Tau, amyloid, & white matter burden interact to impact brain networks in preclinical Alzheimer’s disease

项目摘要 该项目研究了与阿尔茨海默病相关的tau蛋白和淀粉样蛋白病理学的独特和联合影响 疾病和假定血管起源的白色高信号对脑网络功能的影响， 认知，包括记忆和执行能力。最重要的假设是tau蛋白、淀粉样蛋白和白色 物质负担相互作用，专门破坏发生负担的大脑网络的功能，并将 导致与网络中断相关的认知能力下降。拟议的工作建立在 利用磁共振研究个体内功能网络的连接组学的最新进展 成像和最近开发的正电子发射断层扫描标记物，用于可视化tau负荷， 人类第一个特定目标测试tau蛋白、淀粉样蛋白和白色物质的差异和相互作用的影响 当这些病理标志物发生在大脑网络中时，第二个具体目标测试如何 tau蛋白、淀粉样蛋白和白色物质负荷之间的相互作用可能导致3年内认知能力下降 期拟议的工作提供了新的扩展最近的横截面研究结果有关的网络 功能、病理学和认知，以严格测试tau蛋白和淀粉样蛋白负荷是否与白色物质相互作用 在阿尔茨海默病的临床前阶段，影响区域网络完整性和认知的负担。如果 成功的话，这些目标将提供证据表明，局部临床前tau蛋白和淀粉样蛋白病理学和白色 假定血管起源的物质高信号具有交互影响，其有助于功能性 网络和认知能力的下降通常在衰老过程中观察到。这项工作将有助于区分进程 这归因于典型的衰老和与阿尔茨海默病相关的病理学的发展， 最早的阶段如果成功，这项工作将提高我们对病理学位置如何影响 具体的大脑网络和认知能力，并将提供措施，以改善网络的早期诊断 或可归因于个体患者中这些病理标志物的位置的认知功能障碍。

PROJECT SUMMARY This project investigates the unique and joint impact of tau and amyloid pathology associated with Alzheimer's disease and of white matter hyperintensities of presumed vascular origin on brain network function and cognition, including memory and executive abilities. The overarching hypothesis is that tau, amyloid, and white matter burden interact to specifically disrupt the function of brain networks in which the burden occurs, and will lead to declines in cognitive abilities associated with the disrupted networks. The proposed work builds on recent advances in the connectomics of functional networks within individuals using magnetic resonance imaging and a recently-developed positron emission tomography marker for the visualization of tau burden in humans. The first specific aim tests for differential and interactive influences of tau, amyloid and white matter burden when these pathological markers occur within a brain network. The second specific aim tests for how interactions between tau, amyloid, and white matter burden may lead to declines in cognition over a 3-year period. The proposed work provides novel extensions of recent cross-sectional findings relating network function, pathology, and cognition to critically test whether tau and amyloid burden interact with white matter burden to impact regional network integrity and cognition during the preclinical stage of Alzheimer's disease. If successful, these aims will provide evidence that localized preclinical tau and amyloid pathology and white matter hyperintensities of presumed vascular origin have an interactive impact that contributes to the functional network and cognitive declines commonly observed during aging. This work will help to differentiate processes attributed to typical aging and development from the pathology associated with Alzheimer's disease at its earliest stages. If successful, this work will improve our understanding of how the location of pathology impacts specific brain networks and cognitive abilities, and will provide measures to improve early diagnosis of network or cognitive dysfunction attributable to the location of these pathological markers in individual patients.