Circuit-specific tau burden and mechanisms of sleep-dependent memory processing in older adults at risk for Alzheimer’s disease

有阿尔茨海默病风险的老年人的电路特异性 tau 蛋白负担和睡眠依赖性记忆处理机制

• 批准号: 10539903
• 负责人: BRYCE A. MANDER
• 金额: $ 43.18万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10539903
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amygdaloid structure; Amyloid beta-Protein; Behavior Therapy; Brain; Cognitive; Coupling; Data; Deposition; Disease Progression; Elderly; Electroencephalography; Emotional; Episodic memory; Exhibits; Functional Magnetic Resonance Imaging; Goals; Hippocampus (Brain); Impaired cognition; Impairment; Intervention Studies; Knowledge; Link; Magnetic Resonance Imaging; Mediation; Memory; Memory impairment; Methods; Modeling; Multimodal Imaging; Neurodegenerative Disorders; Onset of illness; Outcome; Pathogenesis; Pathologic; Pathology; Pharmacology; Polysomnography; Positron-Emission Tomography; Predisposition; REM Sleep; Resolution; Rest; Risk Factors; Role; Senile Plaques; Site; Sleep; Sleep disturbances; Slow-Wave Sleep; Symptoms; System; Taxes; Testing; Tracer; abeta accumulation; affective disturbance; basal forebrain; basal forebrain cholinergic neurons; cognitive process; cohort; density; design; emotion dysregulation; entorhinal cortex; episodic memory impairment; flexibility; innovation; insight; memory consolidation; memory process; memory retention; mild cognitive impairment; multimodal neuroimaging; neocortical; network architecture; non rapid eye movement; non-demented; novel; pre-clinical; prevent; prospective; rapid eye movement; relating to nervous system; sleep regulation; sleep spindle; tau Proteins; tau aggregation

PROJECT SUMMARY Alzheimer’s disease is a progressive neurodegenerative disorder characterized by the accumulation of beta- amyloid (Aβ) plaques and neurofibrillary tau tangles. While Aβ is an important Alzheimer’s disease risk factor, tau is more closely tied to cognitive outcomes. Tau pathology accumulates locally and spreads through specific brain circuits, initially aggregating within the hippocampal (HC)-entorhinal cortex (EC) circuit and impairing episodic memory. New data, including our own, indicate that the basal forebrain (BF) and amygdala (AMY), regions supporting emotional memory processing, are also early sites of tau deposition. Whether tau deposition within these circuits contributes to distinct impairments in emotional and non-emotional memory function is unknown. HC-EC and BF-AMY circuits exhibit different brain network dynamics, express discrete facets of non- rapid eye movement (NREM) and REM sleep oscillatory activity, and support distinct aspects of sleep-dependent memory consolidation (SDMC). It is possible that tau deposition within these circuits results in deficits in sleep expression as well as dynamic network architecture important for SDMC. To address these critical knowledge gaps, we will use an innovative multimodal neuroimaging design combining high-resolution positron emission tomography with a novel [18F]MK-6240 tau tracer, polysomnography with high-density electroencephalography, and high-resolution resting-state functional magnetic resonance imaging combined with a memory task taxing HC-AMY function. Using these methods, we will test the novel hypothesis that local tau deposition within these circuits is associated with distinct deficits in sleep expression, dynamic resting state network architecture, and SDMC in cognitively unimpaired Aβ+ older adults. In Aim 1, we will test two hypotheses: (1) HC-EC tau will be associated with deficits in NREM slow wave-spindle coupling, which will be associated with impaired overnight memory retention across valence. (2) BF-AMY tau will be associated with reduced REM theta, which will be associated with impaired overnight retention of emotional memories. In Aim 2, will test three hypotheses. (1) HC- EC and BF-AMY tau will be associated with decreased network modularity, which will be associated with impaired SDMC. (2) HC-EC tau will be associated with reduced HC-EC flexibility, which will be associated with diminished sleep-dependent consolidation of non-emotional memories. (3) BF-AMY tau will be associated with lower BF-AMY flexibility, which will be associated with diminished emotional memory consolidation. We will also use mediation models to test if regional tau pathology impacts memory consolidation through these hypothesized mechanisms. Findings from the proposed study will provide novel insight into the mechanisms contributing to distinct deficits in SDMC in older adults at risk for Alzheimer’s disease, potentially guiding prospective intervention studies to minimize cognitive decline associated with Alzheimer’s disease.

项目概要 阿尔茨海默病是一种进行性神经退行性疾病，其特征是β- 淀粉样蛋白 (Aβ) 斑块和神经原纤维 tau 蛋白缠结虽然 Aβ 是阿尔茨海默病的重要危险因素， tau 蛋白与认知结果的关系更为密切。tau 蛋白病理学在局部积累并通过特定的方式传播。 大脑回路，最初聚集在海马（HC）-内嗅皮层（EC）回路内并损害 新的数据，包括我们自己的数据，表明基底前脑（BF）和杏仁核（AMY）， 支持情绪记忆处理的区域，也是 tau 蛋白沉积的早期场所。 这些回路内的神经元会导致情绪和非情绪记忆功能的明显损害 HC-EC 和 BF-AMY 回路表现出不同的大脑网络动态，表达非离散的方面。 快速眼动 (NREM) 和 REM 睡眠振荡活动，并支持睡眠依赖性的不同方面 记忆巩固 (SDMC) 可能是这些回路中的 tau 蛋白沉积导致睡眠不足。 表达以及动态网络架构对于 SDMC 来说很重要，以解决这些关键知识。 差距，我们将使用结合高分辨率正电子发射的创新多模态神经成像设计 使用新型 [18F]MK-6240 tau 示踪剂进行断层扫描，使用高密度脑电图进行多导睡眠图检查， 以及高分辨率静息态功能磁共振成像与记忆任务相结合 使用这些方法，我们将测试 HC-AMY 功能中局部 tau 沉积的新假设。 电路与睡眠表达、动态静息状态网络架构的明显缺陷相关， 认知未受损的 Aβ+ 老年人中的 SDMC 在目标 1 中，我们将测试两个假设：(1) HC-EC tau 将是。 与 NREM 慢波-纺锤体耦合缺陷有关，这将与隔夜受损有关 (2) BF-AMY tau 将与 REM theta 减少相关，这将 与情绪记忆的过夜保留受损有关。在目标 2 中，将检验三个假设 (1) HC-。 EC 和 BF-AMY tau 将与网络模块化程度降低相关，这将与 (2) HC-EC tau 蛋白受损与 HC-EC 灵活性降低有关，而这又与 HC-EC 灵活性降低有关。 (3) BF-AMY tau 将与 BF-AMY 灵活性较低，这与情绪记忆巩固减弱有关。 使用中介模型来测试区域 tau 病理学是否通过这些影响记忆巩固 拟议研究的结果将为促进机制提供新的见解。 有阿尔茨海默病风险的老年人的 SDMC 存在明显缺陷，可能指导未来的研究 旨在尽量减少与阿尔茨海默病相关的认知能力下降的干预研究。