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

基本信息

批准号：
10370614
负责人：
Thor Stein
金额：
$ 82.5万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
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/10370614
关键词：
Abeta clearance Affect Age Alzheimer&apos s Disease Alzheimer&apos 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 Episodic memory Evaluation Extracellular Matrix Fiber Funding Goals Human Immunohistochemistry Impaired cognition Injury Intervention Language Lead Life Mass Spectrum Analysis Measures Metabolism Microcirculation Microscopy Molecular Structure Myelin Nerve Degeneration Neurodegenerative Disorders Neurologic Neurons Neuropsychological Tests Outcome Pathogenesis Pathologic Pathology Perfusion Persons Physiologic pulse Play Population Property 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 base 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

项目摘要

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氏病是痴呆症的最常见原因，也是第六个最常见的死亡原因，折磨阿尔茨海默氏病是我们社会的重大经济焚烧每年成本超过2500亿美元。脑血管完整性对于适当的新陈代谢和灌注至关重要大脑。大脑动脉的依从性至关重要，因为这些动脉该死的脉动压力和保护微循环和血脑屏障免受损伤。脑血管功能障碍可以对大脑的有害影响。越来越多的证据表明脑血管功能障碍起着至关重要的在阿尔茨海默氏病的发病机理中的作用，并有可能用作临床前的生物标志物阿尔茨海默氏病。该项目的总体目标是揭开脑血管之间的密切关系重塑和阿尔茨海默氏病的进展。我们的初步研究表明，随着阿尔茨海默氏病的病理发展，人类脑动脉显示出渐进式僵硬，结构崩溃并增加平滑肌细胞萎缩。因此，我们假设大型脑血管造期的结构和功能变化与神经变性和淀粉样蛋白β，其他有毒代谢产物和tau病理学的积累。基于我们的多学科血管机制专业知识，精密质谱法，高级光学成像，免疫组织化学，血管生物学和阿尔茨海默氏病神经病理学，我们将在三个目的中检验这一假设：目标1）确定脑血管重塑（生物力学，在阿尔茨海默氏病的额叶和临时爱中的结构和组成变化；目标2）确定脑血管重塑与阿尔茨海默氏病的病理变化之间的关联在大脑的额叶和临时爱中；目标3）检查脑血管之间的关联重塑和麻木认知状况和神经心理测试表现。我们将不使用100岁和性别匹配的大脑的动脉粥样硬化脑血管和脑组织 NIA资助的阿尔茨海默氏病研究中心的捐助者，没有阿尔茨海默氏病病理学， 2）低阿尔茨海默氏病病理学和3）中级/高阿尔茨海默氏病病理。这些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具有基于共识的认知诊断。该建议旨在利用现有的进行新发现的资源。大脑血管和脑组织的匹配和平行研究将对脑血管重塑和AD的临时发展提供新的理解。理解血管重塑在阿尔茨海默氏病中的作用可能导致发现新的治疗方案和干预措施的方向避免了阿尔茨海默氏病。