Small vessel disease contributions to neurodegeneration in Alzheimer's disease

小血管疾病对阿尔茨海默病神经变性的影响

• 批准号: 10677799
• 负责人: Alifiya Kapasi
• 金额: $ 11.25万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677799
• 关键词: Affect; African American; African American population; Age; Aging; Alzheimer' s Disease; Alzheimer' s Disease Core Center; Alzheimer' s disease pathology; Amyloid beta-Protein; Area; Arterioloscleroses; Autopsy; Biological Markers; Biological Process; Biometry; Blood Vessels; Brain; Brain region; Cerebral Amyloid Angiopathy; Cerebral small vessel disease; Cognition; Cognitive; Communities; Complex; Data; Dementia; Diagnosis; Disease; Disease Marker; Elderly; Etiology; Goals; Hemorrhage; Hippocampus; Histopathology; Impaired cognition; Inflammation; Magnetic Resonance Imaging; Measures; Memory; Mentorship; Methods; Microglia; Microvascular Dysfunction; Minority; Nerve Degeneration; Pathology; Persons; Postmortem Changes; Predisposition; Prevention; Public Health; Research; Research Methodology; Resources; Role; Testing; Training; Translational Research; White Matter Hyperintensity; Work; aging population; biomarker development; brain tissue; brain volume; burden of illness; career; cerebral atrophy; clinical translation; comorbidity; dementia risk; digital; digital pathology; epidemiology study; experience; health disparity; high risk; hippocampal atrophy; in vivo; magnetic resonance imaging biomarker; neuroimaging; neuropathology; novel; novel strategies; religious order study; research study; tau Proteins; tissue injury

PROJECT SUMMARY/ABSTRACT Brain atrophy is a common correlate of dementia. Majority of older persons with dementia have comorbid cerebral small vessel disease (SVD) and Alzheimer’s disease (AD) pathology. The spectrum of SVD includes both small vessel pathologies and diverse tissue injuries. Differing biologic processes may contribute towards the etiology of brain atrophy in vulnerable brain regions, including the hippocampus, a structural brain change seen on MRI proximate to cognitive decline. The interplay between SVD and AD is complex, with evidence to suggest microglia inflammation may be important. To date, very little research has focused on the interplay between SVD, AD, and microglia inflammation in the context of regional brain volume. The objective of this study is to examine the association of neuropathologic and MRI SVD markers with regional brain volumes and identify the effects of comorbid AD pathology and microglia inflammation. This K01 will integrate neuropathology, neuroimaging, and cognitive data from three community-based studies, the Religious Orders Study, the Memory and Aging Project, and Minority Aging and Research Study. Specifically, this proposal will use state-of-the-art methods to capture novel digital morphometric changes from post-mortem brain tissue, use MRI-defined quantitative volume measures in susceptible brain regions, examine differing SVD markers with regional brain volumes, examine in-vivo longitudinal SVD changes, and extend analyses in African Americans. Primary aims are 1) Examine the relationship between SVD markers, AD pathology, and regional brain volume, 2) Determine the role of microglia inflammation with SVD markers and regional brain volume, and 3) Identify associations between SVD markers, regional brain volume, and cognitive decline. An exploratory aim 4) will examine the relationship between SVD markers and regional brain volume in African Americans. My mentorship team has extensive experience with large epidemiological studies of aging and dementia and will provide expert guidance through the research methods and complimentary training plan. Specific areas of mentorship expertise include translational neuropathology, neuroimaging, biostatistics, health disparities, and cognition . Their expertise will be augmented by the interdisciplinary training programat Rush Alzheimer’s Disease Center (RADC), and cutting- edge resources within the RADC Cores (Neuropathology, Neuroimaging and Biomarker, and Biostatistics). Together, the proposed research and training plan provides the framework from which I can launch a successful independent research career.

项目概要/摘要 脑萎缩是痴呆症的常见相关因素。大多数患有痴呆症的老年人都有合并症 脑小血管病（SVD）和阿尔茨海默病（AD）病理学。 SVD 的频谱包括 小血管病变和各种组织损伤。不同的生物过程可能有助于 包括海马体在内的脆弱大脑区域脑萎缩的病因，这是一种结构性大脑变化 在 MRI 上看到接近认知能力下降。 SVD 和 AD 之间的相互作用很复杂，有证据表明 表明小胶质细胞炎症可能很重要。迄今为止，很少有研究关注相互作用 SVD、AD 和小胶质细胞炎症在区域脑容量的背景下之间的关系。本研究的目的 目的是检查神经病理学和 MRI SVD 标记与区域脑容量的关联，并确定 共病 AD 病理学和小胶质细胞炎症的影响。这个K01将整合神经病理学， 神经影像和来自三项基于社区的研究（宗教秩序研究、记忆研究）的认知数据 和老龄化项目，以及少数民族老龄化和研究。具体来说，该提案将使用最先进的技术 使用 MRI 定义的方法从死后脑组织捕获新的数字形态变化 定量测量易受影响的大脑区域的体积，检查区域大脑的不同 SVD 标记 量，检查体内纵向 SVD 变化，并对非裔美国人进行扩展分析。主要目标 是 1) 检查 SVD 标记、AD 病理学和区域脑容量之间的关系，2) 确定 小胶质细胞炎症与 SVD 标记物和区域脑容量的作用，以及 3) 确定关联 SVD 标记物、区域脑容量和认知能力下降之间的关系。探索性目标 4) 将检查 非裔美国人 SVD 标记与区域脑容量之间的关系。我的导师团队有 在老龄化和痴呆症的大型流行病学研究方面拥有丰富的经验，并将提供专家指导 通过研究方法和免费培训计划。指导专业知识的具体领域包括 转化神经病理学、神经影像学、生物统计学、健康差异和认知。他们的专业知识将 拉什阿尔茨海默氏病中心 (RADC) 的跨学科培训计划得到加强，并削减- RADC 核心（神经病理学、神经影像学和生物标志物以及生物统计学）内的边缘资源。 总之，拟议的研究和培训计划提供了一个框架，我可以从中成功启动 独立的研究生涯。