The episodic autobiographical memory hypothesis of preclinical Alzheimer's disease: Developing a new approach for early cognitive detection and measurement of Alzheimer's disease

临床前阿尔茨海默病的情景自传体记忆假说：开发一种阿尔茨海默病早期认知检测和测量的新方法

基本信息

批准号：
9912065
负责人：
Matthew D Grilli
金额：
$ 7.68万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2022-03-31
项目状态：
已结题

项目摘要

Neuropsychological tests are central to the detection of Alzheimer’s disease (AD), but currently available tests are not sufficiently sensitive to AD neuropathology until the disease has progressed for years. We recently introduced and provided preliminary support for an episodic autobiographical memory (EAM) hypothesis of preclinical AD. This hypothesis states that because EAM places high demands on a neural network that is targeted by the initial stages of AD, EAM testing can improve “preclinical” (i.e., early) cognitive detection of AD. This R03 proposal builds on our novel hypothesis and seeks to advance the development of EAM tests for preclinical AD by filling two gaps in current knowledge. Specifically, our objectives for this proposal are to better understand (1) the cognitive sub- components of EAM that are sensitive to preclinical AD and (2) at what stage of preclinical AD (mild versus severe) EAM disruption is detectable. To achieve these objectives, we formed a team of researchers with expertise in the neuropsychology of autobiographical memory and aging (PI Grilli), the default mode network (DMN) and resting state functional connectivity (RSFC) (Co-I Andrews- Hanna), and the neuroimaging of cognitive aging (Co-I Ryan). Our approach is to study EAM and investigate the relation of EAM to DMN RSFC in cognitively normal older adults, half of whom are carriers of the apolipoprotein E ε4 allele, which increases risk for preclinical AD. We have two specific aims: (1) to reveal that core EAM sub-components are disrupted in cognitively normal older ε4 carriers and (2) to demonstrate that EAM disruption is associated with altered DMN RSFC. Under the first aim, we will investigate established and novel behavioral tasks, each emphasizing a different EAM cognitive sub-component that we hypothesize is compromised in preclinical AD. Under the second aim, we will investigate whether poorer performance on any of the EAM tasks studied under Aim 1 is associated with hyper- and/or hypo-RSFC in regions of the DMN that have been identified as particularly sensitive to preclinical AD. Our reasoning is that if cognitively normal ε4 carriers exhibit worse EAM performance on the behavioral tasks relative to non-carriers, we have gained insight into EAM cognitive sub- components that are vulnerable to preclinical AD. Also, by studying the relation of EAM to DMN RSFC, we can shed light on whether disrupted EAM is sensitive to mild or severe preclinical AD, and by extension, the sensitivity of EAM to two key AD processes. This research is significant because it ultimately could lead to the development of neuropsychological tests and cognitive outcome measures that can detect preclinical AD, which currently do not exist. This research is innovative because the EAM hypothesis is a novel idea for cognitive detection of preclinical AD, and this project will be the first to test whether EAM is related to RSFC signatures of mild or severe preclinical AD.

神经心理学测试对于检测阿尔茨海默氏病（AD）至关重要，但目前在疾病进展之前，可用的测试对AD神经病理学不足以敏感年。我们最近介绍并为情节自传提供了初步支持记忆（EAM）临床前AD的假设。该假设指出，因为EAM的位置很高对AD初始阶段针对的神经元网络的需求，EAM测试可以改善 “临床前”（即早期）AD的认知检测。这个R03提案以我们的新假设为基础并试图通过填补当前的两个空白来推动临床前广告的EAM测试的开发知识。具体而言，我们对该提案的目标是更好地理解（1）认知子 - 对临床前AD敏感的EAM组件，以及（2）在临床前AD的哪个阶段（轻度）与严重的）EAM破坏是可检测的。为了实现这些目标，我们组成了一个团队具有自传记忆和衰老神经心理学专业知识的研究人员（PI Grilli），默认模式网络（DMN）和静止状态功能连接（RSFC）（Co-I Andrews- Hanna），以及认知衰老的神经影像学（Co-I Ryan）。我们的方法是研究EAM和研究EAM与认知正常老年人中EAM与DMN RSFC的关系，其中一半是载脂蛋白Eε4等位基因的载体，这增加了临床前AD的风险。我们有两个特定的目的：（1）揭示核心EAM子材料在认知正常的ε4载体中被破坏（2）证明EAM破坏与DMN RSFC改变有关。在第一个目标下，我们将调查已建立的新型行为任务，每个任务都强调不同的EAM认知我们假设的子组件在临床前AD中受到损害。在第二个目标下，我们将调查AIM 1下研究的任何EAM任务的较差的性能是否与之相关在DMN区域中具有超级和/或Hypo-RSFC，已被确定为特别敏感临床前广告。我们的推理是，如果认知正常ε4载体暴露了EAM性能较差关于相对于非携带者的行为任务，我们已经深入了解了EAM认知子 - 容易受到临床前广告的组件。同样，通过研究EAM与DMN RSFC的关系，我们可以阐明EAM中断是否对轻度或严重的临床前AD敏感，以及扩展，EAM对两个关键AD过程的敏感性。这项研究很重要，因为它最终可能导致神经心理学测试和认知结果指标的发展这可以检测到目前不存在的临床前广告。这项研究具有创新性，因为 EAM假设是临床前AD认知检测的一个新思想，该项目将是首先测试EAM是否与轻度或重度临床前AD的RSFC特征有关。