研究者詳細 - 橋詰　淳

論文 - 橋詰　淳

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The Combined Efficacy of a Two-Year Period of Cybernic Treatment With a Wearable Cyborg Hybrid-Assistive Limb and Leuprorelin Therapy in a Patient With Spinal and Bulbar Muscular Atrophy: A Case Report 査読有り国際誌 Open Access

Nakatsuji, H; Ikeda, T; Hashizume, A; Katsuno, M; Sobue, G; Nakajima, T

FRONTIERS IN NEUROLOGY 13 巻頁： 905613 - 905613 2022年6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：Frontiers in Neurology

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is a rare, slowly progressive, incurable, and hereditary neurodegenerative disease caused by the testosterone-dependent accumulation of pathogenic polyglutamine-expanded androgen receptor protein. After extensive review, two treatments for SBMA have recently been approved in Japan; this decision was based on the results of randomized controlled trials: First, anti-androgen therapy using leuprorelin acetate (leuprorelin), a disease-modifying drug that can inhibit the progression of dysphagia but has not yet been proved to improve gait function; second, cybernic treatment with a wearable cyborg hybrid assistive limb (HAL®) (Cyberdyne Inc. Tsukuba, Japan). The HAL is an innovative walking exercise system that has been shown to significantly improve gait function in eight neuromuscular diseases without reduction in muscle function, including SBMA. It is possible that the combination of these two approaches might yield better outcomes. However, the long-term effects of such a combined approach have yet to be clinically evaluated. Here, we describe the case of a 39-year-old male with SBMA who commenced anti-androgen therapy with leuprorelin 1 year previously; this was followed by cybernic treatment with HAL. The duration of walking exercise with HAL was 20–30 min a day in one session. Over 2 weeks, the patient underwent nine sessions (one course). The efficacy of HAL was evaluated by gait function tests before and after one course of cybernic treatment. Then, leuprorelin treatment was combined with cybernic sessions every 2 months for 2 years (13 courses in total). Walking ability, as evaluated by the 2-min walk test, improved by 20.3% in the first course and peaked 10 months after the commencement of combined therapy (a 59.0% improvement). Walking function was maintained throughout the period. Generally, SBMA is characterized by moderately increased serum levels of creatine kinase (CK), reflecting neuromuscular damage; interestingly, the patient's CK levels decreased dramatically with combined therapy, indicating remarkable functional improvement. Long-term combined therapy improved the patient's gait function with a steady reduction in CK levels. The combination of leuprorelin with cybernic treatment can, therefore, improve and maintain gait function without damaging the motor unit and may also suppress disease progression.

DOI： 10.3389/fneur.2022.905613

Actin-binding protein filamin-A drives tau aggregation and contributes to progressive supranuclear palsy pathology 査読有り国際誌 Open Access

Tsujikawa, K; Hamanaka, K; Riku, Y; Hattori, Y; Hara, N; Iguchi, Y; Ishigaki, S; Hashizume, A; Miyatake, S; Mitsuhashi, S; Miyazaki, Y; Kataoka, M; Li, JY; Yasui, K; Kuru, S; Koike, H; Kobayashi, K; Sahara, N; Ozaki, N; Yoshida, M; Kakita, A; Saito, Y; Iwasaki, Y; Miyashita, A; Iwatsubo, T; Ikeuchi, T; Miyata, T; Sobue, G; Matsumoto, N; Sahashi, K; Katsuno, M

SCIENCE ADVANCES 8 巻 ( 21 ) 頁： eabm5029 2022年5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：Science Advances

While amyloid-β lies upstream of tau pathology in Alzheimer’s disease, key drivers for other tauopathies, including progressive supranuclear palsy (PSP), are largely unknown. Various tau mutations are known to facilitate tau aggregation, but how the nonmutated tau, which most cases with PSP share, increases its propensity to aggregate in neurons and glial cells has remained elusive. Here, we identified genetic variations and protein abundance of filamin-A in the PSP brains without tau mutations. We provided in vivo biochemical evidence that increased filamin-A levels enhance the phosphorylation and insolubility of tau through interacting actin filaments. In addition, reduction of filamin-A corrected aberrant tau levels in the culture cells from PSP cases. Moreover, transgenic mice carrying human filamin-A recapitulated tau pathology in the neurons. Our data highlight that filamin-A promotes tau aggregation, providing a potential mechanism by which filamin-A contributes to PSP pathology.

DOI： 10.1126/sciadv.abm5029

Novel concept to evaluate efficacy of therapeutics for ALS based on patient preference comment 査読有り国際誌 Open Access

Hashizume, A; Katsuno, M

JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 93 巻 ( 5 ) 頁： 457 - 457 2022年5月

Quantitative evaluation of upper limb ataxia in spinocerebellar ataxias 査読有り国際誌 Open Access

Kishimoto, Y; Hashizume, A; Imai, Y; Nakatochi, M; Yamada, S; Ito, D; Torii, R; Nagano, Y; Fujimoto, H; Katsuno, M

ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY 9 巻 ( 4 ) 頁： 529 - 539 2022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：Annals of Clinical and Translational Neurology

Objective: To quantitatively evaluate upper limb ataxia using a novel pen-like sensor device in patients with spinocerebellar ataxia (SCA) and to assess its validity, reliability, and sensitivity to disease progression. Methods: We designed a cross-sectional and longitudinal study of patients with SCA and healthy controls. Upper limb ataxia was evaluated using a device that measures the three-dimensional position every 10 msec. Participants were instructed to move a pen-like part of the device iteratively between two buttons. We evaluated the time, length, velocity, and variation coefficient of the stroke, and calculated the distortion index using the mean squared error. The following scales were also evaluated: Scale for the Assessment and Rating of Ataxia (SARA), the International Cooperative Ataxia Rating Scale (ICARS), and the nine-hole pegboard test. Subjects were followed 12 months after the baseline evaluation. Results: A total of 42 patients with SCA and 33 healthy controls were enrolled and evaluated. For all ataxia indices measured using the device there were significant differences between healthy controls and patients with SCA. Among the ataxia indices, the distortion index showed the strongest correlation with the SARA and ICARS upper limb score (Pearson's r = 0.647 and 0.722, respectively). Test–retest reliability was high for most of the ataxia indices. In the longitudinal analysis, the distortion index showed high standardized response mean and adjusted effect size, regardless of disease severity. Interpretation: Our study demonstrated that the distortion index is a reliable functional marker that is sensitive to longitudinal change in patients with SCA.

DOI： 10.1002/acn3.51528

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神経治療学会における創薬のさらなる推進のために　司会の言葉査読有り

橋詰淳, 三澤園子

神経治療学 39 巻 ( 3 ) 頁： 160 - 160 2022年

球脊髄性筋萎縮症に対するleuprorelin acetate治療とリアルワールドデータ

橋詰淳, 勝野雅央

神経治療学 39 巻 ( 3 ) 頁： 306 - 310 2022年

Titinを標的とした筋萎縮性側索硬化症患者のバイオマーカー開発査読有り

山田晋一郎, 橋詰淳, 伊藤大輔, 岸本祥之, 鳥居良太, 飯田円, 勝野雅央

神経治療学 38 巻 ( 6 ) 頁： S261 - S261 2021年10月

球脊髄性筋萎縮症(SBMA)の女性保因者における臨床的特徴に関する検討査読有り

鳥居良太, 橋詰淳, 山田晋一郎, 伊藤大輔, 岸本祥之, 勝野雅央

神経治療学 38 巻 ( 6 ) 頁： S314 - S314 2021年10月

新規デバイスを用いた上肢運動失調の定量的評価によるバイオマーカーの開発査読有り

岸本祥之, 橋詰淳, 山田晋一郎, 伊藤大輔, 鳥居良太, 中杤昌弘, 勝野雅央

神経治療学 38 巻 ( 6 ) 頁： S274 - S274 2021年10月

Association of serum neurofilament light chain levels with clinicopathology of chronic inflammatory demyelinating polyneuropathy, including NF155 reactive patients 査読有り国際誌

Fukami, Y; Iijima, M; Koike, H; Yamada, S; Hashizume, A; Katsuno, M

JOURNAL OF NEUROLOGY 268 巻 ( 10 ) 頁： 3835 - 3844 2021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：Journal of Neurology

Objectives: To clarify whether serum neurofilament light chains (NfLs) serve as a biomarker of axonal damage in patients with chronic inflammatory demyelinating polyneuropathy (CIDP), especially in patients with anti-neurofascin 155 (NF155) antibodies. Methods: The Simoa system was used to examine serum NfL levels from 58 patients with CIDP, including 13 anti-NF155 antibody-positive patients, and from 14 age- and sex-matched healthy individuals. Serum NfL levels were evaluated before and after treatment in eight patients with anti-NF155 antibodies. Clinical features, electrophysiological findings, and cerebrospinal fluid (CSF) protein levels, were evaluated. The pathological features of sural nerves from 40 patients were also examined. Results: Serum NfL levels were significantly higher in patients with CIDP than in healthy individuals (median 29.63 vs. 7.71 pg/mL, p < 0.001) and were correlated with both modified Rankin Scale scores (r = 0.584, p < 0.001) and CSF protein levels (r = 0.432, p = 0.001). The NfL levels of anti-NF155 antibody-positive patients were higher than those of antibody-negative patients (p = 0.005). Serum NfL levels were negatively correlated with compound muscle action potential amplitudes of the tibial nerves (r = − 0.404, p = 0.004) and positively correlated with the degree of active axonal degeneration in the pathological findings (r = 0.485, p = 0.001). In the antibody-positive group, NfL levels and antibody titers decreased after treatment in all examined patients. Conclusion: Serum NfL correlated with pathological indices of axonal degeneration, and may serve as a biomarker that reflects active axonal damage of CIDP.

DOI： 10.1007/s00415-021-10537-2

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Ratio of urinary N-terminal titin fragment to urinary creatinine is a novel biomarker for amyotrophic lateral sclerosis 査読有り国際誌

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

JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 92 巻 ( 10 ) 頁： 1072 - 1079 2021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：Journal of Neurology, Neurosurgery and Psychiatry

Objective We aimed to investigate the validity of urinary N-terminal titin fragment as a biomarker for amyotrophic lateral sclerosis (ALS). Methods We consecutively enrolled patients with ALS (n=70) and healthy controls (HC) (n=43). We assessed the urinary titin N-terminal fragment, urinary neurotrophin receptor p75 extracellular domain, serum neurofilament light chain (NfL), motor functional measurements and prognosis. We used urinary creatinine (Cr) levels to normalise the urinary levels of titin fragment. Results Compared with HC, patients with ALS had significantly increased urinary levels of titin N-terminal fragment normalised with Cr (titin/Cr) (ALS, 27.2 pmol/mg/dL; HC, 5.8 pmol/mg/dL; p<0.001), which were correlated with the scores of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (r=-0.422, p<0.001). A Cox proportional hazards model demonstrated that the high urinary level of titin/Cr was a survival predictor in patients with ALS. Multivariate analysis of prognostic factors showed that the urinary titin/Cr and serum NfL were independent factors for poor prognosis. Conclusions Our findings indicate that urinary N-terminal titin fragment is a non-invasive measure of muscle damage in ALS, which could be applied in disease monitoring and prediction of disease progression, in combination with serum NfL.

DOI： 10.1136/jnnp-2020-324615

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PubMed

Ratio of urinary N-terminal titin fragment to urinary creatinine is a novel biomarker for amyotrophic lateral sclerosis. 査読有り

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

J Neurol Neurosurg Psychiatry. 2021年3月

球脊髄性筋萎縮症に対するリュープロレリン酢酸塩治療とリアルワールドデータ

橋詰淳

神経治療学 38 巻 ( 6 ) 頁： S132 - S132 2021年

Longitudinal analysis of premotor anthropometric and serological markers of Parkinson's disease 査読有り国際誌 Open Access

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

SCIENTIFIC REPORTS 10 巻 ( 1 ) 頁： 20524 - 20524 2020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：Scientific Reports

Parkinson’s disease (PD) is a debilitating neurodegenerative disorder in which nonmotor symptoms, such as constipation and hyposmia, precede the onset of motor symptoms by 20 years. The aim of this study was to identify biomarkers at the premotor stage of PD. We assessed the differences in longitudinal changes in anthropometric and serological indices obtained from health check-up data before and after the onset of motor symptoms between male and female PD patients and healthy subjects. We enrolled 22 male and 23 female PD patients and 60 male and 60 female healthy controls. A mixed-effects model was used to estimate the trajectory of each clinical marker over the years before and after motor symptoms onset in the PD subjects, which were then compared with the trajectories of the healthy controls. The results showed a premotor blood pressure increase in female PD patients and premotor decreases in haematocrit, total cholesterol and low-density lipoprotein cholesterol in the male patients. Our results indicated that blood pressure, haematocrit and serum cholesterol levels are potential premotor markers of PD. Additionally, the changes in anthropometric and serological indices before PD motor symptoms onset were sex specific.

DOI： 10.1038/s41598-020-77415-1

Association of serum neurofilament light chain levels with clinicopathology and NF155 autoantibodies in patients with CIDP 査読有り

Fukami, Y; Iijima, M; Koike, H; Nishi, R; Hashizume, A; Katsuno, M

JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM 25 巻 ( 4 ) 頁： 464 - 465 2020年12月

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. 査読有り

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

Sci Rep. 25 巻 ( 10 ) 頁： 20524 2020年11月

CIDPにおける血清ニューロフィラメント軽鎖濃度と臨床病理学およびNF155自己抗体との関連査読有り

深見祐樹, 飯島正博, 小池春樹, 橋詰淳, 勝野雅央

神経免疫学 25 巻 ( 1 ) 頁： 117 - 117 2020年10月

【難病研究の進歩】神経・筋球脊髄性筋萎縮症査読有り

山田晋一郎, 橋詰淳, 勝野雅央

生体の科学 71 巻 ( 5 ) 頁： 376 - 377 2020年10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：(公財)金原一郎記念医学医療振興財団

＜文献概要＞近年の研究により,球脊髄性筋萎縮症(SBMA)では,純粋な下位運動ニューロン障害のみならず骨格筋や全身臓器も障害されることが明らかとなってきた。SBMAの治療法開発のためには,骨格筋の変性メカニズムや神経と筋の相互作用を解明することが重要である。本稿では,SBMAの病態とそのモデル,骨格筋障害と病態に即した治療法開発を中心に今後の展望について概説する。

閉塞性水頭症により認知機能低下をきたした一例査読有り

毛利尚裕, 橋詰淳, 竹内和人, 熱田直樹, 勝野雅央

臨床神経学 60 巻 ( 10 ) 頁： 720 - 720 2020年10月

Disease mechanism, biomarker and therapeutics for spinal and bulbar muscular atrophy (SBMA) 査読有り国際誌 Open Access

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

JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 91 巻 ( 10 ) 頁： 1085 - 1091 2020年10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

Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disorder caused by CAG trinucleotide expansion in the gene encoding the androgen receptor (AR). In the central nervous system, lower motor neurons are selectively affected, whereas pathology of patients and animal models also indicates involvement of skeletal muscle including loss of fast-twitch type 2 fibres and increased slow-twitch type 1 fibres, together with a glycolytic-to-oxidative metabolic switch. Evaluation of muscle and fat using MRI, in addition to biochemical indices such as serum creatinine level, are promising biomarkers to track the disease progression. The serum level of creatinine starts to decrease before the onset of muscle weakness, followed by the emergence of hand tremor, a prodromal sign of the disease. Androgen-dependent nuclear accumulation of the polyglutamine-expanded AR is an essential step in the pathogenesis, providing therapeutic opportunities via hormonal manipulation and gene silencing with antisense oligonucleotides. Animal studies also suggest that hyperactivation of Src, alteration of autophagy and a mitochondrial deficit underlie the neuromuscular degeneration in SBMA and provide alternative therapeutic targets.

DOI： 10.1136/jnnp-2020-322949

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論文 - 橋詰　淳