Pathophysiology of glutamate excitotoxicity evaluated with MR spectroscopy

• Project/Area Number: 16K10329
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Radiation science
• Research Institution: Tokyo Women's Medical University
• Principal Investigator: TAKANASHI JUNICHI 東京女子医科大学, 医学部, 教授 (00302555)
• Research Collaborator: Aoki Ichio
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: MRスペクトルスコピー / グルタミン酸 / モデルマウス / 急性脳症 / グルタミン酸毒性 / 放射線科学 / 核磁気共鳴画像（MRI）

Outline of Final Research Achievements

Glutamate (Glu) is a major excitatory neurotransmitter in the central nervous system, and its excess is considered to be the cause of various neurological diseases. We elucidated the pathogenesis of Glu from neurochemical analysis by MR spectroscopy (MRS) using a 7 Tesla magnet.
Glutamate transporter (GLT1) iKO mice have reduced GLT1 activity to 30-40% compared to normal, leading to accumulation of Glu in the synapse. MR spectroscopy showed an increase in glutamine (Gln) and normal Glu. The biomechanism that converts excess Glu into harmless Gln was assumed. MRS in Pnpla7 mutant mice showed low N-acetylaspartate (NAA), Cho and Glu. PNPLA7 contributes to myelination in the central nervous system, and it is considered that the defect may cause neuronal and Glu-Gln cycle abnormality. From the examination of human patients with acute encephalopathy, we found mild encephalopathy with excitotoxicity (MEEX), which shows no abnormality on MRI and transiently high Gln value.

Academic Significance and Societal Importance of the Research Achievements

グルタミン酸（Glu）は中枢神経系における主要な興奮性神経伝達物質であり、その過剰は神経疾患の原因となりうる。７テスラMRI装置を用いたMR spectroscopyによる解析から、シナプス内の過剰なGluをアストロサイトで無害なグルタミンに転換させる生体防御メカニズムが示された。小児急性脳症の一部は、興奮毒性が関与する軽症脳症（mild encephalopathy with excitotoxicity [MEEX]）であり、けいれん重積型（二相性）脳症（AESD）と一連のスペクトラムを呈すると考えられる。これらの知見は興奮毒性の関与する神経疾患の診断・治療効果判定に有用である。

Research Products

• [Journal Article] Loss of myelinated axons and astrocytosis in an autopsy case of acute encephalopathy with biphasic seizures and late reduced diffusion (2018)
  • Author(s): Takanashi J, Yasukawa K, Murofushi Y, Masunaga A, Sakuma H, Hayashi M
  • Journal Title: Brain Dev Volume: 40 Issue: 10 Pages: 947-951
  • DOI: 10.1016/j.braindev.2018.06.004
  • Peer Reviewed
• [Journal Article] Neurochemistry evaluated by MR spectroscopy in a patient with xeroderma pigmentosum group A (2018)
  • Author(s): Yokota K, Sano K, Murofushi Y, Yoshimaru D, Takanashi J
  • Journal Title: Brain Dev Volume: 40 Issue: 10 Pages: 931-933
  • DOI: 10.1016/j.braindev.2018.06.013
  • Peer Reviewed
• [Journal Article] Infantile traumatic brain injury with a biphasic clinical course and late reduced diffusion. (2018)
  • Author(s): Takase N, Igarashi N, Taneichi H, Yasukawa K, Honda T, Hamada H, Takanashi JI.
  • Journal Title: J Neurol Sci. Volume: 390 Pages: 63-66
  • DOI: 10.1016/j.jns.2018.04.010
  • Peer Reviewed
• [Journal Article] Excitotoxicity in encephalopathy associated with STEC O-157 infection. (2018)
  • Author(s): Ishida S, Yasukawa K, Koizumi M, Abe K, Hirai N, Honda T, Sakuma S, Tada H, Takanashi J
  • Journal Title: Brain Dev Volume: 40 Issue: 4 Pages: 357-360
  • DOI: 10.1016/j.braindev.2017.11.008
  • Peer Reviewed
• [Journal Article] An episode of acute encephalopathy with biphasic seizures and late reduced diffusion followed by hemiplegia and intractable epilepsy observed in a patient with a novel frameshift mutation in HNRNPU (2018)
  • Author(s): Shimada Shino、Oguni Hirokazu、Otani Yui、Nishikawa Aiko、Ito Susumu、Eto Kaoru、Nakazawa Tomoyuki、Yamamoto-Shimojima Keiko、Takanashi Jun-ichi、Nagata Satoru、Yamamoto Toshiyuki
  • Journal Title: Brain and Development Volume: 40 Issue: 9 Pages: 813-818
  • DOI: 10.1016/j.braindev.2018.05.010
  • Peer Reviewed
• [Journal Article] A new infectious encephalopathy syndrome, clinically mild encephalopathy associated with excitotoxicity (MEEX) (2017)
  • Author(s): Hirai N, Yoshimaru D, Moriyama Y, Yasukawa K, Takanashi J.
  • Journal Title: J Neurol Sci Volume: 380 Pages: 27-30
  • DOI: 10.1016/j.jns.2017.06.045
  • Peer Reviewed
• [Journal Article] A novel DARS2 mutation in a Japanese patient with leukoencephalopathy with brainstem and spinal cord involvement but no lactate elevation (2017)
  • Author(s): Shimojima K, Higashiguchi T, Kishimoto K, Miyatake S, Miyake N, Takanashi J, Matsumoto N, Yamamoto T
  • Journal Title: Hum Genom Var Volume: 4 Issue: 1 Pages: 17051-17051
  • DOI: 10.1038/hgv.2017.51
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive investigation of CASK mutations and other genetic etiologies in 41 patients with intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH) (2017)
  • Author(s): Hayashi S, Uehara DT, Tanimoto K, Mizuno S, Chinen Y, Furukawa S, Takanashi J, Osaka H, Okamoto N, Inazawa J.
  • Journal Title: PLoS One Volume: 12 Issue: 8 Pages: e0181791-e0181791
  • DOI: 10.1371/journal.pone.0181791
  • NAID: 120006825904
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinically mild infantile encephalopathy associated with excitotoxicity. (2017)
  • Author(s): Hirai N, Yoshimaru D, Moriyama Y, Honda T, Yasukawa K, Takanashi J
  • Journal Title: J Neurol Sci Volume: 373 Pages: 138-141
  • DOI: 10.1016/j.jns.2016.12.043
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Identification of novel SNORD118 mutations in seven patients with leukoencephalopathy with brain calcifications and cysts. (2017)
  • Author(s): Iwama K, Mizuguchi T, Takanashi JI, Shibayama H, Shichiji M, Ito S, Oguni H, Yamamoto T, Sekine A, Nagamine S, Ikeda Y, Nishida H, Kumada S, Yoshida T, Awaya T, Tanaka R, Chikuchi R, Niwa H, Oka YI, Miyatake S, Nakashima M, Takata A, Miyake N, Ito S, Saitsu H, Matsumoto N.
  • Journal Title: Clinical Genetics Volume: - Issue: 2 Pages: 180-187
  • DOI: 10.1111/cge.12991
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Elevated taurine and glutamate in cerebral juvenile xanthogranuloma on MR spectroscopy. (2016)
  • Author(s): Matsubara K, Mori H, Hirai N, Yasukawa K, Honda T, Takanashi J.
  • Journal Title: Brain Dev Volume: 38 Issue: 10 Pages: 964-967
  • DOI: 10.1016/j.braindev.2016.07.001
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Association between invisible basal ganglia and ZNF335 mutations: a case report (2016)
  • Author(s): Sato R, Takanashi J, Tsuyusaki Y, Kato M, Saitsu H, Matsumoto N, Takahashi T
  • Journal Title: Pediatrics Volume: 138 Issue: 3
  • DOI: 10.1542/peds.2016-0897
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Activated microglia in acute encephalopathy with biphasic seizures and late reduced diffusion. J Neurol Sci 366: 91-3, 2016. (2016)
  • Author(s): Fujita Y, Takanashi J, Takei H, Ota S, Fujii K, Sakuma H, Hayashi M
  • Journal Title: J Neurol Sci Volume: 366 Pages: 91-93
  • DOI: 10.1016/j.jns.2016.04.050
  • Peer Reviewed
• [Presentation] MR spectroscopy で診る小児脳病態 (2019)
  • Author(s): 髙梨潤一
  • Organizer: 第42回日本脳神経CI学会
  • Invited
• [Presentation] 自己免疫性脳炎脳症の臨床：NMDA受容体脳炎を中心に (2019)
  • Author(s): 髙梨潤一
  • Organizer: 第38回日本画像医学会
  • Invited
• [Presentation] MR spectroscopy で診る脳病態 (2018)
  • Author(s): 髙梨潤一
  • Organizer: 第60回日本小児神経学会
  • Invited
• [Presentation] 興奮毒性型急性脳症スペクトラムの拡がり (2018)
  • Author(s): 髙梨潤一
  • Organizer: 第60回日本小児神経学会
  • Invited
• [Presentation] 神経放射線と分子遺伝学のコラボレーション (2018)
  • Author(s): 髙梨潤一
  • Organizer: 第60回日本小児神経学会
  • Invited
• [Presentation] 小児の神経学的予後評価における画像診断の有用性 (2018)
  • Author(s): 髙梨潤一
  • Organizer: 日本小児科学会小児救急蘇生シンポジウム
  • Invited
• [Presentation] 興奮毒性型急性脳症 up to date (2017)
  • Author(s): 髙梨潤一
  • Organizer: 第72回 神経放射線カンファレンス
  • Invited
• [Presentation] Neuroimaging: How to interpret brain MRI. (2017)
  • Author(s): Jun-ichi Takanashi
  • Organizer: 14th Asian Oceanian Congress of Child Neurology
  • Int'l Joint Research / Invited
• [Presentation] MRスペクトルスコピーで診る急性期脳病態 (2016)
  • Author(s): 髙梨潤一
  • Organizer: 第35回日本蘇生学会
  • Place of Presentation: 久留米シティプラザ（福岡県久留米市）
  • Year and Date: 2016-11-01
  • Invited
• [Presentation] Neuroimaging in encephalopathy in Japan (2016)
  • Author(s): Takanashi Jun-ichi
  • Organizer: International Symposium on Acute Encephalopathy in Infancy and Its Related Disorders (ISAE 2016)
  • Place of Presentation: 一ツ橋ホール（東京都千代田区）
  • Year and Date: 2016-07-01
  • Int'l Joint Research / Invited
• [Presentation] MRスペクトルスコピーで診る脳代謝 (2016)
  • Author(s): 髙梨潤一
  • Organizer: 第58回日本小児神経学会学術集会
  • Place of Presentation: 新宿京王プラザホテル（東京都新宿区）
  • Year and Date: 2016-06-02
  • Invited
• [Book] Acute Encephalopathy and Encephalitis in Infancy and Its Related Disorders. (2018)
  • Author(s): Takanashi J
  • Total Pages: 244
  • Publisher: Elsevier
  • ISBN: 9780323530880