Cerebrovascular Remodeling and Neurodegenerative Changes in Alzheimer's Disease

阿尔茨海默病的脑血管重塑和神经退行性改变

• 批准号: 10554367
• 负责人: Thor Stein
• 金额: $ 80.77万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10554367
• 关键词: Abeta clearance; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease pathology; Arteries; Atrophic; Attention; Biological Markers; Biology; Biomechanics; Birefringence; Blood - brain barrier anatomy; Blood Vessels; Brain; Cause of Death; Cells; Cerebrovascular Disorders; Cerebrovascular system; Cerebrum; Cessation of life; Clinical; Cognition; Cognitive; Collagen; Consensus; Data Set; Dementia; Development; Diagnosis; Diagnostic; Economic Burden; Elasticity; Episodic memory; Evaluation; Extracellular Matrix; Fiber; Funding; Goals; Homeostasis; Human; Immunohistochemistry; Impaired cognition; Injury; Intervention; Language; Life; Longevity; Mass Spectrum Analysis; Measures; Metabolism; Microcirculation; Microscopy; Modeling; Molecular Structure; Myelin; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurons; Neuropsychological Tests; Outcome; Pathogenesis; Pathologic; Pathology; Perfusion; Persons; Play; Population; Predisposition; Property; Pulse Pressure; Research; Resources; Role; Smooth Muscle Myocytes; Societies; Stress; Structure; Symptoms; Temporal Lobe; Testing; United States; Vascular Diseases; Vascular remodeling; Visit; Visuospatial; abeta accumulation; abeta deposition; anterior cerebral artery; biomechanical test; brain metabolism; brain tissue; cerebral artery; cerebrovascular; cost; design; executive function; frontal lobe; glycoproteomics; mild cognitive impairment; multidisciplinary; multiphoton imaging; neuropathology; optical imaging; performance tests; pre-clinical; pressure; sex; tau Proteins

PROJECT SUMMARY Alzheimer’s disease, the most common cause of dementia and the sixth most common cause of death, afflicts nearly 6 million people in the United States. Alzheimer’s disease is a major economic burden to our society with an annual cost of more than $250 billion. Cerebrovascular integrity is critical for proper metabolism and perfusion of the brain. Compliance of large cerebral arteries is critical as these arteries dampen the pulsatile pressure and protect the microcirculation and blood brain barrier from damage. Cerebrovascular dysfunction can have detrimental impacts on the brain. Growing evidences suggest that cerebrovascular dysfunction plays a crucial role in the pathogenesis of Alzheimer’s disease and can potentially be used as a biomarker for preclinical Alzheimer’s disease. The overall goal of this project is to unravel the close relationship between cerebrovascular remodeling and the progression of Alzheimer’s disease. Our preliminary study suggested that with pathological progression of Alzheimer’s disease, the human cerebral artery showed progressive stiffening, structural breakdown, and increases smooth muscle cell atrophy. We thus hypothesize that the structural and functional changes in large cerebrovasculature is correlated with neurodegeneration and the accumulation of Amyloid-β, other toxic metabolites, and tau pathology in the brain. Building upon our multidisciplinary expertise in vascular mechanobiology, precision mass spectrometry, advanced optical imaging, immunohistochemistry, vascular biology and neuropathology of Alzheimer’s disease, we will test this hypothesis in three aims: Aim 1) to determine cerebrovascular remodeling (biomechanical, structural, and compositional changes) in the frontal and temporal lobes in Alzheimer’s disease; Aim 2) to determine the association between cerebrovascular remodeling and Alzheimer’s disease pathological changes in the frontal and temporal lobes of the brain; and Aim 3) to examine the association between cerebrovascular remodeling and antemortem cognitive status and neuropsychological test performance. We will use no or low atherosclerotic cerebrovascular and brain tissue from 100 age- and sex-matched brain donors from the NIA-funded BU Alzheimer’s Disease Research Center with 1) no Alzheimer’s disease pathology, 2) low Alzheimer’s disease pathology, and 3) intermediate/high Alzheimer’s disease pathology . These brain donors have completed annual National Alzheimer’s Coordinating Center Uniform Data Set evaluations during life and have available consensus-based cognitive diagnoses. This proposal is designed to leverage existing resources to make new discoveries. The matched and parallel studies of cerebral vessels and brain tissue will provide new understandings of the temporal development of cerebrovascular remodeling and AD. Understanding the role of vascular remodeling in Alzheimer’s disease may lead to the discovery of new treatment options and directions for interventions to stave off Alzheimer’s disease.

项目摘要 阿尔茨海默病是痴呆症最常见的原因，也是第六大常见的死亡原因， 在美国有近六百万人。阿尔茨海默病是我们社会的主要经济负担， 每年花费超过2500亿美元。脑血管的完整性对于适当的代谢和灌注至关重要 大脑。大脑动脉的顺应性是至关重要的，因为这些动脉抑制脉动压力， 保护微循环和血脑屏障免受损害。脑血管功能障碍 对大脑的有害影响。越来越多的证据表明，脑血管功能障碍在 在阿尔茨海默病发病机制中的作用，并可潜在地用作临床前 老年痴呆症本项目的总体目标是揭示脑血管疾病与脑血管疾病之间的密切关系。 重塑和阿尔茨海默病的发展。 我们的初步研究表明，随着阿尔茨海默病的病理进展， 脑动脉呈进行性硬化，结构破坏，平滑肌细胞萎缩增加。 因此，我们假设大血管的结构和功能变化与 神经变性和淀粉样蛋白-β、其他毒性代谢物的积累以及脑中的tau病理学。 基于我们在血管机械生物学，精密质谱， 先进的光学成像，免疫组织化学，血管生物学和阿尔茨海默病的神经病理学， 我们将在三个目标中检验该假设：目标1）确定脑血管重塑（生物力学， 结构和成分的变化）在阿尔茨海默病的额叶和颞叶;目的2）， 探讨脑血管重构与阿尔茨海默病病理改变的关系 目的3）检查脑血管疾病与脑血管疾病之间的关系， 重塑和死前认知状态以及神经心理学测试表现。 我们将使用来自100个年龄和性别匹配的脑的无或低动脉粥样硬化的脑血管和脑组织， 来自NIA资助的BU阿尔茨海默病研究中心的捐赠者，1）没有阿尔茨海默病病理学， 2)低度阿尔茨海默病病理学，和3）中度/高度阿尔茨海默病病理学 .这些 大脑 捐助者已经完成了年度国家阿尔茨海默氏症协调中心统一数据集评估， 生活，并有可用的共识为基础的认知诊断。该提案旨在利用现有的 资源来进行新的发现。脑血管和脑组织的匹配和平行研究将有助于 为脑血管重塑和AD的时间发展提供了新的认识。理解 血管重塑在阿尔茨海默病中的作用可能会导致新的治疗选择的发现， 为预防阿尔茨海默病的干预措施提供指导。