Takahashi, Takao



School of Medicine, Department of Pediatrics (Shinanomachi)



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  • 1982年3月 慶應義塾大学医学部卒業 1982年5月 慶應義塾大学医学部研修医(小児科) 1988年9月 米国ハーバード大学、マサチューセッツ総合病院小児神経科 1992年6月 ハーバード大学医学部、Instructor in Neurology 1994年6月 マサチューセッツ総合病院神経科、Assistant in Neurology 1994年8月 慶應義塾大学助手(医学部小児科学) 1996年10月 慶應義塾大学専任講師(医学部小児科学) 1999年4月 慶應義塾大学助教授(医学部小児科学) 2002年4月 慶應義塾大学教授(医学部小児科学) 2007年10月 慶應義塾大学病院 副病院長 2015年10月 慶應義塾大学医学部 医学部長補佐

Academic Background 【 Display / hide

  • 1976.04


    University, Graduated

Academic Degrees 【 Display / hide

  • 医学博士, 慶應義塾大学, 1991.06


Research Keywords 【 Display / hide

  • 大脳皮質発生、神経前駆細胞、高次能機能発達、環境因子、エピジェネティクス

Research Themes 【 Display / hide

  • 大脳皮質発生、神経前駆細胞、高次能機能発達、環境因子、エピジェネティクス, 



Books 【 Display / hide

  • ガイドラインと最新文献で学ぶ小児科学レビュー2016-17

    高橋孝雄,藤村公乃,三橋隆行., 総合医学社, 2016.05

    Scope: 脳形成異常

  • 続・イメージからせまる小児神経疾患50 ―症例から学ぶ 診断・治療プロセス―

    三橋隆行,高橋孝雄., 診断と治療社, 2015.11

    Scope: 脳回形成メカニズムと大脳皮質内神経細胞数の変動について

  • 発達科学入門2 胎児期~児童期

    三橋 隆行,吉井 聡, 高橋 孝雄, 東京大学出版会、東京, 2012.02

    Scope: 3-19

  • Encyclopedia of Neuroscience

    Mitsuhashi T, Takahashi T., Springer-Verlag, Berlin, 2009

    Scope: 588-591

  • 新体系看護学29 小児看護学②


    Scope: 281-291

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Papers 【 Display / hide

  • Pediatric acquired demyelinating syndrome (ADS) in inpatient hospital settings: The hospitalization rate, costs, and outcomes in the US

    Minegishi M., Takahashi T., Testa M.

    Multiple Sclerosis and Related Disorders (Multiple Sclerosis and Related Disorders)  34   150 - 157 2019.09

    ISSN  22110348

     View Summary

    © 2019 Elsevier B.V. Background: Although relatively rare among pediatric patients, acquired demyelinating syndromes of the central nervous system (ADS) is a potentially disabling condition that warrants hospitalization and long-term follow-up. As such, a better understanding of the epidemiology and hospital utilization for this condition could provide critical information for health care planning and resource allocation. Objective: To evaluate the trends of hospital utilization and resource use associated with pediatric ADS in the US. Method: We conducted a serial cross-sectional trend analysis with complex sampling and weighting using nationally representative hospital discharge records, from the Kids´ Inpatient Database (KID), Healthcare Cost and Utilization Project (HCUP), Agency for Healthcare Research and Quality coded with International Classification of Diseases (Healthcare Cost and Utilization Project (HCUP) 2018), Ninth Revision (ICD-9-CM) for the years 2003, 2006, 2009, and 2012. We also conducted a cross-sectional study for the KID2016 dataset coded with ICD10-CM to estimate the pediatric ADS-related hospital utilization for the year. Excluding transferring discharges: we evaluated the discharge records for those aged 0 to 19 years diagnosed with any of ADS of central nervous systems including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), transverse myelitis (TM) and demyelinating disease not specified (DDNS). For the trend analysis, we used variance-weighted regression and Poisson regression for the annual hospitalization rate, total hospital charges and hospital days associated with the ADS hospitalizations for the year 2003 to 2012. Results: We estimated a total of 1,292 ADS-related hospitalizations (95%CI: 1127–1,458) in 2003, 2104 hospitalizations (95%CI: 1823–2385) in 2006, 2851 hospitalizations (95%CI: 2499–3203) in 2009, and 3501 hospitalizations (95%CI: 3058–3945) in 2012 among those aged 19 years or younger with diagnoses of ADS. There was an increase in the proportion of the inpatient hospital cost attributed to ADS from 0.06% in 2003 to 0.20% in 2012. The annual hospitalization rates relative to pediatric ADS were 1.59/100,000 (95%CI: 1.51–1.68) in 2003 and 4.21/100,000 (95%CI: 4.07–4.35) in 2012. In the cross-sectional analysis for the year 2016 coded by ICD10-CM, the number of pediatric ADS related hospitalizations were 4,568, constituting 0.30% of the total pediatric hospitalization cost. The annual hospitalization rate for the year 2016 was estimated to be 5.51/100,000. Conclusion: Hospital utilization by pediatric patients with ADS increased during the period 2003 through 2012. The cross-sectional analysis for the year 2016 indicated that the trend could be ongoing, although the direct comparison was not feasible due to the changes in the coding system of the dataset from ICD9-CM to ICD10-CM. Although relatively rare, pediatric ADS warrant long-term follow-ups and hospitalizations, impacting the developmental trajectory of the affected children and the lives of their family members. Th potentially increasing trend of pediatric ADS hospital utilization should be acknowledged when allocating and planning future resources and supporting programs.

  • Noninvasive diagnosis of TRIT1-related mitochondrial disorder by measuring i<sup>6</sup>A37 and ms<sup>2</sup>i<sup>6</sup>A37 modifications in tRNAs from blood and urine samples

    Takenouchi T., Wei F., Suzuki H., Uehara T., Takahashi T., Okazaki Y., Kosaki K., Tomizawa K.

    American Journal of Medical Genetics, Part A (American Journal of Medical Genetics, Part A)  179 ( 8 ) 1609 - 1614 2019.08

    ISSN  15524825

     View Summary

    © 2019 Wiley Periodicals, Inc. Subsets of mitochondrial transfer RNA (tRNA) contain the N6-isopentenyladenosine (i6A) or 2-methylthio-N6-isopentenyladenosine (ms2i6A) modification at position A37, which is adjacent to an anticodon. These modifications are essential for efficient protein translation in mitochondria and contribute to energy metabolism. The first step in i6A and ms2i6A modifications is catalyzed by tRNA isopentenyltransferase, which is encoded by the TRIT1 gene. Herein, we report a girl with a developmental delay, frequent episodes of seizures induced by febrile illness, and myoclonic epilepsy who had compound heterozygous missense mutations in TRIT1. A mass spectrometry analysis of RNA nucleoside obtained from the subject's peripheral blood and urine showed a marked decrease in both i6A and ms2i6A modifications. These results suggest that the mitochondrial disorder was caused by defective tRNA isopentenylation arising from a loss-of-function mutation in TRIT1. Furthermore, the present observations suggest that noninvasive biochemical analysis using peripheral blood and urine samples are sufficient for the diagnosis of TRIT1-related disorders, making muscle biopsy for the direct measurement of oxidative phosphorylation unnecessary. Such biochemical analyses before the start of antiepileptic medications would be beneficial to avoid hepatotoxicity in patients with possible mitochondrial disorders.

  • Effectiveness of inactivated influenza vaccine in children by vaccine dose, 2013–18

    Shinjoh M., Sugaya N., Furuichi M., Araki E., Maeda N., Isshiki K., Ohnishi T., Nakamura S., Yamada G., Narabayashi A., Nishida M., Taguchi N., Nakata Y., Yoshida M., Tsunematsu K., Shibata M., Munenaga T., Hirano Y., Ookawara I., Sekiguchi S., Kobayashi Y., Yamaguchi Y., Yoshida N., Mitamura K., Takahashi T.

    Vaccine (Vaccine)  37 ( 30 ) 4047 - 4054 2019.07

    ISSN  0264410X

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    © 2019 Elsevier Ltd Objectives: We assessed the vaccine effectiveness (VE) of inactivated influenza vaccine (IIV) by vaccine dose in children aged 6 months to 12 years for whom two doses are recommended in Japan to ascertain the appropriate vaccine doses. Methods: VE was assessed according to a test-negative case-control design based on rapid influenza diagnostic test (RIDT) results. Children aged 6 months to 12 years with a fever ≥38 °C who had received an RIDT in outpatient clinics of 24 hospitals were enrolled for all five seasons since 2013/14. VE by vaccine dose (none vs. once or twice, and once vs. twice) was analyzed. Results: In the dose analysis, 20,033 children were enrolled. Both one- and two-dose regimens significantly reduced cases in preventing any influenza, influenza A, and influenza B, but there was no significant difference in adjusted VE between one- and two-dose regimens overall (adjusted OR, 0.560 [95% CI, 0.505–0.621], 0.550 [95% CI, 0.516–0.586]), 0.549 [95% CI, 0.517–0.583], and 1.014 [95% CI, 0.907–1.135], for none vs. once, none vs. twice, none vs. once or twice, and once vs. twice for any influenza, respectively). Both one- and two-dose regimens significantly reduced cases with any influenza and influenza A every season. Also, both regimens significantly reduced cases of any influenza, influenza A, and influenza B among children aged 1–12 years, especially among those aged 1–5 years. In the 2013/14, 2015/16, and 2016/17 seasons, however, only the two-dose regimen was significantly effective in preventing influenza B. Both one- and two-dose regimens significantly reduced cases involving hospitalization due to any influenza and influenza A. Conclusions: Both one- and two-doses regimens of IIV were effective in preventing influenza for children aged 6 months to 12 years. The two-dose regimen was more effective against influenza B in some seasons.

  • Further evidence of a causal association between AGO1, a critical regulator of microRNA formation, and intellectual disability/autism spectrum disorder

    Sakaguchi A., Yamashita Y., Ishii T., Uehara T., Kosaki K., Takahashi T., Takenouchi T.

    European Journal of Medical Genetics (European Journal of Medical Genetics)  62 ( 6 )  2019.06

    ISSN  17697212

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    © 2018 Elsevier Masson SAS Among the many regulators of microRNA formation, Argonaute 1 (AGO1) plays critical roles in RNA interference, which controls a wide range of biological activities. Recent large-scale genomic studies have identified at least five patients with intellectual disability/autism spectrum disorder who had de novo mutations in AGO1, but detailed clinical information was not available. The recognizable clinical features that are associated with AGO1 mutations remain to be determined. The proposita was a 15-year-old girl with diffuse hypotonia, infrequent seizures, and intellectual disability with an intelligence quotient of 41. She had characteristic facial features consisting of telecanthus, wide nasal bridge with bulbous nasal tip, and a round face with downslanted palpebral fissures. Serial computed tomography scans showed progressive calcification in the globus pallidus that became evident during childhood. A whole exome analysis in trio revealed a de novo heterozygous mutation in AGO1, i.e., c.595G > A p.(Gly199Ser). The distinctive facial features, i.e., telecanthus, wide nasal bridge with bulbous nasal tip, and a round face with downslanted palpebral fissures, closely resembled previously reported patients who had a chromosomal microdeletion encompassing AGO1 locus. The combinatory phenotype of such characteristic facial features and radiographic features, i.e. progressive calcification in the globus pallidus, in the presently reported patient suggest that AGO1 mutations lead to a syndromic form of intellectual disability/autism spectrum disorder. Distinctive facial features with early and progressive calcification in the globus pallidus may be suggestive of the presence of AGO1 mutations.

  • Large-area fluorescence and electron microscopic correlative imaging with multibeam scanning electron microscopy

    Shibata S., Iseda T., Mitsuhashi T., Oka A., Shindo T., Moritoki N., Nagai T., Otsubo S., Inoue T., Sasaki E., Akazawa C., Takahashi T., Schalek R., Lichtman J., Okano H.

    Frontiers in Neural Circuits (Frontiers in Neural Circuits)  13 2019.04

    ISSN  16625110

     View Summary

    © 2019 Shibata, Iseda, Mitsuhashi, Oka, Shindo, Moritoki, Nagai, Otsubo, Inoue, Sasaki, Akazawa, Takahashi, Schalek, Lichtman and Okano. Recent improvements in correlative light and electron microscopy (CLEM) technology have led to dramatic improvements in the ability to observe tissues and cells. Fluorescence labeling has been used to visualize the localization of molecules of interest through immunostaining or genetic modification strategies for the identification of the molecular signatures of biological specimens. Newer technologies such as tissue clearing have expanded the field of observation available for fluorescence labeling; however, the area of correlative observation available for electron microscopy (EM) remains restricted. In this study, we developed a large-area CLEM imaging procedure to show specific molecular localization in large-scale EM sections of mouse and marmoset brain. Target molecules were labeled with antibodies and sequentially visualized in cryostat sections using fluorescence and gold particles. Fluorescence images were obtained by light microscopy immediately after antibody staining. Immunostained sections were postfixed for EM, and silver-enhanced sections were dehydrated in a graded ethanol series and embedded in resin. Ultrathin sections for EM were prepared from fully polymerized resin blocks, collected on silicon wafers, and observed by multibeam scanning electron microscopy (SEM). Multibeam SEM has made rapid, large-area observation at high resolution possible, paving the way for the analysis of detailed structures using the CLEM approach. Here, we describe detailed methods for large-area CLEM in various tissues of both rodents and primates.

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

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Reviews, Commentaries, etc. 【 Display / hide

  • Spontaneous intramural duodenal hematoma as the manifestation of Noonan syndrome

    Yamazawa K., Yamada Y., Kuroda T., Mutai H., Matsunaga T., Komiyama O., Takahashi T.

    American Journal of Medical Genetics, Part A (American Journal of Medical Genetics, Part A)  176 ( 2 ) 496 - 498 2018.02

    ISSN  15524825

  • Proliferation and differentiation characteristics of neural stem cells during course of cerebral cortical histogenesis

    Mitsuhashi T, Takahashi T.

    Congenital Anomalies 56   6 - 11 2016

    Introduction and explanation (scientific journal), Joint Work,  ISSN  1741-4520

     View Summary

    Recent advancements in the research field of stem cell biology have enabled the realization of regenerative medicine in various systems of the body, including the central nervous system. However, fundamental knowledge regarding how neural stem cells divide and generate young neurons in mammals, especially in vivo, is still inadequate. In this article, we shall summarize the concept of cell cycle/division of neural stem cells that generate projection neurons in the murine cerebral cortex. We shall also review the molecular mechanisms that modulate the critical parameters related to the cell cycle regulatory mechanisms, with special reference to the cell cycle regulatory protein p27Kip1 , an inhibitor of progression of the cell cycle at the G1 phase. A better understanding of the mechanisms controlling cell cycle progression is expected to contribute to the development of novel strategies to increase the efficiency of neural cell/tissue production, both in vivo and in vitro.

  • 脳幹・小脳の発生異常 小児疾患診療のための病態生理

    高橋孝雄, 三橋隆行.

    小児内科 48   247 - 251 2016

    Introduction and explanation (commerce magazine), Joint Work

  • 〔長期予後と成人後の医学的問題〕小児神経疾患

    高橋孝雄, 三橋隆行

    日本医師会雑誌 143 ( 10 ) 2135 - 8 2015

    Introduction and explanation (scientific journal), Joint Work

  • 大脳皮質の発生と難治性てんかん

    高橋孝雄, 三橋隆行

    脳と発達 46   187 - 190 2014

    Introduction and explanation (scientific journal), Joint Work

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Presentations 【 Display / hide

  • Neurobiology of Neural Stem/Progenitor Cells and Its Application to Child Neurology.

    Takao Takahashi

    The 14th Asian and Oceanian Congress of Child Neurology, 2017.05, Oral Presentation(key)

  • Valproic acid exposure in utero causes neocortical dysgenesis: Altered proliferation/differentiation pattern of neural progenitor cells


    Neuroscience 2015, 2015.10, Poster (general)

  • In Utero Exposure to Valproic Acid Causes Cerebral Cortical Dysgenesis in Mice

    Kimino Fujimura, Takayuki Mitsuhashi, Shinsuke Shibata, Sachiko Shimozato, Takao Takahashi

    The 13th Asian and Oceania Congress of Child Neurology, 2015.05, Poster (general)

  • バルプロ酸ナトリウム胎内曝露がマウス大脳皮質発生に与える影響


    第49回慶應ニューロサイエンス研究会, 2015.02, Poster (general)

  • 小児急性リンパ性白血病治療関連けいれんの原因の変遷

    小西 順子, 武内 俊樹, 下郷 幸子, 三橋 隆行, 高橋 孝雄

    第55回日本小児神経学会学術集会, 2013.06, Oral Presentation(general)

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

  • 発達期精神疾患の発症基盤に胎内環境が与える影響の解析


    MEXT,JSPS, Grant-in-Aid for Scientific Research, 高橋 孝雄, Grant-in-Aid for Scientific Research (B), Principal Investigator

  • 胎児脳・未熟脳における星状グリアの産生メカニズムの解明と治療応用にむけた 機能解析


    Grant-in-Aid for Scientific Research, 高橋孝雄, Research grant, Principal Investigator

  • 母体低栄養がエピジェネティックに大脳皮質構築に与える影響に関する研究


    Grant-in-Aid for Scientific Research, 三橋隆行, Research grant, Co-investigator

  • 先天奇形症候群の大脳皮質発生異常にエピジェネティクス機構が果たす役割に関する研 究


    Grant-in-Aid for Scientific Research, 高橋孝雄, Research grant, Principal Investigator

  • ヒストンメチル化機構の異常が神経幹細胞の細胞分裂動態に与える影響に関する 研究


    Grant-in-Aid for Scientific Research, 三橋隆行, Research grant, Co-investigator

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Works 【 Display / hide

  • 医学部国際交流委員会委員



  • 総合学習小委員会委員長



  • 入学試験検討委員会委員



  • 臨床実習に関する小委員会委員



  • 学務委員会委員



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Awards 【 Display / hide

  • The Charles A.King Trust Medical Foundation,Young Investigator Award


  • 三四会賞

    1994, マウス胎仔の新皮質発生における細胞分裂様式

  • 成長科学協会研究奨励賞

    Takahashi Takao, 1996.01, 成長科学協会, 大脳新皮質発生における成長因子の役割

  • 東京都医師会研究奨励賞

    Takahashi Takao, 1997.03, 東京都医師会, 大脳皮質における細胞分裂に関する研究

  • 私立大学情報教育協会賞

    2005, 患者データベースを用いた臨床実習システム


Courses Taught 【 Display / hide











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Courses Previously Taught 【 Display / hide

  • 小児科学

    Keio University, 2015

  • メディカル・プロフェッショナルリズムⅥ

    Keio University, 2015


Memberships in Academic Societies 【 Display / hide

  • 日本小児科学会 会長

  • 日本小児神経学会 理事長

  • 日本小児保健協会 理事

  • 日本てんかん学会 評議員