Effect of beta-amyloid and tau pathology on functional network organization and memory in aging

β-淀粉样蛋白和 tau 病理学对衰老过程中功能网络组织和记忆的影响

• 批准号: 10368050
• 负责人: Kaitlin Elizabeth Cassady
• 金额: $ 6.76万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-08-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10368050
• 关键词: Address; Age; Age-associated memory impairment; Aging; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid beta-Protein; Anterior; Attention; Behavioral; Brain; Cognition; Data; Dementia; Early Diagnosis; Elderly; Episodic memory; Exhibits; Functional Magnetic Resonance Imaging; Goals; Impairment; Individual Differences; Inferior; Lead; Link; Measures; Mediating; Memory; Memory Loss; Memory impairment; Modeling; Molecular; Neurobiology; Neurofibrillary Tangles; Neuropsychology; Pathogenesis; Pathologic; Pathology; Performance; Positron-Emission Tomography; Process; Reporting; Research; Rest; Risk Factors; Semantics; Senile Plaques; Symptoms; System; Temporal Lobe; Testing; Time; Work; abeta accumulation; age related; cognitive function; dementia risk; episodic memory impairment; experimental study; healthy aging; insight; neural network; neuromechanism; neuropathology; normal aging; novel strategies; object recognition; pathological aging; public health relevance; relating to nervous system; segregation; tau Proteins; tau aggregation; therapy development; young adult

Project Summary The goal of the proposed research is to investigate a potential mechanism by which the accumulation of beta amyloid (Aβ) plaques and tau tangles could lead to episodic memory impairments. A loss of episodic memory is one of the hallmarks of age-related cognitive decline and is a major risk factor for dementia. Before the symptoms of dementia occur in Alzheimer’s disease (AD), Aβ plaques and neurofibrillary tau tangles begin to appear in the brain. This process typically starts in the neural systems associated with episodic memory and tracks closely with age-related memory impairments. An important open question is how Aβ and tau accumulation lead to memory decline. One possibility is that Aβ and tau may lead to memory loss through the disruption, or ‘dedifferentiation’, of episodic memory networks. For example, large-scale canonical networks, such as the default mode, salience, and attention networks, have been reported to be less segregated in older vs. younger adults, and such dedifferentiation has been associated with impaired performance on a variety of tasks. However, the molecular and pathological substrate of these observations is unknown. I propose to test whether the accumulation of Aβ and tau is associated with network segregation in the episodic memory system and whether network segregation mediates the association between neuropathology and memory decline. In preliminary analyses, I used resting state fMRI to measure functional network segregation in the neural systems most associated with episodic memory (the anterior temporal (AT) and posteromedial (PM) networks) in older and younger adults. I found that the AT and PM networks were significantly less segregated in older relative to younger adults. Building on these findings, I will study older adults with Aβ and tau PET at baseline, and memory performance at three time points over a period of about 6 years. My proposed research will test the following hypotheses: (1) Increased Aβ/tau will be associated with less segregated AT/PM networks, (2) less segregated AT/PM networks will predict worse episodic memory performance at baseline as well as change in performance over time, and (3) more Aβ/tau will predict worse memory performance (at baseline and change in performance over time), and network segregation will mediate the relationship between Aβ/tau and performance. Together, the proposed experiments will test a model in which age-related increases in Aβ and tau lead to neural dedifferentiation of intrinsic functional memory networks, which in turn leads to memory deficits. By studying this episodic memory system in healthy older adults, we can advance our understanding of healthy aging and its similarities to and differences from pathological aging, which could serve as a crucial building block for the early detection of AD.

项目摘要 拟议研究的目标是调查一种潜在的机制，通过这种机制，β-淀粉样蛋白的积累， 淀粉样蛋白（Aβ）斑块和tau蛋白缠结可导致情景记忆障碍。情景记忆的丧失 这是与年龄相关的认知能力下降的标志之一，也是痴呆症的主要危险因素。在症状出现之前 在阿尔茨海默病（AD）中，Aβ斑块和神经元tau蛋白缠结开始出现在阿尔茨海默病（AD）中， 个脑袋这个过程通常始于与情景记忆相关的神经系统， 与年龄有关的记忆障碍一个重要的开放性问题是Aβ和tau积累如何导致 记忆衰退一种可能性是Aβ和tau蛋白可能通过破坏导致记忆丧失，或者 “去分化”，情景记忆网络。例如，大规模的规范网络，如 默认模式，突出性和注意力网络，据报道，在老年人与年轻人相比， 这种去分化与各种任务的表现受损有关。 然而，这些观察结果的分子和病理学基础是未知的。我想测试一下 Aβ和tau的积累与情景记忆系统中的网络分离有关， 网络隔离是否介导了神经病理学和记忆衰退之间的关联。在 在初步分析中，我使用静息状态fMRI来测量神经系统中的功能网络隔离 老年人的情景记忆（前颞（AT）和后内侧（PM）网络）最相关。 和年轻人。我发现，AT和PM网络在老年人中的隔离程度明显低于老年人， 年轻的成年人。基于这些发现，我将研究基线时患有Aβ和tau PET的老年人， 在约6年的时间内在三个时间点的性能。我提议的研究将测试以下内容 假设：（1）Aβ/tau增加与AT/PM网络分离较少相关，（2）分离较少 AT/PM网络将预测基线时更差的情景记忆表现以及表现的变化 随着时间的推移，和（3）更多的Aβ/tau将预测更差的记忆性能（在基线和性能变化 随着时间的推移），网络隔离将介导Aβ/tau和性能之间的关系。在一起， 拟议的实验将测试一个模型，在该模型中，Aβ和tau的年龄相关性增加导致神经系统疾病。 内在功能性记忆网络的去分化，这反过来又导致记忆缺陷。通过研究这个 情景记忆系统，我们可以推进我们对健康老龄化及其 与病理性衰老的相似之处和不同之处，这可能是早期衰老的关键组成部分。 检测AD。