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Pathogenesis of Sleep-Wake Disorders and Psychiatric Disorders Caused by Autoantibodies

Research Project

Project/Area Number 19K08037
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52030:Psychiatry-related
Research InstitutionUniversity of Tsukuba

Principal Investigator

Kanbayashi Takashi  筑波大学, 国際統合睡眠医科学研究機構, 教授 (50323150)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywordsナルコレプシー / オレキシン / 視神経脊髄炎 / NMDA受容体脳炎 / orexin / narcolepsy / NMDA encephalitis / MCH / QRFP / AQP4抗体 / NMDAR抗体 / 自己抗体
Outline of Research at the Start

これまでにナルコレプシーの確定診断を目的として、日本国内とアジアから検体が送られて来ており、その中には症候性の過眠症の症例も多く含まれており、視床下部障害による症候性過眠症の疾患概念を構築できた。特に抗AQP4抗体による症候性過眠症は特徴的な病態であった。抗NMDAR抗体による精神症状に関しても、自己抗体により、精神症状が惹起されることは大きな驚きであった。症例の蓄積を重ねて、精神症状のみの症例においても、160例中6例の抗体陽性例を見いだしている。
認知症に関しては、200検体以上の髄液でのオレキシン測定を行い、うち約100例では、Aβとtauの測定も実施している。

Outline of Final Research Achievements

Narcolepsy (NA) was shown to be caused by loss of orexin neurons in 2000. 90% of patients are positive for HLA-DR*1501 and DQB1*0602, indicating that an immune mechanism is involved, but the mechanism of orexin loss is not clear. To investigate the pathogenesis of idiopathic NA, we have continued to measure orexin levels in patients with hypersomnia, which is considered to be symptomatic. The most frequent cases are neuromyelitis optica (NMO) caused by AQP4 and MOG antibodies. Hypersomnia often improves with treatment of the underlying disease. Less frequently, cases with Ma2 antibodies have also been reported. In the search for the cause of hypersomnia in elderly patients, we found Ma2 antibodies and testicular tumors, but hypersomnia did not improve after removal of the tumors. We assume that BBB vulnerability may be the basis of both diseases. In our study of NMDAR antibodies, the positivity rate was about 0.5% in psychiatric inpatients.

Academic Significance and Societal Importance of the Research Achievements

ナルコレプシー(NA)はオレキシン神経の脱落で発症することが明らかとなり、免疫機序が働いていることは間違いないが、その機序は明らかでは無い。病態を探る目的のため症候性と考えられる過眠症の症例においてもオレキシン値の測定を続けている。頻度が高いのはAQP4抗体とMOG抗体による視神経脊髄炎(NMO)が筆頭である。原疾患の治療により過眠症も改善する場合が多い。Ma2抗体による 症例も存在する。NAの治療中に NMDAR脳炎を発症する症例は散見される。両疾患の共通の基盤にはBBBの脆弱性があるのではと想定してい る。NMDAR抗体の検討では、精神科の入院患者では0.5%程度の陽性率であった。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (35 results)

All 2022 2021 2020 2019

All Journal Article (28 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 25 results,  Open Access: 10 results) Presentation (6 results) (of which Invited: 2 results) Book (1 results)

  • [Journal Article] Status Cataplecticus with Rapid Eye Movement Sleep Excess in Late-onset Narcolepsy Type 12022

    • Author(s)
      Ando Takashi、Wakai Masakazu、Kanbayashi Takashi、Katsuno Masahisa
    • Journal Title

      Internal Medicine

      Volume: 61 Issue: 19 Pages: 2951-2955

    • DOI

      10.2169/internalmedicine.8465-21

    • ISSN
      0918-2918, 1349-7235
    • Year and Date
      2022-10-01
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A rare genetic variant in the cleavage site of prepro-orexin is associated with idiopathic hypersomnia2022

    • Author(s)
      Miyagawa Taku、Tanaka Susumu、Shimada Mihoko、Sakai Noriaki、Kanbayashi Takashi、Imanishi Aya、Nishino Seiji、Mishima Kazuo、Tokunaga Katsushi、Honda Makoto
    • Journal Title

      npj Genomic Medicine

      Volume: 7 Issue: 1 Pages: 29-29

    • DOI

      10.1038/s41525-022-00298-w

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Two cases of Kleine?Levin syndrome with good responses to lithium treatment at low serum levels2022

    • Author(s)
      Uchida Tomoko、Matsuzawa Daisuke、Sawada Daisuke、Kanbayashi Takashi、Fujii Katsunori
    • Journal Title

      Pediatrics International

      Volume: 64 Issue: 1

    • DOI

      10.1111/ped.15103

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effect of sevoflurane preconditioning on sleep reintegration after alteration by lipopolysaccharide2022

    • Author(s)
      Nemoto Tsuyoshi、Irukayama‐Tomobe Yoko、Hirose Yuki、Tanaka Hiromu、Takahashi Genki、Takahashi Satoshi、Yanagisawa Masashi、Kanbayashi Takashi
    • Journal Title

      Journal of Sleep Research

      Volume: - Issue: 5 Pages: 1-11

    • DOI

      10.1111/jsr.13556

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Morning preference is associated with subjective happiness among Japanese female workers: A moderation analysis by sleep characteristics from the SLEPT study2022

    • Author(s)
      Hori Daisuke、Arai Yo、Morita Emi、Ikeda Yu、Muroi Kei、Ishitsuka Mami、Ikeda Tomohiko、Takahashi Tsukasa、Doki Shotaro、Oi Yuichi、Sasahara Shinichiro、Ishihara Asuka、Matsumoto Sumire、Kanbayashi Takashi、Yanagisawa Masashi、Satoh Makoto、Matsuzaki Ichiyo
    • Journal Title

      Chronobiology International

      Volume: 39 Issue: 5 Pages: 690-703

    • DOI

      10.1080/07420528.2022.2028801

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Impairment of early neuronal maturation in anti-NMDA-receptor encephalitis.2022

    • Author(s)
      Okamoto S, Takaki M, Hinotsu K, Kawai H, Sakamoto S, Okahisa Y, Takao S, Tsutsui K, Kanbayashi T, Tanaka K, Yamada N.
    • Journal Title

      Psychopharmacology (Berl)

      Volume: 239 Issue: 2 Pages: 525-531

    • DOI

      10.1007/s00213-021-06036-x

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] “Atypical psychoses” and <scp>anti‐NMDA</scp> receptor encephalitis: A review of literature in the mid‐twentieth century2021

    • Author(s)
      Komagamine Tomoko、Kanbayashi Takashi、Suzuki Keisuke、Hirata Koichi、Nishino Seiji
    • Journal Title

      Psychiatry and Clinical Neurosciences

      Volume: 76 Issue: 2 Pages: 62-63

    • DOI

      10.1111/pcn.13317

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Aripiprazole as a new treatment for the prolonged nocturnal sleep of patient with idiopathic hypersomnia2021

    • Author(s)
      Imanishi Aya、Omori Yuki、Ishido Hideaki、Sagawa Yohei、Han GoEun、Mishima Kazuo、Kanbayashi Takashi、Kondo Hideaki
    • Journal Title

      Psychiatry and Clinical Neurosciences

      Volume: 75 Issue: 10 Pages: 320-322

    • DOI

      10.1111/pcn.13290

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] False‐positive cases in multiple sleep latency test by accumulated sleep debt2021

    • Author(s)
      Kizawa Tetsuya、Hosokawa Keisuke、Nishijima Tsuguo、Takahashi Susumu、Shimizu Tetsuo、Ono Taisuke、Han GoEun、Kanbayashi Takashi、Sakurai Shigeru、Kondo Hideaki
    • Journal Title

      Neuropsychopharmacology Reports

      Volume: 41 Issue: 2 Pages: 192-198

    • DOI

      10.1002/npr2.12169

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Kleine-Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci2021

    • Author(s)
      Ambati Aditya、Hillary Ryan、Leu-Semenescu Smaranda、Ollila Hanna M.、Lin Ling、During Emmanuel H.、Farber Neal、Rico Thomas J.、Faraco Juliette、Leary Eileen、Goldstein-Piekarski Andrea N. Honda Makoto、Kanbayashi Takashi、
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 118 Issue: 12 Pages: 1-8

    • DOI

      10.1073/pnas.2005753118

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Induction of narcolepsy-like symptoms by orexin receptor antagonists in mice2021

    • Author(s)
      Kaushik Mahesh K, Aritake Kosuke, Cherasse Yoan, Imanishi Aya, Kanbayashi Takashi, Urade Yoshihiro, Yanagisawa Masashi
    • Journal Title

      Sleep

      Volume: 44 Issue: 8

    • DOI

      10.1093/sleep/zsab043

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Rituximab was effective for treatment of anti-NMDAR encephalitis in early adolescence in initially suspected dissociative disorder2021

    • Author(s)
      Takashi Shibata, Hiroki Kawai, Shinji Sakamoto, Ko Tsutsui, Takashi Kanbayashi, Keiko Tanaka, Manabu Takaki
    • Journal Title

      Clin Neuropharmacol.

      Volume: in press Issue: 3 Pages: 000-000

    • DOI

      10.1097/wnf.0000000000000443

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Cerebellar Ataxia as a Common Clinical Presentation Associated with DNMT1 p.Y511H and a Review of the Literature2021

    • Author(s)
      Kikuchi Junko Kanda、Nagashima Yu、Mano Tatsuo、Ishiura Hiroyuki、Hayashi Toshihiro、Shimizu Jun、Matsukawa Takashi、Ichikawa Yaeko、Takahashi Yuji、Karino Shotaro、Kanbayashi Takashi、Kira Junichi、Goto Jun、Tsuji Shoji
    • Journal Title

      Journal of Molecular Neuroscience

      Volume: 71 Issue: 9 Pages: 1796

    • DOI

      10.1007/s12031-020-01784-5

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] The anticataplectic and REM suppression effect of milnacipran, an SNRI, on human and canine narcolepsy2021

    • Author(s)
      Kaneko Yoshihiko、Inoue Yuichi、Fujiki Nobuhiro、Han GoEun、Nishino Seiji、Shimizu Tetsuo、Kanbayashi Takashi、Kondo Hideaki
    • Journal Title

      Sleep and Biological Rhythms

      Volume: 19 Issue: 2 Pages: 137-143

    • DOI

      10.1007/s41105-020-00298-2

    • NAID

      40022527852

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Somnolence Preceded the Development of a Subthalamic Lesion in Neuromyelitis Optica Spectrum Disorder2020

    • Author(s)
      Daida Kensuke、Ogaki Kotaro、Hayashida Arisa、Ando Maya、Yokoyama Kazumasa、Noda Kazuyuki、Kanbayashi Takashi、Hattori Nobutaka、Okuma Yasuyuki
    • Journal Title

      Internal Medicine

      Volume: 59 Issue: 4 Pages: 577-579

    • DOI

      10.2169/internalmedicine.2947-19

    • NAID

      130007798428

    • ISSN
      0918-2918, 1349-7235
    • Year and Date
      2020-02-15
    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Association between cerebrospinal fluid Orexin A level and severity of rapid eye movement sleep behaviour disorder in dementia with Lewy bodies2020

    • Author(s)
      Inagawa Yuta、Shimizu Soichiro、Takenoshita Naoto、Tsugawa Akito、Hirose Daisuke、Kanbayashi Takashi、Imanishi Aya、Sakurai Hirofumi、Hanyu Haruo、Kanetaka Hidekazu、Hirao Kentaro
    • Journal Title

      Psychogeriatrics

      Volume: 21 Issue: 1 Pages: 128-130

    • DOI

      10.1111/psyg.12618

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Risk of immunotherapy-related narcolepsy in genetically predisposed patients: a case report of narcolepsy after administration of pembrolizumab2020

    • Author(s)
      Natori Yutaka、Sasaki Eisaku、Soeda Shu、Furukawa Shigenori、Azami Yusuke、Tokuda Emi、Kanbayashi Takashi、Saji Shigehira
    • Journal Title

      Journal for ImmunoTherapy of Cancer

      Volume: 8 Issue: 2 Pages: e001164-e001164

    • DOI

      10.1136/jitc-2020-001164

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Early detection of Niemann-pick disease type C with cataplexy and orexin levels: continuous observation with and without Miglustat2020

    • Author(s)
      Imanishi A.、Kawazoe T.、Hamada Y.、Kumagai T.、Tsutsui K.、Sakai N.、Eto K.、Noguchi A.、Shimizu T.、Takahashi T.、Han G.、Mishima K.、Kanbayashi T.、Kondo H.
    • Journal Title

      Orphanet Journal of Rare Diseases

      Volume: 15 Issue: 1 Pages: 67-89

    • DOI

      10.1186/s13023-020-01531-4

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Examination of the influence of cedar fragrance on cognitive function and behavioral and psychological symptoms of dementia in Alzheimer type dementia2020

    • Author(s)
      Takahashi Yuya、Shindo Sho、Kanbayashi Takashi、Takeshima Masahiro、Imanishi Aya、Mishima Kazuo
    • Journal Title

      Neuropsychopharmacology Reports

      Volume: 40 Issue: 1 Pages: 10-15

    • DOI

      10.1002/npr2.12096

    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ramelteon for Delayed Sleep-wake Phase Disorder: A Case Report2020

    • Author(s)
      Takeshima Masahiro、Shimizu Tetsuo、Ishikawa Hiroyasu、Kanbayashi Takashi
    • Journal Title

      Clinical Psychopharmacology and Neuroscience

      Volume: 18 Issue: 1 Pages: 167-169

    • DOI

      10.9758/cpn.2020.18.1.167

    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Positive Association Between Cognitive Function and Cerebrospinal Fluid Orexin A Levels in Alzheimer’s Disease2020

    • Author(s)
      Shimizu Soichiro、Takenoshita Naoto、Inagawa Yuta、Tsugawa Akito、Hirose Daisuke、Kaneko Yoshitsugu、Ogawa Yusuke、Serisawa Shuntaro、Sakurai Shu、Hirao Kentaro、Kanetaka Hidekazu、Kanbayashi Takashi、Imanishi Aya、Sakurai Hirofumi、Hanyu Haruo
    • Journal Title

      Journal of Alzheimer's Disease

      Volume: 73 Issue: 1 Pages: 117-123

    • DOI

      10.3233/jad-190958

    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Anti-NMDA-receptor antibody in initial diagnosis of mood disorder.2019

    • Author(s)
      Kawai H, Takaki M, Sakamoto S, Shibata T, Tsuchida A, Yoshimura B, Yada Y, Matsumoto N, Sato K, Abe K, Okahisa Y, Kishi Y, Takao S, Tsutsui K, Kanbayashi T, Tanaka K, Yamada N.
    • Journal Title

      Eur Neuropsychopharmacol.

      Volume: 29(9) Issue: 9 Pages: 1041-1050

    • DOI

      10.1016/j.euroneuro.2019.07.137

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Sudden onset of sleep caused by hypothalamic infarction: a case report2019

    • Author(s)
      Matsubara Takeo、Suzuki Keisuke、Kawasaki Akiko、Miyamoto Masayuki、Okamura Madoka、Kanbayashi Takashi、Takekawa Hidehiro、Nakamura Toshiki、Watanabe Yuji、Matsubara Masanori、Hirata Koichi
    • Journal Title

      BMC Neurology

      Volume: 19 Issue: 1 Pages: 182-182

    • DOI

      10.1186/s12883-019-1414-3

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Bilateral oculomotor nerve palsy in a case of anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder2019

    • Author(s)
      Yasuda Ken、Maki Takakuni、Takata Masaki、Kimura Kimitoshi、Takahashi Toshiyuki、Kanbayashi Takashi、Murase Nagako、Ohtani Ryo、Takahashi Ryosuke、Nakamura Michikazu
    • Journal Title

      Journal of Clinical Neuroscience

      Volume: 66 Pages: 271-272

    • DOI

      10.1016/j.jocn.2019.05.043

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Clinical significance of assaying anti-MOG antibody in cerebrospinal fluid in MOG-antibody-associated diseases: A case report.2019

    • Author(s)
      Aoe S, Kume K, Takata T, Touge T, Kaneko K, Nakashima I, Deguchi K, Masaki T.
    • Journal Title

      Mult Scler Relat Disord.

      Volume: 28 Pages: 165-166

    • DOI

      10.1016/j.jocn.2019.03.066

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] ナルコレプシーと神経免疫異常2019

    • Author(s)
      近藤 英明, 神林 崇, 本多 真
    • Journal Title

      睡眠医療

      Volume: 13巻4号 Pages: 399-403

    • Related Report
      2019 Research-status Report
  • [Journal Article] アスリートにみられる睡眠障害 睡眠薬が運動能力に与える影響2019

    • Author(s)
      上村 佐知子, 神林 崇
    • Journal Title

      臨床スポーツ医学

      Volume: 36巻7号 Pages: 778-782

    • Related Report
      2019 Research-status Report
  • [Journal Article] 抗NMDA受容体脳炎2019

    • Author(s)
      筒井 幸, 馬越 秋瀬, 神林 崇, 田中 惠子, 清水 徹男, 三島 和夫
    • Journal Title

      臨床精神医学

      Volume: 48巻1号 Pages: 11-16

    • Related Report
      2019 Research-status Report
  • [Presentation] 日常精神科臨床で遭遇する対処困難な過眠の見立てと対応 中枢性過眠症と症候性過眠2020

    • Author(s)
      神林 崇
    • Organizer
      精神神経学会
    • Related Report
      2020 Research-status Report
  • [Presentation] 睡眠障害の神経治療学 中枢性過眠症と発達障害の関連とそれらの治療2020

    • Author(s)
      神林 崇
    • Organizer
      神経治療学会
    • Related Report
      2020 Research-status Report
  • [Presentation] 過眠は神経症状か、精神症状か? 睡眠-覚醒障害における過眠の位置づけ ナルコレプシーにおける過眠2019

    • Author(s)
      神林 崇
    • Organizer
      精神神経学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] 過眠症の診断をめぐって 症候性過眠症の特徴と病態機序2019

    • Author(s)
      神林 崇
    • Organizer
      日本睡眠学会定期学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] ニーマンピック・タイプCなどの先天性疾患とオレキシン神経系~情動脱力発作を知り早期診断を~2019

    • Author(s)
      神林 崇
    • Organizer
      第61回日本先天代謝異常学会総会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] ナルコレプシーとオレキシン研究から自己免疫性脳炎へ2019

    • Author(s)
      神林 崇
    • Organizer
      茨城県・精神科医会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Book] 今日の治療指針 2019年版[デスク判]過眠症(ナルコレプシー含む)1052-542019

    • Author(s)
      神林 崇
    • Total Pages
      2160
    • Publisher
      医学書院
    • ISBN
      9784260036504
    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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