Cerebral deposition due to excrete promotion indicated by cerebrospinal fluid metabolic pathway impairment of neurotoxic protein

2022 Fiscal Year Final Research Report

• Project/Area Number: 18H02916
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: Juntendo University
• Principal Investigator: ARAI HAJIME 順天堂大学, 医学部, 教授 (70167229)
• Co-Investigator(Kenkyū-buntansha): 中島 円 順天堂大学, 医学部, 准教授 (50317450) ; 宮嶋 雅一 順天堂大学, 医学部, 教授 (60200177) ; 菅野 秀宣 順天堂大学, 医学部, 先任准教授 (90265992) ; 川村 海渡 順天堂大学, 医学部, 助手 (60814895)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 脳代謝 / 認知症 / 脳脊髄液 / 水頭症 / 線毛運動

Outline of Final Research Achievements

Cerebrospinal fluid (CSF) plays a crucial role in maintaining brain function by clearing waste products generated from brain activity. However, in elderly individuals, the elimination of neurotoxic proteins from the brain is hindered due to aging, which is closely associated with the onset of dementia. In this study, we focused on idiopathic normal pressure hydrocephalus (iNPH), a condition unique to the elderly, which arises from CSF malabsorption. We proposed a classification system to assess the severity of iNPH based on the prognosis of treatment through CSF drainage enhancement. This classification considers cognitive impairment, gait disturbance, urinary incontinence symptoms, as well as levels of phosphorylated tau and β amyloid (Aβ) neurotoxic proteins in CSF and blood. Furthermore, we developed an animal model of iNPH that simulates age-related development and demonstrated that the accumulation rate of pathological proteins can be delayed through accelerated CSF metabolism.

Free Research Field

脳神経外科学

Academic Significance and Societal Importance of the Research Achievements

脳脊髄液の排泄障害は，加齢とともに誰しもが起こり得る生理的な変化である．脳脊髄液の代謝は脳の恒常性を保つため，必要不可欠であり，その障害はさまざまな神経変性に関与し，認知症の主要な原因の一つとして解明すべき課題である．本研究では，脳脊髄液の排泄障害を発症原因とした特発性正常圧水頭症病態に着目し，神経活動により産出されるβアミロイド，タウ蛋白などの神経毒性蛋白を測定し，脳脊髄液排泄促進による神経症状の改善と病態ステージを, 臨床研究の知見と線毛運動障害動物モデルによる実験から髄液排泄障害の重症度を提案した．脳脊髄液代謝の調整による脳老廃物の代謝，及び神経症候の変化について新たな知見を提供した．