Relationships between tau pathology, sleep physiology and memory in aging

项目摘要 最近的研究表明，睡眠中断是一个双向特征的病理进展， 老年痴呆症人类研究集中在β-淀粉样蛋白（Aβ）的积累，这已被证明是 预测主观和客观的睡眠质量下降。目前尚不清楚tau蛋白，另一种 阿尔茨海默病的主要病理特征，导致睡眠中断。在啮齿动物模型中， 聚集的tau预测非快速眼动（NREM）睡眠生理学的异常。这一发现 由于NREM睡眠振荡在支持长期记忆中的已知作用， 合并。具体来说，三个NREM睡眠振荡（慢波， 纺锤波和尖波波纹），发生在人类内侧颞叶（MTL），已经被 可以预测一夜之间的记忆力MTL被认为是第一个大脑区域， 累积tau病理学，在阿尔茨海默病发病前的病理学。鉴于这种解剖学上的 重叠，我们假设MTL tau负荷将预测NREM睡眠振荡的协调中断， 认知正常的老年人有患阿尔茨海默病的风险。我们进一步预测这种tau诱导的破坏 振荡耦合的影响将与受损的长期记忆巩固有关。通过结合（i）在体内 tau病理学的脑成像（18F-AV 1451 PET），（ii）过夜高密度EEG，（iii）为期一周的腕表 睡眠的活动记录测量，和（iv）记忆巩固的敏感测量，该建议旨在 描述tau蛋白和睡眠生理学之间的关联，以及它们对依赖于睡眠的大脑皮层的影响。 在阿尔茨海默病临床前的背景下的记忆。目的1将确定早期tau蛋白积累是否 MTL与NREM睡眠振荡的中断有关，如果这种中断导致记忆失败， 合并。目标2旨在确定手表活动记录仪是否可以测量多个 夜晚可以作为tau负荷的敏感和特异性标记。通过阐明tau蛋白与 病理学和多种睡眠测量，这些实验可能提供重要的初步数据， 开发针对阿尔茨海默病预防和治疗的睡眠疗法。

Project Summary Recent work suggests that disrupted sleep is a bi-directional feature in the pathological progression of Alzheimer’s disease. Human studies have focused on β-amyloid (Aβ) accumulation, which has been shown to predict subjective and objective declines in sleep quality. It remains unknown whether tau protein, the other primary pathological feature of Alzheimer’s disease, contributes to sleep disruption. In rodent models, aggregated tau predicts abnormalities in non-rapid eye movement (NREM) sleep physiology. This finding is functionally relevant, due to the known role of NREM sleep oscillations in supporting long-term memory consolidation. Specifically, the strength of coordinated coupling of three NREM sleep oscillations (slow waves, spindles, and sharp-wave ripples), which occurs within the human medial temporal lobe (MTL), has been demonstrated to predict overnight memory retention. MTL is known to be one of the first brain regions to accumulate tau pathology, before the onset of Alzheimer’s disease symptomology. Given this anatomical overlap, we hypothesize that MTL tau burden will predict disrupted coordination of NREM sleep oscillations in cognitively normal older adults at risk for Alzheimer’s disease. We further predict that this tau-induced disruption of oscillatory coupling will be associated with impaired long-term memory consolidation. By combining (i) in vivo brain imaging of tau pathology (18F-AV1451 PET), (ii) overnight high-density EEG, (iii) weeklong wristwatch actigraphy measures of sleep, and (iv) sensitive measures of memory consolidation, this proposal aims to characterize associations between tau and sleep physiology, and their impact on hippocampus-dependent memory in the context of preclinical Alzheimer’s disease. Aim 1 will determine whether early tau accumulation in MTL is associated with the disruption of NREM sleep oscillations, and if this disruption results in failed memory consolidation. Aim 2 seeks to determine whether wristwatch actigraphy measures of sleep quality across multiple nights may serve as a sensitive and specific marker of tau burden. By elucidating the relationship between tau pathology and multiple measures of sleep, these experiments may provide important preliminary data for developing sleep-based therapies targeting Alzheimer’s disease prevention and treatment.