九州大学-研究者情報 [渡邉充 (助教) 九州大学病院脳神経内科]

多発性硬化症患者および視神経脊髄炎スペクトラム障害の血中・髄液中バイオマーカー探索
2018.01
多発性硬化症患者および視神経脊髄炎関連疾患患者の髄液中・血中のGFAPおよびニューロフィラメント軽鎖に加え、好中球関連マーカーの濃度を測定し、臨床データとの相関を評価し、バイオマーカーとしての有用性を評価する。.

多発性硬化症患者のフローサイトメトリー
2018.04
多発性硬化症患者の末梢血免疫細胞の解析を通じて病態解明につなげる.

研究業績

主要原著論文

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1.	Watanabe M, Nakamura Y, Sato S, Niino M, Fukaura H, Tanaka M, Ochi H, Kanda T, Takeshita Y, Yokota T, Nishida Y, Matsui M, Nagayama S, Kusunoki S, Miyamoto K, Mizuno M, Kawachi I, Saji E, Ohashi T, Shimohama S, Hisahara S, Nishiyama K, Iizuka T, Nakatsuji Y, Okuno T, Ochi K, Suzumura A, Yamamoto K, Kawano Y, Tsuji S, Hirata M, Sakate R, Kimura T, Shimizu Y, Nagaishi A, Okada K, Hayashi F, Sakoda A, Masaki K, Shinoda K, Isobe N, Matsushita T, Kira J., HLA genotype-clinical phenotype correlations in multiple sclerosis and neuromyelitis optica spectrum disorders based on Japan MS/NMOSD Biobank data., Scientific Reports, 10.1038/s41598-020-79833-7, 11, 1, 607-607, 2021.01.
2.	Mitsuru Watanabe, Yuri Nakamura, Zuzanna Michalak, Noriko Isobe, Christian Barro, David Leppert, Takuya Matsushita, Fumie Hayashi, Ryo Yamasaki, Jens Kuhle, Jun Ichi Kira, Serum GFAP and neurofilament light as biomarkers of disease activity and disability in NMOSD, Neurology, 10.1212/WNL.0000000000008160, 93, 13, E1299-E1311, 2019.09, [URL], ObjectiveTo test the hypothesis that serum levels of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL), which are an intermediate astrocyte and neuron filaments, respectively, are clinically useful biomarkers of disease activity and disability in neuromyelitis optica spectrum disorders (NMOSD).MethodsLevels of GFAP and NfL in serum (sGFAP and sNfL, respectively) and in CSF samples were measured in healthy controls (HCs) (n = 49; 49 serum samples), patients with NMOSD (n = 33; 42 CSF and 102 serum samples), and patients with multiple sclerosis (MS) (n = 49; 53 CSF and 91 serum samples) by ultrasensitive single-molecule array assays. Association of sGFAP and sNfL levels with clinical parameters was determined.ResultsFor both GFAP and NfL, CSF and serum levels were strongly correlated. Both were higher in the serum of patients with NMOSD than in HCs (both p
3.	Mitsuru Watanabe, Wataru Shiraishi, Ryo Yamasaki, Noriko Isobe, Motohiro Sawatsubashi, Ryuji Yasumatsu, Takashi Nakagawa, Jun-ichi Kira, Oral phase dysphagia in facial onset sensory and motor neuronopathy, Brain and Behavior, 10.1002/brb3.999, 8, 6, 2018.06, [URL], Introduction: Facial onset motor and sensory neuronopathy (FOSMN) is a rare disease whose cardinal features are initial asymmetrical facial sensory deficits followed by bulbar symptoms and spreading of sensory and motor deficits from face to scalp, neck, upper trunk, and upper extremities in a rostral–caudal direction. Although bulbar involvement is frequently observed in FOSMN, dysphagia in these patients has not been fully described. In this study, we aimed to characterize dysphagia as a prognostic factor in FOSMN by investigating our institutional case series. Methods: We retrospectively reviewed the medical records, including swallowing function tests, of six patients with FOSMN (three men and three women) who were thoroughly examined at Kyushu University Hospital between 1 January 2005 and 30 November 2017. Results: Average age at onset was 58.5 years; average disease duration was 5.7 years. All patients developed bulbar dysfunction and dysphagia (at an average of 1.8 and 2.6 years from onset, respectively), resulting in choking episodes in three patients, percutaneous endoscopic gastrostomy placement in three, and recurrent aspiration pneumonia in one. Four of five patients evaluated with videofluoroscopic swallowing studies had poor oral retention, leading to bolus flowing into the pharynx before swallowing; the fifth patient showed poor lingual transfer. Fiberoptic endoscopic evaluation of swallowing revealed leakage of blue-dyed water from the mouth to the pharynx in three patients because of poor oral retention, but only mild pharyngeal phase dysphagia in all four cases evaluated. Conclusions: Oral phase dysphagia predominates in the early stage of FOSMN..
4.	Mitsuru Watanabe, Katsuhisa Masaki, Ryo Yamasaki, Jun Kawanokuchi, Hideyuki Takeuchi, Takuya Matsushita, Akio Suzumura, Jun-ichi Kira, Th1 cells downregulate connexin 43 gap junctions in astrocytes via microglial activation, Scientific Reports, 10.1038/srep38387, 6, 2016.12, [URL], We previously reported early and extensive loss of astrocytic connexin 43 (Cx43) in acute demyelinating lesions of multiple sclerosis (MS) patients. Because it is widely accepted that autoimmune T cells initiate MS lesions, we hypothesized that infiltrating T cells affect Cx43 expression in astrocytes, which contributes to MS lesion formation. Primary mixed glial cell cultures were prepared from newborn mouse brains, and microglia were isolated by anti-CD11b antibody-conjugated magnetic beads. Next, we prepared astrocyte-rich cultures and astrocyte/microglia-mixed cultures. Treatment of primary mixed glial cell cultures with interferon (IFN) γ, interleukin (IL)-4, or IL-17 showed that only IFNβ or IL-17 at high concentrations reduced Cx43 protein levels. Upon treatment of astrocyte-rich cultures and astrocyte/microglia-mixed cultures with IFNγ;, Cx43 mRNA/protein levels and the function of gap junctions were reduced only in astrocyte/microglia-mixed cultures. IFNγ-treated microglia-conditioned media and IL-1β, which was markedly increased in IFNγ-treated microglia-conditioned media, reduced Cx43 protein levels in astrocyte-rich cultures. Finally, we confirmed that Th1 cell-conditioned medium decreased Cx43 protein levels in mixed glial cell cultures. These findings suggest that Th1 cell-derived IFNγ activates microglia to release IL-1β that reduces Cx43 gap junctions in astrocytes. Thus, Th1-dominant inflammatory states disrupt astrocytic intercellular communication and may exacerbate MS..
5.	Mitsuru Watanabe, Takayuki Kondo, Kenji Murakata, Takashi Kageyama, Yoko Shibata, Toshiyuki Takahashi, Kyoichi Nomura, Sadayuki Matsumoto, Antibodies to neural and non-neural autoantigens in Japanese patients with CNS demyelinating disorders, Journal of Neuroimmunology, 10.1016/j.jneuroim.2014.06.020, 274, 1-2, 155-160, 2014.01, [URL], Anti-aquaporin 4 (AQP4) antibodies (Abs) are essential in neuromyelitis optica spectrum disorders (NMOSD), but the relationship between CNS demyelinating disorders (CNSDD) and other neural Abs remains unclear. Here we screened anti-neural Abs in the sera of 70 Japanese CNSDD patients. While two had only demyelinating events among three anti. N-methyl. d-aspartate receptor (NMDAR) Ab-positive subjects, the other subject who also had anti-AQP4 Abs experienced episodes of anti-NMDAR encephalitis and of NMOSD. Major lesions in the three anti-contactin-associated protein 2 Ab-positive subjects were infratentorial, including one co-carrying anti-AQP4 Abs. Thus, autoantibodies can be clinically silent, but multiple autoantibodies may participate in the pathogenesis..

主要総説, 論評, 解説, 書評, 報告書等

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主要学会発表等

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1.	Mitsuru Watanabe, NfL and other candidate biomarkers in MS & NMOSD, PACTRIMS 2023, 2023.11, Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system. In clinical practice, disease activity is mainly assessed by clinical evaluation and neuroimaging. However, more sensitive biomarkers reflecting disease activity are needed to improve the prognosis. The levels of neurofilament light chain (NfL), one of three types of neuronal intermediate filament, elevate upon neuroaxonal damage not only in cerebrospinal fluid but also in blood. In MS, many studies showed that blood NfL can be a good biomarker representing disease activity, treatment response and prognosis. Therefore, blood NfL is expected to be used in daily clinical practice in the future to monitor disease activity and predict prognosis in each individual. Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy mediated by anti-aquaporin 4 antibody that typically presents with severe and recurrent attacks in the optic nerve and spinal cord. Glial fibrillary acidic protein (GFAP), an intermediate filament of astrocytes, in blood is reported to be associated with disease activity and disability in NMOSD. This lecture provides updates on biofluid biomarkers including NfL and GFAP in MS and NMOSD and discuss whether they can be applied to clinical practice..
2.	Mitsuru Watanabe, Noriko Isobe, Takuya Matsushita, Aleksandra Maceski, Yuri Nakamura, Katsuhisa Masaki, Jun-ichi Kira, David Leppert, Jens Kuhle* *These authors contributed equally to the manuscript. , Serum glial fibrillary acidic protein, but not S100B or neurofilament light chain predicts future relapses in neuromyelitis optica spectrum disorders, MSVirtual 2020 (8th Joint ACTRIMS-ECTRIMS Meeting), 2020.09.
3.	Mitsuru Watanabe, Yuri Nakamura, Zuzanna Michalak, Fumie Hayashi, Christian Barro, David Leppert, Noriko Isobe, Takuya Matsushita, Ryo Yamasaki, Jens Kuhle, Jun-ichi Kira, Serum GFAP and neurofilament light as biomarkers of disease activity and disability in NMOSD and MS, 第60回日本神経学会学術大会, 2019.05.
4.	渡邉充, 中村優理, 磯部紀子, 松下拓也, 迫田礼子, 林史恵, 吉良潤一, 日本人多発性硬化症における疾患修飾薬関連進行性多巣性白質脳症のリスクにHLAクラスIIアリルが関与する, 第116回日本内科学会総会・講演会, 2019.04.
5.	Mitsuru Watanabe, Yuri Nakamura, Zuzanna Michalak, Fumie Hayashi, Christian Barro, Noriko Isobe, Takuya Matsushita, Ryo Yamasaki, Jens Kuhle, Jun-ichi Kira , Serum GFAP and NfL as potential biomarkers for disease activity and disability progression in NMOSD and MS , 第5回MSサマーカレッジ, 2018.08.
6.	Mitsuru Watanabe, Yuri Nakamura, Zuzanna Michalak, Fumie Hayashi, Christian Barro, Noriko Isobe, Takuya Matsushita, Ryo Yamasaki, Jens Kuhle, Jun-ichi Kira, Serum glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) in neuromyelitis optica spectrum disorders, ECTRIMS 2018, 2018.10.
7.	渡邉充, 中村優理, 磯部紀子, 松下拓也, 迫田礼子, 林史恵, 吉良潤一 , 日本人多発性硬化症ではHLA-DRB1*15:01が JCV感染リスクを下げDR4がリスクを上げる, 第23回神経感染症学会総会・学術大会, 2018.10.
8.	Mitsuru Watanabe, Yuri Nakamura, Zuzanna Michalak, Fumie Hayashi, Christian Barro, Noriko Isobe, Takuya Matsushita, Ryo Yamasaki, Jens Kuhle, Jun-ichi Kira , Serum glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) as potential biomarkers for disease activity and disability in neuromyelitis optica spectrum disorders and multiple sclerosis , 11th PACTRIMS Congress, 2018.11.
9.	渡邉充、白石渉、山﨑亮、磯部紀子、吉良潤一, Facial onset sensory and motor neuronopathy症候群は早期からoral phase dysphagiaを呈する, 第36回日本神経治療学会学術集会, 2018.11.

学会活動

所属学会名

日本認知症学会

日本臨床免疫学会

日本末梢神経学会

日本内科学会

日本神経内科学会

日本神経免疫学会

日本神経治療学会

日本神経感染症学会

学協会役員等への就任

2022.10, 日本神経免疫学会, 評議員.

2020.04, 日本神経感染症学会, 評議員.

学会大会・会議・シンポジウム等における役割

2023.11.24～2023.11.24, PACTRIMS 2023, Plenary session演者.

2023.09.13～2023.09.13, 第35回日本神経免疫学会学術集会, シンポジウム演者.

2020.08.31～2020.09.02, 第61回日本神経学会学術大会, 教育コース演者.

学術論文等の審査

年度	外国語雑誌査読論文数	日本語雑誌査読論文数	国際会議録査読論文数	国内会議録査読論文数	合計
2022年度	2	0	0	0	2
2021年度	3	1			4
2020年度	5	1			6

受賞

日本神経免疫学会研究創世賞　優秀賞, 日本神経免疫学会, 2022.10.

MSVirtual2020 Educational Grant, 8th Joint ACTRIMS-ECTRIMS Meeting, 2020.09.

優秀演題賞, 日本神経治療学会学術集会, 2018.11.

Investigator Award（最優秀口演賞）, Pan-Asian Committee for Treatment and Research in Multiple Sclerosis, 2018.11.

最優秀口演賞（基礎・臨床研究部門）, 日本神経感染症学会総会・学術大会, 2018.10.

学長賞（最優秀賞）, MS Summer College, 2018.08.

学術委員会委員長賞, MS Summer College, 2016.08.

Travel Award, European Committee for Treatment and Research in Multiple Sclerosis , 2016.09.

Travel Award, European Committee for Treatment and Research in Multiple Sclerosis , 2015.10.

研究資金

科学研究費補助金の採択状況(文部科学省、日本学術振興会)

2015年度～2016年度, 若手研究(B), 代表, T細胞によるグリアコネキシン喪失機構の解明とそれに基づく脱髄疾患の新規治療法開発.

九大関連コンテンツ

pure2017年10月2日から、「九州大学研究者情報」を補完するデータベースとして、Elsevier社の「Pure」による研究業績の公開を開始しました。

QIR　九州大学学術情報リポジトリシステム情報科学研究院

九州大学病院


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