Project 2 - Imaging of Brain Connrectivity, Structure and Function

项目2 -项目概要/摘要 阿尔茨海默病（AD）是老年人认知障碍的最常见原因， 仅在美国就有超过580万人携带载脂蛋白E-ε4（APOE 4）基因的个体在 发生迟发性AD的风险增加。拟议P01更新的项目2“血管对 痴呆症和阿尔茨海默病的遗传风险因素”将为发现 脑连接、结构和功能的变化如何与神经血管和血脑屏障（BBB）相关 与APOE 3相比，APOE 4携带者（e3/e4、e4/e4）的认知功能受损 纯合子（e3/e3）。 项目2将随访402例APOE 4携带者和465例APOE 3纯合子，最初入组为CU（75%） 和MCI（25%），他们将继续纵向评估大脑连接的变化， 与神经血管和认知功能的关系。参与者将继续收到相同的成像协议 以实现纵向分析，包括1）用于白色连接的多壳层DTI; 2）用于 功能连接; 3）灰质形状、体积的结构MRI;以及4）BBB完整性的DCE-MRI （项目1），以及BB B/神经血管单位（NVU）生物流体生物标志物（核心B）。对于临床前AD分期， 我们将遵循AT（N）生物标志物框架。对于认知评估，我们将使用UDS 3.0认知 不同认知领域的测试和补充测试，以评估 神经血管/BBB功能障碍和生物标志物、结构和功能连接以及认知功能 根据AT（N）研究框架。参与者还将完成淀粉样蛋白和tau PET扫描， 淀粉样蛋白和tau蛋白对大脑功能和结构的影响。神经血管的作用 在临床前认知功能减退的病理生理学中的完整性和脑连接性以及 轻度认知障碍（MCI）和AD才刚刚开始被阐明。利用先进的神经成像技术 方法，本项目将采用假设驱动的方法来了解BBB中的损伤如何 与APOE 3纯合子相比，APOE 4携带者的脑结构和功能以及认知能力受到影响。

Project 2 – Project Summary / Abstract Alzheimer’s disease (AD) is the most common cause of cognitive impairment in older adults and affects over 5.8 million people in the US alone. Individuals who carry the apolipoprotein E-ε4 (APOE4) gene are at heightened risk for developing late onset AD. Project 2 of the proposed P01 renewal “Vascular Contributions to Dementia and Genetic Risk Factors for Alzheimer’s Disease” will provide critical advances towards discovering how changes in brain connectivity, structure and function relate to neurovascular and blood-brain barrier (BBB) integrity and ultimately confer cognitive impairment in APOE4 carriers (e3/e4, e4/e4) relative to APOE3 homozygotes (e3/e3). Project 2 will follow 402 APOE4 carriers and 465 APOE3 homozygotes, initially enrolled as CU (75%) and MCI (25%) at baseline, who will continue to be evaluated longitudinally for changes in brain connectivity in relation to neurovascular and cognitive function. Participants will continue to receive the same imaging protocol to enable longitudinal analyses, including 1) multi-shell DTI for white matter connectivity; 2) resting fMRI for functional connectivity; 3) structural MRI for gray matter shape, volume; and 4) DCE-MRI for BBB integrity (Project 1), as well as BBB/neurovascular unit (NVU) biofluid biomarkers (Core B). For preclinical AD staging, we will follow the AT(N) biomarkers framework. For cognitive assessment, we will use the UDS 3.0 cognitive tests and supplemental tests across different cognitive domains to evaluate the relationships between neurovascular/BBB dysfunction and biomarkers, structural and functional connectivity, and cognitive function following the AT(N) research framework. Participants will also complete amyloid and tau PET scans to examine the effect of amyloid and tau on brain function and structure in a prespecified analysis. The role of neurovascular integrity and brain connectivity in the pathophysiology of preclinical cognitive decline and clinical progression to mild cognitive impairment (MCI) and AD have only begun to be elucidated. Using advanced neuroimaging methodology, this project will apply a hypothesis-driven approach to understand how impairment in the BBB impact brain structure and function and cognition in APOE4 carriers relative to APOE3 homozygotes.