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

项目总结 这个项目调查了tau和淀粉样蛋白病理与阿尔茨海默病相关的独特的和联合的影响。 疾病和推测血管起源的白质高信号对大脑网络功能和 认知，包括记忆和执行能力。最重要的假设是tau、淀粉样蛋白和白色 物质负担相互作用，特别是扰乱了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 磁共振在人体内功能网络连接学研究中的新进展 Tau负荷的成像和新近开发的正电子发射断层扫描标记物 人类。首次针对tau、淀粉样蛋白和白质的不同和相互作用的影响进行特定目标测试 当这些病理标记物出现在大脑网络中时，会产生负担。第二个具体目标是测试如何 Tau蛋白、淀粉样蛋白和白质负荷之间的相互作用可能会导致3年内认知能力下降。 句号。拟议的工作提供了最近关于网络的横截面发现的新的扩展 功能、病理和认知，以关键测试tau和淀粉样蛋白负荷是否与白质相互作用 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，这些目标将提供证据，局部的临床前tau和淀粉样蛋白病理和白色 推测起源于血管的物质高信号具有交互影响，有助于功能性 在衰老过程中，通常可以观察到网络和认知能力的下降。这项工作将有助于区分进程 归因于典型的衰老和发展，从与阿尔茨海默病相关的病理在其 最早的阶段。如果成功，这项工作将提高我们对病理位置如何影响的理解 特定的大脑网络和认知能力，将为提高网络的早期诊断提供措施 或可归因于这些病理标记物在个别患者中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.