Faculty Profiles - HASHIZUME Atsushi

Papers - HASHIZUME Atsushi

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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) Reviewed

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 Vol. 58 ( Suppl. ) page： S416 - S416 2018.12

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) Reviewed

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 Vol. 58 ( Suppl. ) page： S416 - S416 2018.12

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) Reviewed

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

臨床神経学 Vol. 58 ( Suppl. ) page： S383 - S383 2018.12

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 Open Access

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

Language：English Publishing type：Research paper (scientific journal)

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

IV. Motor neuron diseases

Atsuta Naoki, Hashizume Atsushi, Sobue Gen, Katsuno Masahisa

Nihon Naika Gakkai Zasshi Vol. 107 ( 8 ) page： 1477 - 1485 2018.8

Preclinical progression of neurodegenerative diseases. Reviewed Open Access

Masahisa Katsuno, Kentaro Sahashi, Yohei Iguchi, Atsushi Hashizume

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

Language：English Publishing type：Research paper (scientific journal)

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. 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 - E1509 2018.4

Language：English Publishing type：Research paper (scientific journal)

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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Scopus

PubMed

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

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

Language：English Publishing type：Research paper (scientific journal)

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

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

Katsuno Masahisa, Hijikata Yasuhiro, Hashizume Atsushi, Sobue Gen

Neurological Therapeutics Vol. 35 ( 4 ) page： 427 - 431 2018

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japanese Society of Neurological Therapeutics

<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 Reviewed

鈴木啓介, 中村治雅, 橋詰淳

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：The Japanese Society of Internal Medicine

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. 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

Language：English Publishing type：Research paper (scientific journal)

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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PubMed

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

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

Language：English Publishing type：Research paper (scientific journal)

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. 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

Language：English Publishing type：Research paper (scientific journal)

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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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 Vol. 381 page： 1084-1084 2017.10

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 - 206 2017.10

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

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

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

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

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 - 462 2017.10

両側声帯麻痺を合併した球脊髄性筋萎縮症1症例の治療経験 Reviewed

辻河高陽, 山田晋一郎, 橋詰淳, 坪井崇, 熱田直樹, 伊藤瑞規, 勝野雅央

臨床神経学 Vol. 57 ( 10 ) page： 608 - 608 2017.10

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Papers - HASHIZUME Atsushi