Mechanisms of Alzheimer's Disease Progression in the Aging Brain

项目摘要 虽然迟发性散发性阿尔茨海默病（AD）通常以健忘症宣布，但聚集性阿尔茨海默病（AD） 蛋白质β-淀粉样蛋白（Aβ）和tau可能在症状发作前在脑中存款多年。这 在正常衰老的背景下，大脑的情景记忆系统中发生了一个过程。越来越多的证据 指出tau蛋白从内侧颞叶扩散到新皮质脑区域， 在从正常衰老到AD的过渡中至关重要，可能由Aβ和神经活动模式驱动， 连通性。在这个项目中，我们将专门研究情景记忆系统的两个子系统， 前颞（AT）系统起源于专门用于物体记忆的外侧内嗅皮层（LEC），以及 起源于内侧内嗅皮层（MEC）的后内侧系统（PM）系统，专门用于空间 记忆这对于区分衰老和AD是重要的，因为tau沉积在老年人的LEC中开始。 Aβ沉积在PM系统中。该应用程序建立在纵向队列的基础上， 近200名认知正常的老年人，他们以前接受过基线淀粉样蛋白PET扫描， [11 C]PIB，纵向结构MRI检查，其中一些人进行了tau-PET成像， [18F]flortaucipir。对于该项目，120名参与者将接受PIB-PET、flortaucipir- PET、结构MRI和记忆和其他认知能力的神经心理学测试;这些程序 将在1.5年和3年后重复。基线检查还将包括功能性MRI实验 参与者对新的物体和场景进行编码，以定义AT和PM情景记忆系统。 神经活动将使用定向功能连接（定向FC）进行检查，这是一种分析方法 采用格兰杰因果关系，评估从一个区域到另一个区域的神经活动。这 directed-FC将在随后的3年内模拟tau通过记忆系统的传播。目标1将 检查tau蛋白扩散与Aβ存在、纵向皮质萎缩的总体模式，以及 认知改变我们假设Aβ会加速tau蛋白的扩散，这反过来又会导致萎缩 和记忆力下降目标2将检查通过AT和PM系统的tau传播。我们假设tau蛋白 主要在AT系统中传播，因此，反映了开始于 大脑老化，而不是解剖学或功能性的新情况。Aim 3将使用定向FC来预测 随着时间的推移，tau蛋白的传播，假设大脑区域与内嗅皮层的联系最紧密 将显示tau病理学的最快速传播，并且这在AT系统中将是最强的。tau如何传播 通过这些系统，以及Aβ和神经连接如何驱动这种传播可能有助于区分 从正常老化的AD的最早阶段，识别处于最高进展风险的正常个体，并提供 为临床试验选择个体的新方法。

PROJECT SUMMARY While late onset sporadic Alzheimer's disease (AD) is usually announced with amnesia, the aggregated proteins β-amyloid (Aβ) and tau probably deposit in the brain for many years before symptom onset. This process occurs in the brain's episodic memory system, on a background of normal aging. Increasing evidence points to the spread of the tau protein out of the medial temporal lobe and into neocortical brain regions as crucial in the transition from normal aging to AD, possibly driven by Aβ and patterns of neural activity and connectivity. In this project we will specifically examine two subsystems of the episodic memory system, an anterior temporal (AT) system originating in lateral entorhinal cortex (LEC) specialized for object memory, and a posteromedial system (PM) system originating in medial entorhinal cortex (MEC) specialized for spatial memory. This is important for differentiating aging and AD because tau deposition begins in the LEC in older brains, while Aβ deposits in the PM system. The application builds upon on a longitudinal cohort consisting of almost 200 cognitively normal older people who have previously had baseline amyloid PET scanning with [11C]PIB, longitudinal structural MRI exams, and some of whom have had tau-PET imaging with [18F]flortaucipir. For this project, 120 participants will undergo a baseline examination of PIB-PET, flortaucipir- PET, structural MRI, and neuropsychological testing of memory and other cognitive abilities; these procedures will be repeated 1.5 and 3 years later. The baseline examination will also include a functional MRI experiment in which participants encode novel objects and scenes to define the AT and PM episodic memory systems. Neural activity will be examined using directed functional connectivity (directed-FC), an analytic approach employing Granger causality with assessment of neural activity directed from one region to another. This directed-FC will model the spread of tau through memory systems over the ensuing 3 years. Aim 1 will examine the overall pattern of tau spread in relation to the presence of Aβ, longitudinal cortical atrophy, and cognitive change. We hypothesize that Aβ will speed tau spread, which in turn will be associated with atrophy and memory decline. Aim 2 will examine tau spread through the AT and PM systems. We hypothesize that tau spreads predominantly in the AT system and, as such, reflects an enhancement of the processes that begin in the aged brain and not an anatomical or functional new condition. Aim 3 will use directed-FC to predict the spread of tau over time, with the hypothesis that brain regions most strongly connected to the entorhinal cortex will show the most rapid spread of tau pathology and this will be strongest in the AT system. How tau spreads through these systems and how Aβ and neural connectivity may drive this spread could help to differentiate the earliest stages of AD from normal aging, identify normal individuals at highest risk of progression, and provide new approaches to the selection of individuals for clinical trials.