Study of Hirosaki Family with dominantly inherited Alzheimer's disease

• Project/Area Number: 18K07385
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Gunma University (2019-2020); Hirosaki University (2018)
• Principal Investigator: Shoji Mikio 群馬大学, 医学部, 非常勤講師 (60171021)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥260,000 (Direct Cost: ¥200,000、Indirect Cost: ¥60,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 常染色体優性遺伝性アルツハイマー病 / バイオマーカー / 脳脊髄液 / 血液 / Abeta / リン酸化タウ / 常染色体優性遺伝アルツハイマー病

Outline of Final Research Achievements

Natural course of Alzheimer's disease (AD) of inherited AD Hirosaki families and sporadic Hirosaki cohort was clarified. Clinical Usefulness of CSF and plasma biomarkers were invented and verified. These CSF and plasma biomarkers were Abeta38, Abeta40, Abeta42, Abeta43, total tau, p181tau, p217tau, alpha-synuclein and neurofilament light chain. All these biomarkers were useful for prediction and diagnosis of preclinical AD stages. Association among APOE genotypes, age and Abeta42, amyloid/tau accumulation and cognitive life stale, cognitive disturbance and microbleeds, AD pathology and mRNA were clarified. These results could contribute and facilitate to development of global cohort study and intervention study by novel disease-modifying drugs.

Academic Significance and Societal Importance of the Research Achievements

本研究により，遺伝性および孤発例アルツハイマー病の自然経過が明らかにされ，臨床応用に有用なバイオマーカーの基礎的検討と臨床的有用性が示された．今後のAlzheimer病の研究と根本的治療薬開発に大きな貢献をもたらすものと考えられる．

Research Products

• [Int'l Joint Research] Washington University/Mayo Clinic/Harvard Medical School(米国)
• [Int'l Joint Research] DZNE center/Tubigen University/Ludwig-Maximillians-University(ドイツ)
• [Int'l Joint Research] FLEN Institute(アルゼンチン)
• [Int'l Joint Research] Melborne University/Edith Cowan University/Macquarie University(オーストラリア)
• [Int'l Joint Research] Queens Square Institute/London University(英国)
• [Int'l Joint Research] Washington University/Mayo Clinic/Harvard Medivcal School(米国)
• [Int'l Joint Research] DZNE Center/Tubibgen University/Ludwig-Maximilians-University(ドイツ)
• [Int'l Joint Research] FLEN Instutute(アルゼンチン)
• [Int'l Joint Research] Melborne University/Edith Cowan University/Macquarie Universiyty(オーストラリア)
• [Int'l Joint Research] Quees Square Instutute/London University(英国)
• [Int'l Joint Research]
• [Int'l Joint Research] Washington University/Mayo Clinic/Harvard Medical School(米国)
• [Int'l Joint Research] DZNE center/Tubingen University/Ludwig-Maximilians-University(ドイツ)
• [Int'l Joint Research] FLEN institute(アルゼンチン)
• [Int'l Joint Research] Melborune University/Edith Cowan University/Macquarie University(オーストリア)
• [Int'l Joint Research] Quees Square Institute/London University(英国)
• [Int'l Joint Research]
• [Journal Article] Longitudinal Accumulation of Cerebral Microhemorrhages in Dominantly Inherited Alzheimer Disease (2021)
  • Author(s): Joseph-Mathurin Nelly、Wang Guoqiao、Kantarci Kejal、Jack Clifford R.、McDade Eric、et al
  • Journal Title: Neurology Volume: 96 Issue: 12
  • DOI: 10.1212/wnl.0000000000011542
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Quantitative Measurement of Cerebrospinal Fluid Amyloid-β Species by Mass Spectrometry (2021)
  • Author(s): Seino Yusuke、Nakamura Takumi、Harada Tomoo、Nakahata Naoko、Kawarabayashi Takeshi、Ueda Tetsuya、Takatama Masamitsu、Shoji Mikio
  • Journal Title: Journal of Alzheimer's Disease Volume: 79 Issue: 2 Pages: 573-584
  • DOI: 10.3233/jad-200987
  • Peer Reviewed / Open Access
• [Journal Article] An autopsy case of primary lateral sclerosis with Alzheimer's disease. (2020)
  • Author(s): Nakamura T, Kon T, Kawarabayashi T, Wakabayashi K, Ikeda Y, Shoji M.
  • Journal Title: J Neurol Sci. Volume: 412 Pages: 116792-116792
  • DOI: 10.1016/j.jns.2020.116792
  • Peer Reviewed / Open Access
• [Journal Article] Amyloid and Tau Pathology Associations With Personality Traits, Neuropsychiatric Symptoms, and Cognitive Lifestyle in the Preclinical Phases of Sporadic and Autosomal Dominant Alzheimer's Disease. (2020)
  • Author(s): Pichet Binette A, Vachon-Presseau E, Morris J, Bateman R, Benzinger T, Collins DL, Poirier J, Breitner JCS, Villeneuve S; Dominantly Inherited Alzheimer Network (DIAN); PREVENT-AD Research Group.
  • Journal Title: Biol Psychiatry. Volume: S0006-3223(20) Issue: 8 Pages: 30058-5
  • DOI: 10.1016/j.biopsych.2020.01.023
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer's disease. (2020)
  • Author(s): Barthelemy NR, Goate AM, Morris JC, Ikeuchi T, Mori H, Shimada H, Shoji M, Suzuki K, Graff-Radford NR, Salloway S, Masters CL, O'Connor A, Fox NC, Levin J, Jucker M, Gabelle A, Lehmann S, Sato C, Bateman RJ, McDade E; Dominantly Inherited Alzheimer Network ,at al.
  • Journal Title: Nat Med. Volume: 26(3) Issue: 3 Pages: 398-407
  • DOI: 10.1038/s41591-020-0781-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Novel ELISAs to measure total and phosphorylated tau in cerebrospinal fluid. (2020)
  • Author(s): Kawarabayashi T, Nakamura T, Miyashita K, Fukamachi I, Seino Y, Shoji M.
  • Journal Title: Neurosci Lett. Volume: 722 Pages: 134826-134826
  • DOI: 10.1016/j.neulet.2020.134826
  • Peer Reviewed
• [Journal Article] A New Serum Biomarker Set to Detect Mild Cognitive Impairment and Alzheimer's Disease by Peptidome Technology. (2020)
  • Author(s): Abe K, Shang J, Shi X, Yamashita T, Hishikawa N, Takemoto M, Morihara R, Nakano Y, Ohta Y, Deguchi K, Ikeda M, Ikeda Y, Okamoto K, Shoji M, Takatama M, Kojo M, Kuroda T, Ono K, Kimura N, Matsubara E, Osakada Y, Wakutani Y, Takao Y, Higashi Y, Asada K, Senga T, Lee LJ, Tanaka K
  • Journal Title: J Alzheimers Dis. Volume: 73(1) Issue: 1 Pages: 217-227
  • DOI: 10.3233/jad-191016
  • NAID: 120006949464
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effect of rovatirelin in patients with cerebellar ataxia: two randomized double-blind placebo-controlled phase 3 trials. (2020)
  • Author(s): Nishizawa M, Onodera O, Hirakawa A, Shimizu Y, Yamada M; Rovatirelin Study Group.
  • Journal Title: J Neurol Neurosurg Psychiatry. Volume: 91(3) Issue: 3 Pages: 254-262
  • DOI: 10.1136/jnnp-2019-322168
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CogEvo, a cognitive function balancer, is a sensitive and easy psychiatric test battery for age-related cognitive decline. (2020)
  • Author(s): Ichii S, Nakamura T, Kawarabayashi T, Takatama M, Ohgami T, Ihara K, Shoji M.
  • Journal Title: Geriatr Gerontol Int. Volume: 20(3) Issue: 3 Pages: 248-255
  • DOI: 10.1111/ggi.13847
  • Peer Reviewed / Open Access
• [Journal Article] Perineuritis Successfully Treated with Early Aggressive Immunotherapy (2019)
  • Author(s): Nakamura T, Kawarabayashi T, Seino Y, Hirohata M, Wakabayashi K, Shoji M.
  • Journal Title: Internal Medicine Volume: 58 Issue: 19 Pages: 2875-2878
  • DOI: 10.2169/internalmedicine.2638-19
  • NAID: 130007722424
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-10-01
  • Peer Reviewed
• [Journal Article] Cerebrospinal Fluid and Plasma Tau as a Biomarker for Brain Tauopathy (2019)
  • Author(s): Shoji M
  • Journal Title: Adv Exp Med Biol. Volume: 1184 Pages: 393-405
  • DOI: 10.1007/978-981-32-9358-8_29
  • ISBN: 9789813293571, 9789813293588
  • Peer Reviewed
• [Journal Article] An atlas of cortical circular RNA expression in Alzheimer disease brains demonstrates clinical and pathological associations. (2019)
  • Author(s): Dube U, Del-Aguila JL, Li Z, Budde JP, Jiang S, Hsu S, Ibanez L, Fernandez MV, Farias F, Norton J, Gentsch J, Wang F; Dominantly Inherited Alzheimer Network (DIAN), Salloway S, Masters CL, Lee JH, Graff-Radford NR, Chhatwal JP, Bateman RJ, Morris JC, Karch CM, Harari O, Cruchaga C.
  • Journal Title: Nat Neurosci. Volume: 22(11) Issue: 11 Pages: 1903-1912
  • DOI: 10.1038/s41593-019-0501-5
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Oral Immunization with Soybean Storage Protein Containing Amyloid-β 4-10 Prevents Spatial Learning Decline. (2019)
  • Author(s): Kawarabayashi T, Terakawa T, Takahashi A, Hasegawa H, Narita S, Sato K, Nakamura T, Seino Y, Hirohata M, Baba N, Ueda T, Harigaya Y, Kametani F, Maruyama N, Ishimoto M, St George-Hyslop P, Shoji M.
  • Journal Title: J Alzheimers Dis. Volume: 70(2) Issue: 2 Pages: 487-503
  • DOI: 10.3233/jad-190023
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MicroRNA expression profiles of neuron-derived extracellular vesicles in plasma from patients with amyotrophic lateral sclerosis. (2019)
  • Author(s): Katsu M, Hama Y, Utsumi J, Takashina K, Yasumatsu H, Mori F, Wakabayashi K, Shoji M, Sasaki H.
  • Journal Title: Neurosci Lett. Volume: 708 Pages: 134176-134176
  • DOI: 10.1016/j.neulet.2019.03.048
  • Peer Reviewed / Open Access
• [Journal Article] Nationwide survey on cerebral amyloid angiopathy in Japan. (2019)
  • Author(s): Sakai K, Ueda M, Fukushima W, Tamaoka A, Shoji M, Ando Y, Yamada M.
  • Journal Title: Eur J Neurol. Volume: 26(12) Issue: 12 Pages: 1487-1493
  • DOI: 10.1111/ene.14031
  • Peer Reviewed
• [Journal Article] Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease (2019)
  • Author(s): Preische Oliver、Kazushi Suzuki (83/91, alphabetical order) et al. Dominantly Inherited Alzheimer Network
  • Journal Title: Nature Medicine Volume: 25 Issue: 2 Pages: 277-283
  • DOI: 10.1038/s41591-018-0304-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cerebrospinal Fluid and Plasma Biomarkers in Neurodegenerative Diseases (2019)
  • Author(s): Seino Yusuke、Nakamura Takumi、Kawarabayashi Takeshi、Hirohata Mie、Narita Sakiko、Wakasaya Yasuhito、Kaito Kozue、Ueda Tetsuya、Harigaya Yasuo、Shoji Mikio
  • Journal Title: Journal of Alzheimer's Disease Volume: 68 Issue: 1 Pages: 395-404
  • DOI: 10.3233/jad-181152
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Aging and APOE-ε4 are determinative factors of plasma Abeta42 levels (2018)
  • Author(s): Nakamura Takumi、Kawarabayashi Takeshi、Seino Yusuke、Hirohata Mie、Nakahata Naoko、Narita Sakiko、Itoh Ken、Nakaji Shigeyuki、Shoji Mikio
  • Journal Title: Annals of Clinical and Translational Neurology Volume: 5 Issue: 10 Pages: 1184-1191
  • DOI: 10.1002/acn3.635
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Cerebrospinal fluid and plasma biomarkers in neurodegenerative diseases (2020)
  • Author(s): Kawarabayashi T， Seino Y， Nakamura T， Takatama M， Shoji M
  • Organizer: 61st annual meeting of Japanese society of Neurology
  • Int'l Joint Research
• [Presentation] Oral immunization with soybean storage protein containing amyloid Abeta 4-10 prevents spatial learning decline (2020)
  • Author(s): Takeshi Kawarabayashi， Takumi Nakamura， Yusuke Seino， Masamitsu Takatama， Mikio Shoji
  • Organizer: Alzheimer’s Association International Conference (AAIC) 2020
  • Int'l Joint Research
• [Presentation] Alzheimer’s Disease: Natural Course and Therapy (2020)
  • Author(s): Mikio Shoji
  • Organizer: The 8th International Symposium of Gunma University Initiative for Advanced Research (GIAR)
  • Int'l Joint Research / Invited
• [Presentation] Oral immunization with soybean storage protein containing Abeta4-10 in Alzheimer ’s model mice (2019)
  • Author(s): Takeshi Kawarabayashi, Takumi Nakamura, Yusuke Seino, Mie Hirohata, Mikio Shoji
  • Organizer: 60th Annual meeting of the Japanese Society of Neurology
• [Presentation] CAA-related intracerebral hemorrhage in younger patients: nationwide study in Japan (2019)
  • Author(s): Kenji Sakai, Mitsuharu Ueda, Wakaba Fukushima, Akira Tamaoka, Mikio Shoji, Yukio Ando, Masahito Yamada
  • Organizer: 60th Annual meeting of the Japanese Society of Neurology
• [Presentation] 認知症の バイオマーカー: 自然経過と臨床応用 (2019)
  • Author(s): 東海林幹夫
  • Organizer: 第31回日本老年医学会総会，シンポジウム
  • Invited
• [Presentation] アルツハイマー病変を合併した原発性側索硬化症の１剖検例 (2019)
  • Author(s): 今 智矢、中村 琢洋、羽賀 敏博、森 文秋、丹治 邦和、鬼島 宏、 東海林 幹夫、若林 孝一
  • Organizer: 第60回日本神経病理学会学術研究会
• [Presentation] 血漿Abeta値は腎機能により強い影響を受け，MMSEと相関する：岩木プロジェクト (2019)
  • Author(s): 中村琢洋、瓦林毅，清野祐輔，笠原浩生，池田将樹，池田佳生，東海林幹夫
  • Organizer: 第10回日本脳血管・認知症学会総会
• [Presentation] Takeshi Kawarabayashi, Masakuni Amari, Masamitsu Takatama, Mikio Shoji (2019)
  • Author(s): Oral immunization with soybean storage protein containing Abeta4-10
  • Organizer: 49th Annual meeting of the Society for Neuroscience
  • Int'l Joint Research
• [Presentation] DIAN研究／家族会議 (2019)
  • Author(s): 東海林幹夫
  • Organizer: 第38回日本認知症学会学術集会
  • Invited
• [Presentation] 組み替え大豆蛋白によるアルツハイマー病経口免疫の作用機序の検討 (2019)
  • Author(s): 瓦林毅，中村琢洋，清野祐輔，亀谷富由樹、池田佳生、高玉真光、東海林幹夫
  • Organizer: 第38回回日本認知症学会学術集会
• [Presentation] 認知症研究の動向と展望 (2018)
  • Author(s): 東海林幹夫
  • Organizer: 第37回日本認知症学会学術集会，札幌
  • Invited
• [Presentation] APOEε4 suppresses age-dependent increase in plasma Abeta42 levels (2018)
  • Author(s): Takumi Nakamura, Takeshi Kawarabayashi, Yusuke Seino, Mie Hirohata, Mikio Shoji,
  • Organizer: Neuroscience 2018, the Society for Neuroscience, 48th Annual Meeting, San Diego,
  • Int'l Joint Research
• [Presentation] Accumulation of Aβ oligomers induces phosphorylated tau in synaptic lipid rafts (2018)
  • Author(s): Takeshi Kawarabayashi, Takumi Nakamura, Mie Hirohata, Yusuke Seino, Mikio Shoji
  • Organizer: Alzheimer’s Association International Conference (AAIC) , Chicago
  • Int'l Joint Research
• [Presentation] 優性遺伝性アルツハイマー病の臨床研究-DIAN-Japan研究 (2018)
  • Author(s): 東海林幹夫
  • Organizer: 33回日本老年精神医学会，ビッグパレットふくしま
  • Invited
• [Presentation] 認知症のバイオマーカー (2018)
  • Author(s): 東海林幹夫
  • Organizer: 第2回日本脳神経外科認知症学会学術総会．タワーホール船掘，東京
  • Invited
• [Book] 新臨床内科学 (2020)
  • Author(s): 東海林幹夫 （分担）
  • Total Pages: 1960
  • Publisher: 医学書院
  • ISBN: 9784260038065
• [Book] 私の治療［2019～20年度版］ (2019)
  • Author(s): 東海林幹夫（分担）
  • Total Pages: 1568
  • Publisher: 日本医事新報社
• [Book] 認知症トータルケア，第147巻・特別号（2） (2018)
  • Author(s): 東海林幹夫
  • Total Pages: 422
  • Publisher: 日本医師会