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

项目总结 阿尔茨海默病是一种进行性神经退行性疾病，其特征是β-内毒素的积聚。 淀粉样蛋白(Aβ)斑块和神经原纤维tau缠结。虽然Aβ是阿尔茨海默病的重要风险因素， Tau与认知结果有更紧密的联系。Tau病理在局部积累，并通过特定的 大脑回路，最初聚集在海马(HC)-内嗅觉皮质(EC)回路内，并损害 情节记忆。包括我们自己在内的新数据表明，基底前脑(BF)和杏仁核(AMY)， 支持情绪记忆处理的区域也是tau沉积的早期场所。是否沉积了牛磺酸 在这些回路内导致情绪和非情绪记忆功能的明显损害 未知。HC-EC和BF-AMY电路表现出不同的脑网络动力学，表达了非 快速眼动(NREM)和REM睡眠振荡活动，并支持睡眠依赖的不同方面 内存整合(SDMC)。这些回路中tau的沉积可能会导致睡眠障碍。 表达以及动态网络体系结构对SDMC非常重要。要解决这些关键知识 ，我们将使用一种创新的多模式神经成像设计，结合高分辨率正电子发射 用新的[18F]MK-6240 tau示踪剂进行断层扫描，用高密度脑电进行多导睡眠图， 结合记忆任务的高分辨率静息功能磁共振成像 HC-AMY功能。使用这些方法，我们将检验这一新的假设，即这些区域内的局部tau沉积 电路与睡眠表达、动态休眠状态网络体系结构以及 认知正常的Aβ+老年人的SDMC。在目标1中，我们将检验两个假设：(1)HC-EC tau将是 与NREM慢波-纺锤波耦合缺陷有关，这将与夜间受损有关 跨价态的内存保留。(2)BF-Amy tau将与REM theta减少相关，这将是 与情绪记忆的过夜保持受损有关。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联，这将与 SDMC受损。(2)HC-EC tau将与HC-EC灵活性降低相关，这将与 减少对睡眠依赖的非情绪性记忆的巩固。(3)BF-Amy tau将与 BF-AMY灵活性较低，这将与情绪记忆巩固程度降低有关。我们还将 使用中介模型来检验局部tau病变是否通过以下假设影响记忆巩固 机械装置。拟议研究的结果将提供对以下机制的新见解： 有阿尔茨海默病风险的老年人的SDMC明显缺陷，可能指导未来 旨在最大限度地减少与阿尔茨海默病相关的认知衰退的干预研究。

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.