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.

项目概要 虽然迟发性散发性阿尔茨海默氏病 (AD) 通常会伴有健忘症，但总体而言 β-淀粉样蛋白 (Aβ) 和 tau 蛋白可能在症状出现前在大脑中沉积多年。 越来越多的证据表明，这一过程发生在大脑的情景记忆系统中。 指出 tau 蛋白从内侧颞叶扩散到新皮质大脑区域，如下所示 在从正常衰老到 AD 的转变中至关重要，可能是由 Aβ 和神经活动模式驱动的 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，一个是 前颞（AT）系统起源于外侧内嗅皮层（LEC），专门负责物体记忆，以及 起源于内侧内嗅皮层 (MEC) 的后内侧系统 (PM) 系统，专门负责空间 这对于区分衰老和 AD 很重要，因为 tau 沉积开始于老年人的 LEC。 大脑中，而 Aβ 沉积在 PM 系统中。该应用程序建立在由以下组成的纵向队列之上。 近 200 名认知正常的老年人以前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]flortaucipir 在该项目中，120 名参与者将接受 PIB-PET、flortaucipir- 的基线检查。 PET、结构 MRI 以及记忆和其他认知能力的神经心理学测试； 基线检查将在 1.5 和 3 年后重复进行，还将包括功能性 MRI 实验。 参与者对新颖的物体和场景进行编码，以定义 AT 和 PM 情景记忆系统。 将使用定向功能连接（directed-FC）（一种分析方法）来检查神经活动 利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。 direct-FC 将在接下来的 3 年内模拟 tau 在记忆系统中的传播。 检查 tau 扩散的整体模式与 Aβ 的存在、纵向皮质萎缩和 我们认为 Aβ 会加速 tau 蛋白的扩散，进而导致萎缩。 目标 2 将检查 tau 在 AT 和 PM 系统中的传播。 主要在 AT 系统中传播，因此反映了始于 Aim 3 将使用定向 FC 来预测老化的大脑，而不是解剖或功能上的新状况。 tau蛋白随着时间的推移而扩散，假设大脑区域与内嗅皮层联系最紧密 将显示 tau 病理学传播最快，并且在 AT 系统中最强。 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 AD 正常衰老的最早阶段，识别进展风险最高的正常个体，并提供 选择临床试验个体的新方法。