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

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.

项目概要 拟议研究的目的是调查β积累的潜在机制 淀粉样蛋白 (Aβ) 斑块和 tau 蛋白缠结可能导致情景记忆障碍。情景记忆的丧失是 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。出现症状之前 阿尔茨海默病 (AD) 中出现痴呆症时，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景记忆相关的神经系统，并密切跟踪 与年龄相关的记忆障碍。一个重要的悬而未决的问题是 Aβ 和 tau 蛋白的积累如何导致 记忆力下降。一种可能性是 Aβ 和 tau 蛋白可能会因干扰而导致记忆丧失，或者 情景记忆网络的“去分化”。例如，大规模规范网络，例如 据报道，老年人与年轻人的默认模式、显着性和注意力网络的隔离程度较小 成年人，这种去分化与多种任务的表现受损有关。 然而，这些观察结果的分子和病​​理基础尚不清楚。我建议测试一下是否 Aβ 和 tau 的积累与情景记忆系统中的网络隔离有关 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，我使用静息态功能磁共振成像来测量神经系统中的功能网络分离 与老年人的情景记忆（前颞叶 (AT) 和后内侧 (PM) 网络）最相关 和年轻人。我发现老年人的 AT 和 PM 网络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 Aβ 和 tau PET 的老年人以及记忆力 大约 6 年期间三个时间点的表现。我提出的研究将测试以下内容 假设：(1) Aβ/tau 增加与 AT/PM 网络隔离程度较低相关，(2) 隔离程度较低 AT/PM 网络将预测基线时更差的情景记忆性能以及性能变化 随着时间的推移，(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），网络隔离将调节 Aβ/tau 与性能之间的关系。一起， 拟议的实验将测试一个模型，其中与年龄相关的 Aβ 和 tau 蛋白的增加会导致神经 内在功能记忆网络的去分化，进而导致记忆缺陷。通过研究这个 健康老年人的情景记忆系统，我们可以加深对健康老龄化及其影响的理解 与病理性衰老的相似点和不同点，这可以作为早期衰老的重要组成部分 AD 的检测。

项目成果

Effect of Alzheimer's Pathology on Task-Related Brain Network Reconfiguration in Aging.

阿尔茨海默病病理学对衰老过程中任务相关大脑网络重构的影响。

• DOI: 10.1523/jneurosci.0023-23.2023
• 发表时间: 2023
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Cassady,KaitlinE;Chen,Xi;Adams,JennaN;Harrison,TheresaM;Zhuang,Kailin;Maass,Anne;Baker,Suzanne;Jagust,William
• 通讯作者: Jagust,William