Faculty Profiles - HASHIZUME Atsushi

The development of real–world evidence of leuprorelin acetate for spinal and bulbar muscular atrophy

Hashizume Atsushi, Katsuno Masahisa

Neurological Therapeutics Vol. 39 ( 3 ) page： 306 - 310 2022

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

Recent progress in molecular biology has elucidated the pathogenesis of neurodegenerative diseases, including SBMA, and this progression has led new disease–modifying drug development being active. In Japan, Nusinersen for spinal muscular atrophy and Leuprorelin acetate for spinal and bulbar muscular atrophy were approved in August 2017, and now, it is expected that many new disease–modifying drugs for neurological diseases will be launched.In neurodegenerative disease, we could hardly obtain sufficient information about the efficacy and safety of the drug before drug approval, so we should continuously collect clinical data after approval. We are now developing a real–world database to create new evoidence of leuprorelin acetate for SBMA. In this symposium, we will present two activities that are still in progress.First, we are creating a new functional composite using real–world data to overcome the weakness of the existing outcome measurements. Based on the results of previous clinical studies on SBMA, we selected the following five quantitative measurements to be integrated into the functional composite : tongue pressure for bulbar function ; grip power for upper limb function ; timed walking test for lower limb function ; peak expiratory flow for truncal function ; and vital capacity for respiratory function. Using Z–score, we computed the following formula as SBMAFC ; SBMAFC = (Tongue Pressure (kPa) − 41.6)/7.84 + (Grip Power (kgw) − 45.0)/6.4 + (%PEF − 116.4)/22.4 + (Timed Walking speed (km/hr) − 7.7)/2.0 + (%FVC − 112.0)/11.8. In the comparison of SBMAFC with the existing rating scales, SBMAFRS and ALSFRS–R, the effect size of SBMAFC was the largest, suggesting that SBMAFC was the most sensitive to the disease progression. Second, we are analyzing the longitudinal data to estimate drug efficacy by comparing the data before and after drug administration. Further accumulation of longitudinal real–world data will enable the development of new real–world evidence for SBMA treatment.The development of disease–modifying drug for neurodegenerative diseases will continue to be active. However, many barriers to success clinical trials, such as extremely small number of patients or slow progression, make it difficult to detect drug efficacy. So, often, we have insufficient evidence of efficacy or safety of the new drugs even after drug approval. Continuous clinical evaluations after approval are essential to establish a new drug profile.

DOI： 10.15082/jsnt.39.3_306

CiNii Research

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 Reviewed

橋詰淳, 三澤園子

神経治療学 Vol. 39 ( 3 ) page： 160 - 160 2022

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 Reviewed

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 Vol. 38 ( 6 ) page： S314 - S314 2021.10

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 Reviewed

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 Vol. 38 ( 6 ) page： S274 - S274 2021.10

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 Reviewed

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 Vol. 38 ( 6 ) page： S261 - S261 2021.10

Association of serum neurofilament light chain levels with clinicopathology of chronic inflammatory demyelinating polyneuropathy, including NF155 reactive patients. Reviewed International journal

Yuki Fukami, Masahiro Iijima, Haruki Koike, Shinichiro Yamada, Atsushi Hashizume, Masahisa Katsuno

Journal of neurology Vol. 268 ( 10 ) page： 3835 - 3844 2021.4

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

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

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

Shinichiro Yamada, Atsushi Hashizume, Yasuhiro Hijikata, Daisuke Ito, Yoshiyuki Kishimoto, Madoka Iida, Haruki Koike, Akihiro Hirakawa, Masahisa Katsuno

Journal of neurology, neurosurgery, and psychiatry Vol. 92 ( 10 ) page： 1072 - 1079 2021.3

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

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

Association of serum neurofilament light chain levels with clinicopathology and NF155 autoantibodies in patients with CIDP Reviewed

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

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 Vol. 38 ( 6 ) page： S132 - S132 2021

Longitudinal analysis of premotor anthropometric and serological markers of Parkinson’s disease Reviewed International journal Open Access

Katsunori Yokoi, Makoto Hattori, Yuki Satake, Yasuhiro Tanaka, Maki Sato, Atsushi Hashizume, Akihiro Hori, Motoshi Kawashima, Akihiro Hirakawa, Hirohisa Watanabe, Masahisa Katsuno

Scientific Reports Vol. 10 ( 1 ) page： 20524 - 20524 2020.12

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media {LLC}

<jats:title>Abstract</jats:title><jats:p>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.</jats:p>

DOI： 10.1038/s41598-020-77415-1

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

JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM Vol. 25 ( 4 ) page： 464 - 465 2020.12

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

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 Reviewed

深見祐樹, 飯島正博, 小池春樹, 橋詰淳, 勝野雅央

神経免疫学 Vol. 25 ( 1 ) page： 117 - 117 2020.10

【難病研究の進歩】神経・筋球脊髄性筋萎縮症 Reviewed

山田晋一郎, 橋詰淳, 勝野雅央

生体の科学 Vol. 71 ( 5 ) page： 376 - 377 2020.10

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：(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 Reviewed

毛利尚裕, 橋詰淳, 竹内和人, 熱田直樹, 勝野雅央

臨床神経学 Vol. 60 ( 10 ) page： 720 - 720 2020.10

Disease mechanism, biomarker and therapeutics for spinal and bulbar muscular atrophy (SBMA). Reviewed International journal Open Access

Atsushi Hashizume, Kenneth H Fischbeck, Maria Pennuto, Pietro Fratta, Masahisa Katsuno

Journal of neurology, neurosurgery, and psychiatry Vol. 91 ( 10 ) page： 1085 - 1091 2020.10

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

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