研究者詳細 - 橋詰　淳

論文 - 橋詰　淳

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球脊髄性筋萎縮症における前臨床バイオマーカーの変化(Preclinical biomarker changes in spinal and bulbar muscular atrophy) 査読有り

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

臨床神経学 58 巻 ( Suppl. ) 頁： S416 - S416 2018年12月

筋萎縮性側索硬化症発症時の血清クレアチンキナーゼ上昇(Elevation of serum creatine kinase at the onset of Amyotrophic Lateral Sclerosis) 査読有り

Ito Daisuke, Hashizume Atsushi, Hijikata Yasuhiro, Yamada Shinichiro, Inagaki Tomonori, Iguchi Yohei, Iida Madoka, Katsuno Masahisa

臨床神経学 58 巻 ( Suppl. ) 頁： S383 - S383 2018年12月

球脊髄性筋萎縮症における寒冷麻痺の病態生理(Pathophysiology of cold paresis in spinal and bulbar muscular atrophy) 査読有り

Yamada Shinichiro, Hashizume Atsushi, Hijikata Yasuhiro, Inagaki Tomonori, Ito Daisuke, Iida Madoka, Sahashi Kentaro, Fukaya Ryota, Nakamura Tomohiko, Kuba Hiroshi, Katsuno Masahisa

臨床神経学 58 巻 ( Suppl. ) 頁： S416 - S416 2018年12月

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) 査読有り国際誌 Open Access

Yamada, S; Hashizume, A; Hijikata, Y; Inagaki, T; Ito, D; Kinoshita, F; Nakatochi, M; Kobayashi, Y; Hirakawa, A; Nakamura, T; Katsuno, M

BMJ OPEN 8 巻 ( 9 ) 頁： e023041 2018年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BMJ Open

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

熱田直樹, 橋詰淳, 祖父江元, 勝野雅央

日本内科学会雑誌 107 巻 ( 8 ) 頁： 1477 - 1485 2018年8月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人日本内科学会

<p>運動ニューロン疾患は，随意運動系を支配する上位運動ニューロンと下位運動ニューロンのいずれか，もしくは両者が変性・脱落することによって，進行性の筋力低下や筋萎縮を呈する難治性疾患である．成人発症の運動ニューロン疾患である筋萎縮性側索硬化症（amyotrophic lateral sclerosis：ALS）と球脊髄性筋萎縮症（spinal and bulbar muscular atrophy：SBMA）の分子メカニズムに基づいた治療法開発が進んでおり，ALSに対してエダラボン，SBMAに対してリュープロレリンがそれぞれ進行抑制薬として薬事承認された．</p>

DOI： 10.2169/naika.107.1477

CiNii Research

Preclinical progression of neurodegenerative diseases 査読有り Open Access

Katsuno, M; Sahashi, K; Iguchi, Y; Hashizume, A

NAGOYA JOURNAL OF MEDICAL SCIENCE 80 巻 ( 3 ) 頁： 289 - 298 2018年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Nagoya Journal of Medical Science

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

Biomarker-based analysis of preclinical progression in spinal and bulbar muscular atrophy 査読有り国際誌

Hijikata, Y; Hashizume, A; Yamada, S; Inagaki, T; Ito, D; Hirakawa, A; Suzuki, K; Atsuta, N; Tsuboi, T; Hattori, M; Hori, A; Banno, H; Sobue, G; Katsuno, M

NEUROLOGY 90 巻 ( 17 ) 頁： e1501-e1509 - E1509 2018年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Neurology

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 andOctober 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

Web of Science

Scopus

PubMed

Treatment with creatine monohydrate in spinal and bulbar muscular atrophy: Protocol for a randomized, double-blind, placebo-controlled trial 査読有り国際誌 Open Access

Hijikata Y., Katsuno M., Suzuki K., Hashizume A., Araki A., Yamada S., Inagaki T., Ito D., Hirakawa A., Kinoshita F., Gosho M., Sobue G.

JMIR Research Protocols 7 巻 ( 3 ) 頁： e69 2018年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JMIR Research Protocols

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.

DOI： 10.2196/resprot.8655

勝野雅央, 土方靖浩, 橋詰淳, 祖父江元

神経治療学 35 巻 ( 4 ) 頁： 427 - 431 2018年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：日本神経治療学会

<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

CiNii Research

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　司会の言葉査読有り

鈴木啓介, 中村治雅, 橋詰淳

神経治療学 34 巻 ( 4 ) 頁： 461 - 462 2018年

Quantitative Assessment of Swallowing Dysfunction in Patients with Spinal and Bulbar Muscular Atrophy 査読有り Open Access

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

INTERNAL MEDICINE 56 巻 ( 23 ) 頁： 3159 - 3165 2017年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人日本内科学会

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

Long-term treatment with leuprorelin for spinal and bulbar muscular atrophy: natural history-controlled study 査読有り国際誌

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

JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 88 巻 ( 12 ) 頁： 1026 - 1032 2017年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Neurology, Neurosurgery and Psychiatry

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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Scopus

PubMed

Distinct pathogenesis in nonsystemic vasculitic neuropathy and microscopic polyangiitis 査読有り国際誌 Open Access

Takahashi, M; Koike, H; Ikeda, S; Kawagashira, Y; Iijima, M; Hashizume, A; Katsuno, M; Sobue, G

NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION 4 巻 ( 6 ) 頁： e407 2017年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Neurology: Neuroimmunology and NeuroInflammation

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.

DOI： 10.1212/NXI.0000000000000407

Cardiac and peripheral vasomotor autonomic functions in late-onset transthyretin Val30Met familial amyloid polyneuropathy 査読有り国際誌

Koike, H; Nakamura, T; Hashizume, A; Nishi, R; Ikeda, S; Kawagashira, Y; Iijima, M; Katsuno, M; Sobue, G

JOURNAL OF NEUROLOGY 264 巻 ( 11 ) 頁： 2293 - 2302 2017年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Neurology

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.

DOI： 10.1007/s00415-017-8629-2

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Scopus

PubMed

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 381 巻頁： 1084-1084 2017年10月