Takizawa, Tsubasa

写真a

Affiliation

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

Position

Senior Assistant Professor (Non-tenured)/Assistant Professor (Non-tenured)
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Career 【 Display / hide 】

  • 2010
    -
    2012

    Kawasaki Municipal Hospital

  • 2016

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

  • 2016
    -
    2018

    Massachusetts General Hospital, Harvard Medical School

  • 2018
    -
    2020

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

  • 2020
    -
    Present

    Keio University, School of Medicine Department of Internal Medicine (Neurology), Assitant Professor

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Academic Background 【 Display / hide 】

  • 2004
    -
    2010

    Keio University, School of Medicine

  • 2012
    -
    2016

    Keio University, Graduate School of Medicine

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Research Areas 【 Display / hide 】

  • Life Science / General internal medicine

  • Life Science / Neurology

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Research Keywords 【 Display / hide 】

  • Migraine

  • Neurology

  • Cluster Headache

  • Headache

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Papers 【 Display / hide 】

  • Treatment patterns and characteristics of patients with migraine: results from a retrospective database study in Japan.

    Tsubasa Takizawa, Takahiro Kitano, Masahiro Iijima, Kanae Togo, Naohiro Yonemoto

    The journal of headache and pain (Journal of Headache and Pain)  25 ( 1 ) 19 - 19 2024.12

    ISSN  11292369

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    BACKGROUND: Clinical characteristics and treatment practice of patients with migraine in Japan in real-world setting have not been fully investigated. We conducted a retrospective cohort study using claims database to understand the clinical practice of migraine in recent years and to characterize patients potentially not managed well by current treatment options. METHODS: Our study used data from the large claims database maintained by JMDC Inc. Patients with diagnosis of headache or migraine between January 1, 2018, and July 31, 2022, were defined as the headache cohort, and those with migraine diagnosis and prescription of migraine treatments among the headache cohort were included in the migraine cohort. In the headache cohort, characteristics of medical facilities and status of imaging tests to distinguish secondary headache were examined. Treatment patterns and characteristics of patients potentially not managed well by acute/preventive treatment were described in migraine cohort. RESULTS: In the headache cohort, 989,514 patients were included with 57.0% females and mean age of 40.3 years; 77.0% patients visited clinics (with ≤ 19 bed capacities) for their primary diagnosis, and 30.3% patients underwent imaging tests (computed tomography and/or magnetic resonance imaging). In the migraine cohort, 165,339 patients were included with 65.0% females and mean age of 38.8 years. In the migraine cohort, 95.6% received acute treatment while 20.8% received preventive treatment. Acetaminophen/non-steroidal anti-inflammatory drugs were most common (54.8%) as the initial prescription for migraine treatment followed by triptan (51.4%). First treatment prescription included preventive treatment in 15.6%, while the proportion increased to 82.2% in the fourth treatment prescription. Among patients with more than 12 months of follow-up, 3.7% had prescription patterns suggestive of risk of medication-overuse headache, and these patients were characterized by a higher percentage of females and a higher prevalence of comorbidities. CONCLUSIONS: This study revealed that approximately one-fifth of the patients with migraine visiting medical facilities use preventive drugs. The presence of potential patients at risk of medication-overuse headache and the role of clinics in migraine treatment were also described.

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

    Tsubasa Takizawa, Keiko Ihara, Narumi Watanabe, Ryo Takemura, Nobuyuki Takahashi, Naoki Miyazaki, Mamoru Shibata, Keisuke Suzuki, Noboru Imai, Norihiro Suzuki, Koichi Hirata, Takao Takeshima, Jin Nakahara

    The journal of headache and pain (Journal of Headache and Pain)  25 ( 1 ) 39 - 39 2024.12

    ISSN  11292369

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    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.

  • The impact of primary headaches on disability outcomes: a literature review and meta-analysis to inform future iterations of the Global Burden of Disease study.

    Marta Waliszewska-Prosół, Danilo Antonio Montisano, Mariola Antolak, Federico Bighiani, Francescantonio Cammarota, Ilaria Cetta, Michele Corrado, Keiko Ihara, Regina Kartamysheva, Igor Petrušić, Maria Magdalena Pocora, Tsubasa Takizawa, Gloria Vaghi, Paolo Martelletti, Barbara Corso, Alberto Raggi

    The journal of headache and pain (Journal of Headache and Pain)  25 ( 1 ) 27 - 27 2024.12

    ISSN  11292369

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    BACKGROUND: The burden and disability associated with headaches are conceptualized and measured differently at patients' and populations' levels. At the patients' level, through patient-reported outcome measures (PROMs); at population level, through disability weights (DW) and years lived with a disability (YLDs) developed by the Global Burden of Disease Study (GBD). DW are 0-1 coefficients that address health loss and have been defined through lay descriptions. With this literature review, we aimed to provide a comprehensive analysis of disability in headache disorders, and to present a coefficient referring to patients' disability which might inform future GBD definitions of DW for headache disorders. METHODS: We searched SCOPUS and PubMed for papers published between 2015 and 2023 addressing disability in headache disorders. The selected manuscript included a reference to headache frequency and at least one PROM. A meta-analytic approach was carried out to address relevant differences for the most commonly used PROMs (by headache type, tertiles of medication intake, tertiles of females' percentage in the sample, and age). We developed a 0-1 coefficient based on the MIDAS, on the HIT-6, and on MIDAS + HIT-6 which was intended to promote future DW iterations by the GBD consortium. RESULTS: A total of 366 studies, 596 sub-samples, and more than 133,000 single patients were available, mostly referred to cases with migraine. Almost all PROMs showed the ability to differentiate disability severity across conditions and tertiles of medication intake. The indexes we developed can be used to inform future iterations of DW, in particular considering their ability to differentiate across age and tertiles of medication intake. CONCLUSIONS: Our review provides reference values for the most commonly used PROMS and a data-driven coefficient whose main added value is its ability to differentiate across tertiles of age and medication intake which underlie on one side the increased burden due to aging (it is likely connected to the increased impact of common comorbidities), and by the other side the increased burden due to medication consumption, which can be considered as a proxy for headache severity. Both elements should be considered when describing disability of headache disorders at population levels.

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

    Tsubasa Takizawa, Keiko Ihara, Miyuki Unekawa, Chisato Iba, Shizuko Kagawa, Narumi Watanabe, Shingo Nakayama, Kaori Sakurai, Naoki Miyazaki, Noriyuki Ishida, Ryo Takemura, Mamoru Shibata, Yoshikane Izawa, Shotaro Chubachi, Koichi Fukunaga, Jin Nakahara

    The journal of headache and pain 25 ( 1 ) 162 - 162 2024.12

    ISSN  11292369

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    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.

  • Hallmarks of primary headache: part 1 - migraine.

    Alberto Raggi, Matilde Leonardi, Marco Arruda, Valeria Caponnetto, Matteo Castaldo, Gianluca Coppola, Adriana Della Pietra, Xiangning Fan, David Garcia-Azorin, Parisa Gazerani, Lou Grangeon, Licia Grazzi, Fu-Jung Hsiao, Keiko Ihara, Alejandro Labastida-Ramirez, Kristin Sophie Lange, Marco Lisicki, Alessia Marcassoli, Danilo Antonio Montisano, Dilara Onan, Agnese Onofri, Lanfranco Pellesi, Mario Peres, Igor Petrušić, Bianca Raffaelli, Eloisa Rubio-Beltran, Andreas Straube, Sebastian Straube, Tsubasa Takizawa, Claudio Tana, Michela Tinelli, Massimiliano Valeriani, Simone Vigneri, Doga Vuralli, Marta Waliszewska-Prosół, Wei Wang, Yonggang Wang, William Wells-Gatnik, Tissa Wijeratne, Paolo Martelletti

    The journal of headache and pain 25 ( 1 ) 189 - 189 2024.12

    ISSN  11292369

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    BACKGROUND AND AIM: Migraine is a common disabling conditions which, globally, affects 15.2% of the population. It is the second cause of health loss in terms of years lived with disability, the first among women. Despite being so common, it is poorly recognised and too often undertreated. Specialty centres and neurologists with specific expertise on headache disorders have the knowledge to provide specific care: however, those who do not regularly treat patients with migraine will benefit from a synopsis on the most relevant and updated information about this condition. This paper presents a comprehensive view on the hallmarks of migraine, from genetics and diagnostic markers, up to treatments and societal impact, and reports the elements that identify migraine specific features. MAIN RESULTS: The most relevant hallmark of migraine is that it has common and individual features together. Besides the known clinical manifestations, migraine presentation is heterogeneous with regard to frequency of attacks, presence of aura, response to therapy, associated comorbidities or other symptoms, which likely reflect migraine heterogeneous genetic and molecular basis. The amount of therapies for acute and for prophylactic treatment is really wide, and one of the difficulties is with finding the best treatment for the single patient. In addition to this, patients carry out different daily life activities, and might show lifestyle habits which are not entirely adequate to manage migraine day by day. Education will be more and more important as a strategy of brain health promotion, because this will enable reducing the amount of subjects needing specialty care, thus leaving it to those who require it in reason of refractory condition or presence of comorbidities. CONCLUSIONS: Recognizing the hallmarks of migraine and the features of single patients enables prescribing specific pharmacological and non-pharmacological treatments. Medical research on headaches today particularly suffers from the syndrome of single-disease approach, but it is important to have a cross-sectional and joint vision with other close specialties, in order to treat our patients with a comprehensive approach that a heterogeneous condition like migraine requires.

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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 】

  • Effects of changes in barometric pressure on mood fluctuations and somatisation: Basic and clinical approaches

    2024.04
    -
    2028.03

    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (A), No Setting

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    我が国で頭痛やめまいの症状を持つ患者数は3,000万人を超えると言われており，それに伴う気分の揺らぎに伴うパフォーマンスの低下は，社会全体の活動低下を招いている．これらの患者のなかには，心的ストレスが原因となって身体の不調を訴える症例が多く含まれているが，なぜそのような身体化の症状が生じるかは十分に解明されていない．本研究では，健常者・身体症状症・片頭痛・メニエール病の患者を対象として，自律神経活動，身体状態の変化を感知する内受容感覚，予測的情報処理に基づく信念形成の特性に着目し，気圧変化に対する身体・認知特性を明らかにする．そして，症状改善に向けたプロトコルの開発に取り組む．

  • Investigation of the Current Epidemiology and Biomarkers of Migraine

    2024.04
    -
    2027.03

    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), No Setting

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    CGRP関連抗体薬が2021年に上市され、片頭痛診療は大きな変革期を迎えている。そのような中、わが国における頭痛・片頭痛の最新の疫学を明らかにすることは重要と考える。
    片頭痛について、有用なバイオマーカーは確立されていない。
    本研究では、頭痛・片頭痛についての疫学調査を実施する。さらには片頭痛のバイオマーカーの検索などを試みる。

  • Investigation of anti-CGRP monoclonal antibodies and novel therapeutics for migraine

    2022.04
    -
    2024.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Early-Career Scientists, Principal investigator

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    片頭痛の病態で重要なカルシトニン遺伝子関連ペプチド（Calcitonin gene-related peptide; CGRP）あるいはその受容体を標的とした抗体治療（CGRP関連抗体薬）が、わが国において2021年に新たに承認となった。
    本研究では、CGRP関連抗体薬を含めた片頭痛の最新治療の実態を明らかにしつつ、今後に向けての新規治療についても検討する。
    慶應義塾大学病院の頭痛外来にてCGRP関連抗体薬のリアルワールドエビデンスを検討した。まず、CGRP関連抗体薬の一つであるガルカネズマブが3回以上投与された片頭痛患者について効果と安全性を検討した。50%反応率（片頭痛日数がベースラインから半分以下になった患者の割合）は62%、100%反応率（片頭痛日数が消失した患者の割合）は10%であった。片頭痛日数のみではなく、随伴症状である光過敏、音過敏、悪心/嘔吐についても65%、50%、64%の患者で改善を認めていた。最も多い有害事象は注射部位反応で、35%の患者で認めていた（Takizawa T et al. BMC Neurology 2022）。
    次に、CGRP関連抗体薬が3回以上投与された片頭痛患者について、どのような臨床的特徴がCGRP関連抗体薬の効果に関連しているのか検討した。治療開始3ヶ月後に、50%反応率を達していた患者をレスポンダー、達していなかった患者をノンレスポンダーと定義した。CGRP関連抗体薬が投与された半数以上の患者がレスポンダーであった。年齢や体重、既往歴、ひと月あたりの片頭痛日数、痛みの程度・性質、予防薬失敗数などのデータを基に解析を行ったところ、①年齢が高く、②予防薬失敗数が少なく、③免疫系疾患の既往がない患者ほどCGRP関連抗体薬のレスポンダーになりやすいことが明らかとなった（Ihara K et al. The Journal of Headache and Pain 2023）。
    その他、わが国におけるCGRP関連抗体薬の学会報告をまとめた総説（大谷星也、井原慶子（co-1st）ら．日本頭痛学会誌 2023）、片頭痛領域の最新治療薬についての総説なども執筆した（Begasse de Dhaem O, Takizawa T (co-1st) et al. Cephalalgia 2023）。
    CGRP関連抗体薬について臨床現場からのリアルワールドデータを基に日本から有効性や安全性、レスポンダーの特徴について初めて英文論文として報告することができた。当初の計画以上に進展していると考えられた。
    CGRP関連抗体薬について、さらに新規を含めた頭痛の治療についても検討を進めていく予定である。

  • 脳血管内皮透過性制御機構の解明による新規神経疾患治療法の確立

    2021.04
    -
    2024.03

    日本学術振興会, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), No Setting

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    脳血管障害は要介護状態となる原因疾患の第一位を占め、2018年に成立した「脳卒中・循環器病対策基本法」の基本理念である、健康寿命延伸の観点から大きな社会的問題となっている。血管内治療など超急性期脳梗塞治療の進歩は目覚ましいが、脳梗塞の発症予防は、いまだ抗血栓療法と血圧管理などに依存し、新規治療法は久しく開発されていない。抗血栓療法は脳出血発症リスクと表裏一体であるなど、脳血管障害の治療で解決すべき課題は多く、脳血管性認知症に至っては治療法が存在しない。安全性と有効性を両立した脳血管障害、さらには脳血管性認知症に対する治療の確立は喫緊の課題である。
    本研究は、内皮に血栓が生じる機序、血管が破綻する機序、神経組織が機能低下する機序の解明を目的とし、脳血管透過性亢進モデルマウスを用いて、血管透過性調節による脳血管障害・血管性認知症の新たな治療概念確立を目指すものである。これにより実臨床で用いられる各抗血栓薬の有効性と安全性の違いや特徴を統一的に説明する理論の確立も目指す。 2021年度は本研究の先行研究結果をまとめた共著論文が提出され、血栓形成（止血）作用を持つトロンビンが脳微小血管障害（血管透過性亢進作用）により脳出血リスクを上昇させる可能性を示したが、これは直感的に想定されるトロンビン作用と真逆の視点を提唱するものである。また、トロンビンが脳微小血管の透過性を上昇させる様子をin vivo、生存下で連続（経時）的に捉えることに成功した。2020年度までの研究成果報告書では統計解析上は、本研究の実験仮説が誤りである可能性も否定できない状況であったが、実験手法改善により、仮説からの予測と一致する結果が蓄積され、統計的評価にも頑健であった。このように、本研究が目標とする「血管透過性制御機構」の解明という観点から、提唱する理論的仮説が真である蓋然性が一定程度高まるデータが得られた。

  • 中枢神経障害下でのNG2グリアの挙動と髄鞘の再生機序の解明

    2021.04
    -
    2024.03

    日本学術振興会, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), No Setting

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    脳は約 140 億個の神経細胞、その 10 倍のグリア細胞からなり、栄養を供給する脳血管と互いに連絡を取りながら神経グリア血管ユニット(neuro-glio-vascular unit; NVU)を形成している。本実験では分化・再生能が高く、髄鞘を形成するオリゴデンドロサイトや周皮細胞、アストロサイトに分化するオリゴデンドロサイト前駆細胞(OPC)として存在するNG2グリアに焦点を当て、慢性頭窓下の同一部位を長期間反復して観察することによって成体における細胞および髄鞘の形態、脳虚血などの病態時の形態学的変化、髄鞘再生を促進あるいは抗炎症作用を増強するメカニズムを検討し、病態改善のための薬剤の探索とその作用機序の解明を目的とする。
    NG2と高い共発現が確認され、OPCおよびオリゴデンドロサイトに発現するされるSox10に蛍光タンパク質Venusを発現させたマウスにTomita-Seylaz法による慢性頭窓を作成し、二光子顕微鏡を用いて長期間観察を行うことにより、細胞レベルでの変化を経日的に観察した。キレート剤であるクプリゾン混餌食(0.2％)を給餌することにより脱髄モデルを作成し、スルホローダミン101の投与によって生体染色されるアストロサイトの形態学的変化を追跡する手法を確立した。観察終了後に脳を摘出し、蛍光細胞や神経細胞の撮像や解析の手法を検討中である。さらに、実験的脳梗塞モデルである中大脳動脈閉塞術を施行した病態モデルマウスを作成するため、基本的な手技を習得するとともに、線条体や大脳皮質における脳血流の変化と梗塞巣の形成との相関、施行時に発生して梗塞巣の形成に影響を及ぼすと考えられている大脳皮質拡延性脱分極(CSD)との関連についても検討した。

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Awards 【 Display / hide 】

  • Young Investigator Award, Keio University School of Medicine Alumni Association (Sanshikai)

    2024, Keio University School of Medicine, Sanshikai

  • Frontiers in Headache Research Scholarship

    2018, American Headache Society

  • Kitamura Award

    2014, The Japanese Headache Society

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Courses Taught 【 Display / hide 】

  • RESEARCH FRONTIERS IN BIOMEDICAL SCIENCE

    2024

  • LECTURE SERIES, INTERNAL MEDICINE (NEUROLOGY)

    2024

  • RESEARCH FRONTIERS IN BIOMEDICAL SCIENCE

    2023

  • LECTURE SERIES, INTERNAL MEDICINE (NEUROLOGY)

    2023

  • RESEARCH FRONTIERS IN BIOMEDICAL SCIENCE

    2022

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