研究者詳細 - 橋詰　淳

筋力低下に加え、廃用も呈した抗SRP（signal recognition particle）抗体陽性壊死性ミオパチー症例に対する理学療法介入の経験査読有り

鄭伃廷, 柴田篤志, 加古誠人, 橋詰淳, 天草善信, 熱田直樹, 勝野雅央, 西田佳弘

理学療法学Supplement 47S1 巻 ( 0 ) 頁： F-171_2 - F-171_2 2020年

Nasometric Scores in spinal and bulbar muscular atrophy - Effects of palatal lift prosthesis on dysarthria and dysphagia. 査読有り

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. 407 巻頁： 116503 2019年12月

Nasometric Scores in spinal and bulbar muscular atrophy - Effects of palatal lift prosthesis on dysarthria and dysphagia 査読有り国際誌

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

JOURNAL OF THE NEUROLOGICAL SCIENCES 407 巻頁： 116503 - 116503 2019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 the Neurological Sciences

Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disease affecting only males characterized by progressive muscular atrophy and weakness in bulbar and limb muscles. The present study aimed to evaluate the features of velopharyngeal dysfunction (VPD) in SBMA subjects by an acoustic analysis of speech. Twenty-three genetically confirmed patients with SBMA were enrolled and assessed their speech by measuring the nasalance score with a Nasometer II. The nasalance scores of the SBMA group was higher than that of healthy controls (p = .035) and significantly correlated with the total score of the revised amyotrophic lateral sclerosis functional rating scale (rs = −0.520, p = .011). On the basis of the results of the VPD study, the efficacy of a palatal lift prosthesis (PLP) was assessed in two patients with SBMA to treat their VPD. The PLP improved dysarthria in both cases, although the impact of the prosthesis on dysphagia was not consistent. The present study suggested that the nasalance score is a useful quantitative measurement to evaluate VPD in patients with SBMA. A PLP may improve dysarthria in SBMA patients by reducing VPD, but the clinical application of this procedure should be considered carefully in view of its possible negative effect on dysphagia.

DOI： 10.1016/j.jns.2019.116503

Elevated serum creatine kinase in the early stage of sporadic amyotrophic lateral sclerosis 査読有り国際誌

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

JOURNAL OF NEUROLOGY 266 巻 ( 12 ) 頁： 2952 - 2961 2019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

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

球脊髄性筋萎縮症におけるHAL医療用下肢タイプを用いた歩行訓練の有用性について査読有り

橋本里奈, 中辻秀朗, 佐藤実咲, 榊原聡子, 見城昌邦, 横川ゆき, 片山泰司, 齋藤由扶子, 饗場郁子, 犬飼晃, 橋詰淳, 勝野雅央

臨床神経学 59 巻 ( Suppl. ) 頁： S367 - S367 2019年11月

Swallowing sound analysis to estimate swallowing dysfunction in spinal and bulbar muscular atrophy(和訳中) 査読有り

Hashizume Atsushi, Tanaka Seiya, Uchino Tatsunori, Hijikata Yasuhiro, Yamada Shinichiro, Ito Daisuke, Kishimoto Yoshiyuki, Moriyoshi Hideyuki, Toda Tomoki, Katsuno Masahisa

臨床神経学 59 巻 ( Suppl. ) 頁： S395 - S395 2019年11月

Body composition in spinal and bulbar muscular atrophy(和訳中) 査読有り

Hijikata Yasuhiro, Hashizume Atsushi, Yamada Shinichiro, Ito Daisuke, Kishimoto Yoshiyuki, Moriyoshi Hideyuki, Katsuno Masahisa

臨床神経学 59 巻 ( Suppl. ) 頁： S395 - S395 2019年11月

New device for evaluation of ataxia quantitatively in the patients with SCD(和訳中) 査読有り

Kishimoto Yoshiyuki, Hashizume Atsushi, Hijikata Yasuhiro, Yamada Shinichiro, Ito Daisuke, Moriyoshi Hideyuki, Katsuno Masahisa

臨床神経学 59 巻 ( Suppl. ) 頁： S381 - S381 2019年11月

Elevation of serum creatine kinase before the disease onset of amyotrophic lateral sclerosis(和訳中) 査読有り

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

臨床神経学 59 巻 ( Suppl. ) 頁： S430 - S430 2019年11月

Development of symptomatic therapy for cold paresis in spinal and bulbar muscular atrophy(和訳中) 査読有り

Yamada Shinichiro, Hashizume Atsushi, Hijikata Yasuhiro, Ito Daisuke, Kishimoto Yoshiyuki, Moriyoshi Hideyuki, Iida Madoka, Nakamura Tomohiko, Katsuno Masahisa

臨床神経学 59 巻 ( Suppl. ) 頁： S395 - S395 2019年11月

Long-term Effects of Androgen Deprivation in a Patient with Spinal and Bulbar Muscular Atrophy - A Case Report with 14 Years of Follow-up 査読有り Open Access

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

INTERNAL MEDICINE 58 巻 ( 15 ) 頁： 2231 - 2234 2019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：一般社団法人日本内科学会

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

TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets. 招待有り査読有り

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. 129 巻 ( 9 ) 頁： 3578 - 3593 2019年7月

TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets 査読有り国際誌 Open Access

Araki, K; Araki, A; Honda, D; Izumoto, T; Hashizume, A; Hijikata, V; 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

JOURNAL OF CLINICAL INVESTIGATION 129 巻 ( 9 ) 頁： 3578 - 3593 2019年7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 Clinical Investigation

TAR DNA-binding protein 43 kDa (TDP-43), encoded by TARDBP, is an RNA-binding protein, the nuclear depletion of which is the histopathological hallmark of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder affecting both upper and lower motor neurons. Besides motor symptoms, patients with ALS often develop nonneuronal signs including glucose intolerance, but the underlying pathomechanism is still controversial, i.e., whether it is impaired insulin secretion and/or insulin resistance. Here, we showed that ALS subjects reduced early-phase insulin secretion and that the nuclear localization of TDP-43 was lost in the islets of autopsied ALS pancreas. Loss of TDP-43 inhibited exocytosis by downregulating CaV1.2 calcium channels, thereby reducing early-phase insulin secretion in a cultured β cell line (MIN6) and β cell-specific Tardbp-knockout mice. Overexpression of CaV1.2 restored early-phase insulin secretion in Tardbp-knocked-down MIN6 cells. Our findings suggest that TDP-43 regulates cellular exocytosis mediated by L-type voltage-dependent calcium channels and, thus, plays an important role in the early phase of insulin secretion by pancreatic islets. Thus, nuclear loss of TDP-43 is implicated in not only the selective loss of motor neurons, but also in glucose intolerance due to impaired insulin secretion at an early stage of ALS.

DOI： 10.1172/JCI124481

特集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査読有り

橋詰淳, 祖父江元, 勝野雅央

内科 123 巻 ( 6 ) 頁： 1259 - 1261 2019年6月

Efficacy and safety of leuprorelin acetate for subjects with spinal and bulbar muscular atrophy: pooled analyses of two randomized-controlled trials 査読有り国際誌

Hashizume, A; Katsuno, M; Suzuki, K; Banno, H; Takeuchi, Y; Kawashima, M; Suga, N; Mano, T; Araki, A; Hijikata, Y; Hirakawa, A; Sobue, G; Sasaki, H; Aoki, M; Nakano, I; Ito, S; Mizusawa, H; Yamamoto, T; Hasegawa, K; Miyajima, H; Kanda, N; Nakajima, K; Tsujino, A; Uchino, M; Morita, M; Kanai, K

JOURNAL OF NEUROLOGY 266 巻 ( 5 ) 頁： 1211 - 1221 2019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：Journal of Neurology

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