NAKAHARA Jin

写真a

Affiliation

School of Medicine, Department of Internal Medicine (Neurology) Department of Neurology, Keio University School of Medicine (Shinanomachi)

Position

Professor

Related Websites

External Links
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Profile 【 Display / hide 】

  • - Japanese Society of Neurology: Delegate
    - Japanese Society of Internal Medicine: Councilor
    - Japanese Society of Neuroimmunology: Director
    - Japanese Society of Neurological Therapeutics: Councilor
    - Japanese Society for Neuroinfectious Diseases: Councilor
    - Japan Multiple Sclerosis Network: Director
    - Japanese Society of Microcirculation: Director
    - Pan-Asian Congress for Treatment and Research in Multiple Sclerosis (PACTRIMS): Central organizing committee member
    - American Academy of Neurology (AAN) and European Academy of Neurology (EAN): Member

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Message from the Faculty Member 【 Display / hide 】

  • We aim to develop actual therapeutics by every conceivable means – from advancement of translational research to home care medicine – to improve the quality of life of patients suffering from various neurological diseases.

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Other Affiliation 【 Display / hide 】

  • Keio University Hospital Stroke Center, Director

  • Keio University Hospital Parkinson's Disease Center, Director

  • iPS Cell Research Center for Intractable Neurological Diseases, Keio University (KiND), Director

  • Kanazawa University, Guest Professor

  • The JIKEI University School of Medicine, Guest Professor

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Career 【 Display / hide 】

  • 2003.04
    -
    2004.03

    慶應義塾大学, COEプログラム（生命科学）, 研究員

  • 2004.04
    -
    2007.03

    独立行政法人日本学術振興会, 特別研究員（DC1）

  • 2007.04
    -
    2008.11

    独立行政法人日本学術振興会, 特別研究員（PD）

  • 2008.12
    -
    2013.03

    慶應義塾大学, 医学部総合医科学研究センター, 特任講師

  • 2013.04
    -
    2018.03

    慶應義塾大学, 医学部内科学教室（神経）, 助教

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Academic Background 【 Display / hide 】

  • 2003.03

    Keio University, School of Medicine

    University, Graduated

  • 2007.03

    Keio University, Graduate School, Division of Medicine, 生理系専攻

    Graduate School, Completed, Doctoral course

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Academic Degrees 【 Display / hide 】

  • 博士（医学）, Keio University, Coursework, 2007.03

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Licenses and Qualifications 【 Display / hide 】

  • Medical license, 2003.05

  • Certified occupational physician, 2011.09

  • Board certified member of the Japanese Society of Internal Medicine, 2013.09

  • Board certified neurologist, 2014.07

  • Fellow of the Japanese Society of Internal Medicine (FJSIM), 2019.12

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Research Areas 【 Display / hide 】

  • Life Science / Neurology

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Research Keywords 【 Display / hide 】

  • Oligodendrocyte

  • Multiple sclerosis

  • Neuroimmunology

  • Neurology

  • Neuromyelitis optica spectrum disorder

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Research Themes 【 Display / hide 】

  • 神経治療学の拠点形成, 

    2018
    -
    Present

  • 多発性硬化症の臨床研究, 

    2011
    -
    Present

  • 中枢神経系髄鞘再生療法の開発, 

    1999
    -
    Present

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Books 【 Display / hide 】

  • Visualization of Myelin for the Diagnosis and Treatment Monitoring of Multiple Sclerosis

    Nakahara J., Advances in Experimental Medicine and Biology, 2019

    　View Summary

    Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) affecting more than two million people worldwide. As the exact etiology of MS remains elusive, the diagnosis of MS is made by referring to the McDonald diagnostic criteria, which utilizes MRI as a tool to identify “demyelinated” MS lesions. In particular, hyperintense lesions on T2-weighted images (T2WI) or so-called “T2-lesions” are considered to represent demyelinated MS lesions. T2WI, however, lacks myelin specificity, and moreover, remyelination could not be depicted by the use of such modality. For the accurate diagnosis and treatment decision-making, or for the future development of remyelination therapeutics, imaging tools to visualize myelin-specific signals are mandatory. In this chapter, the current use and the limitation of imaging modalities in MS diagnosis and treatment will be reviewed, with the introduction of new imaging method, namely q-space Myelin Map (qMM), to be used for visualization of demyelination and remyelination in MS.

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Papers 【 Display / hide 】

  • CGRP-monoclonal antibodies in Japan: insights from an online survey of physician members of the Japanese headache society

    Takizawa T., Ihara K., Watanabe N., Takemura R., Takahashi N., Miyazaki N., Shibata M., Suzuki K., Imai N., Suzuki N., Hirata K., Takeshima T., Nakahara J.

    Journal of Headache and Pain (Journal of Headache and Pain)  25 ( 1 )  2024.12

    ISSN  11292369

    　View Summary

    Background: Anti-calcitonin gene-related peptide monoclonal antibodies (CGRPmAbs) have greatly changed migraine treatment options. In Japan, although CGRPmAb guidelines (≥ 4 monthly migraine days (MMDs) and ≥ 1 previous preventive failure) are well-acknowledged, the actual use of CGRPmAbs and the circumstances of the related headache care are unknown. Methods: We conducted an online survey of Japanese Headache Society members, inquiring about the physicians' experience with CGRPmAbs and how they make decisions related to their use. Results: Of the 397 respondents, 320 had prescribed CGRPmAbs. The threshold number of previous preventive failures for recommending a CGRPmAb was two for the majority of the respondents (n = 170, 54.5%), followed by one (n = 64, 20.5%). The MMD threshold was ≥ 4 for 71 respondents (22.8%), ≥ 6 for 68 (21.8%), ≥ 8 for 76 (24.4%), and ≥ 10 for 81 (26.0%). The respondents tended to assess treatment efficacy after 3 months (episodic migraine: n = 217, 69.6%, chronic migraine: n = 188, 60.3%). The cost of CGRPmAbs was described by many respondents in two questions: (i) any request for a CGRPmAb (27.7%), and (ii) the most frequently reported reason for responders to discontinue CGRPmAbs (24.4%). Conclusions: Most of the respondents recommended CGRPmAbs to patients with ≥ 2 preventive failures, followed by ≥ 1. The MMD threshold ranged mostly from ≥ 4 to ≥ 10. The concern for costs was raised as a major limiting factor for prescribing CGRPmAbs.

  • Proteomic insights into extracellular vesicles in ALS for therapeutic potential of Ropinirole and biomarker discovery

    Kato C., Ueda K., Morimoto S., Takahashi S., Nakamura S., Ozawa F., Ito D., Daté Y., Okada K., Kobayashi N., Nakahara J., Okano H.

    Inflammation and Regeneration (Inflammation and Regeneration)  44 ( 1 )  2024.12

    　View Summary

    Background: Extracellular vesicles (EVs) hold the potential for elucidating the pathogenesis of amyotrophic lateral sclerosis (ALS) and serve as biomarkers. Notably, the comparative and longitudinal alterations in the protein profiles of EVs in serum (sEVs) and cerebrospinal fluid (CSF; cEVs) of sporadic ALS (SALS) patients remain uncharted. Ropinirole hydrochloride (ROPI; dopamine D2 receptor [D2R] agonist), a new anti-ALS drug candidate identified through induced pluripotent stem cell (iPSC)-based drug discovery, has been suggested to inhibit ALS disease progression in the Ropinirole Hydrochloride Remedy for Amyotrophic Lateral Sclerosis (ROPALS) trial, but its mechanism of action is not well understood. Therefore, we tried to reveal longitudinal changes with disease progression and the effects of ROPI on protein profiles of EVs. Methods: We collected serum and CSF at fixed intervals from ten controls and from 20 SALS patients participating in the ROPALS trial. Comprehensive proteomic analysis of EVs, extracted from these samples, was conducted using liquid chromatography/mass spectrometer (LC/MS). Furthermore, we generated iPSC-derived astrocytes (iPasts) and performed RNA sequencing on astrocytes with or without ROPI treatment. Results: The findings revealed notable disparities yet high congruity in sEVs and cEVs protein profiles concerning disease status, time and ROPI administration. In SALS, both sEVs and cEVs presented elevated levels of inflammation-related proteins but reduced levels associated with unfolded protein response (UPR). These results mirrored the longitudinal changes after disease onset and correlated with the revised ALS Functional Rating Scale (ALSFRS-R) at sampling time, suggesting a link to the onset and progression of SALS. ROPI appeared to counteract these changes, attenuating inflammation-related protein levels and boosting those tied to UPR in SALS, proposing an anti-ALS impact on EV protein profiles. Reverse translational research using iPasts indicated that these changes may partly reflect the DRD2-dependent neuroinflammatory inhibitory effects of ROPI. We have also identified biomarkers that predict diagnosis and disease progression by machine learning-driven biomarker search. Conclusions: Despite the limited sample size, this study pioneers in reporting time-series proteomic alterations in serum and CSF EVs from SALS patients, offering comprehensive insights into SALS pathogenesis, ROPI-induced changes, and potential prognostic and diagnostic biomarkers.

  • Effects of passive smoking on cortical spreading depolarization in male and female mice

    Takizawa T., Ihara K., Unekawa M., Iba C., Kagawa S., Watanabe N., Nakayama S., Sakurai K., Miyazaki N., Ishida N., Takemura R., Shibata M., Izawa Y., Chubachi S., Fukunaga K., Nakahara J.

    Journal of Headache and Pain 25 ( 1 )  2024.12

    ISSN  11292369

    　View Summary

    Background: Patients with migraine are typically advised to avoid passive smoking because it may aggravate headaches and other health conditions. However, there is insufficient high-quality evidence on the association between passive smoking and migraine, which warrants further investigation using animal models. Therefore, using a mouse model, we examined the effect of passive smoking on susceptibility to cortical spreading depolarization (CSD), the biological basis of migraine with aura. Findings: Fifty C57BL/6 mice (25 males and 25 females) were exposed for one hour to cigarette smoke or room air. Subsequently, potassium chloride (KCl) was administered under isoflurane anesthesia to induce CSD, and the CSD threshold, frequency of induction, and propagation velocity were determined. The threshold to induce CSD (median [interquartile range (IQR)]) was significantly lower in female mice (adjusted p = 0.01) in the smoking group (0.05 [0.05, 0.088]) than in the sham group (0.125 [0.1, 0.15]); however, there was no significant difference in the male mice (adjusted p = 0.77). CSD frequency or propagation velocity did not differ significantly between the two groups for either sex. Conclusions: Female mice in the smoking group showed lower CSD threshold compared to the sham group, suggesting a potential sex-specific difference in the effect of smoking on the pathogenesis of CSD and migraine with aura. This finding may contribute to the understanding of migraine pathophysiology in association with passive smoking and sex difference.

  • Prevalence of, and Disability Due to, Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder in Japan by the Fifth Nationwide Survey

    Watanabe M., Isobe N., Niino M., Nakashima I., Matsushita T., Sakai Y., Nakahara J., Kawachi I., Ochi H., Nakatsuji Y., Nakamura Y., Nakamura K., Sakata K., Matsui M., Kuwabara S., Kira J.I.

    Neurology 103 ( 10 )  2024.11

    　View Summary

    BACKGROUND AND OBJECTIVES: All 4 previous nationwide surveys of multiple sclerosis (MS) in Japan were conducted before the discovery of anti-aquaporin-4 (AQP4) antibodies; thus, neuromyelitis optica spectrum disorder (NMOSD) was included in MS, as optic-spinal MS. We aimed to clarify the epidemiologic features and trends of MS and NMOSD in Japan separately using a fifth nationwide survey. METHODS: The primary survey, in which a questionnaire was sent to 3,799 selected departments (including neurology/internal medicine, pediatrics, and ophthalmology), explored the estimated number and prevalence of patients with MS or NMOSD in 2017, and the secondary survey collected detailed characteristics of the patients using a second questionnaire. RESULTS: The response rates for the primary and secondary surveys were 60.1% and 53.9%, respectively. The estimated total number of patients with MS or NMOSD was 24,800, 2.5-fold higher than that in the fourth survey in 2003. The crude prevalence was 19.6 per 100,000 patients (14.2 for MS and 5.4 for NMOSD), compared with 7.7 per 100,000 patients in the fourth survey. Patients with MS showed milder disability (median Expanded Disability Status Scale [EDSS] score: 2.0 [interquartile range 1.0-4.5] vs 2.5 [1.0-6.0]), decreased secondary progression (8.5% vs 15.2%), and increased usage of disease-modifying drugs (63.7% vs 37.2%) compared with those with conventional MS in the fourth survey. The proportions of oligoclonal bands and Barkhof criteria fulfillment on MRI, which are features of classical MS, increased with advancing year of birth. Patients with NMOSD also showed less disability and shorter disease duration than patients with optic-spinal MS in the fourth survey (EDSS score: 3.5 [2.0-5.5] vs 3.8 [2.0-6.0]; disease duration: 8.0 [3.9-14.8] vs 10.0 [5.0-16.0]). Among patients with NMOSD, disability was exacerbated by a history of longitudinally extensive spinal cord lesions and anti-AQP4 antibody positivity, which both decreased with advancing year of birth. DISCUSSION: The prevalences of MS (particularly with classical features) and NMOSD have been increasing in Japan, suggesting the contribution of environmental factors. However, disabilities in patients with MS and NMOSD have been mitigated. Extensive usage of various disease-modifying drugs could be a factor contributing to this disability mitigation in MS.

  • The Icelandic Mutation (APP-A673T) Is Protective against Amyloid Pathology In Vivo

    Shimohama S., Fujioka R., Mihira N., Sekiguchi M., Sartori L., Joho D., Saito T., Saido T.C., Nakahara J., Hino T., Hoshino A., Sasaguri H.

    Journal of Neuroscience 44 ( 47 )  2024.11

    ISSN  02706474

    　View Summary

    A previous epidemiological study in Northern Europe showed that the A673T mutation (Icelandic mutation) in the amyloid precursor protein gene (APP) can protect against Alzheimer’s disease (AD). While the effect of the A673T mutation on APP processing has been investigated primarily in vitro, its in vivo impact has not been evaluated. This is mainly because most existing AD mouse models carry the Swedish mutation. The Swedish and Icelandic mutations are both located near the β-cleavage site, and each mutation is presumed to have the opposite effect on β-cleavage. Therefore, in the AD mouse models with the Swedish mutation, its effects could compete with the effects of the Icelandic mutation. Here, we introduced the A673T mutation into App knock-in mice devoid of the Swedish mutation (AppG-F mice) to avoid potential deleterious effects of the Swedish mutation and generated AppG-F-A673T mice. APP-A673T significantly downregulated β-cleavage and attenuated the production of Aβ and amyloid pathology in the brains of these animals. The Icelandic mutation also reduced neuroinflammation and neuritic alterations. Both sexes were studied. This is the first successful demonstration of the protective effect of the Icelandic mutation on amyloid pathology in vivo. Our findings indicate that specific inhibition of the APP-BACE1 interaction could be a promising therapeutic approach. Alternatively, the introduction of the disease-protective mutation such as APP-A673T using in vivo genome editing technology could be a novel treatment for individuals at high risk for AD, such as familial AD gene mutation carriers and APOE ε4 carriers.

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Papers, etc., Registered in KOARA 【 Display / hide 】

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Reviews, Commentaries, etc. 【 Display / hide 】

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Research Projects of Competitive Funds, etc. 【 Display / hide 】

  • Precision medicine research for neuromyelitis optica-spectrum disorders

    2023.04
    -
    2028.03

    基盤研究(B), Principal investigator

  • ミエリンマップ法を用いた多発性硬化症における髄鞘病理の画像解析

    2018.04
    -
    2023.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

  • 髄鞘を標的とした神経変性疾患・脊髄損傷に対する新規治療戦略に関する研究

    2013.04
    -
    2016.03

    文部科学省, Grant-in-Aid for Scientific Research, Principal investigator

  • 髄鞘の可視化技術による多発性硬化症の病型分類に関する研究

    2013.04
    -
    2016.03

    文部科学省, Grant-in-Aid for Scientific Research, Principal investigator

  • アストロサイトによるin vivoケトン体生合成機構の解明

    2010.04
    -
    2013.03

    文部科学省, Grant-in-Aid for Scientific Research, Principal investigator

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Intellectual Property Rights, etc. 【 Display / hide 】

  • Drug delivery system toward demyelinating lesion and biochemical marker of demyelinating lesions

    Date applied： 8252540  2012.08 

    Date issued： 8252540  2012.08

    Patent, Joint

  • Medicinal compositions containing Fc receptor γ chain activator

    Date applied： 7901678  2011.03 

    Date issued： 7901678  2011.03

    Patent, Joint

  • Fc受容体γ鎖活性化物質を含有する医薬組成物

    Date applied： 4214249  2008.11 

    Date issued： 4214249  2008.11

    Patent, Joint

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Awards 【 Display / hide 】

  • Best Presentation Award

    2017, Sendai Conference

  • MSJ-PACTRIMS investigator award

    2014, Pan-Asian Committee for Treatment and Research in Multiple Sclerosis (PACTRIMS)

  • 優秀指導教官賞

    2014, 日本内科学会

  • MSJ-PACTRIMS Investigator Award

    2014, PACTRIMS

  • 優秀指導教官賞

    2014, 内科学サミット2014

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Courses Taught 【 Display / hide 】

  • LECTURE SERIES, INTERNAL MEDICINE (NEUROLOGY)

    2024

  • INTERNAL MEDICINE: SEMINAR

    2024

  • INTERNAL MEDICINE: PRACTICE

    2024

  • INTERNAL MEDICINE

    2024

  • CLINICAL CLERKSHIP IN NEUROLOGY

    2024

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Memberships in Academic Societies 【 Display / hide 】

  • 日本内科学会

    　

  • 日本神経学会

    　

  • 日本神経免疫学会

    　

  • 日本神経治療学会

    　

  • 日本脳卒中学会

    　

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