Updated on 2021/08/05

写真a

 
HASHIZUME Atsushi
 
Organization
Graduate School of Medicine Program in Integrated Medicine Lecturer
Graduate School
Graduate School of Medicine
Undergraduate School
School of Medicine Department of Medicine
Title
Lecturer

Degree 1

  1. 医学博士 ( 2012.3   名古屋大学 ) 

Research Interests 5

  1. clinical research, neurology, drug evaluation

  2. Neurodegenerative diseases

  3. Neurology

  4. Clinical trials

  5. New drug development

Research Areas 2

  1. Life Science / Neurology  / Neurodegenerative diseases

  2. Life Science / Neurology

Current Research Project and SDGs 1

  1. Clinical research, Neurology

Research History 9

  1. Nagoya University   Clinical Research Education   Lecturer

    2021.7

  2. Nagoya University hospital   Neurology   Lecturer of hospital

    2020.10 - 2021.6

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    Country:Japan

  3. Nagoya University hospital   Neurology   Assistant professor of hospital

    2019.4 - 2020.9

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    Country:Japan

  4. Nagoya University Graduate school of medicine   Department of Neurology   Designated assistant professor

    2018.9 - 2019.3

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    Country:Japan

  5. Nagoya University hospital   Neurology   Clinical fellow

    2014.4 - 2018.8

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    Country:Japan

  6. Pharmaceuticals and Medical Devices Agency   New Drug Ⅱ

    2013.4 - 2014.3

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    Country:Japan

  7. Nagoya University hospital   Neurology   Clinical fellow

    2012.4 - 2013.3

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    Country:Japan

  8. Nagoya University Graduate school of medicine   Department of Neuology

    2008.4 - 2012.3

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    Country:Japan

  9. Nagoya Daini Red-cross hospital   Neurology   Clinical fellow

    2002.4 - 2008.3

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    Country:Japan

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Education 3

  1. Nagoya University   Graduate School of Medicine

    2008.4 - 2012.3

  2. Nagoya University   school of medicine   department of medicine

    - 2002.3

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    Country: Japan

  3. The University of Tokyo   school of medicine   department of health science

    - 1996.3

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    Country: Japan

Professional Memberships 4

  1. Japanese society of neurological therapeutics

  2. The Japanese Society of. Clinical Pharmacology and Therapeutics   academic member

  3. Japanese society of neurology   academic member

  4. The Japanese society of internal medicine   academic member

Committee Memberships 1

  1. Pharmaceutical and Medical Device Agency   Expert Advisor  

    2014.4   

Awards 2

  1. 2019年 日本神経治療学会 治療学術賞

    2019.11   日本神経治療学会  

  2. 第56回日本神経学会学術大会 学術大会最優秀賞

    2015.5   日本神経学会  

 

Papers 46

  1. Disease mechanism, biomarker and therapeutics for spinal and bulbar muscular atrophy (SBMA). Invited Reviewed

    Hashizume A, Fischbeck KH, Pennuto M, Fratta P, Katsuno M.

    J Neurol Neurosurg Psychiatry.   Vol. 91 ( 10 ) page: 123 - 130   2020.10

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    Authorship:Lead author  

  2. Elevated serum creatine kinase in the early stage of sporadic amyotrophic lateral sclerosis. Reviewed

    Ito D, Hashizume A, Hijikata Y, Yamada S, Iguchi Y, Iida M, Kishimoto Y, Moriyoshi H, Hirakawa A, Katsuno M.

    J Neurol.   Vol. 266 ( 12 ) page: 2952 - 2961   2019.12

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    Authorship:Corresponding author   Language:English  

  3. Ratio of urinary N-terminal titin fragment to urinary creatinine is a novel biomarker for amyotrophic lateral sclerosis. Reviewed

    Yamada S, Hashizume A, Hijikata Y, Ito D, Kishimoto Y, Iida M, Koike H, Hirakawa A, Katsuno M.

    J Neurol Neurosurg Psychiatry.     2021.3

  4. Longitudinal analysis of premotor anthropometric and serological markers of Parkinson's disease. Yokoi K, Hattori M, Satake Y, Tanaka Y, Sato M, Hashizume A, Hori A, Kawashima M, Hirakawa A, Watanabe H, Katsuno M. Reviewed

    Yokoi K, Hattori M, Satake Y, Tanaka Y, Sato M, Hashizume A, Hori A, Kawashima M, Hirakawa A, Watanabe H, Katsuno M.

    Sci Rep.   Vol. 25 ( 10 ) page: 20524   2020.11

  5. Longitudinal Change of DAT SPECT in Parkinson's Disease and Multiple System Atrophy. Reviewed International journal

    Satoko Sakakibara, Rina Hashimoto, Taiji Katayama, Masakuni Kenjyo, Yuki Yokokawa, Yufuko Saito, Akihiro Hirakawa, Mizuki Ito, Tomohiko Nakamura, Kazuhiro Hara, Atsushi Hashizume, Ikuko Aiba, Akira Inukai, Masahisa Katsuno

    Journal of Parkinson's disease   Vol. 10 ( 1 ) page: 123 - 130   2020

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    BACKGROUND: Both Parkinson's disease (PD) and multiple system atrophy (MSA) are neurodegenerative disorder affecting striatonigral system. Although various lines of evidence demonstrate that dopaminergic neuron degeneration emerges before the onset of motor symptoms in PD, preclinical/prodromal progression of neurodegeneration is far less understood in MSA. OBJECTIVE: The aim of this study was to clarify the difference in the progression of dopaminergic degeneration in MSA and PD using dopamine transporter single-photon emission computed tomography (DAT SPECT). METHODS: We analyzed longitudinal data of the specific binding ratio (SBR), a measure of striatal radiotracer uptake, in DAT SPECT from 7 patients with MSA-C, 5 patients with MSA-P, and 18 patients with PD. We performed 2.7±0.7 scans with an interval of 9.85±6.00 months for MSA and 2 scans with an interval of 2.16±0.16 years for PD. RESULTS: The rate of SBR decline was faster in both subtypes of MSA compared with PD, but the value was similar between MSA-P and MSA-C. The estimated SBR at the onset of initial motor symptoms was lower in PD and MSA-P than in MSA-C, especially in the predominantly affected side. SBR of the predominantly affected side starts to decrease before the onset of motor symptoms in PD and MSA-P, whereas the initiation of SBR decline is around the onset in MSA-C individuals. The decline of SBR in the less affected side was not clearly shown before the onset in MSA-P or MSA-C. CONCLUSIONS: Our results suggest that the SBR in DAT SPECT analysis is an important pathophysiological marker reflecting the disease- and subtype-specific progression of dopaminergic degeneration in MSA and PD.

    DOI: 10.3233/JPD-191710

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  6. Nasometric Scores in spinal and bulbar muscular atrophy - Effects of palatal lift prosthesis on dysarthria and dysphagia. Reviewed

    Tanaka S, Hashizume A, Hijikata Y, Yamada S, Ito D, Nakayama A, Kurita K, Yogo H, Banno H, Suzuki K, Yamamoto M, Sobue G, Katsuno M

    J Neurol Sci.   Vol. 407   page: 116503   2019.12

  7. Elevated serum creatine kinase in the early stage of sporadic amyotrophic lateral sclerosis. Reviewed International journal

    Daisuke Ito, Atsushi Hashizume, Yasuhiro Hijikata, Shinichiro Yamada, Yohei Iguchi, Madoka Iida, Yoshiyuki Kishimoto, Hideyuki Moriyoshi, Akihiro Hirakawa, Masahisa Katsuno

    Journal of neurology   Vol. 266 ( 12 ) page: 2952 - 2961   2019.12

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    OBJECTIVE: To assess the changes of muscle-related biomarkers at the early stage of amyotrophic lateral sclerosis, and to confirm these findings in an experimental animal model. METHODS: Thirty-nine subjects with sporadic amyotrophic lateral sclerosis and 20 healthy controls were enrolled and longitudinally evaluated. We evaluated serum creatine kinase and creatinine levels and appendicular lean soft-tissue mass using dual X-ray absorptiometry. The levels of biomarkers at early ALS stages were estimated using linear mixed models with unstructured correlation and random intercepts. We also analyzed the longitudinal changes of serum creatine kinase and creatinine, together with the mRNA levels of acetylcholine receptor subunit γ (Chrng) and muscle-associated receptor tyrosine kinase, markers of denervation, in the gastrocnemius muscle of superoxide dismutase 1 (SOD1)G93A transgenic mice, an animal model of amyotrophic lateral sclerosis. RESULTS: The estimated levels of creatine kinase were higher in subjects with amyotrophic lateral sclerosis at the early stage than in healthy controls, although the estimated appendicular lean soft-tissue mass and creatinine levels were equivalent between both groups, suggesting that the elevation of creatine kinase precedes both muscular atrophy and subjective motor symptoms in sporadic amyotrophic lateral sclerosis. In SOD1G93A mice, the serum levels of creatine kinase were elevated at 9 weeks of age (peri-onset) when Chrng started to be up-regulated, and were then down-regulated at 15 weeks of age, consistent with the clinical data from patients with sporadic amyotrophic lateral sclerosis. INTERPRETATION: Creatine kinase elevation precedes muscular atrophy and reflects muscle denervation at the early stage.

    DOI: 10.1007/s00415-019-09507-6

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  8. Long-term Effects of Androgen Deprivation in a Patient with Spinal and Bulbar Muscular Atrophy - A Case Report with 14 Years of Follow-up. Reviewed

    Yasuhiro Hijikata, Atsushi Hashizume, Shinichiro Yamada, Daisuke Ito, Haruhiko Banno, Keisuke Suzuki, Gen Sobue, Masahisa Katsuno

    Internal medicine (Tokyo, Japan)   Vol. 58 ( 15 ) page: 2231 - 2234   2019.8

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    Spinal and bulbar muscular atrophy (SBMA) is a progressive hereditary neuromuscular disease caused by the testosterone-dependent accumulation of pathogenic polyglutamine-expanded androgen receptor protein. A 41-year-old man with SBMA received the androgen deprivation agent leuprorelin acetate for 7 years in clinical trials and underwent castration following the trial. Suppression of testosterone levels for 14 years resulted in a slower disease progression, as measured prospectively with quantitative measurements, than the historical control data reported in previous studies. This suggests that long-term androgen deprivation delays disease progression in SBMA.

    DOI: 10.2169/internalmedicine.1592-18

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  9. TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets. Invited Reviewed

    Araki K, Araki A, Honda D, Izumoto T, Hashizume A, Hijikata Y, Yamada S, Iguchi Y, Hara A, Ikumi K, Kawai K, Ishigaki S, Nakamichi Y, Tsunekawa S, Seino Y, Yamamoto A, Takayama Y, Hidaka S, Tominaga M, Ohara-Imaizumi M, Suzuki A, Ishiguro H, Enomoto A, Yoshida M, Arima H, Muramatsu SI, Sobue G, Katsuno M.

    J Clin Invest.   Vol. 129 ( 9 ) page: 3578 - 3593   2019.7

  10. Efficacy and safety of leuprorelin acetate for subjects with spinal and bulbar muscular atrophy: pooled analyses of two randomized-controlled trials. Reviewed International journal

    Atsushi Hashizume, Masahisa Katsuno, Keisuke Suzuki, Haruhiko Banno, Yu Takeuchi, Motoshi Kawashima, Noriaki Suga, Tomoo Mano, Amane Araki, Yasuhiro Hijikata, Akihiro Hirakawa, Gen Sobue

    Journal of neurology   Vol. 266 ( 5 ) page: 1211 - 1221   2019.5

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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.

    DOI: 10.1007/s00415-019-09251-x

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  11. DNA methylation inhibitor attenuates polyglutamine-induced neurodegeneration by regulating Hes5. Reviewed International journal

    Naohide Kondo, Genki Tohnai, Kentaro Sahashi, Madoka Iida, Mayumi Kataoka, Hideaki Nakatsuji, Yutaka Tsutsumi, Atsushi Hashizume, Hiroaki Adachi, Haruki Koike, Keiko Shinjo, Yutaka Kondo, Gen Sobue, Masahisa Katsuno

    EMBO molecular medicine   Vol. 11 ( 5 )   2019.5

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    Spinal and bulbar muscular atrophy (SBMA) is a polyglutamine-mediated neuromuscular disease caused by a CAG repeat expansion in the androgen receptor (AR) gene. While transcriptional dysregulation is known to play a critical role in the pathogenesis of SBMA, the underlying molecular pathomechanisms remain unclear. DNA methylation is a fundamental epigenetic modification that silences the transcription of various genes that have a CpG-rich promoter. Here, we showed that DNA methyltransferase 1 (Dnmt1) is highly expressed in the spinal motor neurons of an SBMA mouse model and in patients with SBMA. Both genetic Dnmt1 depletion and treatment with RG108, a DNA methylation inhibitor, ameliorated the viability of SBMA model cells. Furthermore, a continuous intracerebroventricular injection of RG108 mitigated the phenotype of SBMA mice. DNA methylation array analysis identified hairy and enhancer of split 5 (Hes5) as having a CpG island with hyper-methylation in the promoter region, and the Hes5 expression was strongly silenced in SBMA. Moreover, Hes5 over-expression rescued the SBMA cells possibly by inducing Smad2 phosphorylation. Our findings suggest DNA hyper-methylation underlies the neurodegeneration in SBMA.

    DOI: 10.15252/emmm.201708547

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  12. Novel therapeutic approach for spinal and bulbar muscular atrophy (SBMA)

    Katsuno Masahisa, Hijikata Yasuhiro, Hashizume Atsushi, Sobue Gen

    Neurological Therapeutics   Vol. 35 ( 4 ) page: 427-431   2019

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    <p>Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular degenerative disease characterized by slowly progressive muscle weakness and atrophy. The cause of SBMA is the expansion of a trinucleotide CAG repeat encoding a polyglutamine tract within the first exon of the androgen receptor (AR) gene. The ligand–dependent nuclear accumulation of the polyglutamine–expanded AR protein is central to the gender–specific pathogenesis of SBMA. The pathogenic AR–mediated neurodegeneration is suppressed by androgen inactivation, the efficacy of which has been tested in randomized controlled trials. Decreases in serum creatinine, a biomarker of SBMA, occurred approximately 15 years before the onset of subjective muscle weakness. The mean serum creatinine concentration is ∼0.6mg/dl and ∼0.8mg/dl at the onset of weakness and hand tremor, respectively. The low serum creatinine concentration in subjects with SBMA is caused by impaired muscle uptake of creatine due to the pathogenic AR–mediated down–regulation of creatine transporter SLC6A8, in addition to being caused by neurogenic atrophy.</p>

    DOI: 10.15082/jsnt.35.4_427

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  13. IGF-1 for spinal and bulbar muscular atrophy: hope and challenges. Reviewed International journal

    Atsushi Hashizume, Masahisa Katsuno

    The Lancet. Neurology   Vol. 17 ( 12 ) page: 1026 - 1027   2018.12

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    DOI: 10.1016/S1474-4422(18)30359-4

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  14. Study protocol for the MEXiletine hydrochloride administration trial: a placebo-controlled, randomised, double-blind, multicentre, crossover study of its efficacy and safety in spinal and bulbar muscular atrophy (MEXPRESS). Reviewed International journal

    Shinichiro Yamada, Atsushi Hashizume, Yasuhiro Hijikata, Tomonori Inagaki, Daisuke Ito, Fumie Kinoshita, Masahiro Nakatochi, Yumiko Kobayashi, Akihiro Hirakawa, Tomohiko Nakamura, Masahisa Katsuno

    BMJ open   Vol. 8 ( 9 ) page: e023041   2018.9

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    INTRODUCTION: Spinal and bulbar muscular atrophy (SBMA) is a slowly progressive neuromuscular disease. Cold exposure often leads to worsening of motor symptoms including paresis. Although mexiletine hydrochloride administration has been shown to be effective for the treatment of several muscular diseases, its effectiveness in SBMA has not been validated to date. The trial will test it as a symptomatic drug for cold paresis. This study is the first trial to evaluate the efficacy and safety of mexiletine hydrochloride administration in patients with SBMA. METHODS AND ANALYSIS: A placebo-controlled, randomised, double-blind, multicentre, crossover clinical trial will be conducted to assess the safety and efficacy of mexiletine hydrochloride in patients with SBMA. The eligible patients will be assigned randomly in a 1:1 ratio to two groups in a double-blind manner. Participants will take mexiletine hydrochloride (300 mg/day) or a placebo orally three times a day for 4 weeks (period 1). After a 1-week washout period, participants will take the other drug for 4 weeks (period 2). The primary endpoint is the difference in distal latencies between room temperature and cold exposure conditions. ETHICS AND DISSEMINATION: This study will be conducted in compliance with the Helsinki Declaration and the Ethical Guidelines for Medical and Health Research Involving Human Subjects by the Japanese government and has been approved by the ethics committee of Nagoya University Graduate School of Medicine, as a central institutional review board, and by each facility. The results will be disseminated in peer-reviewed journals and at scientific conferences. TRIAL REGISTRATION NUMBER: UMIN000026150; Pre-results.

    DOI: 10.1136/bmjopen-2018-023041

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  15. Preclinical progression of neurodegenerative diseases. Reviewed

    Masahisa Katsuno, Kentaro Sahashi, Yohei Iguchi, Atsushi Hashizume

    Nagoya journal of medical science   Vol. 80 ( 3 ) page: 289 - 298   2018.8

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    Neurodegenerative diseases are disorders that are characterized by a progressive decline of the motor and/or cognitive function caused by a selective loss of neurons within the central nervous system. Recent advancements in the translational research have facilitated extensive insights into the molecular pathophysiology of neurodegenerative diseases. Nonetheless, a myriad of compounds that suppressed the disease progression in cellular and animal models did not exhibit efficacy in clinical trials. Perhaps, various biological, medical, and methodological factors could be attributed to unfavorable results of clinical trials of such disease-modifying therapies. Primarily, the fact that pathological changes at molecular and cellular levels precede the clinical onset by several years underscores a pressing need for the initiation of interventions before the emergence of neurological symptoms. Using exquisite biomarkers, recent studies revealed the preclinical and prodromal progression of pathophysiology, as well as compensatory brain responses in several neurodegenerative diseases. This review aims to discuss the recent advancement of biomarker studies on presymptomatic subjects and the perspective on a preventive trial of disease-modifying therapies for devastating neurological disorders.

    DOI: 10.18999/nagjms.80.3.289

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  16. Biomarker-based analysis of preclinical progression in spinal and bulbar muscular atrophy. Reviewed International journal

    Yasuhiro Hijikata, Atsushi Hashizume, Shinichiro Yamada, Tomonori Inagaki, Daisuke Ito, Akihiro Hirakawa, Keisuke Suzuki, Naoki Atsuta, Takashi Tsuboi, Makoto Hattori, Akihiro Hori, Haruhiko Banno, Gen Sobue, Masahisa Katsuno

    Neurology   Vol. 90 ( 17 ) page: e1501-e1509   2018.4

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    OBJECTIVE: To identify a candidate biomarker reflecting biological changes during the preclinical progression of spinal and bulbar muscular atrophy (SBMA). METHODS: We analyzed longitudinal changes in biochemical parameters obtained during health examinations before and after the diagnosis of SBMA. We estimated trajectories of clinical markers across years from the onset of weakness using linear mixed models and compared these trajectories with those estimated for male healthy controls and patients with amyotrophic lateral sclerosis (ALS) and Parkinson disease (PD). Moreover, we examined the relationship between serum creatinine level and the onset of symptoms using Kaplan-Meier curves. RESULTS: Between October 2014 and October 2017, we enrolled 40 patients with genetically confirmed SBMA, 48 healthy controls, 25 patients with ALS, and 20 patients with PD. In patients with SBMA, we evaluated the patients' data for a period of 17.3 ± 7.5 years, including 11.4 ± 7.1 years of preclinical phase. Decreases in serum creatinine occurred >10 years before the onset. The mean serum creatinine concentration was 0.56 mg/dL at the onset of weakness in patients with SBMA compared to 0.88 ± 0.10 mg/dL on final evaluation in healthy controls. Serum levels of alanine transaminase and aspartate transaminase showed tendencies to increase in preclinical SBMA. These preclinical changes of biomarkers were not observed in either ALS or PD. CONCLUSIONS: Our findings suggest that serum creatinine begins to decrease before the onset of clinical symptoms and is a biomarker for disease progression and the efficacy of therapeutics in preclinical SBMA.

    DOI: 10.1212/WNL.0000000000005360

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  17. Treatment with Creatine Monohydrate in Spinal and Bulbar Muscular Atrophy: Protocol for a Randomized, Double-Blind, Placebo-Controlled Trial. Reviewed International journal

    Yasuhiro Hijikata, Masahisa Katsuno, Keisuke Suzuki, Atsushi Hashizume, Amane Araki, Shinichiro Yamada, Tomonori Inagaki, Daisuke Ito, Akihiro Hirakawa, Fumie Kinoshita, Masahiko Gosho, Gen Sobue

    JMIR research protocols   Vol. 7 ( 3 ) page: e69   2018.3

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    BACKGROUND: Although spinal and bulbar muscular atrophy (SBMA) has been classified as a motor neuron disease, several reports have indicated the primary involvement of skeletal muscle in the pathogenesis of this devastating disease. Recent studies reported decreased intramuscular creatine levels in skeletal muscles in both patients with SBMA and transgenic mouse models of SBMA, which appears to contribute to muscle weakness. OBJECTIVE: The present study aimed to examine the efficacy and safety of oral creatine supplementation to improve motor function in patients with SBMA. METHODS: A randomized, double-blind, placebo-controlled, three-armed clinical trial was conducted to assess the safety and efficacy of creatine therapy in patients with SBMA. Patients with SBMA eligible for this study were assigned randomly in a 1:1:1 ratio to each group of placebo, 10 g, or 15 g daily dose of creatine monohydrate in a double-blind fashion. Participants took creatine or placebo orally 3 times a day for 8 weeks. Outcome measurements were results of neurological assessments, examinations, and questionnaires collected at baseline and at weeks 4, 8, and 16 after a washout period. The primary endpoint was the change in handgrip strength values from baseline to week 8. The secondary endpoints included the following: results of maximum voluntary isometric contraction tests of extremities; tongue pressure; results of the 15-foot timed walk test and the rise from bed test; modified quantitative myasthenia gravis score; respiratory function test results; activities of daily living assessed with the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale and the Spinal and Bulbar Muscular Atrophy Functional Rating Scale; skeletal muscle mass measured with dual-energy X-ray absorptiometry; urinary 8-hydroxydeoxyguanosine levels; and questionnaires examining the quality of life, swallowing function, and fatigue. RESULTS: Participant enrollment in the trial started from June 2014 and follow-up was completed in July 2015. The study is currently being analyzed. CONCLUSIONS: This is the first clinical trial evaluating creatine therapy in SBMA. Given that creatine serves as an energy source in skeletal muscles, recovery of intramuscular creatine concentration is expected to improve muscle strength. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry UMIN000012503; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000014611 (Archived by WebCite at http://www.webcitation.org/6xOlbPkg3).

    DOI: 10.2196/resprot.8655

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  18. 臨床研究デザインワークショップ:臨床の疑問を研究で解決する方法を導き出す 司会の言葉

    鈴木 啓介, 中村 治雅, 橋詰 淳

    神経治療学   Vol. 34 ( 4 ) page: 461-462   2018

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    DOI: 10.15082/jsnt.34.4_461

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  19. Quantitative Assessment of Swallowing Dysfunction in Patients with Spinal and Bulbar Muscular Atrophy. Reviewed

    Atsushi Hashizume, Haruhiko Banno, Masahisa Katsuno, Yasuhiro Hijikata, Shinichiro Yamada, Tomonori Inagaki, Keisuke Suzuki, Gen Sobue

    Internal medicine (Tokyo, Japan)   Vol. 56 ( 23 ) page: 3159 - 3165   2017.12

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    Objective This study aimed to evaluate swallowing dysfunction in patients with spinal and bulbar muscular atrophy and to identify the most appropriate method of assessing swallowing dysfunction using a videofluoroscopic swallowing study. Methods In the videofluoroscopic swallowing study, patients were instructed to swallow 3 mL of 40% weight/volume barium sulfate twice, and the pharyngeal residue was measured. We used three different methods to quantify the pharyngeal barium residue and an eight-point scale to evaluate the laryngeal penetration leading to aspiration pneumoniae. Patients We assessed 111 patients with spinal and bulbar muscular atrophy who weren't undergoing disease-specific treatment. Results Our results showed that the pharyngeal barium residue after initial swallowing correlated better with the bulbar-related functional rating scales than that after multiple deglutition. This correlation was vague when the data from patients whose barium residue was >50% were eliminated. In addition, evaluating the pharyngeal residue after initial swallowing proved to be the most sensitive method with regard to laryngeal penetration. Conclusion This study showed that the pharyngeal barium residue after initial swallowing was the most appropriate parameter for quantitatively assessing the degree of dysphagia using a videofluoroscopic swallowing study and suggests that this method may predict laryngeal penetration and aspiration in patients with spinal and bulbar muscular atrophy.

    DOI: 10.2169/internalmedicine.8799-16

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  20. Long-term treatment with leuprorelin for spinal and bulbar muscular atrophy: natural history-controlled study. Reviewed International journal

    Atsushi Hashizume, Masahisa Katsuno, Keisuke Suzuki, Akihiro Hirakawa, Yasuhiro Hijikata, Shinichiro Yamada, Tomonori Inagaki, Haruhiko Banno, Gen Sobue

    Journal of neurology, neurosurgery, and psychiatry   Vol. 88 ( 12 ) page: 1026 - 1032   2017.12

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    OBJECTIVE: To evaluate the prognosis and progression of spinal and bulbar muscular atrophy (SBMA), a rare X-linked motor neuron disorder caused by trinucleotide repeat expansion in the AR (androgen receptor) gene, after long-term androgen suppression with leuprorelin acetate treatment. METHODS: In the present natural history-controlled study, 36 patients with SBMA treated with leuprorelin acetate for up to 84 months (leuprorelin acetate-treated group; LT group) and 29 patients with SBMA with no specific treatment (non-treated group; NT group) were analysed. Disease progression was evaluated by longitudinal quantitative assessment of motor functioning using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and the modified Norris score. In addition, we selected two major clinical endpoint events, namely the occurrence of pneumonia requiring hospitalisation and death, to evaluate disease prognosis following long-term leuprorelin acetate treatment. RESULTS: In our analysis of the longitudinal disease progression using the random slope model, we observed a significant difference in the ALSFRS-R total score, the Limb Norris Score, and the Norris Bulbar Score (p=0.005, 0.026 and 0.020, respectively), with the LT group exhibiting a slower per-12-months decline compared with the NT group. As for the event analysis, the prognosis of the LT group was better in comparison to the NT group as for the event-free survival period (p=0.021). CONCLUSION: Long-term treatment with leuprorelin acetate appears to delay the functional decline and suppress the incidence of pneumonia and death in subjects with SBMA.

    DOI: 10.1136/jnnp-2017-316015

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  21. Distinct pathogenesis in nonsystemic vasculitic neuropathy and microscopic polyangiitis. Reviewed International journal

    Mie Takahashi, Haruki Koike, Shohei Ikeda, Yuichi Kawagashira, Masahiro Iijima, Atsushi Hashizume, Masahisa Katsuno, Gen Sobue

    Neurology(R) neuroimmunology & neuroinflammation   Vol. 4 ( 6 ) page: e407   2017.11

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    OBJECTIVE: To investigate the mechanisms of vasculitis in nonsystemic vasculitic neuropathy (NSVN) and microscopic polyangiitis (MPA), focusing on complement- and antineutrophil cytoplasmic antibody (ANCA)-associated pathogenesis. METHODS: Sural nerve biopsy specimens taken from twenty-four patients with NSVN and 37 with MPA-associated neuropathy (MPAN) were examined. Twenty-two patients in the MPAN group tested positive for ANCA. RESULTS: Immunostaining for complement component C3d deposition showed more frequent positive staining of epineurial small vessels in NSVN than in MPAN (p = 0.002). The percentages of C3d-positive blood vessels were higher in the NSVN group than those in the ANCA-positive MPAN and ANCA-negative MPAN groups (p = 0.002 and p = 0.009, respectively). Attachment of neutrophils to the endothelial cells of epineurial small vessels was frequently observed in the MPAN groups, irrespective of the presence or absence of ANCA, but was scarce in the NSVN group. Immunohistochemistry using antimyeloperoxidase (MPO) antibodies revealed that the number of MPO-positive cells attached to the endothelial cells of epineurial vessels was lower in the NSVN group than that in the ANCA-positive MPAN and ANCA-negative MPAN groups (p < 0.001 and p = 0.011, respectively). CONCLUSIONS: NSVN and MPA have distinct mechanisms of vasculitis. In MPA, the attachment of neutrophils to vascular endothelial cells seems to be an initial lesion of vasculitis, regardless of the presence or absence of ANCA. Complement participated in the pathogenesis of vasculitis in NSVN.

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  22. Cardiac and peripheral vasomotor autonomic functions in late-onset transthyretin Val30Met familial amyloid polyneuropathy. Reviewed International journal

    Haruki Koike, Tomohiko Nakamura, Atsushi Hashizume, Ryoji Nishi, Shohei Ikeda, Yuichi Kawagashira, Masahiro Iijima, Masahisa Katsuno, Gen Sobue

    Journal of neurology   Vol. 264 ( 11 ) page: 2293 - 2302   2017.11

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    The objective of this study was to systematically investigate cardiac and peripheral vasomotor autonomic functions in late-onset transthyretin Val30Met familial amyloid polyneuropathy (FAP ATTR Val30Met) patients from non-endemic areas. The coefficient of variation of R-R intervals (CVR-R), responses to the Valsalva manoeuvre, head-up tilt test with impedance cardiography, noradrenaline infusion test, and (123)I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy were assessed in eight patients. Although only four patients manifested orthostatic hypotension during the head-up tilt test, CVR-R, responses to the Valsalva manoeuvre, and myocardial MIBG uptake indicated a higher prevalence of cardiac sympathetic and parasympathetic dysfunction. Total peripheral resistance at 60° tilt did not increase from baseline values in five of six examined patients. An infusion of low-dose noradrenaline induced an increase in systolic blood pressure in all patients. The extent of the change in systolic blood pressure negatively correlated to that in total peripheral resistance (p < 0.05). Patients with poor vasoconstrictor responses to orthostatic stress tended to exhibit severe reduction of unmyelinated fibres in sural nerve biopsy specimens. In conclusion, both cardiac and peripheral vasomotor autonomic dysfunctions were prevalent in late-onset FAP ATTR Val30Met patients from non-endemic areas, even in those without orthostatic intolerance. However, vasoconstriction by alpha-adrenoceptor agonists was preserved even after denervation, carrying important implications for the management of orthostatic hypotension in FAP.

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  23. The impact of cold exposure in spinal and bulbar muscular atrophy

    Yamada S., Hashizume A., Hijikata Y., Inagaki T., Ito D., Nakamura T., Katsuno M.

    JOURNAL OF THE NEUROLOGICAL SCIENCES   Vol. 381   page: 1084-1084   2017.10

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  24. Development of a quantitative composite functional measure for spinal and bulbar muscular atrophy (SBMA)

    Inagaki T., Hashizume A., Yasuhiro H., Shinichiro Y., Daisuke I., Masahisa K.

    JOURNAL OF THE NEUROLOGICAL SCIENCES   Vol. 381   page: 210-210   2017.10

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    DOI: 10.1016/j.jns.2017.08.601

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  25. Estimation of skeletal muscle mass, serum creatinine and creatine kinase at the onset of amyotrophic lateral sclerosis

    Ito D., Hashizume A., Hijikata Y., Yamada S., Inagaki T., Katsuno M.

    JOURNAL OF THE NEUROLOGICAL SCIENCES   Vol. 381   page: 212-212   2017.10

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    DOI: 10.1016/j.jns.2017.08.606

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  26. Preclinical biomarkers in spinal and bulbar muscular atrophy

    Hijikata Y., Hashizume A., Yamada S., Inagaki T., Ito D., Hirakawa A., Suzuki K., Banno H., Sobue G., Katsuno M.

    JOURNAL OF THE NEUROLOGICAL SCIENCES   Vol. 381   page: 462-462   2017.10

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    DOI: 10.1016/j.jns.2017.08.3512

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  27. Long-term treatment with leuprorelin for spinal and bulbar muscular atrophy

    Hashizume A., Katsuno M., Suzuki K., Hirakawa A., Hijikata Y., Yamada S., Inagaki T., Banno H., Sobue G.

    JOURNAL OF THE NEUROLOGICAL SCIENCES   Vol. 381   page: 205-206   2017.10

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    DOI: 10.1016/j.jns.2017.08.588

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  28. Swallowing markers in spinal and bulbar muscular atrophy. Reviewed International journal

    Haruhiko Banno, Masahisa Katsuno, Keisuke Suzuki, Seiya Tanaka, Noriaki Suga, Atsushi Hashizume, Tomoo Mano, Amane Araki, Hirohisa Watanabe, Yasushi Fujimoto, Masahiko Yamamoto, Gen Sobue

    Annals of clinical and translational neurology   Vol. 4 ( 8 ) page: 534 - 543   2017.8

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    OBJECTIVE: We examined the characteristics of dysphagia in spinal and bulbar muscular atrophy, a hereditary neuromuscular disease causing weakness of limb, facial, and oropharyngeal muscles via a videofluoroscopic swallowing study, and investigated the plausibility of using these outcome measures for quantitative analysis. METHODS: A videofluoroscopic swallowing study was performed on 111 consecutive patients with genetically confirmed spinal and bulbar muscular atrophy and 53 age- and sex-matched healthy controls. Swallowing of 3-mL liquid barium was analyzed by the Logemann's Videofluorographic Examination of Swallowing worksheet. RESULTS: Of more than 40 radiographic findings, the most pertinent abnormal findings in patients with spinal and bulbar muscular atrophy, included vallecular residue after swallow (residue just behind the tongue base), nasal penetration, and insufficient tongue movement (P < 0.001 for each) compared with healthy controls. Quantitative analyses showed that pharyngeal residue after initial swallowing, oral residue after initial swallowing, multiple swallowing sessions, and the penetration-aspiration scale were significantly worse in these patients (P ≤ 0.005 for each) than in controls. In patients with spinal and bulbar muscular atrophy, laryngeal penetration was observed more frequently in those without subjective dysphagia. INTERPRETATION: Dysphagia of spinal and bulbar muscular atrophy was characterized by impaired tongue movement in the oral phase and nasal penetration followed by pharyngeal residues, which resulted in multiple swallowing sessions and laryngeal penetration. Although major limitations of reproducibility and radiation exposure still exist with videofluoroscopy, pharyngeal residue after initial swallowing and the penetration-aspiration scale might serve as potential outcome measures in clinical studies.

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  29. Correlation of insulin resistance and motor function in spinal and bulbar muscular atrophy. Reviewed International journal

    Hideaki Nakatsuji, Amane Araki, Atsushi Hashizume, Yasuhiro Hijikata, Shinichiro Yamada, Tomonori Inagaki, Keisuke Suzuki, Haruhiko Banno, Noriaki Suga, Yohei Okada, Manabu Ohyama, Tohru Nakagawa, Ken Kishida, Tohru Funahashi, Iichiro Shimomura, Hideyuki Okano, Masahisa Katsuno, Gen Sobue

    Journal of neurology   Vol. 264 ( 5 ) page: 839 - 847   2017.5

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    This study aimed to evaluate various metabolic parameters in patients with spinal and bulbar muscular atrophy (SBMA), to investigate the association between those indices and disease severity, and to explore the underlying molecular pathogenesis. We compared the degree of obesity, metabolic parameters, and blood pressure in 55 genetically confirmed SBMA patients against those in 483 age- and sex-matched healthy control. In SBMA patients, we investigated the correlation between these factors and motor functional indices. SBMA patients had lower body mass index, blood glucose, and Hemoglobin A1c, but higher blood pressure, homeostasis model assessment of insulin resistance (HOMA-IR, a marker of insulin resistance), total cholesterol, and adiponectin levels than the control subjects. There were no differences in visceral fat areas, high-density lipoprotein-cholesterol (HDL-C), or triglyceride levels in two groups. Revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) correlated positively with HDL-C, but negatively with HOMA-IR. Through stepwise multiple regression analysis, we identified HOMA-IR as a significant metabolic determinant of ALSFRS-R. In biochemical analysis, we found that decreased expressions of insulin receptors, insulin receptor substrate-1 and insulin receptor-β, in autopsied muscles and fibroblasts of SBMA patients. This study demonstrates that SBMA patients have insulin resistance, which is associated with the disease severity. The expressions of insulin receptors are attenuated in the skeletal muscle of SBMA, providing a possible pathomechanism of metabolic alterations. These findings suggested that insulin resistance is a metabolic index reflecting disease severity and pathogenesis as well as a potential therapeutic target for SBMA.

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  30. Patient Registry and Biobank for Reverse Translational Research on Neurodegenerative Diseases

    KATSUNO Masahisa, INOUE Takahiro, KUSAMA Makiko, MIZUSHIMA Hiroshi, FUJIMOTO Yoko, AKIMOTO Makoto, KOBAYASHI Kiyoshi, OHWAKI Kenji, UESUGI Koji, HASHIZUME Atsushi, NAKAMURA Harumasa, ONO Kenjiro, YUJI Koichiro, YAMADA Masanobu, WATANABE Takuya, ICHIMARU Katsuhiko, KATO Naoto

    Rinsho yakuri/Japanese Journal of Clinical Pharmacology and Therapeutics   Vol. 48 ( 4 ) page: 141-147   2017

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    DOI: 10.3999/jscpt.48.141

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  31. Progress toward the development of treatment of spinal and bulbar muscular atrophy

    Sahashi Kentaro, Hashizume Atsushi, Sobue Gen, Katsuno Masahisa

    EXPERT OPINION ON ORPHAN DRUGS   Vol. 5 ( 6 ) page: 503-514   2017

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    DOI: 10.1080/21678707.2017.1329088

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  32. Impaired muscle uptake of creatine in spinal and bulbar muscular atrophy. Reviewed International journal

    Yasuhiro Hijikata, Masahisa Katsuno, Keisuke Suzuki, Atsushi Hashizume, Amane Araki, Shinichiro Yamada, Tomonori Inagaki, Madoka Iida, Seiya Noda, Hirotaka Nakanishi, Haruhiko Banno, Tomoo Mano, Akihiro Hirakawa, Hiroaki Adachi, Hirohisa Watanabe, Masahiko Yamamoto, Gen Sobue

    Annals of clinical and translational neurology   Vol. 3 ( 7 ) page: 537 - 46   2016.7

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    OBJECTIVE: The aim of this study was to explore the pathomechanism underlying the reduction of serum creatinine (Cr) concentrations in spinal and bulbar muscular atrophy (SBMA). METHODS: We evaluated blood chemistries, motor function, and muscle mass measured by dual-energy X-ray absorptiometry in male subjects with SBMA (n = 65), amyotrophic lateral sclerosis (ALS; n = 27), and healthy controls (n = 25). We also examined the intramuscular concentrations of creatine, a precursor of Cr, as well as the protein and mRNA expression levels of the creatine transporter (SLC6A8) in autopsy specimens derived from subjects who had SBMA and ALS and disease controls. Furthermore, we measured the mRNA expression levels of SLC6A8 in cultured muscle cells (C2C12) transfected with the polyglutamine-expanded androgen receptor (AR-97Q). RESULTS: Serum Cr concentrations were significantly lower in subjects with SBMA than in those with ALS (P < 0.001), despite similar muscle mass values. Intramuscular creatine concentrations were also lower in with the autopsied specimen of SBMA subjects than in those with ALS subjects (P = 0.018). Moreover, the protein and mRNA expression levels of muscle SLC6A8 were suppressed in subjects with SBMA. The mRNA levels of SLC6A8 were also suppressed in C2C12 cells bearing AR-97Q. INTERPRETATION: These results suggest that low serum Cr concentration in subjects with SBMA is caused by impaired muscle uptake of creatine in addition to being caused by neurogenic atrophy. Given that creatine serves as an energy source in skeletal muscle, increasing muscle creatine uptake is a possible therapeutic approach for treating SBMA.

    DOI: 10.1002/acn3.324

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  33. Decreased Peak Expiratory Flow Associated with Muscle Fiber-Type Switching in Spinal and Bulbar Muscular Atrophy. Reviewed International journal

    Shinichiro Yamada, Atsushi Hashizume, Yasuhiro Hijikata, Tomonori Inagaki, Keisuke Suzuki, Naohide Kondo, Kaori Kawai, Seiya Noda, Hirotaka Nakanishi, Haruhiko Banno, Akihiro Hirakawa, Haruki Koike, Katherine Halievski, Cynthia L Jordan, Masahisa Katsuno, Gen Sobue

    PloS one   Vol. 11 ( 12 ) page: e0168846   2016

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    The aim of this study was to characterize the respiratory function profile of subjects with spinal and bulbar muscular atrophy (SBMA), and to explore the underlying pathological mechanism by comparing the clinical and biochemical indices of this disease with those of amyotrophic lateral sclerosis (ALS). We enrolled male subjects with SBMA (n = 40) and ALS (n = 25) along with 15 healthy control subjects, and assessed their respiratory function, motor function, and muscle strength. Predicted values of peak expiratory flow (%PEF) and forced vital capacity were decreased in subjects with SBMA compared with controls. In SBMA, both values were strongly correlated with the trunk subscores of the motor function tests and showed deterioration relative to disease duration. Compared with activities of daily living (ADL)-matched ALS subjects, %PEF, tongue pressure, and grip power were substantially decreased in subjects with SBMA. Both immunofluorescence and RT-PCR demonstrated a selective decrease in the expression levels of the genes encoding the myosin heavy chains specific to fast-twitch fibers in SBMA subjects. The mRNA levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha and peroxisome proliferator-activated receptor delta were up-regulated in SBMA compared with ALS and controls. In conclusion, %PEF is a disease-specific respiratory marker for the severity and progression of SBMA. Explosive muscle strength, including %PEF, was selectively affected in subjects with SBMA and was associated with activation of the mitochondrial biogenesis-related molecular pathway in skeletal muscles.

    DOI: 10.1371/journal.pone.0168846

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  34. Myotonia-like symptoms in a patient with spinal and bulbar muscular atrophy. Reviewed International journal

    Kunihiko Araki, Hirotaka Nakanishi, Tomohiko Nakamura, Naoki Atsuta, Shinichiro Yamada, Yasuhiro Hijikata, Atsushi Hashizume, Keisuke Suzuki, Masahisa Katsuno, Gen Sobue

    Neuromuscular disorders : NMD   Vol. 25 ( 11 ) page: 913 - 5   2015.11

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    We describe the case of a 33-year-old man with a 4-year history of worsening muscle stiffness and weakness in his right hand. He showed elevated serum creatine kinase levels at the onset of muscle stiffness that was characterized by delayed muscle relaxation after voluntary contraction. This symptom often occurred during cold exposure, and was partially attenuated by sodium channel blockade. Electrodiagnostic findings in repetitive nerve stimulation, short-exercise, and cooling tests were normal. Electromyography showed chronic denervation potentials in his cranial, cervical, thoracic, and lumbosacral myotomes without myotonic discharge. He exhibited facial and tongue fasciculations, hypernasality, gynecomastia, neurogenic changes in muscle biopsy, and increased serum testosterone levels. Spinal and bulbar muscular atrophy (SBMA) was diagnosed on the basis of the CAG trinucleotide expansion in the gene coding androgen receptor. A myotonia-like symptom without myotonic discharge may present as an early neurological sign of SBMA, which possibly reflects a sodium channel dysfunction in skeletal muscles.

    DOI: 10.1016/j.nmd.2015.08.006

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  35. A functional scale for spinal and bulbar muscular atrophy: Cross-sectional and longitudinal study. Reviewed International journal

    Atsushi Hashizume, Masahisa Katsuno, Keisuke Suzuki, Haruhiko Banno, Noriaki Suga, Tomoo Mano, Amane Araki, Yasuhiro Hijikata, Christopher Grunseich, Angela Kokkinis, Akihiro Hirakawa, Hirohisa Watanabe, Masahiko Yamamoto, Kenneth H Fischbeck, Gen Sobue

    Neuromuscular disorders : NMD   Vol. 25 ( 7 ) page: 554 - 62   2015.7

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    We aimed to develop, validate, and evaluate a disease-specific outcome measure for SBMA: the Spinal and Bulbar Muscular Atrophy Functional Rating Scale (SBMAFRS). We examined the Japanese version (SBMAFRS-J) in 80 Japanese SBMA subjects to evaluate its validity and reliability. We then assessed this scale longitudinally in 41 additional SBMA subjects. The English version (SBMAFRS-E) was also tested in 15 US subjects. The total score of the SBMAFRS-J was distributed normally without an extreme ceiling or floor effect. For SBMAFRS-J, the high intra- and inter-rater agreement was confirmed (intra-class correlation coefficients [ICCs] 0.910 and 0.797, respectively), and internal consistency was satisfactory (Cronbach's alpha 0.700-0.822). In addition, SBMAFRS-J demonstrated concurrent, convergent, and discriminant validity, except for the respiratory subscale. The inter-rater reliability and internal consistency of SBMAFRS-E were also satisfactory. Longitudinally, SBMAFRS-J showed a higher sensitivity to disease progression than the existing clinical measures. In conclusion, we developed and validated a disease-specific functional rating scale for SBMA in both Japanese and English versions, although it needs to be re-assessed in interventional studies with a larger sample size including English speaking subjects.

    DOI: 10.1016/j.nmd.2015.03.008

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  36. Head Lift Exercise Improves Swallowing Dysfunction in Spinal and Bulbar Muscular Atrophy. Reviewed International journal

    Tomoo Mano, Masahisa Katsuno, Haruhiko Banno, Keisuke Suzuki, Noriaki Suga, Atsushi Hashizume, Amane Araki, Yasuhiro Hijikata, Seiya Tanaka, Jun Takatsu, Hirohisa Watanabe, Masahiko Yamamoto, Gen Sobue

    European neurology   Vol. 74 ( 5-6 ) page: 251 - 8   2015

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    BACKGROUND: Dysphagia due to bulbar involvement is a major symptom of patients with spinal and bulbar muscular atrophy (SBMA). The aim of this pilot study was to test the efficacy and safety of the head lift exercise for swallowing dysfunction in SBMA. METHODS: We enrolled 6 subjects with genetically confirmed SBMA and instructed them to perform the head lift exercise for 6 weeks. The efficacy outcome measures were the changes from baseline in tongue pressure, the scores of swallowing functional questionnaires, and the motor functional scales and parameters of videofluorography (VF). RESULTS: All subjects completed the study and no major adverse effects were recorded. Tongue pressure significantly increased by 19.2 ± 0.15% (p < 0.05) after the 6-week head lift exercise. The scores for oral dysphagia also improved, although there was no significant change in VF parameters or other variables examined pre- and post-exercise. CONCLUSION: Our findings suggested that the head lift exercise may improve swallowing dysfunction, particularly tongue pressure, in SBMA.

    DOI: 10.1159/000431088

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  37. Schwann cell involvement in the peripheral neuropathy of spinocerebellar ataxia type 3. Reviewed International journal

    Noriaki Suga, Masahisa Katsuno, Haruki Koike, Haruhiko Banno, Keisuke Suzuki, Atsushi Hashizume, Tomoo Mano, Masahiro Iijima, Yuichi Kawagashira, Masaaki Hirayama, Tomohiko Nakamura, Hirohisa Watanabe, Fumiaki Tanaka, Gen Sobue

    Neuropathology and applied neurobiology   Vol. 40 ( 5 ) page: 628 - 39   2014.8

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    AIMS: Spinocerebellar ataxia type 3 (SCA3) is an inherited spinocerebellar ataxia caused by the expansion of trinucleotide CAG repeats in the gene encoding ataxin-3. The clinical manifestations of SCA3 include peripheral neuropathy, which is an important cause of disability in a subset of patients. Although the loss of neurones in the dorsal root ganglion (DRG) has been postulated to be the cause of this neuropathy, the precise mechanism remains to be elucidated. METHODS: To clarify the clinicopathological characteristics of SCA3-associated peripheral neuropathy, we performed nerve conduction studies and histopathological analyses. Nerve conduction studies were carried out in 18 SCA3 patients. Immunohistochemical analyses of the anterior and posterior roots of the spinal cord and peripheral nerves were performed in five SCA3 patients. We also employed immunohistochemistry and immunoelectron microscopy analyses with an anti-polyglutamine antibody. RESULTS: The mean sensory nerve action potentials of the SCA3 patients were half of the normal values. The motor conduction velocities were decreased, and the distal latencies were also significantly prolonged in the nerves studied relative to the those in normal controls. Histopathological analyses detected axonal sprouting and myelin thinning in all cases. Ataxin-3 aggregates were found in the cytoplasm of Schwann cells in all of the SCA3 patients examined but not in control subjects. CONCLUSIONS: In addition to the previously reported neuronopathy, the results of the present study indicate that Schwann cells are involved in the formation of the pathogenic intracytoplasmic ataxin-3 protein aggregates in patients with SCA3-associated neuropathy.

    DOI: 10.1111/nan.12055

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  38. Brugada syndrome in spinal and bulbar muscular atrophy. Reviewed International journal

    Amane Araki, Masahisa Katsuno, Keisuke Suzuki, Haruhiko Banno, Noriaki Suga, Atsushi Hashizume, Tomoo Mano, Yasuhiro Hijikata, Hideaki Nakatsuji, Hirohisa Watanabe, Masahiko Yamamoto, Takeru Makiyama, Seiko Ohno, Megumi Fukuyama, Shin-Ichiro Morimoto, Minoru Horie, Gen Sobue

    Neurology   Vol. 82 ( 20 ) page: 1813 - 21   2014.5

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    OBJECTIVE: The aim of this study was to clarify myocardial involvement and its clinical implications in subjects with spinal and bulbar muscular atrophy (SBMA), a neuromuscular disease affecting both neuronal and nonneuronal tissues. METHODS: Two independent cardiologists evaluated ECGs from a total of 144 consecutive subjects with SBMA. We performed immunohistochemical, immunoblot, and quantitative real-time PCR analyses of autopsied myocardium. RESULTS: Abnormal ECGs were detected in 70 (48.6%) of 144 subjects. The most frequent findings were ST-segment abnormalities in V1-3 (19.4%), followed by ST-segment abnormalities in V5-6 (18.1%). We detected Brugada-type ECGs in 17 of 28 subjects with ST-segment abnormalities in V1-3. Of those, one subject presented with syncope that required an implantable cardioverter defibrillator and led to eventual sudden death, and another subject also died suddenly. No subjects with Brugada-type ECGs had mutations in SCN5A, CACNA1C, or CACNB2 genes. In autopsied cases, we detected nuclear accumulation of the mutant androgen receptor protein and decreased expression levels of SCN5A in the myocardium. CONCLUSIONS: Subjects with SBMA often show Brugada-type ECG. The accumulation of the pathogenic androgen receptor may have a role in the myocardial involvement in SBMA.

    DOI: 10.1212/WNL.0000000000000434

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  39. Distinct acoustic features in spinal and bulbar muscular atrophy patients with laryngospasm. Reviewed International journal

    Seiya Tanaka, Haruhiko Banno, Masahisa Katsuno, Keisuke Suzuki, Noriaki Suga, Atsushi Hashizume, Tomoo Mano, Amane Araki, Hirohisa Watanabe, Hiroaki Adachi, Hiroshi Tatsumi, Masahiko Yamamoto, Gen Sobue

    Journal of the neurological sciences   Vol. 337 ( 1-2 ) page: 193 - 200   2014.2

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    OBJECTIVE: Laryngospasm is a sudden onset of transient respiratory difficulty that is perceived as life-threatening by patients with spinal and bulbar muscular atrophy (SBMA). The purpose of the study was to analyze the voice characteristics of SBMA patients with laryngospasm using acoustic voice analysis. METHODS: Acoustic measurements were obtained from 39 consecutive Japanese patients with genetically confirmed SBMA. A comparison was made between the acoustic voice profiles of 16 patients with laryngospasm and 23 patients without laryngospasm within 6 months before the evaluation. Computerized acoustic analysis was performed for a prolonged vowel (/a:/) using the Multi-Dimensional Voice Program (MDVP). RESULTS: SBMA patients with laryngospasm had smaller fluctuations of vocal fold vibration and the turbulent noise component, indicating stronger vocal fold closure than in those without laryngospasm. Receiver operating characteristic curve analysis showed that the noise-to-harmonic ratio, which globally measures the noise components of voice, is the most useful acoustic parameter to distinguish laryngospasm (area under the curve = 0.767, p = 0.007). CONCLUSIONS: The smaller noise component in patients with laryngospasm suggests that the vocal folds of these patients are more adducted during phonation than those of the patients without laryngospasm, even in the absence of laryngospasm. Quantitative laryngeal analysis using the MDVP helps to detect laryngeal dysfunction and provides physiological insight into the pathophysiology of laryngospasm in SBMA.

    DOI: 10.1016/j.jns.2013.12.010

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  40. Tongue pressure as a novel biomarker of spinal and bulbar muscular atrophy. Reviewed International journal

    Tomoo Mano, Masahisa Katsuno, Haruhiko Banno, Keisuke Suzuki, Noriaki Suga, Atsushi Hashizume, Amane Araki, Hirohisa Watanabe, Seiya Tanaka, Masahiko Yamamoto, Gen Sobue

    Neurology   Vol. 82 ( 3 ) page: 255 - 62   2014.1

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    OBJECTIVE: This study aimed to explore the reliability and validity of tongue pressure measurement as a quantitative evaluation of swallowing function in patients with spinal and bulbar muscular atrophy (SBMA). METHODS: This study enrolled 47 genetically confirmed patients with SBMA and 38 age- and sex-matched healthy controls. In both groups we measured tongue pressure using an intraoral pressure probe and assessed questionnaires that evaluated swallowing functions. We then analyzed the relationship between tongue pressure, functional scales, and the muscle weakness of other regions. RESULTS: Levels of tongue pressure were decreased in patients with SBMA within 3 years from the onset of the disease compared to healthy controls (SBMA 15.3 ± 6.4 kPa; healthy controls 37.3 ± 9.6 kPa; p < 0.001). Test-retest analysis showed a high reliability in patients with SBMA (intraclass correlation coefficient = 0.986). Tongue pressure showed a strong correlation with bulbar-related functional scales. Decrease of tongue pressure was detected in patients who reported no subjective dysphagia, and repetition of swallowing compensated for tongue weakness in such subjects. In patients with SBMA, tongue pressure more strongly correlates with the strength of pharyngeal, neck, and upper limb musculatures than with that of the lower limbs. CONCLUSION: Tongue pressure measurement is reliable and reflects swallowing function in patients with SBMA. The muscle strength of the tongue appears to decrease in SBMA before the awareness of subjective dysphagia, suggesting that tongue pressure measurement is a novel biomarker of SBMA and is applicable to early-stage detection.

    DOI: 10.1212/WNL.0000000000000041

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  41. Cross-sectional and longitudinal analysis of an oxidative stress biomarker for spinal and bulbar muscular atrophy. Reviewed International journal

    Tomoo Mano, Masahisa Katsuno, Haruhiko Banno, Keisuke Suzuki, Noriaki Suga, Atsushi Hashizume, Fumiaki Tanaka, Gen Sobue

    Muscle & nerve   Vol. 46 ( 5 ) page: 692 - 7   2012.11

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    INTRODUCTION: Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease caused by a CAG repeat expansion in the androgen receptor gene. The aim of this study was to verify whether urinary 8-hydroxydeoxyguanosine (8-OHdG), an oxidative stress marker, is a biomarker for SBMA. METHODS: We measured the levels of urinary 8-OHdG in 33 genetically confirmed SBMA patients and 32 age-matched controls over a 24-month period at 6-month intervals. RESULTS: Urinary 8-OHdG levels in SBMA patients were significantly elevated compared with those of controls and correlated well with motor function scores. During the follow-up period, urinary 8-OHdG levels increased and correlated with motor function at each time-point. In addition, urinary 8-OHdG levels at baseline were correlated with changes in the 6-minute walk test during 24 months. CONCLUSIONS: Urinary 8-OHdG is a biomarker for SBMA, reflecting the severity and possibly predicting the deterioration of motor function.

    DOI: 10.1002/mus.23413

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  42. [109th Scientific Meeting of the Japanese Society of Internal Medicine: symposium: 2. Translational research and evidence-based medicine (EBM) in internal medicine in Japan, translational research; 1) Translational research on neurodegenerative diseases]. Reviewed

    Masahisa Katsuno, Haruhiko Banno, Keisuke Suzuki, Atsushi Hashizume, Hiroaki Adachi, Fumiaki Tanaka, Gen Sobue

    Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine   Vol. 101 ( 9 ) page: 2533 - 8   2012.9

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  43. Longitudinal changes of outcome measures in spinal and bulbar muscular atrophy. Reviewed International journal

    Atsushi Hashizume, Masahisa Katsuno, Haruhiko Banno, Keisuke Suzuki, Noriaki Suga, Tomoo Mano, Naoki Atsuta, Hiroaki Oe, Hirohisa Watanabe, Fumiaki Tanaka, Gen Sobue

    Brain : a journal of neurology   Vol. 135 ( Pt 9 ) page: 2838 - 48   2012.9

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    Spinal and bulbar muscular atrophy is an adult-onset, hereditary motor neuron disease caused by the expansion of a trinucleotide CAG repeat within the gene encoding the androgen receptor. To date, several agents have been shown to prevent or slow disease progression in animal models of this disease. For the translational research of these agents, it is necessary to perform the detailed analysis of natural history with quantitative outcome measures and to establish sensitive and validated disease-specific endpoints in the clinical trials. To this end, we performed a prospective observation of disease progression over 3 years in 34 genetically confirmed Japanese patients with spinal and bulbar muscular atrophy by using quantitative outcome measures, including functional and blood parameters. The baseline evaluation revealed that CAG repeat length in the androgen receptor gene correlated not only with the age of onset but also with the timing of substantial changes in activity of daily living. Multiple regression analyses indicated that the serum level of creatinine is the most useful blood parameter that reflects the severity of motor dysfunction in spinal and bulbar muscular atrophy. In 3-year prospective analyses, a slow but steady progression was affirmed in most of the outcome measures we examined. In the analyses using random coefficient models that summarize the individual data into a representative line, disease progression was not affected by CAG repeat length or onset age. These models showed large interindividual variation, which was also independent of the differences of CAG repeat size. Analyses using these models also demonstrated that the subtle neurological deficits at an early or preclinical stage were more likely to be detected by objective motor functional tests such as the 6-min walk test and grip power or serum creatinine levels than by functional rating scales, such as the revised amyotrophic lateral sclerosis functional rating scale or modified Norris scale. Categorization of the clinical phenotypes using factor analysis showed that upper limb function is closely related to bulbar function, but not to lower limb function at baseline, whereas the site of onset had no substantial effects on disease progression. These results suggest that patients with spinal and bulbar muscular atrophy show a slow but steady progression of motor dysfunction over time that is independent of CAG repeat length or clinical phenotype, and that objective outcome measures may be used to evaluate disease severity at an early stage of this disease.

    DOI: 10.1093/brain/aws170

    PubMed

  44. Difference in chronological changes of outcome measures between untreated and placebo-treated patients of spinal and bulbar muscular atrophy. Reviewed International journal

    Atsushi Hashizume, Masahisa Katsuno, Haruhiko Banno, Keisuke Suzuki, Noriaki Suga, Fumiaki Tanaka, Gen Sobue

    Journal of neurology   Vol. 259 ( 4 ) page: 712 - 9   2012.4

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    Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, X-linked motor neuron disease characterized by muscle atrophy, weakness, and bulbar involvement. The aim of this study was to analyze the differential change of various outcome measures by comparing the progression of motor impairment in the two independent groups: placebo-treated group (PTG) and natural history group (NHG). For the PTG, we analyzed 99 patients who participated in a previous double-blind phase III clinical trial and received placebo. For the NHG, a total of 34 patients were followed with no specific treatment. The characteristics of both groups did not differ at baseline except for disease duration. Although the 6 min walk distance (6MWD) showed almost the same progression in both groups (-14.7 ± 7.3 m in NHG, -14.0 ± 4.7 m in PTG; NS), there was a significant difference of progression in the ALSFRS-R between the NHG and PTG (-1.18 ± 0.38, -0.14 ± 0.24; p = 0.03). A similar tendency was also seen in the subgroup analysis of the patients whose disease durations were less than 10 years. Although the relationship between the ALSFRS-R and 6MWD at week 48 was similar to that at baseline in the NHG, the slope of the regression at week 48 was significantly milder than at baseline in the PTG (p = 0.04). In conclusion, these two groups demonstrated a large difference in the chronological analysis of a motor function score, but showed similar changes in objective measures of walking capacity. These findings should be thoroughly considered when designing clinical trials for slowly progressive neurodegenerative diseases such as SBMA.

    DOI: 10.1007/s00415-011-6251-2

    PubMed

  45. [Anti-androgen therapy for spinal and bulbar muscular atrophy (SBMA)]. Reviewed

    Masahisa Katsuno, Haruhiko Banno, Keisuke Suzuki, Atsushi Hashizume, Hiroaki Adachi, Fumiaki Tanaka, Gen Sobue

    Rinsho shinkeigaku = Clinical neurology   Vol. 52 ( 11 ) page: 1207 - 9   2012

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    Spinal and bulbar muscular atrophy (SBMA), or Kennedy's disease, is an adult-onset lower motor neuron disease caused by the expansion of a trinucleotide CAG repeat encoding a polyglutamine tract within the first exon of the androgen receptor (AR) gene. The testosterone-dependent nuclear accumulation of polyglutamine-expanded AR protein is central to the pathogenesis. This hypothesis is supported by pre-clinical studies showing that testosterone deprivation ameliorates motor neuron degeneration in animal modes of SBMA. In a randomized placebo-controlled multi-centric clinical trial, leuprorelin, which suppresses secretion of testosterone, showed no definite effect on motor functions, although there was the improvement of swallowing function in a subgroup of patients whose disease duration was less than 10 years. Elucidation of the entire disease mechanism, early initiation of therapeutic intervention, and sensitive outcome measures to evaluate drug effect appear to be the key to a successful translational research on SBMA.

    PubMed

  46. The profile of motor unit number estimation (MUNE) in spinal and bulbar muscular atrophy. Reviewed International journal

    Keisuke Suzuki, Masahisa Katsuno, Haruhiko Banno, Yu Takeuchi, Motoshi Kawashima, Noriaki Suga, Atsushi Hashizume, Tetsuo Hama, Kei Uchida, Fumitada Yamashita, Tomohiko Nakamura, Masaaki Hirayama, Fumiaki Tanaka, Gen Sobue

    Journal of neurology, neurosurgery, and psychiatry   Vol. 81 ( 5 ) page: 567 - 71   2010.5

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    OBJECTIVE: Spinal and bulbar muscular atrophy (SBMA) is a lower motor neuron disease caused by the expansion of a trinucleotide CAG repeat in the androgen receptor (AR) gene. The fundamental histopathological finding of this disease is an extensive loss of lower motor neurons in the spinal cord and brainstem. It is, however, difficult to evaluate clinically the degree of motor neuron degeneration, which stresses the need for biomarkers to detect the remaining neuronal function. METHODS: The authors performed motor unit number estimation (MUNE) in 52 patients with SBMA, to investigate whether this method could be a potential biomarker of SBMA, and re-evaluated MUNE 1 year later in a subgroup of the patients. RESULTS: The number of functioning motor units was remarkably reduced in patients with SBMA compared with controls, and was correlated with both ipsilateral grip power and disease duration. A longitudinal analysis demonstrated a further reduction in motor units within 1 year. CONCLUSIONS: The results suggest that MUNE is an electrophysiological parameter that reflects the severity and progression of motor neuron degeneration in patients with SBMA.

    DOI: 10.1136/jnnp.2009.190462

    PubMed

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MISC 17

  1. 【遺伝性疾患治療の最前線】球脊髄性筋萎縮症

    橋詰 淳, 勝野 雅央

    遺伝子医学   Vol. 10 ( 2 ) page: 26 - 31   2020.4

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    球脊髄性筋萎縮症(spinal and bulbar muscular atrophy:SBMA)は,アンドロゲン受容体遺伝子上のCAG繰り返し配列の異常延長を特徴とするポリグルタミン病である。異常アンドロゲン受容体タンパク質が運動ニューロンの細胞核へ蓄積することで,緩徐な運動ニューロンの神経変性を生じる。テストステロン依存性の変異タンパク質の核内移行がSBMAの病態の本幹であると考えられており,テストステロンの抑制をすることがSBMAの治療につながることが動物モデルに対する基礎的研究で明らかになった。これらの基礎研究結果に基づき医師主導型の医薬品開発臨床試験を実施した結果,2017年8月にLH-RHアナログであるリュープロレリン酢酸塩の効能に「球脊髄性筋萎縮症の進行抑制」が追加された。現在は,真のエンドポイント(死亡や死亡関連イベント)に関する十分なエビデンスを構築するため,疾患登録システム(患者レジストリ)にデータの蓄積を開始している。また,さらなる基礎的検討の結果,核内に集積した変異ARがDNMT1の発現を誘導し,Hes5などの遺伝子のDNAメチル化を亢進させることでニューロン変性を惹起すること,変異ARがSrcの活性化を介して神経・筋システム変性を惹起すること,など新たな知見も集積されつつあり,新規治療開発も期待されている。(著者抄録)

  2. 【神経疾患の現在とこれから】診療の最前線 球脊髄性筋萎縮症

    橋詰 淳, 祖父江 元, 勝野 雅央

    内科   Vol. 123 ( 6 ) page: 1259 - 1261   2019.6

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    <文献概要>Summary ▼球脊髄性筋萎縮症(SBMA)は,アンドロゲン受容体遺伝子上のCAG繰り返し配列の異常延長を特徴とするポリグルタミン病である.▼異常アンドロゲン受容体蛋白質が運動ニューロンの細胞核に蓄積することで,緩徐な運動ニューロンの神経変性を生じる.▼テストステロン依存性の変異蛋白質の核内移行がSBMAの病態の本幹であり,テストステロンを抑制することはSBMAの治療につながるということが,動物モデルに対する基礎的研究で明らかになった.▼医師主導治験の結果,2017年8月にLH-RHアナログであるleuprorelin acetateの効能に「球脊髄性筋萎縮症の進行抑制」が追加された.▼真のエンドポイント(死亡や死亡関連イベント)に関する十分なエビデンスを構築するため,疾患登録システム(患者レジストリ)にデータの蓄積を開始している.

    Other Link: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J00974&link_issn=&doc_id=20190611090009&doc_link_id=issn%3D0022-1961%26volume%3D123%26issue%3D6%26spage%3D1259&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0022-1961%26volume%3D123%26issue%3D6%26spage%3D1259&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

  3. 【運動ニューロン疾患-治療の展望】球脊髄性筋萎縮症(SBMA)のリュープロレリンによる治療

    祖父江 元, 橋詰 淳, 鈴木 啓介, 足立 弘明, 勝野 雅央

    脳神経内科   Vol. 90 ( 2 ) page: 122 - 130   2019.2

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  4. 【研修医が知っておきたい神経疾患の診断と治療】運動ニューロン疾患

    山田 晋一郎, 橋詰 淳, 勝野 雅央

    月刊レジデント   Vol. 11 ( 10 ) page: 31 - 39   2018.12

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    Language:Japanese   Publisher:(株)医学出版  

    <Point1>運動ニューロンの疾患概念を説明できる。<Point2>運動ニューロンの特徴や症候を知り、鑑別診断を進めていくことができる。<Point3>運動ニューロンにおける新しい治療法を知り、治療可能な疾病に対応できる。(著者抄録)

  5. 【神経・筋疾患に対する治療の進歩】運動ニューロン疾患

    熱田 直樹, 橋詰 淳, 祖父江 元, 勝野 雅央

    日本内科学会雑誌   Vol. 107 ( 8 ) page: 1477 - 1485   2018.8

  6. 球脊髄性筋萎縮症 これからの治療

    勝野 雅央, 土方 靖浩, 橋詰 淳, 祖父江 元

    神経治療学   Vol. 35 ( 4 ) page: 427 - 431   2018.7

  7. 【神経・筋難病治療の最前線】球脊髄性筋萎縮症における疾患修飾療法の開発

    橋詰 淳, 祖父江 元, 勝野 雅央

    BIO Clinica   Vol. 33 ( 8 ) page: 729 - 734   2018.7

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    特定のニューロンが選択的に変性・脱落し、神経症状が進行性に悪化する神経変性疾患には、希少疾患(orphan disease)も数多く存在する。近年の分子生物学の進歩に伴い、神経変性疾患の分子病態が明らかになりつつあり、神経変性の分子メカニズムそのものを阻止しようとする疾患修飾療法(disease-modifying therapy)をコンセプトとした医薬品開発が盛んになりつつある。上市後の市場規模の問題や、患者の希少性によって、診療経験のある医師や医療機関の確保が困難であるという問題から、製薬企業が開発に着手しにくい分野でもあり、アカデミアが主体となって医薬品開発を進めることが求められる分野でもある。特に、ドラッグリポジショニングによる医薬品開発の場合、臨床薬理試験や、初期の安全性および忍容性の確認にあたる試験を省略できる可能性もあることから、アカデミアが開発に着手しやすい分野でもある。本稿では、アカデミアにおいて、モデル動物を使った基礎的実験から臨床試験までを一貫して行い、最終的に、効能追加の薬事承認を得ることが出来た、球脊髄性筋萎縮症(Spinal and Bulbar Muscular Atrophy:SBMA)に対するリュープロレリン酢酸塩の開発について概説する。(著者抄録)

  8. 【ドラッグリポジショニング-新たな治療戦略】基礎研究とドラッグリポジショニングの治験計画と実施

    橋詰 淳, 鈴木 啓介, 足立 弘明, 祖父江 元, 勝野 雅央

    カレントテラピー   Vol. 36 ( 5 ) page: 453 - 459   2018.5

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  9. 【神経内科 診断推論】主訴で神経内科診断を推論する 脱力・運動麻痺

    土方 靖浩, 橋詰 淳, 勝野 雅央

    Modern Physician   Vol. 37 ( 7 ) page: 687 - 690   2017.7

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    Language:Japanese   Publisher:(株)新興医学出版社  

  10. 神経変性疾患に対するリバーストランスレーショナルリサーチの基盤としての患者レジストリおよびバイオバンク

    勝野 雅央, 橋詰 淳, 中村 治雅, 小野 賢二郎, 湯地 晃一郎, 山田 雅信, 渡邉 琢也, 一丸 勝彦, 加藤 直人, 井上 隆弘, 草間 真紀子, 水島 洋, 藤本 陽子, 秋元 周, 小林 潔, 大脇 健二, 上杉 幸嗣

    臨床薬理   Vol. 48 ( 4 ) page: 141 - 147   2017.7

  11. 人工呼吸療法 球脊髄性筋萎縮症患者の呼吸機能

    山田 晋一郎, 橋詰 淳, 勝野 雅央

    難病と在宅ケア   Vol. 23 ( 3 ) page: 37 - 40   2017.6

  12. 【神経疾患の早期診断】球脊髄性筋萎縮症の早期診断

    土方 靖浩, 橋詰 淳, 祖父江 元, 勝野 雅央

    神経内科   Vol. 86 ( 1 ) page: 17 - 22   2017.1

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  13. 【アカデミア発の創薬・研究治療】球脊髄性筋萎縮症(SBMA)に対する抗アンドロゲン療法

    鈴木 啓介, 勝野 雅央, 橋詰 淳, 坂野 晴彦, 祖父江 元

    神経内科   Vol. 83 ( 4 ) page: 271 - 276   2015.10

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  14. アカデミア発の創薬 球脊髄性筋萎縮症(SBMA)に対する抗アンドロゲン療法

    勝野 雅央, 坂野 晴彦, 鈴木 啓介, 橋詰 淳, 足立 弘明, 田中 章景, 祖父江 元

    臨床神経学   Vol. 52 ( 11 ) page: 1207 - 1209   2012.11

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    球脊髄性筋萎縮症(SBMA)はアンドロゲン受容体(AR)遺伝子におけるCAGくりかえし塩基配列の異常延長を原因とする運動ニューロン疾患であり,伸長ポリグルタミン鎖を有する異常AR蛋白質がテストステロンと結合することによってニューロンの核内に蓄積することが病態の本質と考えられている.テストステロンの分泌を抑制するリュープロレリン酢酸塩のSBMAに対する第III相臨床試験では,主要評価項目である咽頭部バリウム残留率について,被験者全体の解析では統計学的有意差はみとめられなかったが,罹病期間が10年以内の被験者のみを対象としたサブ解析では残留率が酢酸リュープロレリン群で有意に低下したことから,発症からの期間が薬効に影響をおよぼすことが示唆された.早期の治療介入や鋭敏なエンドポイントの開発が今後のトランスレーショナルリサーチに重要であると考えられる.(著者抄録)

    Other Link: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2012&ichushi_jid=J01550&link_issn=&doc_id=20121213290135&doc_link_id=10.5692%2Fclinicalneurol.52.1207&url=https%3A%2F%2Fdoi.org%2F10.5692%2Fclinicalneurol.52.1207&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

  15. 【神経筋疾患の分子標的治療開発】神経変性疾患の分子標的治療への問題点 SBMAを中心に

    坂野 晴彦, 勝野 雅央, 鈴木 啓介, 橋詰 淳, 祖父江 元

    BIO Clinica   Vol. 27 ( 10 ) page: 946 - 950   2012.9

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    我々は神経変性疾患の一つである球脊髄性筋萎縮症(SBMA)に対し、動物モデルの作製・病態解析から医師主導治験へと研究を進めてきた。SBMAの病因タンパク質である変異アンドロゲン受容体の細胞内局在は、リガンドである男性ホルモンの濃度に大きく影響されることから、テストステロン分泌を抑制するリュープロレリン酢酸塩をSBMA患者に投与したところ、嚥下機能が改善する可能性が示唆された。今後、神経変性疾患の分子標的治療開発を推進するためには、客観的指標を用いて自然歴を明らかにし、薬効評価に有用なバイオマーカーを確立することが重要である。(著者抄録)

  16. 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 神経変性疾患のトランスレーショナルリサーチ

    勝野 雅央, 坂野 晴彦, 鈴木 啓介, 橋詰 淳, 足立 弘明, 田中 章景, 祖父江 元

    日本内科学会雑誌   Vol. 101 ( 9 ) page: 2533 - 2538   2012.9

  17. 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 神経変性疾患のトランスレーショナルリサーチ

    勝野 雅央, 坂野 晴彦, 鈴木 啓介, 橋詰 淳, 足立 弘明, 田中 章景, 祖父江 元

    日本内科学会雑誌   Vol. 101 ( Suppl. ) page: 113 - 113   2012.2

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KAKENHI (Grants-in-Aid for Scientific Research) 12

  1. 球脊髄性筋萎縮症の適正治療に関するエビデンス構築のための臨床研究

    Grant number:18950395  2018.4 - 2021.3

    国立研究開発法人日本医療研究開発機構  日本医療研究開発機構研究費 

    勝野雅央 橋詰淳 土方靖浩 山本知孝 森田光哉

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    Grant amount:\43200000 ( Direct Cost: \33230771 、 Indirect Cost:\9969229 )

  2. 球脊髄性筋萎縮症に対するリュープリロレリン酢酸塩長期投与時の有効性評価

    Grant number:18973939  2018.4 - 2021.3

    文部科学省  科学研究費助成事業  基盤研究(C)

    橋詰淳 勝野雅央

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    Grant type:Competitive

    Grant amount:\6500000 ( Direct Cost: \5000000 、 Indirect Cost:\1500000 )

  3. 球脊髄性筋萎縮症の神経筋システム変性を標的とした革新的治療法開発

    Grant number:17929518  2017.4 - 2019.3

    国立研究開発法人日本医療研究開発機構  日本医療研究開発機構研究費 

    勝野雅央 佐橋健太郎 橋詰淳 近藤直英

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    Grant amount:\87690000 ( Direct Cost: \67454000 、 Indirect Cost:\20236000 )

  4. レジストリ構築による球脊髄性筋萎縮症の早期バイオマーカー開発

    Grant number:15565388  2015.4 - 2018.3

    文部科学省  科学研究費助成事業 

    橋詰淳 勝野雅央 祖父江元

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\6500000 ( Direct Cost: \5000000 )

  5. 球脊髄性筋萎縮症レジストリデータを用いた病態進行に関わる因子の同定

    Grant number:21K07458  2021.4 - 2024.3

    橋詰 淳

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    Authorship:Principal investigator 

    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

  6. 球脊髄性筋萎縮症に対するメキシレチン塩酸塩の安全性及び有効性を検討する医師主導治験実施のためのプロトコール作成研究

    Grant number:20350292  2020.4 - 2021.3

    国立研究開発法人日本医療研究開発機構  医療研究開発推進事業費補助金  革新的医療シーズ実用化研究事業

    山田晋一郎 橋詰淳 勝野雅央 清水忍 木下文恵

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    Grant amount:\3900000 ( Direct Cost: \3000000 、 Indirect Cost:\900000 )

  7. 球脊髄性筋萎縮症に対する骨格筋トランスポーターを標的とした治療法開発

    Grant number:18973938  2018.4 - 2021.3

    文部科学省  科学研究費助成事業  基盤研究(C)

    土方靖浩 橋詰淳 勝野雅央

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    Grant amount:\6500000 ( Direct Cost: \5000000 、 Indirect Cost:\1500000 )

  8. 球脊髄性筋萎縮症に対する骨格筋トランスポーターを標的とした治療法開発

    Grant number:18K07497  2018.4 - 2021.3

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    土方 靖浩, 橋詰 淳, 勝野 雅央

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    Authorship:Coinvestigator(s) 

    本研究の目的は、球脊髄性筋萎縮症(SBMA)患者の、骨格筋内クレアチン取り込み障害を促進することによる病態改善をめざした新規治療法開発である。変異AR蛋白質がクレアチントランスポーターSLC6A8遺伝子の転写を障害し、骨格筋クレアチン取り込みを障害しているという研究結果に基づき、SLC6A8蛋白質発現上昇に寄与する化合物を、化合物ライブラリを用いたスクリーニングにより探索し、患者fibroblastおよびiPSから誘導した骨格筋細胞を用いて検証を行い、治療薬候補となる化合物を同定、モデル動物を用いた前臨床試験を施行するものである。
    平成30年度では、クレアチントランスポーターSLC6A8を標的とした既存薬スクリーニングを行い、SLC6A8の転写活性および蛋白質発現を上昇させるヒット化合物を同定した。はじめに、pNL2.2(NlucP/Hygro) vectorにSLC6A8のプロモーターを挿入し、マウス骨格筋細胞株であるC2C12およびSBMA細胞モデルに導入、SLC6A8プロモーター安定発現株を作成した。そして、2%馬血清を用いて分化させたこれらの細胞株に化合物ライブラリを作用させた。化合物ライブラリについては、名古屋大学創薬科学研究科より提供を受けた35種類の化合物、第一三共株式会社のTaNeDSプログラムより供与を受けた48種類の化合物(うち3化合物がDMSO)を用いた。SLC6A8のプロモーター活性を上昇させるような化合物をNano-Glo Luciferase assay systemを用いて、1nMから100μMの濃度でルシフェラーゼアッセイを行った。さらにSBMA細胞モデルに対して化合物を投与し細胞活性の測定(WSTアッセイ)を行った。ルシフェラーゼ活性が高値であった化合物を用いてRT-PCRで検証を行い、5化合物に注目した。

  9. Long-term effect of leuprorelin acetate on the patients with spinal and bulbar muscular atrophy

    Grant number:18K07523  2018.4 - 2021.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

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    Authorship:Principal investigator 

    Grant amount:\4420000 ( Direct Cost: \3400000 、 Indirect Cost:\1020000 )

  10. 運動ニューロン疾患における神経コミュニケーション異常の分子病態解明と治療法開発

    Grant number:17917025   2017.4 - 2020.3

    文部科学省  科学研究費助成事業  基盤研究(B)

    勝野雅央 橋詰淳 井口洋平 佐橋健太郎

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    Grant amount:\16770000 ( Direct Cost: \12900000 、 Indirect Cost:\3870000 )

  11. Elucidation of defective neural communication in motor neuron diseases

    Grant number:17H04195  2017.4 - 2020.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

    Katsuno Masahisa

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    Authorship:Coinvestigator(s) 

    Nuclear depletion of TDP-43 is the histopathological hallmark of amyotrophic lateral sclerosis. In this research, we showed that loss of TDP-43 inhibited exocytosis by down-regulating CaV1.2 calcium channels, thereby reducing early-phase insulin secretion. Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by a CAG repeat expansion in the androgen receptor (AR) gene. In this research, we showed that DNA methyltransferase 1 is highly expressed in the motor neurons of an SBMA mouse model, and in patients with SBMA. Treatment with RG108, a DNA methylation inhibitor, ameliorated the viability of SBMA model cells and s the motor function of SBMA mice. We also found that the level of phosphorylated Src was markedly increased in the spinal cords and skeletal muscles of SBMA mice prior to the onset, by utilizing a phosphoprotein assay. Intraperitoneal administration of a Src kinase inhibitor improved the behavioral and histopathological phenotypes of SBMA mice.

  12. Biomarker study in the early phase patients with spinal and bulbar muscular atrophy

    Grant number:15K09311  2015.4 - 2018.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Hashizume Atsushi

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    Authorship:Principal investigator 

    Grant amount:\4810000 ( Direct Cost: \3700000 、 Indirect Cost:\1110000 )

    To develop new disease-modifying drugs for neurodegenerative diseases, a valid, reliable, and sensitive outcome measurement would be necessary. The present study aimed to develop a new composite measurement which reflects disease severty well. In this study, a total of 81 patients with SBMA and 23 normal contols were recruited. In the cross-sectional study, five components, tongue pressure, grip power, %PEF, 4.6 m timed walking test, and %VC, were appropriate to be combined with to develop a new composite mesurement.
    We followed-up the subjects for at most 96 weeks to confirm the usefulness of this new measurement. The results of this longitudinal study indicated that the composite measurement was meaningful as for sensitiveness.

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Teaching Experience (On-campus) 11

  1. 大学院ベーシックトレーニング

    2020

  2. 大学院ベーシックトレーニング

    2019

  3. 大学院ベーシックトレーニング

    2018

  4. 脳神経内科臨床実習

    2020

  5. PBLチュートリアル教育

    2020

  6. 脳卒中

    2020

  7. 脳神経内科臨床実習

    2019

  8. PBLチュートリアル教育

    2019

  9. 脳卒中

    2019

  10. 脳神経内科臨床実習

    2018

  11. PBLチュートリアル教育

    2018

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