients in Japan. FUS/TLS screening is recommended in patients with FALS with this phenotype. Muscle Nerve 54: 398-404, 2016.

  381. The binding property of a monoclonal antibody against the extracellular domains of aquaporin-4 directs aquaporin-4 toward endocytosis Peer-reviewed

    Ping Huang, Yoshiki Takai, Osamu Kusano-Arai, Julia Ramadhanti, Hiroko Iwanari, Takayuki Miyauchi, Toshiko Sakihama, Jing-Yan Han, Masashi Aoki, Takao Hamakubo, Kazuo Fujihara, Masato Yasui, Yoichiro Abe

    Biochemistry and Biophysics Reports 7 77-83 2016/09/01

    Publisher: Elsevier B.V.

    DOI: 10.1016/j.bbrep.2016.05.017  

    ISSN: 2405-5808

  382. Functional links between SQSTM1 and ALS2 in the pathogenesis of ALS: cumulative impact on the protection against mutant SOD1-mediated motor dysfunction in mice. International-journal Peer-reviewed

    Hadano S, Mitsui S, Pan L, Otomo A, Kubo M, Sato K, Ono S, Onodera W, Abe K, Chen X, Koike M, Uchiyama Y, Aoki M, Warabi E, Yamamoto M, Ishii T, Yanagawa T, Shang HF, Yoshii F

    Human molecular genetics 25 (15) 3321-3340 2016/08

    DOI: 10.1093/hmg/ddw180  

    ISSN: 0964-6906

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    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by a selective loss of motor neurons in the brain and spinal cord. Multiple toxicity pathways, such as oxidative stress, misfolded protein accumulation, and dysfunctional autophagy, are implicated in the pathogenesis of ALS. However, the molecular basis of the interplay between such multiple factors in vivo remains unclear. Here, we report that two independent ALS-linked autophagy-associated gene products; SQSTM1/p62 and ALS2/alsin, but not antioxidant-related factor; NFE2L2/Nrf2, are implicated in the pathogenesis in mutant SOD1 transgenic ALS models. We generated SOD1H46R mice either on a Nfe2l2-null, Sqstm1-null, or Sqstm1/Als2-double null background. Loss of SQSTM1 but not NFE2L2 exacerbated disease symptoms. A simultaneous inactivation of SQSTM1 and ALS2 further accelerated the onset of disease. Biochemical analyses revealed that loss of SQSTM1 increased the level of insoluble SOD1 at the intermediate stage of the disease, whereas no further elevation occurred at the end-stage. Notably, absence of SQSTM1 rather suppressed the mutant SOD1-dependent accumulation of insoluble polyubiquitinated proteins, while ALS2 loss enhanced it. Histopathological examinations demonstrated that loss of SQSTM1 accelerated motor neuron degeneration with accompanying the preferential accumulation of ubiquitin-positive aggregates in spinal neurons. Since SQSTM1 loss is more detrimental to SOD1H46R mice than lack of ALS2, the selective accumulation of such aggregates in neurons might be more insulting than the biochemically-detectable insoluble proteins. Collectively, two ALS-linked factors, SQSTM1 and ALS2, have distinct but additive protective roles against mutant SOD1-mediated toxicity by modulating neuronal proteostasis possibly through the autophagy-endolysosomal system.

  383. A mismatch between MRI lesions and SPECT hypoperfusion in tacrolimus-related encephalopathy. Peer-reviewed

    Shijo T, Nishiyama S, Mukai Y, Tateyama M, Kuroda H, Aoki M

    Journal of the neurological sciences 367 308-310 2016/08

    DOI: 10.1016/j.jns.2016.06.037  

    ISSN: 0022-510X

  384. Pseudo-perifascicular atrophy in the healing phase of Jo-1 antisynthetase syndrome. Peer-reviewed

    Tateyama M, Shibuya S, Sato H, Fujihara K, Aoki M

    Neuromuscular disorders : NMD 26 (8) 521-522 2016/08

    DOI: 10.1016/j.nmd.2016.06.003  

    ISSN: 0960-8966

  385. Prominent sensory involvement in a case of familial amyotrophic lateral sclerosis carrying the L8V SOD1 mutation Peer-reviewed

    Nisiyama A, Warita H, Takahashi T, Suzuki N, Nishiyama S, Tano O, Akiyama T, Watanabe Y, Takahashi K, Kuroda H, Kato M, Tateyama M, Niihori T, Aoki Y, Aoki M

    Clinical Neurology and Neurosurgery 150 194-196 2016/08

    DOI: 10.1016/j.clineuro.2016.08.008  

    ISSN: 0303-8467

    eISSN: 1872-6968

  386. A rapid functional decline type of amyotrophic lateral sclerosis is linked to low expression of TTN Peer-reviewed

    Hazuki Watanabe, Naoki Atsuta, Akihiro Hirakawa, Ryoichi Nakamura, Masahiro Nakatochi, Shinsuke Ishigaki, Aritoshi Iida, Shiro Ikegawa, Michiaki Kubo, Daichi Yokoi, Hirohisa Watanabe, Mizuki Ito, Masahisa Katsuno, Yuishin Izumi, Mitsuya Morita, Kazuaki Kanai, Akira Taniguchi, Ikuko Aiba, Koji Abe, Koichi Mizoguchi, Masaya Oda, Osamu Kano, Koichi Okamoto, Satoshi Kuwabara, Kazuko Hasegawa, Takashi Imai, Akihiro Kawata, Masashi Aoki, Shoji Tsuji, Kenji Nakashima, Ryuji Kaji, Gen Sobue

    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 87 (8) 851-858 2016/08

    DOI: 10.1136/jnnp-2015-311541  

    ISSN: 0022-3050

    eISSN: 1468-330X

  387. Brain Metabolic Changes of Cervical Dystonia with Spinocerebellar Ataxia Type 1 after Botulinum Toxin Therapy. Peer-reviewed

    Kikuchi A, Takeda A, Sugeno N, Miura E, Kato K, Hasegawa T, Baba T, Konno M, Oshima R, Watanuki S, Hiraoka K, Tashiro M, Aoki M

    Intern Med. 55 (14) 1919-1922 2016/07/15

    Publisher: The Japanese Society of Internal Medicine

    DOI: 10.2169/internalmedicine.55.5843.  

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    <p>We occasionally observe long-term remission of cervical dystonia after several botulinum toxin treatments. However, botulinum toxin transiently acts on neuromuscular junctions. We herein report that a cervical dystonia patient with spinocerebellar ataxia type 1 could have long-term remission as a result of the depression of hypermetabolism in the bilateral putamen and primary sensorimotor cortex after botulinum toxin therapy. We suggest that botulinum toxin impacts the central nervous system, causing prolonged improvement through the normalization of basal ganglia circuits in addition to its effects at neuromuscular junctions. </p>

  388. 近位筋優位の筋力低下を呈したFUS/TLS遺伝子変異を伴う家族性ALS(ALS6)の一例

    江浦 信之, 泉 哲石, 桐山 敬生, 島倉 奈緒子, 鈴木 直輝, 加藤 昌昭, 杉江 和馬, 青木 正志, 上野 聡

    臨床神経学 56 (7) 528-528 2016/07

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  389. Establishment of In Vitro FUS-Associated Familial Amyotrophic Lateral Sclerosis Model Using Human Induced Pluripotent Stem Cells. International-journal Peer-reviewed

    Naoki Ichiyanagi, Koki Fujimori, Masato Yano, Chikako Ishihara-Fujisaki, Takefumi Sone, Tetsuya Akiyama, Yohei Okada, Wado Akamatsu, Takuya Matsumoto, Mitsuru Ishikawa, Yoshinori Nishimoto, Yasuharu Ishihara, Tetsushi Sakuma, Takashi Yamamoto, Hitomi Tsuiji, Naoki Suzuki, Hitoshi Warita, Masashi Aoki, Hideyuki Okano

    Stem cell reports 6 (4) 496-510 2016/04/12

    DOI: 10.1016/j.stemcr.2016.02.011  

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    Amyotrophic lateral sclerosis (ALS) is a late-onset motor neuron disorder. Although its neuropathology is well understood, the cellular and molecular mechanisms are yet to be elucidated due to limitations in the currently available human genetic data. In this study, we generated induced pluripotent stem cells (iPSC) from two familial ALS (FALS) patients with a missense mutation in the fused-in sarcoma (FUS) gene carrying the heterozygous FUS H517D mutation, and isogenic iPSCs with the homozygous FUS H517D mutation by genome editing technology. These cell-derived motor neurons mimicked several neurodegenerative phenotypes including mis-localization of FUS into cytosolic and stress granules under stress conditions, and cellular vulnerability. Moreover, exon array analysis using motor neuron precursor cells (MPCs) combined with CLIP-seq datasets revealed aberrant gene expression and/or splicing pattern in FALS MPCs. These results suggest that iPSC-derived motor neurons are a useful tool for analyzing the pathogenesis of human motor neuron disorders.

  390. MRI and retinal abnormalities in isolated optic neuritis with myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies: a comparative study Peer-reviewed

    Tetsuya Akaishi, Douglas Kazutoshi Sato, Ichiro Nakashima, Takayuki Takeshita, Toshiyuki Takahashi, Hiroshi Doi, Kazuhiro Kurosawa, Kimihiko Kaneko, Hiroshi Kuroda, Shuhei Nishiyama, Tatsuro Misu, Toru Nakazawa, Kazuo Fujihara, Masashi Aoki

    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 87 (4) 446-+ 2016/04

    DOI: 10.1136/jnnp-2014-310206  

    ISSN: 0022-3050

    eISSN: 1468-330X

  391. Lesion length of optic neuritis impacts visual prognosis in neuromyelitis optica Peer-reviewed

    Tetsuya Akaishi, Ichiro Nakashima, Takayuki Takeshita, Shunji Mugikura, Douglas Kazutoshi Sato, Toshiyuki Takahashi, Shuhei Nishiyama, Kazuhiro Kurosawa, Tatsuro Misu, Toru Nakazawa, Masashi Aoki, Kazuo Fujihara

    JOURNAL OF NEUROIMMUNOLOGY 293 28-33 2016/04

    DOI: 10.1016/j.jneuroim.2016.02.004  

    ISSN: 0165-5728

    eISSN: 1872-8421

  392. On the Utility of MIBG SPECT/CT in Evaluating Cardiac Sympathetic Dysfunction in Lewy Body Diseases Peer-reviewed

    Hayato Odagiri, Toru Baba, Yoshiyuki Nishio, Osamu Iizuka, Minoru Matsuda, Kentaro Inoue, Akio Kikuchi, Takafumi Hasegawa, Masashi Aoki, Atsushi Takeda, Yasuyuki Taki, Etsuro Mori

    PLOS ONE 11 (4) e0152746 2016/04

    DOI: 10.1371/journal.pone.0152746  

    ISSN: 1932-6203

  393. ESCRT-0 dysfunction compromises autophagic degradation of protein aggregates and facilitates ER stress-mediated neurodegeneration via apoptotic and necroptotic pathways Peer-reviewed

    Ryuji Oshima, Takafumi Hasegawa, Keiichi Tamai, Naoto Sugeno, Shun Yoshida, Junpei Kobayashi, Akio Kikuchi, Toru Baba, Akira Futatsugi, Ikuro Sato, Kennichi Satoh, Atsushi Takeda, Masashi Aoki, Nobuyuki Tanaka

    SCIENTIFIC REPORTS 6 24997 2016/04

    DOI: 10.1038/srep24997  

    ISSN: 2045-2322

  394. Astrocyte Injury and Secondary Demyelination Induced by Intracerebral Injection of AQP4-IgG and Complement in Mouse Brain Peer-reviewed

    Takai Yoshiki, Abe Yoichiro, Misu Tasturo, Kurosawa Kazuhiro, Takahashi Toshiyuki, Kuroda Hiroshi, Nakashima Ichiro, Nishiyama Shuhei, Yasui Masato, Fujihara Kazuo, Aoki Masashi

    MULTIPLE SCLEROSIS JOURNAL 22 (3) 403-404 2016/03

    ISSN: 1352-4585

  395. RESPIRATORY AND CARDIAC FUNCTION IN JAPANESE PATIENTS WITH DYSFERLINOPATHY Peer-reviewed

    Atsuko Nishikawa, Madoka Mori-Yoshimura, Kazuhiko Segawa, Yukiko K. Hayashi, Toshiaki Takahashi, Yuko Saito, Ikuya Nonaka, Martin Krahn, Nicolas Levy, Jun Shimizu, Jun Mitsui, En Kimura, Jun Goto, Naohiro Yonemoto, Masashi Aoki, Ichizo Nishino, Yasushi Oya, Miho Murata

    MUSCLE & NERVE 53 (3) 394-401 2016/03

    DOI: 10.1002/mus.24741  

    ISSN: 0148-639X

    eISSN: 1097-4598

  396. Next-generation sequencing of 28 ALS-related genes in a Japanese ALS cohort Peer-reviewed

    Ryoichi Nakamura, Jun Sone, Naoki Atsuta, Genki Tohnai, Hazuki Watanabe, Daichi Yokoi, Masahiro Nakatochi, Hirohisa Watanabe, Mizuki Ito, Jo Senda, Masahisa Katsuno, Fumiaki Tanaka, Yuanzhe Li, Yuishin Izumi, Mitsuya Morita, Akira Taniguchi, Osamu Kano, Masaya Oda, Satoshi Kuwabara, Koji Abe, Ikuko Aiba, Koichi Okamoto, Kouichi Mizoguchi, Kazuko Hasegawa, Masashi Aoki, Nobutaka Hattori, Shoji Tsuji, Kenji Nakashima, Ryuji Kaji, Gen Sobue

    NEUROBIOLOGY OF AGING 39 219.e1-8 2016/03

    DOI: 10.1016/j.neurobiolaging.2015.11.030  

    ISSN: 0197-4580

    eISSN: 1558-1497

  397. Dorsal root enhancement in paraneoplastic sensory ataxic neuropathy with anti-Hu antibody Peer-reviewed

    Aya Shibui, Junpei Kobayashi, Hiroshi Kuroda, Masashi Aoki

    NEUROLOGY AND CLINICAL NEUROSCIENCE 4 (1) 22-24 2016/01

    DOI: 10.1111/ncn3.12020  

    ISSN: 2049-4173

  398. Altered white matter metabolism in delayed neurologic sequelae after carbon monoxide poisoning: A proton magnetic resonance spectroscopic study Peer-reviewed

    Hiroshi Kuroda, Kazuo Fujihara, Shunji Mugikura, Shoki Takahashi, Shigeki Kushimoto, Masashi Aoki

    JOURNAL OF THE NEUROLOGICAL SCIENCES 360 161-169 2016/01

    DOI: 10.1016/j.jns.2015.12.006  

    ISSN: 0022-510X

    eISSN: 1878-5883

  399. Corticotropin-Releasing Hormone Receptor 2 Gene Variants in Irritable Bowel Syndrome. International-journal Peer-reviewed

    Hazuki Komuro, Naoko Sato, Ayaka Sasaki, Naoki Suzuki, Michiko Kano, Yukari Tanaka, Yumi Yamaguchi-Kabata, Motoyori Kanazawa, Hitoshi Warita, Masashi Aoki, Shin Fukudo

    PloS one 11 (1) e0147817 2016

    DOI: 10.1371/journal.pone.0147817  

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    BACKGROUND: Corticotropin-releasing hormone (CRH) plays an important role in the pathophysiology of irritable bowel syndrome (IBS) and regulates the stress response through two CRH receptors (R1 and R2). Previously, we reported that a CRHR1 gene polymorphism (rs110402, rs242924, and rs7209436) and haplotypes were associated with IBS. However, the association between the CRHR2 gene and IBS was not investigated. We tested the hypothesis that genetic polymorphisms and haplotypes of CRHR2 are associated with IBS pathophysiology and negative emotion in IBS patients. METHODS: A total of 142 IBS patients and 142 healthy controls participated in this study. Seven single nucleotide polymorphisms (SNPs) of the CRHR2 gene (rs4722999, rs3779250, rs2240403, rs2267710, rs2190242, rs2284217, and rs2284220) were genotyped. Subjects' psychological states were evaluated using the Perceived-Stress Scale, the State-Trait Anxiety Inventory, and the Self-Rating Depression Scale. RESULTS: We found that rs4722999 and rs3779250, located in intronic region, were associated with IBS in terms of genotype frequency (rs4722999: P = 0.037; rs3779250: P = 0.017) and that the distribution of the major allele was significantly different between patients and controls. There was a significant group effect (controls vs. IBS), and a CRHR2 genotype effect was observed for three psychological scores, but the interaction was not significant. We found a haplotype of four SNPs (rs4722999, rs3779250, rs2240403, and rs2267710) and two SNPs (rs2284217 and rs2284220) in strong linkage disequilibrium (D' > 0.90). We also found that haplotypes of the CRHR2 gene were significantly different between IBS patients and controls and that they were associated with negative emotion. CONCLUSION: Our findings support the hypothesis that genetic polymorphisms and haplotypes of CRHR2 are related to IBS. In addition, we found associations between CRHR2 genotypes and haplotypes and negative emotion in IBS patients and controls. Further studies on IBS and the CRH system are warranted.

  400. Associations between Single-Nucleotide Polymorphisms in Corticotropin-Releasing Hormone-Related Genes and Irritable Bowel Syndrome. International-journal Peer-reviewed

    Ayaka Sasaki, Naoko Sato, Naoki Suzuki, Michiko Kano, Yukari Tanaka, Motoyori Kanazawa, Masashi Aoki, Shin Fukudo

    PloS one 11 (2) e0149322 2016

    DOI: 10.1371/journal.pone.0149322  

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    UNLABELLED: Irritable bowel syndrome (IBS) is a common functional disorder with distinct features of stress-related pathophysiology. A key mediator of the stress response is corticotropin-releasing hormone (CRH). Although some candidate genes have been identified in stress-related disorders, few studies have examined CRH-related gene polymorphisms. Therefore, we tested our hypothesis that single-nucleotide polymorphisms (SNPs) in CRH-related genes influence the features of IBS. METHODS: In total, 253 individuals (123 men and 130 women) participated in this study. They comprised 111 IBS individuals and 142 healthy controls. The SNP genotypes in CRH (rs28364015 and rs6472258) and CRH-binding protein (CRH-BP) (rs10474485) were determined by direct sequencing and real-time polymerase chain reaction. The emotional states of the subjects were evaluated using the State-Trait Anxiety Inventory, Perceived Stress Scale, and the Self-rating Depression Scale. RESULTS: Direct sequencing of the rs28364015 SNP of CRH revealed no genetic variation among the study subjects. There was no difference in the genotype distributions and allele frequencies of rs6472258 and rs10474485 between IBS individuals and controls. However, IBS subjects with diarrhea symptoms without the rs10474485 A allele showed a significantly higher emotional state score than carriers. CONCLUSIONS: These results suggest that the CRH and CRH-BP genes have no direct effect on IBS status. However, the CRH-BP SNP rs10474485 has some effect on IBS-related emotional abnormalities and resistance to psychosocial stress.

  401. Cancer-related Stroke due to Mural Thrombus in the Extracranial Carotid Artery Peer-reviewed

    Daisuke Ando, Junpei Kobayashi, Hiroshi Kuroda, Masashi Aoki

    INTERNAL MEDICINE 55 (11) 1497-1499 2016

    DOI: 10.2169/internalmedicine.55.6013  

    ISSN: 0918-2918

    eISSN: 1349-7235

  402. Intractable Hiccup in Demyelinating Disease with Anti-Myelin Oligodendrocyte Glycoprotein (MOG) Antibody Peer-reviewed

    Tetsuya Akaishi, Masatoshi Konno, Ichiro Nakashima, Masashi Aoki

    INTERNAL MEDICINE 55 (19) 2905-2906 2016

    DOI: 10.2169/internalmedicine.55.7146  

    ISSN: 0918-2918

    eISSN: 1349-7235

  403. Questionnaire survey on recruitment for Japanese Neurology Society Peer-reviewed

    Kazutoshi Nishiyama, Takahiro Amano, Masashi Aoki, Takashi Inuzuka, Takayuki Taniwaki, Itaru Toyoshima, Yoichiro Hashimoto, Toshio Fukutake, Fumihito Yoshii, Yukio Ando

    Clinical Neurology 56 (12) 866-872 2016

    Publisher: Societas Neurologica Japonica

    DOI: 10.5692/clinicalneurol.cn-000949  

    ISSN: 0009-918X

  404. Sporadic Inclusion Body Myositis Manifesting as Isolated Muscle Weakness of the Finger Flexors Three Years after Disease Onset Peer-reviewed

    Yuichi Suwa, Naoki Suzuki, Temma Soga, Ryuhei Harada, Aya Shibui, Hiroshi Kuroda, Rumiko Izumi, Maki Tateyama, Ichiro Nakashima, Masahiro Sonoo, Masashi Aoki

    INTERNAL MEDICINE 55 (23) 3521-3524 2016

    DOI: 10.2169/internalmedicine.55.7285  

    ISSN: 0918-2918

    eISSN: 1349-7235

  405. 球脊髄性筋萎縮症患者に対するリュープロレリン酢酸塩長期使用の効果

    橋詰 淳, 勝野 雅央, 鈴木 啓介, 坂野 晴彦, 須賀 徳明, 矢部 一郎, 青木 正志, 森田 光哉, 金井 数明, 水澤 英洋, 山本 知孝, 長谷川 一子, 西澤 正豊, 宮嶋 裕明, 苅田 典生, 中島 健二, 辻野 彰, 内野 誠, 田中 章景, 祖父江 元

    臨床神経学 55 (Suppl.) S200-S200 2015/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  406. Severely exacerbated neuromyelitis optica rat model with extensive astrocytopathy by high affinity anti-aquaporin-4 monoclonal antibody Peer-reviewed

    Kazuhiro Kurosawa, Tatsuro Misu, Yoshiki Takai, Douglas Kazutoshi Sato, Toshiyuki Takahashi, Yoichiro Abe, Hiroko Iwanari, Ryo Ogawa, Ichiro Nakashima, Kazuo Fujihara, Takao Hamakubo, Masato Yasui, Masashi Aoki

    ACTA NEUROPATHOLOGICA COMMUNICATIONS 3 82 2015/12

    DOI: 10.1186/s40478-015-0259-2  

    ISSN: 2051-5960

  407. Genetic profile for suspected dysferlinopathy identified by targeted next-generation sequencing. International-journal Peer-reviewed

    Rumiko Izumi, Tetsuya Niihori, Toshiaki Takahashi, Naoki Suzuki, Maki Tateyama, Chigusa Watanabe, Kazuma Sugie, Hirotaka Nakanishi, Gen Sobue, Masaaki Kato, Hitoshi Warita, Yoko Aoki, Masashi Aoki

    Neurology. Genetics 1 (4) e36 2015/12

    DOI: 10.1212/NXG.0000000000000036  

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    OBJECTIVE: To investigate the genetic causes of suspected dysferlinopathy and to reveal the genetic profile for myopathies with dysferlin deficiency. METHODS: Using next-generation sequencing, we analyzed 42 myopathy-associated genes, including DYSF, in 64 patients who were clinically or pathologically suspected of having dysferlinopathy. Putative pathogenic mutations were confirmed by Sanger sequencing. In addition, copy-number variations in DYSF were investigated using multiplex ligation-dependent probe amplification. We also analyzed the genetic profile for 90 patients with myopathy with dysferlin deficiency, as indicated by muscle specimen immunohistochemistry, including patients from a previous cohort. RESULTS: We identified putative pathogenic mutations in 38 patients (59% of all investigated patients). Twenty-three patients had DYSF mutations, including 6 novel mutations. The remaining 16 patients, including a single patient who also carried the DYSF mutation, harbored putative pathogenic mutations in other genes. The genetic profile for 90 patients with dysferlin deficiency revealed that 70% had DYSF mutations (n = 63), 10% had CAPN3 mutations (n = 9), 2% had CAV3 mutations (n = 2), 3% had mutations in other genes (in single patients), and 16% did not have any identified mutations (n = 14). CONCLUSIONS: This study clarified the heterogeneous genetic profile for myopathies with dysferlin deficiency. Our results demonstrate the importance of a comprehensive analysis of related genes in improving the genetic diagnosis of dysferlinopathy as one of the most common subtypes of limb-girdle muscular dystrophy. Unresolved diagnoses should be investigated using whole-genome or whole-exome sequencing.

  408. 抗glutamic acid decarboxylase抗体に関連した側頭葉てんかん4例の臨床的特徴

    赤石 哲也, 神 一敬, 加藤 量広, 板橋 尚, 三須 建郎, 竪山 真規, 岩崎 真樹, 青木 正志, 中里 信和

    臨床神経学 55 (11) 804-809 2015/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  409. Recurrent cerebral infarction synchronous with menorrhagia caused by endometrial stromal sarcoma Peer-reviewed

    Tetsuya Akaishi, Hiroshi Kuroda, Maki Tateyama, Yoko Yoshida, Takeo Otsuki, Mika Watanabe, Nobuo Yaegashi, Masashi Aoki

    JOURNAL OF THE NEUROLOGICAL SCIENCES 358 (1-2) 509-511 2015/11

    DOI: 10.1016/j.jns.2015.09.367  

    ISSN: 0022-510X

    eISSN: 1878-5883

  410. Dysferlin遺伝子診断への次世代シークエンサーの導入 Peer-reviewed

    高橋 俊明, 井泉 瑠美子, 八木沼 智香子, 加藤 昌昭, 島倉 奈緒子, 鈴木 直輝, 新堀 哲也, 青木 洋子, 小野 洋也, 谷口 さやか, 大泉 英樹, 田中 洋康, 吉岡 勝, 武田 篤, 青木 正志

    国立病院総合医学会講演抄録集 69回 O-5 2015/10

    Publisher: 国立病院総合医学会

  411. FALS with FUS mutation in Japan, with early onset, rapid progress and basophilic inclusion. International-journal Peer-reviewed

    Naoki Suzuki, Masashi Aoki, Hitoshi Warita, Masaaki Kato, Hideki Mizuno, Naoko Shimakura, Tetsuya Akiyama, Hirokazu Furuya, Toshihiro Hokonohara, Akiko Iwaki, Shinji Togashi, Hidehiko Konno, Yasuto Itoyama

    Journal of human genetics 60 (10) 653-4 2015/10

    DOI: 10.1038/jhg.2015.93  

    ISSN: 1434-5161

  412. Isolated inclusion body myopathy caused by a multisystem proteinopathy-linked hnRNPA1 mutation. International-journal Peer-reviewed

    Rumiko Izumi, Hitoshi Warita, Tetsuya Niihori, Toshiaki Takahashi, Maki Tateyama, Naoki Suzuki, Ayumi Nishiyama, Matsuyuki Shirota, Ryo Funayama, Keiko Nakayama, Satomi Mitsuhashi, Ichizo Nishino, Yoko Aoki, Masashi Aoki

    Neurology. Genetics 1 (3) e23 2015/10

    DOI: 10.1212/NXG.0000000000000023  

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    OBJECTIVE: To identify the genetic cause of isolated inclusion body myopathy (IBM) with autosomal dominant inheritance in 2 families. METHODS: Genetic investigations were performed using whole-exome and Sanger sequencing of the heterogeneous nuclear ribonucleoprotein A1 gene (hnRNPA1). The clinical and pathologic features of patients in the 2 families were evaluated with neurologic examinations, muscle imaging, and muscle biopsy. RESULTS: We identified a missense p.D314N mutation in hnRNPA1, which is also known to cause familial amyotrophic lateral sclerosis, in 2 families with IBM. The affected individuals developed muscle weakness in their 40s, which slowly progressed toward a limb-girdle pattern. Further evaluation of the affected individuals revealed no apparent motor neuron dysfunction, cognitive impairment, or bone abnormality. The muscle pathology was compatible with IBM, lacking apparent neurogenic change and inflammation. Multiple immunohistochemical analyses revealed the cytoplasmic aggregation of hnRNPA1 in close association with autophagosomes and myonuclei. Furthermore, the aberrant accumulation was characterized by coaggregation with ubiquitin, sequestome-1/p62, valosin-containing protein/p97, and a variety of RNA-binding proteins (RBPs). CONCLUSIONS: The present study expands the clinical phenotype of hnRNPA1-linked multisystem proteinopathy. Mutations in hnRNPA1, and possibly hnRNPA2B1, will be responsible for isolated IBM with a pure muscular phenotype. Although the mechanisms underlying the selective skeletal muscle involvement remain to be elucidated, the immunohistochemical results suggest a broad sequestration of RBPs by the mutated hnRNPA1.

  413. Japanese amyotrophic lateral sclerosis patient with learning disabilities with a deletion mutation in the C-terminal of the FUS/TLS gene Peer-reviewed

    Onohara Akiko, Koh Kishin, Nagasaka Takamura, Shindo Kazumasa, Kato Masaaki, Aoki Masashi, Takiyama Yoshihisa

    NEUROLOGY AND CLINICAL NEUROSCIENCE 3 (5) 192-193 2015/09

    DOI: 10.1111/ncn3.180  

    ISSN: 2049-4173

  414. Lennox-Gastaut症候群を呈した視床下部過誤腫の一例

    渡辺 靖章, 神 一敬, 高橋 健太, 柿坂 庸介, 北澤 悠, 藤川 真由, 中里 信和, 加藤 量広, 青木 正志, 岩崎 真樹

    臨床神経学 55 (7) 510-510 2015/07

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  415. 過敏性腸症候群に対するグルココルチコイド受容体遺伝子多型の影響について

    佐々木 彩加, 小室 葉月, 佐藤 菜保子, 金澤 素, 青木 正志, 福土 審

    心身医学 55 (6) 728-728 2015/06

    Publisher: (一社)日本心身医学会

    ISSN: 0385-0307

  416. Factors affecting longitudinal functional decline and survival in amyotrophic lateral sclerosis patients Peer-reviewed

    Hazuki Watanabe, Naoki Atsuta, Ryoichi Nakamura, Akihiro Hirakawa, Hirohisa Watanabe, Mizuki Ito, Jo Senda, Masahisa Katsuno, Yuishin Izumi, Mitsuya Morita, Hiroyuki Tomiyama, Akira Taniguchi, Ikuko Aiba, Koji Abe, Kouichi Mizoguchi, Masaya Oda, Osamu Kano, Koichi Okamoto, Satoshi Kuwabara, Kazuko Hasegawa, Takashi Imai, Masashi Aoki, Shoji Tsuji, Imaharu Nakano, Ryuji Kaji, Gen Sobue

    AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION 16 (3-4) 230-236 2015/06

    DOI: 10.3109/21678421.2014.990036  

    ISSN: 2167-8421

    eISSN: 2167-9223

  417. Depressive state and chronic fatigue in multiple sclerosis and neuromyelitis optica Peer-reviewed

    Tetsuya Akaishi, Ichiro Nakashima, Tatsuro Misu, Kazuo Fujihara, Masashi Aoki

    JOURNAL OF NEUROIMMUNOLOGY 283 70-73 2015/06

    DOI: 10.1016/j.jneuroim.2015.05.007  

    ISSN: 0165-5728

    eISSN: 1872-8421

  418. Novel clinical grading of delayed neurologic sequelae after carbon monoxide poisoning and factors associated with outcome Peer-reviewed

    Hiroshi Kuroda, Kazuo Fujihara, Shigeki Kushimoto, Masashi Aoki

    NEUROTOXICOLOGY 48 35-43 2015/05

    DOI: 10.1016/j.neuro.2015.03.002  

    ISSN: 0161-813X

    eISSN: 1872-9711

  419. Heparin-responsive angiopathy in the central nervous system caused by intravascular large B-cell lymphoma Peer-reviewed

    Shun Yoshida, Hiroshi Kuroda, Noriko Fukuhara, Hidehiko Konno, Mika Watanabe, Tetsuya Akaishi, Maki Tateyama, Masashi Aoki

    JOURNAL OF THE NEUROLOGICAL SCIENCES 352 (1-2) 117-119 2015/05

    DOI: 10.1016/j.jns.2015.03.026  

    ISSN: 0022-510X

    eISSN: 1878-5883

  420. Severe demyelination but no astrocytopathy in clinically definite neuromyelitis optica with anti-myelin-oligodendrocyte glycoprotein antibody Peer-reviewed

    Kensuke Ikeda, Naoki Kiyota, Hiroshi Kuroda, Douglas Kazutoshi Sato, Shuhei Nishiyama, Toshiyuki Takahashi, Tatsuro Misu, Ichiro Nakashima, Kazuo Fujihara, Masashi Aoki

    MULTIPLE SCLEROSIS JOURNAL 21 (5) 656-659 2015/04

    DOI: 10.1177/1352458514551455  

    ISSN: 1352-4585

    eISSN: 1477-0970

  421. Serotonin Transporter Gene Polymorphism Modulates Activity and Connectivity within an Emotional Arousal Network of Healthy Men during an Aversive Visceral Stimulus Peer-reviewed

    Lisa A. Kilpatrick, Emeran A. Mayer, Jennifer S. Labus, Arpana Gupta, Toyohiro Hamaguchi, Tomoko Mizuno, Hazuki Komuro, Michiko Kano, Motoyori Kanazawa, Masashi Aoki, Shin Fukudo

    PLOS ONE 10 (4) e0123183 2015/04

    DOI: 10.1371/journal.pone.0123183  

    ISSN: 1932-6203

  422. Variants associated with Gaucher disease in multiple system atrophy Peer-reviewed

    Jun Mitsui, Takashi Matsukawa, Hidenao Sasaki, Ichiro Yabe, Masaaki Matsushima, Alexandra Duerr, Alexis Brice, Hiroshi Takashima, Akio Kikuchi, Masashi Aoki, Hiroyuki Ishiura, Tsutomu Yasuda, Hidetoshi Date, Budrul Ahsan, Atsushi Iwata, Jun Goto, Yaeko Ichikawa, Yasuo Nakahara, Yoshio Momose, Yuji Takahashi, Kenju Hara, Akiyoshi Kakita, Mitsunori Yamada, Hitoshi Takahashi, Osamu Onodera, Masatoyo Nishizawa, Hirohisa Watanabe, Mizuki Ito, Gen Sobue, Kinya Ishikawa, Hidehiro Mizusawa, Kazuaki Kanai, Takamichi Hattori, Satoshi Kuwabara, Kimihito Arai, Shigeru Koyano, Yoshiyuki Kuroiwa, Kazuko Hasegawa, Tatsuhiko Yuasa, Kenichi Yasui, Kenji Nakashima, Hijiri Ito, Yuishin Izumi, Ryuji Kaji, Takeo Kato, Susumu Kusunoki, Yasushi Osaki, Masahiro Horiuchi, Tomoyoshi Kondo, Shigeo Murayama, Nobutaka Hattori, Mitsutoshi Yamamoto, Miho Murata, Wataru Satake, Tatsushi Toda, Alessandro Filla, Thomas Klockgether, Ullrich Wuellner, Garth Nicholson, Sid Gilman, Caroline M. Tanner, Walter A. Kukull, Mathew B. Stern, Virginia M. -Y. Lee, John Q. Trojanowski, Eliezer Masliah, Phillip A. Low, Paola Sandroni, Laurie J. Ozelius, Tatiana Foroud, Shoji Tsuji

    ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY 2 (4) 417-426 2015/04

    DOI: 10.1002/acn3.185  

    ISSN: 2328-9503

  423. Surprise signals in the supplementary eye field: rectified prediction errors drive exploration-exploitation transitions Peer-reviewed

    Norihiko Kawaguchi, Kazuhiro Sakamoto, Naohiro Saito, Yoshito Furusawa, Jun Tanji, Masashi Aoki, Hajime Mushiake

    JOURNAL OF NEUROPHYSIOLOGY 113 (3) 1001-1014 2015/02

    DOI: 10.1152/jn.00128.2014  

    ISSN: 0022-3077

    eISSN: 1522-1598

  424. Clinical values of FDG PET in polymyositis and dermatomyositis syndromes: imaging of skeletal muscle inflammation Peer-reviewed

    Maki Tateyama, Kazuo Fujihara, Tatsuro Misu, Akira Arai, Tomohiro Kaneta, Masashi Aoki

    BMJ OPEN 5 (1) e006763 2015

    DOI: 10.1136/bmjopen-2014-006763  

    ISSN: 2044-6055

  425. [A case of focal epilepsy manifesting multiple psychiatric auras]. Peer-reviewed

    Michinori Ezura, Yosuke Kakisaka, Kazutaka Jin, Kazuhiro Kato, Masaki Iwasaki, Mayu Fujikawa, Masashi Aoki, Nobukazu Nakasato

    Brain and nerve = Shinkei kenkyu no shinpo 67 (1) 105-9 2015/01

    DOI: 10.11477/mf.1416200093  

    ISSN: 1881-6096

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    We present a case of epilepsy with multiple types of focal seizures that were misdiagnosed as psychiatric disorders. A 20-year-old female patient presented with a variety of episodes, including loss of consciousness, deja vu, fear, delusion of possession, violent movements, and generalized convulsions. Each of these symptoms appeared in a stereotypic manner. She was initially diagnosed with a psychiatric disorder and treated with psychoactive medications, which had no effect. Long-term video electroencephalography revealed that her episodes of violent movement with impaired consciousness and secondarily generalized seizure were epileptic events originating in the right hemisphere. High-field brain magnetic resonance imaging for detecting subtle lesions revealed bilateral lesions from periventricular nodular heterotopia. Her final diagnosis was right hemispheric focal epilepsy. Carbamazepine administration was started, which successfully controlled all seizures. The present case demonstrates the pitfall of diagnosing focal epilepsy when it presents with multiple types of psychiatric aura. Epilepsy should thus be included in differential diagnoses, considering the stereotypic nature of symptoms, to avoid misdiagnosis.

  426. Girdle Sensation Caused by Radiculitis due to Neurosarcoidosis Peer-reviewed

    Junpei Kobayashi, Naoto Sugeno, Aya Shibui, Masashi Aoki

    INTERNAL MEDICINE 54 (12) 1567-1568 2015

    DOI: 10.2169/internalmedicine.54.4242  

    ISSN: 0918-2918

    eISSN: 1349-7235

  427. [Clinical characteristics of four patients with temporal lobe epilepsy associated with elevated anti-GAD antibodies]. Peer-reviewed

    Tetsuya Akaishi, Kazutaka Jin, Kazuhiro Kato, Hisashi Itabashi, Tatsuro Misu, Maki Tateyama, Masaki Iwasaki, Masashi Aoki, Nobukazu Nakasato

    Rinsho shinkeigaku = Clinical neurology 55 (11) 804-9 2015

    DOI: 10.5692/clinicalneurol.cn-000740  

    ISSN: 0009-918X

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    Anti-glutamic acid decarboxylase (GAD) antibodies are known to be associated with insulin-dependent diabetes mellitus (IDDM), stiff-person syndrome, and other neurological symptoms including temporal lobe epilepsy (TLE), known as autoimmune epilepsy. We treated four patients with TLE who had elevated titers of serum anti-GAD antibody (anti-GAD-Ab), higher than 100 U/ml. Three of the four patients started to have epileptic seizures in their 5th or 6th decade. Characteristic symptoms suggesting encephalitis or encephalopathy were absent at onset of these symptoms, which led to delayed diagnosis. All four patients developed two or three of cerebellar ataxia, neuropsychological impairment, and IDDM, by several years or decades after onset of TLE, even after seizure freedom in two patients. These abnormalities were indicators for suspecting the involvement of anti-GAD-Ab in the pathogenesis. Anti-GAD-Ab levels in the cerebrospinal fluid (CSF) were measured, which detected elevated CSF/serum anti-GAD-Ab ratio (≥ 1.0), suggesting intrathecal anti-GAD-Ab synthesis, in three of the four patients. The TLE symptoms were somewhat prolonged, but three of the four patients eventually achieved seizure freedom after immunotherapies with combinations of two or three anti-epileptic drugs. Serum anti-GAD Ab is recommended to be measured in patients with middle-aged onset TLE. Moreover, immune-modulating therapies including steroid pulse and intravenous immunoglobulin therapies could have ameliorated neurological complications, even in the chronic phase.

  428. Proteasome dysfunction induces muscle growth defects and protein aggregation. International-journal Peer-reviewed

    Yasuo Kitajima, Yoshitaka Tashiro, Naoki Suzuki, Hitoshi Warita, Masaaki Kato, Maki Tateyama, Risa Ando, Rumiko Izumi, Maya Yamazaki, Manabu Abe, Kenji Sakimura, Hidefumi Ito, Makoto Urushitani, Ryoichi Nagatomi, Ryosuke Takahashi, Masashi Aoki

    Journal of cell science 127 (Pt 24) 5204-17 2014/12/15

    DOI: 10.1242/jcs.150961  

    ISSN: 0021-9533

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    The ubiquitin-proteasome and autophagy-lysosome pathways are the two major routes of protein and organelle clearance. The role of the proteasome pathway in mammalian muscle has not been examined in vivo. In this study, we report that the muscle-specific deletion of a crucial proteasomal gene, Rpt3 (also known as Psmc4), resulted in profound muscle growth defects and a decrease in force production in mice. Specifically, developing muscles in conditional Rpt3-knockout animals showed dysregulated proteasomal activity. The autophagy pathway was upregulated, but the process of autophagosome formation was impaired. A microscopic analysis revealed the accumulation of basophilic inclusions and disorganization of the sarcomeres in young adult mice. Our results suggest that appropriate proteasomal activity is important for muscle growth and for maintaining myofiber integrity in collaboration with autophagy pathways. The deletion of a component of the proteasome complex contributed to myofiber degeneration and weakness in muscle disorders that are characterized by the accumulation of abnormal inclusions.

  429. てんかんは日本人における睡眠呼吸障害の危険因子とはならない

    加藤 量広, 神 一敬, 中村 美輝, 横田 恵理, 岩崎 真樹, 柿坂 庸介, 青木 正志, 中里 信和

    臨床神経学 54 (Suppl.) S112-S112 2014/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  430. dysferlinopathy患者における呼吸機能、心機能の検討 Peer-reviewed

    西川 敦子, 森 まどか, 大矢 寧, 齊藤 祐子, 瀬川 和彦, 林 由起子, 高橋 俊明, 青木 正志, 西野 一三, 村田 美穂

    臨床神経学 54 (Suppl.) S257-S257 2014/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  431. 舞踏運動を呈したdysferlin異常症の1例

    高橋 俊明, 今井 尚志, 田中 洋康, 吉岡 勝, 今野 秀彦, 日向野 修一, 小野寺 好明, 斎藤 博, 木村 格, 糸山 泰人, 武田 篤, 青木 正志

    運動障害 24 (2) 51-54 2014/12

    Publisher: 日本運動障害研究会

    ISSN: 0917-5601

  432. GNE myopathy associated with congenital thrombocytopenia: a report of two siblings. International-journal Peer-reviewed

    Rumiko Izumi, Tetsuya Niihori, Naoki Suzuki, Yoji Sasahara, Takeshi Rikiishi, Ayumi Nishiyama, Shuhei Nishiyama, Kaoru Endo, Masaaki Kato, Hitoshi Warita, Hidehiko Konno, Toshiaki Takahashi, Maki Tateyama, Takeshi Nagashima, Ryo Funayama, Keiko Nakayama, Shigeo Kure, Yoichi Matsubara, Yoko Aoki, Masashi Aoki

    Neuromuscular disorders : NMD 24 (12) 1068-72 2014/12

    DOI: 10.1016/j.nmd.2014.07.008  

    ISSN: 0960-8966

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    GNE myopathy is an autosomal recessive muscular disorder caused by mutations in the gene encoding the key enzyme in sialic acid biosynthesis, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE/MNK). Here, we report two siblings with myopathy with rimmed vacuoles and congenital thrombocytopenia who harbored two compound heterozygous GNE mutations, p.V603L and p.G739S. Thrombocytopenia, which is characterized by shortened platelet lifetime rather than ineffective thrombopoiesis, has been observed since infancy. We performed exome sequencing and array CGH to identify the underlying genetic etiology of thrombocytopenia. No pathogenic variants were detected among the known causative genes of recessively inherited thrombocytopenia; yet, candidate variants in two genes that followed an autosomal recessive mode of inheritance, including previously identified GNE mutations, were detected. Alternatively, it is possible that the decreased activity of GNE/MNK itself, which would lead to decreased sialic content in platelets, is associated with thrombocytopenia in these patients. Further investigations are required to clarify the association between GNE myopathy and the pathogenesis of thrombocytopenia.

  433. Confirmatory double-blind, parallel-group, placebo-controlled study of efficacy and safety of edaravone (MCI-186) in amyotrophic lateral sclerosis patients Peer-reviewed

    Koji Abe, Yasuto Itoyama, Gen Sobue, Shoji Tsuji, Masashi Aoki, Manabu Doyu, Chikuma Hamada, Kazuoki Kondo, Takatomo Yoneoka, Makoto Akimoto, Hiide Yoshino

    AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION 15 (7-8) 610-617 2014/12

    DOI: 10.3109/21678421.2014.959024  

    ISSN: 2167-8421

    eISSN: 2167-9223

  434. VPS35 dysfunction impairs lysosomal degradation of alpha-synuclein and exacerbates neurotoxicity in a Drosophila model of Parkinson's disease Peer-reviewed

    Emiko Miura, Takafumi Hasegawa, Masatoshi Konno, Mari Suzuki, Naoto Sugeno, Nobuhiro Fujikake, Sven Geisler, Mitsuaki Tabuchi, Ryuji Oshima, Akio Kikuchi, Toru Baba, Keiji Wada, Yoshitaka Nagai, Atsushi Takeda, Masashi Aoki

    NEUROBIOLOGY OF DISEASE 71 1-13 2014/11

    DOI: 10.1016/j.nbd.2014.07.014  

    ISSN: 0969-9961

    eISSN: 1095-953X

  435. Earlier tachycardia onset in right than left mesial temporal lobe seizures Peer-reviewed

    Kazuhiro Kato, Kazutaka Jin, Hisashi Itabashi, Masaki Iwasaki, Yosuke Kakisaka, Masashi Aoki, Nobukazu Nakasato

    NEUROLOGY 83 (15) 1332-1336 2014/10

    DOI: 10.1212/WNL.0000000000000864  

    ISSN: 0028-3878

    eISSN: 1526-632X

  436. Neural Substrates of Cognitive Subtypes in Parkinson's Disease: A 3-Year Longitudinal Study Peer-reviewed

    Yumiko Shoji, Yoshiyuki Nishio, Toru Baba, Makoto Uchiyama, Kayoko Yokoi, Toshiyuki Ishioka, Yoshiyuki Hosokai, Kazumi Hirayama, Hiroshi Fukuda, Masashi Aoki, Takafumi Hasegawa, Atsushi Takeda, Etsuro Mori

    PLOS ONE 9 (10) e110547 2014/10

    DOI: 10.1371/journal.pone.0110547  

    ISSN: 1932-6203

  437. 左右半球に独立性の発作起始を認めるてんかん患者における発作時心拍変化

    加藤 量広, 神 一敬, 柿坂 庸介, 北澤 悠, 岩崎 真樹, 青木 正志, 中里 信和

    てんかん研究 32 (2) 490-490 2014/09

    Publisher: (一社)日本てんかん学会

    ISSN: 0912-0890

    eISSN: 1347-5509

  438. Anti-N-Methyl-D-Aspartate Receptor Encephalitis with Multiphasic Demyelination Peer-reviewed

    Kimihiko Kaneko, Douglas Kazutoshi Sato, Tatsuro Misu, Kazuhiro Kurosawa, Ichiro Nakashima, Kazuo Fujihara, Masashi Aoki

    ANNALS OF NEUROLOGY 76 (3) 462-464 2014/09

    DOI: 10.1002/ana.24224  

    ISSN: 0364-5134

    eISSN: 1531-8249

  439. Insights into the Classification of Myasthenia Gravis Peer-reviewed

    Tetsuya Akaishi, Takuhiro Yamaguchi, Yasushi Suzuki, Yuriko Nagane, Shigeaki Suzuki, Hiroyuki Murai, Tomihiro Imai, Masakatsu Motomura, Kazuo Fujihara, Masashi Aoki, Kimiaki Utsugisawa

    PLOS ONE 9 (9) e106757 2014/09

    DOI: 10.1371/journal.pone.0106757  

    ISSN: 1932-6203

  440. Cerebrospinal fluid CXCL13 is a prognostic marker for aseptic meningitis Peer-reviewed

    Fujimori, Juichi, Nakashima, Ichiro, Kuroda, Hiroshi, Fujihara, Kazuo, Aoki, Masashi

    JOURNAL OF NEUROIMMUNOLOGY 273 (1-2) 77-84 2014/08

    DOI: 10.1016/j.jneuroim.2014.05.008  

    ISSN: 0165-5728

    eISSN: 1872-8421

  441. Cerebrospinal Fluid Aquaporin-4 Antibody Levels in Neuromyelitis Optica Attacks Peer-reviewed

    Douglas Kazutoshi Sato, Dagoberto Callegaro, Frederico M. de Haidar Jorge, Ichiro Nakashima, Shuhei Nishiyama, Toshiyuki Takahashi, Renata Faria Simm, Samira Luisa Apostolos-Pereira, Tatsuro Misu, Lawrence Steinman, Masashi Aoki, Kazuo Fujihara

    ANNALS OF NEUROLOGY 76 (2) 305-309 2014/08

    DOI: 10.1002/ana.24208  

    ISSN: 0364-5134

    eISSN: 1531-8249

  442. A novel mutation in PNPLA2 causes neutral lipid storage disease with myopathy and triglyceride deposit cardiomyovasculopathy: A case report and literature review Peer-reviewed

    Kimihiko Kaneko, Hiroshi Kuroda, Rumiko Izumi, Maki Tateyama, Masaaki Kato, Koichiro Sugimura, Yasuhiko Sakata, Yoshihiko Ikeda, Ken-ichi Hirano, Masashi Aoki

    NEUROMUSCULAR DISORDERS 24 (7) 634-641 2014/07

    DOI: 10.1016/j.nmd.2014.04.001  

    ISSN: 0960-8966

    eISSN: 1873-2364

  443. Retrospective analysis of Guillain-Barre syndrome and Fisher syndrome after the Great East Japan Earthquake Peer-reviewed

    Tsuboi, Hirofumi, Sugeno, Naoto, Tateyama, Maki, Nakashima, Ichiro, Hasegawa, Takafumi, Kuroda, Hiroshi, Kaneko, Kimihiko, Kobayashi, Michiko, Ishigaki, Aya, Fujimori, Juichi, Aoki, Masashi

    BRAIN AND BEHAVIOR 4 (4) 595-597 2014/07

    DOI: 10.1002/brb3.234  

    ISSN: 2162-3279

  444. Lys-63-linked Ubiquitination by E3 Ubiquitin Ligase Nedd4-1 Facilitates Endosomal Sequestration of Internalized alpha-Synuclein Peer-reviewed

    Naoto Sugeno, Takafumi Hasegawa, Nobuyuki Tanaka, Mitsunori Fukuda, Koichi Wakabayashi, Ryuji Oshima, Masashi Konno, Emiko Miura, Akio Kikuchi, Toru Baba, Tadashi Anan, Mitsuyoshi Nakao, Sven Geisler, Masashi Aoki, Atsushi Takeda

    JOURNAL OF BIOLOGICAL CHEMISTRY 289 (26) 18137-18151 2014/06

    DOI: 10.1074/jbc.M113.529461  

    ISSN: 0021-9258

    eISSN: 1083-351X

  445. Postural leg tremor in X-linked spinal and bulbar muscular atrophy Peer-reviewed

    Ayumi Nishiyama, Naoto Sugeno, Maki Tateyama, Shuhei Nishiyama, Masaaki Kato, Masashi Aoki

    JOURNAL OF CLINICAL NEUROSCIENCE 21 (5) 799-802 2014/05

    DOI: 10.1016/j.jocn.2013.07.026  

    ISSN: 0967-5868

    eISSN: 1532-2653

  446. Aquaporin-4 antibody-positive myelitis initially biopsied for suspected spinal cord tumors: Diagnostic considerations Peer-reviewed

    Douglas Kazutoshi Sato, Tatsuro Misu, Cristiane Franklin Rocha, Dagoberto Callegaro, Ichiro Nakashima, Masashi Aoki, Kazuo Fujihara, Marco Aurelio Lana-Peixoto

    MULTIPLE SCLEROSIS JOURNAL 20 (5) 621-626 2014/04

    DOI: 10.1177/1352458513505350  

    ISSN: 1352-4585

    eISSN: 1477-0970

  447. A case of steroid-responsive MADSAM with late appearance of a partial conduction block in the forearm Peer-reviewed

    Shun Yoshida, Akio Kikuchi, Maki Tateyama, Ohito Tano, Ayumi Nishiyama, Tetsuya Akaishi, Masaaki Kato, Masashi Aoki

    JOURNAL OF NEUROLOGY 261 (4) 825-827 2014/04

    DOI: 10.1007/s00415-014-7271-5  

    ISSN: 0340-5354

    eISSN: 1432-1459

  448. Changes in Th17 and regulatory T cells after fingolimod initiation to treat multiple sclerosis Peer-reviewed

    Douglas Kazutoshi Sato, Ichiro Nakashima, Amit Bar-Or, Tatsuro Misu, Chihiro Suzuki, Shuhei Nishiyama, Hiroshi Kuroda, Kazuo Fujihara, Masashi Aoki

    JOURNAL OF NEUROIMMUNOLOGY 268 (1-2) 95-98 2014/03

    DOI: 10.1016/j.jneuroim.2014.01.008  

    ISSN: 0165-5728

    eISSN: 1872-8421

  449. Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders Peer-reviewed

    Douglas Kazutoshi Sato, Dagoberto Callegaro, Marco Aurelio Lana-Peixoto, Patrick J. Waters, Frederico M. de Haidar Jorge, Toshiyuki Takahashi, Ichiro Nakashima, Samira Luisa Apostolos-Pereira, Natalia Talim, Renata Faria Simm, Angelina Maria Martins Lino, Tatsuro Misu, Maria Isabel Leite, Masashi Aoki, Kazuo Fujihara

    NEUROLOGY 82 (6) 474-481 2014/02

    DOI: 10.1212/WNL.0000000000000101  

    ISSN: 0028-3878

    eISSN: 1526-632X

  450. A case of myelitis with anti-aquaporin 4 antibody concomitant with immune thrombocytopenic purpura Peer-reviewed

    Hideki Mizuno, Shigeru Sato, Yasushi Ohnishi, Toshiyuki Takahashi, Ichiro Nakashima, Kazuo Fujihara, Masashi Aoki, Ayumu Ohnuma

    Clinical Neurology 54 (3) 195-199 2014

    Publisher: Societas Neurologica Japonica

    DOI: 10.5692/clinicalneurol.54.195  

    ISSN: 0009-918X

  451. Improvement of freezing of gait in patients with Parkinson's disease by imagining bicycling Peer-reviewed

    Akio Kikuchi, Toru Baba, Takafumi Hasegawa, Naoto Sugeno, Masatoshi Konno, Emiko Miura, Ryuji Oshima, Masashi Aoki, Atsushi Takeda

    Case Reports in Neurology 6 (1) 92-95 2014

    Publisher: S. Karger AG

    DOI: 10.1159/000362119  

    ISSN: 1662-680X

  452. The actual state and problems in neurology training in medical schools Peer-reviewed

    Takayuki Taniwaki, Takashi Inuzuka, Fumihito Yoshii, Masashi Aoki, Takahiro Amano, Itaru Toyoshima, Toshio Fukutake, Yoichiro Hashimoto, Jun-Ichi Kira

    Clinical Neurology 54 (4) 335-340 2014

    Publisher: Societas Neurologica Japonica

    DOI: 10.5692/clinicalneurol.54.335  

    ISSN: 0009-918X

  453. The actual state and problems in neurology training at hospital Peer-reviewed

    Toshio Fukutake, Yoichiro Hashimoto, Takayuki Taniwaki, Itaru Toyoshima, Takahiro Amano, Masashi Aoki, Fumihito Yoshii, Takashi Inuzuka, Jun-Ichi Kira

    Clinical Neurology 54 (4) 341-348 2014

    Publisher: Societas Neurologica Japonica

    DOI: 10.5692/clinicalneurol.54.341  

    ISSN: 0009-918X

  454. The actual state and problems in neurology training at graduate school Peer-reviewed

    Jun-Ichi Kira, Yasumasa Ohyagi, Takayuki Taniwaki, Takashi Inuzuka, Fumihito Yoshii, Masashi Aoki, Takahiro Amano, Itaru Toyoshima, Toshio Fukutake, Yoichiro Hashimoto

    Clinical Neurology 54 (4) 349-358 2014

    Publisher: Societas Neurologica Japonica

    DOI: 10.5692/clinicalneurol.54.349  

    ISSN: 0009-918X

  455. An autopsy case involving a 12-year history of amyotrophic lateral sclerosis with CIDP-like polyneuropathy. Peer-reviewed

    Tetsuya Akaishi, Maki Tateyama, Kazuhiro Kato, Emiko Miura, Rumiko Izumi, Kaoru Endo, Naoto Sugeno, Naoki Suzuki, Toru Baba, Tatsuro Misu, Akio Kikuchi, Takafumi Hasegawa, Sachiko Konosu-Fukaya, Fumiyoshi Fujishima, Hiroyoshi Suzuki, Ichiro Nakashima, Masashi Aoki

    Internal medicine (Tokyo, Japan) 53 (12) 1371-5 2014

    DOI: 10.2169/internalmedicine.53.0774  

    ISSN: 0918-2918

    eISSN: 1349-7235

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    Demyelinating polyneuropathy associated with amyotrophic lateral sclerosis (ALS) is quite rare. We herein present the case of a woman patient with a 12-year history of chronic inflammatory demyelinating polyneuropathy (CIDP)-like polyneuropathy who later developed bulbar palsy and respiratory failure. The autopsy findings revealed neuronal loss in the anterior horn and primary motor cortex with degeneration of the corticospinal tracts. Diffuse phosphorylated TAR DNA-binding protein of 43 kDa inclusions were observed in the anterior horn and cerebral cortices, including the temporal lobe. The final diagnosis was ALS with CIDP-like polyneuropathy. Compared with other reports of ALS with CIDP-like polyneuropathy, the present patient was younger and followed a relatively long clinical course, with no upper motor neuron signs.

  456. [Recent progress in diagnosis and pathomechanism of inclusion body myositis]. Peer-reviewed

    Masashi Aoki, Naoki Suzuki, Masaaki Kato, Hitoshi Warita

    Rinsho shinkeigaku = Clinical neurology 54 (12) 1115-8 2014

    DOI: 10.5692/clinicalneurol.54.1115  

    ISSN: 0009-918X

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    Sporadic inclusion body myositis (sIBM) is an intractable and progressive skeletal muscle disease of unknown etiology and without effective treatment. Muscle biopsy typically reveals endomysial inflammation, invasion of mononuclear cells into non-necrotic fibers and rimmed vacuoles, suggesting inflammation and degeneration co-exist as part of the pathomechanism. We estimated the prevalence of sIBM in Japan is 1,000-1,500 in 2003 and an increase in the number of sIBM in Japan in the decade. TDP43 can be a whole mark of the muscle pathology of sIBM patients. Anti-cytosolic 5'-nucleotidase 1A (cN1A) can be a diagnostic marker of sIBM. Elucidation of the pathomechanism of sIBM is the most important to therapy. We'll also review the status of the therapeutics and clinical trials in sIBM.

  457. 筋萎縮性側索硬化症モデルラット徴小血管の壁細胞を標的とした運動ニューロン保障

    割田 仁, 水野 秀紀, 加藤 昌昭, 鈴木 直輝, 青木 正志

    臨床神経学 53 (12) 1638-1638 2013/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  458. 頸部屈筋の筋力低下はALSにおける独立した予後予測指標である

    中村 亮一, 熱田 直樹, 渡辺 はづき, 渡辺 宏久, 伊藤 瑞規, 千田 譲, 平川 晃弘, 和泉 唯信, 梶 龍兒, 森田 光哉, 富山 弘幸, 谷口 彰, 溝口 功一, 岡本 幸市, 長谷川 一子, 青木 正志, 中野 今治, 祖父江 元

    臨床神経学 53 (12) 1412-1412 2013/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  459. Neck weakness is a potent prognostic factor in sporadic amyotrophic lateral sclerosis patients Peer-reviewed

    Ryoichi Nakamura, Naoki Atsuta, Hazuki Watanabe, Akihiro Hirakawa, Hirohisa Watanabe, Mizuki Ito, Jo Senda, Masahisa Katsuno, Fumiaki Tanaka, Yuishin Izumi, Mitsuya Morita, Kotaro Ogaki, Akira Taniguchi, Ikuko Aiba, Koichi Mizoguchi, Koichi Okamoto, Kazuko Hasegawa, Masashi Aoki, Akihiro Kawata, Koji Abe, Masaya Oda, Masaaki Konagaya, Takashi Imai, Masanori Nakagawa, Shoji Tsuji, Ryuji Kaji, Imaharu Nakano, Gen Sobue

    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 84 (12) 1365-1371 2013/12

    DOI: 10.1136/jnnp-2013-306020  

    ISSN: 0022-3050

    eISSN: 1468-330X

  460. 記憶誘導下の連続的手指運動において、ヒト補足運動野のγ帯域の活動が上昇する

    川口 典彦, 大沢 伸一郎, 岩崎 真樹, 丹治 和世, 冨永 悌二, 中里 信和, 青木 正志, 虫明 元

    臨床神経生理学 41 (5) 451-451 2013/10

    Publisher: (一社)日本臨床神経生理学会

    ISSN: 1345-7101

    eISSN: 2188-031X

  461. 認知症を伴った肢帯型筋ジストロフィー2B型の1家系 Peer-reviewed

    和田 千鶴, 小原 講二, 阿部 エリカ, 小林 道雄, 石原 傳幸, 豊島 至, 菅原 正伯, 高橋 俊明, 青木 正志

    臨床神経学 53 (9) 754-754 2013/09

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  462. ITIH4 and Gpx3 are potential biomarkers for amyotrophic lateral sclerosis Peer-reviewed

    Hirotaka Tanaka, Masamitsu Shimazawa, Masafumi Takata, Hideo Kaneko, Kazuhiro Tsuruma, Tsunehiko Ikeda, Hitoshi Warita, Masashi Aoki, Mitsunori Yamada, Hitoshi Takahashi, Isao Hozumi, Hiroshi Minatsu, Takashi Inuzuka, Hideaki Hara

    JOURNAL OF NEUROLOGY 260 (7) 1782-1797 2013/07

    DOI: 10.1007/s00415-013-6877-3  

    ISSN: 0340-5354

    eISSN: 1432-1459

  463. DPP-4阻害薬が原因として疑われた首下がり症候群の1例

    赤石 哲也, 菊池 昭夫, 長谷川 隆文, 竪山 真規, 青木 正志

    日本内科学会雑誌 102 (6) 1464-1466 2013/06

    Publisher: (一社)日本内科学会

    DOI: 10.2169/naika.102.1464  

    ISSN: 0021-5384

    eISSN: 1883-2083

  464. Presence of six different lesion types suggests diverse mechanisms of tissue injury in neuromyelitis optica Peer-reviewed

    Tatsuro Misu, Romana Hoeftberger, Kazuo Fujihara, Isabella Wimmer, Yoshiki Takai, Shuhei Nishiyama, Ichiro Nakashima, Hidehiko Konno, Monika Bradl, Ferenc Garzuly, Yasuto Itoyama, Masashi Aoki, Hans Lassmann

    ACTA NEUROPATHOLOGICA 125 (6) 815-827 2013/06

    DOI: 10.1007/s00401-013-1116-7  

    ISSN: 0001-6322

    eISSN: 1432-0533

  465. Aquaporin-4 antibody-positive cases beyond current diagnostic criteria for NMO spectrum disorders Peer-reviewed

    Douglas Kazutoshi Sato, Ichiro Nakashima, Toshiyuki Takahashi, Tatsuro Misu, Patrick Waters, Hiroshi Kuroda, Shuhei Nishiyama, Chihiro Suzuki, Yoshiki Takai, Kazuo Fujihara, Yasuto Itoyama, Masashi Aoki

    NEUROLOGY 80 (24) 2210-2216 2013/06

    DOI: 10.1212/WNL.0b013e318296ea08  

    ISSN: 0028-3878

    eISSN: 1526-632X

  466. [Case report; suspected DPP-4 inhibitor-induced dropped head syndrome]. Peer-reviewed

    Akaishi T, Kikuchi A, Hasegawa T, Tateyama M, Aoki M

    Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 102 (6) 1464-1466 2013/06

    ISSN: 0021-5384

  467. Exome sequencing identifies a novel TTN mutation in a family with hereditary myopathy with early respiratory failure. International-journal Peer-reviewed

    Rumiko Izumi, Tetsuya Niihori, Yoko Aoki, Naoki Suzuki, Masaaki Kato, Hitoshi Warita, Toshiaki Takahashi, Maki Tateyama, Takeshi Nagashima, Ryo Funayama, Koji Abe, Keiko Nakayama, Masashi Aoki, Yoichi Matsubara

    Journal of human genetics 58 (5) 259-66 2013/05

    DOI: 10.1038/jhg.2013.9  

    ISSN: 1434-5161

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    Myofibrillar myopathy (MFM) is a group of chronic muscular disorders that show the focal dissolution of myofibrils and accumulation of degradation products. The major genetic basis of MFMs is unknown. In 1993, our group reported a Japanese family with dominantly inherited cytoplasmic body myopathy, which is now included in MFM, characterized by late-onset chronic progressive distal muscle weakness and early respiratory failure. In this study, we performed linkage analysis and exome sequencing on these patients and identified a novel c.90263G>T mutation in the TTN gene (NM_001256850). During the course of our study, another groups reported three mutations in TTN in patients with hereditary myopathy with early respiratory failure (HMERF, MIM #603689), which is characterized by overlapping pathologic findings with MFMs. Our patients were clinically compatible with HMERF. The mutation identified in this study and the three mutations in patients with HMERF were located on the A-band domain of titin, suggesting a strong relationship between mutations in the A-band domain of titin and HMERF. Mutation screening of TTN has been rarely carried out because of its huge size, consisting of 363 exons. It is possible that focused analysis of TTN may detect more mutations in patients with MFMs, especially in those with early respiratory failure.

  468. 橈骨神経麻痺が前景に立った神経痛性筋萎縮症の1例

    坪井 博文, 菅野 直人, 西山 亜由美, 竪山 真規, 青木 正志

    臨床神経学 53 (4) 312-315 2013/04

    Publisher: (一社)日本神経学会

    DOI: 10.5692/clinicalneurol.53.312  

    ISSN: 0009-918X

  469. ドパミン作動薬誘発性開顎ジストニアを合併した進行性核上性麻痺の1例

    田野 大人, 金子 仁彦, 菊池 昭夫, 長谷川 隆文, 武田 篤, 青木 正志

    臨床神経学 53 (4) 308-311 2013/04

    Publisher: (一社)日本神経学会

    DOI: 10.5692/clinicalneurol.53.308  

    ISSN: 0009-918X

  470. Clinical features and a mutation with late onset of limb girdle muscular dystrophy 2B. International-journal Peer-reviewed

    Toshiaki Takahashi, Masashi Aoki, Naoki Suzuki, Maki Tateyama, Chikako Yaginuma, Hitomi Sato, Miho Hayasaka, Hitomi Sugawara, Mariko Ito, Emi Abe-Kondo, Naoko Shimakura, Tohru Ibi, Satoshi Kuru, Tadashi Wakayama, Gen Sobue, Naoki Fujii, Toshio Saito, Tsuyoshi Matsumura, Itaru Funakawa, Eiichiro Mukai, Toru Kawanami, Mitsuya Morita, Mineo Yamazaki, Takashi Hasegawa, Jun Shimizu, Shoji Tsuji, Shigeki Kuzuhara, Hiroyasu Tanaka, Masaru Yoshioka, Hidehiko Konno, Hiroshi Onodera, Yasuto Itoyama

    Journal of neurology, neurosurgery, and psychiatry 84 (4) 433-40 2013/04

    DOI: 10.1136/jnnp-2011-301339  

    ISSN: 0022-3050

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    OBJECTIVE AND METHODS: Dysferlin encoded by DYSF deficiency leads to two main phenotypes, limb girdle muscular dystrophy (LGMD) 2B and Miyoshi myopathy. To reveal in detail the mutational and clinical features of LGMD2B in Japan, we observed 40 Japanese patients in 36 families with LGMD2B in whom dysferlin mutations were confirmed. RESULTS AND CONCLUSIONS: Three mutations (c.1566C>G, c.2997G>T and c.4497delT) were relatively more prevalent. The c.2997G>T mutation was associated with late onset, proximal dominant forms of dysferlinopathy, a high probability that muscle weakness started in an upper limb and lower serum creatine kinase (CK) levels. The clinical features of LGMD2B are as follows: (1) onset in the late teens or early adulthood, except patients homozygous for the c.2997G>T mutation; (2) lower limb weakness at onset; (3) distal change of lower limbs on muscle CT at an early stage; (4) impairment of lumbar erector spinal muscles on muscle CT at an early stage; (5) predominant involvement of proximal upper limbs; (6) preservation of function of the hands at late stage; (7) preservation of strength in neck muscles at late stage; (8) lack of facial weakness or dysphagia; (9) avoidance of scoliosis; (10) hyper-Ckaemia; (11) preservation of cardiac function; and (12) a tendency for respiratory function to decline with disease duration. It is important that the late onset phenotype is found with prevalent mutations.

  471. Dopaminergic drug-induced jaw-opening dystonia in a patient with progressive supranuclear palsy Peer-reviewed

    Ohito Tano, Kimihiko Kaneko, Akio Kikuchi, Takafumi Hasegawa, Atsushi Takeda, Masashi Aoki

    Clinical Neurology 53 (4) 308-311 2013/04

    DOI: 10.5692/clinicalneurol.53.308  

    ISSN: 0009-918X

  472. Radial nerve palsy as a presenting feature of neuralgic amyotrophy Peer-reviewed

    Hirofumi Tsuboi, Naoto Sugeno, Ayumi Nishiyama, Maki Tateyama, Masashi Aoki

    Clinical Neurology 53 (4) 312-315 2013/04

    DOI: 10.5692/clinicalneurol.53.312  

    ISSN: 0009-918X

  473. Late-onset Charcot-Marie-Tooth disease type 1B due to a novel mutation in the extracellular disulfide bridge of MPZ gene Peer-reviewed

    Shuhei Nishiyama, Naoto Sugeno, Maki Tateyama, Masashi Aoki

    CLINICAL NEUROLOGY AND NEUROSURGERY 115 (2) 208-209 2013/02

    DOI: 10.1016/j.clineuro.2012.04.016  

    ISSN: 0303-8467

  474. Familial amyotrophic lateral sclerosis with novel A4DSOD1mutation with late age at onset and rapid progressive course

    Hiroya Naruse, Atsushi Iwata, Yuji Takahashi, Kazuaki Ichihara, Satoshi Kamei, Masato Yamatoku, Toshikazu Hirayama, Naoki Suzuki, Masashi Aoki, Toji Miyagawa, Jun Shimizu, Shoji Tsuji, Jun Goto

    Neurology and Clinical Neuroscience 1 (1) 45-47 2013/01

    Publisher: Wiley

    DOI: 10.1002/ncn3.8  

    ISSN: 2049-4173

  475. 維持透析中の4度肥満患者に発症したGuillain-Barre症候群に対して免疫グロブリン静注療法を行った1例

    平出 桜, 菅野 直人, 坪井 博文, 竪山 真規, 石山 勝也, 青木 正志

    神経治療学 30 (1) 57-60 2013/01

    Publisher: 日本神経治療学会

    ISSN: 0916-8443

  476. Increase of complement fragment C5a in cerebrospinal fluid during exacerbation of neuromyelitis optica Peer-reviewed

    Hiroshi Kuroda, Kazuo Fujihara, Rina Takano, Yoshiki Takai, Toshiyuki Takahashi, Tatsuro Misu, Ichiro Nakashima, Shigeru Sato, Yasuto Itoyama, Masashi Aoki

    JOURNAL OF NEUROIMMUNOLOGY 254 (1-2) 178-182 2013/01

    DOI: 10.1016/j.jneuroim.2012.09.002  

    ISSN: 0165-5728

    eISSN: 1872-8421

  477. Anti-voltage-gated potassium channel antibody is associated with chronic autonomic and sensory neuropathy Peer-reviewed

    Kimihiko Kaneko, Ohito Tano, Akio Kikuchi, Takafumi Hasegawa, Maki Tateyama, Masaru Yoshioka, Hiroshi Saito, Osamu Watanabe, Atsushi Takeda, Masashi Aoki

    JOURNAL OF NEUROLOGY 260 (1) 315-317 2013/01

    DOI: 10.1007/s00415-012-6730-0  

    ISSN: 0340-5354

  478. Hypometabolism in the supplementary and anterior cingulate cortices is related to dysphagia in parkinson's disease: A cross-sectional and 3-year longitudinal cohort study Peer-reviewed

    Akio Kikuchi, Toru Baba, Takafumi Hasegawa, Michiko Kobayashi, Naoto Sugeno, Masatoshi Konno, Emiko Miura, Yoshiyuki Hosokai, Toshiyuki Ishioka, Yoshiyuki Nishio, Kazumi Hirayama, Kyoko Suzuki, Masashi Aoki, Shoki Takahashi, Hiroshi Fukuda, Yasuto Itoyama, Etsuro Mori, Atsushi Takeda

    BMJ Open 3 (3) 2013

    DOI: 10.1136/bmjopen-2012-002249  

    ISSN: 2044-6055

  479. T2-hyperintensity of the Middle Cerebellar Peduncles in a Patient with SCA7 Peer-reviewed

    Shun Yoshida, Akio Kikuchi, Maki Tateyama, Masashi Aoki

    INTERNAL MEDICINE 52 (12) 1433-1434 2013

    DOI: 10.2169/internalmedicine.52.0302  

    ISSN: 0918-2918

  480. The clinical utility of makeshift beds in disaster shelters Peer-reviewed

    Masayuki Nara, Shinsaku Ueda, Masashi Aoki, Tsutomu Tamada, Takuhiro Yamaguchi, Michio Hongo

    Disaster Medicine and Public Health Preparedness 7 (6) 573-577 2013

    Publisher: Lippincott Williams and Wilkins

    DOI: 10.1017/dmp.2013.107  

    ISSN: 1938-744X 1935-7893

  481. 日本人家族性ALSにおける遺伝子変異と臨床型の検討

    加藤 昌昭, 割田 仁, 鈴木 直輝, 島倉 奈緒子, 青木 正志

    臨床神経学 52 (12) 1601-1601 2012/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  482. 筋萎縮性側索硬化症モデルラット新生グリア細胞が形成する脊髄微小環境

    割田 仁, 加藤 昌昭, 鈴木 直輝, 水野 秀紀, 青木 正志

    臨床神経学 52 (12) 1603-1603 2012/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  483. リュープロレリン酢酸塩の球脊髄性筋萎縮症患者に対する第3相長期継続投与試験(JASMITT-07OP試験)

    鈴木 啓介, 勝野 雅央, 坂野 晴彦, 須賀 徳明, 橋詰 淳, 矢部 一郎, 青木 正志, 中野 今治, 金井 数明, 水澤 英洋, 山本 知孝, 長谷川 一子, 西澤 正豊, 宮嶋 裕明, 苅田 典生, 中島 健二, 辻野 彰, 内野 誠, 田中 章景, 祖父江 元

    臨床神経学 52 (12) 1484-1484 2012/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  484. A case with anti-galactocerebroside antibody-positive Mycoplasma pneumoniae meningoencephalitis presenting secondary hypersomnia Peer-reviewed

    Naoto Sugeno, Norihiko Kawaguchi, Takafumi Hasegawa, Takashi Kuroda, Ichiro Nakashima, Takashi Kanbayashi, Susumu Kusunoki, Masashi Aoki

    NEUROLOGICAL SCIENCES 33 (6) 1473-1476 2012/12

    DOI: 10.1007/s10072-012-1009-x  

    ISSN: 1590-1874

  485. Lower motor neuron disease caused by a novel FUS/TLS gene frameshift mutation. International-journal Peer-reviewed

    Makoto Hara, Masayuki Minami, Satoshi Kamei, Naoki Suzuki, Masaaki Kato, Masashi Aoki

    Journal of neurology 259 (10) 2237-9 2012/10

    DOI: 10.1007/s00415-012-6542-2  

    ISSN: 0340-5354

  486. Neutralizing Antibodies Are Associated with a Reduction of Interferon-beta Efficacy during the Treatment of Japanese Multiple Sclerosis Patients Peer-reviewed

    Douglas Kazutoshi Sato, Ichiro Nakashima, Toshiyuki Fukazawa, Yuko Shimizu, Yuji Tomizawa, Kazumasa Yokoyama, Tatsuro Misu, Paul I. Creeke, Rachel Farrell, Gavin Giovannoni, Yasuto Itoyama, Kazuo Fujihara, Masashi Aoki

    TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE 228 (2) 85-92 2012/10

    DOI: 10.1620/tjem.228.85  

    ISSN: 0040-8727

    eISSN: 1349-3329

  487. TWO CASES OF LUMBOSACRAL MYELORADICULITIS WITH ANTI-AQUAPORIN-4 ANTIBODY Peer-reviewed

    Yoshiki Takai, Tatsuro Misu, Ichiro Nakashima, Toshiyuki Takahashi, Yasuto Itoyama, Kazuo Fujihara, Masashi Aoki

    NEUROLOGY 79 (17) 1826-1828 2012/10

    DOI: 10.1212/WNL.0b013e3182703ff7  

    ISSN: 0028-3878

  488. FUS/TLS-immunoreactive neuronal and glial cell inclusions increase with disease duration in familial amyotrophic lateral sclerosis with an R521C FUS/TLS mutation. International-journal Peer-reviewed

    Naoki Suzuki, Shinsuke Kato, Masako Kato, Hitoshi Warita, Hideki Mizuno, Masaaki Kato, Naoko Shimakura, Haruhiko Akiyama, Zen Kobayashi, Hidehiko Konno, Masashi Aoki

    Journal of neuropathology and experimental neurology 71 (9) 779-88 2012/09

    DOI: 10.1097/NEN.0b013e318264f164  

    ISSN: 0022-3069

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    Basophilic inclusions (BIs) are pathological features of a subset of frontotemporal lobar degeneration disorders, including sporadic amyotrophic lateral sclerosis (ALS) and familial ALS (FALS). Mutations in the fused in sarcoma/translocated in liposarcoma (FUS/TLS) gene have recently been identified as a cause of FALS. The FUS/TLS-immunoreactive inclusions are consistently found in cases of frontotemporal lobar degeneration with BIs; however, the association between ALS cases with BIs and FUS/TLS accumulation is not well understood. We used immunohistochemistry to analyze 3 autopsy cases of FALS with the FUS/TLS mutation and with BIs using anti-FUS/TLS antibodies. The disease durations were 1, 3, and 9 years. As the disease duration becomes longer, there were broader distributions of neuronal and glial FUS/TLS-immunoreactive inclusions. As early as 1 year after the onset, BIs, neuronal cytoplasmic inclusions and glial cytoplasmic inclusions were found in the substantia nigra in addition to the anterior horn of the spinal cord. Glial cytoplasmic inclusions are found earlier and in a wider distribution than neuronal cytoplasmic inclusions. The distribution of FUS/TLS-immunoreactive inclusions in FUS/TLS-mutated FALS with BIs was broader than that of BIs alone, suggesting that the pathogenetic mechanism may have originated from the FUS/TLS proteinopathy.

  489. Two cases of elderly-onset hereditary neuropathy with liability to pressure palsy manifesting bilateral peroneal nerve palsies. International-journal Peer-reviewed

    Norihiko Kawaguchi, Naoki Suzuki, Maki Tateyama, Yoshiki Takai, Tatsuro Misu, Ichiro Nakashima, Yasuto Itoyama, Masashi Aoki

    Case reports in neurology 4 (3) 149-55 2012/09

    DOI: 10.1159/000342132  

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    Hereditary neuropathy with liability to pressure palsy (HNPP) is characterized by recurrent focal neuropathies, which usually become symptomatic in the second or third decade of life. However, clinical phenotypic heterogeneity among patients with HNPP has recently been reported. Certain patients show polyneuropathy-type diffuse nerve injuries, whereas others remain asymptomatic at older ages. We present two cases of elderly-onset bilateral peroneal nerve palsies with diffuse muscle weakness in the lower limbs and glove-and-stocking type sensory disturbance. Both patients were diagnosed with HNPP by genetic analyses that detected deletions of chromosome 17p11.2 in peripheral myelin protein 22 genes. Their clinical courses suggested that the Japanese sitting style termed 'seiza', a way of sitting on the floor with the lower legs crossed under the thighs, was a precipitating factor for the bilateral peroneal nerve palsies.

  490. 脳脊髄液中にのみ好酸球増多をみとめた再発性脳脊髄炎の1例

    鈴木 潤, 菅野 直人, 西山 修平, 金子 仁彦, 三須 建郎, 竪山 真規, 遠藤 俊毅, 青木 正志

    臨床神経学 52 (8) 571-575 2012/08

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  491. Suppression of dynamin GTPase decreases alpha-synuclein uptake by neuronal and oligodendroglial cells: a potent therapeutic target for synucleinopathy Peer-reviewed

    Masatoshi Konno, Takafumi Hasegawa, Toru Baba, Emiko Miura, Naoto Sugeno, Akio Kikuchi, Fabienne C. Fiesel, Tsutomu Sasaki, Masashi Aoki, Yasuto Itoyama, Atsushi Takeda

    MOLECULAR NEURODEGENERATION 7 38 2012/08

    DOI: 10.1186/1750-1326-7-38  

    ISSN: 1750-1326

  492. A case of recurrent encephalomyelitis associated with eosinophilia in CSF Peer-reviewed

    Jun Suzuki, Naoto Sugeno, Shuhei Nishiyama, Kimihiko Kaneko, Tatsuro Misu, Maki Tateyama, Toshiki Endo, Masashi Aoki

    Clinical Neurology 52 (8) 571-575 2012/08

    DOI: 10.5692/clinicalneurol.52.571  

    ISSN: 0009-918X

  493. Heterozygous UDP-GlcNAc 2-epimerase and N-acetylmannosamine kinase domain mutations in the GNE gene result in a less severe GNE myopathy phenotype compared to homozygous N-acetylmannosamine kinase domain mutations. International-journal Peer-reviewed

    Madoka Mori-Yoshimura, Kazunari Monma, Naoki Suzuki, Masashi Aoki, Toshihide Kumamoto, Keiko Tanaka, Hiroyuki Tomimitsu, Satoshi Nakano, Masahiro Sonoo, Jun Shimizu, Kazuma Sugie, Harumasa Nakamura, Yasushi Oya, Yukiko K Hayashi, May Christine V Malicdan, Satoru Noguchi, Miho Murata, Ichizo Nishino

    Journal of the neurological sciences 318 (1-2) 100-5 2012/07/15

    DOI: 10.1016/j.jns.2012.03.016  

    ISSN: 0022-510X

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    BACKGROUND: Glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase (GNE) myopathy, also called distal myopathy with rimmed vacuoles (DMRV) or hereditary inclusion body myopathy (HIBM), is a rare, progressive autosomal recessive disorder caused by mutations in the GNE gene. Here, we examined the relationship between genotype and clinical phenotype in participants with GNE myopathy. METHODS: Participants with GNE myopathy were asked to complete a questionnaire regarding medical history and current symptoms. RESULTS: A total of 71 participants with genetically confirmed GNE myopathy (27 males and 44 females; mean age, 43.1±13.0 (mean±SD) years) completed the questionnaire. Initial symptoms (e.g., foot drop and lower limb weakness) appeared at a mean age of 24.8±8.3 years. Among the 71 participants, 11 (15.5%) had the ability to walk, with a median time to loss of ambulation of 17.0±2.1 years after disease onset. Participants with a homozygous mutation (p.V572L) in the N-acetylmannosamine kinase domain (KD/KD participants) had an earlier disease onset compared to compound heterozygous participants with mutations in the uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase and N-acetylmannosamine kinase domains (ED/KD participants; 26.3±7.3 vs. 21.2±11.1 years, respectively). KD/KD participants were more frequently non-ambulatory compared to ED/KD participants at the time of survey (80% vs. 50%). Data were verified using medical records available from 17 outpatient participants. CONCLUSIONS: Homozygous KD/KD participants exhibited a more severe phenotype compared to heterozygous ED/KD participants.

  494. 一過性の筋力低下から回復し、10年間無症状であるdysferlin異常症の1例

    小林 芳人, 高橋 俊明, 隅 寿恵, 藤村 晴俊, 青木 正志, 高橋 正紀, 佐古田 三郎

    臨床神経学 52 (7) 495-498 2012/07

    Publisher: (一社)日本神経学会

    DOI: 10.5692/clinicalneurol.52.495  

    ISSN: 0009-918X

    eISSN: 1882-0654

  495. Involvement of activated microglia in increased vulnerability of motoneurons after facial nerve avulsion in presymptomatic amyotrophic lateral sclerosis model rats Peer-reviewed

    Tomomi Sanagi, Yasuko Nakamura, Eri Suzuki, Shigeo Uchino, Masashi Aoki, Hitoshi Warita, Yasuto Itoyama, Shinichi Kohsaka, Keiko Ohsawa

    GLIA 60 (5) 782-793 2012/05

    DOI: 10.1002/glia.22308  

    ISSN: 0894-1491

  496. Increase in number of sporadic inclusion body myositis (sIBM) in Japan. International-journal Peer-reviewed

    Naoki Suzuki, Masashi Aoki, Madoka Mori-Yoshimura, Yukiko K Hayashi, Ikuya Nonaka, Ichizo Nishino

    Journal of neurology 259 (3) 554-6 2012/03

    DOI: 10.1007/s00415-011-6185-8  

    ISSN: 0340-5354

  497. Unusual visual impairments in a case of MPO-ANCA associated hypertrophic pachymeningitis Peer-reviewed

    Seiya Hayashi, Naoto Sugeno, Syuhei Nishiyama, Takafumi Hasegawa, Masashi Aoki

    Clinical Neurology 52 (3) 152-155 2012/03

    DOI: 10.5692/clinicalneurol.52.152  

    ISSN: 0009-918X

  498. Continuous administration of poloxamer 188 reduces overload-induced muscular atrophy in dysferlin-deficient SJL mice. International-journal Peer-reviewed

    Naoki Suzuki, Tetsuya Akiyama, Toshiaki Takahashi, Hazuki Komuro, Hitoshi Warita, Maki Tateyama, Yasuto Itoyama, Masashi Aoki

    Neuroscience research 72 (2) 181-6 2012/02

    DOI: 10.1016/j.neures.2011.10.005  

    ISSN: 0168-0102

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    Dysferlin-deficient SJL mice are commonly used to study dysferlinopathy. We demonstrated that poloxamer 188 (P188), a membrane sealant, is effective in reducing the loss of muscle mass in SJL mice when administered using an osmotic pump for 6 weeks. We did not observe significant changes over a 2-week administration period, suggesting that longthier observation is necessary to determine the effectiveness of P188. We also examined exercise endurance in P188-administered SJL mice using a rolling cage. Phosphorylated p38 was found to be reduced in P188-administered SJL mice; additionally, using microarray analysis, we found diminished expression of atrogin-1, an E3 ubiquitin ligase, as the effector of muscular atrophy. Chronic infusion of P188 to dysferlin-deficient SJL mice reduced muscular atrophy, and administering p38 and atrogin-1 in the gastrocnemius muscle improved its motor function. These results provide a basis for potential treatments for dysferlin-deficient skeletal muscle fibers.

  499. An autopsy case of a dysferlinopathy patient with cardiac involvement. International-journal Peer-reviewed

    Naoki Suzuki, Toshiaki Takahashi, Yasushi Suzuki, Koichi Narikawa, Sonoko Kudo, Hiroyoshi Suzuki, Maki Tateyama, Masashi Aoki

    Muscle & nerve 45 (2) 298-9 2012/02

    DOI: 10.1002/mus.22247  

    ISSN: 0148-639X

  500. ヒトカルジオウイルスと免疫性神経疾患の関連<第二報>

    93-94 2012

  501. Serotonin Transporter Gene Promoter Polymorphism and Alexithymia Peer-reviewed

    Michiko Kano, Tomoko Mizuno, Yuko Kawano, Masashi Aoki, Motoyori Kanazawa, Shin Fukudo

    NEUROPSYCHOBIOLOGY 65 (2) 76-82 2012

    DOI: 10.1159/000329554  

    ISSN: 0302-282X

  502. Severe olfactory dysfunction is a prodromal symptom of dementia associated with Parkinson's disease: a 3 year longitudinal study Peer-reviewed

    Toru Baba, Akio Kikuchi, Kazumi Hirayama, Yoshiyuki Nishio, Yoshiyuki Hosokai, Shigenori Kanno, Takafumi Hasegawa, Naoto Sugeno, Masatoshi Konno, Kyoko Suzuki, Shoki Takahashi, Hiroshi Fukuda, Masashi Aoki, Yasuto Itoyama, Etsuro Mori, Atsushi Takeda

    BRAIN 135 (Pt 1) 161-169 2012/01

    DOI: 10.1093/brain/awr321  

    ISSN: 0006-8950

  503. [A case of dysferlinopathy asymptomatic for 10 years after an episode of transient muscle weakness]. Peer-reviewed

    Yoshito Kobayashi, Toshiaki Takahashi, Hisae Sumi, Harutoshi Fujimura, Masashi Aoki, Masanori P Takahashi, Saburo Sakoda

    Rinsho shinkeigaku = Clinical neurology 52 (7) 495-8 2012

    DOI: 10.5692/clinicalneurol.52.495  

    ISSN: 0009-918X

    eISSN: 1882-0654

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    We report a 28-year-old male with dysferlinopathy, who has remained asymptomatic for 10 years from a rhabdomyolysis-like episode. He had been in good health since birth, but felt difficulty in walking after a month and a half of manual labor at 18 years old (at the year 2000). Rhabdomyolysis was suspected because of muscle weakness and elevated serum CK of 28,094U/L. He was hospitalized and his muscle weakness improved. He was referred to us, because his serum CK remained around 2,000U/L. Histological analysis of muscle, when anti-dysferlin antibody was unavailable, was not informative but later analysis at the age of 23 using preserved specimen showed loss of dysferlin immunoreactivity. Subsequently, a missense mutation (c.2997G>T) and a deletion (c.3373delG) of the dysferlin gene, both of which are common in Miyoshi myopathy in Japanese, were identified. He continuously showed hyper-CKemia, but no apparent muscle weakness emerged for more than ten years. Reports on asymptomatic dysferlinopathy over such a long duration are rare. This case may suggest that genetic factors, environmental factors such as intensity of work-load, or both, might affect the clinical course of dysferlinopathy. Further follow-up is necessary.

  504. Corticotropin-releasing hormone receptor 1 gene variants in irritable bowel syndrome. International-journal Peer-reviewed

    Naoko Sato, Naoki Suzuki, Ayaka Sasaki, Emiko Aizawa, Takeshi Obayashi, Motoyori Kanazawa, Tomoko Mizuno, Michiko Kano, Masashi Aoki, Shin Fukudo

    PloS one 7 (9) e42450 2012

    DOI: 10.1371/journal.pone.0042450  

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    BACKGROUND: Corticotropin-releasing hormone (CRH) acts mainly via the CRH receptor 1 (CRH-R1) and plays a crucial role in the stress-induced pathophysiology of irritable bowel syndrome (IBS). Several studies have demonstrated that variants of the CRH-R1 gene carry a potential risk for depression, but evidence for an association between CRH-R1 genotypes and IBS is lacking. We tested the hypothesis that genetic polymorphisms and haplotypes of CRH-R1 moderate the IBS phenotype and negative emotion in IBS patients. METHODS: A total of 103 patients with IBS and 142 healthy controls participated in the study. Three single-nucleotide polymorphisms of the CRH-R1 gene (rs7209436, rs242924, and rs110402) were genotyped. Subjects' emotional states were evaluated using the Perceived-Stress Scale, the State-Trait Anxiety Inventory, and the Self-rating Depression Scale. RESULTS: The TT genotype of rs7209436 (P = 0.01) and rs242924 (P = 0.02) was significantly more common in patients with IBS than in controls. Total sample analysis showed significant association between bowel pattern (normal, diarrhea, constipation, or mixed symptoms) and the T allele of rs7209436 (P = 0.008), T allele of rs242924 (P = 0.019), A allele of rs110402 (P = 0.047), and TAT haplocopies (P = 0.048). Negative emotion was not associated with the examined CRH-R1 SNPs. CONCLUSION: These findings suggest that genetic polymorphisms and the CRH-R1 haplotypes moderate IBS and related bowel patterns. There was no clear association between CRH-R1 genotypes and negative emotion accompanying IBS. Further studies on the CRH system are therefore warranted.

  505. HyperCKemia Related to the Initial and Recurrent Attacks of Neuromyelitis Optica Peer-reviewed

    Shoko Deguchi, Kentaro Deguchi, Kota Sato, Taijun Yunoki, Yoshio Omote, Nobutoshi Morimoto, Tomoko Kurata, Masami Ikeda, Toshiyuki Takahashi, Masashi Aoki, Koji Abe

    INTERNAL MEDICINE 51 (18) 2617-2620 2012

    DOI: 10.2169/internalmedicine.51.7898  

    ISSN: 0918-2918

  506. FUS/TLS遺伝子異常に伴う日本人家族性ALSにおける遺伝子変異と臨床型、病理に関する検討

    青木 正志, 鈴木 直輝, 割田 仁, 加藤 昌昭, 水野 秀紀, 島倉 奈緒子, 今野 秀彦, 加藤 信介, 糸山 泰人

    臨床神経学 51 (12) 1225-1225 2011/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  507. 筋萎縮性側索硬化症モデルラットにおける骨格筋再生

    割田 仁, 水野 秀紀, 鈴木 直輝, 糸山 泰人, 青木 正志

    臨床神経学 51 (12) 1317-1317 2011/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  508. ALS患者の縦断像(JaCALSからの解析)

    中村 亮一, 熱田 直樹, 加藤 重典, 千田 譲, 伊藤 瑞規, 渡辺 宏久, 田中 章景, 饗場 郁子, 小長谷 正明, 阿部 康二, 川田 明広, 青木 正志, 岡本 幸市, 長谷川 一子, 谷口 彰, 溝口 功一, 森田 光哉, 和泉 唯信, 梶 龍兒, 中野 今治, 祖父江 元

    臨床神経学 51 (12) 1360-1360 2011/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  509. 日本人三好型遠位型筋ジストロフィーの遺伝子変異の特徴と自然歴 肢帯型筋ジストロフィー2B型との比較 Peer-reviewed

    高橋 俊明, 青木 正志, 鈴木 直輝, 竪山 真規, 吉岡 勝, 今野 秀彦, 小野寺 宏, 西野 一三, 糸山 泰人

    臨床神経学 51 (12) 1301-1301 2011/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  510. The AAA-ATPase VPS4 Regulates Extracellular Secretion and Lysosomal Targeting of alpha-Synuclein Peer-reviewed

    Takafumi Hasegawa, Masatoshi Konno, Toru Baba, Naoto Sugeno, Akio Kikuchi, Michiko Kobayashi, Emiko Miura, Nobuyuki Tanaka, Keiichi Tamai, Katsutoshi Furukawa, Hiroyuki Arai, Fumiaki Mori, Koichi Wakabayashi, Masashi Aoki, Yasuto Itoyama, Atsushi Takeda

    PLOS ONE 6 (12) e29460 2011/12

    DOI: 10.1371/journal.pone.0029460  

    ISSN: 1932-6203

  511. [Pathomechanism and prevalence of sporadic inclusion body myositis (sIBM)]. Peer-reviewed

    Naoki Suzuki, Maki Tateyama, Hitoshi Warita, Rumiko Izumi, Ichizo Nishino, Masashi Aoki

    Rinsho shinkeigaku = Clinical neurology 51 (11) 964-6 2011/11

    eISSN: 1882-0654

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    Sporadic inclusion body myositis (sIBM) is an intractable and progressive skeletal muscle disease of unknown cause and without effective treatment. The etiology of sIBM is still unknown, however genetic factors, aging, life styles, environmental factors may be involved. sIBM is generally refractory to current therapy, such as steroid or immunosuppressants. To elucidate the pathomechanism of sIBM is the most important way to make therapeutic approach. In this review we estimated the prevalence of sIBM in Japan and discuss the pathomechanism of sIBM.

  512. Human Hepatocyte Growth Factor Promotes Functional Recovery in Primates after Spinal Cord Injury Peer-reviewed

    Kazuya Kitamura, Kanehiro Fujiyoshi, Jun-ichi Yamane, Fumika Toyota, Keigo Hikishima, Tatsuji Nomura, Hiroshi Funakoshi, Toshikazu Nakamura, Masashi Aoki, Yoshiaki Toyama, Hideyuki Okano, Masaya Nakamura

    PLOS ONE 6 (11) e27706 2011/11

    DOI: 10.1371/journal.pone.0027706  

    ISSN: 1932-6203

  513. [Regenerative therapies for amyotrophic lateral sclerosis using hepatocyte growth factor]. Peer-reviewed

    Masashi Aoki, Hitoshi Warita, Naoki Suzuki, Masaaki Kato, Yasuto Itoyama

    Rinsho shinkeigaku = Clinical neurology 51 (11) 1195-8 2011/11

    DOI: 10.5692/clinicalneurol.51.1195  

    ISSN: 0009-918X

    eISSN: 1882-0654

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    Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disorder characterized by the death of upper and lower motor neurons. Approximately 20% of familial ALS cases are caused by mutations in the superoxide dismutase 1 (SOD1) gene. We have developed rats that express a human SOD1 transgene with two different ALS-associated mutations develop striking motor neuron degeneration and paralysis. The larger size of this rat model as compared with the ALS mice will facilitate studies involving manipulations of spinal fluid (implantation of intrathecal catheters for chronic therapeutic studies; CSF sampling) and spinal cord (e.g., direct administration of viral- and cell-mediated therapies). Hepatocyte growth factor (HGF) is one of the most potent survival-promoting factors for motor neurons. To examine both its protective effect on motor neurons and its therapeutic potential, we administered human recombinant HGF (hrHGF) by continuous intrathecal delivery to the transgenic rats at the onset of paralysis for 4 weeks. Intrathecal administration of hrHGF attenuates motor neuron degeneration and prolonged the duration of the disease by 63%. Our results indicated the therapeutic efficacy of continuous intrathecal administration of hrHGF in ALS rats. These results should prompt further clinical trials in ALS using continuous intrathecal administration of hrHGF.

  514. A functional variant in ZNF512B is associated with susceptibility to amyotrophic lateral sclerosis in Japanese Peer-reviewed

    Aritoshi Iida, Atsushi Takahashi, Michiaki Kubo, Susumu Saito, Naoya Hosono, Yozo Ohnishi, Kazuma Kiyotani, Taisei Mushiroda, Masahiro Nakajima, Kouichi Ozaki, Toshihiro Tanaka, Tatsuhiko Tsunoda, Shuichi Oshima, Motoki Sano, Tetsumasa Kamei, Torao Tokuda, Masashi Aoki, Kazuko Hasegawa, Koichi Mizoguchi, Mitsuya Morita, Yuji Takahashi, Masahisa Katsuno, Naoki Atsuta, Hirohisa Watanabe, Fumiaki Tanaka, Ryuji Kaji, Imaharu Nakano, Naoyuki Kamatani, Shoji Tsuji, Gen Sobue, Yusuke Nakamura, Shiro Ikegawa

    HUMAN MOLECULAR GENETICS 20 (18) 3684-3692 2011/09

    DOI: 10.1093/hmg/ddr268  

    ISSN: 0964-6906

    eISSN: 1460-2083

  515. Optineurin is co-localized with FUS in basophilic inclusions of ALS with FUS mutation and in basophilic inclusion body disease. International-journal Peer-reviewed

    Hidefumi Ito, Kengo Fujita, Masataka Nakamura, Reika Wate, Satoshi Kaneko, Shoichi Sasaki, Kiyomi Yamane, Naoki Suzuki, Masashi Aoki, Noriyuki Shibata, Shinji Togashi, Akihiro Kawata, Yoko Mochizuki, Toshio Mizutani, Hirofumi Maruyama, Asao Hirano, Ryosuke Takahashi, Hideshi Kawakami, Hirofumi Kusaka

    Acta neuropathologica 121 (4) 555-7 2011/04

    DOI: 10.1007/s00401-011-0809-z  

    ISSN: 0001-6322

  516. Feasibility study for functional test battery of SOD transgenic rat (H46R) and evaluation of edaravone, a free radical scavenger. International-journal Peer-reviewed

    Masashi Aoki, Hitoshi Warita, Hideki Mizuno, Naoki Suzuki, Satoshi Yuki, Yasuto Itoyama

    Brain research 1382 321-5 2011/03/25

    DOI: 10.1016/j.brainres.2011.01.058  

    ISSN: 0006-8993

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    We evaluated a battery of functional tests for investigating the effects of edaravone, a free radical scavenger, in SOD1 transgenic (H46R) rat model of amyotrophic lateral sclerosis. Edaravone (1.5 or 3.0mg/kg/h) or saline was administered intravenously to rats by continuous infusion (1h per day) for 2days, followed by a 2-day holiday. Lifetime and duration of illness were evaluated, and motor function was assessed using the hind-foot reflex test, landing foot-splay test, rota rod test and inclined plate test at a predetermined time point at which half of the control animals had died. Statistical comparison of motor functions of edaravone-treated and control SOD1 transgenic rats at an objectively determined time point was confirmed to be feasible. Edaravone-treated male rats showed significantly better performance in the landing foot-splay test. The present model seems suitable for evaluating motor function of H46R SOD1 transgenic rats, and be useful for examining the therapeutic potential of edaravone to treat amyotrophic lateral sclerosis.

  517. A case of late onset riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency manifesting as recurrent rhabdomyolysis and acute renal failure. Peer-reviewed

    Rumiko Izumi, Naoki Suzuki, Mari Nagata, Takafumi Hasegawa, Yu Abe, Yuka Saito, Hiroshi Mochizuki, Maki Tateyama, Masashi Aoki

    Internal medicine (Tokyo, Japan) 50 (21) 2663-8 2011

    DOI: 10.2169/internalmedicine.50.5172  

    ISSN: 0918-2918

    eISSN: 1349-7235

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    We report an adult case of late-onset riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (MADD) characterized by episodic recurrent rhabdomyolysis and acute renal failure after the age of 46. Muscle biopsy revealed lipid storage myopathy and the finding of serum acylcarnitine and urine organic acid analyses were consistent with MADD. A compound heterozygous mutation was identified in the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene, including a novel missense mutation, which confirmed the diagnosis of MADD. After administration of riboflavin and L-carnitine, the muscle weakness and fatigability gradually improved. Acylcarnitine and urine organic acid were also normalized after supplementation. Thus, MADD should be included in one of the differential diagnoses for adult recurrent rhabdomyolysis. Gene analysis is useful to confirm the diagnosis, and early diagnosis is important because riboflavin treatment has been effective in a significant number of patients with MADD.

  518. 若年発症・急速進行・好塩基性封入体を特徴としFUS遺伝子変異を伴う家族性ALSの5家系

    青木 正志, 鈴木 直輝, 割田 仁, 加藤 昌昭, 水野 秀紀, 島倉 奈緒子, 秋山 徹也, 今野 秀彦, 糸山 泰人

    臨床神経学 50 (12) 1084-1084 2010/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  519. 微小血管新生促進によるALSモデルラット神経保護の試み

    割田 仁, 青木 正志, 水野 秀紀, 鈴木 直輝, 船越 洋, 中村 敏一, 糸山 泰人

    臨床神経学 50 (12) 1198-1198 2010/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  520. 日本人のdysferlin遺伝子変異の確定した肢帯型筋ジストロフィー2B型の特徴 Peer-reviewed

    高橋 俊明, 青木 正志, 鈴木 直輝, 竪山 真規, 吉岡 勝, 今野 秀彦, 林 由起子, 西野 一三, 埜中 征哉, 小野寺 宏, 糸山 泰人

    臨床神経学 50 (12) 1088-1088 2010/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  521. An Inducer of VGF Protects Cells against ER Stress-Induced Cell Death and Prolongs Survival in the Mutant SOD1 Animal Models of Familial ALS Peer-reviewed

    Masamitsu Shimazawa, Hirotaka Tanaka, Yasushi Ito, Nobutaka Morimoto, Kazuhiro Tsuruma, Michinori Kadokura, Shigeki Tamura, Teruyoshi Inoue, Mitsunori Yamada, Hitoshi Takahashi, Hitoshi Warita, Masashi Aoki, Hideaki Hara

    PLOS ONE 5 (12) e15307 2010/12

    DOI: 10.1371/journal.pone.0015307  

    ISSN: 1932-6203

  522. Appearance of Phagocytic Microglia Adjacent to Motoneurons in Spinal Cord Tissue From a Presymptomatic Transgenic Rat Model of Amyotrophic Lateral Sclerosis Peer-reviewed

    Tomomi Sanagi, Shigeki Yuasa, Yasuko Nakamura, Eri Suzuki, Masashi Aoki, Hitoshi Warita, Yasuto Itoyama, Shigeo Uchino, Shinichi Kohsaka, Keiko Ohsawa

    JOURNAL OF NEUROSCIENCE RESEARCH 88 (12) 2736-2746 2010/09

    DOI: 10.1002/jnr.22424  

    ISSN: 0360-4012

  523. Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study): a multicentre, randomised, double-blind, placebo-controlled trial Peer-reviewed

    Masahisa Katsuno, Haruhiko Banno, Keisuke Suzuki, Yu Takeuchi, Motoshi Kawashima, Ichiro Yabe, Hidenao Sasaki, Masashi Aoki, Mitsuya Morita, Imaharu Nakano, Kazuaki Kanai, Shoichi Ito, Kinya Ishikawa, Hidehiro Mizusawa, Tomotaka Yamamoto, Shoji Tsuji, Kazuko Hasegawa, Takayoshi Shimohata, Masatoyo Nishizawa, Hiroaki Miyajima, Fumio Kanda, Yasuhiro Watanabe, Kenji Nakashima, Akira Tsujino, Taro Yamashita, Makoto Uchino, Yasushi Fujimoto, Fumiaki Tanaka, Gen Sobue

    LANCET NEUROLOGY 9 (9) 875-884 2010/09

    DOI: 10.1016/S1474-4422(10)70182-4  

    ISSN: 1474-4422

    eISSN: 1474-4465

  524. グリア細胞の機能変調と脳疾患 神経変性疾患におけるミクログリアの動態変化(Glia pathology and brain diseases Dynamic behavior of microglia in neurodegenerative diseases)

    大澤 圭子, 佐柳 友規, 中村 泰子, 鈴木 恵理, 青木 正志, 割田 仁, 糸山 泰人, 高坂 新一

    神経化学 49 (2-3) 443-443 2010/08

    Publisher: (一社)日本神経化学会

    ISSN: 0037-3796

  525. 顔面神経軸索損傷負荷後のALSモデルラットにおける運動ニューロン脆弱性に関与するミクログリアの機能の解析(Involvement of phagocytic microglia in increased vulnerability of motoneurons after facial nerve avulsion in presymptomatic ALS model rats)

    佐柳 友規, 大澤 圭子, 中村 泰子, 鈴木 恵里, 青木 正志, 割田 仁, 糸山 泰人, 内野 茂夫, 高坂 新一

    神経化学 49 (2-3) 699-699 2010/08

    Publisher: (一社)日本神経化学会

    ISSN: 0037-3796

  526. Neuronal NOS is dislocated during muscle atrophy in amyotrophic lateral sclerosis. International-journal Peer-reviewed

    Naoki Suzuki, Hideki Mizuno, Hitoshi Warita, Shin'ichi Takeda, Yasuto Itoyama, Masashi Aoki

    Journal of the neurological sciences 294 (1-2) 95-101 2010/07/15

    DOI: 10.1016/j.jns.2010.03.022  

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    Previously, we demonstrated that neuronal nitric oxide synthase (nNOS) is activated and promotes muscle atrophy in skeletal muscle during tail suspension, a model of unloading and denervation. Here, we examined patients with amyotrophic lateral sclerosis (ALS) and mutant (H46R) SOD1 transgenic (Tg) mice model using immunohistochemistry, Western blotting and real time PCR. We found cytoplasmic nNOS staining of angulated muscle fibers in patients with ALS. We also examined mutant SOD1 Tg mice and found cytoplasmic nNOS staining even before the onset of clinical muscle atrophy. In the Tg mice, nNOS was largely extracted with 100 mM NaCl and barely detected in the pellet fraction, suggesting fragile anchoring of nNOS to the sarcolemma. We also showed an elevated expression of atrogin-1, key molecules in muscle atrophy at the end stage. A common nNOS dislocation/atrogin-1/muscle atrophy pathway among tail suspension, denervation and ALS is suggested. nNOS modulation therapy may be beneficial in several types of muscle atrophy.

  527. Neuronal NOS is dislocated during muscle atrophy in amyotrophic lateral sclerosis. International-journal Peer-reviewed

    Naoki Suzuki, Hideki Mizuno, Hitoshi Warita, Shin'ichi Takeda, Yasuto Itoyama, Masashi Aoki

    Journal of the neurological sciences 294 (1-2) 95-101 2010/07/15

    DOI: 10.1016/j.jns.2010.03.022  

    ISSN: 0022-510X

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    Previously, we demonstrated that neuronal nitric oxide synthase (nNOS) is activated and promotes muscle atrophy in skeletal muscle during tail suspension, a model of unloading and denervation. Here, we examined patients with amyotrophic lateral sclerosis (ALS) and mutant (H46R) SOD1 transgenic (Tg) mice model using immunohistochemistry, Western blotting and real time PCR. We found cytoplasmic nNOS staining of angulated muscle fibers in patients with ALS. We also examined mutant SOD1 Tg mice and found cytoplasmic nNOS staining even before the onset of clinical muscle atrophy. In the Tg mice, nNOS was largely extracted with 100 mM NaCl and barely detected in the pellet fraction, suggesting fragile anchoring of nNOS to the sarcolemma. We also showed an elevated expression of atrogin-1, key molecules in muscle atrophy at the end stage. A common nNOS dislocation/atrogin-1/muscle atrophy pathway among tail suspension, denervation and ALS is suggested. nNOS modulation therapy may be beneficial in several types of muscle atrophy.

  528. Proteome profiling reveals gender differences in the composition of human serum Peer-reviewed

    Koichiro Miike, Masashi Aoki, Ryo Yamashita, Yumiko Takegawa, Hideyuki Saya, Teruhisa Miike, Ken-ichi Yamamura

    PROTEOMICS 10 (14) 2678-2691 2010/07

    DOI: 10.1002/pmic.200900496  

    ISSN: 1615-9853

  529. Effective viscosity for nematic-liquid-crystal viscosity measurement using a shear horizontal wave Peer-reviewed

    Ryotaro Ozaki, Masashi Aoki, Katsumi Yoshino, Kohji Toda, Hiroshi Moritake

    Physical Review E - Statistical, Nonlinear, and Soft Matter Physics 81 (6) 061703 2010/06/18

    DOI: 10.1103/PhysRevE.81.061703  

    ISSN: 1539-3755 1550-2376

  530. Occurrence of basophilic inclusions and FUS-immunoreactive neuronal and glial inclusions in a case of familial amyotrophic lateral sclerosis Peer-reviewed

    Zen Kobayashi, Kuniaki Tsuchiya, Tetsuaki Arai, Masashi Aoki, Masato Hasegawa, Hideki Ishizu, Haruhiko Akiyama, Hidehiro Mizusawa

    JOURNAL OF THE NEUROLOGICAL SCIENCES 293 (1-2) 6-11 2010/06

    DOI: 10.1016/j.jns.2010.03.029  

    ISSN: 0022-510X

  531. Occurrence of basophilic inclusions and FUS-immunoreactive neuronal and glial inclusions in a case of familial amyotrophic lateral sclerosis Peer-reviewed

    Zen Kobayashi, Kuniaki Tsuchiya, Tetsuaki Arai, Masashi Aoki, Masato Hasegawa, Hideki Ishizu, Haruhiko Akiyama, Hidehiro Mizusawa

    JOURNAL OF THE NEUROLOGICAL SCIENCES 293 (1-2) 6-11 2010/06

    DOI: 10.1016/j.jns.2010.03.029  

    ISSN: 0022-510X

  532. Mutations of optineurin in amyotrophic lateral sclerosis. International-journal Peer-reviewed

    Hirofumi Maruyama, Hiroyuki Morino, Hidefumi Ito, Yuishin Izumi, Hidemasa Kato, Yasuhito Watanabe, Yoshimi Kinoshita, Masaki Kamada, Hiroyuki Nodera, Hidenori Suzuki, Osamu Komure, Shinya Matsuura, Keitaro Kobatake, Nobutoshi Morimoto, Koji Abe, Naoki Suzuki, Masashi Aoki, Akihiro Kawata, Takeshi Hirai, Takeo Kato, Kazumasa Ogasawara, Asao Hirano, Toru Takumi, Hirofumi Kusaka, Koichi Hagiwara, Ryuji Kaji, Hideshi Kawakami

    Nature 465 (7295) 223-6 2010/05/13

    DOI: 10.1038/nature08971  

    More details Close

    Amyotrophic lateral sclerosis (ALS) has its onset in middle age and is a progressive disorder characterized by degeneration of motor neurons of the primary motor cortex, brainstem and spinal cord. Most cases of ALS are sporadic, but about 10% are familial. Genes known to cause classic familial ALS (FALS) are superoxide dismutase 1 (SOD1), ANG encoding angiogenin, TARDP encoding transactive response (TAR) DNA-binding protein TDP-43 (ref. 4) and fused in sarcoma/translated in liposarcoma (FUS, also known as TLS). However, these genetic defects occur in only about 20-30% of cases of FALS, and most genes causing FALS are unknown. Here we show that there are mutations in the gene encoding optineurin (OPTN), earlier reported to be a causative gene of primary open-angle glaucoma (POAG), in patients with ALS. We found three types of mutation of OPTN: a homozygous deletion of exon 5, a homozygous Q398X nonsense mutation and a heterozygous E478G missense mutation within its ubiquitin-binding domain. Analysis of cell transfection showed that the nonsense and missense mutations of OPTN abolished the inhibition of activation of nuclear factor kappa B (NF-kappaB), and the E478G mutation revealed a cytoplasmic distribution different from that of the wild type or a POAG mutation. A case with the E478G mutation showed OPTN-immunoreactive cytoplasmic inclusions. Furthermore, TDP-43- or SOD1-positive inclusions of sporadic and SOD1 cases of ALS were also noticeably immunolabelled by anti-OPTN antibodies. Our findings strongly suggest that OPTN is involved in the pathogenesis of ALS. They also indicate that NF-kappaB inhibitors could be used to treat ALS and that transgenic mice bearing various mutations of OPTN will be relevant in developing new drugs for this disorder.

  533. Mutations of optineurin in amyotrophic lateral sclerosis. International-journal Peer-reviewed

    Hirofumi Maruyama, Hiroyuki Morino, Hidefumi Ito, Yuishin Izumi, Hidemasa Kato, Yasuhito Watanabe, Yoshimi Kinoshita, Masaki Kamada, Hiroyuki Nodera, Hidenori Suzuki, Osamu Komure, Shinya Matsuura, Keitaro Kobatake, Nobutoshi Morimoto, Koji Abe, Naoki Suzuki, Masashi Aoki, Akihiro Kawata, Takeshi Hirai, Takeo Kato, Kazumasa Ogasawara, Asao Hirano, Toru Takumi, Hirofumi Kusaka, Koichi Hagiwara, Ryuji Kaji, Hideshi Kawakami

    Nature 465 (7295) 223-6 2010/05/13

    DOI: 10.1038/nature08971  

    ISSN: 0028-0836

    More details Close

    Amyotrophic lateral sclerosis (ALS) has its onset in middle age and is a progressive disorder characterized by degeneration of motor neurons of the primary motor cortex, brainstem and spinal cord. Most cases of ALS are sporadic, but about 10% are familial. Genes known to cause classic familial ALS (FALS) are superoxide dismutase 1 (SOD1), ANG encoding angiogenin, TARDP encoding transactive response (TAR) DNA-binding protein TDP-43 (ref. 4) and fused in sarcoma/translated in liposarcoma (FUS, also known as TLS). However, these genetic defects occur in only about 20-30% of cases of FALS, and most genes causing FALS are unknown. Here we show that there are mutations in the gene encoding optineurin (OPTN), earlier reported to be a causative gene of primary open-angle glaucoma (POAG), in patients with ALS. We found three types of mutation of OPTN: a homozygous deletion of exon 5, a homozygous Q398X nonsense mutation and a heterozygous E478G missense mutation within its ubiquitin-binding domain. Analysis of cell transfection showed that the nonsense and missense mutations of OPTN abolished the inhibition of activation of nuclear factor kappa B (NF-kappaB), and the E478G mutation revealed a cytoplasmic distribution different from that of the wild type or a POAG mutation. A case with the E478G mutation showed OPTN-immunoreactive cytoplasmic inclusions. Furthermore, TDP-43- or SOD1-positive inclusions of sporadic and SOD1 cases of ALS were also noticeably immunolabelled by anti-OPTN antibodies. Our findings strongly suggest that OPTN is involved in the pathogenesis of ALS. They also indicate that NF-kappaB inhibitors could be used to treat ALS and that transgenic mice bearing various mutations of OPTN will be relevant in developing new drugs for this disorder.

  534. Neuromyelitis optica preceded by hyperCKemia episode. Peer-reviewed

    Aoki M, Fujihara K, Itoyama Y, Kameya S, Konohana S, Kumagai T, Misu T, Okumura T, Suzuki N, Takahashi H, Takahashi T, Yamaki K

    Neurology 74 (19) 1543-1545 2010/05

    DOI: 10.1212/WNL.0b013e3181dd445b  

  535. FALS with FUS mutation in Japan, with early onset, rapid progress and basophilic inclusion. International-journal Peer-reviewed

    Naoki Suzuki, Masashi Aoki, Hitoshi Warita, Masaaki Kato, Hideki Mizuno, Naoko Shimakura, Tetsuya Akiyama, Hirokazu Furuya, Toshihiro Hokonohara, Akiko Iwaki, Shinji Togashi, Hidehiko Konno, Yasuto Itoyama

    Journal of human genetics 55 (4) 252-4 2010/04

    DOI: 10.1038/jhg.2010.16  

    ISSN: 1434-5161

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    Mutations in the fused in sarcoma (FUS, also known as translated in liposarcoma) gene have been recently discovered to be associated with familial amyotrophic lateral sclerosis (FALS) in African, European and American populations. In a Japanese family with FALS, we found the R521C FUS mutation, which has been reported to be found in various ethnic backgrounds. The family history revealed 23 patients with FALS among 46 family members, suggesting a 100% penetrance rate. They developed muscle weakness at an average age of 35.3 years, followed by dysarthria, dysphagia, spasticity and muscle atrophy. The average age of death was 37.2 years. Neuropathological examination of the index case revealed remarkable atrophy of the brainstem tegmentum characterized by cytoplasmic basophilic inclusion bodies in the neurons of the brainstem. We screened 40 FALS families in Japan and found 4 mutations (S513P, K510E, R514S, H517P) in exon 14 and 15 of FUS. Even in Asian races, FALS with FUS mutations may have the common characteristics of early onset, rapid progress and high penetrance rate, although in patients with the S513P mutation it was late-onset. Degeneration in multiple systems and cytoplasmic basophilic inclusion bodies were found in the autopsied cases.

  536. Loss of ALS2/Alsin Exacerbates Motor wDysfunction in a SOD1(H46R)-Expressing Mouse ALS Model by Disturbing Endolysosomal Trafficking Peer-reviewed

    Shinji Hadano, Asako Otomo, Ryota Kunita, Kyoko Suzuki-Utsunomiya, Akira Akatsuka, Masato Koike, Masashi Aoki, Yasuo Uchiyama, Yasuto Itoyama, Joh-E Ikeda

    PLOS ONE 5 (3) e9805-e9805 2010/03

    DOI: 10.1371/journal.pone.0009805  

    ISSN: 1932-6203

  537. Loss of ALS2/Alsin Exacerbates Motor wDysfunction in a SOD1(H46R)-Expressing Mouse ALS Model by Disturbing Endolysosomal Trafficking Peer-reviewed

    Shinji Hadano, Asako Otomo, Ryota Kunita, Kyoko Suzuki-Utsunomiya, Akira Akatsuka, Masato Koike, Masashi Aoki, Yasuo Uchiyama, Yasuto Itoyama, Joh-E Ikeda

    PLOS ONE 5 (3) e9805 2010/03

    DOI: 10.1371/journal.pone.0009805  

    ISSN: 1932-6203

  538. Rapid Screening for Japanese Dysferlinopathy by Fluorescent Primer Extension Peer-reviewed

    Saori Hayashi, Yutaka Ohsawa, Toshiaki Takahashi, Naoki Suzuki, Tadashi Okada, Mitsue Rikimaru, Tatsufumi Murakami, Masashi Aoki, Yoshihide Sunada

    INTERNAL MEDICINE 49 (24) 2693-2696 2010

    DOI: 10.2169/internalmedicine.49.3771  

    ISSN: 0918-2918

  539. 筋萎縮性側索硬化症マウスに対する一酸化窒素合成酵素阻害剤による治療の検討

    鈴木 直輝, 青木 正志, 割田 仁, 水野 秀紀, 武田 伸一, 糸山 泰人

    臨床神経学 49 (12) 1020-1020 2009/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  540. ALSモデルラット脊髄活性化アストロサイトにおける再生阻害因子発現

    水野 秀紀, 割田 仁, 青木 正志, 糸山 泰人

    臨床神経学 49 (12) 1144-1144 2009/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  541. 逐次的な再生誘導因子投与によるALSモデルラット脊髄の内在性再生機転促進

    割田 仁, 青木 正志, 水野 秀紀, 船越 洋, 糸山 泰人

    臨床神経学 49 (12) 1144-1144 2009/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  542. 肢帯型筋ジストロフィー2B型におけるG3370T変異と臨床経過 Peer-reviewed

    高橋 俊明, 青木 正志, 鈴木 直輝, 竪山 真規, 吉岡 勝, 今野 秀彦, 林 由起子, 西野 一三, 埜中 征哉, 小野寺 宏, 糸山 泰人

    臨床神経学 49 (12) 1053-1053 2009/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  543. Cutaneous accumulation of abnormal polyglutamine proteins of patients with dentatorubral-pallidoluysian atrophy Peer-reviewed

    M. Ohta, R. Okuyama, E. Ogawa, K. Kisu, H. Sato, M. Aoki, S. Aiba

    EUROPEAN JOURNAL OF NEUROLOGY 16 (11) 1246-1249 2009/11

    DOI: 10.1111/j.1468-1331.2009.02658.x  

    ISSN: 1351-5101

  544. [Development of motor neuron restorative therapy in amyotrophic lateral sclerosis using hepatocyte growth factor]. Peer-reviewed

    Masashi Aoki, Hitoshi Warita, Naoki Suzuki, Yasuto Itoyama

    Rinsho shinkeigaku = Clinical neurology 49 (11) 814-7 2009/11

    DOI: 10.5692/clinicalneurol.49.814  

    ISSN: 0009-918X

    More details Close

    Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disorder characterized by the death of upper and lower motor neurons. Approximately 20% of familial ALS cases are caused by mutations in the superoxide dismutase 1 (SOD1) gene. Mutations in the fused in sarcoma/translated in liposarcoma (FUS/TLS) gene have been recently discovered to be associated with familial ALS. We found FUS/TLS mutations in familial ALS cases in Japan. Even in Asian races, ALS with FUS/TLS mutations may have common characteristics of early onset, rapid progress, high penerence trait. We developed rats that express a human SOD1 transgene with two different ALS-associated mutations (G93A and H46R) develop striking motor neuron degeneration and paralysis. The larger size of this rat model as compared with the ALS mice will facilitate studies involving manipulations of spinal fluid (implantation of intrathecal catheters for chronic therapeutic studies; CSF sampling) and spinal cord (e.g., direct administration of viral- and cell-mediated therapies). Hepatocyte growth factor (HGF) is one of the most potent survival-promoting factors for motor neurons. To examine its both protective effect on motor neurons and therapeutic potential, we administered human recombinant HGF (hrHGF) by continuous intrathecal delivery to G93A transgenic rats at onset of paralysis for 4 weeks. Intrathecal administration of hrHGF attenuates motor neuron degeneration and prolonged the duration of the disease by 63%. Our results indicated the therapeutic efficacy of continuous intrathecal administration of hrHGF in ALS rats. In addition, HGF is capable of reducing astrocytosis and microglial accumulation, and thus supports the attention of a glial-dependent mechanism of ALS progression. These results should prompt further clinical trials in ALS using continuous intrathecal administration of hrHGF.

  545. Dorsal-roots enhancement and Wallerian degeneration of dorsal cord in the patient of acute sensory ataxic neuropathy. International-journal Peer-reviewed

    Kaoru Endo, Naoki Suzuki, Tatsuro Misu, Masashi Aoki, Yasuto Itoyama

    Journal of neurology 256 (10) 1765-6 2009/10

    DOI: 10.1007/s00415-009-5186-3  

    ISSN: 0340-5354

  546. SNPを用いた大規模関連解析による筋萎縮性側索硬化症感受性遺伝子の同定

    飯田 有俊, 高橋 篤, 久保 充明, 鎌谷 直之, 青木 正志, 梶 龍兒, 中野 今治, 祖父江 元, 中村 祐輔, 池川 志郎

    日本生化学会大会プログラム・講演要旨集 82回 4T9a-12 2009/09

    Publisher: (公社)日本生化学会

  547. Impact of serotonin transporter gene polymorphism on brain activation by colorectal distention Peer-reviewed

    S. Fukudo, M. Kanazawa, T. Mizuno, T. Hamaguchi, M. Kano, S. Watanabe, Y. Sagami, T. Shoji, Y. Endo, M. Hongo, Y. Itoyama, K. Yanai, M. Tashiro, M. Aoki

    NEUROIMAGE 47 (3) 946-951 2009/09

    DOI: 10.1016/j.neuroimage.2009.04.083  

    ISSN: 1053-8119

  548. A CASE OF NMO SEROPOSITIVE FOR AQUAPORIN-4 ANTIBODY MORE THAN 10 YEARS BEFORE ONSET Peer-reviewed

    S. Nishiyama, T. Ito, T. Misu, T. Takahashi, A. Kikuchi, N. Suzuki, K. Jin, M. Aoki, K. Fujihara, Y. Itoyama

    NEUROLOGY 72 (22) 1960-1961 2009/06

    DOI: 10.1212/WNL.0b013e3181a82621  

    ISSN: 0028-3878

  549. 遺伝子治療と再生医療 HGFを用いたALSに対する治療法の開発

    青木 正志, 割田 仁, 糸山 泰人

    神経治療学 26 (3) 289-289 2009/05

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  550. Mitochondrial alterations in transgenic mice with an H46R mutant Cu/Zn superoxide dismutase gene. Peer-reviewed

    Sasaki Shoichi, Aoki Masashi, Nagai Makiko, Kobayashi Makio, Itoyama Yasuto

    J Neuropathol Exp Neurol 68 (4) 365-373 2009/04

    DOI: 10.1097/NEN.0b013e31819ba185  

    ISSN: 0022-3069

  551. 頭痛を伴うMarfan症候群患者のdural ectasia Peer-reviewed

    加藤量広, 鈴木直輝, 遠藤 薫, 青木正志, 糸山泰人

    神経内科 70 417-418 2009/04

  552. 血清aldolase値の上昇がみられたperifascicular atrophyをともなう非好酸球性筋膜滑膜炎の1例

    小野 紘彦, 鈴木 直輝, 水野 秀紀, 竪山 真規, 青木 正志, 糸山 泰人

    臨床神経学 49 (2-3) 119-122 2009/03

    Publisher: (一社)日本神経学会

    DOI: 10.5692/clinicalneurol.49.119  

    ISSN: 0009-918X

  553. PROCALCITONIN MIGHT HELP IN DISCRIMINATION BETWEEN MENINGEAL NEURO-BEHCET DISEASE AND BACTERIAL MENINGITIS Peer-reviewed

    N. Suzuki, H. Mizuno, M. Nezu, Y. Takai, T. Misu, H. Kuroda, M. Aoki, I. Nakashima, Y. Itoyama

    NEUROLOGY 72 (8) 762-763 2009/02

    DOI: 10.1212/01.wnl.0000343046.88848.76  

    ISSN: 0028-3878

  554. PROCALCITONIN MIGHT HELP IN DISCRIMINATION BETWEEN MENINGEAL NEURO-BEHCET DISEASE AND BACTERIAL MENINGITIS

    N. Suzuki, H. Mizuno, M. Nezu, Y. Takai, T. Misu, H. Kuroda, M. Aoki, I. Nakashima, Y. Itoyama

    NEUROLOGY 72 (8) 762-763 2009/02

    DOI: 10.1212/01.wnl.0000343046.88848.76  

    ISSN: 0028-3878

  555. Elevated serum aldolase activity in a patient of non-eosinophilic myofasciitis and synovitis with perifascicular atrophy Peer-reviewed

    Hirohiko Ono, Naoki Suzuki, Hideki Mizuno, Maki Tateyama, Masashi Aoki, Yasuto Itoyama

    Clinical Neurology 49 (2-3) 119-122 2009/02

    DOI: 10.5692/clinicalneurol.49.119  

    ISSN: 0009-918X

  556. 08-006 内臓刺激に対する中枢反応におけるセロトニントランスポーター遺伝子多型の影響(精神生理,脳生理,神経科学2,一般演題(ポスター発表),近未来医療を担う心身医学,第1回日本心身医学5学会合同集会)

    小室 葉月, 鈴木 直輝, 渡辺 諭史, 青木 正志, 糸山 泰人, 金澤 素, 福土 審

    心身医学 49 (6) 533-533 2009

    Publisher: 一般社団法人 日本心身医学会

    DOI: 10.15064/jjpm.49.6_533_2  

  557. Age at onset influences on wide-ranged clinical features of sporadic amyotrophic lateral sclerosis Peer-reviewed

    Naoki Atsuta, Hirohisa Watanabe, Mizuki Ito, Fumiaki Tanaka, Akiko Tamakoshi, Imaharu Nakano, Masashi Aoki, Shoji Tsuji, Tatsuhiko Yuasa, Hirold Takano, Hideaki Hayashi, Shigeld Kuzuhara, Gen Sobue

    JOURNAL OF THE NEUROLOGICAL SCIENCES 276 (1-2) 163-169 2009/01

    DOI: 10.1016/j.jns.2008.09.024  

    ISSN: 0022-510X

    eISSN: 1878-5883

  558. Intravenous immunoglobulin treatment successfully improved subacute progressive polyradiculoneuropathy with polyclonal gammopathy. Peer-reviewed

    Kaoru Endo, Naoki Suzuki, Taro Ikenishi, Masashi Aoki, Yasuto Itoyama

    Internal medicine (Tokyo, Japan) 48 (23) 2037-9 2009

    DOI: 10.2169/internalmedicine.48.2545  

    ISSN: 0918-2918

    eISSN: 1349-7235

    More details Close

    The present case was an elderly man with a history of gastric cancer, diffuse biliary duct stenosis and liver cirrhosis. He had markedly elevated IgG, suggesting chronic infection or inflammatory changes in the biliary duct. He developed weakness in his arms and became unable to use his hands within one month and 2 weeks later, he had difficulty walking. Based on his progressive disease course, elevated serum IgG, nerve conduction study and enhanced MRI findings, we diagnosed him as suffering from immune-mediated subacute polyradiculoneuropathy with polyclonal gammopathy, which might be related to Guillain-Barré syndrome. Intravenous immunoglobulin (IVIg) was dramatically effective in this patient. In the follow-up 6 months later he was stable and could walk without a cane. Even in patients with polyclonal gammopathy in chronic inflammatory disease of another organ, IVIg may be effective and beneficial for the patients's quality of life.

  559. Age at onset influences on wide-ranged clinical features of sporadic amyotrophic lateral sclerosis Peer-reviewed

    Naoki Atsuta, Hirohisa Watanabe, Mizuki Ito, Fumiaki Tanaka, Akiko Tamakoshi, Imaharu Nakano, Masashi Aoki, Shoji Tsuji, Tatsuhiko Yuasa, Hirold Takano, Hideaki Hayashi, Shigeld Kuzuhara, Gen Sobue

    JOURNAL OF THE NEUROLOGICAL SCIENCES 276 (1-2) 163-169 2009/01

    DOI: 10.1016/j.jns.2008.09.024  

    ISSN: 0022-510X

    eISSN: 1878-5883

  560. 内因性肝細胞増殖因子(HGF)によるALSラット脊髄再生阻害因子発現の抑制

    青木 正志, 割田 仁, 水野 秀紀, 船越 洋, 糸山 泰人

    臨床神経学 48 (12) 1117-1117 2008/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  561. ALSモデルラット脊髄における血管内皮細胞新生

    割田 仁, 青木 正志, 水野 秀紀, 糸山 泰人

    臨床神経学 48 (12) 1149-1149 2008/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  562. ALSモデルラット脊髄におけるコンドロイチン硫酸プロテオグリカンの発現変動

    水野 秀紀, 割田 仁, 青木 正志, 糸山 泰人

    臨床神経学 48 (12) 1151-1151 2008/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  563. 日本人のdysferlin遺伝子変異の確定した肢帯型筋ジストロフィーの臨床経過 Peer-reviewed

    高橋 俊明, 青木 正志, 鈴木 直輝, 竪山 真規, 吉岡 勝, 今野 秀彦, 林 由起子, 西野 一三, 埜中 征哉, 小野寺 宏, 糸山 泰人

    臨床神経学 48 (12) 1232-1232 2008/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  564. ALSの研究・治療はどこまできたか SOD1遺伝子変異とALS

    青木 正志, 割田 仁, 糸山 泰人

    臨床神経学 48 (11) 966-969 2008/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  565. Development of a high-throughput microarray-based resequencing system for neurological disorders and its application to molecular genetics of amyotrophic lateral sclerosis. Peer-reviewed

    Takahashi Yuji, Seki Naomi, Ishiura Hiroyuki, Mitsui Jun, Matsukawa Takashi, Kishino Atsushi, Onodera Osamu, Aoki Masashi, Shimozawa Nobuyuki, Murayama Shigeo, Itoyama Yasuto, Suzuki Yasuyuki, Sobue Gen, Nishizawa Masatoyo, Goto Jun, Tsuji Shoji

    Arch Neurol 65 (10) 1326-1332 2008/10

    DOI: 10.1001/archneur.65.10.1326  

    ISSN: 0003-9942

  566. Severe symptoms of 16q-ADCA coexisting with SCA8 repeat expansion Peer-reviewed

    Keiko Ohnari, Masashi Aoki, Takenori Uozumi, Sadatoshi Tsuji

    JOURNAL OF THE NEUROLOGICAL SCIENCES 273 (1-2) 15-18 2008/10

    DOI: 10.1016/j.jns.2008.06.003  

    ISSN: 0022-510X

  567. 細菌性髄膜炎との鑑別を要した神経ベーチェット病の1例

    祢津 昌広, 鈴木 直輝, 水野 秀紀, 高井 良樹, 三須 達郎, 青木 正志, 中島 一郎, 糸山 泰人

    臨床神経学 48 (10) 750-753 2008/10

    Publisher: (一社)日本神経学会

    DOI: 10.5692/clinicalneurol.48.750  

    ISSN: 0009-918X

  568. Severe symptoms of 16q-ADCA coexisting with SCA8 repeat expansion Peer-reviewed

    Keiko Ohnari, Masashi Aoki, Takenori Uozumi, Sadatoshi Tsuji

    JOURNAL OF THE NEUROLOGICAL SCIENCES 273 (1-2) 15-18 2008/10

    DOI: 10.1016/j.jns.2008.06.003  

    ISSN: 0022-510X

  569. [Case of Neuro-Behçet disease resembling bacterial meningitis]. Peer-reviewed

    Masahiro Nezu, Naoki Suzuki, Hideki Mizuno, Yoshiki Takai, Tatsuro Misu, Masashi Aoki, Ichiro Nakashima, Yasuto Itoyama

    Rinsho shinkeigaku = Clinical neurology 48 (10) 750-3 2008/10

    DOI: 10.5692/clinicalneurol.48.750  

    ISSN: 0009-918X

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    A 30-year-old man with intractable headache and high fever came to the emergency room. He presented skin eruption, aphtha, drowsiness (E3, V4, M6/GCS), meningeal sign, hyperreflexia, and bilateral papilloedema. He also showed pleocytosis (1,066/microl, polymorphonuclear cells predominantly) and pressure increase in CSF. WBC count and CRP were elevated. Two years before, he had meningeal sign, cervical myelitis, skin eruption, uveitis, and aphtha, and was diagnosed as Neuro-BehCet (NBD) disease. HLA-B52 and B55 were positive. We suspected recurrent NBD, but we couldn't exclude bacterial meningitis because of his symptoms and cell-pattern in CSF. We treated him with intravenous methylpredonisolone and antibiotics (MEPM 6 g/day and VCM 2 g/day). His symptoms dramatically improved within a few days. The rapid improvement might be attributed to the steroids. Furthermore, MRI FLAIR images showed multiple small high lesions in the brainstem, hemispheres, subcortical area, putamen and left cerebellar hemisphere. Serum procalcitonin was not increased. We diagnosed the recurrence of NBD retrospectively. Procalcitonin may be a useful marker for discrimination between meningitis due to NBD and septic meningitis.

  570. ALS2/alsin機能喪失は変異SOD1H46R発現マウスの運動機能障害と軸索損傷を悪化させる(Loss of ALS2/alsin exacerbates motor dysfunction and axonal damage in SOD1H46R transgenic mice)

    秦野 伸二, 大友 麻子, 國田 竜太, 鈴木 恭子[宇都宮], 尾上 久一郎, 大須賀 等, 青木 正志, 糸山 泰人, 池田 穰衛

    神経化学 47 (2-3) 234-234 2008/08

    Publisher: (一社)日本神経化学会

    ISSN: 0037-3796

  571. Accumulation of chondroitin sulfate proteoglycans in the micro environment of spinal motor neurons in amyotrophic lateral sclerosis transgenic rats Peer-reviewed

    Hideki Mizuno, Hitoshi Warita, Masashi Aoki, Yasuto Itoyama

    JOURNAL OF NEUROSCIENCE RESEARCH 86 (11) 2512-2523 2008/08

    DOI: 10.1002/jnr.21702  

    ISSN: 0360-4012

  572. Accumulation of chondroitin sulfate proteoglycans in the micro environment of spinal motor neurons in amyotrophic lateral sclerosis transgenic rats Peer-reviewed

    Hideki Mizuno, Hitoshi Warita, Masashi Aoki, Yasuto Itoyama

    JOURNAL OF NEUROSCIENCE RESEARCH 86 (11) 2512-2523 2008/08

    DOI: 10.1002/jnr.21702  

    ISSN: 0360-4012

  573. A dopamine receptor antagonist L-745,870 suppresses microglia activation in spinal cord and mitigates the progression in ALS model mice Peer-reviewed

    Kazunori Tanaka, Yoshinori Okada, Takuya Kanno, Asako Otomo, Yoshiko Yanagisawa, Junko Shouguchi-Miyata, Etsuko Suga, Eri Kohiki, Kyuichiro Onoe, Hitoshi Osuga, Masashi Aoki, Shinji Hadano, Yasuto Itoyama, Joh-E Ikeda

    EXPERIMENTAL NEUROLOGY 211 (2) 378-386 2008/06

    DOI: 10.1016/j.expneurol.2008.02.004  

    ISSN: 0014-4886

  574. 筋萎縮性側索硬化症に対する肝細胞増殖因子を用いた新規治療法の開発

    青木 正志, 石垣 あや, 割田 仁, 船越 洋, 中村 雅也, 岡野 栄之, 糸山 泰人

    神経治療学 25 (3) 288-288 2008/05

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  575. Up-regulation of insulin-like growth factor-II receptor in reactive astrocytes in the spinal cord of amyotrophic lateral sclerosis transgenic rats. Peer-reviewed

    Byambasuren Dagvajantsan, Masashi Aoki, Hitoshi Warita, Naoki Suzuki, Yasuto Itoyama

    The Tohoku journal of experimental medicine 214 (4) 303-10 2008/04

    DOI: 10.1620/tjem.214.303  

    ISSN: 0040-8727

    eISSN: 1349-3329

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    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by selective motor neuron death. We developed a rat model of ALS expressing a human cytosolic copper-zinc superoxide dismutase (SOD1) transgene with two ALS-associated mutations: glycine to alanine at position 93 (G93A) and histidine to arginine at position 46 (H46R). Although the mechanism of ALS is still unclear, there are many hypotheses concerning its cause, including loss of neurotrophic support to motor neurons. Recent evidence suggests that insulin-like growth factors (IGFs) act as neurotrophic factors, and promote the survival and differentiation of neuronal cells including motor neurons. Their ability to enhance the outgrowth of spinal motor neurons suggests their potential as a therapeutic agent for the patients with ALS. In this study, we investigated IGF-II receptor immunoreactivity in the anterior horns of the lumbar level of the spinal cord in SOD1 transgenic rats with the H46R mutation of different ages as well as in normal littermates. The double-immunostaining for IGF-II receptor and glial fibrillary acidic protein (GFAP) demonstrated co-localization on reactive astrocytes ((**)p < 0.001) in the end-stage transgenic rats, whereas it was not evident at the pre-symptomatic stage or at the onset of the disease. Our results demonstrated the IGF-II receptor up-regulation in reactive astrocytes in the spinal cord of transgenic rats, which may reflect a protective response against the loss of IGF-related trophic factors. We suggest that IGF receptors may play a key role in the pathogenesis, and may have therapeutic implications in ALS.

  576. Neurofibromatosis type 1 (NF1) tumor suppressor, neurofibromin, regulates the neuronal differentiation of PC12 cells via its associating protein, CRMP-2 Peer-reviewed

    Siriporn Patrakitkomjorn, Daiki Kobayashi, Takashi Morikawa, Masayo Morifuji Wilson, Nobuyuki Tsubota, Atsushi Irie, Tatsuya Ozawa, Masashi Aoki, Nariko Arimura, Kozo Kaibuchi, Hideyuki Saya, Norie Araki

    JOURNAL OF BIOLOGICAL CHEMISTRY 283 (14) 9399-9413 2008/04

    DOI: 10.1074/jbc.M708206200  

    ISSN: 0021-9258

    eISSN: 1083-351X

  577. Clinical manifestations in patients with SOS1 mutations range from Noonan syndrome to CFC syndrome. International-journal Peer-reviewed

    Yoko Narumi, Yoko Aoki, Tetsuya Niihori, Masahiro Sakurai, Hélène Cavé, Alain Verloes, Kimio Nishio, Hirofumi Ohashi, Kenji Kurosawa, Nobuhiko Okamoto, Hiroshi Kawame, Seiji Mizuno, Tatsuro Kondoh, Marie-Claude Addor, Anne Coeslier-Dieux, Catherine Vincent-Delorme, Koichi Tabayashi, Masashi Aoki, Tomoko Kobayashi, Afag Guliyeva, Shigeo Kure, Yoichi Matsubara

    Journal of human genetics 53 (9) 834-41 2008

    DOI: 10.1007/s10038-008-0320-0  

    ISSN: 1434-5161

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    Noonan syndrome (NS) and cardio-facio-cutaneous (CFC) syndrome are autosomal dominant disorders characterized by heart defects, facial dysmorphism, ectodermal abnormalities, and mental retardation. There is a significant clinical overlap between NS and CFC syndrome, but ectodermal abnormalities and mental retardation are more frequent in CFC syndrome. Mutations in PTPN11 and KRAS have been identified in patients with NS and those in KRAS, BRAF and MAP2K1/2 have been identified in patients with CFC syndrome, establishing a new role of the RAS/MAPK pathway in human development. Recently, mutations in the son of sevenless gene (SOS1) have also been identified in patients with NS. To clarify the clinical spectrum of patients with SOS1 mutations, we analyzed 24 patients with NS, including 3 patients in a three-generation family, and 30 patients with CFC syndrome without PTPN11, KRAS, HRAS, BRAF, and MAP2K1/2 (MEK1/2) mutations. We identified two SOS1 mutations in four NS patients, including three patients in the above-mentioned three-generation family. In the patients with a CFC phenotype, three mutations, including a novel three amino-acid insertion, were identified in one CFC patient and two patients with both NS and CFC phenotypes. These three patients exhibited ectodermal abnormalities, such as curly hair, sparse eyebrows, and dry skin, and two of them showed mental retardation. Our results suggest that patients with SOS1 mutations range from NS to CFC syndrome.

  578. 長期人工呼吸管理下に気管腕頭動脈瘻からの急性出血で死亡した家族性ALSの1例

    加藤 量広, 鈴木 直輝, 青木 正志, 割田 仁, 神 一敬, 糸山 泰人

    臨床神経学 48 (1) 60-62 2008/01

    Publisher: (一社)日本神経学会

    DOI: 10.5692/clinicalneurol.48.60  

    ISSN: 0009-918X

  579. [Massive bleeding from tracheoarterial fistula in an amyotrophic lateral sclerosis patient treated with long-term invasive ventilation: an autopsy case report]. Peer-reviewed

    Kazuhiro Kato, Naoki Suzuki, Masashi Aoki, Hitoshi Warita, Kazutaka Jin, Yasuto Itoyama

    Rinsho shinkeigaku = Clinical neurology 48 (1) 60-2 2008/01

    DOI: 10.5692/clinicalneurol.48.60  

    ISSN: 0009-918X

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    We report a 43-year-old woman with familial amyotrophic lateral sclerosis (FALS) who died of massive bleeding from a tracheoarterial fistula. Four years after the onset of the disease, she received invasive ventilation by tracheostomy because of respiratory failure. Four years and 7 months later, she showed an abrupt hemorrhage from the tracheostomy and died. The postmortem examination revealed a fistulous tract between the tracheal mucosal ulcer and the brachiocephalic trunk. The ulcer was in close proximity to the tracheostomy tube. In order to avoid such unexpected complications, we should observe the contact site between the tracheal mucosa and the tracheal tube in chronic tracheostomy patients.

  580. Amyotrophic lateral sclerosis with the SOD1 mutations Peer-reviewed

    Masashi Aoki, Hitoshi Warita, Yasuto Itoyama

    Clinical Neurology 48 (11) 966-969 2008

    Publisher: Societas Neurologica Japonica

    DOI: 10.5692/clinicalneurol.48.966  

    ISSN: 0009-918X

  581. ALSモデルラット脊髄におけるコンドロイチン硫酸プロテオグリカンの変化

    水野 秀紀, 割田 仁, 青木 正志, 糸山 泰人

    臨床神経学 47 (12) 996-996 2007/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  582. ALSモデルラット脊髄変性における内因性HGF/c-Met機構の意義

    青木 正志, 割田 仁, 石垣 あや, 糸山 泰人, 船越 洋

    臨床神経学 47 (12) 1095-1095 2007/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  583. ALSモデルラット髄腔内へのコンドロイチン分解酵素持続投与

    割田 仁, 水野 秀紀, 青木 正志, 糸山 泰人

    臨床神経学 47 (12) 1121-1121 2007/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  584. 神経難病と難病ネットワーク あきらめないで治療とケア 神経難病患者に私共は何が出来るか(ALSの治療薬開発とネットワーク)

    糸山 泰人, 青木 正志, 割田 仁, 永井 真貴子, 中村 敏一, 船越 洋

    日本医学会総会会誌 27回 (学術講演要旨) 133-133 2007/12

    Publisher: 日本医学会

  585. 肢帯型筋ジストロフィー2B型におけるdysferlin遺伝子変異と臨床型の関係 Peer-reviewed

    高橋 俊明, 青木 正志, 小野寺 好明, 鈴木 直輝, 竪山 真規, 吉岡 勝, 今野 秀彦, 林 由起子, 西野 一三, 埜中 征哉, 小野寺 宏, 糸山 泰人

    臨床神経学 47 (12) 1056-1056 2007/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  586. Intrathecal Delivery of Hepatocyte Growth Factor From Amyotrophic Lateral Sclerosis Onset Suppresses Disease Progression in Rat Amyotrophic Lateral Sclerosis Model. Peer-reviewed

    Ishigaki A, Aoki M, Nagai M, Warita H, Kato S, Kato M, Nakamura T, Funakoshi H, Itoyama Y

    J Neuropathol Exp Neurol 66 (11) 1037-1044 2007/11

    DOI: 10.1097/nen.0b013e318159886b  

    ISSN: 0022-3069

  587. A novel compound heterozygous dysferlin mutation in Miyoshi myopathy siblings responding to dantrolene. Peer-reviewed

    Hattori H, Nagata E, Oya Y, Takahashi T, Aoki M, Ito D, Suzuki N

    Eur J Neurol 14 (11) 1288-1291 2007/11

    DOI: 10.1111/j.1468-1331.2007.01958.x  

  588. An In Vitro Model for Lewy Body-Like Hyaline Inclusion/Astrocytic Hyaline Inclusion: Induction by ER Stress with an ALS-Linked SOD1 Mutation Peer-reviewed

    Satoru Yamagishi, Yoshihisa Koyama, Taiichi Katayama, Manabu Taniguchi, Junichi Hitomi, Masaaki Kato, Masashi Aoki, Yasuto Itoyama, Shinsuke Kato, Masaya Tohyama

    PLOS ONE 2 (10) e1030-e1030 2007/10

    DOI: 10.1371/journal.pone.0001030  

    ISSN: 1932-6203

  589. Distal anterior compartment myopathy with early ankle contractures. International-journal Peer-reviewed

    Hiroshi Saito, Naoki Suzuki, Hideaki Ishiguro, Koichi Hirota, Yasuto Itoyama, Toshiaki Takahashi, Masashi Aoki

    Muscle & nerve 36 (4) 525-7 2007/10

    DOI: 10.1002/mus.20836  

    ISSN: 0148-639X

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    Dysferlinopathies exhibit marked heterogeneity in the initial distribution of muscle involvement at the onset of the disease. We describe a Japanese patient with dysferlinopathy who exhibited distal anterior compartment myopathy (DACM) with early contractures of the ankle, whose pedigree included patients with two other types of dysferlinopathy. The existence of three phenotypes of dysferlinopathy in one pedigree is reported, indicating the involvement of molecules other than dysferlin in the pathogenesis.

  590. An In Vitro Model for Lewy Body-Like Hyaline Inclusion/Astrocytic Hyaline Inclusion: Induction by ER Stress with an ALS-Linked SOD1 Mutation Peer-reviewed

    Satoru Yamagishi, Yoshihisa Koyama, Taiichi Katayama, Manabu Taniguchi, Junichi Hitomi, Masaaki Kato, Masashi Aoki, Yasuto Itoyama, Shinsuke Kato, Masaya Tohyama

    PLOS ONE 2 (10) e1030 2007/10

    DOI: 10.1371/journal.pone.0001030  

    ISSN: 1932-6203

  591. NO production results in suspension-induced muscle atrophy through dislocation of neuronal NOS. International-journal Peer-reviewed

    Naoki Suzuki, Norio Motohashi, Akiyoshi Uezumi, So-ichiro Fukada, Tetsuhiko Yoshimura, Yasuto Itoyama, Masashi Aoki, Yuko Miyagoe-Suzuki, Shin'ichi Takeda

    The Journal of clinical investigation 117 (9) 2468-76 2007/09

    DOI: 10.1172/JCI30654  

    ISSN: 0021-9738

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    Forkhead box O (Foxo) transcription factors induce muscle atrophy by upregulating the muscle-specific E3 ubiquitin ligases MuRF-1 and atrogin-1/MAFbx, but other than Akt, the upstream regulators of Foxos during muscle atrophy are largely unknown. To examine the involvement of the dystrophin glycoprotein complex (DGC) in regulation of Foxo activities and muscle atrophy, we analyzed the expression of DGC members during tail suspension, a model of unloading-induced muscle atrophy. Among several DGC members, only neuronal NOS (nNOS) quickly dislocated from the sarcolemma to the cytoplasm during tail suspension. Electron paramagnetic resonance spectrometry revealed production of NO in atrophying muscle. nNOS-null mice showed much milder muscle atrophy after tail suspension than did wild-type mice. Importantly, nuclear accumulation of dephosphorylated Foxo3a was not evident in nNOS-null muscle, and neither MuRF-1 nor atrogin-1/MAFbx were upregulated during tail suspension. Furthermore, an nNOS-specific inhibitor, 7-nitroindazole, significantly prevented suspension-induced muscle atrophy. The NF-kappaB pathway was activated in both wild-type and nNOS-null muscle during tail suspension. We also show that nNOS was involved in the mechanism of denervation-induced atrophy. We conclude that nNOS/NO mediates muscle atrophy via regulation of Foxo transcription factors and is a new therapeutic target for disuse-induced muscle atrophy.

  592. Motor neuron disease in transgenic mice with an H46R mutant SOD1 gene. Peer-reviewed

    Sasaki Shoichi, Nagai Makiko, Aoki Masashi, Komori Takashi, Itoyama Yasuto, Iwata Makoto

    J Neuropathol Exp Neurol 66 (6) 517-524 2007/06

    DOI: 10.1097/01.jnen.0000263868.84188.3b  

    ISSN: 0022-3069

  593. DNA single-strand break repair is impaired in aprataxin-related ataxia Peer-reviewed

    Makito Hirano, Aya Yamamoto, Toshio Mori, Li Lan, Taka-aki Iwamoto, Masashi Aoki, Keiji Shimada, Yoshiko Furiya, Shingo Kariya, Hirohide Asai, Akira Yasui, Tomohisa Nishiwaki, Kyoko Imoto, Nobuhiko Kobayashi, Takao Kiriyama, Tetsuya Nagata, Noboru Konishi, Yasuto Itoyama, Satoshi Ueno

    ANNALS OF NEUROLOGY 61 (2) 162-174 2007/02

    DOI: 10.1002/ana.21078  

    ISSN: 0364-5134

  594. 発症後のALSモデルラットにおける再生誘導因子の髄腔内複合投与

    割田 仁, 青木 正志, 船越 洋, 岡野 栄之, 糸山 泰人

    臨床神経学 46 (12) 983-983 2006/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  595. 東北地方の16q-ADCAの頻度および臨床型

    小野寺 好明, 青木 正志, 水野 秀紀, 割田 仁, 志賀 裕正, 糸山 泰人

    臨床神経学 46 (12) 1018-1018 2006/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  596. 変異SOD1トランスジェニックラットの脊髄運動ニューロンのGolgi装置の形態変化

    藤田 行雄, 青木 正志, 割田 仁, 糸山 泰人, 岡本 幸市

    臨床神経学 46 (12) 1020-1020 2006/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  597. 抗HGF抗体の髄腔内投与によるALSラット病態進行の促進

    青木 正志, 割田 仁, 石垣 あや, 松本 有史, 水野 秀樹, 永井 真貴子, 船越 洋, 中村 敏一, 糸山 泰人

    臨床神経学 46 (12) 1091-1091 2006/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  598. ALSモデルラット脊髄における再生阻害因子の発現

    水野 秀紀, 割田 仁, 青木 正志, 糸山 泰人

    臨床神経学 46 (12) 1091-1091 2006/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  599. Dysferlin遺伝子変異の確定した肢帯型筋ジストロフィー(LGMD)2B型の筋障害の分布 Peer-reviewed

    高橋 俊明, 青木 正志, 小野寺 好明, 鈴木 直輝, 竪山 真規, 今野 秀彦, 林 由起子, 西野 一三, 埜中 征哉, 木村 格, 糸山 泰人

    臨床神経学 46 (12) 1120-1120 2006/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  600. Clinical features of chromosome 16q22.1 linked autosomal dominant cerebellar ataxia in Japanese Peer-reviewed

    Y. Onodera, M. Aoki, H. Mizuno, H. Warita, Y. Shiga, Y. Itoyama

    NEUROLOGY 67 (7) 1300-1302 2006/10

    DOI: 10.1212/01.wnl.0000238507.85436.20  

    ISSN: 0028-3878

  601. A case of dysferlinopathy presenting choreic movements Peer-reviewed

    Toshiaki Takahashi, Masashi Aoki, Takashi Imai, Masaru Yoshioka, Hidehiko Konno, Shuichi Higano, Yoshiaki Onodera, Hiroshi Saito, Itaru Kimura, Yasuto Itoyama

    MOVEMENT DISORDERS 21 (9) 1513-1515 2006/09

    DOI: 10.1002/mds.21027  

    ISSN: 0885-3185

  602. Histological recovery of the hepatocytes is based on the redox system upregulation in the animal models of mutant superoxide dismutase (SOD)1-linked amyotrophic lateral sclerosis Peer-reviewed

    M Kato, S Kato, Y Abe, T Nishino, E Ohama, M Aoki, Y Itoyama

    HISTOLOGY AND HISTOPATHOLOGY 21 (7) 729-742 2006/07

    ISSN: 0213-3911

  603. Plectin遺伝子変異の確定した先天性表皮水疱症を伴う筋ジストロフィーの1例 Peer-reviewed

    高橋 俊明, 大隅 悦子, 吉岡 勝, 今野 秀彦, 小野寺 宏, 澤村 大輔, 小野寺 好明, 竪山 真規, 青木 正志, 糸山 泰人

    臨床神経学 46 (5) 364-364 2006/05

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  604. Alteration of familial ALS-linked mutant SOD1 solubility with disease progression: Its modulation by the proteasome and Hsp70 Peer-reviewed

    S Koyama, S Arawaka, R Chang-Hong, M Wada, T Kawanami, K Kurita, M Kato, M Nagai, M Aoki, Y Itoyama, G Sobue, PH Chan, T Kato

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 343 (3) 719-730 2006/05

    DOI: 10.1016/j.bbrc.2006.02.170  

    ISSN: 0006-291X

  605. Alteration of familial ALS-linked mutant SOD1 solubility with disease progression: Its modulation by the proteasome and Hsp70 Peer-reviewed

    S Koyama, S Arawaka, R Chang-Hong, M Wada, T Kawanami, K Kurita, M Kato, M Nagai, M Aoki, Y Itoyama, G Sobue, PH Chan, T Kato

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 343 (3) 719-730 2006/05

    DOI: 10.1016/j.bbrc.2006.02.170  

    ISSN: 0006-291X

  606. Gender difference in association between polymorphism of serotonin transporter gene regulatory region and anxiety Peer-reviewed

    T Mizuno, M Aoki, Y Shimada, M Inoue, K Nakaya, T Takahashi, Y Itoyama, M Kanazawa, A Utsumi, Y Endo, T Nomura, M Hiratsuka, M Mizugaki, J Goto, M Hongo, S Fukudo

    JOURNAL OF PSYCHOSOMATIC RESEARCH 60 (1) 91-97 2006/01

    DOI: 10.1016/j.jpsychores.2005.06.068  

    ISSN: 0022-3999

  607. Underediting of GluR2 mRNA, a neuronal death inducing molecular change in sporadic ALS, does not occur in motor neurons in ALS1 or SBMA Peer-reviewed

    Y Kawahara, H Sun, K Ito, T Hideyama, M Aoki, G Sobue, S Tsuji, S Kwak

    NEUROSCIENCE RESEARCH 54 (1) 11-14 2006/01

    DOI: 10.1016/j.neures.2005.09.006  

    ISSN: 0168-0102

  608. Disease progression of human SOD1 (G93A) transgenic ALS model rats Peer-reviewed

    A Matsumoto, Y Okada, M Nakamichi, M Nakamura, Y Toyama, G Sobue, M Nagai, M Aoki, Y Itoyama, H Okano

    JOURNAL OF NEUROSCIENCE RESEARCH 83 (1) 119-133 2006/01

    DOI: 10.1002/jnr.20708  

    ISSN: 0360-4012

  609. ALSラットに対する肝細胞増殖因子髄腔内投与による病態進行抑制の機序

    青木 正志, 石垣 あや, 永井 真貴子, 割田 仁, 船越 洋, 加藤 信介, 加藤 昌昭, 糸山 泰人

    臨床神経学 45 (12) 1079-1079 2005/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  610. 外来性再生誘導因子投与によるALSモデルラット脊髄神経前駆細胞賦活の試み

    割田 仁, 青木 正志, 石垣 あや, 永井 真貴子, 岡野 栄之, 船越 洋, 糸山 泰人

    臨床神経学 45 (12) 1080-1080 2005/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  611. ALSトランスジェニックラットへのZ-VAD-fmk髄腔内投与時のグリア系細胞の病態解析

    石垣 あや, 青木 正志, 永井 真貴子, 割田 仁, 加藤 昌昭, 糸山 泰人

    臨床神経学 45 (12) 1080-1080 2005/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  612. Dysferlin遺伝子変異の確定した肢帯型筋ジストロフィー2B型の臨床型の解析 Peer-reviewed

    高橋 俊明, 青木 正志, 小野寺 好明, 鈴木 直輝, 竪山 真規, 今野 秀彦, 林 由起子, 西野 一三, 埜中 征哉, 齋藤 博, 木村 格, 糸山 泰人

    臨床神経学 45 (12) 1016-1016 2005/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  613. Development of a rat model of amyotrophic lateral sclerosis expressing a human SOD1 transgene Peer-reviewed

    M Aoki, S Kato, M Nagai, Y Itoyama

    NEUROPATHOLOGY 25 (4) 365-370 2005/12

    DOI: 10.1111/j.1440-1789.2005.00611.x  

    ISSN: 0919-6544

  614. Late-onset distal myopathy with rimmed vacuoles without mutation in the GNE or dysferlin genes. International-journal Peer-reviewed

    Naoki Suzuki, Masashi Aoki, Hideki Mizuno, Yoshiaki Onodera, Toshiaki Takahashi, Tetsuya Nagata, Maki Tateyama, Yasuto Itoyama

    Muscle & nerve 32 (6) 812-4 2005/12

    DOI: 10.1002/mus.20417  

    ISSN: 0148-639X

    More details Close

    We report two brothers from a Japanese family with a late-onset distal myopathy characterized by rimmed vacuoles and dysferlin deficiency with no inflammatory infiltration and dystrophic changes in muscle biopsy. Mutations in the GNE, dysferlin, caveolin 3, emerin, and lamin A/C genes were excluded. We speculate that dysferlin is involved in the pathogenesis of the myopathy in these patients, which may represent a new disease entity presenting as a distal myopathy.

  615. [Mutational and clinical features of Japanese patients with dysferlinopathy (Miyoshi myopathy and limb girdle muscular dystrophy type 2B)]. Peer-reviewed

    Masashi Aoki, Toshiaki Takahashi

    Rinsho shinkeigaku = Clinical neurology 45 (11) 938-42 2005/11

    ISSN: 0009-918X

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    Mutations in the dysferlin gene cause both Miyoshi myopathy (MM) and limb girdle muscular dystrophy 2B (LGMD2B). We examined patients with dysferlinopathy in Japan, and identified 28 and 12 different mutations respectively in MM and LGMD2B patients. The mean age at onset of the patients with MM was 22 +/- 9 years (range 12-48 years) and that of the patients with LGMD2B was 26 +/- 10 years (range 11-43 years). On the average, the first use of a cane was at 33 years (14 years after the onset) for MM and 39 years (15 years after onset) for LGMD 2B. Patients became wheelchair-bound at 41 years (21 years after onset) in MM and 45 years (21 years after onset) for LGMD2B. The mean maximum serum CK level at any age of the patients was 5,829 +/- 4,273 IU/l (range 1,289-12,566 IU/l ) for MM and 3,787 +/- 2,493 IU/l (627-10,000 IU/l) for LGMD2B: in both disorders, the serum CK level fell in proportion to the duration of the illness. We have identified four common four mutations (C1939G, G3370T, 3746delG, and 4870delT) in Japanese patients with MM, accounting for 48 percent of all MM mutations in this population. Two of the four mutations (G3370T, and 4870delT) accounted for 52 percent of the mutations in LGMD2B patients, while the 3746delG mutation was not found in patients with LGMD2B. The G3370T mutation may be associated with a milder form of MM and LGMD2B. By contrast, the G3510A mutation appears to be associated with a severe form of MM.

  616. Motoneuron degeneration after facial nerve avulsion is exacerbated in presymptomatic transgenic rats expressing human mutant Cu/Zn superoxide dismutase Peer-reviewed

    K Ikeda, M Aoki, Y Kawazoe, T Sakamoto, Y Hayashi, A Ishigaki, M Nagai, R Kamii, S Kato, Y Itoyama, K Watabe

    JOURNAL OF NEUROSCIENCE RESEARCH 82 (1) 63-70 2005/10

    DOI: 10.1002/jnr.20621  

    ISSN: 0360-4012

  617. Motoneuron degeneration after facial nerve avulsion is exacerbated in presymptomatic transgenic rats expressing human mutant Cu/Zn superoxide dismutase Peer-reviewed

    K Ikeda, M Aoki, Y Kawazoe, T Sakamoto, Y Hayashi, A Ishigaki, M Nagai, R Kamii, S Kato, Y Itoyama, K Watabe

    JOURNAL OF NEUROSCIENCE RESEARCH 82 (1) 63-70 2005/10

    DOI: 10.1002/jnr.20621  

    ISSN: 0360-4012

  618. ERにおける変異SOD1凝集とERストレスによってもたらされる大きなヒアリン封入体の組織学的解析(Histlogic analysis of mutant SOD1 aggregation in ER and large hyaline inclusions induced by ER stress)

    小山 佳久, 山岸 覚, 片山 泰一, 加藤 昌昭, 青木 正志, 糸山 泰人, 加藤 信介, 遠山 正彌

    神経化学 44 (2-3) 197-197 2005/08

    Publisher: 日本神経化学会

    ISSN: 0037-3796

  619. Redox system expression in the motor neurons in amyotrophic lateral sclerosis (ALS): immunohistochemical studies on sporadic ALS, superoxide dismutase 1 (SOD1)-mutated familial ALS, and SOD1-mutated ALS animal models Peer-reviewed

    S Kato, M Kato, Y Abe, T Matsumura, T Nishino, M Aoki, Y Itoyama, K Asayama, A Awaya, A Hirano, E Ohama

    ACTA NEUROPATHOLOGICA 110 (2) 101-112 2005/08

    DOI: 10.1007/s00401-005-1019-3  

    ISSN: 0001-6322

  620. Neuroprotective effect of oxidized galectin-1 in a transgenic mouse model of amyotrophic lateral sclerosis Peer-reviewed

    R Chang-Hong, M Wada, S Koyama, H Kimura, S Arawaka, T Kawanami, K Kurita, T Kadoya, M Aoki, Y Itoyama, T Kato

    EXPERIMENTAL NEUROLOGY 194 (1) 203-211 2005/07

    DOI: 10.1016/j.expneurol.2005.02.011  

    ISSN: 0014-4886

  621. Hoarseness due to bilateral vocal cord paralysis as an initial manifestation of familial amyotrophic lateral sclerosis Peer-reviewed

    J Fukae, SI Kubo, N Hattori, K Komatsu, M Kato, M Aoki, Y Mizuno

    AMYOTROPHIC LATERAL SCLEROSIS AND OTHER MOTOR NEURON DISORDERS 6 (2) 122-124 2005/06

    DOI: 10.1080/14660820510034451  

    ISSN: 1466-0822

  622. Expression profiling with progression of dystrophic change in dysferlin-deficient mice (SJL). International-journal Peer-reviewed

    Naoki Suzuki, Masashi Aoki, Yuji Hinuma, Toshiaki Takahashi, Yoshiaki Onodera, Aya Ishigaki, Masaaki Kato, Hitoshi Warita, Maki Tateyama, Yasuto Itoyama

    Neuroscience research 52 (1) 47-60 2005/05

    DOI: 10.1016/j.neures.2005.01.006  

    ISSN: 0168-0102

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    The SJL mouse is a model for human dysferlinopathy (limb-girdle muscular dystrophy type 2B and Miyoshi myopathy). We used cDNA microarrays to compare the expression profiles of 10,012 genes in control and SJL quadriceps femoris muscles in order to find genes involved in the degeneration and regeneration process and in dysferlin's functional network. Many genes involved in the process of muscle regeneration are observed to be up-regulated in SJL mice, including cardiac ankyrin repeated protein (CARP), Neuraminidase 2, interleukin-6, insulin-like growth factor-2 and osteopontin. We found the upregulation of S100 calcium binding proteins, neural precursor cell expressed, developmentally down-regulated gene 4-like (NEDD4L) with C2 domain, and intracellular protein traffic associated proteins (Rab6 and Rab2). These proteins have the potential to interact with dysferlin. We must reveal some other molecules which may work with dysferlin in order to clarify the pathological network of dysferlinopathy. This process may lead to future improvements in the therapy for human dysferlinopathy.

  623. [Toxoplasma encephalitis in a patient receiving cyclosporine monotherapy for Behcet disease] Peer-reviewed

    Nakamura Masashi, Nagai Makiko, Shiga Yusei, Aoki Masashi, Abe Toshiaki, Kaku Mitsuo, Yano Akihiko, Itoyama Yasuto

    Rinsho Shinkeigaku 45 (2) 105-110 2005/02

  624. ベーチェット病に対するシクロスポリン単剤投与中にトキソプラズマ脳炎を合併した1例

    中村 正史, 永井 真貴子, 志賀 裕正, 青木 正志, 阿部 俊明, 賀来 満夫, 矢野 明彦, 糸山 泰人

    臨床神経学 45 (2) 105-110 2005/02

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

  625. Toxoplasma encephalitis in a patient receiving cyclosporine monotherapy for Behçet disease

    Masashi Nakamura, Makiko Nagai, Yusei Shiga, Masashi Aoki, Toshiaki Abe, Mitsuo Kaku, Akihiko Yano, Yasuto Itoyama

    Clinical Neurology 45 (2) 105-110 2005/02

    ISSN: 0009-918X

  626. ALSトランスジェニックラットにおける未分化な内在性神経前駆細胞の増殖

    割田 仁, 青木 正志, 石垣 あや, 加藤 昌昭, 永井 真貴子, 糸山 泰人

    臨床神経学 44 (12) 1091-1091 2004/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  627. ALSラットに対する発症直前からの肝細胞増殖因子の髄腔内投与による病態進行の抑制

    青木 正志, 石垣 あや, 永井 真貴子, 割田 仁, 加藤 昌昭, 船越 洋, 糸山 泰人

    臨床神経学 44 (12) 1091-1091 2004/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  628. ALSトランスジェニックラットに対するpan caspase inhibitorの髄腔内投与

    石垣 あや, 青木 正志, 永井 真貴子, 割田 仁, 加藤 昌昭, 糸山 泰人

    臨床神経学 44 (12) 1092-1092 2004/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  629. ALSモデルマウスの神経細胞死における小胞体ストレスの関与

    加藤 昌昭, 青木 正志, 割田 仁, 石垣 あや, 神位 りえ子, 桃井 隆, 糸山 泰人

    臨床神経学 44 (12) 1135-1135 2004/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  630. Dysferlinopathy associated with rigid spine syndrome Peer-reviewed

    T Nagashima, T Chuma, Y Mano, Y Goto, YK Hayashi, N Minami, Nishino, I, Nonaka, I, T Takahashi, H Sawa, M Aoki, K Nagashima

    NEUROPATHOLOGY 24 (4) 341-346 2004/12

    DOI: 10.1111/j.1440-1789.2004.00573.x  

    ISSN: 0919-6544

  631. Amyotrophic lateral sclerosis: Recent insights from transgenic animal models with SOD1 mutations Peer-reviewed

    Masashi Aoki

    Clinical Neurology 44 (11) 788-791 2004/11

    ISSN: 0009-918X

  632. [A patient with distal muscular dystrophy without mutations in dysferlin gene but with abnormal dysferlin localization in muscle fibers]. Peer-reviewed

    Isao Hozumi, Toshiaki Takahashi, Masashi Aoki, Yukiko K Hayashi, Naoteru Suzuki, Zenjiro Matsuyama, Takashi Inuzuka, Ikuya Nonaka

    Rinsho shinkeigaku = Clinical neurology 44 (10) 699-702 2004/10

    ISSN: 0009-918X

    More details Close

    We report a 40-year-old man who noticed difficulty in standing on his tiptoe from approximately 36 years-old. He presented with selective calf muscle weakness on flexion. The serum creatine kinase (CK) level slightly increased to 569IU/l. Muscle computed tomography (CT) revealed selective gastrocnemius and soleus muscle atrophy with fat tissue replacement. A biopsy of the left gastrocnemius muscle revealed a marked variation in muscle fiber size and some necrotic and regenerating fibers. Immunohistochemical analysis using an anti-dysferlin antibody showed a faint and irregular immunostaining of the muscle surface membrane and abnormal immunoreactive depositions in the cytoplasm, although normal dysferlin content was detected by Western blotting. The sequence analysis of all exons of the dysferlin gene revealed no responsible mutations. The case had clinical and pathological findings similar to those of Miyoshi myopathy. The present study indicates that there may be a secondary abonormality of dysferlin derived from some other factors in patients with clinical and pathological findings similar to those of Miyoshi myopathy. The mechanism of dysferlin expression should be elucidated to obtain a conclusive pathogenetic mechanism underlying this disorder.

  633. Dysferlin遺伝子に変異をみとめず,dysferlin蛋白の筋線維内局在異常をみとめた遠位型筋ジストロフィーの1例

    保住 功, 高橋 俊明, 青木 正志, 林 由起子, 鈴木 直輝, 松山 善次郎, 犬塚 貴, 埜中 征哉

    臨床神経学 44 (10) 699-702 2004/10

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  634. Increased arterial carboxy-haemoglobin concentrations in patients with sporadic amyotrophic lateral sclerosis

    H Yasuda, S Ebihara, M Yamaya, M Asada, H Sasaki

    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 75 (7) 1076-1077 2004/07

    DOI: 10.1136/jnnp.2003.027532  

    ISSN: 0022-3050

  635. [A patient with limb girdle muscular dystrophy type 2B (LGMD2B) manifesting cardiomyopathy] Peer-reviewed

    Kuru Satoshi, Yasuma Fumihiko, Wakayama Tadashi, Kimura Seigo, Konagaya Masaaki, Aoki Masashi, Tanabe Masaki, Takahashi Toshiaki

    Rinsho Shinkeigaku 44 (6) 375-378 2004/06

  636. 心筋障害をきたした肢帯型筋ジストロフィー(LGMD)2Bの1例

    久留 聡, 安間 文彦, 若山 忠士, 木村 正剛, 小長谷 正明, 青木 正志, 田辺 正樹, 高橋 俊明

    臨床神経学 44 (6) 375-378 2004/06

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

  637. Novel dysferlin mutations and characteristic muscle atrophy in late-onset Miyoshi myopathy. Peer-reviewed

    Suzuki Naoki, Aoki Masashi, Takahashi Toshiaki, Takano Daiki, Asano Masahiro, Shiga Yusei, Onodera Yoshiaki, Tateyama Maki, Itoyama Yasuto

    Muscle Nerve 29 (5) 721-723 2004/05

    DOI: 10.1002/mus.20025  

  638. NEDL1, a novel ubiquitin-protein isopeptide ligase for dishevelled-1, targets mutant superoxide dismutase-1 Peer-reviewed

    K Miyazaki, T Fujita, T Ozaki, C Kato, Y Kurose, M Sakamoto, S Kato, T Goto, Y Itoyama, M Aoki, A Nakagawara

    JOURNAL OF BIOLOGICAL CHEMISTRY 279 (12) 11327-11335 2004/03

    DOI: 10.1074/jbc.M312389200  

    ISSN: 0021-9258

  639. Histological evidence of redox system breakdown caused by superoxide dismutase 1 (SOD1) aggregation is common to SOD1-mutated motor neurons in humans and animal models

    S Kato, Y Saeki, M Aoki, M Nagai, A Ishigaki, Y Itoyama, M Kato, K Asayama, A Awaya, A Hirano, E Ohama

    ACTA NEUROPATHOLOGICA 107 (2) 149-158 2004/02

    DOI: 10.1007/s00401-003-0791-1  

    ISSN: 0001-6322

  640. 舞踏様運動を呈したdysferlinopathyの1例 Peer-reviewed

    高橋 俊明, 篠江 隆, 今井 尚志, 吉岡 勝, 今野 秀彦, 木村 格, 武弓 俊一, 青木 正志, 糸山 泰人

    臨床神経学 44 (1) 69-69 2004/01

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  641. Piracetamが動作性ミオクローヌスに有効であった歯状核赤核淡蒼球ルイ体萎縮症の1例

    廣瀬 三恵子, 横山 浩之, 野口 里恵, 萩野谷 和裕, 青木 正志, 飯沼 一宇

    脳と発達 36 (1) 75-79 2004/01

    Publisher: (一社)日本小児神経学会

    DOI: 10.11251/ojjscn1969.36.75  

    ISSN: 0029-0831

  642. Improvement of Action Myoclonus in a Patient with Dentatorubral-Pallidoluysian Atrophy by Piracetam

    Mieko Hirose, Hiroyuki Yokoyama, Rie Noguchi, Kazuhiro Haginoya, Masashi Aoki, Kazuie Iinuma

    No To Hattatsu 36 (1) 75-79 2004

    DOI: 10.11251/ojjscn1969.36.75  

    ISSN: 0029-0831

  643. HGF髄腔内持続投与によるALSトランスジェニックラットにおける運動ニューロン死の抑制

    青木 正志, 永井 真貴子, 加藤 昌昭, 石垣 あや, 松本 有史, 割田 仁, 船越 洋, 中村 敏一, 糸山 泰人

    臨床神経学 43 (12) 922-922 2003/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  644. ALSトランスジェニックラット脊髄前駆細胞のグリア系細胞への分化

    割田 仁, 青木 正志, 永井 真貴子, 石垣 あや, 加藤 昌昭, 糸山 泰人

    臨床神経学 43 (12) 1083-1083 2003/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  645. SJLマウスの骨格筋における筋細胞膜構成蛋白の発現と炎症細胞浸潤に関する検討 Peer-reviewed

    日沼 雄二, 青木 正志, 竪山 真規, 高橋 俊明, 小野寺 好明, 根本 博, 栗原 照幸, 斉藤 博, 糸山 泰人

    臨床神経学 43 (12) 1038-1038 2003/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  646. 肢帯型筋ジストロフィーの表現型をしめすdysferlinopathyの検討 Peer-reviewed

    高橋 俊明, 青木 正志, 竪山 真規, 小野寺 好明, 日沼 雄二, 吉岡 勝, 今野 秀彦, 西野 一三, 埜中 征哉, 斎藤 博, 糸山 泰人

    臨床神経学 43 (12) 937-937 2003/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  647. 日本人三好型遠位型筋ジストロフィーにおけるジスフェルリン遺伝子変異 表現型との関連 Peer-reviewed

    高橋 俊明, 青木 正志, 竪山 真規, 近藤 恵美, 水野 資子, 小野寺 好明, 高野 里菜, 安藤 正子, 佐々木 和雄, 今野 秀彦, 川井 充, 松村 剛, 中井 博史, 鴻巣 武, 埜中 征哉, 荒畑 喜一, 木村 格, 齋藤 博, 糸山 泰人

    医療 57 (増刊) 297-297 2003/10

    Publisher: (一社)国立医療学会

    ISSN: 0021-1699

  648. 心筋障害を呈したLGMD2Bの一例 Peer-reviewed

    久留 聡, 若山 忠士, 木村 正剛, 酒井 素子, 小長谷 正明, 田辺 正樹, 中野 赳, 大西 勝也, 犬飼 晃, 青木 正志, 高橋 俊明

    臨床神経学 43 (7) 452-452 2003/07

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  649. 筋ジストロフィーに関連する疾患の病態解明と治療法の開発に関する研究 SJLマウス骨格筋における筋細胞膜構成蛋白の発現と炎症細胞浸潤に関する検討 Peer-reviewed

    青木 正志, 日沼 雄二, 竪山 真規, 高橋 俊明, 小野寺 好明, 根本 博, 栗原 照幸, 斎藤 博, 糸山 泰人

    厚生労働省精神・神経疾患研究委託費研究報告集 平成14年度 574-574 2003/06

    Publisher: 国立精神・神経センター

  650. Dysferlin mutations in Japanese Miyoshi myopathy - Relationship to phenotype Peer-reviewed

    T Takahashi, M Aoki, M Tateyama, E Kondo, T Mizuno, Y Onodera, R Takano, H Kawai, K Kamakura, H Mochizuki, M Shizuka-Ikeda, M Nakagawa, Y Yoshida, J Akanuma, K Hoshino, H Saito, M Nishizawa, S Kato, K Saito, T Miyachi, H Yamashita, M Kawai, T Matsumura, S Kuzuhara, T Ibi, K Sahashi, H Nakai, T Kohnosu, Nonaka, I, K Arahata, RH Brown, H Saito, Y Itoyama

    NEUROLOGY 60 (11) 1799-1804 2003/06

    ISSN: 0028-3878

  651. Mutant SOD1 linked to familial amyotrophic lateral sclerosis, but not wild-type SOD1, induces ER stress in COS7 cells and transgenic mice Peer-reviewed

    S Tobisawa, Y Hozumi, S Arawaka, S Koyama, M Wada, M Nagai, M Aoki, Y Itoyama, K Goto, T Kato

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 303 (2) 496-503 2003/04

    DOI: 10.1016/S0006-291X(03)00353-X  

    ISSN: 0006-291X

  652. 変異SOD1遺伝子導入ラット脊髄前駆細胞に関する検討

    割田 仁, 青木 正志, 永井 真貴子, 加藤 昌昭, 神位 りえ子, 糸山 泰人

    臨床神経学 42 (12) 1338-1338 2002/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  653. 日本人dysferlinopathyにおける遺伝子変異と臨床型 Peer-reviewed

    高橋 俊明, 青木 正志, 水野 資子, 近藤 恵美, 佐藤 仁美, 伊藤 真理子, 中井 博史, 鴻巣 武, 今野 秀彦, 埜中 征哉, 荒畑 喜一, 斎藤 博, 糸山 泰人

    臨床神経学 42 (12) 1290-1290 2002/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  654. SJLマウスの骨格筋におけるdysferlin mRNA発現量の増加及びnNOSの低下 Peer-reviewed

    日沼 雄二, 青木 正志, 高橋 俊明, 竪山 真規, 小野寺 好明, 糸山 泰人

    臨床神経学 42 (12) 1331-1331 2002/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  655. Miyoshi myopathy patients with novel 5 ' splicing donor site mutations showed different dysferlin immunostaining at the sarcolemma Peer-reviewed

    A Saito, Higuchi, I, M Nakagawa, M Saito, K Hirata, M Suehara, Y Yoshida, T Takahashi, M Aoki, M Osame

    ACTA NEUROPATHOLOGICA 104 (6) 615-620 2002/12

    DOI: 10.1007/s00401-002-0593-x  

    ISSN: 0001-6322

  656. Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body myopathy Peer-reviewed

    Nishino, I, S Noguchi, K Murayama, A Driss, K Sugie, Y Oya, T Nagata, K Chida, T Takahashi, Y Takusa, T Ohi, J Nishimiya, N Sunohara, E Ciafaloni, M Kawai, M Aoki, Nonaka, I

    NEUROLOGY 59 (11) 1689-1693 2002/12

    ISSN: 0028-3878

  657. Dysferlin遺伝子診断に基づいた肢帯型筋ジストロフィー2B型の臨床的特徴の検討 Peer-reviewed

    高橋 俊明, 鴻巣 武, 吉岡 勝, 今野 秀彦, 齋藤 博, 近藤 恵美, 伊藤 真理子, 佐藤 仁美, 安藤 正子, 中井 博史, 青木 正志, 糸山 泰人

    医療 56 (増刊1) 2-2 2002/09

    Publisher: (一社)国立医療学会

    ISSN: 0021-1699

  658. 多発筋炎として免疫学的治療が継続されていたdysferlinopathyの2例 Peer-reviewed

    高橋 俊明, 篠江 隆, 吉岡 勝, 今野 秀彦, 斎藤 博, 金原 禎子, 青木 正志, 竪山 真規, 長谷川 隆文, 志賀 裕正, 糸山 泰人

    臨床神経学 42 (7) 643-643 2002/07

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  659. 筋ジストロフィー及び関連疾患の臨床病態解明と治療法開発に関する研究 日本人三好型遠位型筋ジストロフィーに多くみられるdysferlin遺伝子変異とその臨床的特徴 Peer-reviewed

    青木 正志, 高橋 俊明, 水野 資子, 小野寺 好明, 日沼 雄二, 竪山 真規, 近藤 恵美, 中井 博史, 鴻巣 武, 斎藤 博, 埜中 征哉, 荒畑 喜一, 糸山 泰人

    厚生省精神・神経疾患研究委託費による研究報告集 平成12年度 408-408 2002/03

    Publisher: 国立精神・神経センター

  660. Dysferlinopathy(ジスフェルリン異常を原因とする筋ジストロフィー)における遺伝子変異と臨床型 Peer-reviewed

    青木 正志, 高橋 俊明, 水野 資子, 小野寺 好明, 日沼 雄二, 竪山 真規, 近藤 恵美, 中井 博史, 鴻巣 武, 斎藤 博, 埜中 征哉, 荒畑 喜一, 糸山 泰人

    厚生労働省精神・神経疾患研究委託費研究報告書 筋ジストロフィー及び関連疾患の臨床病態解明と治療法開発に関する研究 平成11〜13年度 25-26 2002/03

    Publisher: 厚生労働省精神・神経疾患研究班

  661. 日本人三好型遠位型筋ジストロフィーにおけるdysferlin遺伝子変異とその臨床的特徴 Peer-reviewed

    今野 秀彦, 高橋 俊明, 鴻巣 武, 斎藤 博, 近藤 恵美, 中井 博史, 埜中 征哉, 荒畑 喜一, 青木 正志, 水野 資子, 糸山 泰人

    厚生労働省精神・神経疾患研究委託費研究報告書 筋ジストロフィーの遺伝相談法及び病態に基づく治療法の開発に関する研究 平成11〜13年度 261-261 2002/03

    Publisher: 厚生労働省精神・神経疾患研究班

  662. Mutation in the caveolin-3 gene causes a peculiar form of distal myopathy Peer-reviewed

    M Tateyama, M Aoki, Nishino, I, YK Hayashi, S Sekiguchi, Y Shiga, T Takahashi, Y Onodera, K Haginoya, K Kobayashi, K Iinuma, Nonaka, I, K Arahata, Y Itoyoma

    NEUROLOGY 58 (2) 323-325 2002/01

    ISSN: 0028-3878

  663. Rats expressing human cytosolic copper-zinc superoxide dismutase transgenes with amyotrophic lateral sclerosis: Associated mutations develop motor neuron disease Peer-reviewed

    M Nagai, M Aoki, Miyoshi, I, M Kato, P Pasinelli, N Kasai, RH Brown, Y Itoyama

    JOURNAL OF NEUROSCIENCE 21 (23) 9246-9254 2001/12

    ISSN: 0270-6474

  664. ABCD1 translation-initiator mutation demonstrates genotype-phenotype correlation for AMN Peer-reviewed

    GN O'Neill, M Aoki, RH Brown

    NEUROLOGY 57 (11) 1956-1962 2001/12

    ISSN: 0028-3878

  665. 日本人三好型遠位型筋ジストロフィーにおけるdysferlin遺伝子変異とその臨床的特徴 Peer-reviewed

    高橋 俊明, 青木 正志, 水野 資子, 竪山 真規, 近藤 恵美, 中井 博史, 鴻巣 武, 斎藤 博, Brown,Jr. Robert H., 埜中 征哉

    臨床神経学 41 (11) 844-844 2001/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  666. SJL/Jマウスにおける筋ジストロフィー発症の病態に関する検討 Peer-reviewed

    日沼 雄二, 青木 正志, 高橋 俊明, 竪山 真規, 小野寺 好明, 糸山 泰人

    臨床神経学 41 (11) 957-957 2001/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  667. 日本人三好型遠位型筋ジストロフィーにおけるdysferlin遺伝子変異とその臨床的特徴 Peer-reviewed

    高橋 俊明, 鴻巣 武, 斎藤 博, 近藤 恵美, 中井 博史, 埜中 征哉, 荒畑 喜一, Brown Jr. Robert H., 青木 正志, 水野 資子

    医療 55 (増刊1) 47-47 2001/10

    Publisher: (一社)国立医療学会

    ISSN: 0021-1699

  668. 肢帯型筋ジストロフィーにおけるジスフェルリン遺伝子変異の検討 Peer-reviewed

    近藤 恵美, 伊藤 真理子, 佐藤 仁美, 安藤 正子, 高橋 俊明, 鴻巣 武, 斎藤 博, 青木 正志, 糸山 泰人

    医療 55 (増刊1) 47-47 2001/10

    Publisher: (一社)国立医療学会

    ISSN: 0021-1699

  669. The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin Peer-reviewed

    MC Moreira, C Barbot, N Tachi, N Kozuka, E Uchida, T Gibson, P Mendonca, M Costa, J Barros, T Yanagisawa, M Watanabe, Y Ikeda, M Aoki, T Nagata, P Coutinho, J Sequeiros, M Koenig

    NATURE GENETICS 29 (2) 189-193 2001/10

    DOI: 10.1038/ng1001-189  

    ISSN: 1061-4036

  670. Marked reduction of the Cu/Zn superoxide dismutase polypeptide in a case of familial amyotrophic lateral sclerosis with the homozygous mutation Peer-reviewed

    M Kato, M Aoki, M Ohta, M Nagai, F Ishizaki, S Nakamura, Y Itoyama

    NEUROSCIENCE LETTERS 312 (3) 165-168 2001/10

    DOI: 10.1016/S0304-3940(01)02212-1  

    ISSN: 0304-3940

  671. The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle. Peer-reviewed

    Matsuda C, Hayashi Y K, Ogawa M, Aoki M, Murayama K, Nishino I, Nonaka I, Arahata K, Brown R H J

    Hum Mol Genet 10 (17) 1761-1766 2001/08/15

  672. Establishment of a local cooling model against spinal cord ischemia representing prolonged induction of heat shock protein Peer-reviewed

    N Motoyoshi, M Sakurai, T Hayashi, M Aoki, K Abe, Y Itoyama, K Tabayashi

    JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY 122 (2) 351-357 2001/08

    DOI: 10.1067/mtc.2001.113935  

    ISSN: 0022-5223

  673. 日本人三好型遠位型及び肢帯型筋ジストロフィーにおけるdysferlin遺伝子変異の検討 Peer-reviewed

    高橋 俊明, 鴻巣 武, 金原 禎子, 嶋崎 茂, 佐久間 博明, 斎藤 博, 大村 清, 青木 正志, 水野 資子, 糸山 泰人

    臨床神経学 41 (7) 449-449 2001/07

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  674. [An autopsy case of atypical Friedreich's ataxia with chronic idiopathic intestinal pseudo-obstruction] Peer-reviewed

    Nagata T, Aoki M, Hasegawa T, Shiga Y, Hayashi T, Higuchi J, Abe K, Tanno T, Konno H, Itoyama Y

    Rinsho Shinkeigaku 41 (7) 412-417 2001/07

  675. Genomic organization of the dysferlin gene and novel mutations in Miyoshi myopathy Peer-reviewed

    M Aoki, J Liu, Richard, I, R Bashir, S Britton, SM Keers, J Oeltjen, HEV Brown, S Marchand, N Bourg, C Beley, D McKenna-Yasek, K Arahata, S Bohlega, E Cupler, Illa, I, Majneh, I, RJ Barohn, JA Urtizberea, M Fardeau, A Amato, C Angelini, K Bushby, JS Beckmann, RH Brown

    NEUROLOGY 57 (2) 271-278 2001/07

    ISSN: 0028-3878

  676. イントロンにdysferlin遺伝子変異を認めた三好型ミオパチーの一例 Peer-reviewed

    望月 仁志, 元吉 和夫, 鎌倉 恵子, 高橋 俊明, 青木 正志, 埜中 征哉

    臨床神経学 41 (6) 341-341 2001/06

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  677. 小児期に高CK血症で発見され,その後特異な筋萎縮分布を呈したカベオリン3異常によるdistal myopathy Peer-reviewed

    青木 正志, 竪山 真規, 糸山 泰人, 萩野谷 和裕, 飯沼 一宇, 林 由起子, 荒畑 喜一, 西野 一三, 埜中 征哉

    脳と発達 33 (Suppl.) S138-S138 2001/05

    Publisher: (一社)日本小児神経学会

    ISSN: 0029-0831

    eISSN: 1884-7668

  678. Familial amyotrophic lateral sclerosis with posterior column degeneration and basophilic inclusion bodies: a clinical, genetic and pathological study Peer-reviewed

    K Tsuchiya, T Matsunaga, M Aoki, C Haga, K Ooe, K Abe, K Ikeda, Nakano, I

    CLINICAL NEUROPATHOLOGY 20 (2) 53-59 2001/03

    ISSN: 0722-5091

  679. Amyotrophic lateral sclerosis-linked glutamate transporter mutant has impaired glutamate clearance capacity. Peer-reviewed

    Trotti D, Aoki M, Pasinelli P, Berger U V, Danbolt N C, Brown R H Jr, Hediger M A

    J Biol Chem 276 (1) 576-582 2001/01/05

    DOI: 10.1074/jbc.M003779200  

  680. [A family of early childhood-onset Charcot-Marie-Tooth disease type 2] Peer-reviewed

    Hinuma Y, Aoki M, Takahashi T, Tateyama M, Nagai M, Yoshioka M, Itoyama Y

    Rinsho Shinkeigaku 41 (1) 64-67 2001/01

  681. 小児期早期より発症したCharcot-Marie-Tooth病2型の親子例

    日沼 雄二, 青木 正志, 高橋 俊明, 竪山 真規, 永井 真貴子, 吉岡 勝, 糸山 泰人

    臨床神経学 41 (1) 64-67 2001/01

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  682. An autopsy case of atypical friedreich's ataxia with chronic idiopathic intestinal pseudo-obstruction

    Tetsuya Nagata, Masashi Aoki, Takafumi Hasegawa, Yusei Shiga, Takeshi Hayashi, Jun Higuchi, Koji Abe, Takashi Tanno, Hidehiko Konno, Yasuto Itoyama

    Clinical Neurology 41 (8) 412-417 2001

    ISSN: 0009-918X

  683. 筋ジストロフィー及び関連疾患の臨床病態解明と治療法開発に関する研究 日本人三好型遠位型筋ジストロフィー患者におけるdysferlin遺伝子解析 Peer-reviewed

    青木 正志, 高橋 俊明, 鴻巣 武, 斎藤 博, 中井 博史, 荒畑 喜一, 糸山 泰人

    厚生省精神・神経疾患研究委託費による研究報告集 平成11年度 527-527 2000/12

    Publisher: 国立精神・神経センター

  684. 小児期より下肢筋萎縮を認めたCharcot-Marie-Tooth病(CMT)2型の親子例 Peer-reviewed

    日沼 雄二, 青木 正志, 高橋 俊明, 永井 真貴子, 竪山 真規, 糸山 泰人, 吉岡 勝

    臨床神経学 40 (12) 1473-1473 2000/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  685. 日本人三好型遠位型筋ジストロフィーにおけるdysferlin遺伝子異常 Peer-reviewed

    高橋 俊明, 青木 正志, 小野寺 好明, 糸山 泰人, 鴻巣 武, 斎藤 博

    臨床神経学 40 (12) 1322-1322 2000/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  686. High prevalence of spinocerebellar ataxia type 1 (SCA1) in an isolated region of Japan. Peer-reviewed

    Onodera Y, Aoki M, Tsuda T, Kato H, Nagata T, Kameya T, Abe K, Itoyama Y

    J Neurol Sci 178 (2) 153-158 2000/09/15

    DOI: 10.1016/S0022-510X(00)00390-7  

  687. 妹は頸部と上肢近位筋優位の,兄は下肢近位筋優位の筋力低下をみとめた(GCG)9変異をもつ眼咽頭筋ジストロフィーの1家系 Peer-reviewed

    高橋 俊明, 竪山 真規, 青木 正志, 志賀 裕正, 宇山 英一郎, 糸山 泰人

    臨床神経学 40 (9) 911-914 2000/09

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  688. [A family with oculopharyngeal muscular dystrophy with (GCG)9 expansion in which a sister had neck as well as proximal and her brother proximal lower limb muscle weakness] Peer-reviewed

    Takahashi T, Tateyama M, Aoki M, Shiga Y, Uyama E, Itoyama Y

    Rinsho Shinkeigaku 40 (9) 911-914 2000/09

  689. Familial spinal arachnoiditis with secondary syringomyelia: clinical studies and MRI findings. Peer-reviewed

    Nagai M, Sakuma R, Aoki M, Abe K, Itoyama Y

    J Neurol Sci 177 (1) 60-64 2000/08/01

    DOI: 10.1016/S0022-510X(00)00338-5  

  690. 【ゲノム時代の脳神経医学】分子遺伝学 三好型遠位型筋ジストロフィー及び肢帯型筋ジストロフィー2B型 dysferlin異常に伴う筋ジストロフィー Peer-reviewed

    青木 正志, 高橋 俊明

    Molecular Medicine 37 (臨増 ゲノム時代の脳神経医学) 71-75 2000/05

    Publisher: (株)中山書店

    ISSN: 0918-6557

  691. 高CK血症にて発見されたdysferlinopathyの1例 Peer-reviewed

    瀬川 昌巳, 諸岡 啓一, 星野 恭子, 秋草 由香里, 青木 正志, 高橋 俊明, 埜中 征哉

    脳と発達 32 (Suppl.) S271-S271 2000/05

    Publisher: (一社)日本小児神経学会

    ISSN: 0029-0831

    eISSN: 1884-7668

  692. 三好型遠位型筋ジストロフィー及び肢帯型筋ジストロフィーにおけるdysferlin遺伝子異常 Peer-reviewed

    青木 正志, 高橋 俊明, 中井 博史, 星野 恭子, 斎藤 加代子, 大澤 真木子, 荒畑 喜一, 埜中 征哉, 糸山 泰人

    脳と発達 32 (Suppl.) S96-S96 2000/05

    Publisher: (一社)日本小児神経学会

    ISSN: 0029-0831

    eISSN: 1884-7668

  693. Altered ischemic induction of immediate early gene and heat shock protein 70 mRNAs after preconditioning in rat hearts Peer-reviewed

    Y Nitta-Komatsubara, K Abe, M Aoki, S Isoyama

    LIFE SCIENCES 66 (13) 1261-1270 2000/02

    DOI: 10.1016/S0024-3205(00)00430-6  

    ISSN: 0024-3205

  694. Altered ischemic induction of immediate early gene and heat shock protein 70 mRNAs after preconditioning in rat hearts

    Y Nitta-Komatsubara, K Abe, M Aoki, S Isoyama

    LIFE SCIENCES 66 (13) 1261-1270 2000/02

    DOI: 10.1016/S0024-3205(00)00430-6  

    ISSN: 0024-3205

  695. 日本人三好型遠位型筋ジストロフィーにおけるdysferlin遺伝子異常の検討 Peer-reviewed

    高橋 俊明, 青木 正志, 糸山 泰人, 鴻巣 武, 斎藤 博, 中井 博史

    臨床神経学 40 (1) 74-74 2000/01

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  696. [A case of rhabdomyolysis with water intoxication confirmed by muscle biopsy] Peer-reviewed

    Nagata T, Aoki M, Kato H, Mochizuki H, Tateyama M, Itoyama Y

    No To Shinkei 52 (1) 53-57 2000/01

  697. 筋生検にて急性横紋筋融解症を確認した水中毒による高CK血症の1例

    永田 哲也, 青木 正志, 加藤 宏之, 望月 廣, 竪山 真規, 糸山 泰人

    脳と神経 52 (1) 53-57 2000/01

    Publisher: (株)医学書院

    ISSN: 0006-8969

  698. A case of rhabdomyolysis with water intoxication confirmed by muscle biopsy

    Tetsuya Nagata, Masashi Aoki, Hiroyuki Kato, Hiroshi Mochizuki, Maki Tateyama, Yasuto Itoyama

    Brain and Nerve 52 (1) 53-57 2000

    ISSN: 0006-8969

  699. A family with oculopharyngeal muscular dystrophy with (GCG)9 expansion in which a sister had neck as well as proximal and her brother proximal lower limb muscle weakness

    T. Takahashi, M. Tateyama, M. Aoki, Y. Shiga, E. Uyama, Y. Itoyama

    Clinical Neurology 40 (9) 911-914 2000

    ISSN: 0009-918X

  700. Therapeutic efficacy of transcranial magnetic stimulation for hereditary spinocerebellar degeneration Peer-reviewed

    H Shimizu, T Tsuda, Y Shiga, K Miyazawa, Y Onodera, M Matsuzaki, Nakashima, I, K Furukawa, M Aoki, H Kato, T Yamazaki, Y Itoyama

    TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE 189 (3) 203-211 1999/11

    ISSN: 0040-8727

    eISSN: 1349-3329

  701. Dysferlin is a surface membrane-associated protein that is absent in Miyoshi myopathy. Peer-reviewed

    Matsuda C, Aoki M, Hayashi Y K, Ho M F, Arahata K, Brown R H J

    Neurology 53 (5) 1119-1122 1999/09/22

  702. Analysis of spinocerebellar ataxia type 2 gene and haplotype analysis: (CCG)1-2 polymorphism and contribution to founder effect. Peer-reviewed

    Mizushima K, Watanabe M, Kondo I, Okamoto K, Shizuka M, Abe K, Aoki M, Shoji M

    J Med Genet 36 (2) 112-114 1999/02

  703. Stress protein inductions after brain ischemia. Invited Peer-reviewed

    Abe K, Kawagoe J, Aoki M, Kogure K, Itoyama Y

    Cell Mol Neurobiol 18 (6) 709-719 1998/12

    DOI: 10.1023/A:1020230220971  

  704. Molecular analyses of the Cu/Zn superoxide dismutase gene in patients with familial amyotrophic lateral sclerosis (ALS) in Japan. (Cell Mol Neurobiol)

    Aoki M, Abe K, Itoyama Y

    Cell Mol Neurobiol 18 (6) 639-647 1998/12

    DOI: 10.1023/A:1020217818245  

  705. Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy Peer-reviewed

    J Liu, M Aoki, Illa, I, CY Wu, M Fardeau, C Angelini, C Serrano, JA Urtizberea, F Hentati, M Ben Hamida, S Bohlega, EJ Culper, AA Amato, K Bossie, T Oeltjen, K Bejaoui, D McKenna-Yasek, BA Hosler, E Schurr, K Arahata, PJ de Jong, RH Brown

    NATURE GENETICS 20 (1) 31-36 1998/09

    DOI: 10.1038/1682  

    ISSN: 1061-4036

  706. Mutations in the glutamate transporter EAAT2 gene do not cause abnormal EAAT2 transcripts in amyotrophic lateral sclerosis Peer-reviewed

    M Aoki, CLG Lin, JD Rothstein, BA Geller, BA Hosler, TL Munsat, HR Horvitz, RH Brown

    ANNALS OF NEUROLOGY 43 (5) 645-653 1998/05

    DOI: 10.1002/ana.410430514  

    ISSN: 0364-5134

  707. Enhancement of heat shock protein expression after transient ischemia in the preconditioned spinal cord of rabbits. Peer-reviewed

    Sakurai M, Hayashi T, Abe K, Aoki M, Sadahiro M, Tabayashi K

    J Vasc Surg 27 (4) 720-725 1998/04

    DOI: 10.1016/S0741-5214(98)70238-1  

  708. Mitochondrial DNA deletion is a predisposing cause for sensorineural hearing loss Peer-reviewed

    N Ueda, T Oshima, K Ikeda, K Abe, M Aoki, T Takasaka

    LARYNGOSCOPE 108 (4) 580-584 1998/04

    ISSN: 0023-852X

  709. Analysis of spinocerebellar ataxia type 2 in Gunma Prefecture in Japan: CAG trinucleotide expansion and clinical characteristics. Peer-reviewed

    Mizushima K, Watanabe M, Abe K, Aoki M, Itoyama Y, Shizuka M, Okamoto K, Shoji M

    J Neurol Sci 156 (2) 180-185 1998/04/01

    DOI: 10.1016/S0022-510X(98)00040-9  

  710. Enhancement of heat shock protein expression after transient ischemia in the preconditioned spinal cord of rabbits

    M. Sakurai, T. Hayashi, K. Abe, M. Aoki, M. Sadahiro, K. Tabayashi

    Journal of Vascular Surgery 27 (4) 720-725 1998

    Publisher: Mosby Inc.

    DOI: 10.1016/S0741-5214(98)70238-1  

    ISSN: 0741-5214

  711. Blood distribution in the facial nerve in temporal bones acquired from cases with subarachnoid hemorrhage

    Narihisa Ueda, Takeshi Oshima, Katsuhisa Ikeda, Koji Abe, Masashi Aoki, Tomonori Takasaka

    Laryngoscope 108 (4) 580-584 1998

    DOI: 10.1097/00005537-199804000-00022  

    ISSN: 1531-4995 0023-852X

  712. Analysis of the McLeod syndrome gene in three patients with neuroacanthocytosis. Peer-reviewed

    Shizuka M, Watanabe M, Aoki M, Ikeda Y, Mizushima K, Okamoto K, Itoyama Y, Abe K, Shoji M

    J Neurol Sci 150 (2) 133-135 1997/09/10

    DOI: 10.1016/S0022-510X(97)00067-1  

  713. Ocular changes in patients with spinocerebellar degeneration and repeated trinucleotide expansion of spinocerebellar ataxia type 1 gene Peer-reviewed

    T Abe, K Abe, M Aoki, Y Itoyama, M Tamai

    ARCHIVES OF OPHTHALMOLOGY 115 (2) 231-236 1997/02

    ISSN: 0003-9950

  714. Selective motor neuron death and heat shock protein induction after spinal cord ischemia in rabbits Peer-reviewed

    M Sakurai, M Aoki, K Abe, M Sadahiro, K Tabayashi

    JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY 113 (1) 159-164 1997/01

    DOI: 10.1016/S0022-5223(97)70411-2  

    ISSN: 0022-5223

  715. A novel missense point mutation (S134N) of the Cu/Zn superoxide dismutase gene in a patient with familal motor neuron disease Peer-reviewed

    M Watanabe, M Aoki, K Abe, M Shoji, T Iizuka, Y Ikeda, S Hirai, K Kurokawa, T Kato, H Sasaki, Y Itoyama

    HUMAN MUTATION 9 (1) 69-71 1997

    DOI: 10.1002/(SICI)1098-1004(1997)9:1<69::AID-HUMU14>3.0.CO;2-N  

    ISSN: 1059-7794

  716. Ocular changes in patients with spinocerebellar degeneration and repeated trinucleotide expansion of spinocerebellar ataxia type 1 gene

    Toshiaki Abe, Koji Abe, Masashi Aohi, Yasuto Itoyama, Makoto Tamai

    Archives of Ophthalmology 115 (2) 231-236 1997

    Publisher: American Medical Association

    DOI: 10.1001/archopht.1997.01100150233013  

    ISSN: 0003-9950

  717. A presenilin-1 mutation in a Japanese family with Alzheimer's disease and distinctive abnormalities on cranial MRI

    M. Aoki, K. Abe, N. Oda, M. Ikeda, T. Tsuda, M. Kanai, M. Shoji, P. H. St. George-Hyslop, Y. Itoyama

    Neurology 48 (4) 1118-1120 1997

    Publisher: Lippincott Williams and Wilkins

    DOI: 10.1212/WNL.48.4.1118  

    ISSN: 0028-3878

  718. The clinical phenotype of two missense mutations in the presenilin I gene in Japanese patients Peer-reviewed

    M Ikeda, Sharma, V, M Sumi, EA Rogaeva, P Poorkaj, R Sherrington, L Nee, T Tsuda, N Oda, M Watanabe, M Aoki, M Shoji, K Abe, Y Itoyama, S Hirai, GD Schellenberg, TD Bird, PH StGeorgeHyslop

    ANNALS OF NEUROLOGY 40 (6) 912-917 1996/12

    DOI: 10.1002/ana.410400614  

    ISSN: 0364-5134

  719. Molecular analyses of Cu/Zn superoxide dismutase gene in patients with familial amyotrophic lateral sclerosis (ALS)

    Masashi Aoki, Koji Abe, Masahito Ogasawara, Yoko Aoki, Yoichi Matsubara, Kuniaki Narisawa, Mitsunori Watanabe, Masaki Ikeda, Kouji Houi, Soichiro Mocfflo, Katsuro Kurokawa, Takeo Kato, Hideo Sasaki, Ryo Sakuma, Takeshi Kameya, Shyozo Nakamura, Yasuto Itoyama

    Japanese Journal of Human Genetics 41 28 1996/12/01

    ISSN: 0916-8478

  720. Analysis of CAO trinucleotide expansion associated with Machado-Joseph Disease (MJD)

    Mitsunori Watanabe, Koji Abe, Masashi Aoki, Takeshi Kameya, Mikio Shoji, Tomomiclull Zuka, Yoshio Ikeda, Shunsakv Thirap, Yasuto Itoyama

    Japanese Journal of Human Genetics 41 27 1996/12/01

    ISSN: 0916-8478

  721. Reduction of CAG expansions in cerebellar cortex and spinal cord of DRPLA Peer-reviewed

    M Aoki, K Abe, M Tobita, T Kameya, M Watanabe, Y Itoyama

    CLINICAL GENETICS 50 (4) 199-201 1996/10

    ISSN: 0009-9163

  722. Dissociation of HSP72 and HSC73 heat shock mRNA inductions after spinal cord ischemia in rabbit Peer-reviewed

    M Sakurai, M Aoki, K Abe, M Sadahiro, K Tabayashi

    NEUROSCIENCE LETTERS 217 (2-3) 113-116 1996/10

    ISSN: 0304-3940

  723. Mitotic and meiotic stability of the CAG repeat in the X-linked spinal and bulbar muscular atrophy gene Peer-reviewed

    M Watanabe, K Abe, M Aoki, K Yasuo, Y Itoyama, M Shoji, Y Ikeda, T Iizuka, M Ikeda, M Shizuka, K Mizushima, S Hirai

    CLINICAL GENETICS 50 (3) 133-137 1996/09

    ISSN: 0009-9163

  724. Founder effect in spinal and bulbar muscular atrophy (SBMA). Peer-reviewed

    Tanaka F, Doyu M, Ito Y, Matsumoto M, Mitsuma T, Abe K, Aoki M, Itoyama Y, Fischbeck K H, Sobue G

    Hum Mol Genet 5 (9) 1253-1257 1996/09

    DOI: 10.1093/hmg/5.9.1253  

  725. Inductions of Cu/Zn superoxide dismutase- and nitric oxide synthase-like immunoreactivities in rabbit spinal cord after transient ischemia Peer-reviewed

    M Watanabe, M Sakurai, K Abe, M Aoki, M Sadahiro, K Tabayashi, K Okamoto, M Shoji, Y Itoyama

    BRAIN RESEARCH 732 (1-2) 69-74 1996/09

    DOI: 10.1016/0006-8993(96)00490-8  

    ISSN: 0006-8993

  726. Clinical characteristics of familial amyotrophic lateral sclerosis with Cu/Zn superoxide dismutase gene mutations Peer-reviewed

    K Abe, M Aoki, M Ikeda, M Watanabe, S Hirai, Y Itoyama

    JOURNAL OF THE NEUROLOGICAL SCIENCES 136 (1-2) 108-116 1996/03

    DOI: 10.1016/0022-510X(95)00314-R  

    ISSN: 0022-510X

  727. Analysis of CAG trinucleotide expansion associated with Machado-Joseph disease Peer-reviewed

    M Watanabe, K Abe, M Aoki, T Kameya, J Kaneko, M Shoji, M Ikeda, M Shizuka, Y Ikeda, T Iizuka, S Hirai, Y Itoyama

    JOURNAL OF THE NEUROLOGICAL SCIENCES 136 (1-2) 101-107 1996/03

    DOI: 10.1016/0022-510X(95)00307-N  

    ISSN: 0022-510X

  728. A reproducible assay of polymerase chain reaction to detect trinucleotide repeat expansion of Huntington's disease and senile chorea Peer-reviewed

    M Watanabe, K Abe, M Aoki, T Kameya, Y Itoyama, M Shoji, M Ikeda, T Iizuka, S Hirai

    NEUROLOGICAL RESEARCH 18 (1) 16-18 1996/02

    ISSN: 0161-6412

  729. A novel two-base mutation in the Cu/Zn superoxide dismutase gene associated with familial amyotrophic lateral sclerosis in Japan Peer-reviewed

    M Morita, M Aoki, K Abe, T Hasegawa, R Sakuma, Y Onodera, N Ichikawa, M Nishizawa, Y Itoyama

    NEUROSCIENCE LETTERS 205 (2) 79-82 1996/02

    DOI: 10.1016/0304-3940(96)12378-8  

    ISSN: 0304-3940

  730. Clinical characteristics of familial ALS with SOD1 mutations, and upregulation of protein tyrosine nitration Peer-reviewed

    K Abe, M Aoki, M Ikeda, M Watanabe, S Hirai, Y Itoyama

    AMYOTROPHIC LATERAL SCLEROSIS 1104 248-258 1996

    ISSN: 0531-5131

  731. Variable clinical symptoms in the pedigrees of familial amyotrophic lateral sclerosis with novel missense point mutations in the Cu/Zn superoxide dismutase gene Peer-reviewed

    M Ikeda, K Abe, M Aoki, M Watanabe, M Shoji, PH StGeorgeHyslop, S Hirai, Y Itoyama

    AMYOTROPHIC LATERAL SCLEROSIS 1104 285-288 1996

    ISSN: 0531-5131

  732. Analysis of CAG trinucleotide expansion associated with Machado-Joseph disease

    Mitsunori Watanabe, Koji Abe, Masashi Aoki, Takeshi Kameya, Jin Kaneko, Mikio Shoji, Masaki Ikeda, Masami Shizuka, Yoshio Ikeda, Tomomichi Iizuka, Shunsaku Hirai, Yasuto Itoyama

    Journal of the Neurological Sciences 136 (1-2) 101-107 1996

    Publisher: Elsevier B.V.

    DOI: 10.1016/0022-510X(95)00307-N  

    ISSN: 0022-510X

  733. Clinical characteristics of familial amyotrophic lateral sclerosis with Cu/Zn superoxide dismutase gene mutations

    K. Abe, M. Aoki, M. Ikeda, M. Watanabe, S. Hirai, Y. Itoyama

    Journal of the Neurological Sciences 136 (1-2) 108-116 1996

    Publisher: Elsevier B.V.

    DOI: 10.1016/0022-510X(95)00314-R  

    ISSN: 0022-510X

  734. A reproducible assay of polymerase chain reaction to detect trinucleotide repeat expansion of Huntington's disease and senile chorea

    Mitsunori Watanabe, Koji Abe, Masashi Aoki, Takeshi Kameya, Yasuto Itoyama, Mikio Shoji, Masaki Ikeda, Tomomichi Iizuka, Shunsaku Hirai

    Neurological Research 18 (1) 16-18 1996

    Publisher: Maney Publishing

    DOI: 10.1080/01616412.1996.11740370  

    ISSN: 0161-6412

  735. Chorea with prominent spasticity associated with an expansion of the CAG trinucleotide repeat in the IT15 gene. A case report

    J. Akanuma, N. Saito, M. Aoki, K. Abe, T. Yamamoto

    Clinical Neurology 35 (11) 1253-1255 1996

    ISSN: 0009-918X

  736. [Chorea with prominent spasticity associated with an expansion of the CAG trinucleotide repeat in the IT15 gene: a case report] Peer-reviewed

    Akanuma J, Saito N, Aoki M, Abe K, Yamamoto T

    Rinsho Shinkeigaku 35 (11) 1253-1255 1995/11

  737. VARIABLE CLINICAL SYMPTOMS IN FAMILIAL AMYOTROPHIC-LATERAL-SCLEROSIS WITH A NOVEL POINT MUTATION IN THE CU/ZN SUPEROXIDE-DISMUTASE GENE Peer-reviewed

    M IKEDA, K ABE, M AOKI, M SAHARA, M WATANABE, M SHOJI, PH STGEORGEHYSLOP, S HIRAI, Y ITOYAMA

    NEUROLOGY 45 (11) 2038-2042 1995/11

    ISSN: 0028-3878

  738. HD遺伝子異常を認めた痙縮を伴う舞踏病の1例

    赤沼 順, 斎藤 直史, 青木 正志

    臨床神経学 35 (11) 1253-1255 1995/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

  739. A CLINICAL VARIANCE IN FAMILIAL AMYOTROPHIC-LATERAL-SCLEROSIS WITH A POINT MUTATION IN CU/ZN SUPEROXIDE-DISMUTASE GENE Peer-reviewed

    R SAKUMA, K ABE, M AOKI, M IKEDA, N OKITA, M HIWATARI, M SAKURAI, Y ITOYAMA

    EUROPEAN JOURNAL OF NEUROLOGY 2 (4) 369-374 1995/09

    ISSN: 1351-5101

  740. ISCHEMIC DELAYED NEURONAL DEATH - A MITOCHONDRIAL HYPOTHESIS Peer-reviewed

    K ABE, M AOKI, J KAWAGOE, T YOSHIDA, A HATTORI, K KOGURE, Y ITOYAMA

    STROKE 26 (8) 1478-1489 1995/08

    ISSN: 0039-2499

  741. ANALYSIS OF SPINOCEREBELLAR ATAXIA TYPE-1 (SCA1)-RELATED CAG TRINUCLEOTIDE EXPANSION IN JAPAN Peer-reviewed

    T KAMEYA, K ABE, M AOKI, M SAHARA, M TOBITA, H KONNO, Y ITOYAMA

    NEUROLOGY 45 (8) 1587-1594 1995/08

    ISSN: 0028-3878

  742. A novel point mutation in the Cu/Zn superoxide dismutase gene in a patient with familial amyotrophic lateral sclerosis. Peer-reviewed

    Ikeda M, Abe K, Aoki M, Ogasawara M, Kameya T, Watanabe M, Shoji M, Hirai S, Itoyama Y

    Hum Mol Genet 4 (3) 491-492 1995/03

  743. Early immunohistochemical changes of microtubule based motor proteins in gerbil hippocampus after transient ischemia. (Brain Res)

    Aoki M, Abe K, Yoshida T, Hattori A, Kogure K, Itoyama Y

    Brain Res 669 (2) 189-196 1995/01/16

    DOI: 10.1016/0006-8993(94)01227-9  

  744. Variable clinical symptoms in familial amyotrophic lateral sclerosis with a novel point mutation in the Cu/Zn superoxide dismutase gene

    M. Ikeda, Koji Abe, M. Aoki, M. Sahara, M. Watanabe, M. Shoji, P. H. St. George-Hyslop, S. Hirai, Y. Itoyama

    Neurology 45 (11) 2038-2042 1995

    DOI: 10.1212/WNL.45.11.2038  

    ISSN: 1526-632X 0028-3878

  745. A Japanese family with Machado‐Joseph disease characterized by initial emaciation and myoclonus

    M. Aoki, K. Abe, T. Nagata, T. Kameya, M. Watanabe, H. Onodera, H. Mochizuki, Y. Itoyama

    European Journal of Neurology 2 (5) 477-482 1995

    DOI: 10.1111/j.1468-1331.1995.tb00159.x  

    ISSN: 1468-1331 1351-5101

  746. Variance of age at onset in a Japanese family with amyotrophic lateral sclerosis associated with a novel cu/zn superoxide dismutase mutation

    Masashi Aoki, Koji Abe, Kouji Houi, Masahito Ogasawara, Yoichi Matsubara, Takaaki Kobayashi, Soichiro Mochio, Kuniaki Narisawa, Yasuto Itoyama

    Annals of Neurology 37 (5) 676-679 1995

    DOI: 10.1002/ana.410370518  

    ISSN: 1531-8249 0364-5134

  747. Ischemic delayed neuronal death: A mitochondrial hypothesis

    K. Abe, M. Aoki, J. Kawagoe, T. Yoshida, A. Hattori, K. Kogure, Y. Itoyama

    Stroke 26 (8) 1478-1489 1995

    DOI: 10.1161/01.STR.26.8.1478  

    ISSN: 1524-4628 0039-2499

  748. Differential diagnosis of early stage Huntington's disease from dentatorubral‐pallidoluysian atrophy by DNA analysis

    K. Abe, M. Aoki, Y. Itoyama

    European Journal of Neurology 2 (3) 239-240 1995

    DOI: 10.1111/j.1468-1331.1995.tb00125.x  

    ISSN: 1468-1331 1351-5101

  749. Analysis of spinocerebellar ataxia type 1 (sca1)-related cag trinucleotide expansion in japan

    T. Kameya, K. Abe, M. Aoki, M. Sahara, M. Tobita, H. Konno, Y. Itoyama

    Neurology 45 (8) 1587-1594 1995

    DOI: 10.1212/WNL.45.8.1587  

    ISSN: 1526-632X 0028-3878

  750. A family with mild clinical manifestations of spinocerebellar ataxia type 1 (SCA1): correlation with smaller CAG repeats

    T. Kameya, K. Abe, M. Aoki, Y. Itoyama

    European Journal of Neurology 2 (4) 349-355 1995

    DOI: 10.1111/j.1468-1331.1995.tb00138.x  

    ISSN: 1468-1331 1351-5101

  751. EARLY IMMUNOHISTOCHEMICAL CHANGES OF MICROTUBULE-BASED MOTOR PROTEINS IN GERBIL HIPPOCAMPUS AFTER TRANSIENT ISCHEMIA

    M AOKI, K ABE, T YOSHIDA, A HATTORI, K KOGURE, Y ITOYAMA

    BRAIN RESEARCH 669 (2) 189-196 1995/01

    DOI: 10.1016/0006-8993(94)01227-9  

    ISSN: 0006-8993

  752. Diminished heat shock protein 70 mRNA induction in aged rat hearts after ischemia. Peer-reviewed

    Nitta Y, Abe K, Aoki M, Ohno I, Isoyama S

    Am J Physiol 267 (5 Pt 2) H1795-803 1994/11

  753. THE PROTECTIVE EFFECT OF L-THREO-3,4-DIHYDROXYPHENYLSERINE ON ISCHEMIC HIPPOCAMPAL NEURONAL DEATH IN GERBILS Peer-reviewed

    TH LEE, K ABE, M AOKI, M NAKAMURA, K KOGURE, Y ITOYAMA

    STROKE 25 (7) 1425-1431 1994/07

    ISSN: 0039-2499

    eISSN: 1524-4628

  754. MATERNAL ANTICIPATION OF DRPLA

    M AOKI, K ABE, T KAMEYA, M WATANABE, Y ITOYAMA

    HUMAN MOLECULAR GENETICS 3 (7) 1197-1198 1994/07

    DOI: 10.1093/hmg/3.7.1197  

    ISSN: 0964-6906

  755. Diminished heat shock protein 70 mRNA induction in aged rat hearts after ischemia

    Y. Nitta, K. Abe, M. Aoki, I. Ohno, S. Isoyama

    American Journal of Physiology - Heart and Circulatory Physiology 267 (5) H1795-H1803 1994

    ISSN: 0363-6135

  756. Responses to Hemodynamic Stress in the Aged Heart

    Shogen Isoyama, Nobuhiko Ito, Masashi Komatsu, Yuko Nitta, Koji Abe, Masashi Aoki, Tamotsu Takishima

    Japanese Heart Journal 35 (4) 403-418 1994

    DOI: 10.1536/ihj.35.403  

    ISSN: 1348-673X 0021-4868

  757. The protective effect of l-threo-3,4-dihydroxyphenylserine on ischemic hippocampal neuronal death in gerbils

    Tsong-Hai Lee, Koji Abe, Masashi Aoki, Mitsutaka Nakamura, Kyuya Kogure, Yasuto Itoyama

    Stroke 25 (7) 1425-1431 1994

    DOI: 10.1161/01.STR.25.7.1425  

    ISSN: 1524-4628 0039-2499

  758. Preproenkephalin gene expression in the rat cerebral cortex during chronic tracheal stenosis

    M. Aoki, Y. Kikuchi, K. Abe, H. Kurosawa, H. Ogawa, A. Mizusawa, W. Hida

    Neurological Research 16 (3) 213-216 1994

    Publisher: Maney Publishing

    DOI: 10.1080/01616412.1994.11740230  

    ISSN: 0161-6412

  759. Familial amyotrophic lateral sclerosis (ALS) in Japan associated with H46R mutation in Cu Zn superoxide dismutase gene: A possible new subtype of familial ALS

    Masashi Aoki, Masahito Ogasawara, Yoichi Matsubara, Kuniaki Narisawa, Shozo Nakamura, Yasuto Itoyama, Koji Abe

    Journal of the Neurological Sciences 126 (1) 77-83 1994

    DOI: 10.1016/0022-510X(94)90097-3  

    ISSN: 0022-510X

  760. Preferential expression of HSC70 heat shock mRNA in gerbil heart after transient brain ischemia. Peer-reviewed

    Abe K, Lee T H, Aoki M, Nitta Y, Isoyama S

    J Mol Cell Cardiol 25 (10) 1131-1135 1993/10

    DOI: 10.1006/jmcc.1993.1126  

  761. CHANGES OF MITOCHONDRIAL-DNA AND HEAT-SHOCK PROTEIN GENE EXPRESSIONS IN GERBIL HIPPOCAMPUS AFTER TRANSIENT FOREBRAIN ISCHEMIA Peer-reviewed

    K ABE, J KAWAGOE, M AOKI, K KOGURE

    JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM 13 (5) 773-780 1993/09

    ISSN: 0271-678X

  762. ACCELERATION OF HSP70 AND HSC70 HEAT-SHOCK GENE-EXPRESSION FOLLOWING TRANSIENT ISCHEMIA IN THE PRECONDITIONED GERBIL HIPPOCAMPUS Peer-reviewed

    M AOKI, K ABE, J KAWAGOE, S NAKAMURA, K KOGURE

    JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM 13 (5) 781-788 1993/09

    ISSN: 0271-678X

    eISSN: 1559-7016

  763. INDUCTION OF HSP90-ALPHA HEAT-SHOCK MESSENGER-RNA AFTER TRANSIENT GLOBAL-ISCHEMIA IN GERBIL HIPPOCAMPUS

    J KAWAGOE, K ABE, M AOKI, K KOGURE

    BRAIN RESEARCH 621 (1) 121-125 1993/09

    DOI: 10.1016/0006-8993(93)90306-8  

    ISSN: 0006-8993

  764. DISTURBANCE OF A MITOCHONDRIAL-DNA EXPRESSION IN GERBIL HIPPOCAMPUS AFTER TRANSIENT FOREBRAIN ISCHEMIA Peer-reviewed

    K ABE, J KAWAGOE, TH LEE, M AOKI, K KOGURE

    MOLECULAR BRAIN RESEARCH 19 (1-2) 69-75 1993/07

    ISSN: 0169-328X

  765. REDUCTION OF HSP70 AND HSC70 MESSENGER-RNA INDUCTIONS BY BIFEMELANE HYDROCHLORIDE AFTER TRANSIENT ISCHEMIA IN GERBIL BRAIN Peer-reviewed

    M AOKI, K ABE, XH LIU, TH LEE, H KATO, K KOGURE

    NEUROSCIENCE LETTERS 154 (1-2) 69-72 1993/05

    ISSN: 0304-3940

    eISSN: 1872-7972

  766. THE PRECONDITIONED HIPPOCAMPUS ACCELERATES HSP70 HEAT-SHOCK GENE-EXPRESSION FOLLOWING TRANSIENT ISCHEMIA IN THE GERBIL Peer-reviewed

    M AOKI, K ABE, J KAWAGOE, S NAKAMURA, K KOGURE

    NEUROSCIENCE LETTERS 155 (1) 7-10 1993/05

    DOI: 10.1016/0304-3940(93)90661-4  

    ISSN: 0304-3940

  767. Dysferlinopathy

    Masashi Aoki, Toshiaki Takahashi

    1993

    Publisher: University of Washington, Seattle

    More details Close

    CLINICAL CHARACTERISTICS: Dysferlinopathy includes a spectrum of muscle disease characterized by two major phenotypes: Miyoshi muscular dystrophy (MMD) and limb-girdle muscular dystrophy type 2B (LGMD2B); and two minor phenotypes: asymptomatic hyperCKemia and distal myopathy with anterior tibial onset (DMAT). MMD (median age of onset 19 years) is characterized by muscle weakness and atrophy, most marked in the distal parts of the legs, especially the gastrocnemius and soleus muscles. Over a period of years, the weakness and atrophy spread to the thighs and gluteal muscles. The forearms may become mildly atrophic with decrease in grip strength; the small muscles of the hands are spared. LGMD2B is characterized by early weakness and atrophy of the pelvic and shoulder girdle muscles in adolescence or young adulthood, with slow progression. Other phenotypes in this spectrum are scapuloperoneal syndrome and congenital muscular dystrophy. Asymptomatic hyperCKemia is characterized by marked elevation of serum CK concentration only. DMAT is characterized by early and predominant distal muscle weakness, particularly of the muscles of the anterior compartment of the legs. DIAGNOSIS/TESTING: The diagnosis of dysferlinopathy is established in a proband with suggestive findings and biallelic pathogenic variants in DYSF identified by molecular genetic testing. MANAGEMENT: Treatment of manifestations: There is no approved therapy for dysferlinopathy. Treatment is symptomatic only. Management should be tailored to the individual and the specific subtype. Individualized management may include physical therapy, use of mechanical aids, surgical intervention for orthopedic complications, respiratory aids, and social and emotional support. Surveillance: Annual monitoring of muscle strength, physical function, activities of daily living, joint range of motion, balance, and respiratory function, and for evidence of cardiomyopathy for individuals with cardiac involvement. Agents/circumstances to avoid: Weight control to avoid obesity. GENETIC COUNSELING: Dysferlinopathy is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a DYSF pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the DYSF pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

  768. DISSOCIATION OF HSP70 AND HSC70 HEAT-SHOCK MESSENGER-RNA INDUCTIONS AS AN EARLY BIOCHEMICAL MARKER OF ISCHEMIC NEURONAL DEATH Peer-reviewed

    K ABE, J KAWAGOE, M AOKI, K KOGURE

    NEUROSCIENCE LETTERS 149 (2) 165-168 1993/01

    DOI: 10.1016/0304-3940(93)90762-A  

    ISSN: 0304-3940

  769. TEMPORAL PROFILE OF THE INDUCTION OF HEAT-SHOCK PROTEIN-70 AND HEAT-SHOCK COGNATE PROTEIN-70 MESSENGER-RNAS AFTER TRANSIENT ISCHEMIA IN GERBIL BRAIN Peer-reviewed

    M AOKI, K ABE, J KAWAGOE, S SATO, S NAKAMURA, K KOGURE

    BRAIN RESEARCH 601 (1-2) 185-192 1993/01

    ISSN: 0006-8993

    eISSN: 1872-6240

  770. PROTECTIVE EFFECT OF BIFEMELANE HYDROCHLORIDE ON ISCHEMIC HIPPOCAMPAL CA1 NEURONAL DAMAGE IN THE GERBIL - RELATION TO INDUCTION OF HSP70 Peer-reviewed

    XH LIU, K ABE, M AOKI, TH LEE, H KATO, K KOGURE

    LIFE SCIENCES 53 (2) 161-167 1993

    DOI: 10.1016/0024-3205(93)90663-N  

    ISSN: 0024-3205

  771. Changes of mitochondrial DNA and heat shock protein gene expressions in gerbil hippocampus after transient forebrain ischemia

    K. Abe, J. Kawagoe, M. Aoki, K. Kogure

    Journal of Cerebral Blood Flow and Metabolism 13 (5) 773-780 1993

    Publisher: Lippincott Williams and Wilkins

    DOI: 10.1038/jcbfm.1993.98  

    ISSN: 0271-678X

  772. A selective impairment in the phonological output lexicon

    T. Imamura, A. Yamadori, M. Aoki, R. Mochizuki, K. Kogure

    Behavioural Neurology 6 (1) 37-41 1993

    DOI: 10.3233/BEN-1993-6106  

    ISSN: 1875-8584 0953-4180

  773. Mild ALS in Japan associated with novel SOD mutation

    Masahito Ogasawara, Yoichi Matsubara, Kuniaki Narisawa, Masashi Aoki, Shozo Nakamura, Yasuto Itoyama, Koji Abe

    Nature Genetics 5 (4) 323-324 1993

    DOI: 10.1038/ng1293-323  

    ISSN: 1546-1718 1061-4036

  774. Acceleration of HSP70 and HSC70 heat shock gene expression following transient ischemia in the preconditioned gerbil hippocampus

    M. Aoki, K. Abe, J. Kawagoe, S. Nakamura, K. Kogure

    Journal of Cerebral Blood Flow and Metabolism 13 (5) 781-788 1993

    Publisher: Lippincott Williams and Wilkins

    DOI: 10.1038/jcbfm.1993.99  

    ISSN: 0271-678X

  775. Preferential Expression of HSC70 Heat Shock mRNA in Gerbil Heart After Transient Brain Ischemia

    K. Abe, T. H. Lee, M. Aoki, Y. Nitta, S. Isoyama

    Journal of Molecular and Cellular Cardiology 25 (10) 1131-1135 1993

    DOI: 10.1006/jmcc.1993.1126  

    ISSN: 0022-2828

  776. Disturbance of a mitochondrial DNA expression in gerbil hippocampus after transient forebrain ischemia

    K. Abe, J. Kawagoe, T-H. Lee, M. Aoki, K. Kogure

    Molecular Brain Research 19 (1-2) 69-75 1993

    DOI: 10.1016/0169-328X(93)90150-N  

    ISSN: 0169-328X

  777. PROTECTIVE EFFECT OF BIFEMELANE HYDROCHLORIDE ON ISCHEMIC HIPPOCAMPAL CA1 NEURONAL DAMAGE IN THE GERBIL - RELATION TO INDUCTION OF HSP70

    XH LIU, K ABE, M AOKI, TH LEE, H KATO, K KOGURE

    LIFE SCIENCES 53 (2) 161-167 1993

    DOI: 10.1016/0024-3205(93)90663-N  

    ISSN: 0024-3205

  778. Phospholipid metabolism and second messenger system after brain ischemia

    K. Abe, T. Araki, J. I. Kawagoe, M. Aoki, K. Kogure

    Advances in Experimental Medicine and Biology 318 183-195 1992/01/01

    ISSN: 0065-275X

  779. Differential expression of heat shock protein 70 gene between the cortex and caudate after transient focal cerebral ischaemia in rats

    K. Abe, J. Kawagoe, T. Araki, M. Aoki, K. Kogure

    Neurological Research 14 (5) 381-385 1992

    DOI: 10.1080/01616412.1992.11740089  

    ISSN: 0161-6412

  780. Isolation of complementary DNAs for heat shock protein (HSP) 70 and heat shock cognate protein (HSC) 70 genes and the expressions in post-ischaemic gerbil brain

    S. Sato, K. Abe, J. I. Kawagoe, M. Aoki, K. Kogure

    Neurological Research 14 (5) 375-380 1992

    DOI: 10.1080/01616412.1992.11740088  

    ISSN: 0161-6412

Show all ︎Show first 5

Misc. 390

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    日本薬理学雑誌 160 (1) 2025

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    月刊難病と在宅ケア 31 (1) 14-17 2025

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  3. 遺伝性神経筋疾患overview

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    臨床神経学 64 (Suppl.) S214-S214 2024/10

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    日本内科学会雑誌 113 (8) 1386-1391 2024/08

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    神経治療学 41 (6) S176-S176 2024

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    DOI: 10.15082/jsnt.41.6_s176  

    ISSN: 0916-8443

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  10. 歩行障害の臨床(No.14) 筋疾患に伴う歩行障害

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  11. 【ALS-どこまでわかり,どこまで治るか】原因と発症機序 SOD1

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  12. 【骨格筋のすべて-メカニズムからサルコペニアまで】筋症状を伴う疾患 筋萎縮性側索硬化症-骨格筋の症状と分子病態

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    Clinical Neuroscience 41 (2) 256-259 2023/02

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  13. Re-analyses of scRNA-seq from human midbrain-like organoids

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  14. Transcriptome analysis of alpha synuclein overexpression in SH-SY5Y cells

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  16. 遺伝性筋疾患研究の進歩 3.ジスフェルリン異常症

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    遺伝子医学 13 (4) 29-34 2023

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  17. Analysis of CSF complement profile in myelin oligodendrocyte glycoprotein associated disease.

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    補体 60 (1) 2023

    ISSN: 2188-8205

  18. Myelin oligodendrocyte glycoprotein抗体関連疾患の脳波所見の特徴

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  19. 【日本発の神経疾患-発見の歴史からのメッセージ】遺伝性疾患 三好型遠位型筋ジストロフィー 原因究明の歴史

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  20. 【遺伝性神経・筋疾患-診療と研究の最前線】ミオパチー,筋ジストロフィーの病態・診断・治療法開発 Dysferlin遺伝子異常に伴う筋ジストロフィー Dysferlinopathy

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  23. ALS治療の現状とこれから 改訂中のガイドラインについて

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  25. 【炎症性筋疾患に関する最新の知見】封入体筋炎

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  26. 【革新脳と関連プロジェクトから見えてきた新しい脳科学】ヒト疾患研究 b)神経変性疾患 iPS細胞技術を用いたALSの病態解析

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  27. ALSおよび希少筋疾患に対する治療法の開発

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  28. 希少疾病(難病)患者への薬局薬剤師の関わり 難病診療の課題および治療法の開発

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  29. 【炎症性筋疾患に関する最新の知見】封入体筋炎

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  30. 大規模レジストリデータベースを活用したALS治験(ROPALS試験)におけるロピニロール塩酸塩の有効性の検証

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  31. 難治性疾患(難病)を学ぶ 筋萎縮性側索硬化症(ALS)

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  32. α-シヌクレイン線維に対する膜結合型受容体の包括的スクリーニングと同定(Comprehensive screening and identification of membrane-associated receptor for α-synuclein fibrils)

    石山 駿, 長谷川 隆文, 小林 潤平, 菅野 直人, 吉田 隼, 中村 貴彬, 江面 道典, 菊池 昭夫, 武田 篤, 青木 正志

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  34. 脳神経疾患克服に向けた研究推進の提言2020、各論(方法論別)

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  41. 筋萎縮性側索硬化症では片側のみで正中神経刺激巨大体性感覚誘発電位を認めることがある

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    ISSN: 0915-0374

  48. 大規模レジストリデータベースを活用したALS治験(ROPALS試験)におけるロピニロール塩酸塩の有効性の検証

    高橋愼一, 高橋愼一, 高橋愼一, 森本悟, 森本悟, 伊東大介, 伊東大介, 伊達悠岳, 岡田健佑, CHAI Muh Chyi, CHAI Muh Chyi, 西山亜由美, 鈴木直輝, 平井美和, 加部泰明, 末松誠, 陣崎雅弘, 青木正志, 佐藤泰憲, 中原仁, 鈴木則宏, 岡野栄之

    脳循環代謝(Web) 34 (1) 2022

    ISSN: 2188-7519

  49. PNPLA2遺伝子新規変異を伴った中性脂肪蓄積症ミオパチー/中性脂肪蓄積心筋血管症の1例

    坂田 花美, 森川 みゆき, 中村 尚子, 寒川 真, 平野 牧人, 西野 一三, 井泉 瑠美子, 鈴木 直輝, 黒田 宙, 滋賀 健介, 青木 正志, 楠 進

    臨床神経学 62 (1) 55-55 2022/01

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  50. SARS-CoV-2ワクチン後免疫性神経疾患の臨床的特徴と予後

    金子仁彦, 松本勇貴, 藤盛寿一, 生田目千尋, 高井良樹, 中島一郎, 三須建郎, 青木正志

    Neuroinfection (Web) 27 (2) 2022

    ISSN: 2435-2225

  51. 日本人一般集団に高頻度で見出され病的バリアントであると判断しがたいジスフェルリン遺伝子のc.3725G>A(p.R1242H)の神経筋疾患での頻度

    高橋 俊明, 井泉 瑠美子, 鈴木 直輝, 八木沼 智香子, 島倉 奈緒子, 小野 洋也, 戸恒 智子, 杉村 容子, 谷口 さやか, 下瀬川 康子, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 割田 仁, 新堀 哲也, 武田 篤, 青木 洋子, 青木 正志

    筋ジストロフィー医療研究 8 41-41 2021/11

    Publisher: 筋ジストロフィー医療研究会

    ISSN: 2433-1708

  52. 脳神経疾患克服に向けた研究推進の提言2020、総論

    望月 秀樹, 青木 正志, 池中 建介, 井上 治久, 岩坪 威, 宇川 義一, 岡澤 均, 小野 賢二郎, 小野寺 理, 北川 一夫, 齊藤 祐子, 下畑 享良, 高橋 良輔, 戸田 達史, 中原 仁, 松本 理器, 水澤 英洋, 三井 純, 村山 繁雄, 勝野 雅央, 青木 吉嗣, 石浦 浩之, 和泉 唯信, 小池 春樹, 島田 斉, 高橋 祐二, 徳田 隆彦, 中嶋 秀人, 波田野 琢, 三澤 園子, 渡辺 宏久, 水澤 英洋, 阿部 康二, 宇川 義一, 梶 龍兒, 亀井 聡, 神田 隆, 吉良 潤一, 楠 進, 鈴木 則宏, 祖父江 元, 高橋 良輔, 辻 省次, 中島 健二, 西澤 正豊, 服部 信孝, 福山 秀直, 峰松 一夫, 村山 繁雄, 望月 秀樹, 山田 正仁, 日本神経学会将来構想委員会

    臨床神経学 61 (11) 709-721 2021/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  53. 【筋疾患診療の進歩】遠位型ミオパチーのシアル酸治療

    青木 正志, 井泉 瑠美子, 鈴木 直輝

    BIO Clinica 36 (9) 838-842 2021/08

    Publisher: (株)北隆館

    ISSN: 0919-8237

  54. 【高齢者脳神経内科疾患】高齢発症の重症筋無力症仮面うつ病、多発脳梗塞との違い

    赤石 哲也, 槍沢 公明, 白木 達也, 青木 正志

    脳神経内科 95 (2) 248-253 2021/08

    Publisher: (有)科学評論社

    ISSN: 2434-3285

  55. α-シヌクレイン線維の神経細胞への取り込みと伝搬への関与が予想される受容体の同定(Identification of putative receptor for neuronal uptake and propagation of alpha-synuclein fibril)

    石山 駿, 長谷川 隆文, 小林 潤平, 菅野 直人, 吉田 隼, 中村 貴彬, 菊池 昭夫, 武田 篤, 青木 正志

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集 15回 91-91 2021/07

    Publisher: Movement Disorder Society of Japan (MDSJ)

  56. Digestシリーズ ALS創薬の現状(Vol.1) 「ALS創薬の現状」連載によせて

    青木 正志

    Medical Science Digest 47 (8) 397-399 2021/07

    Publisher: (株)ニュー・サイエンス社

    ISSN: 1347-4340

  57. 【多系統蛋白質症に関する最近の進歩】RNP顆粒生成・分解からみた多系統蛋白質症

    割田 仁, 池田 謙輔, 青木 正志

    脳神経内科 95 (1) 112-120 2021/07

    Publisher: (有)科学評論社

    ISSN: 2434-3285

  58. 骨格筋疾患の動物モデルの実験的治療 Dysferlinopathyに対する治療法の開発

    小野 洋也, 青木 正志

    神経治療学 38 (3) 278-281 2021/05

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  59. 骨格筋疾患の動物モデルの実験的治療 Dysferlinopathyに対する治療法の開発

    小野 洋也, 青木 正志

    神経治療学 38 (3) 278-281 2021/05

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  60. ニューロンでの取り込みとα-synuclein fibril伝播のための受容体の同定(Identification of receptor for neuronal uptake and propagation of alpha-synuclein fibril)

    石山 駿, 長谷川 隆文, 小林 潤平, 菅野 直人, 吉田 準, 中村 貴彬, 菊池 昭夫, 江面 道典, 武田 篤, 青木 正志

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集 14回 76-76 2021/02

    Publisher: Movement Disorder Society of Japan (MDSJ)

  61. α-シヌクレインによるヒストン修飾を介した転写応答に関する分析(Analysis of the transcription responses through histone modifications triggered by alpha-synuclein)

    中村 貴彬, 菅野 直人, 長谷川 隆文, 石山 駿, 吉田 隼, 小林 潤平, 江面 道典, 菊池 昭夫, 武田 篤, 青木 正志

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集 14回 109-109 2021/02

    Publisher: Movement Disorder Society of Japan (MDSJ)

  62. 【希少・難治性疾患の診断と治療の最前線2021】遠位型ミオパチー

    青木 正志

    Progress in Medicine 41 (2) 109-113 2021/02

    Publisher: (株)ライフ・サイエンス

    ISSN: 0287-3648

  63. 成人期に長時間ビデオ脳波モニタリング検査を行った環状20番染色体症候群の2例

    曽我天馬, 曽我天馬, 神一敬, 柿坂庸介, 浮城一司, 伊澤理香子, 青木正志, 中里信和

    臨床神経生理学(Web) 49 (5) 2021

    ISSN: 2188-031X

  64. 神経免疫疾患のエビデンスに基づく診断基準・重症度分類・ガイドラインの妥当性と患者QOLの検証 抗MOG抗体関連疾患と抗AQP4陽性視神経脊髄炎の頭部MRI画像における病変分布の比較検討

    藤原一男, 松本勇貴, 三須建郎, 麦倉俊司, 高井良樹, 西山修平, 黒田宙, 高橋利幸, 藤盛寿一, 中島一郎, 青木正志

    神経免疫疾患のエビデンスに基づく診断基準・重症度分類・ガイドラインの妥当性と患者QOLの検証 令和2年度 総括・分担研究報告書(Web) 2021

  65. Results Of A Randomized Clinical Trial of Ropinirole Hydrochloride For ALS (ROPALS)

    高橋愼一, 高橋愼一, 高橋愼一, 森本悟, 森本悟, 伊東大介, 伊達悠岳, 岡田健佑, CHAI Muh Chyi, 西山亜由美, 鈴木直輝, 平井美和, 加部泰明, 末松誠, 陣崎雅弘, 青木正志, 佐藤泰憲, 中原仁, 鈴木則宏, 岡野栄之

    脳循環代謝(Web) 33 (1) 2021

    ISSN: 2188-7519

  66. 多系統蛋白質症(MSP)患者の全国実態調査と診療体制構築に関する研究 HNRNPA1変異を伴う多系統蛋白質症(MSP3型)新規家系の同定

    青木正志, 割田仁, 井泉瑠美子, 井泉瑠美子, 池田謙輔, 鈴木直輝, 高橋俊明, 竪山真規, 西山亜由美, 城田松之, 舟山亮, 中山啓子, 三橋里美, 西野一三, 新堀哲也, 青木洋子

    多系統蛋白質症(MSP)患者の全国実態調査と診療体制構築に関する研究 令和2年度 総括・分担研究報告書(Web) 2021

  67. Mutant DNAJC13 impairs retrograde trafficking by inhibiting clathrin assembly

    吉田隼, 吉田隼, 長谷川隆文, 菅野直人, 小林潤平, 小林潤平, 石山駿, 中村貴彬, 菊池昭夫, 武田篤, 青木正志

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集 15th 2021

  68. 吃音と右下肢の失行様歩行がみられた一例

    渡部聡, 菅野直人, 菅野直人, 中村貴彬, 石山駿, 長谷川隆文, 青木正志

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集 15th 2021

  69. Alpha-synuclein affects neuronal gene expression through histone H4R3 symmetrical dimethylation

    中村貴彬, 菅野直人, 長谷川隆文, 石山駿, 吉田隼, 小林潤平, 江面道典, 菊池昭夫, 武田篤, 青木正志

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集 15th 2021

  70. Can scalp EEG findings predict seizure outcome after anterior temporal lobectomy in patients with MRI-negative FDG-PET-positive temporal lobe epilepsy?

    曽我天馬, 曽我天馬, 神一敬, 大沢伸一郎, 岩崎真樹, 青木正志, 中里信和

    てんかん研究 39 (2) 2021

    ISSN: 0912-0890

  71. 抗MOG抗体関連疾患における髄液中の抗MOG抗体測定の意義

    松本勇貴, 金子仁彦, 三須建郎, 生田目知尋, 高井良樹, 黒田宙, 高橋利幸, 中島一郎, 藤原一男, 藤原一男, 青木正志

    Neuroimmunology 26 (1) 2021

    ISSN: 0918-936X

  72. iPS細胞創薬に基づいた筋萎縮性側索硬化症(ALS)に対するロピニロール塩酸塩の医師主導治験(ROPALS試験)

    森本悟, 森本悟, 高橋愼一, 高橋愼一, 高橋愼一, 伊東大介, 伊達悠岳, 岡田健佑, CHAI Muh Chyi, CHAI Muh Chyi, 西山亜由美, 鈴木直輝, 平井美和, 加部泰明, 末松誠, 陣崎雅弘, 青木正志, 佐藤泰憲, 中原仁, 鈴木則宏, 岡野栄之

    神経治療学(Web) 38 (6) 2021

    ISSN: 2189-7824

  73. 当院におけるサトラリズマブの使用経験

    松本勇貴, 三須建郎, 小野紘彦, 高井良樹, 藤原一男, 藤原一男, 青木正志

    神経治療学(Web) 38 (6) 2021

    ISSN: 2189-7824

  74. エイジング C.加齢と神経疾患 運動ニューロン疾患

    山下賢, 青木正志

    Clinical Neuroscience 39 (1) 2021

    ISSN: 0289-0585

  75. Elevated cerebrospinal fluid-CRMP5 levels in acute phase of NMOSD with AQP4-IgG and the prognostic implication

    Shuhei Nishiyama, Tatsuro Misu, Yoshiki Takai, Toshiyuki Takahashi, Ichiro Nakashima, Kazuo Fujihara, Masashi Aoki

    MULTIPLE SCLEROSIS JOURNAL 26 (9) NP77-NP77 2020/08

    ISSN: 1352-4585

    eISSN: 1477-0970

  76. 遺伝性筋疾患におけるトランスレーショナル・リサーチ GNEミオパチーの治療法開発

    青木 正志, 鈴木 直輝, 井泉 瑠美子, 割田 仁, 森 まどか, 勝野 雅央, 高橋 正紀, 山下 賢, 西野 一三

    神経治療学 37 (4) 656-660 2020/07

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  77. 【筋炎の診断と治療の新たな展開】増えてきた封入体筋炎

    鈴木 直輝, 井泉 瑠美子, 青木 正志

    神経治療学 37 (2) 135-140 2020/03

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  78. Current status of drug development for amyotrophic lateral sclerosis

    青木正志, 割田仁

    Bio Clinica 35 (8) 712-716 2020

    Publisher: (株)北隆館

    ISSN: 0919-8237

  79. 封入体筋炎患者を対象とするBYM338の後期第II相/第III相試験(RESILIENT) 日本人部分集団データ

    森 まどか, 山下 賢, 鈴木 直輝, 勝野 雅央, 村田 顕也, 野寺 裕之, 手島 梨恵, 稲村 達海, 西野 一三, 青木 正志

    臨床神経学 59 (12) 806-813 2019/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  80. [Late phase II/III study of BYM338 in patients with sporadic inclusion body myositis (RESILIENT): Japanese cohort data]. Peer-reviewed

    Madoka Mori-Yoshimura, Satoshi Yamashita, Naoki Suzuki, Masahisa Katsuno, Kenya Murata, Hiroyuki Nodera, Rie Teshima, Tatsumi Inamura, Ichizo Nishino, Masashi Aoki

    Rinsho shinkeigaku = Clinical neurology 59 (12) 806-813 2019/12

    Publisher: Societas Neurologica Japonica

    DOI: 10.5692/clinicalneurol.cn-001325  

    ISSN: 0009-918X

    eISSN: 1882-0654

  81. ALS患者の生存期間に与える非侵襲的換気補助療法の影響 レジストリを用いた解析

    熱田 直樹, 横井 大知, 平川 晃弘, 林 直毅, 中村 良一, 伊藤 瑞規, 渡辺 宏久, 勝野 雅央, 和泉 唯信, 森田 光哉, 谷口 彰, 狩野 修, 桑原 聡, 青木 正志, 金井 数明, 小野寺 理, 梶 龍兒, 祖父江 元, JaCALS

    臨床神経学 59 (Suppl.) S358-S358 2019/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  82. 多施設共同前向きコホートでみたALS患者の背景と予後因子の検討

    林 直毅, 熱田 直樹, 横井 大知, 中村 亮一, 勝野 雅央, 和泉 唯信, 金井 数明, 服部 信孝, 谷口 彰, 森田 光哉, 狩野 修, 澁谷 和幹, 桑原 聡, 鈴木 直輝, 青木 正志, 餐場 育子, 溝口 功一, 梶 龍兒, 祖父江 元, JaCALS

    臨床神経学 59 (Suppl.) S359-S359 2019/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  83. 【ALS 2019】家族性ALS

    鈴木 直輝, 西山 亜由美, 加藤 昌昭, 割田 仁, 青木 正志

    BRAIN and NERVE: 神経研究の進歩 71 (11) 1169-1181 2019/11

    Publisher: (株)医学書院

    ISSN: 1881-6096

    eISSN: 1344-8129

  84. [Application of Hepatocyte Growth Factor for Amyotrophic Lateral Sclerosis]. Peer-reviewed

    Masashi Aoki, Hitoshi Warita, Masaaki Kato, Naoki Suzuki

    Brain and nerve = Shinkei kenkyu no shinpo 71 (11) 1253-1260 2019/11

    Publisher: 医学書院

    DOI: 10.11477/mf.1416201435  

    ISSN: 1881-6096

    eISSN: 1344-8129

  85. [Familial Amyotrophic Lateral Sclerosis]. Peer-reviewed

    Naoki Suzuki, Ayumi Nishiyama, Masaaki Kato, Hitoshi Warita, Masashi Aoki

    Brain and nerve = Shinkei kenkyu no shinpo 71 (11) 1169-1181 2019/11

    Publisher: 医学書院

    DOI: 10.11477/mf.1416201427  

    ISSN: 1881-6096

    More details Close

    Amyotrophic lateral sclerosis (ALS) is the most rapidly progressive motor neuron disease (MND) in adults, characterized by the selective death of motor neurons in the motor cortex, brainstem, and spinal cord. Riluzole and edaravone are the only approved drugs available in Japan to date. Approximately 10% of ALS cases are familial in rature, defined as the existence of disease-causing mutation. SOD1 is the most frequent causative gene for ALS among Japanese individuals, while C9orf72 mutation is more prevalent in Western countries. Genotype-phenotype correlation described in the literature of familial ALS enables to establish models of the disease. This review article describes the clinical characteristics of familial ALS based on each disease-causing mutation. The pathomechanism of ALS including proteostasis, RNA metabolism, and axonal pathology are discussed in detail. We also reviewed the status of development of therapeutic strategies for familial ALS based on analysis of animal models and induced pluripotent stem cells.

  86. 治療抵抗性の重症抗MOG抗体関連疾患に対するリツキシマブの使用経験

    松本 勇貴, 三須 建郎, 高井 良樹, 西山 修平, 小野 紘彦, 黒田 宙, 割田 仁, 青木 正志, 黒澤 和大, 清水 洋, 藤原 一男

    神経治療学 36 (6) S288-S288 2019/10

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  87. 封入体筋炎の患者アンケート調査

    鈴木直輝, 森まどか, 山下賢, 木村円, 竪山真規, 井泉瑠美子, 小野洋也, 高橋俊明, 西野一三, 青木正志

    日本筋学会学術集会プログラム・抄録集 5th 191 2019/08/02

    ISSN: 2433-975X

  88. 難治性疾患に対するトランスレーショナルリサーチ

    青木 正志

    臨床神経学 59 (8) 545-545 2019/08

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  89. 18F-THK5351 PETによる進行性核上性麻痺とパーキンソン病の鑑別の検討

    菊池 昭夫, 江面 道典, 岡村 信行, 長谷川 隆文, 石木 愛子, 原田 龍一, 菅野 直人, 吉田 隼, 小林 潤平, 荒井 啓行, 谷内 一彦, 古本 祥三, 田代 学, 工藤 幸司, 武田 篤, 青木 正志

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集 13回 129-129 2019/07

    Publisher: Movement Disorder Society of Japan (MDSJ)

  90. 【指定難病ペディア2019】個別の指定難病 神経・筋系 封入体筋炎[指定難病15]

    鈴木 直輝, 青木 正志

    日本医師会雑誌 148 (特別1) S100-S101 2019/06

    Publisher: (公社)日本医師会

    ISSN: 0021-4493

  91. 神経疾患と呼吸障害 重症筋無力症と呼吸障害

    赤石哲也, 青木正志, 白石裕一, 本村政勝

    月刊脳神経内科 90 (5) 512‐519 2019/05/25

    ISSN: 2434-3285

  92. 嚥下障害と誤嚥性肺炎 各論:主な神経疾患の嚥下障害の臨床 筋萎縮性側索硬化症

    加藤昌昭, 加藤健吾, 青木正志

    Clinical Neuroscience 37 (5) 561‐564 2019/05/01

    ISSN: 0289-0585

  93. 神経病理 2 封入体筋炎は炎症か

    山下賢, 青木正志

    Annual Review 神経 2019 22‐32 2019/03/10

  94. The relevance of cerebrospinal fluid polymorphonuclear leukocytes in diagnosis of inflammatory CNS diseases

    Hiroshi Kuroda, Kimihiko Kaneko, Ryo Ogawa, Yoshiki Takai, Shuhei Nishiyama, Toshiyuki Takahashi, Tatsuro Misu, Ichiro Nakashima, Kazuo Fujihara, Masashi Aoki

    MULTIPLE SCLEROSIS JOURNAL 25 (3) 479-479 2019/03

    ISSN: 1352-4585

    eISSN: 1477-0970

  95. 運動ニューロン疾患―治療の展望 筋萎縮性側索硬化症のHGFによる治療開発

    青木正志, 割田仁, 鈴木直輝, 加藤昌昭

    月刊脳神経内科 90 (2) 146‐153 2019/02/25

    ISSN: 2434-3285

  96. Perivenous inflammatory demyelination is the prominent pathology in myelin oligodendrocyte glycoprotein antibody-associated disease

    Yoshiki Takai, Misu Tatsuro, Kaneko Kimihiko, Norio Chihara, Kouidhi Narikawa, Satoko Tsuchida, Hiroya Nishida, Takahashi Toshiyuki, Masashi Aoki, Fujihara Kazuo

    BRAIN PATHOLOGY 29 13-13 2019/02

    ISSN: 1015-6305

    eISSN: 1750-3639

  97. 脳生検により炎症性脱髄性疾患である可能性が示唆された嗜眠性脳炎の1例

    大野尭之, 高井良樹, 鈴木直輝, 菅野直人, 小野理佐子, 黒田宙, 勝木将人, 西嶌泰生, 新妻邦泰, 渡辺みか, 神林崇, 青木正志

    臨床神経学(Web) 59 (7) 2019

    ISSN: 1882-0654

  98. Clinical trial using hepatocyte growth factor for amyotrophic lateral sclerosis

    長野清一, 割田仁, 望月秀樹, 青木正志

    神経治療学(Web) 36 (4) 2019

    ISSN: 2189-7824

  99. GNEミオパチーの治療法開発

    青木 正志, 鈴木 直輝, 割田 仁, 森 まどか, 勝野 雅央, 高橋 正紀, 山下 賢, 西野 一三

    神経治療学 36 (6) S163-S163 2019

    Publisher: 日本神経治療学会

    ISSN: 0916-8443

  100. Therapeutic development of amyotrophic lateral sclerosis based on rodent model

    鈴木直輝, 青木正志

    神経治療学(Web) 35 (4) 488‐493(J‐STAGE) 2019

    DOI: 10.15082/jsnt.35.4_488  

    ISSN: 2189-7824

  101. Amyotrophic Lateral Sclerosis

    青木正志

    Progress in Medicine 38 (12) 1319‐1324 2018/12/10

    ISSN: 0287-3648

  102. 大脳皮質基底核症候群における18F-THK5351 PETの経時的変化

    菊池 昭夫, 江面 道典, 岡村 信行, 長谷川 隆文, 石木 愛子, 原田 龍一, 菅野 直人, 吉田 隼, 小林 潤平, 荒井 啓行, 谷内 一彦, 古本 祥三, 田代 学, 工藤 幸司, 武田 篤, 青木 正志

    臨床神経学 58 (Suppl.) S212-S212 2018/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  103. 日本人dysferlin遺伝子解析で見出された全バリアントの検討

    高橋 俊明, 鈴木 直輝, 井泉 瑠美子, 八木沼 智香子, 小野 洋也, 倉島 奈緒子, 大城 咲, 谷口 さやか, 下瀬川 康子, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 武田 篤, 青木 洋子, 青木 正志

    国立病院総合医学会講演抄録集 72回 737-737 2018/11

    Publisher: 国立病院総合医学会

  104. ミオパチー―最近の話題―GNEミオパチーに対するシアル酸療法

    井泉瑠美子, 鈴木直輝, 青木正志

    月刊神経内科 89 (5) 481‐488 2018/11

    ISSN: 0386-9709

  105. 辺縁系脳炎患者の病因による頭部MRI異常部位の差異

    黒田宙, 藤原一男, 青木正志

    Neuroinfection 23 (2) 212 2018/10/10

    ISSN: 1348-2718

  106. 辺縁系脳炎患者の病因による頭部MRI異常部位の差異

    黒田 宙, 藤原 一男, 青木 正志

    NEUROINFECTION 23 (2) 212-212 2018/10

    Publisher: 日本神経感染症学会

    ISSN: 1348-2718

  107. 【神経疾患治療の進歩 2017】運動ニューロン疾患の治療の進歩

    秋山 徹也, 鈴木 直輝, 割田 仁, 青木 正志

    神経治療学 35 (5) 609-613 2018/09

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  108. 日本人に見出されたdysferlin遺伝子のコード上ストップコドンの出現しないSNPsの病的意義の検討

    高橋俊明, 鈴木直輝, 井泉瑠美子, 八木沼智香子, 小野洋也, 島倉奈緒子, 大城咲, 谷口さやか, 下瀬川康子, 馬場徹, 大泉英樹, 田中洋康, 吉岡勝, 武田篤, 青木正志

    日本筋学会学術集会プログラム・抄録集 4th 190-190 2018/08/01

    Publisher: 日本筋学会

    ISSN: 2433-975X

  109. α-synucleinは核においていくつかのエピジェネティクス調節複合体と相互作用する(Alpha-synuclein interacts with some epigenetic complex in nucleus)

    菅野 直人, 長谷川 隆文, 小林 潤平, 吉田 隼, 江面 道典, 菊池 昭夫, 武田 篤, 青木 正志

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集 12回 102-102 2018/07

    Publisher: Movement Disorder Society of Japan (MDSJ)

  110. 筋萎縮性側索硬化症(ALS)の創薬の展望 (特集 神経難病と創薬)

    青木 正志

    医薬ジャーナル 54 (7) 89-97 2018/07

    Publisher: 医薬ジャーナル社

    ISSN: 0287-4741

  111. 運動ニューロン疾患 治療の展望 齧歯類モデルを基盤とした筋萎縮性側索硬化症の治療開発

    鈴木 直輝, 青木 正志

    神経治療学 35 (4) 488-493 2018/07

    Publisher: (一社)日本神経治療学会

    ISSN: 0916-8443

    eISSN: 2189-7824

  112. 【神経難病と創薬】 筋萎縮性側索硬化症(ALS)の創薬の展望

    青木 正志

    医薬ジャーナル 54 (7) 1631-1639 2018/07

    Publisher: (株)医薬ジャーナル社

    ISSN: 0287-4741

  113. 各種難病の最新治療情報 縁取り空胞を伴う遠位型(GNE)ミオパチーに対するシアル酸治療の開発

    鈴木 直輝, 青木 正志

    難病と在宅ケア 24 (1) 28-30 2018/04

    Publisher: 日本プランニングセンター

    ISSN: 1880-9200

  114. 縁取り空胞を伴う遠位型(GNE)ミオパチーに対するシアル酸治療の開発

    鈴木直輝, 青木正志

    月刊難病と在宅ケア 24 (1) 28‐30 2018/04/01

    ISSN: 1880-9200

  115. Discrimination of Spinal Cord Sarcoidosis from Neuromyelitis Optica Spectrum Disorer or Spondylotic Myelopathy

    Hiroshi Kuroda, Toshiyuki Takahashi, Douglas Kazutoshi Sato, Ryo Ogawa, Kimihiko Kaneko, Yoshiki Takai, Shuhei Nishiyama, Tatsuro Misu, Ichiro Nakashima, Kazuo Fujihara, Masashi Aoki

    MULTIPLE SCLEROSIS JOURNAL 24 (3) 380-380 2018/03

    ISSN: 1352-4585

    eISSN: 1477-0970

  116. Cerebrospilnal Fluid-Actin Related Protein 2/3 Complex Subunit 4 as an Astrocytic Foot Process Damage Marker of Aquaporin-4-Igg Positive Neuromyelitis Optica Spectrum Disorders

    Shuhei Nishiyama, Tatsuro Misu, Ichiro Nakashima, Douglas Kazutoshi Sato, Kimihiko Kaneko, Ryo Ogawa, Hirohiko Ono, Kazuhiro Kurosawa, Yoshiki Takai, Toshiyuki Takahashi, Hiroshi Kuroda, Kazuo Fujihara, Masashi Aoki

    MULTIPLE SCLEROSIS JOURNAL 24 (3) 380-380 2018/03

    ISSN: 1352-4585

    eISSN: 1477-0970

  117. Fingolimod-Associated PML with Mild Immune Reconstitution Inflammatory Syndrome in Multiple Sclerosis

    Shuhei Nishiyama, Tatsuro Misu, Yukiko Shishido-Hara, Kazuo Nakamichi, Masayuki Saijo, Yoshiki Takai, Kentarou Takei, Naoki Yamamoto, Hiroshi Kuroda, Ryuta Saito, Mika Watanabe, Teiji Tominaga, Ichiro Nakashima, Kazuo Fujihara, Masashi Aoki

    MULTIPLE SCLEROSIS JOURNAL 24 (3) 381-382 2018/03

    ISSN: 1352-4585

    eISSN: 1477-0970

  118. 神経疾患の再生医療 iPS細胞による再生医療研究 ALS(筋萎縮性側索硬化症)

    割田仁, 割田仁, 青木正志, 青木正志

    Clinical Neuroscience 36 (3) 320‐324 2018/03/01

    ISSN: 0289-0585

  119. ガイドライン作成に向けた筋強直性ジストロフィーの患者・医療者対象診療実態調査

    高橋正紀, 高田博仁, 久留聡, 木村円, 小牧宏文, 尾方克久, 齊藤利雄, 石崎雅俊, 中村昭則, 青木正志, 石垣景子, 松浦徹, 砂田芳秀, 松村剛

    筋ジストロフィーの標準的医療普及のための調査研究 平成29年度 総括・分担研究報告書(Web) 2018

  120. 【難病研究up-to-date 臨床病態解析と新たな診断・治療法開発をめざして】 (第4章)難病の治療法 タンパク質・酵素補充療法 筋萎縮性側索硬化症(ALS)に対するHGF

    青木 正志

    遺伝子医学MOOK (32) 161-167 2017/12

    Publisher: (株)メディカルドゥ

    ISSN: 1349-2527

  121. 視神経脊髄炎関連疾患に対する経口ステロイド維持療法の最適化

    高井 良樹, 中島 一郎, 三須 建郎, 黒田 宙, 西山 修平, 高橋 利幸, 藤原 一男, 青木 正志

    神経治療学 34 (6) S221-S221 2017/11

    Publisher: 日本神経治療学会

    ISSN: 0916-8443

  122. Prognosis of japanese patients with amyotrophic lateral sclerosis according to motor phenotype

    Atsuta N, Yokoi D, Nakamura R, Watanabe H, Hayashi N, Ito M, Watanabe H, Katsuno M, Izumi Y, Morita M, Taniguchi A, Oda M, Abe K, Mizoguchi K, Kano O, Kuwabara S, Aoki M, Hattori N, Kaji R, Sobue G

    JOURNAL OF THE NEUROLOGICAL SCIENCES 381 103-103 2017/10/15

    DOI: 10.1016/j.jns.2017.08.330  

    ISSN: 0022-510X

  123. Clinical, MRI and laboratory features of myelin oligodendrocyte glycoprotein (MOG)-antibody-associated neurologic disease: a study of 259 cases

    K. Kaneko, D. K. Sato, T. Takahashi, R. Ogawa, T. Akaishi, Y. Takai, S. Nishiyama, T. Misu, H. Kuroda, I. Nakashima, K. Fujihara, M. Aoki

    MULTIPLE SCLEROSIS JOURNAL 23 100-100 2017/10

    ISSN: 1352-4585

    eISSN: 1477-0970

  124. Cerebrospilnal fluid-Actin related protein 2/3 complex subunit 4 as an astrocytic foot process damage marker of aquaporin-4-IgG positive neuromyelitis optica spectrum disorders

    S. Nishiyama, T. Misu, I. Nakashima, D. K. Sato, K. Kaneko, R. Ogawa, Y. Takai, T. Toshiyuki, H. Kuroda, K. Fujihara, M. Aoki

    MULTIPLE SCLEROSIS JOURNAL 23 585-585 2017/10

    ISSN: 1352-4585

    eISSN: 1477-0970

  125. Autoimmune encephalitis in patients with anti-myelin oligodendrocyte glycoprotein-antibody

    R. Ogawa, I. Nakashima, T. Takahashi, K. Kaneko, T. Akaishi, Y. Takai, D. K. Sato, S. Nishiyama, J. Fujimori, T. Misu, H. Kuroda, T. Ikeda, A. Uchibori, T. Ohashi, K. Fujihara, M. Aoki

    MULTIPLE SCLEROSIS JOURNAL 23 439-440 2017/10

    ISSN: 1352-4585

    eISSN: 1477-0970

  126. 細胞外α-シヌクレインはドパミントーンを調節してDATエンドサイトーシスを乗っ取り細胞内へ侵入する(Extracellular α-synuclein regulates dopamine tone and gets into cell by hijacking DAT endocytosis)

    小林 潤平, 長谷川 隆文, 菅野 直人, 吉田 隼, 江面 道典, 菊池 昭夫, 武田 篤, 青木 正志

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集 11回 68-68 2017/10

    Publisher: Movement Disorder Society of Japan (MDSJ)

  127. 18F-THK5351 PETによるタウオパチーでの鑑別診断の検討

    江面 道典, 菊池 昭夫, 岡村 信行, 長谷川 隆文, 石木 愛子, 原田 龍一, 荒井 啓行, 谷内 一彦, 古本 祥三, 田代 学, 工藤 幸司, 武田 篤, 青木 正志

    パーキンソン病・運動障害疾患コングレスプログラム・抄録集 11回 89-89 2017/10

    Publisher: Movement Disorder Society of Japan (MDSJ)

  128. 抗MOG抗体陽性脱髄疾患の調査報告 国内259例の抗MOG抗体陽性例の臨床的特徴

    金子 仁彦, 佐藤 ダグラス, 高橋 利幸, 赤石 哲也, 小川 諒, 高井 良樹, 西山 修平, 三須 建郎, 中島 一郎, 藤原 一男, 青木 正志

    神経免疫学 22 (1) 87-87 2017/10

    Publisher: 日本神経免疫学会

    ISSN: 0918-936X

  129. Discrimination of spinal cord sarcoidosis from neuromyelitis optica spectrum disorder or spondylotic myelopathy

    H. Kuroda, T. Takahashi, D. Sato, Y. Takai, S. Nishiyama, T. Misu, I. Nakashima, K. Fujihara, M. Aoki

    EUROPEAN JOURNAL OF NEUROLOGY 24 113-113 2017/07

    ISSN: 1351-5101

    eISSN: 1468-1331

  130. 神経内科専門医育成の現状についてのアンケートの解析結果

    園生 雅弘, 西山 和利, 安藤 哲朗, 進藤 克郎, 神田 隆, 青木 正志, 亀井 聡, 菊地 誠志, 楠 進, 鈴木 則宏, 祖父江 元, 中島 健二, 原 英夫, 平田 幸一, 水澤 英洋, 村井 弘之, 村田 美穂, 望月 秀樹, 高橋 良輔, 吉良 潤一

    臨床神経学 57 (7) 402-410 2017/07

    Publisher: (一社)日本神経学会

    DOI: 10.5692/clinicalneurol.cn-001061  

    ISSN: 0009-918X

  131. Mutant DNAJC13 modulates accumulation and toxicity of alpha-synuclein through altered endosomal trafficking in cell and fly models of Parkinson's disease

    T. Hasegawa, S. Yoshida, M. Suzuki, J. Kobayashi, N. Sugeno, K. Sekiguchi, M. Edura, A. Kikuchi, A. Takeda, Y. Nagai, M. Aoki

    MOVEMENT DISORDERS 32 2017/06

    ISSN: 0885-3185

    eISSN: 1531-8257

  132. Extracellular alpha-synuclein internalizes into cells by hijacking endocytic trafficking of dopamine transporter

    J. Kobayashi, T. Hasegawa, N. Sugeno, S. Yoshida, A. Kikuchi, A. Takeda, M. Aoki

    MOVEMENT DISORDERS 32 2017/06

    ISSN: 0885-3185

    eISSN: 1531-8257

  133. Hypoxic response in skeletal muscle contributes to the adaptation of muscle fibers in mice

    Aki Nunomiya, Junchul Shin, Yasuo Kitajima, Takashi Dan, Toshio Miyata, Naoki Suzuki, Masashi Aoki, Ryoichi Nagatomi

    FASEB JOURNAL 31 2017/04

    ISSN: 0892-6638

    eISSN: 1530-6860

  134. The detection of the proteasomal proteolysis efficiency in C2C12 myoblast Peer-reviewed

    Shion Osana, Naoki Suzuki, Masashi Aoki, Ryoichi Nagatomi

    FASEB JOURNAL 31 (1) 2017/04

    ISSN: 0892-6638

    eISSN: 1530-6860

  135. 筋肉研究の最前線 縁取り空胞を伴う遠位型(GNE)ミオパチーの治療開発

    鈴木直輝, 井泉瑠美子, 加藤昌昭, 割田仁, 青木正志

    Clinical Calcium 27 (3) 429‐434 2017/02/28

    ISSN: 0917-5857

  136. Cytokine/Chemokine Profile in MOG-Ab plus Disorder

    K. Kaneko, D. K. Sato, R. Ogawa, T. Akaishi, Y. Takai, S. Nishiyama, T. Takahashi, T. Misu, H. Kuroda, S. Tanaka, Nakashima, I, K. Nomura, K. Fujihara, M. Aoki

    MULTIPLE SCLEROSIS JOURNAL 23 (2) 318-318 2017/02

    ISSN: 1352-4585

    eISSN: 1477-0970

  137. Hypoxia-like Tissue Injury and Glial Response Contribute to the Development of Balo's Concentric Demyelination

    Y. Takai, T. Misu, S. Nishiyama, H. Ono, H. Kuroda, I. Nakashima, R. Saito, M. Kanamori, S. Mugikura, M. Watanabe, M. Aoki, K. Fujihara

    MULTIPLE SCLEROSIS JOURNAL 23 (2) 349-350 2017/02

    ISSN: 1352-4585

    eISSN: 1477-0970

  138. 上部消化管内視鏡検査後に脳塞栓を発症した一例

    池之内初, 菅野直人, 中村貴彬, 大嶋龍司, 小林潤平, 黒田宙, 青木正志

    臨床神経学(Web) 57 (6) 2017

    ISSN: 1882-0654

  139. 多核球優位の細胞増多を呈し,神経ベーチェット病との鑑別を要した悪性リンパ腫の一例

    中村貴彬, 高井良樹, 黒田宙, 三須建郎, 青木正志

    臨床神経学(Web) 57 (6) 2017

    ISSN: 1882-0654

  140. プリオン病のサーベイランスと感染予防に関する調査研究 サーベイランスデータに基づくわが国のプリオン病の疫学像(1999‐2016年データ)

    水澤英洋, 中村好一, 山田正仁, 齊藤延人, 北本哲之, 金谷泰宏, 村山繁雄, 佐藤克也, 原田雅史, 太組一朗, 佐々木秀直, 青木正志, 小野寺理, 田中章景, 犬塚貴, 望月秀樹, 阿部康二, 村井弘之, 古賀雄一, 黒岩義之, 桑田一夫, 三條伸夫, 塚本忠

    プリオン病のサーベイランスと感染予防に関する調査研究 平成28年度 総括・分担研究報告書(Web) 25‐40 (WEB ONLY) 2017

  141. プリオン病及び遅発性ウイルス感染症に関する調査研究 プリオン病のサーベイランス,感染予防,および臨床研究コンソーシアムJACOPの推進

    水澤英洋, 塚本忠, 三條伸夫, 森若文雄, 佐々木秀直, 青木正志, 西澤正豊, 小野寺理, 田中章景, 犬塚貴, 武田雅俊, 望月秀樹, 阿部康二, 村井弘之, 佐藤克也, 北本哲之, 中村好一, 村山繁雄, 黒岩義之, 原田雅史, 齊藤延人, 太組一朗, 金谷泰宏, 田村智英子, 山田正仁

    プリオン病及び遅発性ウイルス感染症に関する調査研究 平成26-28年度 総合研究報告書(Web) 72‐77 (WEB ONLY) 2017

  142. プリオン病及び遅発性ウイルス感染症に関する調査研究 プリオン病のサーベイランスと感染予防に関する調査研究:JACOP自然歴調査との統合によるサーベイランスの発展

    水澤英洋, 塚本忠, 三條伸夫, 佐々木秀直, 青木正志, 小野寺理, 田中章景, 犬塚貴, 望月秀樹, 阿部康二, 村井弘之, 佐藤克也, 北本哲之, 中村好一, 村山繁雄, 黒岩義之, 原田雅史, 齊藤延人, 太組一朗, 金谷泰宏, 田村智英子, 山田正仁, 桑田一夫

    プリオン病及び遅発性ウイルス感染症に関する調査研究 平成28年度 総括・分担研究報告書(Web) 15‐17 (WEB ONLY) 2017

  143. 多系統プロテイノパチー連鎖性hnRNPA1変異に起因する孤立性封入体ミオパチー(Isolated inclusion body myopathy caused by a multisystem proteinopathy-linked hnRNPA1 mutation)

    井泉 瑠美子, 割田 仁, 新堀 哲也, 高橋 俊明, 竪山 真規, 鈴木 直輝, 西山 亜由美, 城田 松之, 舟山 亮, 中山 啓子, 三橋 里美, 西野 一三, 青木 洋子, 青木 正志

    臨床神経学 56 (Suppl.) S280-S280 2016/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  144. Research for the pathogenesis and therapy of dysferlinopathy using proteomics approach

    H. Ono, N. Suzuki, S. Kanno, K. Miyake, Y. Kitajima, R. Izumi, T. Takahashi, H. Warita, A. Yasui, M. Aoki

    NEUROMUSCULAR DISORDERS 26 S151-S152 2016/10

    DOI: 10.1016/j.nmd.2016.06.240  

    ISSN: 0960-8966

    eISSN: 1873-2364

  145. 医学と医療の最前線 筋萎縮性側索硬化症の治療開発の現状

    青木 正志

    日本内科学会雑誌 105 (10) 2055-2062 2016/10

    Publisher: (一社)日本内科学会

    DOI: 10.2169/naika.105.2055  

    ISSN: 0021-5384

  146. Clinical and radiological characteristics of optic neuritis in demyelinating disorder with serum anti-MOG antibody

    I. Nakashima, T. Akaishi, T. Takeshita, D. K. Sato, K. Kaneko, T. Nakazawa, M. Aoki, K. Fujihara

    MULTIPLE SCLEROSIS JOURNAL 22 151-151 2016/09

    ISSN: 1352-4585

    eISSN: 1477-0970

  147. Elevated cerebrospinal fluid-CRMP5 as a biomarker of damage to astrocyte foot process and growth corn in AQP4-IgG-seropositve NMOSD

    S. Nishiyama, T. Misu, I. Nakashima, T. Takahashi, K. Fujihara, M. Aoki

    MULTIPLE SCLEROSIS JOURNAL 22 579-580 2016/09

    ISSN: 1352-4585

    eISSN: 1477-0970

  148. Temporal changes of pathological features in NMO spectrum disorders with aquaporin4 antibody

    Y. Takai, T. Misu, I. Nakashima, H. Kuroda, T. Takahashi, S. Nishiyama, K. Kaneko, T. Akaishi, R. Ogawa, K. Fujihara, M. Aoki

    MULTIPLE SCLEROSIS JOURNAL 22 156-157 2016/09

    ISSN: 1352-4585

    eISSN: 1477-0970

  149. Pro-inflammatory cytokine elevation in MOG-Ab+, AQP4-Ab+ disorder and MS

    K. Kaneko, D. K. Sato, R. Ogawa, T. Akaishi, Y. Takai, S. Nishiyama, T. Takahashi, T. Misu, H. Kuroda, S. Tanaka, I. Nakashima, K. Nomura, D. Callegaro, K. Fujihara, M. Aoki

    MULTIPLE SCLEROSIS JOURNAL 22 155-156 2016/09

    ISSN: 1352-4585

    eISSN: 1477-0970

  150. Adult MOG-IgG-positive, benign, unilateral, cerebral cortical encephalitis with epileptic seizure

    R. Ogawa, I. Nakashima, T. Takahashi, H. Ono, K. Kaneko, T. Akaishi, K. Kurosawa, Y. Takai, D. K. Sato, S. Nishiyama, T. Misu, K. Fujihara, M. Aoki

    MULTIPLE SCLEROSIS JOURNAL 22 711-711 2016/09

    ISSN: 1352-4585

    eISSN: 1477-0970

  151. Severely exacerbated neuromyelitis optica rat model with extensive tissue damage including astrocytopathy and axonal damage by high affinity anti-aquaporin-4 monoclonal antibody

    K. Kurosawa, T. Misu, Y. Takai, D. K. Sato, T. Takahashi, Y. Abe, H. Iwanari, R. Ogawa, I. Nakashima, K. Fujihara, T. Hamakubo, M. Yasui, M. Aoki

    MULTIPLE SCLEROSIS JOURNAL 22 160-161 2016/09

    ISSN: 1352-4585

    eISSN: 1477-0970

  152. けいれんを伴う成人の抗MOG抗体陽性、良性、片側性、大脳皮質性脳炎

    小川 諒, 中島 一郎, 高橋 利幸, 金子 仁彦, 高井 良樹, 佐藤 ダグラス, 三須 建郎, 黒田 宙, 藤原 一男, 青木 正志

    神経免疫学 21 (1) 106-106 2016/09

    Publisher: 日本神経免疫学会

    ISSN: 0918-936X

  153. 【認知症・神経変性疾患の克服への挑戦】 新たな技術開発によるチャレンジ HGFによる筋萎縮性側索硬化症(ALS)に対する治療法の開発

    青木 正志, 割田 仁, 鈴木 直輝, 加藤 昌昭

    生体の科学 67 (4) 344-348 2016/08

    Publisher: (公財)金原一郎記念医学医療振興財団

    DOI: 10.11477/mf.2425200466  

    ISSN: 0370-9531

  154. 【神経疾患治療の進歩2015年】 運動ニューロン疾患の治療の進歩

    鈴木 直輝, 加藤 昌昭, 割田 仁, 青木 正志

    神経治療学 33 (4) 529-532 2016/07

    Publisher: 日本神経治療学会

    ISSN: 0916-8443

  155. Parkinson's disease-linked mutation in DNAJC13 causes specific trafficking defect in endosomal pathway

    S. Yoshida, T. Hasegawa, R. Oshima, J. Kobayashi, N. Sugeno, A. Kikuchi, A. Takeda, M. Aoki

    MOVEMENT DISORDERS 31 S404-S404 2016/06

    ISSN: 0885-3185

    eISSN: 1531-8257

  156. Forebrain-specific knockout of ESCRT-0/Hrs disrupts protein quality control and facilitates ER stress-mediated neurodegeneration via apoptotic and necroptotic pathways

    Ryuji Oshima, Takafumi Hasegawa, Keiichi Tamai, Atsushi Takeda, Nobuyuki Tanaka, Masashi Aoki

    MOVEMENT DISORDERS 31 S60-S60 2016/03

    ISSN: 0885-3185

    eISSN: 1531-8257

  157. Prolonged exercise testにより診断した低カリウム性周期性四肢麻痺の一例

    武井健太郎, 小野理佐子, 中村貴彬, 西山修平, 黒田宙, 長谷川隆文, 青木正志

    臨床神経学(Web) 56 (11) 2016

    ISSN: 1882-0654

  158. A Case Of Pulmonary Interstitial Lesions Developed In The Early-Stage Of Neuromyelitis Optica Spectrum Disorder

    Y. Asato, T. Kamitani, M. Kuramochi, K. Nakanishi, T. Shimada, T. Misu, T. Takahashi, M. Aoki, K. Fujihara, Y. Kawabata

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 193 2016

    ISSN: 1073-449X

    eISSN: 1535-4970

  159. HGFを用いた筋萎縮性側索硬化症に対する治療法の開発

    青木 正志

    臨床評価 43 (2) 426-428 2016/01

    Publisher: (株)臨床評価刊行会

    ISSN: 0300-3051

  160. 縁取り空胞を伴う遠位型ミオパチーにおけるN-アセチルノイラミン酸の補充療法

    青木 正志

    臨床評価 43 (2) 444-447 2016/01

    Publisher: (株)臨床評価刊行会

    ISSN: 0300-3051

  161. 遺伝性ニューロパチーの最近の進歩 家族性運動ニューロン病と遺伝性ニューロパチーの類似点・相違点

    青木 正志

    末梢神経 26 (2) 167-170 2015/12

    Publisher: 日本末梢神経学会

    ISSN: 0917-6772

  162. 【アカデミア発の創薬・研究治療】 ALSに対するHGF療法

    青木 正志, 割田 仁, 鈴木 直輝

    神経内科 83 (4) 277-282 2015/10

    Publisher: (有)科学評論社

    ISSN: 0386-9709

  163. 【免疫性神経疾患-病態解明と治療の最前線】 筋炎 封入体筋炎

    青木 正志, 鈴木 直輝

    医学のあゆみ 255 (5) 473-478 2015/10

    Publisher: 医歯薬出版(株)

    ISSN: 0039-2359

  164. Cerebrospinal fluid lactic dehydrogenation enzyme levels in acute attacks of inflammatory demyelinating diseases

    S. Nishiyama, T. Misu, Y. Takai, R. Takano, T. Takahashi, I. Nakashima, K. Fujihara, M. Aoki

    MULTIPLE SCLEROSIS JOURNAL 21 352-352 2015/09

    ISSN: 1352-4585

    eISSN: 1477-0970

  165. Astrocyte injury and secondary demyelination induced by intracerebral injection of AQP4-IgG and complement in mouse brain

    Y. Takai, T. Misu, Y. Abe, K. Kurosawa, T. Takahashi, H. Kuroda, I. Nakashima, S. Nishiyama, D. Sato, M. Yasui, K. Fujihara, M. Aoki

    MULTIPLE SCLEROSIS JOURNAL 21 426-426 2015/09

    ISSN: 1352-4585

    eISSN: 1477-0970

  166. Astrocyte and myelin injury in neuroinflammatory disorders with myelin oligodendrocyte glycoprotein or aquaporin-4 antibody positive cerebrospinal fluid

    K. Kaneko, D. K. Sato, I. Nakashima, S. Nishiyama, S. Tanaka, R. Marignier, J. W. Hyun, H. J. Kim, L. M. Oliveira, D. Callegaro, M. Reindl, T. Berger, T. Seifert-Held, A. Saiz, M. Sepulveda, S. Siritho, N. Prayoonwiwat, P. J. Waters, K. Kurosawa, T. Akaishi, H. Kuroda, T. Misu, K. Nomura, K. Fujihara, M. Aoki

    MULTIPLE SCLEROSIS JOURNAL 21 134-135 2015/09

    ISSN: 1352-4585

    eISSN: 1477-0970

  167. Clinical phenotypes of pediatric and adult patients with anti-MOG antibodies

    D. K. Sato, K. Kaneko, I. Nakashima, S. Tanaka, N. Fukuyo, L. M. Oliveira, L. Pandit, S. Siritho, P. J. Waters, T. Takahashi, H. Kuroda, S. Nishiyama, T. Akaishi, K. Kurosawa, T. Misu, N. Prayoonwiwat, K. Nomura, D. Callegaro, K. Fujihara, M. Aoki

    MULTIPLE SCLEROSIS JOURNAL 21 87-88 2015/09

    ISSN: 1352-4585

    eISSN: 1477-0970

  168. 【ALSとパーキンソン病-最近の進歩-】 ALSに対するHGF治験

    青木 正志

    BIO Clinica 30 (8) 742-746 2015/08

    Publisher: (株)北隆館

    ISSN: 0919-8237

  169. 【神経疾患治療の進歩2014年】 運動ニューロン疾患の治療の進歩

    鈴木 直輝, 加藤 昌昭, 割田 仁, 青木 正志

    神経治療学 32 (4) 475-478 2015/07

    Publisher: 日本神経治療学会

    ISSN: 0916-8443

  170. CSF derived exosomal microRNA profile in patients with Parkinson's disease

    T. Hasegawa, N. Sugeno, A. Kikuchi, R. Oshima, S. Yoshida, A. Takeda, M. Aoki

    MOVEMENT DISORDERS 30 S404-S404 2015/06

    ISSN: 0885-3185

    eISSN: 1531-8257

  171. Predictive risk factors for delayed neurologic sequelae after carbon monoxide poisoning

    H. Kuroda, K. Fujihara, S. Kushimoto, M. Aoki

    EUROPEAN JOURNAL OF NEUROLOGY 22 384-384 2015/06

    ISSN: 1351-5101

    eISSN: 1468-1331

  172. Parkinson's disease-linked mutation in DNAJC13 causes specific trafficking defect in endosomal pathway

    S. Yoshida, T. Hasegawa, E. Miura, R. Oshima, N. Sugeno, A. Kikuchi, A. Takeda, M. Aoki

    MOVEMENT DISORDERS 30 S53-S53 2015/06

    ISSN: 0885-3185

    eISSN: 1531-8257

  173. 【再生医療-新たな医療を求めて-】 再生医療の臨床研究・治験 HGFタンパク質による筋萎縮性側索硬化症の治療

    青木 正志

    日本臨床 73 (増刊5 再生医療) 523-528 2015/06

    Publisher: (株)日本臨床社

    ISSN: 0047-1852

  174. Cerebrospinal Fluid Aquaporin-4 Antibody Levels in Neuromyelitis Optica Attacks

    D. K. Sato, D. Callegaro, F. M. H. Jorge, I. Nakashima, S. Nishiyama, T. Takahashi, R. F. Simm, S. L. Apostolos-Pereira, T. Misu, L. Steinman, M. Aoki, K. Fujihara

    MULTIPLE SCLEROSIS JOURNAL 21 (6) 827-827 2015/05

    ISSN: 1352-4585

    eISSN: 1477-0970

  175. Autoantibodies against MOG in Neuromyelitis Optica Spectrum Disorders

    D. K. Sato, D. Callegaro, M. A. Lana-Peixoto, P. J. Waters, S. Tanaka, F. Jorge, T. Takahashi, T. Misu, S. L. Apostolos-Pereira, N. Talim, R. F. Simm, A. M. M. Lino, I. Nakashima, K. Nomura, M. Aoki, K. Fujihara

    MULTIPLE SCLEROSIS JOURNAL 21 (6) 804-805 2015/05

    ISSN: 1352-4585

    eISSN: 1477-0970

  176. Anti-NMDAR plus /anti-MOG plus recurrent ADEM

    K. Kaneko, D. K. Sato, T. Misu, K. Kurosawa, I. Nakashima, K. Fujihara, M. Aoki

    MULTIPLE SCLEROSIS JOURNAL 21 (6) 836-836 2015/05

    ISSN: 1352-4585

    eISSN: 1477-0970

  177. The Lesion Localization of Passive Transfer NMO-IgG Model in Lewis Rats

    K. Kurosawa, T. Misu, T. Takahashi, D. Sato, S. Nishiyama, H. Kuroda, I. Nakashima, K. Fujihara, M. Aoki

    MULTIPLE SCLEROSIS JOURNAL 21 (6) 830-830 2015/05

    ISSN: 1352-4585

    eISSN: 1477-0970

  178. 【骨格筋症候群(第2版)-その他の神経筋疾患を含めて-】[上] 筋ジストロフィーおよび膜イオンチャネル異常症 肢帯型筋ジストロフィー 常染色体劣性型LGMD LGMD2B(dysferlin欠損)

    高橋 俊明, 青木 正志

    日本臨床 別冊 (骨格筋症候群(上)) 111-114 2015/05

    Publisher: (株)日本臨床社

    ISSN: 0047-1852

  179. 【骨格筋症候群(第2版)-その他の神経筋疾患を含めて-】[上] 炎症性筋疾患 非感染性筋炎 多発筋炎・皮膚筋炎・封入体筋炎 封入体筋炎

    鈴木 直輝, 青木 正志

    日本臨床 別冊 (骨格筋症候群(上)) 324-328 2015/05

    Publisher: (株)日本臨床社

    ISSN: 0047-1852

  180. 【筋萎縮性側索硬化症(ALS)の分子遺伝学update】 ALSの分子遺伝学 オーバービュー

    青木 正志

    神経内科 82 (4) 343-348 2015/04

    Publisher: (有)科学評論社

    ISSN: 0386-9709

  181. 【臨床医学の展望-30領域のトピックス】 神経病学

    青木 正志

    日本医事新報 (4740) 65-68 2015/02

    Publisher: (株)日本医事新報社

    ISSN: 0385-9215

  182. Lennox-Gastaut症候群を呈した視床下部過誤腫の一例

    渡辺靖章, 神一敬, 高橋健太, 柿坂庸介, 北澤悠, 藤川真由, 中里信和, 加藤量広, 青木正志, 岩崎真樹

    臨床神経学(Web) 55 (7) 2015

    ISSN: 1882-0654

  183. Clinical characteristics of four patients with temporal lobe epilepsy associated with elevated anti-GAD antibodies

    赤石哲也, 赤石哲也, 神一敬, 加藤量広, 加藤量広, 板橋尚, 三須建郎, 竪山真規, 岩崎真樹, 青木正志, 中里信和

    臨床神経学(Web) 55 (11) 2015

    ISSN: 1882-0654

  184. 疾患由来iPS細胞を用いた家族性筋萎縮性側索硬化症の病態解析

    一柳直希, 藤崎央子, 矢野真人, 岡田洋平, 赤松和土, 赤松和土, 割田仁, 青木正志, 岡野栄之

    再生医療 14 2015

    ISSN: 1347-7919

  185. 初発時と異なり,精神症状のみで再発した抗NMDAR脳炎の一例

    川口典彦, 石垣あや, 小林理子, 藤盛寿一, 吉澤亮, 伊藤文晃, 金子仁彦, 佐藤ダグラス, 中島一郎, 藤原一男, 青木正志, 田中惠子

    臨床神経学(Web) 55 (7) 2015

    ISSN: 1882-0654

  186. 複数の発作周辺期精神症状を含む多彩な発作症状を呈した部分てんかんの1例

    江面 道典, 柿坂 庸介, 神 一敬, 加藤 量広, 岩崎 真樹, 藤川 真由, 青木 正志, 中里 信和

    BRAIN and NERVE: 神経研究の進歩 67 (1) 105-109 2015/01

    Publisher: (株)医学書院

    ISSN: 1881-6096

    eISSN: 1344-8129

  187. Case of autoantibodies against N-methyl-D-aspartate receptor+/antibodies against myelin-oligodendrocyte glycoprotein+ multiphasic acute disseminated encephalomyelitis (ADEM)

    Kimihiko Kaneko, Douglas Kazutoshi Sato, Kazuhiro Kurosawa, Tatsuro Misu, Ichiro Nakashima, Kazuo Fujihara, Masashi Aoki

    Clinical and Experimental Neuroimmunology 5 (1) 49-51 2014/12/01

    Publisher: Wiley-Blackwell

    DOI: 10.1111/cen3.12164  

    ISSN: 1759-1961

  188. パーキンソン病における脳内α-シヌクレイン蛋白凝集体のPETによる画像化

    菊池 昭夫, 馬場 徹, 長谷川 隆文, 菅野 直人, 今野 昌俊, 三浦 永美子, 大嶋 龍司, 岡村 信行, 古本 祥三, 谷内 一彦, 田代 学, 工藤 幸司, 糸山 泰人, 武田 篤, 青木 正志

    臨床神経学 54 (Suppl.) S51-S51 2014/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  189. 【神経変性疾患・神経免疫疾患-診断と治療の最前線-】 運動ニューロン病

    青木 正志

    BIO Clinica 29 (13) 1269-1273 2014/12

    Publisher: (株)北隆館

    ISSN: 0919-8237

  190. Functional ESCRT machinery is required for the clearance of aggregate-prone proteins associated with neurodegenerative diseases

    Ryuji Oshima, Takafumi Hasegawa, Keiichi Tamai, Emiko Miura, Akio Kikuchi, Nobuyuki Tanaka, Atsushi Takeda, Masashi Aoki

    MOVEMENT DISORDERS 29 S62-S62 2014/11

    ISSN: 0885-3185

    eISSN: 1531-8257

  191. ステロイド反応性の再発性多発神経障害をきたし、馬尾生検で確診にいたったDLBCLの1例

    江面 道典, 西山 修平, 小野 紘彦, 向井 由幸, 竪山 真規, 黒田 宙, 青木 正志, 遠藤 俊毅

    臨床神経学 54 (11) 925-925 2014/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

  192. Dysferlinopathy in Egypt: Clinical, Pathological and Genetic characteristics

    N. A. Fahmy, A. Abd Elhady, A. Abd El-Naser, S. Ashour, A. Etribi, I. Nonaka, N. Minami, N. Suzuki, T. Takahashi, M. Aoki

    NEUROMUSCULAR DISORDERS 24 (9-10) 903-904 2014/10

    DOI: 10.1016/j.nmd.2014.06.364  

    ISSN: 0960-8966

    eISSN: 1873-2364

  193. Clinical features of sarcoid myelopathy focusing on age, distribution, and concomitant spinal disease

    Hiroshi Kuroda, Kazuo Fujihara, Yasuto Itoyama, Masashi Aoki

    JOURNAL OF NEUROIMMUNOLOGY 275 (1-2) 104-104 2014/10

    DOI: 10.1016/j.jneuroim.2014.08.280  

    ISSN: 0165-5728

    eISSN: 1872-8421

  194. The lesion localization of passive transfer NMO-IgG model in Lewis rats

    K. Kurosawa, T. Misu, Y. Takahashi, D. Sato, S. Nishiyama, H. Kuroda, I. Nakashima, K. Fujihara, M. Aoki

    MULTIPLE SCLEROSIS JOURNAL 20 238-239 2014/09

    ISSN: 1352-4585

    eISSN: 1477-0970

  195. Aquaporin-4 antibody-seropositive myelitis initially biopsied due to suspected spinal cord tumors: diagnostic considerations

    T. Misu, D. Sato, C. Rocha, D. Callegaro, I. Nakashima, M. Aoki, K. Fujihara, M. A. Lana-Peixoto

    MULTIPLE SCLEROSIS JOURNAL 20 170-170 2014/09

    ISSN: 1352-4585

    eISSN: 1477-0970

  196. Subanalysis of a multicentric cross-sectional study of CSF-GFAP in the diagnosis of inflammatory demyelinating diseases

    S. Nishiyama, T. Misu, Y. Shimizu, K. Yokoyama, T. Kageyama, Y. Takai, R. Takano, T. Takahashi, J. Fujimori, S. Sato, I. Nakashima, K. Fujihara, M. Aoki

    MULTIPLE SCLEROSIS JOURNAL 20 187-188 2014/09

    ISSN: 1352-4585

    eISSN: 1477-0970

  197. Autoantibodies against MOG and aquaporin-4 identify distinct neuromyelitis optica spectrum disorders subgroups

    D. K. Sato, D. Callegaro, M. A. Lana-Peixoto, P. J. Waters, S. Tanaka, F. M. H. Jorge, T. Takahashi, T. Misu, S. L. Apostolos-Pereira, N. Talim, R. F. Simm, I. Nakashima, K. Nomura, M. Aoki, K. Fujihara

    MULTIPLE SCLEROSIS JOURNAL 20 24-25 2014/09

    ISSN: 1352-4585

    eISSN: 1477-0970

  198. Drug-induced dropped head syndrome Invited

    Tetsuya Akaishi, Akio Kikuchi, Takafumi Hasegawa, Maki Tateyama, Masashi Aoki

    Neurological Medicine 81 (1) 88-92 2014/07

  199. 【アミロイド関連神経疾患のすべて-封入体筋炎からアルツハイマー病まで】 封入体筋炎とアミロイド

    青木 正志, 鈴木 直輝

    BRAIN and NERVE: 神経研究の進歩 66 (7) 739-748 2014/07

    Publisher: (株)医学書院

    ISSN: 1881-6096

  200. A Multicenter, Cross-Sectional Study of the Usefulness of CSF-GFAP in the Diagnosis and the Prognosis of Inflammatory CNS Diseases

    S. Nishiyama, T. Misu, Y. Simizu, K. Yokoyama, T. Kageyama, Y. Takai, R. Takano, T. Takahashi, J. Fujimori, S. Sato, I. Nakashima, Y. Itoyama, K. Fujihara, M. Aoki

    MULTIPLE SCLEROSIS JOURNAL 20 (7) 911-911 2014/06

    ISSN: 1352-4585

    eISSN: 1477-0970

  201. MRI Findings in Optic Neuritis: Neuromyelitis Optica Spectrum Disorder Versus Multiple Sclerosis

    K. Kurosawa, T. Misu, S. Nishiyama, D. Sato, H. Kuroda, T. Takahashi, I. Nakashima, K. Fujihara, M. Aoki

    MULTIPLE SCLEROSIS JOURNAL 20 (7) 940-940 2014/06

    ISSN: 1352-4585

    eISSN: 1477-0970

  202. Impact Of The Great East Japan Earthquake In 2011 On MS And NMO: A Study In Sendai, Japan

    K. Fujihara, Y. Kanamori, Nakashima, I, Y. Takai, D. K. Sato, T. Misu, S. Sato, J. Fujimori, J. Higuchi, H. Kuroda, Y. Itoyama, M. Aoki

    MULTIPLE SCLEROSIS JOURNAL 20 (7) 914-914 2014/06

    ISSN: 1352-4585

    eISSN: 1477-0970

  203. Functional ESCRT machinery is required for the clearance of aggregate-prone proteins associated with neurodegenerative diseases

    R. Oshima, T. Hasegawa, N. Sugeno, M. Konno, E. Miura, A. Kikuchi, K. Tamai, A. Takeda, N. Tanaka, M. Aoki

    MOVEMENT DISORDERS 29 S25-S25 2014/05

    ISSN: 0885-3185

    eISSN: 1531-8257

  204. VPS35 dysfunction impairs lysosomal degradation of alpha-synuclein and exacerbates neurotoxicity in a drosophila model of Parkinson's disease

    T. Hasegawa, E. Miura, M. Konno, M. Suzuki, N. Sugeno, N. Fujikake, S. Geisler, M. Tabuchi, R. Oshima, A. Kikuchi, T. Baba, K. Wada, Y. Nagai, A. Takeda, M. Aoki

    MOVEMENT DISORDERS 29 S13-S14 2014/05

    ISSN: 0885-3185

    eISSN: 1531-8257

  205. Proteasome Dysfunction Induces Muscle Growth Defects And Protein Aggregation

    Yasuo Kitajima, Naoki Suzuki, Yoshitaka Tashiro, Hitoshi Warita, Masaaki Kato, Maki Tateyama, Risa Ando, Rumiko Izumi, Maya Yamazaki, Manabu Abe, Kenji Sakimura, Hidefumi Ito, Urushitani Makoto, Ryoichi Nagatomi, Ryosuke Takahashi, Masashi Aoki

    MEDICINE AND SCIENCE IN SPORTS AND EXERCISE 46 (5) 352-352 2014/05

    ISSN: 0195-9131

    eISSN: 1530-0315

  206. 【神経系の慢性炎症】 慢性炎症による神経疾患 封入体筋炎

    青木 正志

    別冊Bio Clinica: 慢性炎症と疾患 3 (1) 54-60 2014/05

    Publisher: (株)北隆館

  207. 神経内科教育の実態と課題 医学部

    谷脇 考恭, 犬塚 貴, 吉井 文均, 青木 正志, 天野 隆弘, 豊島 至, 福武 敏夫, 橋本 洋一郎, 吉良 潤一

    臨床神経学 54 (4) 335-340 2014/04

    Publisher: (一社)日本神経学会

    DOI: 10.5692/clinicalneurol.54.335  

    ISSN: 0009-918X

  208. 神経内科教育の実態と課題 研修病院

    福武 敏夫, 橋本 洋一郎, 谷脇 考恭, 豊島 至, 天野 隆弘, 青木 正志, 吉井 文均, 犬塚 貴, 吉良 潤一

    臨床神経学 54 (4) 341-348 2014/04

    Publisher: (一社)日本神経学会

    DOI: 10.5692/clinicalneurol.54.341  

    ISSN: 0009-918X

  209. 神経内科教育の実態と課題 大学院

    吉良 潤一, 大八木 保政, 谷脇 考恭, 犬塚 貴, 吉井 文均, 青木 正志, 天野 隆弘, 豊島 至, 福武 敏夫, 橋本 洋一郎

    臨床神経学 54 (4) 349-358 2014/04

    Publisher: (一社)日本神経学会

    DOI: 10.5692/clinicalneurol.54.335  

    ISSN: 0009-918X

  210. 【東日本大震災から学ぶ内科学】 大災害における内科医の役割と連携 提言 人工呼吸器使用患者の広域医療搬送

    青木 正志

    日本内科学会雑誌 103 (3) 613-616 2014/03

    Publisher: (一社)日本内科学会

    DOI: 10.2169/naika.103.613  

    ISSN: 0021-5384

  211. てんかんは日本人における睡眠呼吸障害の危険因子とはならない

    加藤量広, 加藤量広, 神一敬, 中村美輝, 横田恵理, 岩崎真樹, 柿坂庸介, 青木正志, 中里信和

    日本神経学会学術大会プログラム・抄録集 55th 2014

  212. 筋ジストロフィーおよび関連疾患の診断・治療開発を目指した基盤研究 次世代シークエンサーを用いた遠位型ミオパチーにおけるゲノム解析

    青木正志, 井泉瑠美子, 高橋俊明, 加藤昌昭, 鈴木直輝, 竪山真規, 割田仁, 島倉奈緒子, 安藤里紗, 舟山亮, 長嶋剛史, 中山啓子, 新堀哲也, 青木洋子

    筋ジストロフィーおよび関連疾患の診断・治療開発を目指した基盤研究 平成23-25年度 総括研究報告書 15-16 2014

  213. ショウジョウバエモデルを用いたVps35遺伝子異常によるParkinson病発症機構の解析

    今野 昌俊, 長谷川 隆文, 鈴木 マリ, 藤掛 伸宏, 永井 義隆, 三浦 永美子, 菅野 直人, 菊池 昭夫, 青木 正志, 武田 篤

    臨床神経学 53 (12) 1429-1429 2013/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  214. 免疫グロブリン大量療法が奏効した両側腕神経叢炎の1例

    西山 亜由美, 菅野 直人, 割田 仁, 竪山 真規, 青木 正志

    末梢神経 24 (2) 414-414 2013/12

    Publisher: 日本末梢神経学会

    ISSN: 0917-6772

  215. 炎症性脱髄性疾患の診断・予後における脳脊髄液中GFAP濃度有用性の多施設横断的検討

    西山 修平, 三須 建郎, 清水 優子, 横山 和正, 景山 卓, 高井 良樹, 高野 里菜, 高橋 利幸, 藤盛 寿一, 佐藤 滋, 中島 一郎, 糸山 泰人, 藤原 一男, 青木 正志

    臨床神経学 53 (12) 1461-1461 2013/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  216. 視神経脊髄炎におけるアストロサイトパチー病変とアクアポリン1の関係

    三須 建郎, 藤原 一男, 高井 良樹, 西山 修平, 中島 一郎, 今野 秀彦, 糸山 泰人, 青木 正志

    臨床神経学 53 (12) 1530-1530 2013/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  217. Myofibrillar myopathyの大家系での次世代シークエンサーを用いた原因遺伝子の同定

    井泉 瑠美子, 新堀 哲也, 青木 洋子, 鈴木 直輝, 加藤 昌昭, 割田 仁, 高橋 俊明, 竪山 真規, 長嶋 剛史, 舟山 亮, 中山 啓子, 松原 洋一, 青木 正志

    臨床神経学 53 (12) 1450-1450 2013/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  218. 東日本大震災におけるギラン・バレー、フィッシャー症候群の発生状況についての検討

    坪井 博文, 菅野 直人, 竪山 真規, 長谷川 隆文, 中島 一郎, 黒田 宙, 藤盛 寿一, 菊池 昭夫, 西山 修平, 加藤 量広, 金子 仁彦, 小林 理子, 石垣 あや, 青木 正志

    臨床神経学 53 (12) 1589-1589 2013/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  219. 一酸化炭素中毒後遅発性脳症の重症度分類と予後関連因子について

    黒田 宙, 藤原 一男, 久志本 成樹, 青木 正志

    臨床神経学 53 (12) 1636-1636 2013/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

  220. 【神経再生の最前線】 HGFを用いた筋萎縮性側索硬化症の治療法の開発

    青木 正志

    BIO Clinica 28 (13) 1223-1227 2013/12

    Publisher: (株)北隆館

    ISSN: 0919-8237

  221. 脊髄長大病変に髄液多形核白血球増多を伴う疾患群について

    黒田 宙, 高橋 利幸, 佐藤 ダグラス, 西山 亜由美, 三浦 永美子, 西山 修平, 三須 建郎, 中島 一郎, 藤原 一男, 青木 正志

    神経免疫学 18 (1) 113-113 2013/11

    Publisher: 日本神経免疫学会

    ISSN: 0918-936X

  222. 【神経変性疾患-研究と診療の進歩】 神経変性疾患の治療の新しい展開 アカデミア主導による筋萎縮性側索硬化症に対する新規治療法の開発

    青木 正志

    医学のあゆみ 247 (5) 486-492 2013/11

    Publisher: 医歯薬出版(株)

    ISSN: 0039-2359

  223. 運動ニューロン疾患の遺伝学 Update FUS変異によるALS臨床病理と病態

    青木 正志

    臨床神経学 53 (11) 1080-1083 2013/11

    Publisher: (一社)日本神経学会

    DOI: 10.5692/clinicalneurol.53.1080  

    ISSN: 0009-918X

  224. 神経疾患患者救済のための神経学会災害対策ネットワーク作り 在宅人工呼吸器使用患者への対応をどうするか

    青木 正志

    臨床神経学 53 (11) 1149-1151 2013/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

  225. MRI findings in optic neuritis of patients with neuromyelitis optica (NMO)-spectrum disorder versus multiple sclerosis

    K. Kurosawa, T. Misu, S. Nishiyama, D. Sato, H. Kuroda, T. Takahashi, I. Nakashima, K. Fujihara, M. Aoki

    MULTIPLE SCLEROSIS JOURNAL 19 (11) 173-173 2013/10

    ISSN: 1352-4585

    eISSN: 1477-0970

  226. A case series of longitudinally-extended spinal cord lesion with increased polymorphonuclear leukocytes in CSF

    H. Kuroda, T. Takahashi, D. Sato, A. Nishiyama, E. Miura, S. Nishiyama, N. Sugeno, T. Misu, I. Nakashima, K. Fujihara, M. Aoki

    MULTIPLE SCLEROSIS JOURNAL 19 (11) 316-317 2013/10

    ISSN: 1352-4585

    eISSN: 1477-0970

  227. 呼吸筋麻痺を伴った抗signal recognition particle(SRP)抗体陽性筋症の1例

    黒澤和大, 西山修平, 吉田隼, 大嶋龍司, 鈴木直輝, 竪山真規, 青木正志

    神経治療学 30 (5) 690 2013/09/25

    ISSN: 0916-8443

  228. Influence of Serotonin Transporter Gene Variation and Anxiety-related Personality on Brain Activity during Fear Conditioning in Japanese Subjects: an fMRI study

    M. Kano, T. Mizuno, M. Brammer, M. Aoki, R. Kawashima, S. Fukudo

    PSYCHOTHERAPY AND PSYCHOSOMATICS 82 51-51 2013/09

    ISSN: 0033-3190

    eISSN: 1423-0348

  229. E3ユビキチンリガーゼNedd4はαシヌクレインのendosomeへのtargetingに重要である(Nedd4 E3 ubiquitin ligase facilitates the endosomal targeting of extracellular alpha-synuclein)

    菅野 直人, 長谷川 隆文, 今野 昌俊, 三浦 永美子, 大嶋 龍司, 菊池 昭夫, 青木 正志, 武田 篤

    日本生化学会大会プログラム・講演要旨集 86回 2P-206 2013/09

    Publisher: (公社)日本生化学会

  230. 妊娠中に発症した抗NMDA受容体抗体脳炎の1例

    大嶋 龍司, 菅野 直人, 三須 建郎, 中島 一郎, 竪山 真規, 青木 正志

    臨床神経学 53 (9) 755-755 2013/09

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  231. 【神経疾患の新しい治療-現場で必須の知識と今後の展望-】 筋萎縮性側索硬化症

    青木 正志

    日本内科学会雑誌 102 (8) 1978-1985 2013/08

    Publisher: (一社)日本内科学会

    DOI: 10.2169/naika.102.1978  

    ISSN: 0021-5384

  232. [New and future treatments for neurological disorders--knowledge essential to daily clinics and future prospects. Topics: 10. Amyotrophic lateral sclerosis]. Peer-reviewed

    Aoki M

    Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 102 (8) 1978-1985 2013/08

    ISSN: 0021-5384

  233. レトロマー構成因子VPS35異常に基づくパーキンソン病の病態解明

    三浦永美子, 長谷川隆文, 今野昌俊, 菅野直人, 菊池昭夫, 馬場徹, 大嶋龍司, 青木正志, 武田篤

    脳21 16 (3) 368 2013/07/20

    ISSN: 1344-0128

  234. 視神経脊髄炎増悪時における髄液中C5a上昇

    黒田 宙, 高橋 利幸, 高野 里菜, 三須 建郎, 中島 一郎, 藤原 一男, 青木 正志

    補体シンポジウム講演集 50 56-57 2013/07

    Publisher: (一社)日本補体学会

    ISSN: 2185-8470

  235. Differentiating Parkinson's disease from multiple system atrophy by [I-123] meta-iodobenzylguanidine myocardial scintigraphy and olfactory test

    A. Kikuchi, T. Baba, T. Hasegawa, N. Sugeno, M. Konno, M. Aoki, A. Takeda

    MOVEMENT DISORDERS 28 S156-S156 2013/06

    ISSN: 0885-3185

  236. CIDPを含めた末梢神経病変とALSの合併に関する検討

    赤石 哲也, 竪山 真規, 加藤 量広, 三浦 永美子, 井泉 瑠美子, 遠藤 薫, 菅野 直人, 鈴木 直輝, 馬場 徹, 三須 建郎, 菊池 昭夫, 長谷川 隆文, 中島 一郎, 青木 正志

    末梢神経 24 (1) 85-89 2013/06

    Publisher: 日本末梢神経学会

    ISSN: 0917-6772

  237. 【神経内科検査のみかた-脳のイメージングを中心に】 神経内科のトピックス 筋萎縮性側索硬化症の最新のトピックス FUS/TLS遺伝子異常に伴うALS

    青木 正志

    Modern Physician 33 (5) 668-673 2013/05

    Publisher: (株)新興医学出版社

    ISSN: 0913-7963

  238. 治験の基礎知識 現状から今後の展望まで 筋萎縮性側索硬化症に対する治療法開発への挑戦

    青木 正志

    神経治療学 30 (3) 341-346 2013/05

    Publisher: 日本神経治療学会

    ISSN: 0916-8443

  239. 筋萎縮性側索硬化症(ALS)に対するHGFを用いた新規治療法の開発

    青木 正志

    Medical Science Digest 39 (4) 158-159 2013/04

    Publisher: (株)ニュー・サイエンス社

    ISSN: 1347-4340

  240. 発作時徐脈を呈した側頭葉てんかんの3例

    向井 由幸, 加藤 量広, 神 一敬, 板橋 尚, 中里 信和, 岩崎 真樹, 青木 正志

    臨床神経学 53 (3) 263-263 2013/03

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

  241. Clinical Classification of Delayed Encephalopathy after Carbon Monoxide Poisoning and Utility of Myelin Basic Protein in Cerebrospinal Fluid

    Hiroshi Kuroda, Kazuo Fujihara, Shigeki Kushimoto, Masashi Aoki

    NEUROLOGY 80 2013/02

    ISSN: 0028-3878

    eISSN: 1526-632X

  242. 筋萎縮性側索硬化症に対するHGF治療

    青木 正志

    BIO Clinica 28 (2) 176-181 2013/02

    Publisher: (株)北隆館

    ISSN: 0919-8237

  243. 神経疾患における医療ネットワークの構築と東北大学病院の役割

    青木 正志

    宮城県医師会報 (805) 102-105 2013/02

    Publisher: (公社)宮城県医師会

  244. 内側側頭葉てんかん患者における発作時心拍・心拍変動

    加藤量広, 加藤量広, 神一敬, 板橋尚, 岩崎真樹, 青木正志, 中里信和

    日本神経学会学術大会プログラム・抄録集 54th 2013

  245. 東日本大震災におけるギラン・バレー,フィッシャー症候群の発生状況についての検討

    坪井博文, 菅野直人, 竪山真規, 長谷川隆文, 中島一郎, 黒田宙, 藤盛寿一, 菊池昭夫, 西山修平, 加藤量広, 金子仁彦, 小林理子, 石垣あや, 青木正志

    日本神経学会学術大会プログラム・抄録集 54th 480 2013

  246. 東北大学における家族性ALS遺伝子検査の検討

    加藤昌昭, 割田仁, 井泉瑠美子, 島倉奈緒子, 安藤里紗, 鈴木直輝, 青木正志

    日本神経学会学術大会プログラム・抄録集 54th 456 2013

  247. Myofibrillar myopathyの大家系における次世代型シークエンサーを用いた新たな原因遺伝子の同定

    井泉瑠美子, 新堀哲也, 青木洋子, 鈴木直輝, 加藤昌昭, 割田仁, 高橋俊明, 竪山真規, 長嶋剛史, 舟山亮, 阿部康二, 中山啓子, 青木正志, 松原洋一

    日本人類遺伝学会大会プログラム・抄録集 58th 136 2013

  248. 【内科疾患と関連する認知症〜treatable dementiaを見逃さないために】 《内科で見逃せないtreatable dementia》悪性腫瘍に関連する認知機能障害

    高井 良樹, 青木 正志

    Modern Physician 33 (1) 38-42 2013/01

    Publisher: (株)新興医学出版社

    ISSN: 0913-7963

  249. Amyotrophic lateral sclerosis (ALS) with the mutations in the fused insarcoma/translocated in liposarcoma gene Peer-reviewed

    Masashi Aoki

    Clinical Neurology 53 (11) 1080-1083 2013

    DOI: 10.5692/clinicalneurol.53.1080  

    ISSN: 0009-918X

  250. The management of patients receiving home respiratory care with tracheostomy and positive-pressure ventilation Peer-reviewed

    Masashi Aoki

    Clinical Neurology 53 (11) 1149-1151 2013

    DOI: 10.5692/clinicalneurol.53.1149  

    ISSN: 0009-918X

  251. Dysferlinopathyが疑われる患者の血清CK値

    高橋 俊明, 鈴木 直輝, 加藤 昌昭, 井泉 瑠美子, 竪山 真規, 安藤 里紗, 八木沼 智香子, 佐藤 仁美, 島倉 奈緒子, 田中 洋康, 吉岡 勝, 今野 秀彦, 小野寺 宏, 西野 一三, 青木 正志

    臨床神経学 52 (12) 1548-1548 2012/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  252. 12年近いCIDP様の末梢神経障害の経過中に球症状を呈し,呼吸不全で死亡した48歳女性

    赤石哲也, 加藤量広, 三浦永美子, 井泉瑠美子, 遠藤薫, 菅野直人, 鈴木直輝, 馬場徹, 三須建郎, 菊池昭夫, 長谷川隆文, 黒田宙, 竪山真規, 中島一郎, 青木正志

    末梢神経 23 (2) 235-236 2012/12/01

    ISSN: 0917-6772

  253. アカデミア発の創薬への挑戦

    青木 正志

    東北医学雑誌 124 (2) 181-183 2012/12

    Publisher: 東北医学会

    ISSN: 0040-8700

  254. Restorative therapy in amyotrophic lateral sclerosis Peer-reviewed

    Masashi Aoki

    Japanese Journal of Neuropsychopharmacology 32 (5-6) 287-292 2012/11

    ISSN: 1340-2544

  255. 【難治性神経疾患克服のための再生医療研究の最前線】 筋萎縮性側索硬化症に対する再生医療の開発

    青木 正志

    日本神経精神薬理学雑誌 32 (5-6) 287-292 2012/11

    Publisher: (一社)日本神経精神薬理学会

    ISSN: 1340-2544

  256. ALSの遺伝学Update

    青木 正志, 割田 仁, 鈴木 直輝, 加藤 昌昭

    臨床神経学 52 (11) 844-847 2012/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

  257. 東日本大震災 あれから一年 宮城県の1年

    青木 正志

    臨床神経学 52 (11) 1336-1338 2012/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

  258. 炎症性筋疾患研究の最近の進歩 封入体筋炎の病態

    鈴木直輝, 竪山真規, 井泉瑠美子, 青木正志

    月刊神経内科 77 (4) 396-404 2012/10/25

    ISSN: 0386-9709

  259. Neutralising antibodies against interferon-beta and their correlation with clinical and magnetic resonance imaging activity in Japanese multiple sclerosis patients

    D. Sato, I. Nakashima, T. Fukazawa, Y. Shimizu, Y. Tomizawa, K. Yokoyama, T. Misu, Y. Itoyama, M. Aoki, K. Fujihara

    MULTIPLE SCLEROSIS JOURNAL 18 471-471 2012/10

    ISSN: 1352-4585

    eISSN: 1477-0970

  260. The effect of NMO-IgG and complement against primary human astrocytes in culture

    S. Nishiyama, T. Misu, N. Sugeno, T. Takahashi, I. Nakashima, M. Aoki, K. Fujihara

    MULTIPLE SCLEROSIS JOURNAL 18 295-296 2012/10

    ISSN: 1352-4585

    eISSN: 1477-0970

  261. PATHOLOGICAL FEATURES OF AQUAPORIN-4 AUTOIMMUNITY WITH CYTOTOXIC EDEMA: THE LESSON FROM NEUROMYELITIS OPTICA AND RELATED DISORDERS

    T. Misu, Y. Takai, H. Lassmann, I. Nakashima, Y. Itoyama, M. Aoki, K. Fujihara

    ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH 36 46A-46A 2012/09

    ISSN: 0145-6008

  262. Guillain-Barre症候群急性期の自律神経障害に対するpregabalinの効果

    黒田 宙, 金子 仁彦, 吉田 隼, 中島 一郎, 竪山 真規, 楠 進, 藤原 一男, 青木 正志

    神経治療学 29 (5) 655-655 2012/09

    Publisher: 日本神経治療学会

    ISSN: 0916-8443

  263. 両側側頭葉てんかん患者における発作時無呼吸・心拍変化の検討

    加藤 量広, 神 一敬, 板橋 尚, 岩崎 真樹, 青木 正志, 中里 信和

    てんかん研究 30 (2) 463-463 2012/09

    Publisher: (一社)日本てんかん学会

    ISSN: 0912-0890

  264. 我が国の内科領域のトランスレーショナルリサーチとEBM トランスレーショナルリサーチ 難治性神経筋疾患 筋萎縮性側索硬化症および遠位型ミオパチーに対する治療法の開発

    青木 正志

    日本内科学会雑誌 101 (9) 2544-2551 2012/09

    Publisher: (一社)日本内科学会

    DOI: 10.2169/naika.101.2544  

    ISSN: 0021-5384

  265. 【内科疾患と脳神経疾患:診断と治療の進歩】 癌と脳神経疾患

    黒田 宙, 青木 正志

    日本内科学会雑誌 101 (8) 2249-2256 2012/08

    Publisher: (一社)日本内科学会

    DOI: 10.2169/naika.101.2249  

    ISSN: 0021-5384

  266. Ictal central apneaを認めた家族性側頭葉てんかんの一例

    加藤 量広, 板橋 尚, 神 一敬, 岩崎 真樹, 中里 信和, 青木 正志

    臨床神経学 52 (7) 524-524 2012/07

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

  267. Dynamin GTPase activity decreases alpha-synuclein uptake in neuronal and oligodendroglial cells

    M. Konno, T. Hasegawa, T. Baba, E. Miura, N. Sugeno, A. Kikuchi, M. Aoki, A. Takeda

    MOVEMENT DISORDERS 27 S485-S486 2012/06

    ISSN: 0885-3185

  268. 【神経変性疾患の新規治療法の開発】 東北大学病院における家族性ALS遺伝子解析

    青木 正志

    難病と在宅ケア 18 (3) 21-23 2012/06

    Publisher: (株)日本プランニングセンター

    ISSN: 1880-9200

  269. 【わが国の遺伝性ALS】 ALS6(FUS/TLS)

    青木 正志, 鈴木 直輝, 加藤 昌昭, 割田 仁

    神経内科 76 (5) 477-482 2012/05

    Publisher: (有)科学評論社

    ISSN: 0386-9709

  270. 封入体筋炎 診療の現状と展望

    青木 正志, 鈴木 直輝

    日本臨床 70 (5) 895-906 2012/05

    Publisher: (株)日本臨床社

    ISSN: 0047-1852

  271. Stratifying Patients at Risk for Neurologic Sequelae after Carbon Monoxide Poisoning by Monitoring Serum Bilirubin Response

    Hiroshi Kuroda, Kazuo Fujihara, Shigeki Kushimoto, Masashi Aoki

    NEUROLOGY 78 2012/04

    ISSN: 0028-3878

  272. Aquaporin-4 antibody-positive Male Patients: A Study of 151 Cases from Japan

    D. K. Sato, T. Takahashi, Nakashima, I, T. Misu, C. Kanaoka-Suzuki, Y. Kanamori, Y. Takai, S. Nishiyama, H. Kuroda, Y. Itoyama, K. Fujihara, M. Aoki

    MULTIPLE SCLEROSIS JOURNAL 18 (4) 527-527 2012/04

    ISSN: 1352-4585

  273. The Effect of NMO-IgG and Complement against Primary Human Astrocytes in Culture

    S. Nishiyama, T. Misu, T. Takahashi, Nakashima, I, M. Aoki, K. Fujihara

    MULTIPLE SCLEROSIS JOURNAL 18 (4) 540-541 2012/04

    ISSN: 1352-4585

  274. Hepatocyte growth factor therapy for amyotrophic lateral sclerosis Peer-reviewed

    Masashi Aoki

    Brain and Nerve 64 (3) 245-254 2012/03/01

    ISSN: 1881-6096

  275. 【アカデミアから新規治療の実現へ-トランスレーショナルリサーチの現状】 筋萎縮性側索硬化症に対するHGF治療

    青木 正志

    BRAIN and NERVE: 神経研究の進歩 64 (3) 245-254 2012/03

    Publisher: (株)医学書院

    ISSN: 1881-6096

  276. 大災害時の神経疾患治療としての問題点 8ヵ月後の今 東北大震災後8ヵ月における課題

    青木 正志

    神経治療学 29 (2) 193-196 2012/03

    Publisher: 日本神経治療学会

    ISSN: 0916-8443

  277. αシヌクレインのユビキチン化におけるNedd4の関与

    菅野直人, 武田篤, 長谷川隆文, 今野昌俊, 三浦永美子, 菊池昭夫, 馬場徹, 青木正志

    日本神経学会学術大会プログラム・抄録集 53rd 428 2012

  278. 【筋萎縮性側索硬化症の診断と治療】 ALSに対する再生医療の開発

    割田 仁, 青木 正志

    脳21 15 (1) 57-61 2012/01

    Publisher: (株)金芳堂

    ISSN: 1344-0128

  279. [Clinical genetics of amyotrophic lateral sclerosis in Japan: an update]. Peer-reviewed

    Masashi Aoki, Hitoshi Warita, Naoki Suzuki, Masaaki Kato

    Rinsho shinkeigaku = Clinical neurology 52 (11) 844-7 2012

    DOI: 10.5692/clinicalneurol.52.844  

    ISSN: 0009-918X

    eISSN: 1882-0654

    More details Close

    Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disorder characterized by the death of upper and lower motor neurons. In familial ALS kinders with mutations in the SOD1 gene, the age of onset of weakness varies greatly but the duration of illness appears to be characteristic to each mutation. Mutations in the fused in sarcoma/translated in liposarcoma (FUS/TLS) gene have been discovered to be associated with familial ALS. In a Japanese family with familial ALS, we found the R521C FUS mutation, which has been reported to be found in various ethnic backgrounds. The family history revealed 23 patients with ALS among 46 family members, suggesting a 100% penetrance rate. They developed muscle weakness at an average age of 35.3 years, and the average age of death was 37.2 years. Neuropathological examination revealed remarkable atrophy of the brainstem tegmentum characterized by cytoplasmic basophilic inclusion bodies in the neurons of the brainstem. The frequency of a hexanucleotide repeat expansion in C9ORF72 with familial ALS has been estimated as approximately 5% in Japan, although the one Japanese patient was identified as a carrier of the C9ORF72 expansion carried the Finnish risk haplotype.

  280. [Clinical translation of hepatocyte growth factor for amyotrophic lateral sclerosis]. Peer-reviewed

    Hitoshi Warita, Masaaki Kato, Naoki Suzuki, Yasuto Itoyama, Masashi Aoki

    Rinsho shinkeigaku = Clinical neurology 52 (11) 1214-7 2012

    DOI: 10.5692/clinicalneurol.52.1214  

    ISSN: 0009-918X

    eISSN: 1882-0654

    More details Close

    Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by selective loss of motor neurons. Approximately 20% of familial ALS cases are linked to mutations in Cu/Zn superoxide dismutase (SOD1) gene. Previously, we developed a transgenic rat model of ALS overexpressing mutant SOD1 protein. The rat model facilitates preclinical ALS research employing various therapeutic approaches such as intrathecal administration, cell transplantation, and viral vector-mediated gene transduction to the affected central nervous system. Hepatocyte growth factor (HGF) is a pleiotropic growth factor and also a potent survival-promoting factor for motor neurons. To examine its therapeutic effect on ALS, we administered human recombinant HGF (hrHGF) to the transgenic ALS rats. In contrast with vehicle-treated rats, continuous intrathecal infusion of hrHGF attenuated spinal motor neuron degeneration and prolonged the duration of the disease, even with administration from the onset of symptoms. To translate the strategy to human treatment, we performed dose-finding and safety studies using non-human primate model of contusive cervical spinal cord injury. Introducing exogenous HGF protein also revealed a distinct therapeutic effect with functional recovery. Given the therapeutic potential of hrHGF on ALS, we started a novel phase I clinical trial for ALS patients in Tohoku University Hospital.

  281. One year after the great Tohoku disaster Peer-reviewed

    Masashi Aoki

    Clinical Neurology 52 (11) 1336-1338 2012

    DOI: 10.5692/clinicalneurol.52.1336  

    ISSN: 0009-918X

  282. 各種疾患 神経筋疾患 ALS最近の進歩

    青木 正志

    Annual Review神経 2012 282-289 2012/01

    Publisher: (株)中外医学社

  283. 【認知症学 下-その解明と治療の最新知見-】 臨床編 前頭側頭葉変性症とその関連疾患 筋萎縮性側索硬化症とFUS/TLS

    鈴木 直輝, 青木 正志

    日本臨床 69 (増刊10 認知症学(下)) 389-393 2011/12

    Publisher: (株)日本臨床社

    ISSN: 0047-1852

  284. 【筋疾患update】 封入体筋炎

    鈴木 直輝, 青木 正志

    BRAIN and NERVE: 神経研究の進歩 63 (11) 1205-1215 2011/11

    Publisher: (株)医学書院

    ISSN: 1881-6096

  285. 筋炎研究最近の進歩 封入体筋炎の病態と頻度

    鈴木 直輝, 竪山 真規, 割田 仁, 井泉 瑠美子, 西野 一三, 青木 正志

    臨床神経学 51 (11) 964-966 2011/11

    Publisher: (一社)日本神経学会

    DOI: 10.5692/clinicalneurol.51.964  

    ISSN: 0009-918X

    eISSN: 1882-0654

  286. The effect of NMO-IgG and complement against primary human astrocytes in culture

    S. Nishiyama, T. Misu, T. Takahashi, I. Nakashima, M. Aoki, K. Fujihara

    MULTIPLE SCLEROSIS JOURNAL 17 S352-S352 2011/10

    ISSN: 1352-4585

    eISSN: 1477-0970

  287. Two cases of lumbosacral myeloradiculitis with anti aquaporin-4 antibody

    Y. Takai, T. Misu, I. Nakashima, M. Aoki, K. Fujihara

    MULTIPLE SCLEROSIS JOURNAL 17 S237-S238 2011/10

    ISSN: 1352-4585

    eISSN: 1477-0970

  288. Histopathological examination of astrocytopathy in tumefactive inflammatory diseases

    T. Misu, Y. Takai, M. Watanabe, I. Nakashima, Y. Itoyama, M. Aoki, K. Fujihara

    MULTIPLE SCLEROSIS JOURNAL 17 S289-S290 2011/10

    ISSN: 1352-4585

    eISSN: 1477-0970

  289. Effects of immunosuppressants on in vitro production of anti-aquaporin-4 antibody from peripheral B cells of neuromyelitis optica

    C. Kanaoka-Suzuki, I. Nakashima, T. Takahashi, T. Misu, K. Fujihara, M. Aoki

    MULTIPLE SCLEROSIS JOURNAL 17 S203-S203 2011/10

    ISSN: 1352-4585

    eISSN: 1477-0970

  290. 動き出したアカデミア発シーズの治験 各拠点からの報告 東北大学 縁取り空胞を伴う遠位型ミオパチー患者におけるN-アセチルノイラミン酸の安全性および薬物動態の検討

    浅田 隆太, 青木 正志

    臨床評価 39 (2) 238-243 2011/10

    Publisher: (株)臨床評価刊行会

    ISSN: 0300-3051

  291. 【東日本大震災の教訓】 [第1部]東日本大震災の医療現場とその教訓

    青木 正志

    難病と在宅ケア 17 (6) 8-11 2011/09

    Publisher: (株)日本プランニングセンター

    ISSN: 1880-9200

  292. 【神経系におけるiPS細胞 iPS細胞の活用も含めた神経機能修復の現状と将来】 神経栄養因子による神経系の再構築

    青木 正志

    脳21 14 (3) 239-243 2011/07

    Publisher: (株)金芳堂

    ISSN: 1344-0128

  293. 筋萎縮性側索硬化症における遺伝子異常と新規治療法の開発

    青木 正志

    東北医学雑誌 123 (1) 24-28 2011/06

    Publisher: 東北医学会

    ISSN: 0040-8700

  294. 【今後の難病対策のあり方について】 筋萎縮性側索硬化症に対する治療法の開発

    青木 正志

    保健医療科学 60 (2) 125-129 2011/04

    Publisher: 国立保健医療科学院

    ISSN: 1347-6459

  295. 「筋萎縮性側索硬化症の病態に基づく画期的治療法の開発」細胞外微小環境と内在性神経幹/前駆細胞を標的としたALS再生誘導療法開発の試み

    糸山泰人, 青木正志, 割田仁, 水野秀紀, 鈴木直輝, 船越洋, 中村敏一

    筋萎縮性側索硬化症の病態に基づく画期的治療法の開発 平成20-22年度 総合研究報告書 45-49 2011

  296. 知って得する最新情報 筋萎縮性側索硬化症のHGF治療

    青木 正志

    Clinical Neuroscience 28 (11) 1312-1314 2010/11

    Publisher: (株)中外医学社

    ISSN: 0289-0585

  297. Clinical features of limb-girdle muscular dystrophy type 2B with the c.2997G &gt; T mutation

    T. Takahashi, M. Aoki, N. Suzuki, C. Yaginuma, H. Sato, M. Hayasaka, H. Sugawara, E. Abe, M. Ito, M. Tateyama, M. Yoshioka, H. Konno, H. Onodera, Y. Itoyama

    NEUROMUSCULAR DISORDERS 20 (9-10) 606-606 2010/10

    DOI: 10.1016/j.nmd.2010.07.035  

    ISSN: 0960-8966

  298. Prevalence of inclusion body myositis (IBM) in Japanese population

    N. Suzuki, M. Aoki, M. Tateyama, R. Izumi, H. Warita, Y. Itoyama, M. Mori, H. Kusaka, I. Higuchi, T. Kondo, M. Uchino, R. Kaji, I. Nishino

    NEUROMUSCULAR DISORDERS 20 (9-10) 631-631 2010/10

    DOI: 10.1016/j.nmd.2010.07.113  

    ISSN: 0960-8966

  299. DMRV and GNE mutations: genotype-phenotype correlation in 100 Japanese patients

    H. Tomimitsu, A. Arai, K. Murayama, J. Shimizu, N. Suzuki, T. Nagata, M. Aoki, H. Mizusawa, K. Tanaka, I. Nishino

    NEUROMUSCULAR DISORDERS 20 (9-10) 619-619 2010/10

    DOI: 10.1016/j.nmd.2010.07.076  

    ISSN: 0960-8966

  300. Myogenesis in skeletal muscles with slowly progressive denervation in a rat model of amyotrophic lateral sclerosis

    H. Warita, M. Aoki, H. Mizuno, N. Suzuki, Y. Itoyama

    NEUROMUSCULAR DISORDERS 20 (9-10) 652-652 2010/10

    DOI: 10.1016/j.nmd.2010.07.179  

    ISSN: 0960-8966

  301. 肝細胞増殖因子を用いた中枢神経再生 ―筋萎縮性側索硬化症および脊髄損傷― (脊椎脊髄ジャーナル)

    青木正志, 割田 仁, 船越 洋, 北村和也, 中村雅也, 岡野栄之

    脊椎脊髄ジャーナル 23 (9) 867-875 2010/09/25

  302. 神経難病の新展開 筋萎縮性側索硬化症 (Bio Clinica)

    青木正志

    Bio Clinica 25 (10) 48-53 2010/09/10

  303. 【脊髄再生基礎科学の現状と近未来の展望】 肝細胞増殖因子を用いた中枢神経再生 筋萎縮性側索硬化症および脊髄損傷

    青木 正志, 割田 仁, 船越 洋, 北村 和也, 中村 雅也, 岡野 栄之

    脊椎脊髄ジャーナル 23 (9) 867-875 2010/09

    Publisher: (株)三輪書店

    ISSN: 0914-4412

  304. PABPN1遺伝子のGCNリピートの非延長を確認した眼咽頭遠位型ミオパチーの1例

    高橋俊明, 田中洋康, 吉岡勝, 今野秀彦, 小野寺宏, 八木沼智香子, 早坂美保, 佐藤仁美, 小野寺淳一, 大沼歩, 千田圭二, 小林和夫, 竪山真規, 鈴木直輝, 青木正志, 糸山泰人

    臨床神経学 50 (3) 205 2010/03/01

    ISSN: 0009-918X

  305. Involvement of phagocytic microglia in increased vulnerability of motoneurons after facial nerve avulsion in presymptomatic ALS model rats

    Tomomi Sanagi, Keiko Ohsawa, Yasuko Nakamura, Eri Suzuki, Masashi Aoki, Hitoshi Warita, Yasuto Itoyama, Shigeo Uchino, Shinichi Kohsaka

    NEUROSCIENCE RESEARCH 68 E347-E348 2010

    DOI: 10.1016/j.neures.2010.07.1540  

    ISSN: 0168-0102

  306. Dynamic behavior of microglia in neurodegenerative diseases

    Keiko Ohsawa, Tomomi Sanagi, Yasuko Nakamura, Eri Suzuki, Masashi Aoki, Hitoshi Warita, Yasuto Itoyama, Shinichi Kohsaka

    NEUROSCIENCE RESEARCH 68 E15-E15 2010

    DOI: 10.1016/j.neures.2010.07.301  

    ISSN: 0168-0102

  307. Amyotrophic lateral sclerosis associated with mutations in the SOD1 gene Peer-reviewed

    Masashi Aoki

    Clinical Neurology 50 (11) 861 2010

    DOI: 10.5692/clinicalneurol.50.861  

    ISSN: 0009-918X

  308. ALS治療法開発の将来 神経栄養因子によるALSの治療戦略

    青木 正志, 割田 仁, 鈴木 直輝, 糸山 泰人

    臨床神経学 49 (11) 814-817 2009/11

    Publisher: (一社)日本神経学会

    DOI: 10.5692/clinicalneurol.49.814  

    ISSN: 0009-918X

  309. Dislocation of neuronal nitric oxide synthase contributes to muscle atrophy in amyotrophic lateral sclerosis

    N. Suzuki, M. Aoki, H. Warita, S. Takeda, Y. Itoyama

    NEUROMUSCULAR DISORDERS 19 (8-9) 566-566 2009/09

    DOI: 10.1016/j.nmd.2009.06.075  

    ISSN: 0960-8966

  310. ALSに対するHGFを用いた治療法の開発 (JALSA)

    青木正志, 割田 仁, 糸山泰人

    JALSA 78 22-25 2009/08/21

  311. 再生医療の成果を社会に還元するためには (細胞工学)

    青木正志

    細胞工学 28 (5) 478-479 2009/05

  312. ALSに対する再生医療および新薬開発の状況

    青木 正志

    難病と在宅ケア 15 (1) 30-34 2009/04

    Publisher: (株)日本プランニングセンター

    ISSN: 1880-9200

  313. 眼で見る神経内科 頭痛を伴うMarfan症候群患者のdural ectasia

    加藤 量広, 鈴木 直輝, 遠藤 薫, 青木 正志, 糸山 泰人

    神経内科 70 (4) 417-418 2009/04

    Publisher: (有)科学評論社

    ISSN: 0386-9709

  314. Appearance of phagocytic microglia in facial nuclei after nerve avulsion in presymptomatic ALS model rats

    Tomomi Sanagi, Shigeki Yuasa, Yasuko Nakamura, Masashi Aoki, Hitoshi Warita, Yasuto Itoyama, Shinichi Kahsaka, Keiko Ohsawa

    NEUROSCIENCE RESEARCH 65 S87-S88 2009

    DOI: 10.1016/j.neures.2009.09.353  

    ISSN: 0168-0102

  315. Aquaporin-4-antibody seroconversion occurs before the onset of neuromyelitis optica

    S. Nishiyama, A. Kikuchi, N. Suzuki, K. Jin, M. Aoki, T. Takahashi, T. Misu, K. Fujihara, Y. Itoyama

    MULTIPLE SCLEROSIS 15 (1) 145-145 2009/01

    ISSN: 1352-4585

  316. Microvascular regeneration in the spinal cord of transgenic rats with motor neuron degeneration

    Hitoshi Warita, Masashi Aoki, Hiroshi Funakoshi, Toshikazu Nakamura, Yasuto Itoyama

    NEUROSCIENCE RESEARCH 65 S120-S120 2009

    DOI: 10.1016/j.neures.2009.09.566  

    ISSN: 0168-0102

  317. 発症前長期にわたりAQP4抗体が陽性であったNMOの1例

    西山修平, 伊藤孝, 三須建郎, 高橋利幸, 菊池昭夫, 鈴木直輝, 神一敬, 青木正志, 藤原一男, 糸山泰人

    日本神経学会総会プログラム・抄録集 50th 190 2009

  318. ALSに対する再生医療および新薬開発の状況 (難病と在宅ケア)

    青木正志

    難病と在宅ケア 15 (1) 30-34 2009/01

  319. 神経難病の遺伝カウンセリング:総論およびALSに対する遺伝カウンセリング (難病と在宅ケア)

    青木正志

    難病と在宅ケア 13 (12) 7-9 2008/12

  320. 筋萎縮性側索硬化症(ALS)に対する神経再生誘導の試み (再生医療)

    青木正志, 割田 仁, 水野秀紀, 糸山泰人

    再生医療 7 366-370 2008/11

  321. 【神経再生の現状と課題】 筋萎縮性側索硬化症(ALS)に対する神経再生誘導の試み

    青木 正志, 割田 仁, 水野 秀紀, 糸山 泰人

    再生医療 7 (4) 366-370 2008/11

    Publisher: (株)メディカルレビュー社

    ISSN: 1347-7919

  322. Sjoegren症候群を合併したCADASILの2例

    川口典彦, 高井良樹, 鈴木直輝, 菊池昭夫, 竪山真規, 青木正志, 中島一郎, 糸山泰人

    臨床神経学 48 (10) 458 2008/10/01

    ISSN: 0009-918X

  323. Aquaporin-4-antibody seroconversion occurs before the onset of neuromyelitis optica

    Shuhei Nishiyama, Akio Kikuchi, Naoki Suzuki, Kazutaka Jin, Masashi Aoki, Toshiyuki Takahashi, Tatsuro Misu, Kazuo Fujihara, Yasuto Itoyama

    MULTIPLE SCLEROSIS 14 S237-S237 2008/09

    ISSN: 1352-4585

  324. ALS1(SOD1遺伝子変異によるALS)の臨床 (Clinical Neuroscience)

    青木正志

    Clinical Neuroscience 26 316-318 2008/03

  325. ALSの神経栄養因子治療 (Clinical Neuroscience)

    青木正志, 糸山泰人

    Clinical Neuroscience 26 330-332 2008/03

  326. 【神経難病の遺伝カウンセリング】 総論およびALSに対する遺伝カウンセリング

    青木 正志

    難病と在宅ケア 13 (12) 7-9 2008/03

    Publisher: (株)日本プランニングセンター

    ISSN: 1880-9200

  327. 【ALS 臨床と研究の最新情報】 家族性ALSとは ALS1(SOD1遺伝子変異によるALS)の臨床

    青木 正志

    Clinical Neuroscience 26 (3) 316-318 2008/03

    Publisher: (株)中外医学社

    ISSN: 0289-0585

  328. 【ALS 臨床と研究の最新情報】 ALSの治療とケア ALSの神経栄養因子治療

    青木 正志, 糸山 泰人

    Clinical Neuroscience 26 (3) 330-332 2008/03

    Publisher: (株)中外医学社

    ISSN: 0289-0585

  329. ジスフェルリノパチー(Dysferlinopathyおよび三好型遠位型筋ジストロフィー) (Clinical Neuroscience)

    青木正志

    Clinical Neuroscience 26 157-159 2008/02

  330. 【筋ジストロフィー 現在と未来】 分子病態と臨床 ジスフェルリノパチー(Dysferlinopathyおよび三好型遠位型筋ジストロフィー)

    青木 正志

    Clinical Neuroscience 26 (2) 157-159 2008/02

    Publisher: (株)中外医学社

    ISSN: 0289-0585

  331. ドーパミンD4受容体拮抗剤:L-745,870はALS病態モデルマウスの神経症候を改善する

    田中一則, 岡田義則, 菅野拓也, 菅野拓也, 大友麻子, 柳澤佳子, 柳澤佳子, 尾上久一郎, 大須賀等, 青木正志, 秦野伸二, 秦野伸二, 糸山泰人, 池田穰衛, 池田穰衛, 池田穰衛, 池田穰衛

    生化学 2008

    ISSN: 0037-1017

  332. Loss of ALS2 exacerbates motor dysfunction in a mutant SOD1-expressing mouse ALS model

    Shinji Hadano, Asako Otomo, Kyoko Suzuki-Utsunomiya, Ryota Kunita, Masashi Aoki, Yasuto Itoyama, Joh-E Ikeda

    NEUROSCIENCE RESEARCH 61 S268-S268 2008

    ISSN: 0168-0102

  333. In vivo DNA damage accumulation in aprataxin-related ataxia

    Makito Hirano, Hirohide Asai, Masashi Aoki, Keiji Shimada, Yoshiko Furiya, Takao Kiriyama, Masanori Ikeda, Nohoru Konishi, Yasuto Itoyama, Satoshi Ueno

    ANNALS OF NEUROLOGY 64 S37-S37 2008

    ISSN: 0364-5134

  334. Intrathecal delivery of HGF from the ALS onset suppresses disease progression in a rat ALS model

    Masashi Aoki, Hitoshi Warita, Yasuto Itoyama

    NEUROSCIENCE RESEARCH 61 S15-S15 2008

    ISSN: 0168-0102

  335. Impact of serotonin receptor-3 gene polymorphism on irritable bowel syndrome

    Lisa Aibiki, Tomoko Mizuno, Norio Ozaki, Ryoko Ishihara, Masashi Aoki, Yasuto Itoyama, Motoyon Kanazawa, Shin Fukudo

    GASTROENTEROLOGY 132 (4) A134-A135 2007/04

    ISSN: 0016-5085

  336. Intrathecal infusion of growth factors stimulates NG2-expressing progenitors in mutant SOD1-transgenic rats

    Hitoshi Warita, Masashi Aoki, Hideki Mizuno, Yasuto Itoyama

    NEUROSCIENCE RESEARCH 58 S84-S84 2007

    ISSN: 0168-0102

  337. Nitric oxide production results in disuse-induced muscle atrophy through dislocation of neuronal nitric oxide synthase

    Naoki Suzuki, Norio Motohashi, Yuko Suzuki, Yasuto Itoyama, Masashi Aoki, Shin'ichi Takeda

    NEUROSCIENCE RESEARCH 58 S177-S177 2007

    ISSN: 0168-0102

  338. nNOS/NOを介した筋萎縮の分子機構の解析

    鈴木直輝, 青木正志, 鈴木友子, 糸山泰人, 武田伸一

    日本神経学会総会プログラム・抄録集 48th 278 2007

  339. 【各種難病治療法の話題】 ALS治療薬の開発の現状

    青木 正志

    難病と在宅ケア 12 (8) 9-12 2006/11

    Publisher: (株)日本プランニングセンター

    ISSN: 1880-9200

  340. Dislocated neuronal nitric oxide synthase results in muscle atrophy during tail suspension

    N. Suzuki, N. Motohashi, A. Uezumi, S. Fukada, Y. Miyagoe-Suzuki, T. Yoshimura, Y. Itoyama, M. Aoki, S. Takeda

    NEUROMUSCULAR DISORDERS 16 (9-10) 692-693 2006/10

    DOI: 10.1016/j.nmd.2006.05.162  

    ISSN: 0960-8966

  341. Clinical features of the limb-girdle muscular dystrophy type 2B

    T. Takahashi, M. Aoki, H. Aiba, H. Sato, E. Abe, M. Ito, Y. Onodera, N. Suzuki, M. Tateyama, H. Konno, H. Onodera, Y. Itoyama

    NEUROMUSCULAR DISORDERS 16 (9-10) 696-696 2006/10

    DOI: 10.1016/j.nmd.2006.05.172  

    ISSN: 0960-8966

  342. Immunohistochemical dynamics of the redox system in the motor neurons in ALS: Self-survival mechanism under ALS stress

    Shinsuke Kato, Masako Kato, Eisaku Ohama, Yasuko Abe, Takeshi Nishino, Masashi Aoki, Yasuto Itoyama, Asao Hirano

    BRAIN PATHOLOGY 16 S8-S8 2006/09

    ISSN: 1015-6305

  343. ALS治療薬の開発の現状 (難病と在宅ケア)

    青木正志

    難病と在宅ケア 12 (8) 9-12 2006/08

  344. マウス尾部懸垂モデルにおけるnNOS/NOを介した筋萎縮の分子機構の解析

    鈴木直輝, 本橋紀夫, 上住聡芳, 深田宗一朗, 鈴木友子, 吉村哲彦, 糸山泰人, 青木正志, 武田伸一

    Inflamm Regen 26 (4) 371 2006/07/01

    ISSN: 1880-9693

  345. 肢帯型筋ジストロフィー (小児科診療)

    青木正志

    小児科診療 69 506-509 2006/04

  346. 単一遺伝子病とゲノム--テーマ1 脳神経変性疾患(4)筋萎縮性側索硬化症

    青木 正志

    ゲノム医学 5 (6) 589-593 2005/12

    Publisher: メディカルレビュー社

    ISSN: 1346-4671

  347. 筋萎縮性側索硬化症(ALS)における細胞内封入体の意義と神経栄養因子を用いた新規治療法の開発

    青木 正志

    Proceedings of Clinical Electron Microscopy 26 19-23 2005/12

    Publisher: 東北臨床超微形態懇話会世話人会

  348. 筋疾患の新しい展開 Dysferlinopathy(Miyoshi myopathy,LGMD2B)

    青木 正志, 高橋 俊明

    臨床神経学 45 (11) 938-942 2005/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  349. Differential brain activation during fear conditioning by serotonin transporter gene polymorphism

    T Mizuno, M Kano, J Watanabe, N Miura, Y Kawano, T Hattori, K Nakaya, S Sato, K Horie, M Aoki, Y Itoyama, R Kawashima, S Fukudo

    JOURNAL OF PSYCHOSOMATIC RESEARCH 58 (6) S93-S93 2005/06

    ISSN: 0022-3999

  350. 【精神神経疾患とゲノム 最近の動向】 筋萎縮性側索硬化症

    青木 正志

    ゲノム医学 5 (3) 283-291 2005/06

    Publisher: (株)メディカルレビュー社

    ISSN: 1346-4671

  351. 筋疾患 Dysferlinopathy(dysferlin異常症)

    青木 正志, 高橋 俊明

    Annual Review神経 2005 277-283 2005/01

    Publisher: (株)中外医学社

  352. 【神経疾患のメカニズムと新しい診断法&治療薬開発】 筋萎縮性側索硬化症(ALS)の治療薬の開発

    青木 正志

    Bioベンチャー 4 (6) 36-40 2004/11

    Publisher: (株)羊土社

    ISSN: 1346-5376

  353. 脊髄小脳変性症と運動ニューロン疾患 優性遺伝の運動ニューロン疾患 SOD1変異と神経細胞死

    青木 正志

    臨床神経学 44 (11) 788-791 2004/11

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

  354. 【神経変性疾患治療への展望 病態機序に基づく治療戦略】 筋萎縮性側索硬化症 神経栄養因子HGFの髄腔内投与による筋萎縮性側索硬化症治療法の開発

    青木 正志, 永井 真貴子, 石垣 あや, 糸山 泰人

    最新医学 59 (7) 1635-1641 2004/07

    Publisher: (株)最新医学社

    ISSN: 0370-8241

  355. 「進化」する疾患モデル動物 新世代の筋萎縮性側索硬化症(ALS)の動物モデル

    青木 正志

    細胞工学 23 (7) 838-841 2004/06

    Publisher: (株)学研メディカル秀潤社

    ISSN: 0287-3796

  356. Dysferlin遺伝子異常に伴う筋ジストロフィーマウス(SJLマウス)における遺伝子発現解析

    鈴木直輝, 青木正志, 高橋俊明, 日沼雄二, 小野寺好明, 竪山真規, 加藤昌昭, 石垣あや, 割田仁

    日本神経学会総会プログラム・抄録集 45th 371 2004/04/01

  357. Development of a new treatment technique for amyotrophic lateral sclerosis. Influence of endoplasmic reticulum stress on development of amyotrophic lateral sclerosis (ALS).

    山岸覚, 山口淳, 人見淳一, 片山泰一, 遠山正弥, 加藤昌昭, 青木正志, 糸山泰人

    筋萎縮性側索硬化症の病因・病態に関わる新規治療法の開発に関する研究班 平成15年度 研究報告書 2004

  358. 【神経難病の代表的疾患である筋萎縮性側索硬化症に対する治療への挑戦】 治療戦略に有用な筋萎縮性側索硬化症(ALS)の動物モデルの開発

    青木 正志, 糸山 泰人

    神経治療学 20 (5) 527-532 2003/09

    Publisher: 日本神経治療学会

    ISSN: 0916-8443

  359. 変異SOD1導入ラットにおける顔面神経外傷後の運動ニューロン易傷害性 : H46R導入ラットとG93A導入ラットの比較検討

    池田 憲, 渡部 和彦, 坂本 剛, 青木 正志, 川添 陽子, 永井 真貴子, 石垣 あや, 神位 りえ子, 岩崎 泰雄, 木下 真男, 糸山 泰人

    Neuropathology : official journal the Japanese Society of Neuropathology 23 102-102 2003/05/01

    ISSN: 0919-6544

  360. Facial nerve avulsion accelerates motoneuron degeneration in pre-symptomatic transgenic rats expressing mutant human Cu/Zn superoxide dismutase

    K Ikeda, K Watabe, M Aoki, T Sakamoto, A Ishigaki, M Nagai, R Kamii, Y Iwasaki, E Satoyoshi, Y Itoyama

    ANNALS OF NEUROLOGY 54 S53-S53 2003

    ISSN: 0364-5134

  361. 臨床に必要な神経化学 トランスジェニックラットによる新しいALSモデル

    青木 正志

    Clinical Neuroscience 20 (8) 858-859 2002/08

    Publisher: (株)中外医学社

    ISSN: 0289-0585

  362. 最新創薬 薬の分子メカニズム 筋萎縮性側索硬化症に対する治療薬の開発 グルタミン酸仮説からトランスジェニックラットモデルを用いた新規治療法の開発

    青木 正志

    Molecular Medicine 39 (9) 1074-1078 2002/08

    Publisher: (株)中山書店

    ISSN: 0918-6557

  363. ベーチェット病に対する免疫抑制療法施行中にトキソプラズマ脳炎を合併した一例

    中村 正史, 永井 真貴子, 志賀 裕正, 青木 正志, 糸山 泰人, 賀来 満夫, 矢野 明彦

    臨床神経学 42 (7) 646-646 2002/07

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

    eISSN: 1882-0654

  364. 【神経疾患と再生医療】 新しい筋萎縮性側索硬化症(ALS)モデル動物

    青木 正志, 永井 真貴子, 加藤 昌昭, 糸山 泰人

    最新医学 57 (7) 1622-1627 2002/07

    Publisher: (株)最新医学社

    ISSN: 0370-8241

  365. 筋ジストロフィーおよび関連疾患の臨床病態の解析

    佐橋 功, 衣斐 達, 田中 雅嗣, 青木 正志, 高橋 俊明, 南 成祐, 荒畑 喜一, 丸山 和佳子, 直井 信, 加藤 陽二, Faulkner Georgine

    厚生労働省精神・神経疾患研究委託費研究報告書 筋ジストロフィー及び関連疾患の臨床病態解明と治療法開発に関する研究 平成11〜13年度 30-31 2002/03

    Publisher: 厚生労働省精神・神経疾患研究班

  366. ALS Models by Transgenic Animals

    53 (9) 799-807 2001/09

    Publisher: 医学書院

    ISSN: 1881-6096

  367. [ALS models by transgenic animals] (No To Shinkei)

    Aoki M, Nagai M, Kato M, Itoyama Y

    No To Shinkei 53 (9) 799-807 2001/09

  368. 【遺伝子改変動物から神経変性疾患へのアプローチ】 トランスジェニック動物によるALSモデル

    青木 正志, 永井 真貴子, 加藤 昌昭, 糸山 泰人

    脳と神経 53 (9) 799-807 2001/09

    Publisher: (株)医学書院

    ISSN: 0006-8969

  369. 新規aprataxin遺伝子に変異を認めた低アルブミン血症を伴う脊髄小脳変性症の剖検例

    永田 哲也, 千田 圭二, 青木 正志, 長谷川 隆文, 志賀 裕正, 糸山 泰人, 丹野 尚, 樋口 じゅん, 今野 秀彦

    臨床神経学 41 (7) 448-448 2001/07

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

  370. LGMD2B(dysferlin deficiency)

    M. Aoki

    Ryōikibetsu shōkōgun shirīzu 84-87 2001/01/01

  371. ALS models by transgenic animals

    M. Aoki, M. Nagai, M. Kato, Y. Itoyama

    Brain and Nerve 53 (9) 799-807 2001

    ISSN: 0006-8969

  372. 【グルタミン酸 毒性からトランスポーターまで】 グルタミン酸トランスポーターとALS

    青木 正志

    Brain Medical 12 (2) 194-198 2000/06

    Publisher: (株)メディカルレビュー社

    ISSN: 0915-5759

  373. 【ミオパチー研究最前線】 遠位型筋ジストロフィー(三好型)におけるdysferlin遺伝子異常

    青木 正志

    神経研究の進歩 44 (2) 204-211 2000/04

    Publisher: (株)医学書院

    DOI: 10.11477/mf.1431901139  

    ISSN: 0001-8724

  374. 遠位型筋ジストロフィー(三好型)におけるdysferlin遺伝子異常 (特集 ミオパチー研究最前線)

    青木 正志

    神経研究の進歩 44 (2) 204-211 2000/04

    Publisher: 医学書院

    DOI: 10.11477/mf.1431901139  

    ISSN: 0001-8724

  375. 【三好型ミオパチー 臨床から遺伝子まで】 三好型遠位型筋ジストロフィーの原因遺伝子dysferlinの同定

    青木 正志

    神経内科 52 (3) 289-296 2000/03

    Publisher: (有)科学評論社

    ISSN: 0386-9709

  376. 筋疾患 三好型遠位型筋ジストロフィー/肢帯型筋ジストロフィーLGMD2Bとdysferlin

    青木 正志

    Annual Review神経 2000 271-277 2000/01

    Publisher: (株)中外医学社

  377. LGMD(肢帯型筋ジストロフィー)の概観 ポジショナルクローニングによる三好型遠位型筋ジストロフィーの原因遺伝子dysferlinの同定

    青木 正志, 荒畑 喜一, Brown Robert H.Jr

    臨床神経学 39 (12) 1272-1275 1999/12

    Publisher: (一社)日本神経学会

    ISSN: 0009-918X

  378. Positional cloning of the gene for Miyoshi myopathy and limb-girdle muscular dystrophy

    Masashi Aoki, Kiichi Arahata, Robert H. Brown Jr.

    Clinical Neurology 39 (12) 1272-1275 1999/12

    ISSN: 0009-918X

  379. ALSとグルタミン酸トランスポーター (運動ニューロン疾患)

    青木 正志

    医学のあゆみ 191 (8) 817-820 1999/11/20

    Publisher: 医歯薬出版

    ISSN: 0039-2359

  380. 【ミオパチー update】 進行性筋ジストロフィーとその類縁疾患 三好型遠位型筋ジストロフィー ポジショナルクローニングによる原因遺伝子dysferlinの同定

    青木 正志

    Clinical Neuroscience 17 (10) 1146-1148 1999/10

    Publisher: (株)中外医学社

    ISSN: 0289-0585

  381. Amyotrophic lateral sclerosis with abundant Bunina body

    M Nagai, Y Siga, M Aoki, H Konno, T Kitamoto, Y Itoyama

    NEUROLOGY 52 (6) A529-A529 1999/04

    ISSN: 0028-3878

  382. A presenilin-1 mutation in a Japanese family with Alzheimer's disease

    M Aoki, K Abe, T Tsuda, M Morita, Y Itoyama, N Oda, M Kanai, M Watanabe, M Shoji, M Ikeda

    NEUROLOGY 48 (3) 1096-1096 1997/03

    ISSN: 0028-3878

  383. 本邦における家族性筋萎縮性側索硬化症(FALS)におけるCu/ZnSOD遺伝子変異と臨床像

    長谷川 隆文, 阿部 康二, 青木 正志

    日本臨床 54 (11) 3157-3162 1996/11

    Publisher: (株)日本臨床社

    ISSN: 0047-1852

  384. Clinical characteristics of familial amyotrophic lateral sclerosis with Cu/Zn superoxide dismutase gene mutations in Japan

    T. Hasegawa, K. Abe, M. Aoki, Y. Itoyama

    Nippon rinsho. Japanese journal of clinical medicine 54 3157-3162 1996/11/01

    ISSN: 0047-1852

  385. Cu/Zn SOD遺伝子にH46R点突然変異のみられた家族性筋萎縮性側索硬化症 : 家族性ALSの新しいサブタイプの可能性

    青木 正志

    東北医学雑誌 108 (1) 79-82 1996/03

    ISSN: 0040-8700

  386. MITOTIC AND MEIOTIC STABILITY OF X-LINKED SPINAL AND BULBAR MUSCULAR-ATROPHY GENE

    Y IKEDA, M WATANABE, K ABE, M AOKI, Y ITOYAMA, M SHOJI, S HIRAI

    AMERICAN JOURNAL OF HUMAN GENETICS 57 (4) 1402-1402 1995/10

    ISSN: 0002-9297

  387. ANALYSIS OR CAG TRINUCLEOTIDE EXPANSION ASSOCIATED WITH MACHADO-JOSEPH DISEASE (MJD)

    M WATANABE, K ABE, M AOKI, M SHOJI, Y IKEDA, S HIRAI, Y ITOYAMA

    AMERICAN JOURNAL OF HUMAN GENETICS 57 (4) 582-582 1995/10

    ISSN: 0002-9297

  388. 虚血性脳疾患up to date 虚血におけるタンパク質,遺伝子の変化

    青木 正志, 阿部 康二

    カレントテラピー 11 (1) 150-154 1992/12

    Publisher: (株)ライフメディコム

    ISSN: 0287-8445

  389. 脳虚血の病態生化学

    松尾 嘉之, 青木 正志, 川越 淳一

    蛋白質・核酸・酵素 37 (8) 1382-1393 1992/06

    Publisher: 共立出版(株)

    ISSN: 0039-9450

  390. Pathophysiology of cerebral ischemia

    Y. Matsuo, M. Aoki, J. Kawagoe, K. Kogure

    Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme 37 1382-1393 1992/06/01

    ISSN: 0039-9450

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Books and Other Publications 10

  1. 筋萎縮性側索硬化症(ALS)診療ガイドライン2023

    筋萎縮性側索硬化症診療ガイドライン作成委員会, 日本神経学会

    南江堂 2023/05

    ISBN: 9784524204557

  2. 脳神経疾患最新の治療

    園生, 雅弘, 北川, 一夫, 青木, 正志

    南江堂 2021/02

    ISBN: 9784524227853

  3. 運動ニューロン疾患 (神経内科Clinical Questions & Pearl)

    鈴木則宏, 青木正志

    中外医学社 2017/11

    ISBN: 449822888X

  4. 筋萎縮性側索硬化症診療ガイドライン2013

    編集, 筋萎縮性側索硬化症診療ガイドライン, 作成委員会

    南江堂 2013/12

    More details Close

    https://www.neurology-jp.org/guidelinem/als2013_index.html

  5. 筋疾患診療ハンドブック

    青木正志, 内野誠

    中外医学社 2013/05/01

    ISBN: 4498228081

  6. イラストでわかる神経症候 : 機能・解剖学から診断へのアプローチ

    Alberstone Cary D, Benzel Edward C, Najm Imad M, Steinmetz Michael P, Kanasz Joseph, Norviel Michael, Rhoton Albert L. Jr, 青木 正志, 近藤 智善, 野元 正弘

    丸善出版 2012

    ISBN: 9784621086292

  7. からだの科学265 神経内科の病気のすべて

    鈴木則宏, 青木正志

    日本評論社 2010/05

  8. 神経疾患の遺伝子診断ガイドライン2009

    編集, 神経疾患の遺伝子診断ガイドライン, 作成委員会

    医学書院 2009/10/01

  9. EBM神経疾患の治療(2009-2010)

    岡本幸市, 棚橋紀夫, 水澤英洋, d. 青木正志

    中外医学社 2009/05

  10. 難病患者入院施設確保マニュアル

    厚生労働省, 重症難病患者の地域医療体制の構築に関する研究班, 難病患者入院確保プロジェクト委員会, d, 青木正志, 糸山泰人

    厚生労働省 2008/01

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Presentations 28

  1. Prevalence of inclusion body myositis (IBM) in Japanese population International-presentation

    Suzuki N, Aoki M, Tateyama M, Izumi R, Akiyama T, Warita H, Itoyama Y, Mori, M Kusaka H, Higuchi I, Kondo T, Uchino M, Kaji R, Nishino I

    12th International Congress on Neuromuscular Diseases 2010/07/17

  2. Angiogenesis in the spinal cord of transgenic rats with motor neuron degeneration International-presentation

    Warita H, Aoki M, Mizuno H, Suzuki N, Itoyama Y

    12th International Congress on Neuromuscular Diseases 2010/07/17

  3. FALS with FUS mutation in Japan with early onset, rapid progress and basophilic inclusion International-presentation

    Aoki M, Suzuki N, Warita H, Kato M, Mizuno H, Shimakura N, Akiyama T, Furuya H, Hokonohara T, Iwaki A, Togashi S, Konno H, Itoyama Y

    12th International Congress on Neuromuscular Diseases 2010/07/17

  4. SOD1変異による家族性ALS

    青木正志

    第51回日本神経学会総会 2010/05/21

  5. FUS遺伝子異常に伴う筋萎縮性側索硬化症(ALS)

    青木正志

    第31回神経組織培養研究会 2010/03/13

  6. Generation and characterization of congenic lines of mutant SOD1 transgenic and ALS2 knockout mice International-presentation

    Hadano S, Otomo A, Kunita R, Suzuki-Utsunomiya K, Yoshii Y, Aoki M, Itoyama Y, Iwasaki Y, Ikeda JE

    20th International Symposium on ALS/MND 2009/12/08

  7. A therapeutic agent (NDDPX08) delays disease progression, improves motor function and prolongs survival in a mouse model of ALS International-presentation

    Tanaka K, Kanno T, Yanagisawa Y, Aoki M, Hadano S, Itoyama Y, Ogino M, Iwasaki Y, Yoshii F, Ikeda J-E

    20th International Symposium on ALS/MND 2009/12/08

  8. Endothelial proliferation in the spinal cord microvasculature of ALS transgenic rats International-presentation

    Warita H, Aoki M, Mizuno H, Itoyama Y

    20th International Symposium on ALS/MND 2009/12/08

  9. Dislocation of neuronal nitric oxide synthase contributes to muscle atrophy in amyotrophic lateral sclerosis International-presentation

    Suzuki N, Aoki M, Warita H, Takeda S, Itoyama Y

    14th International Congress of World Muscle Society 2009/09/09

  10. HGFを用いたALSに対する治療法の開発

    青木正志

    第27回日本神経治療学会総会 2009/06/11

  11. 神経栄養因子によるALSの治療戦略

    青木正志

    神経栄養因子によるALSの治療戦略 2009/05/20

  12. ALSの臨床と研究の進歩

    青木正志

    第18回日本神経学会東北地区 生涯教育講演会 2009/03/06

  13. Effects of edaravone, a free radical scavenger approved in Japan for indications of acute ischemic stroke, in a transgenic rat model of amyotrophic lateral sclerosis International-presentation

    Aoki M, Warita H, Mizuno H, Yuki S, Takahashi I, Itoyama Y

    19th International Symposium on ALS/MND 2008/11/03

  14. Digestion of the extracellular chondroitin sulfate promotes an intrinsic regenerative process in the spinal cord of ALS transgenic rats International-presentation

    Warita H, Aoki M, Mizuno H, Itoyama Y

    19th International Symposium on ALS/MND 2008/11/03

  15. Hadano S, Otomo A, Kunita R, Suzuki-Utsunomiya K, Onoe K, Osuga H, Aoki M, Itoyama Y, Ikeda JE International-presentation

    ALS, alsin-deficient SOD, transgenic mice exhibit increased accumulation of, insoluble, roteins in, the, spinal cord

    19th International Symposium on ALS/MND 2008/11/03

  16. In vivo DNA damage accumulation in aprataxin-related ataxia International-presentation

    Hirano M, Asai H, Aoki M, Shimada K, Furiya Y, Kiriyama T, Ikeda M, Konishi N, Itoyama Y, Ueno S

    133rd Annual Meeting of the American Neurological Association 2008/09/21

  17. Development of new therapy for amyotrophic lateral sclerosis using transgenic rodent models International-presentation

    Aoki M, Itoyama Y

    Brain Science Summer Retreat in Matsushima “New Era of Neuroscience –From molecules to Society” 2008/08/20

  18. Intrathecal delivery of HGF from the ALS onset suppresses disease progression in a rat ALS model

    Aoki M, Warita H, Itoyama Y

    The 31st Annual Meeting of the Japan Neuroscience Society 2008/07/09

  19. SOD1遺伝子変異とALS

    青木正志

    第49回日本神経学会総会 2008/05/15

  20. Loss of ALS2/alsin exacerbates motor dysfunction in a mutant SOD1-expressing mouse ALS model International-presentation

    Hadano S, Otomo A, Suzuki-Utsunomiya K, Kunita R, Aoki M, Itoyama Y, Ikeda JE

    18th International Symposium on ALS/MND 2007/12/01

  21. Aoki M, Ishigaki A, Nagai M, Warita H, kato S, Kato M, Nakamura T, Funakoshi H, Itoyama Y. International-presentation

    Intrathecal delivery of hepatocyte growth factor at, the onset of paralysis slows disease progression in, a, rat of ALS

    17th International Symposium on ALS/MND 2006/11/30

  22. Intrathecal infusion of antihepatocyte growth factor antibody exacerbates disease progression in a rat model of ALS. International-presentation

    Warita H, Aoki M, Nagai M, Ishizaki A, Mizuno H, Funakoshi H, Itoyama Y

    17th International Symposium on ALS/MND 2006/11/30

  23. Redox system up-regulation in ALS motor neurons is a survival mechanism under stress. International-presentation

    Kato S, Kato M, Ohama E, Abe Y, Nishino T, Aoki M, Itoyama Y, Hirano A

    17th International Symposium on ALS/MND 2006/11/30

  24. Clinical features of ALS in Japan from the registration system of intractable diseases. International-presentation

    Atsuta N, Watanabe H, Ito M, Aoki M, Nakano I, Yuasa T, Takano H, Tshuji S, Kuzuhara s, Sobue G

    17th International Symposium on ALS/MND 2006/11/30

  25. Protein synthesizing system in the motor neurons in the spinal cord in amyotrophic lateral sclerosis: Pursuing the beginning of the alterations. International-presentation

    Oyanagi K, Nagasao I, Yamazaki M, Okamoto K, Aoki M, Watabe K, Wada M, Morita T, Takahashi H, Mizutani T, Hayashi H

    17th International Symposium on ALS/MND 2006/11/30

  26. Immunohistochemical dynamics of the redox system in the motor neurons in ALS: Self-survival mechanism under ALS stress. International-presentation

    Kato S, Kato M, Ohama E, Abe Y, Nishino T, Aoki M, Itoyama Y, Hirano A

    XVI th International Congress of Neuropathology 2006/09/10

  27. ALS治療実現の見通し、栄養因子からのアプローチ

    青木正志

    厚生労働科学研究費補助金難治性疾患克服研究事業「筋萎縮性側索硬化症の画期的診断・治療法に関する研究」班ワークショップ 2006/07/08

  28. 運動ニューロン疾患、特にALSの治療戦略

    糸山泰人, 青木正志

    第41回 脳のシンポジウム 2006/02/18

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Industrial Property Rights 4

  1. 細胞膜の損傷修復促進剤

    青木 正志, 菅野 新一郎, 鈴木 直輝, 小野 洋也

    Property Type: Patent

  2. ALSモデルラット

    青木 正志, 糸山 泰人, 三好 一郎, 笠井 憲雪

    Property Type: Patent

  3. 運動ニューロン疾患の予防剤及び/又は治療剤

    加藤丈夫, 佐藤裕康, 加藤 肇, 青木正志ら

    Property Type: Patent

  4. 神経軸索分岐異常の改善

    国立大学法人東北大学, 学校法人慶應義塾, 一般財団法人生産技術研究奨励会, 株式会社Jiksak Bioengineering

    Property Type: Patent

Research Projects 35

  1. Elucidation of the molecular pathogenesis of ALS using a motor neuron-skeletal muscle cell model

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2023/04/01 - 2026/03/31

  2. Elucidation of the molecular pathogenesis of ALS using a motor neuron-skeletal muscle cell model

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2023/04/01 - 2026/03/31

  3. Aberrant RNA splicing in sporadic inclusion body myositis

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Challenging Research (Exploratory)

    Institution: Tohoku University

    2023/06/30 - 2025/03/31

  4. 筋萎縮性側索硬化症モデルにおける軸索分岐異常の分子基盤の解明

    鈴木 直輝, 割田 仁, 青木 正志

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 基盤研究(C)

    Category: 基盤研究(C)

    Institution: 東北大学

    2021/04/01 - 2024/03/31

    More details Close

    筋萎縮性側索硬化症(ALS)は運動ニューロンが系統的に障害され根本的な治療が未だ無い難病である。ALSの多くを占める孤発性ALSの剖検脳・脊髄ではTDP-43の封入体が見られる。TDP-43をコードするTARDBPはFUSやhnRNPA1と共に家族性ALSの原因遺伝子であり、またRNA結合蛋白でもある。RNA代謝異常は、軸索障害とともに家族性・孤発性ALSに共通して見られる病態機序である。独自開発したマイクロ流体デバイスを用いiPS細胞由来運動ニューロン軸索を大量に回収・網羅的解析し、FUS、hnRNPA1、TDP-43といった代表的なRNA結合蛋白変異における病態を比較解析してきた。 本年度はRNA-seq解析により、TARDBP変異による軸索局所でのRNA代謝異常を転写レベルで解析した。PHOX2Bを見出し、その発現抑制で健常者運動ニューロンの突起伸長抑制が再現された。動物モデルとして、ゼブラフィッシュでも、モルフォリノによるPHOX2Bの発現抑制実験で、細胞モデルと同様に脊髄軸索長が低下し、さらに運動機能も低下した。PHOX2Bは、ALSで発症後長期まで保たれる動眼神経や自律神経において発現が高いことから、変異運動ニューロンの選択的変性に関わる可能性が考えられる。上記の新しい知見をStem Cell Reports誌に報告した(Mitsuzawa S, et al. Stem Cell Reports 2021)。各遺伝子変異の共通分子の解析や動物モデルを用いた検証を行っていく。

  5. ALS共通病態としての軸索変性と軸索再生:細胞種選択的な治療法開発

    青木 正志, 割田 仁, 鈴木 直輝

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 基盤研究(B)

    Category: 基盤研究(B)

    Institution: 東北大学

    2020/04/01 - 2023/03/31

  6. Elucidation of the pathogenesis of inclusion body myositis by focusing on the abnormal aggregation protein clearance system

    AOKI Masashi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Research (Exploratory)

    Category: Grant-in-Aid for Challenging Research (Exploratory)

    Institution: Tohoku University

    2020/07/30 - 2022/03/31

    More details Close

    Inclusion body myositis (sIBM) is a chronic, progressive and refractory muscle disease seen in middle-aged and older people. sIBM patients' skeletal muscles show abnormal aggregates such as amyloid-beta, TDP-43 and FUS, suggesting a degenerative disease in the muscle. Using an originally developed human skeletal muscle electrical pulse culture system, we found cytoplasmic deposition of TDP-43, one of the aggregation proteins found in ALS. The results were reported in SciRep journal. Myoblasts were established from three new cases of sIBM muscle biopsies. B-cell follicle in sIBM muscle tissue were also observed in a case. It was summarised and reported in NeuromusDisord journal.

  7. Analysis of axonal pathomechanism in amyotrophic lateral sclerosis using human iPS cell-derived nerve organoid.

    Suzuki Naoki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2018/04/01 - 2021/03/31

    More details Close

    RNA sequencing analysis of axonal fraction of nerve organoid revealed a gene, Fos-B, associated with the pathogenesis of FUS mutations. We demonstrated that Fos-B is involved in the formation of abnormal axon branching associated with FUS mutations in motor neurons using overexpression and inhibition experiments. Furthermore, using zebrafish overexpression of Fos-B and human autopsy spinal cord, we clarified the relationship between Fos-B and ALS pathology. These results were reported in EBioMedicine in 2019. We wrote a review on omics analysis of axons, which was published in Frontiers in Neuroscience in 2020. In 2021, we found decreased expression of Phox2B using TARDBP mutant iPS cells, the causative gene of ALS, and it was accepted by Stem Cell Reports. We will continue to investigate the axonal pathology underlying motor neuron vulnerability.

  8. Elucidating the mechanism of abnormal protein aggregation in sporadic inclusion body myositis by single molecule nanoimaging

    Aoki Masashi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Research (Exploratory)

    Category: Grant-in-Aid for Challenging Research (Exploratory)

    Institution: Tohoku University

    2018/06/29 - 2020/03/31

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    In this study, myoblasts were harvested from sporadic inclusion body myositis (sIBM) patients during muscle biopsy, and a total of six lines were stocked during these two years. Cellular stress was applied to human skeletal muscle using electro-pulse-constriction-culture-system (EPS) which reproduces long-lasting muscle contraction. Analysis was performed by RNA sequencing using cells before and after contraction stress. The characteristics of the co-culture system (EPS culture) were reported in an international journal. In addition, TDP-43, which is a component of the aggregates, is labeled by single-molecule nanoimaging, and the presence or absence of aggregate formation before and after EPS culture was evaluated. Furthermore, analysis of the myoblast specific proteasome deficient mouse revealed that p53 is important for the maintenance of myoblasts pool.

  9. Unraveling common mechanisms underlying neuromuscular degeneration in multisystem proteinopathy

    Aoki Masashi, OKANO HIDEYUKI

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2016/04/01 - 2019/03/31

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    Multisystem proteinopathy (MSP) is an inherited neuromuscular syndrome characterized by progressive and selective degeneration of skeletal muscle, bone, cerebrocortical, and motor neuron with aberrant protein aggregates, resulting in a combination of amyotrophic lateral sclerosis, frontotemporal dementia, inclusion body myopathy (IBM), and Paget disease of bone. In this study, using patient-derived induced pluripotent stem cells (iPSCs), we have developled motor neurons and skeletal muscle cells with an MSP type 3 (MSP3)-linked hnRNPA1 gene mutation. Isogenic control iPSCs are also under development. To reveal the underlying pathomechanisms particularly related to assembly/disassembly of RNA granules, we are trying to recapitulate pathological phenotypes in these human cellular models of MSP3.

  10. Elucidating the molecular pathology of inclusion body myositis using novel culture system and next generation sequencer

    Aoki Masashi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: Tohoku University

    2016/04/01 - 2018/03/31

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    As for sIBM, patient samples were collected and clinical information was also collected at the same time. The significance of autoantibody pathology in patient serum was analyzed by human serum and mouse experiment in collaboration with Kumamoto University. CD56 positive skeletal myoblasts from some skeletal muscles were collected and established from 8 sIBM cases. RNA sequencing was performed on 4 cases of sIBM. Including comparison with 9 hereditary inclusive body myopathies, disease-related reported mutations and rare variants were extracted. We are also analyzing mice model based on proteasome dysfunction hypothesis.

  11. A research of immune mechanism and treatment in neuromyelitis optica

    MISU TATSURO, Aoki Masashi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2015/04/01 - 2018/03/31

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    We made a new high-affinity antibody against the extradomain of aquaporin-4(AQP4)and studied about its pathogenic roles in experimental rat models. We revealed that high-affinity IgG could make a diffuse astrocytophaty with extensively diffuse lesion lacking AQP4 compared with human IgG, suggesting the important role of antibody-related affinity in the pathogenesis of neuromyelitis optica (NMO). In addition, a rat model injected with AQP4-specific T cell lines and human-derived AQP4-IgG, we could make a new rat model with typical perivascular loss of AQP4 in cerebrum, periventriculum, spinal cord, retina, and optic chiasm with secondary demyelination and diffuse axonal damage, which is close to the pathological findings of tiffuse injury in NMO patients in post-mortem.

  12. 異常タンパク伝播阻止に立脚した神経変性疾患の進行予防治療開発

    青木 正志

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 新学術領域研究(研究領域提案型)

    Category: 新学術領域研究(研究領域提案型)

    Institution: 東北大学

    2015/04/01 - 2017/03/31

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    本年度は (i) 細胞内輸送とαシヌクレイン(aS)代謝および (ii) aS細胞間伝播に関する2課題に注力した。第一の課題では、エンドソーム分子DNAJC13遺伝子変異による家族性パーキンソン病(PD)の分子病態を検証した。同研究にて、ヒトN855S変異型DNAJC13発現ショウジョウバエにヒトaS遺伝子を共発現することで、複眼変性が顕著に増強されると共にハエ脳内にproteinase K耐性不溶性aS蓄積を生じること、またclimbing assayによる運動機能が低下することを確認した。培養細胞系を用いた検討では、変異型DNAJC13発現によりエンドソーム内にaSの異常蓄積を認めること、初期-後期エンドソーム/リサイクルエンドソームの輸送が障害さることを明らかにした。さらに、変異型DNAJC13陽性エンドソーム上では、アクチン骨格形成が阻害されるとともに、エンドソームへのRabタンパクリクルートメント異常が起こっていることを明らかにした(※現在投稿中)。もう一つの課題として、aS細胞間伝播のメカニズム解析を進めた。この過程で細胞外aSは細胞膜上のドパミントランスポータ-(DAT)パーティションを変調させるとともに、エンドサイトーシスによる同分子の内在化・不活性化を誘導し、ドパミン神経機能に影響を与えていることを確認した。また、一部の細胞外aSはDATエンドサイトーシスに伴って細胞内へ取り込まれていることが確認された。(投稿準備中)。また、安定した線維化aS脳内接種を可能とする超音波印加装置を用いた改良型マウスモデルを作出し、先行実験で線維化aS細胞内取込阻害効果が確認されたセルトラリンの治療効果検証を進めている。

  13. Genetic analysis and establishment of in vitro model for inclusion body myositis

    Aoki Masashi, Kato MASAAKI, SUZUKI Naoki, WARITA Hitoshi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: Tohoku University

    2014/04/01 - 2016/03/31

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    Sporadic inclusion body myositis (sIBM) is an intractable and progressive skeletal muscle disease of unknown etiology and without effective treatment. Muscle biopsy typically reveals endomysial inflammation, invasion of mononuclear cells into non-necrotic fibers and rimmed vacuoles, suggesting inflammation and degeneration co-exist as part of the pathomechanism. We made muscle specific proteasomal deficient mice and reported in JCS paper. We also found familial case of inclusion body myopathy with the mutation in hnRNPA1. We also established iPS cells from these patients.

  14. Elucidating the RNA pathomechanism in FUS-FALS iPS induced motor neurons

    Aoki Masashi, Kato MASAAKI, Naoki SUZUKI, Hitoshi WARITA, OKANO Hideyuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2013/04/01 - 2016/03/31

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    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting in the selective death of motor neurons. ALS symptoms are associated with muscle weakness and paralysis and approximately 80% of ALS patients die within 5 years after the onset of these symptoms. We generated induced pluripotent stem cells (iPSC) from familial ALS (FALS) patients with a missense mutation in the fused-in sarcoma (FUS) gene carrying the heterozygous FUS H517D mutation These cell-derived motor neurons mimicked several neurodegenerative phenotypes including mis-localization of FUS into cytosolic and stress granules under stress conditions, and cellular vulnerability (Ichiyanagi et al. Stem Cell Reports 2016).

  15. Identification of glycoprotein nonmetastatic melanoma protein B (GPNMB) receptor and effect of GPNMB in higher brain function

    Hara Hideaki, TSURUMA Kazuhiro

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Gifu Pharmaceutical University

    2013/04/01 - 2016/03/31

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    The aim of this study was to lead to development of effective novel treatment for GPNMB related diseases by investigating whether GPNMB affects to memory and by identifying of novel GPNMB extracellular fragment receptors. We found that GPNMB promoted hippocampus-dependent memory by increasing expression levels of total GluA1 proteins and phosphorylated GluA1 proteins. Moreover, we also found that GPNMB extracellular fragment bound to Na+, K+-ATPase (NKA) α1 and NKA α3 and activated PI3K/Akt pathway and MEK/ERK pathway via NKA α1 and α3. Therefore, it was suggested that NKA α1 and α3 work as a novel GPNMB extracellular fragment receptor.

  16. Role of Nrf1 activation in progressive neurodegeneration

    NISHIJIMA Ichiko, KATSUOKA Fumiki, AOKI Masashi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2012/04/01 - 2016/03/31

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    Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons. Although defective ubiquitin-proteasome system is associated with neurodegenerative diseases commonly, the underlying molecular mechanisms are still unknown. To understand defense mechanisms using ubiquitin-proteasome system against progressive degeneration of neurons, we have analyzed Nrf1 activation in neurodegenerative disease condition using the compound transgenic mice carrying Nrf1 and mutant human SOD1 genes. The compound transgenic mice overexpressed Nrf1 and mutant human SOD1 have similar onset of neurodegeneration to mutant SOD1 transgenic mice. However, their degenerative progression was faster than mutant SOD1 transgenic mice. Our data indicate that Nrf1 activation may contribute acceleration of neurodegenerative disorders.

  17. The clinical utility of makeshift beds in the Great East Japan Earthquake shelters

    NARA Masayuki, AOKI Masashi, TAMADA Tsutomu, FUKUDO Shin

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: Tohoku University

    2012/04/01 - 2014/03/31

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    Strong earthquake have been reported to increase the incidence of diseases. One reason for these increases may be the stress from the poor living environment for evacuees in disaster shelters. To reduce stress, makeshift cardboard beds were introduced in shelters in the Ishinomaki region, one of the areas heavily damaged by the Great East Japan Earthquake. The study was performed to determine whether use of the beds offered a reduction in the disease burden. Blood pressure measurements, Timed Up & Go test which assesses functional mobility, and questionnaire survey scores improved significantly 1 month after the introduction of the beds. Makeshift beds of cardboard could be very useful in disaster shelters.

  18. Analysis to reveal a disease causing gene in a family with hereditary myopathy with inclusion body

    AOKI Masashi, KATO Masaaki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: Tohoku University

    2012/04/01 - 2014/03/31

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    Myofibrillar myopathy (MFM) is a group of chronic muscular disorders that show the focal dissolution of myofibrils and accumulation of degradation products. In this study, we performed linkage analysis and exome sequencing on the family of MFM patients and identified a novel c.90263G4T mutation in the TTN gene (NM_001256850). Mutations in TTN in patients with hereditary myopathy with early respiratory failure (HMERF, MIM #603689) was reported very recently. The mutation identified in this study is located on the A-band domain of titin, suggesting a strong relationship between mutations in the A-band domain of titin and HMERF. It is possible that focused analysis of TTN may detect more mutations in patients with MFMs, especially in those with early respiratory failure.

  19. Demonstration of the abnormal conformational transition of amyloid proteins and it's application as an early diagnostic tool

    POPIEL HELENA Akiko, NAGAI Yoshitaka, AOKI Masashi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Innovative Areas (Research a proposed research project)

    Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research a proposed research project)

    Institution: National Center of Neurology and Psychiatry

    2009 - 2012

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    In the prion diseases, the abnormal structure of the disease-causing protein is transmitted to proteins with a normal structure. In this study, we aimed to elucidate whether the abnormal structure of the disease-causing proteins of the polyglutamine (polyQ) neurodegenerative diseases can also be transmitted, and whether this phenomenon could be used for detection of minute levels of abnormal polyQ proteins. We found that addition of a minute level of abnormal polyQ protein to normal polyQ proteins causes acceleration of the structural transition of the proteins. Furthermore, for detection of proteins with an abnormal structure, we analyzed systems involving both turbidity as well as fluorescence, and found that they both had equal sensitivity. We also determined a purification method of the polyQ protein that allows structural transition of the protein at high efficiency.

  20. Elucidate the pathomechanism of inclusion body myositis(IBM)

    ITOYAMA Yasuto, AOKI Masashi, SUZUKI Naoki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: National Center of Neurology and Psychiatry

    2010 - 2011

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    Sporadic inclusion body myositis(sIBM) is an intractable and progressive skeletal muscle disease of unknown cause and without effective treatment. Our purpose is to elucidate the pathomechanism of sIBM exploring the autoantibody in the serum of sIBM patients using protein array. We also produced muscle specific proteasome deficient mice as the disease model of sIBM.

  21. Induction of regenerative microenvironment around spinal motor neurons by exogenous factors

    AOKI Masashi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2009 - 2011

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    Amyotrophic lateral sclerosis (ALS)is an adult-onset neurodegenerative disease characterized by selective loss of motor neurons. As compared with vehicle-treated ALS rats, a sequential intrathecal infusion of FGF-2 and EGF followed by hepatocyte growth factor (HGF)resulted in increased neuroblastic cells in the spinal cord of ALS rats, even after the onset of motor neuron disease. It was accompanied by significant suppression of gliogenesis and deposition of chondroitin sulfate. Moreover, angiogenic factors such as FGF-2 and HGF revealed significant neuroprotective effects in ALS rats. Therefore, motor neuron-surrounding microenvironment may be a potential therapeutic target in the future development of regenerative therapy for ALS.

  22. Development a novel therapeutic strategy based on neural stem cells activation in amyotrophic lateral sclerosis using trophic factors

    AOKI Masashi, ITOYAMA Yasuto

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2007 - 2008

  23. Identification of new genes associated with distal type of muscular dystrophies

    AOKI Masashi, ITOYAMA Yasuto

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2005 - 2006

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    Muscular dystrophies with an autosomal recessive mode of inheritance constitute a genetically heterogeneous group of disorders. Distal myopathies (also designated distal muscular dystrophies) are by definition disorders with weakness and atrophy predominantly in the distal muscles. Miyoshi myopathy (MM) is an autosomal recessive distal muscular dystrophy characterized by mid-to late childhood or early adulthood onset, with preferential involvement of the calf muscles and highly elevated levels of the enzyme serum creatine kinase. MM was first described by Miyoshi in Japan. The main locus for MM was mapped to chromosome 2p13. However the MM pedigrees showed non-linkage to chromosome 2p, indicating there is genetic heterogeneity in this disease. Mutations in the dysferlin gene cause both MM and limb girdle muscular dystrophy 2B (LGMD2B). However, dysferlinopathy exhibits marked heterogeneity in the initial distribution of muscle involvement at the onset of the disease. Some additional factors distinct from dysferlin are considered to be involved in the pathomechanism. We describe a Japanese patient with dysferlinopathy who exhibited distal anterior compartment myopathy (DACM) with early contractures of the ankle, whose pedigree included patients with two other types of dysferlinopathy. Gene analysis confirmed that all the patients in the family shared the same homozygous dysferlin 4870delT mutation. The existence of three phenotypes of dysferlinopathy in one pedigree is reported for the first time, indicating the involvement of molecules other than dysferlin in the pathomechanism.

  24. Role of Stress-related Peptide CRH in Brain-Gut Interactions

    FUKUDO Shin, AOKI Masashi, KANAZAWA Motoyori

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2003 - 2006

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    Brain-gut interactions are functional and reciprocal connection between the brain and the gut. Brain-gut interactions are the developmentally old phenomena but are not fully investigated. There are two major directions in these phenomena. One is changing the gut function by stress-induced excitation of the brain via autonomic and/or endocrine pathways. The other is changing the brain function by the perception signal from the gut via visceral afferent pathways. We hypothesized that corticotropin-releasing hormone (CRH) and related neurotransmitters may be released in the specific regions of the brain by psychosocial stress or visceral stimulation and that these phenomena may be augmented in patients with irritable bowel syndrome (IBS). The main objective of this research is to test our hypotheses by animal experiments and clinical brain-gut examination including positron emission tomography (PET) and quantitative analysis of electroencephalography (EEG). Using this grant (2003-2006), we successfully developed rats mimicking pathophysiology of IBS. Administration of specific CRH-Rl antagonist reversed the IBS-like pathophysiology of rats. Visceral stimulation in humans induced abdominal pain and increase in regional cerebral blood flow. The specific regions activated by visceral stimulation were thalamus and the limbic cortices. EEG power spectra and topogram were also changed by visceral stimulation. The visceral stimulation also changed visceral sensation, anxiety, and gastrointestinal motility. These phenomena were exaggerated in IBS patients and administration of CRH antagonist reversed the IBS pathophysiology. These findings suggest that released CRH in the specific brain or in the other organs may play a major role of IBS and animals mimicking IBS. Thus using this grant (2003-2006), we succeeded to clarify some fundamental roles of CRH in brain-gut interactions. Further investigation on this paradigm is highly expected by our research group.

  25. 過敏性腸症候群のストレス感受性と遺伝子多型の日米比較

    福土 審, 辻 一郎, 青木 正志

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 萌芽研究

    Category: 萌芽研究

    Institution: 東北大学

    2003 - 2005

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    過敏性腸症候群は、患者のQuality of Lifeの著しい低下を招き、21世紀に重視されることが確実視される重要な消化器病である。過敏性腸症候群の罹患数は多く、欧米では全人口の8-15%を占め、国の医療費に対する負担も巨額となる。過敏性腸症候群の病態においてはストレス感受性と抑うつ、不安を代表とする心理的異常が深く関与する。しかし、わが国における実態は不明である。ここから、過敏性腸症候群の病態形成における遺伝と環境の相互作用をクロスカルチャー分析することにより、本疾患の発症機序に迫ることができると仮説づけた。本年度の目的は欧米の調査法と調和させたわが国における過敏性腸症候群の実態を調査することである。対象は一般ボランティア304例である。消化器症状をRome II Modular Questionnaire (RIIMQ)で、ストレス感受性をPerceived Stress Scale Scale (PSS)、Self-rating Depression Scale (SDS)、State-Trait Anxiety Inventory (STAI)、Tronto Alexithymia Scale 20-items (TAS-20)で分析した。上肢より静脈採血し、末梢血からDNAを抽出し、PCRで増幅し、電気泳動によりセロトニントランスポーター遺伝子多型(5-HTTLPR)分析を実行した。5-HTTLPRの頻度はs/s型61.4%、s/l型30.2%、l/l型5.9%であり、明らかに白人の5-HTTLPRよりもsアリルを持つ者の割合が高かった。非定型なs/extra-l型0.9%、l/extra-l型1.5%も認めた。非定型を除外した296例では、RIIMQの34.5%が過敏性腸症候と判定された。5-HTTLPRと過敏性腸症候群には関連性はなかった。しかし、l/l型において腹部膨満感が有意に強く(p<0.05)、TAS-20の総得点が有意に高かった(p=0.004)。これらがsアリルを持つ者の割合が高いわが国における過敏性腸症候群の遺伝的背景の特徴である可能性がある。過敏性腸症候群の病態形成における遺伝と環境の相互作用をクロスカルチャー分析する研究はきわめて将来性が高く、今後の検討が期待できる。

  26. ALSラットモデルにおける神経前駆細胞の解析と新規治療法の開発

    青木 正志

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 特定領域研究

    Category: 特定領域研究

    Institution: 東北大学

    2004 - 2004

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    筋萎縮性側索硬化症(Amyotrophic Lateral Sclerosis以下ALS)は神経疾患のなかで最も過酷な疾患とされており、早期に病因の解明と有効な治療法の確立が求められている。本研究ではALSの新しい動物モデルとして確立したヒト変異Cu/Zn SOD遺伝子導入ラット(以下Tgラット)を用いて、再生医療の開発を念頭に内在性神経前駆細胞の解析を開始した。これまでにTgラットにブロモデオキシウリジン(BrdU)を投与して脊髄の増殖性細胞を標識、病態下における脊髄神経前駆細胞の増殖と分化を検討したところTgラットでは運動ニューロン脱落前より有意に脊髄神経前駆細胞が増殖していたが、その多くはグリア系細胞に分化していることが示された。本年度は、発症前(10,15週齢)、運動ニューロン脱落開始直後(20週齢)、発症後早期(21週齢)、および末期(24週齢)のH46R変異Tgラットと週齢一致非Tgラット(各群n=4-5)に対して、BrdUを7日間連日投与し増殖性細胞を標識、脊髄の灌流固定後凍結切片を作成して多重免疫組織化学により解析した。1)内在性未分化NPCsの増殖は運動ニューロン脱落開始直後や発症後早期には検出されず、末期に至って中心管周囲にようやく検出された。このことから運動ニューロン脱落に対する内在性NPCsの増殖には一定の閾値の存在が示唆された。一方、2)このような未分化NPCsを外来性再生誘導因子によって賦活する方法として、肝細胞増殖因子(HGF)を運動ニューロン脱落開始後(22週齢)のTgラットに2週間持続髄腔内投与した。その結果、非投与群に比べさらにBrdU陽性細胞の増加を認めた。このことからHGFには内在性NPCsを賦活増殖させる作用があると想定された。

  27. Dysferlionpathy manifesting Limb-girdle type of muscular dystrophy

    AOKI Masashi, ITOYAMA Yasuto

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2003 - 2004

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    Mutations in the dysferlin gene cause both Miyoshi myopathy (MM) and limb girdle muscular dystrophy 2B (LGMD2B). In this study, we examined 26 patients with LGMD2B in Japan. Genomic DNA was extracted from the peripheral lymphocytes of the patients with informed consents. The PCR products of each 55 exon were screened by single strand conformation polymorphism (SSCP) or direct sequencing from the PCR fragments. We identified 11 different mutations in the dysferlin gene in the patients with LGMD2B. Although the two mutations (G3370T and 4870delT) accounted for 52 percent of the mutations in LGMD2B patients, the 3746delG mutation, which is relatively prevalent in MM, was not found in patients with LGMD2B. We could analyze of clinical features in 13 patients out of them. The mean age at onset of the patients with LGMD2B was 25 ± 7 years (with G3370T mutation 32 ± 6 years ; without G3370T mutation 21 ± 3 years). The serum CK level was very high, although the serum CK level fell in parallel to duration of the illness. The G3370T mutation may be associated with the late onset of LGMD2B, the progression rate of the disease was the same among the mutations.

  28. トランスジェニックラットによるALSモデルの病態解析と新規治療法の開発

    青木 正志

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 特定領域研究

    Category: 特定領域研究

    Institution: 東北大学

    2003 - 2003

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    筋萎縮性側索硬化症(Amyotrophic Lateral Sclerosis以下ALS)は神経疾患のなかで最も過酷な疾患とされており、早期に病因の解明と有効な治療法の確立が求められている。本研究ではALSの新しい動物モデルとして確立したヒト変異Cu/Zn SOD遺伝子導入ラット(以下Tgラット)を用いて、再生医療の開発を念頭に内在性神経前駆細胞の解析を開始した。これまでにTgラットにブロモデオキシウリジン(BrdU)を投与して脊髄の増殖性細胞を標識、病態下における脊髄神経前駆細胞の増殖と分化を検討した。その結果,Tgラットでは運動ニューロン脱落前より有意に脊髄神経前駆細胞が増殖していたが、その多くはグリア系細胞に分化していることが示された。 本年度は、増殖している脊髄神経前駆細胞の挙動をさらに明らかにするため、(1)増殖した神経前駆細胞の局在の検討、(2)神経幹細胞に近い、より幼若で未分化な細胞のマーカーを共発現するBrdU陽性増殖性細胞の検索、(3)外来性の再生因子投与による内在性神経細胞の賦活の試みを行っていた。これまでの結果では、Tgラットでは前角を含めた灰白質・白質にGFAP陽性、APC陽性のアストログリア、OX42陽性のマイクログリアが広汎に増殖していた。またnestin陽性細胞が中心管上衣層と白質に認め、BrdU/nestin二重陽性細胞も確認され、より未分化な段階の細胞の存在が示唆された。このような未分化な細胞をうまく分化誘導し、組織修復に役立てる方法を探っていくことが新規治療法につながる可能性がある。

  29. トランスジェニックラットによる新しいALS動物モデルの病態解析

    青木 正志

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 特定領域研究

    Category: 特定領域研究

    Institution: 東北大学

    2002 - 2002

    More details Close

    筋萎縮性側索硬化症(Amyotrophic Lateral Sclerosis以下ALS)は神経疾患のなかで最も過酷な疾患とされており、早期に病因の解明と有効な治療法の確立が求められている。1993年Cu/Zn supcroxidc dismutase(Cu/Zn SOD)遺伝子が一部の家族性ALSの原因遺伝子であることが発見されたが、Cu/Zn SODの異常がなぜ運動ニューロンに選択的な細胞死をもたらすかは依然として不明である。本研究ではALSの新しい動物モデルとして、1)わが国で報告された特異な臨床的特徴を持つH46Rと2)トランスジェニック(Tg)マウスが普及しているG93Aの2種類の変異を導入したTgラットの作製を行った。従来のマウスに比較してラットの脊髄および脊髄前角細胞は極めて大きく、Tgラットによる新しいALSモデルは病態のダイナミックな解析および将来的な遺伝子治療や神経幹細胞移植を含めた新しい治療法開発のために非常に有用と考えられる。 BrdU投与による検討の結果、本モデルの病態下では、脊髄前駆細胞の増殖が起こっていたが、その多くはグリア系細胞へ分化している可能性が示唆された。また、ダブルTgマウスの作製によりG93A変異Tgマウスに対する効果が報告された肝細胞増殖因子(HGF)の臨床応用の目的に、HGFリコンビナント蛋白の髄腔内持続投与をG93A変異Cu/Zn SOD-Tgラットの100日令から1ヶ月間行い、脊髄前角の運動神経細胞数を観察した。HGF投与群においてはコントロール投与群に比較して有意に運動神経細胞数が保たれていることが明らかとなり、このことはHGF投与量に依存的であった。HGF蛋白の髄腔内持続投与がALSに対する新しい治療法として有効である可能性が示された。

  30. SOD活性中心に遺伝子変異を導入したALSモデルマウスに関する研究

    青木 正志

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 若手研究(B)

    Category: 若手研究(B)

    Institution: 東北大学

    2001 - 2002

    More details Close

    筋萎縮性側索硬化症(Amyotrophic Lateral Sclerosis以下ALS)は進行性の神経変性疾患で、その予後はきわめて不良である。近年、家族性ALSにおいてCu/Zn superoxide dismutase(以下Cu/Zn SOD)遺伝子の変異が報告され、それによる運動ニューロン選択的細胞死の機序の解明が待たれている。本研究ではCu/Zn SOD遺伝子異常による運動ニューロンの選択的細胞死の機序を解明するために、研究代表者である青木が既に報告している日本人独自の点突然変異をマウスに導入し、ALSの新しいモデルマウスの作成を行った。遺伝子変異による臨床経過の違いのメカニズムを検討するために、常法により臨床的に非常に急速な経過をとるALS家系での点突然変異(L84V)と極めて緩徐な経過をとるALS家系の突然変異(H46R)を持つ2種類のトランスジェニックマウスの作成を行った。どちらの変異を導入したトランスジェニックマウスもCu/Zn SOD活性の上昇はなく、病理像として空胞変性の少ないヒトのALSに近いモデルと考えられた。脊髄前角の神経細胞脱落、グリオーシスは両変異ともに認められた。しかし神経細胞、ダリア細胞内に認められるLewy-body like inclusionがH46R変異マウスにおいて著明に認められるのに対して、L84V変異マウスではその頻度は低かった。変異の異なる2種類のトランスジェニックマウスを比較すると、Cu/Zn SOD遺伝子変異を伴う家族性ALSにおける臨床像と相似した結果であった。新しいモデルマウスの作成により、神経細胞およびダリア細胞に見られるinclusion bodyは神経細胞死に直接関与するものではない可能性および神経細胞死には小胞体ストレスが関与している可能性が示唆された。

  31. トランスジェニックラットによる新しいALS動物モデルの作製とその病態解析

    青木 正志

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 特定領域研究(C)

    Category: 特定領域研究(C)

    Institution: 東北大学

    2001 - 2001

    More details Close

    筋萎縮性側索硬化症(Amyotrophic Lateral Sclerosis以下ALS)は神経疾患のなかで最も過酷な疾患とされており、早期に病因の解明と有効な治療法の確立が求められている。1993年Cu/Zn superoxide dismutase(Cu/Zn SOD)遺伝子が一部の家族性ALSの原因遺伝子であることが発見されたが、Cu/ZnSODの異常がなぜ運動ニューロンに選択的な細胞死をもたらすかは依然として不明である。本研究ではALSの新しい動物モデルとしてトランスジェニック(Tg)ラットの作製行う。従来のマウスに比較してラットの脊髄および脊髄前角細胞は極めて大きく、生化学的あるいは生理的な解析が容易となる。また、脊髄の運動ニューロンに対して効率良くしかも副作用を回避できる薬物の投与ルートとして髄腔内投与が注目されており、Tgラットではこの髄腔内投与が容易である。このようにTgラットによる新しいALSモデルは将来的な遺伝子治療や神経幹細胞移植を含めた新しい治療法開発のために非常に有用と考えられる。ヒト家族性ALSにおいて臨床経過が非常に緩徐なH46R変異およびTgマウスが世界的に供給されているG93A変異を持つCu/ZnSOD遺伝子をSDラット受精卵にマイクロインジェクションし、遺伝子の導入を確認した。H46R変異およびG93A変異を持つTgラット共に導入された変異ヒトCu/Zn SOD蛋白が多く発現した系統(H46R-4およびG93A-39)において運動ニューロン病の症状の発現が認められた。変異Cu/Zn SOD蛋白の発現量はG93A-39の方がH46R-4に比較して少ないのにもかかわらず、G93A-39はより早期に発症し、かつ非常に急速な進行を示している。これは導入した変異がG93A変異の家系は速い経過を示し、H46R変異が非常に緩徐な経過を取ることと相関していると考えられた。

  32. CAG repeat expansion in familial moyamoya disease

    IKEDA Hidetoshi, KONDO Takeo, AOKI Masashi, YOSHIMOTO Takashi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2000 - 2001

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    To determine whether clinical anticipation found in familial moyamoya family is caused by the genetic molecular mechanism such as CAG repeat expansion, we examine CAG repeat expansion in familial and idiopathic moyamoya diseases. CAG repeat expansion in genomic DNA from 27 cases of familial cases (12 cases with moyamoya disease, 15 cases without moyamoya disease), and 24 cases of idiopathic cases were screened by repeat expansion detecting method. CAG repeat expansion was found in 5 cases in the familial cases, and none in idiopathic cases. The persons with CAG repeat expansion in familial cases were all females, but no correlation with or without moyamoya disease. These results suggest that CAG repeat expansion may influence the background of hereditary factor for familial moyamoya disease, but be not the direct causative factor for moyamoya disease.

  33. Mutational analysis in dysferlin gene in patients with muscular dystrophy in Japanese populations.

    ITOYAMA Yasuto, AOKI Masashi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2000 - 2001

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    MM is an autosomal recessive distal muscular dystrophy that arises from mutations in the gene dysferlin. This gene is also mutated in families with limb girdle muscular dystrophy (LGMD) 2B. To study dysferlin gene mutations in Japanese patients with Miyoshi myopathy (MM) and undertake genotype-phenotype correlations in this disease, we examined 57 Japanese families with MM or LGMD. Genomic DNA was extracted from the peripheral lymphocytes of the patients. The PCR products of each of 55 exons were screened by single strand conformation polymorphism (SSCP) or direct sequencing from the PCR fragments. We identified mutations in 34 families with MM patients and 24 families with LGMD. Mutations in Japanese patients are distributed along the entire length of the gene. Five mutations (G1310+1A, C1939G, G3370T, 3746delG, and 4870delT) are relatively more prevalent in this population, accounting for 59 percent of the mutations in this study. We speculated that most patients with MM were selectively affected in the paravertebral muscles even in the very early stage. This study revealed that the G3370T and G3510A mutations are respectively associated with the mild and more severe forms of MM.

  34. Genetic analysis in families with amyotrophic lateral sclerosis

    ITOYAMA Yasuto, AOKI Masashi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B).

    Category: Grant-in-Aid for Scientific Research (B).

    Institution: Tohoku University

    1999 - 2000

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    Amyotrophic lateral screlosis (ALS) is a fatal neurodegenerative disease caused by selective death of motor neurons. Pathological studies of postmortem ALS patients revealed motor neuron loss in the anterior horn of the spinal cord, the nucleus of brainstem and the cortex. Approximately 10% of cases of ALS are inherited, usually as an autosomal dominant trait. Mutations of the cytosolic cupper-zinc superoxide dismutase (Cu/Zn SOD) gene were detected in about 25% of patients with familial ALS and until now more than 70 different mutations are known. In this study, we carry out a linkage analysis using a large Japanese family with ALS to identify loci that contain genes whose defects cause ALS.We did not detect any genetic linkage to the known locus of motor neuron diseases and now going on a genome-wide linkage analysis. In addition, we identified a novel missense mutation of the Cu/Zn SOD gene (Leu126Ser) in a Japanese family with ALS that included a patient with the homozygous mutation. The expression of the Cu/Zn SOD polypeptide in erythrocytes was markedly reduced in the case with the homozygous mutation compared to those with the heterozygous mutation. We speculated that this reduction of the mutant Cu/Zn SOD molecule may be related to the severe clinical phenotype of the case.

  35. SOD活性中心の点突然変異を導入したALSマウスモデルの作成に関する研究

    青木 正志

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 奨励研究(A)

    Category: 奨励研究(A)

    Institution: 東北大学

    1999 - 2000

    More details Close

    筋萎縮性側索硬化症(Amyotrophic Lateral Sclerosis以下ALS)は進行性の難治性神経疾患で、その予後はきわめて不良である。ALS発症者の5-10%は家族性ALSで、通常は常染色体優性遺伝形式をとる。近年、家族性ALSにおいてCu/Zn superoxide dismutase(以下Cu/Zn SOD)遺伝子の変異が報告され、それによる運動ニューロン選択的細胞死の機序の解明が待たれている。本研究はCu/Zn SOD遺伝子異常による運動ニューロンの選択的細胞死の機序を解明するために、研究代表者である青木が既に報告している日本人独自の点突然変異をマウスに導入し、ALSの新しいモデルマウスを作成する。臨床的に非常に急速な経過をとることALS家系での点突然変異(L84V)と極めて緩徐な経過をとるALS家系の突然変異(H46R)を持つ2種類のトランスジェニックマウスを作成し、その表現型の違いを検討することにより、神経細胞死の機序を解明することを目的とする。H46R変異はCu/Zn SOD遺伝子の活性中心に存在している。まずプロモーター領域を含むゲノムCu/Zn SOD遺伝子内にミスマッチプライマー法を用いて、前述の日本人家族性ALS患者における点突然変異の導入を行った。その変異遺伝子をマウス受精卵の前核へ微量注入することによりトランスジェニックマウスの作成を行った。生まれてきたマウスの尾部からDNAを抽出しサザンブロット法により導入遺伝子を確認し、生まれたマウスの各臓器における変異Cu/Zn SOD蛋白の発現をウエスタンブロッド法にて確認した。H46R変異を導入したラインのうち変異Cu/Zn SOD蛋白発現量の高いトランススジェニックマウスのラインでは生後約150日で運動ニューロン病の発症がみられ、経過約30日で死亡にいたることが明らかになった。

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Works 11

  1. GNEミオパチー診療の手引き

    難治性疾患等政策研究事業希少難治性筋疾患に関する調査研究班

    https://www.neurology-jp.org/guidelinem/pdf/om_tebiki.pdf 2020/01 -

    Type: Web Service

  2. 眼咽頭遠位型ミオパチー診療の手引き

    難治性疾患等政策研究事業希少難治性筋疾患に関する調査研究班

    https://www.neurology-jp.org/guidelinem/pdf/om_tebiki.pdf 2020/01 -

    Type: Web Service

  3. 自己貪食空胞性ミオパチー・診療の手引き

    日本神経学会自己貪食空胞性ミオパチー, 診療の手引き, 作成委員会, 杉江和馬ら

    https://www.neurology-jp.org/guidelinem/pdf/avm_tebiki.pdf 2019/01 -

    Type: Web Service

  4. 封入体筋炎診療の手引き

    青木 正志

    2017/09 -

    Type: Web Service

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    日本神経学会封入体筋炎・診療の手引き作成委員会 目次1.疾患概要2.疫学・経過・予後3.病因・病態4.診察・電気生理5.病理・血清マーカー6.リハビリテーション四肢・嚥下7.治療8.結語9.付記:厚生労働省指定難病疾患概要・診断基準・重症度分類

  5. 難病ALSの解明と治療に挑む

    青木 正志

    フクロウ博士の森の教室 シリーズ2 脳の不思議を考えよう 2017 -

    Type: Web Service

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    テルモ生命科学芸術財団 ▼若い人たちにALSの根本的な治療・研究にチャレンジしてほしい。

  6. 産学官連携ジャーナル 科学技術振興機構

    青木 正志

    2016/07 -

    Type: Web Service

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    研究者リレーエッセイ 筋萎縮性側索硬化症(ALS)に対する治療開発への挑戦

  7. 三好型ミオパチー(MIM# 254130, Miyoshi myopathy, Distal dysferlinopathy)診断基準

    青木 正志

    2016/01 -

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    ●診断に有用な特徴A. 臨床的特徴a-c全て必要a. 常染色体劣性遺伝または孤発性b. 進行性の筋力低下および筋萎縮:下肢後面特に腓腹筋が侵されるc. 歩行可能な時期に血清CK値が異常高値(1,000IU/L以上)を示す(以下は参考所見)・発症年齢は30歳までに多い・進行すれば近位筋の筋力低下が出現する・針筋電図で筋原性変化B. dysferlinの評価a, bのどちらかを満たすa. dysferlin欠損(骨格筋免疫染色またはウェスタンブロット解析)b.DYSF(dysferlin)遺伝子のホモ接合型または複合ヘテロ接合型変異

  8. 宮城県神経難病連携センター 災害時対応ハンドブック

    青木 正志

    2014 -

    Type: Web Service

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    宮城県神経難病医療連携センターと宮城県では、厚生労働省西澤班からの支援を受け、東日本大震災の体験から普段の療養から自助力を高めて災害にも対応できるようなハンドブックを作成しました。

  9. 日本せきずい基金ニュース

    青木 正志

    2013/08 -

    Type: Web Service

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    HGFによるALSおよび脊髄損傷に対する再生医療の開発

  10. 宇宙兄弟 ALSに挑む

    青木 正志

    宇宙兄弟ムック特設サイト Vol.6 2012/04 -

    Type: Other

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    日々ALS患者の治療に従事しながら、根本的治療法の開発へ向けての研究も続けているのが、東北大学大学院医学系研究科・神経内科教授の青木正志先生です。 医大の大学院生時代にALSを専門にしようと志して以来およそ25年。ずっとALS研究をリードしてきました。 「私が研究を始めたころなんて、ALSは『完全犯罪』だなどと言われていたものですけどね」

  11. 科研費NEWSレター

    青木 正志

    2011/03 -

    Type: Web Service

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Social Activities 5

  1. [日本国内] 遠位型ミオパチー患者会

    2008/12 - Present

  2. [日本国内] 財団法人 難病医学研究財団 難病情報センター情報企画委員

    2005/04 - Present

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    難病医学研究財団で運営している難病情報センターにおける情報提供の支援

  3. あなたに知ってほしい。「ALS」という難病があることを

    2017/02/28 -

  4. [日本国内] 東北大、ALS治療法開発へ 神経増やす物質活用

    2009/11/04 -

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    筋萎縮性側索硬化症に対する私たちの取り組みが1面トップに掲載された

  5. [日本国内] 難病ALSの進行を抑制 東北大がラットで確認

    2008/03/13 -

Media Coverage 23

  1. SOD1変異型ALSに「待ちに待った原因療法」トフェルセン

    日経メディカル

    2025/04/22

    Type: Newspaper, magazine

  2. ALS新薬早期投与が鍵

    毎日新聞

    2025/03/05

    Type: Newspaper, magazine

  3. 「アセノベル徐放錠」を新発売‐世界初のGNEミオパチー薬

    薬事新報

    2024/11/27

    Type: Newspaper, magazine

  4. 東北大主導の希少難病「遠位型ミオパチー」治療薬が世界初承認 「新薬開発のモデルケースに」

    河北新報

    2024/04/30

    Type: Newspaper, magazine

  5. 筋力弱る難病「遠位型ミオパチー」世界初の治療薬を薬事承認 患者自ら研究者ら説得

    日本テレビ

    2024/03/28

    Type: TV or radio program

  6. 国内患者は300人の超希少疾患「採算取れない薬」の開発を実現させた患者の思い 診断から20年、「遠位型ミオパチー」の治療薬が世界で初めて承認へ

    共同通信

    2024/03/25

    Type: Newspaper, magazine

  7. ALS患者のドキュメンタリー映画 仙台市で公開中 「希望を感じていただけたら」

    KHB東日本放送チャージ

    2024/01/16

    Type: TV or radio program

  8. 希少疾患の治療薬開発 患者たちの熱意が後押し

    NHK総合 NEWS おはよう日本

    2023/02/04

    Type: TV or radio program

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    遠位型ミオパチーに対する治療法の開発

  9. 世界初の治療薬申請へ 筋力低下の難病「GNEミオパチー」 東北大グループが治験

    河北新報 朝刊

    2022/11/11

    Type: Newspaper, magazine

  10. ALSが治る未来への挑戦~NO LIMIT, YOUR LIFE【テレメンタリー2021】

    テレビ朝日系列(ANN)

    2021/09

    Type: TV or radio program

  11. ALSの進行に関わる遺伝子を特定 東北大チーム

    河北新報

    2021/06/07

    Type: Newspaper, magazine

  12. 東北⼤出資ファンド投資の創薬企業初上場 ALS治療薬開発へ

    河北新報

    2020/12/29

    Type: Newspaper, magazine

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    東北⼤100%出資のファンド運営会社「東北⼤ベンチャーパートナーズ」(THVP、仙台市)は28⽇、投資先である⼤阪⼤発創薬ベンチャー「クリングルファーマ」(⼤阪府茨⽊市)が東証マザーズ市場に同⽇上場したと発表した。2015年8⽉設⽴のファンド「THVP-1号投資事業有限責任組合」の投資先として初の上場企業となる。 ALSについては東北⼤の⻘⽊正志教授(神経内科)と⼤阪⼤の研究チームによる治験が第2段階まで進展。病状進⾏に伴う運動能⼒の低下を抑える効果を調べている。

  13. 筋ジス発症に関わるたんぱく質を特定

    日本経済新聞

    2020/03/30

    Type: Newspaper, magazine

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    ■東北大学 青木正志教授らは筋ジストロフィーの発症に関わるたんぱく質を特定した。マウスの実験では、このたんぱく質の働きを既存の糖尿病治療薬などで活発にすると、病気に伴う筋力の低下が収まった。治療薬の実現につながる成果だという。 筋ジストロフィーは筋肉細胞にあるたんぱく質「ジスフェルリン」が欠損して起こる。筋肉組織を修復する機能が失われ、徐々に体が動かせなくなる。

  14. ALS患者の運動神経細胞異常 東北大チームが原因遺伝子をiPSで特定 治療法確立に道

    河北新報

    2019/07/09

    Type: Newspaper, magazine

    More details Close

    東北大大学院医学系研究科の青木正志教授(神経内科)らの研究チームが、人工多能性幹細胞(iPS細胞)を用いて「筋萎縮性側索硬化症(ALS)」患者の運動神経細胞に異常を引き起こす因子となる遺伝子を新たに特定したと発表した。ALSの進行を抑えられる可能性があり、数年以内の臨床試験を目指す。

  15. 気になる症状 手や足に力が入らない

    河北新報

    2018/11/02

    Type: Newspaper, magazine

  16. 私が30年来、ALSに取り組み続けている理由

    宇宙兄弟 せりか基金インタビュー

    2018/05/17

    Type: Internet

  17. CRIETO臨床研究ネットワーク部門長インタビュー

    東北大学病院臨床研究推進センター

    2017/09

    Type: Promotional material

  18. ALS新薬の臨床試験開始へ 東北大、進行抑制を検証

    産経新聞、東京新聞、河北新報など

    2017/05/13

    Type: Newspaper, magazine

  19. 難病・ALS「進行遅らせる」薬・効果確かめる臨床試験開始

    テレビ朝日 報道ステーション

    2017/05/13

    Type: TV or radio program

  20. 筋肉が消えていく…”闘病ママ”の試練(遠位型ミオパチー)

    フジテレビ スーパーニュース

    2011/10/14

    Type: TV or radio program

  21. ALS新治療薬 臨床試験へ

    NHK

    2011/07/10

    Type: TV or radio program

  22. ALSの進行遅らせる治療薬、東北大が治験へ

    時事通信社ほか

    2011/07/08

    Type: Newspaper, magazine

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    東北大学は8日、全身の筋肉が次第に動かなくなっていく難病、筋萎縮性側索硬化症(ALS)の進行を遅らせる新薬の臨床試験(治験)を8月にも始めると発表した。神経細胞を保護する働きのあるたんぱく質を投与し、安全性や効果を調べる。3~4年後にも実用化したい考えだ。

  23. 筋疾患「遠位型ミオパチー」 世界初シアル酸投与治験

    河北新報

    2010/10/31

    Type: Newspaper, magazine

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