Approach to cerebral small vessel disease: lesson from CARASIL.

• Project/Area Number: 25293200
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Niigata University
• Principal Investigator: Onodera Osamu 新潟大学, 脳研究所, 教授 (20303167)
• Co-Investigator(Kenkyū-buntansha): SATO Toshiya 北里大学, 医学部, 教授 (90359703) ; TOYOSHIMA Yasuko 新潟大学, 脳研究所, 准教授 (20334675) ; KOYAMA Akihide 新潟大学, 研究推進機構, 助教 (90622209)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2015: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2014: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2013: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000)
• Keywords: 脳血管 / 神経病態 / 脳循環 / 神経病帯 / 脳小血管

Outline of Final Research Achievements

Cerebral small-vessel disease (CSVD) is a neurological disorder involving white matter lesions. CSVD is frequently observed in an elderly population and causes cognitive impairment and motor dysfunction. However little is known about a molecular pathogenesis for CSVD. Cerebral autosomal-recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), an autosomal-recessive inherited cerebral small vessel disease (CSVD), involves severe leukoaraiosis, multiple lacunar infarcts, early-onset alopecia, and spondylosis deformans without hypertension. High-temperature requirement serine peptidase A1 (HTRA1) gene mutations cause CARASIL by decreasing HTRA1 protease activity. We have investigated the HTRA1 deficit mouse. We found that these mice showed mural cell and internal elastic membrane degeneration. We found fibronectin and protein X accumulates at the internal membrane. The pathological findings of the mouse resemble those of CARASIL as well as sporadic CSVD.

Research Products

• [Journal Article] Distinct molecular mechanisms of HTRA1 mutants in manifesting heterozygotes with CARASIL (2016)
  • Author(s): Nozaki H, Kato T, Nihonmatsu M, Saito Y, Mizuta I, Noda T, Koike R, Miyazaki K, Kaito M, Ito S, Makino M, Koyama A, Shiga A, Uemura M, Sekine Y, Murakami A, Moritani S, Hara K, Yokoseki A, Kuwano R, Endo N, Momotsu T, Yoshida M, Nishizawa M, Mizuno T, Onodera O.
  • Journal Title: Neurology Volume: 未定
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Characteristic features and progression of abnormalities on MRI for CARASIL. (2015)
  • Author(s): Nozaki H, Sekine Y, Fukutake T, Nishimoto Y, Shimoe Y, Shirata A, Yanagawa S, Hirayama M, Tamura M, Nishizawa M, Onodera O.
  • Journal Title: Neurology. Volume: 85 Issue: 5 Pages: 459-463
  • DOI: 10.1212/wnl.0000000000001803
  • Peer Reviewed
• [Journal Article] Characteristic features and progression of abnormalities on MRI for CARASIL (2015)
  • Author(s): Hiroaki Nozaki, Yumi Sekine, Toshio Fukutake, Yoshinori Nishimoto, Yutaka Shimoe, Akiko Shirata, Sohei Yanagawa, Mikio Hirayama, Masato Tamura, Masatoyo Nishizawa, and Osamu Onodera
  • Journal Title: Neurology Volume: 未定
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Emerging molecular mechanism for cerebral small vessel disease: Lessons from hereditary small vessel disease (2015)
  • Author(s): Onodera, O., Sekine, Y., Kato, T., Koyama, A., Nozaki, H. and Nishizawa, M
  • Journal Title: Neurology and Clinical Neuroscience Volume: 1 Issue: 1 Pages: 7-13
  • DOI: 10.1111/ncn3.134
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Features of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy. (2014)
  • Author(s): Nozaki H, Nishizawa M, Onodera O.
  • Journal Title: Stroke. Volume: 45 Issue: 11 Pages: 3447-3453
  • DOI: 10.1161/strokeaha.114.004236
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Haploinsufficiency of CSF-1R and clinicopathological characterization in patients with HDLS. (2014)
  • Author(s): Konno T, Tada M, Tada M, Koyama A, Nozaki H, Harigaya Y, Nishimiya J, Matsunaga A, Yoshikura N, Ishihara K, Arakawa M, Isami A, Okazaki K, Yokoo H, Ihoh K, Yoneda M, Kawamura M, Inuzuka T, Takahashi H, Nishizawa M, Onodera O, Kakita A, Ikeuchi T
  • Journal Title: Neurology Volume: 82 Issue: 2 Pages: 139-148
  • DOI: 10.1212/wnl.0000000000000046
  • Peer Reviewed
• [Journal Article] [Hereditary cerebral small-vessel disease]. (2013)
  • Author(s): Nozaki H, Nishizawa M, Onodera O.
  • Journal Title: Nihon Rinsho. Volume: 71 Pages: 545-554
  • NAID: 40017342931
• [Presentation] Dominant Negative HTRA1 Mutations in Cerebral Small Vessel Disease. (2015)
  • Author(s): Nozaki H, Kato T, Nihonmatsu M, Saito Y, Mizuta I, Noda T, Koike R, Miyazaki K, Kaito M, Ito S, Makino M, Koyama A, Shiga A, Uemura M, Sekine Y, Murakami A, Moritani S, Hara K, Yokoseki A, Kuwano R, Endo N, Momotsu T, Yoshida M, Nishizawa M, Mizuno T, Onodera O.
  • Organizer: 9th International Congress on Vascular Dementia; ICVD 2015
  • Place of Presentation: Ljubljana, Slovenija
  • Year and Date: 2015-10-16
  • Int'l Joint Research
• [Presentation] Characteristic brain MRI features in HTRA1 mutation heterozygotes. (2015)
  • Author(s): Masahiro Uemura, Hiroaki Nozaki, Yumi Sekine, Ikuko Mizuta, Tomoko Noda, Kazuhide Miyazaki, Muichi Kaito, Yoshinori Nishimoto, Yutaka Shimoe, Akiko Shirata, Kiyomi Yamane, Sohei Yanagawa, Mikio Hirayama, Masato Tamura, Toshiki Mizuno, Masatoyo Nishizawa, and Osamu Onodera.
  • Organizer: 9th International Congress on Vascular Dementia; ICVD 2015
  • Place of Presentation: Ljubljana, Slovenija
  • Year and Date: 2015-10-16
  • Int'l Joint Research
• [Presentation] GFβ1過剰発現マウスでは脳小血管壁細胞の異常をきたす (2014)
  • Author(s): 関根有美、加藤泰介、野崎洋明、廣川祥子、佐藤俊哉、志賀篤、笹岡敏邦、西澤正豊、小野寺理
  • Organizer: 第55回日本神経学会学術大会
  • Place of Presentation: 福岡市 福岡国際会議場
  • Year and Date: 2014-05-21 – 2014-05-24
• [Presentation] MRI Features of Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy. (2013)
  • Author(s): Hiroaki Nozaki, Yumi Sekine, Toshio Fukutake, Yoshinori Nishimoto, Mamoru Shibata, Akiko Shirata, Kiyomi Yamane, Yutaka Shimoe, Sohei Yanagawa, Mikio Hirayama, Imaharu Nakano, Norihiro Suzuki, Masatoyo Nishizawa, Osamu Onodera.
  • Organizer: The 8th International Congress on Vascular Dementia
  • Place of Presentation: アテネ ギリシャ
• [Presentation] An emerging molecular mechanism for the cerebral small vessel disease (2013)
  • Author(s): Osamu Onodera
  • Organizer: 54th Annual Meeting of the Japanese Society of Neurology
  • Place of Presentation: Tokyo
  • Invited