Establishment of diagnosis and prognostic factors in cerebrospinal fluid based on the condition of inflammatory central nervous disease

• Project/Area Number: 16K19504
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: Tohoku University
• Principal Investigator: Nishiyama Shuhei 東北大学, 大学病院, 助教 (60636017)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 視神経脊髄炎 / バイオマーカー / アストロサイト / 脳脊髄液 / アクアポリン4 / 仮足 / CRMP5 / ARPC4 / 抗アクアポリン4抗体 / 炎症性脱髄性疾患 / 脳神経疾患 / 免疫学

Outline of Final Research Achievements

Inflammatory central nervous system (CNS) diseases such as multiple sclerosis and neuromyelitis optica spectrum disorder (NMOSD) have occasionally difficulty in diagnosis and prognosis. In NMOSD, Aquaporin-4 (AQP4) autoimmune-mediated astrocyte functional change by pseudopodal movement disorder has been clarified recently. We measured pseudopodium-related and cell destruction related proteins in cerebrospinal fluid (CSF) based on the pathological condition of inflammatory CNS disease, and examined whether it could be diagnostic and prognostic biomarkers. CSF samples of various inflammatory CNS diseases were analyzed, and CRMP5 and ARPC4 in CSF were significantly elevated in NMOSD with AQP4-IgG, reflecting astrocyte foot process damages. Especially in the group with CSF-CRMP5 elevation, the prognosis is relatively good. It is considered to be one of the good prognostic factors in NMOSD. A therapeutic strategy targeting the astrocytic foot process can be expected in the future.

Academic Significance and Societal Importance of the Research Achievements

多発性硬化症や視神経脊髄炎といった炎症性中枢神経疾患の多くは原因不明で、時に診断や治療に苦慮する。このうちアクアポリン4抗体陽性視神経脊髄炎の脳脊髄液では、アストロサイト足突起に存在する蛋白が上昇しており、このうち脳脊髄液中CRMP5が上昇している患者さんではより予後が良い結果が出た。今後アストロサイト足突起をターゲットとした治療戦略の開発が期待できる。

Research Products

• [Presentation] CSF biomarkers for NMOSD (2018)
  • Author(s): Shuhei Nishiyama
  • Organizer: PACTRIMS 2018
  • Int'l Joint Research / Invited
• [Presentation] Early pathological features in Fingolimod-associated PML with mild IRIS. (2018)
  • Author(s): Nishiyama S, Misu T, Shishido-Hara Y, Nakamichi K, Saijo M, Takai Y, Kuroda H, Nakashima I, Fujihara K, Aoki M
  • Organizer: 日本神経学会学術集会
• [Presentation] Cerebrospilnal fluid-Actin related protein 2/3 complex subunit 4 as an astrocytic foot process damage marker of aquaporin-4-IgG positive neuromyelitis optica spectrum disorders. (2017)
  • Author(s): Shuhei Nishiyama, Tatsuro Misu, Ichiro Nakashima, Douglas Kazutoshi Sato, Kimihiko Kaneko, Ryo Ogawa, Hirohiko Ono, Kazuhiro Kurosawa, Yoshiki Takai, Toshiyuki Takahashi, Hiroshi Kuroda, Kazuo Fujihara, Masashi Aoki
  • Organizer: World Congress of Neurology
  • Int'l Joint Research
• [Presentation] Cerebrospilnal fluid-Actin related protein 2/3 complex subunit 4 as an astrocytic foot process damage marker of aquaporin-4-IgG positive neuromyelitis optica spectrum disorders. (2017)
  • Author(s): Shuhei Nishiyama, Tatsuro Misu, Ichiro Nakashima, Douglas Kazutoshi Sato, Kimihiko Kaneko, Ryo Ogawa, Hirohiko Ono, Kazuhiro Kurosawa, Yoshiki Takai, Toshiyuki Takahashi, Hiroshi Kuroda, Kazuo Fujihara, Masashi Aoki
  • Organizer: MSParis 2017 (ECTRIMS/ACTRIMS joint meeting)
  • Int'l Joint Research
• [Presentation] Cerebrospilnal fluid-Actin related protein 2/3 complex subunit 4 as an astrocytic foot process damage marker of aquaporin-4-IgG positive neuromyelitis optica spectrum disorders. (2017)
  • Author(s): Shuhei Nishiyama, Tatsuro Misu, Ichiro Nakashima, Douglas Kazutoshi Sato, Kimihiko Kaneko, Ryo Ogawa, Hirohiko Ono, Kazuhiro Kurosawa, Yoshiki Takai, Toshiyuki Takahashi, Hiroshi Kuroda, Kazuo Fujihara, Masashi Aoki
  • Organizer: PACTRIMS 2017
  • Int'l Joint Research
• [Presentation] Elevated cerebrospinal fluid －CRMP5 as a biomarker of damage to astrocyte foot process and growth corn in AQP4-IgG-seropositve NMOSD (2016)
  • Author(s): Shuhei Nishiyama, Tatsuro Misu, Ichiro Nakashima, Toshiyuki Takahashi, Kazuo Fujihara, Masashi Aoki
  • Organizer: PACTRIMS (The Pan-Asian Committee for Treatment and Research in Multiple Sclerosis) 2016
  • Place of Presentation: Bangkok, Thailand
  • Year and Date: 2016-10-26
  • Int'l Joint Research
• [Presentation] Elevated cerebrospinal fluid －CRMP5 as a biomarker of damage to astrocyte foot process and growth corn in AQP4-IgG-seropositve NMOSD (2016)
  • Author(s): Shuhei Nishiyama, Tatsuro Misu, Ichiro Nakashima, Toshiyuki Takahashi, Kazuo Fujihara, Masashi Aoki
  • Organizer: ECTRIMS (The European Committee for Treatment and Research in Multiple Sclerosis) 2016
  • Place of Presentation: London, UK
  • Year and Date: 2016-09-14
  • Int'l Joint Research