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: 10524890
• 负责人: Alifiya Kapasi
• 金额: $ 10.88万
• 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/10524890
• 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; Autopsy; Biological Process; Biometry; Brain; Brain region; Cerebral Amyloid Angiopathy; Cerebral small vessel disease; Cognition; Cognitive; Communities; Complex; Data; Dementia; Diagnosis; Disease; Disease Marker; Elderly; Etiology; Goals; Hippocampus (Brain); Histopathology; Impaired cognition; Inflammation; Magnetic Resonance Imaging; Measures; Memory; Mentorship; Methods; Microglia; Microvascular Dysfunction; Minority; Nerve Degeneration; Pathology; Persons; Postmortem Changes; Prevention; Public Health; Research; Research Methodology; Research Training; Resources; Role; Testing; Training; Translational Research; White Matter Hyperintensity; Work; aging population; base; 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; neuroimaging; neuroimaging marker; 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.

项目摘要/摘要 脑萎缩是痴呆症的常见相关性。大多数患有痴呆症的老年人都患有 脑部小血管疾病(SVD)和阿尔茨海默病(AD)的病理。奇异值分解的频谱包括 既有小血管病变，也有多种组织损伤。不同的生物过程可能有助于 包括海马体在内的脆弱脑区的脑萎缩的病因，这是一种脑结构变化 在核磁共振上可见认知功能减退。SVD和AD之间的相互作用是复杂的，有证据表明 提示小胶质细胞炎症可能很重要。到目前为止，很少有研究关注这种相互作用。 在局部脑体积的背景下，SVD、AD和小胶质细胞炎症之间的关系。这项研究的目的是 是检查神经病理和MRI SVD标记物与局部脑体积的关系，并确定 阿尔茨海默病病理与小胶质细胞炎症的关系。这款K01将整合神经病理学， 神经成像和认知数据来自三个基于社区的研究，宗教秩序研究，记忆 和老龄化项目，以及少数民族老龄化和研究研究。具体地说，这项提案将使用最先进的 方法使用MRI定义的方法，从死后脑组织捕捉新的数字形态变化 定量测量易感脑区的体积，与区域脑检查不同的SVD标志物 卷，检查体内纵向SVD变化，并扩展对非裔美国人的分析。主要目标 1)检查SVD标志物、AD病理和局部脑体积之间的关系，2)确定 小胶质细胞炎症与SVD标记物和局部脑体积的作用，以及3)确定相关性 SVD标记物、局部脑体积和认知功能减退之间的关系。一个探索性的目标将考察 非裔美国人SVD标志物与局部脑体积的关系我的导师团队已经 在老龄化和痴呆症的大型流行病学研究方面有丰富的经验，并将提供专家指导 通过研究方法和赠送的培训计划。导师制专业知识的具体领域包括 翻译神经病理学、神经成像、生物统计学、健康差异和认知。他们的专业知识将 通过拉什阿尔茨海默病中心(RADC)的跨学科培训计划得到加强，并切割- RADC核心内的边缘资源(神经病理学、神经成像和生物标记物以及生物统计学)。 总之，拟议的研究和培训计划提供了一个框架，我可以从中启动一个成功的 独立研究生涯。