Small vessel disease contributions to neurodegeneration in Alzheimer's disease

项目总结/摘要 脑萎缩是痴呆症的常见相关因素。大多数老年痴呆症患者患有共病 脑小血管病（SVD）和阿尔茨海默病（AD）病理学。SVD的频谱包括 小血管病变和多种组织损伤。不同的生物过程可能有助于 脑萎缩的病因在脆弱的大脑区域，包括海马，一个结构性的大脑变化 在核磁共振成像上看到的是认知能力下降。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，很少有研究集中在相互作用 SVD、AD和小胶质细胞炎症之间的关系。本研究的目的 是检查神经病理学和MRI SVD标记物与局部脑体积的相关性， 共病AD病理学和小胶质细胞炎症的影响。这个K 01将整合神经病理学， 神经影像学，以及来自三个社区研究的认知数据，宗教秩序研究，记忆研究， 和老龄化项目，和少数民族老龄化和研究。具体而言，该提案将使用最先进的 从死后脑组织中捕获新的数字形态测量变化的方法，使用MRI定义的 在敏感脑区的定量体积测量，检查不同的SVD标记物与区域脑 体积，检查体内纵向SVD变化，并在非裔美国人中扩展分析。主要目标 1）检查SVD标志物、AD病理学和局部脑体积之间的关系，2）确定 小胶质细胞炎症与SVD标志物和局部脑体积的作用，以及3）确定相关性 SVD标志物、局部脑容量和认知能力下降之间的关系。一个探索性的目标将考察 非裔美国人SVD标记物与局部脑容量的关系我的导师团队 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。指导专长的具体领域包括 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 通过拉什阿尔茨海默病中心（RADC）的跨学科培训计划， RADC核心内的边缘资源（神经病理学、神经影像学和生物标志物以及生物统计学）。 总的来说，拟议的研究和培训计划提供了一个框架，我可以从这个框架中成功地开展一项 独立的研究生涯。

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.