Mechanisms of Alzheimer's Disease Progression in the Aging Brain

项目总结 虽然晚发型散发性阿尔茨海默病(AD)通常被宣布为健忘症，但聚集的 β-淀粉样蛋白(A-β)和tau蛋白可能在症状出现之前在大脑中沉积了多年。这 这个过程发生在大脑的间歇性记忆系统中，在正常衰老的背景下进行。越来越多的证据 指出tau蛋白从内侧颞叶扩散到新皮质区域的原因是 在从正常衰老到AD的转变中至关重要，可能是由Aβ和神经活动模式和 连通性。在这个项目中，我们将具体研究情节记忆系统的两个子系统，一个 前颞叶(AT)系统起源于专门负责物体记忆的外侧内嗅皮层(LEC)，以及 起源于内侧内嗅皮质的后内侧系统(PM) 记忆。这对于区分衰老和阿尔茨海默病很重要，因为tau沉积开始于老年人的LEC 大脑，而Aβ则存放在PM系统中。这个应用程序建立在一个纵向队列的基础上，该队列包括 近200名认知正常的老年人，他们以前曾接受过基线淀粉样蛋白PET扫描 [11C]PIB、纵向结构MRI检查，其中一些人进行了tau-PET成像 [18F]氟他西平。在这个项目中，120名参与者将接受PIB-PET、氟他西平- PET，结构核磁共振，以及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核磁共振实验 其中参与者编码新的物体和场景以定义AT和PM情节记忆系统。 神经活动将使用一种分析方法--定向功能连接(Directed-FC)进行检查 使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将在接下来的3年中模拟tau通过存储系统的传播。目标1将 检查tau扩散的总体模式与β、纵向皮质萎缩的存在的关系，以及 认知变化。我们假设Aβ会加速tau扩散，而tau扩散又与萎缩有关 记忆力下降。AIM 2将检查通过AT和PM系统传播的tau。我们假设Tau 主要在AT系统中传播，因此反映了从 老化的大脑，而不是解剖学上或功能上的新情况。目标3将使用定向FC来预测 Tau随着时间的推移而扩散，假设大脑区域与内嗅觉皮质连接最强烈 将显示tau病理传播最快，这在AT系统中将是最强的。牛磺酸是如何传播的 通过这些系统以及β和神经连接如何驱动这种传播可能有助于区分 AD从正常衰老的早期阶段，识别进展风险最高的正常个体，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.