Mechanisms of Alzheimer's Disease Progression in the Aging Brain

衰老大脑中阿尔茨海默氏病进展的机制

• 批准号: 10418727
• 负责人: William J. Jagust
• 金额: $ 84.92万
• 依托单位: UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10418727
• 关键词: Age; Aging; Alzheimer' s Disease; Amnesia; Amyloid; Amyloid beta-Protein; Anatomy; Animal Model; Animals; Anterior; Apolipoprotein E; Architecture; Atrophic; Autopsy; Brain; Brain region; Clinical Trials; Cognitive; Data; Deposition; Descriptor; Development; Disease Progression; Dorsal; Elderly; Episodic memory; Etiology; Functional Magnetic Resonance Imaging; Genotype; Human; Individual; Inferior; Intervention; Lateral; Lead; Left; Link; Longitudinal cohort; Magnetic Resonance Imaging; Measures; Medial; Memory; Memory Loss; Methods; Modeling; Multimodal Imaging; Nerve Degeneration; Neurofibrillary Tangles; Neuropsychological Tests; Participant; Pathogenesis; Pathology; Pattern; Positron-Emission Tomography; Prevention; Procedures; Process; Research; Research Project Grants; Retrieval; Scanning; Semantics; Speed; Stream; Symptoms; Synapses; System; Tauopathies; Temporal Lobe; Time; abeta accumulation; abeta deposition; aging brain; cerebral atrophy; cognitive ability; cognitive change; cognitive testing; entorhinal cortex; experimental study; follow-up; high risk; imaging approach; improved; memory encoding; neocortical; neural patterning; normal aging; novel; novel strategies; object recognition; protein aggregation; regional atrophy; relating to nervous system; sex; spatial memory; support network; tau Proteins; tau aggregation; visual processing

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.

项目摘要 虽然迟发性零星阿尔茨海默氏病（AD）通常在健忘症中宣布 蛋白质β-淀粉样蛋白（Aβ）和tau可能在症状发作之前多年沉积在大脑中。这 过程发生在大脑的情节记忆系统中，在正常衰老的背景下。越来越多的证据 指向tau蛋白从内侧临时叶和新皮层大脑区域的传播指向 从正常衰老到AD的过渡至关重要，可能通过Aβ驱动以及神经活动的模式和 连接性。在这个项目中，我们将专门检查情节内存系统的两个子系统，一个 前临时（AT）系统源自外侧内嗅皮层（LEC），专门用于对象存储器，并且 源自内侧内嗅皮层（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很重要，因为Tau沉积在较旧的LEC中开始 大脑，而Aβ沉积在PM系统中。该申请基于一个纵向队列，由 几乎有200个以前有基线淀粉样蛋白pet扫描的认知正常老年人 [11C] PIB，纵向结构MRI检查，其中一些人与Tau-Pet成像 [18f] flortaucipir。对于这个项目，120名参与者将对PIB-PET进行基线检查，Flortaucipir- 宠物，结构性MRI和神经心理学测试对记忆和其他认知能力；这些程序 将在1.5和3年后重复。基线检查还将包括功能性MRI实验 参与者编码新颖的对象和场景以定义AT和PM情节记忆系统。 神经活动将使用定向功能连通性（定向FC）检查，一种分析方法 利用Granger因果关系，评估从一个地区到另一个地区的神经活动。这 定向FC将在随后的3年中对Tau通过存储系统的传播建模。目标1意志 检查与Aβ，纵向皮质萎缩和 认知变化。我们假设Aβ会加快tau的扩散，这反过来将与萎缩有关 记忆力下降。 AIM 2将检查Tau通过AT和PM系统扩散。我们假设tau 主要在AT系统中传播，因此反映了开始的过程的增强 老化的大脑，而不是解剖或功能性新疾病。 AIM 3将使用定向FC预测 随着时间的流逝，tau的传播是，大脑区域最强烈地连接到内嗅皮层的假设 将显示Tau病理学最快的传播，这将在AT系统中很强。陶如何传播 通过这些系统以及Aβ和神经连通性如何推动这种扩散可以帮助区分 正常衰老的AD最早阶段，确定正常人的进展风险最高，并提供 为临床试验选择个体选择的新方法。