Genetic Profiles of the Spatiotemporal Causality of Tau and Amyloid in the Elderly Brain

项目摘要（摘要） 异常tau蛋白和淀粉样β（A β）蛋白沿着沿着神经元回路的进展现象是 这对于了解阿尔茨海默病（AD）病理学的基础至关重要。个体风险发展晚 发病AD涉及赋予异常和进行性AD易感性的生物学和遗传学特征， tau和A β在脑中的积累。多模态神经影像学与遗传生物标志物研究进展 为检测AD的早期阶段并研究其网络性质和遗传提供了新的前景 基础然而，该领域的一个主要研究挑战是整合和执行 神经成像和遗传数据的综合联合分析。因此，迫切需要新的战略 检测tau蛋白相关和A β相关蓄积的传播途径和遗传机制， 人脑结合对进展的个体神经影像学特征的详细描述， 遗传脆弱性风险将提高反倾销轨迹的可探测性。该提案旨在解决 这些新出现的挑战，重点是识别tau和A β沉积物的体内扩散途径， 和他们的遗传弱点在一个纵向样本的老年参与者从哈佛老化大脑 研究（HABS）。在目标1中，我们将开发定制的图论指标来检测病理进展， 在横截面和纵向PET图像中的网络水平。在Aim2中，我们将专注于构建个性化的 分期框架的基础上的进展和扩散模式的病理使用PET成像，我们将 将分期评估与临床和神经心理学特征相关联。在目标3中，我们将描述 在艾伦人脑图谱的帮助下， 神经影像扩散图在本提案结束时，我们将能够检测和识别早期和 体内分子成像和遗传特征，赋予老年人AD易感性。

Project Summary (Abstract) The progression phenomenon of abnormal tau and amyloid-β (Aβ) proteins along neuronal circuits is critical to understand the foundations of Alzheimer's disease (AD) pathology. The individual risk to develop late onset AD relates to the biological and genetic profiles that confer susceptibility for abnormal and progressive accumulation of tau and Aβ in the brain. Recent advances in multi-modal neuroimaging and genetic biomarkers provide new prospects to detect very early stages of AD and to study its network nature and genetic underpinnings. However, a major research challenge in this field has been to integrate and perform comprehensive joint analysis of neuroimaging and genetic data. Thus, there is a critical need for new strategies to detect the spreading pathways and genetic mechanisms of tau-related and Aβ-related accumulation in the human brain. The combination of detailed descriptions of individual neuroimaging profiles of progression and genetic vulnerability risk will offer enhanced detectability of AD trajectories. This proposal purposes to solve these emerging challenges by focusing on identification of in vivo spreading pathways of tau and Aβ deposits and their genetic vulnerabilities in a longitudinal sample of elderly participants from the Harvard Aging Brain Study (HABS). In Aim 1, we will develop customized graph theory metrics to detect progression of pathology at the network level in cross-sectional and longitudinal PET images. In Aim2, we will focus on building individualized staging frameworks based on progression and spreading patterns of pathology using PET imaging, and we will correlate staging estimates with clinical and neuropsychological profiles. In Aim 3, we will characterize the genetic brain transcriptome –assisted by the Allen Human Brain Atlas- that are associated to the HABS neuroimaging spreading profiles. At the end of this proposal, we will be able to detect and identify the early and in vivo molecular imaging and genetic features that confer AD susceptibility in elderly individuals.