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: 10614920
• 负责人: Kaitlin Elizabeth Cassady
• 金额: $ 7.18万
• 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/10614920
• 关键词: Address; Age-associated memory impairment; Aging; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease pathology; Amygdaloid structure; 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; Medial; Mediating; Memory; Memory Loss; Memory impairment; Modeling; Molecular; Neurobiology; Neurofibrillary Tangles; Neuropsychology; Pathogenesis; Pathologic; Pathology; Performance; Positron-Emission Tomography; Process; Reporting; Research; Rest; Semantics; Senile Plaques; Symptoms; System; Temporal Lobe; Testing; Time; Work; abeta accumulation; age related; beta amyloid pathology; cognitive function; dementia risk; episodic memory impairment; experimental study; healthy aging; human old age (65+); insight; neural; neural network; neuromechanism; neuropathology; normal aging; novel strategies; pathological aging; public health relevance; segregation; tau Proteins; tau aggregation; therapy development; young adult; Address; Age-associated memory impairment; Aging; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease pathology; Amygdaloid structure; 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; Medial; Mediating; Memory; Memory Loss; Memory impairment; Modeling; Molecular; Neurobiology; Neurofibrillary Tangles; Neuropsychology; Pathogenesis; Pathologic; Pathology; Performance; Positron-Emission Tomography; Process; Reporting; Research; Rest; Semantics; Senile Plaques; Symptoms; System; Temporal Lobe; Testing; Time; Work; abeta accumulation; age related; beta amyloid pathology; cognitive function; dementia risk; episodic memory impairment; experimental study; healthy aging; human old age (65+); insight; neural; neural network; neuromechanism; neuropathology; normal aging; novel strategies; pathological aging; public health relevance; 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 拟议的研究的目的是研究β的积累的潜在机制 淀粉样蛋白（Aβ）斑块和Tau缠结可能导致情节记忆障碍。情节记忆的丧失是 与年龄相关的认知能力下降的标志之一，是痴呆症的主要危险因素。在症状之前 在阿尔茨海默氏病（AD）中发生的痴呆症，Aβ斑块和神经原纤维tau缠结开始出现在 脑。这个过程通常始于与情节记忆相关的神经元系统，并紧密跟踪 与年龄相关的记忆障碍。一个重要的开放问题是Aβ和TAU积累如何导致 记忆力下降。一种可能性是Aβ和TAU可能通过中断导致记忆丧失，或者 情节内存网络的“脱依性”。例如，大规模的规范网络，例如 据报道，默认模式，显着性和注意力网络在较旧的与年轻人中的隔离程度较小 成人以及这种去分化与各种任务的表现受损有关。 但是，这些观察结果的分子和病​​理底物尚不清楚。我建议测试是否 Aβ和TAU的积累与情节记忆系统中的网络分离有关 网络隔离是否介导神经病理学和记忆力下降之间的关联。在 初步分析，我使用静止状态fMRI测量神经系统中的功能网络隔离 大多数与剧集记忆（前临时（AT）和后膜（PM）网络）相关的较旧 和年轻人。我发现AT和PM网络在较旧的情况下明显较小 年轻人。在这些发现的基础上，我将在基线时研究老年人，并记忆 大约6年的三个时间点的性能。我提出的研究将测试以下 假设：（1）增加的Aβ/TAU将与较小的AT/PM网络隔离相关，（2）隔离较少 AT/PM网络将预测基线时的情节记忆性能和性能的变化 随着时间的流逝，（3）更多的Aβ/TAU将预测记忆力较差（基线和性能的变化 随着时间的流逝），网络分离将介导Aβ/TAU与性能之间的关系。一起， 提出的实验将测试一个模型，在该模型中，与年龄相关的Aβ和TAU导致中性 固有功能内存网络的去分化，这又导致内存不足。通过研究这个 健康老年人的情节记忆系统，我们可以提高对健康衰老及其健康的理解 与病理衰老的相似性和差异，这可以作为早期的重要组成部分 检测AD。