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Digital 3D Neuropathology: Methodological Platform Creation

Research Project

Project/Area Number 20K20468
Project/Area Number (Other) 19H05559 (2019)
Research Category

Grant-in-Aid for Challenging Research (Pioneering)

Allocation TypeMulti-year Fund (2020)
Single-year Grants (2019)
Review Section Medium-sized Section 51:Brain sciences and related fields
Research InstitutionNiigata University

Principal Investigator

Kakita Akiyoshi  新潟大学, 脳研究所, 教授 (80281012)

Co-Investigator(Kenkyū-buntansha) 北浦 弘樹  新潟大学, 脳研究所, 特任准教授 (80401769)
田井中 一貴  新潟大学, 脳研究所, 教授 (80506113)
齋藤 理恵  新潟大学, 脳研究所, 助教 (80829078)
Project Period (FY) 2019-06-28 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥25,870,000 (Direct Cost: ¥19,900,000、Indirect Cost: ¥5,970,000)
Fiscal Year 2021: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
Fiscal Year 2020: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000)
Fiscal Year 2019: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000)
Keywordsヒト脳組織 / 透明化 / 3次元イメージング / 脳病変 / 神経病理学 / デジタル画像 / 組織病理 / デジタル
Outline of Research at the Start

神経病理学的診断を行っていると、通常の組織標本、つまり2次元平面に薄切した標本の観察では、脳病変を正しく評価できないのではないか、と思うことがある。脳は、つくりが複雑で機能単位がことさら立体的だからである。本研究では、ヒト脳組織透明化・3Dイメージング技術を用いて、ヒト脳における神経細胞やグリア細胞の配列やネットワーク、更には微小血管の分布を3次元で鮮明に捉え、‘立体的機能ユニット’ における正常と異常を明らかにする。つまり定量的なデジタル3D神経病理学を創成し、ブレインサイエンスにおける形態学的イノベーションを開拓する。

Outline of Final Research Achievements

The brain is a complex structure, and its functional units are especially three-dimensional. In this study, we developed a technological platform to capture the arrangement and network of neurons and glial cells, as well as the distribution of microvessels, in three dimensions by using transparency of human brain tissue and 3D imaging technology. First, we overcame the biggest optical challenges in human brain tissue, autofluorescence and browning, and succeeded in developing transparency reagents specifically for human brain tissue. Next, we established various general fluorescent staining and whole-mount immunostaining techniques for 3D. As a result, we have established an imaging platform for whole-mount visualization of many types of structures, including neurons, glial cells, microvessels, myelin sheaths, and senile plaques.

Academic Significance and Societal Importance of the Research Achievements

神経病理学的診断を行なっていると、通常の組織標本、つまり2次元平面に薄切した標本の観察では脳病変を正しく評価できないのではないか、と思うことがある。脳はつくりが複雑で機能単位がことさら立体的だからである。本研究ではヒト脳組織を丸ごと立体的に観察する手法の開発に挑戦したものである。本研究の成果から、病理診断の現場や研究において使用可能な方法論の確立に向け、基盤的技術開発を行うことができた。これまで専門家にも見えてこなかった立体病変が、誰の目にも明らかなものとして可視化できるイメージング基盤が整った。

Report

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

    (35 results)

All 2021 2020 2019 Other

All Int'l Joint Research (1 results) Journal Article (16 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 16 results,  Open Access: 8 results) Presentation (18 results) (of which Int'l Joint Research: 4 results,  Invited: 10 results)

  • [Int'l Joint Research] ワシントン大学(米国)

    • Related Report
      2019 Annual Research Report
  • [Journal Article] GLI3?Is Associated With Neuronal Differentiation in SHH-Activated and WNT-Activated Medulloblastoma2021

    • Author(s)
      Natsumeda Manabu、Miyahara Hiroaki、Yoshimura Junichi、Nakata Satoshi、Tsukamoto Yoshihiro、Okada Masayasu、Oishi Makoto、Hirato Junko、Wataya Takafumi、Tateishi Kensuk、Rodriguez Fausto J、Hovestadt Volker、Suva Mario L、Taylor Michael D、Eberhart Charles G、Fujii Yukihiko、et al.
    • Journal Title

      Journal of Neuropathology & Experimental Neurology

      Volume: 80 Issue: 2 Pages: 129-136

    • DOI

      10.1093/jnen/nlaa141

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cytosolic dsDNA of mitochondrial origin induces cytotoxicity and neurodegeneration in cellular and zebrafish models of Parkinson’s disease.2021

    • Author(s)
      Matsui, H.*, Ito, J., Matsui, N., Uechi, T., Onodera, O., Kakita, A.
    • Journal Title

      Nat. Commun.

      Volume: - Issue: 1 Pages: 3101-3101

    • DOI

      10.1038/s41467-021-23452-x

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A novel splicing variant of ANXA11 in a patient with amyotrophic lateral sclerosis: histologic and biochemical features.2021

    • Author(s)
      Sainouchi M, Hatano Y, Tada M, Ishihara T, Ando S, Kato T, Tokunaga J, Ito G, Miyahara H, Toyoshima Y, Yokoseki A, Ozawa T, Akazawa K, Onodera O, Kakita A.
    • Journal Title

      Acta Neuropathol Commun

      Volume: 9 Issue: 1 Pages: 106-106

    • DOI

      10.1186/s40478-021-01202-w

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Predicting BRAF V600E mutation in glioblastoma: utility of radiographic features2021

    • Author(s)
      Natsumeda M, Chang M, Gabdulkhaev R, Takahashi H, Tsukamoto Y, Kanemaru Y, Okada M, Oishi M, Okamoto K, Rodriguez FJ, Kakita A, Fujii Y, Schreck KC.
    • Journal Title

      Brain Tumor Pathol

      Volume: 38 Issue: 3 Pages: 228-233

    • DOI

      10.1007/s10014-021-00407-0

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Genetic variations and neuropathologic features of patients with PARK2.2021

    • Author(s)
      Seike N, Yokoseki A, Takeuchi R, Saito K, Miyahara H, Miyashita A, Ikeda T, Aida I, Nakajima T, Kanazawa M, Wakabayashi M, Toyoshima Y, Takahashi H, Matumoro R, Toda T, Onodera O, Ishikawa A, Ikeuchi T, Kakita A.
    • Journal Title

      Mov Disord

      Volume: 36 Issue: 7 Pages: 1634-1643

    • DOI

      10.1002/mds.28521

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Primary non-dural central nervous system marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue type mimicking CNS inflammatory diseases.2021

    • Author(s)
      Sugita Y, Takahashi K, Fukuda K, Kimura Y, Furuta T, Arakawa F, Ohshima K, Nakamura H, Miyata H, Watanabe M, Kakita A.
    • Journal Title

      J Neuropathol Exp Neurol

      Volume: 80 Issue: 8 Pages: 789-799

    • DOI

      10.1093/jnen/nlab058

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Hemiplegic-type ALS: clinicopathological features of two autopsied patients.2021

    • Author(s)
      Makoto Sainouchi, Hidetomo Tanaka, Hiroshi Shimizu, Takuya Mashima, Takao Fukushima, Yuya Hatano, Tomohiko Ishihara, Kunihiko Makino, Osamu Onodera, Akiyoshi Kakita
    • Journal Title

      Journal of Neurologoy, Neurosurgery and Psychiatry

      Volume: 92 Issue: 9 Pages: 1014-1016

    • DOI

      10.1136/jnnp-2021-326257

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Autoimmune glial fibrillary acidic protein astrocytopathy resembling isolated central nervous system lymphomatoid granulomatosis.2021

    • Author(s)
      Akio Kimura, Shinei Kato, Akira Takekoshi, Nobuaki Yoshikura, Narufumi Yanagida, Hiroshi Kitaguchi, Daisuke Akiyama, Hiroshi Shimizu, Akiyoshi Kakita, Takayoshi Shimohata
    • Journal Title

      J Neuroimmunology

      Volume: 361 Pages: 577748-577748

    • DOI

      10.1016/j.jneuroim.2021.577748

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Parkinson's disease and parkinsonism: Clinicopathological discrepancies on diagnosis in three patients2021

    • Author(s)
      Toyoshima Yasuko、Takahashi Hitoshi、Katada Shinnichi、Kojima Naoyuki、Tada Mari、Tani Takashi、Koike Ryoko、Nozawa Takanori、Aida Izumi、Nakajima Takashi、Onodera Osamu、Kakita Akiyoshi
    • Journal Title

      Neuropathology

      Volume: 41 Issue: 6 Pages: 450-456

    • DOI

      10.1111/neup.12777

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Progressive supranuclear palsy: Neuropathology of patients with a short disease duration due to unexpected death2020

    • Author(s)
      Lu Zhang, Yasuko Toyoshima, Akari Takeshima, Hiroshi Shimizu, Itsuro Tomita, Osamu Onodera, Hitoshi Takahashi, Akiyoshi Kakita
    • Journal Title

      Neuropathology. 2020 Nov 17.

      Volume: - Issue: 3 Pages: 174-182

    • DOI

      10.1111/neup.12707

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Proteomic profile differentiating between mesial temporal lobe epilepsy with and without hippocampal sclerosis2020

    • Author(s)
      Furukawa Ayako、Kakita Akiyoshi、Chiba Yoichi、Kitaura Hiroki、Fujii Yukihiko、Fukuda Masafumi、Kameyama Shigeki、Shimada Atsuyoshi
    • Journal Title

      Epilepsy Research

      Volume: 168 Pages: 106502-106502

    • DOI

      10.1016/j.eplepsyres.2020.106502

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Novel CHP1 mutation in autosomal-recessive cerebellar ataxia: autopsy features of two siblings2020

    • Author(s)
      Saito Rie、Hara Norikazu、Tada Mari、Honma Yoshiaki、Miyashita Akinori、Onodera Osamu、Ikeuchi Takeshi、Kakita Akiyoshi
    • Journal Title

      Acta Neuropathologica Communications

      Volume: 8 Issue: 1 Pages: 134-134

    • DOI

      10.1186/s40478-020-01008-2

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Oculopharyngodistal myopathy with coexisting histology of systemic neuronal intranuclear inclusion disease: Clinicopathologic features of an autopsied patient harboring CGG repeat expansions in LRP122020

    • Author(s)
      Rie Saito, Hiroshi Shimizu, Takeshi Miura, Norikazu Hara, Naomi Mezaki, Yo Higuchi, Akinori Miyashita, Izumi Kawachi, Kazuhiro Sanpei, Yoshiaki Honma, Osamu Onodera, Takeshi Ikeuchi, Akiyoshi Kakita
    • Journal Title

      Acta Neuropathologica Communications

      Volume: 8 Issue: 1 Pages: 75-75

    • DOI

      10.1186/s40478-020-00945-2

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Versatile whole-organ/body staining and imaging based on electrolyte-gel properties of biological tissues2020

    • Author(s)
      Susaki Etsuo A.、Shimizu Chika、Kuno Akihiro、Tainaka Kazuki、Li Xiang、Shibayama Mitsuhiro、Ueda Hiroki R. et al.
    • Journal Title

      Nature Communications

      Volume: 11 Issue: 1 Pages: 1982-1982

    • DOI

      10.1038/s41467-020-15906-5

    • NAID

      120006956725

    • Related Report
      2020 Research-status Report 2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and -independent cellular responses in Alzheimer’s disease.2020

    • Author(s)
      Zhou Y, Song WM, Andhey PS, Swain A, Levy T, Miller KR, Poliani PL, Cominelli M, Grover S, Gilfillan S, Cella M, Ulland TK, Zaitsev K, Miyashita A, Ikeuchi T, Sainouchi M, Kakita A, Bennett DA, Schneider JA, Nichols MR, Beausoleil SA, Ulrich J, Holtzman DM, Artyomov M, Colonna M.
    • Journal Title

      Nat Med

      Volume: 26 Issue: 1 Pages: 131-142

    • DOI

      10.1038/s41591-019-0695-9

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Rapid chemical clearing of white matter in the post-mortem human brain by 1,2-hexanediol delipidation.2019

    • Author(s)
      Inoue M, Saito R, Kakita A, Tainaka K.
    • Journal Title

      Bioorg. Med. Chem. Lett.

      Volume: 29 Issue: 15 Pages: 1886-1890

    • DOI

      10.1016/j.bmcl.2019.05.049

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Presentation] 2D and 3D histopathologic features of degenerative white matter of cerebral small vessel diseases.2021

    • Author(s)
      Saito R, Nozaki H, Tainaka K, Uemura M, Suzuki M, Tanaka M, Hasegawa A, Abe T, Sato A, Hashidate H, Igarashi S, Koike R, Onodera O, Kakita A.
    • Organizer
      第62回日本神経学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] SYNE1 ataxia: Clinicopathologic features of an autopsied patient with a compound heterozygous SYNE1 mutation.2021

    • Author(s)
      Saito R, Tada M, Hara N, Wakabayashi M, Miyashita A, Onodera O, Ikeuchi T, Kakita A.
    • Organizer
      第62回日本神経病理学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Morphological and functional features associated with epileptogenesis in the hippocampus of MTLE.2021

    • Author(s)
      Kitaura H, Itoh Y, Fukuda M, Tainaka K, Fujii Y, Kakita A.
    • Organizer
      第62回日本神経病理学会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] シンポジウム:海馬をめぐるバイオロジーとパソロジー. 海馬硬化症のてんかん原性:外科病理標本を用いた機能異常と形態異常の接点.2021

    • Author(s)
      北浦弘樹、柿田明美.
    • Organizer
      第54回日本てんかん学会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Small vessel diseases: 3D characteristics of the vasculature and white matter.2021

    • Author(s)
      Saito R, Tainaka K, Onodera O, Kakita A.
    • Organizer
      AOCN-NPSICON 2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 3D pathology of cerebral amyloid antipathy based on tissue clearing technique.2020

    • Author(s)
      Inoue M, Saito R, Kakita A, Tainaka K.
    • Organizer
      第61回日本神経病理学会
    • Related Report
      2020 Research-status Report
  • [Presentation] 結節性硬化症のてんかん焦点組織特性.2020

    • Author(s)
      北浦弘樹、福多真史、藤井幸彦、柿田明美.
    • Organizer
      第61回日本神経病理学会
    • Related Report
      2020 Research-status Report
  • [Presentation] てんかん外科病理学の実際:症例から学ぶ病態.2020

    • Author(s)
      柿田明美.
    • Organizer
      第11回 アルツハイマー病とてんかんを考える会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] Pathologic features of juvenile parkinsonism.2020

    • Author(s)
      Kakita A.
    • Organizer
      MDS-AON
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Pathologic features of cerebellar ataxia disorders.2020

    • Author(s)
      Kakita A.
    • Organizer
      MDS-AON
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] てんかんの外科病理.2020

    • Author(s)
      柿田明美.
    • Organizer
      第44回 日本てんかん外科学会.
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] Small vessel characteristics of autopsied patients with CADASIL and heterozygous HTRA1 mutations: 3D analysis using tissue clearing technique CUBIC.2019

    • Author(s)
      Saito R, Tainaka K, Kakita A.
    • Organizer
      American Association of Neurology
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 3D analysis of small vessels of patients with CADASIL and those heterozygous for HTRA1 mutations.2019

    • Author(s)
      Saito R, Tainaka K, Kakita A.
    • Organizer
      日本神経学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 3D神経病理学に向けたホールマウント染色手法の開発.2019

    • Author(s)
      田井中一樹、齋藤理恵、井上雅文、柿田明美.
    • Organizer
      日本神経病理学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] CADASILとCARASILヘテロ接合体患者の剖検脳における小血管の特徴:CUBIC組織透明化手法を用いた3D解析.2019

    • Author(s)
      齋藤理恵、田井中一貴、柿田明美.
    • Organizer
      日本神経病理学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 神経変性疾患:病理学的解析のポイント.2019

    • Author(s)
      柿田明美.
    • Organizer
      日本病理学会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 中枢神経病理:コアイメージ・キーワード.2019

    • Author(s)
      柿田明美.
    • Organizer
      日本神経学会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 小児神経疾患の画像と病理:イメージングプラクティス.2019

    • Author(s)
      柿田明美、岡本浩一郎
    • Organizer
      小児神経画像研究会
    • Related Report
      2019 Annual Research Report
    • Invited

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Published: 2019-07-04   Modified: 2024-03-26  

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