Relationships between tau pathology, sleep physiology and memory in aging

项目摘要 最近的研究表明，睡眠障碍在糖尿病的病理发展过程中是一个双向特征 阿尔茨海默氏症。人类研究的重点是β-淀粉样蛋白(Aβ)的积累，这已被证明是 预测睡眠质量的主观和客观下降。目前还不清楚tau蛋白是不是另一种 阿尔茨海默病的主要病理特征是导致睡眠障碍。在啮齿动物模型中， 聚集的tau可以预测非快速眼动(NREM)睡眠生理的异常。这一发现是 由于NREM睡眠振荡在支持长期记忆方面的已知作用，因此在功能上相关 整合。具体地说，三个NREM睡眠振荡(慢波， 纺锤波和尖波纹波)，发生在人类内侧颞叶(MTL)，已经被 证明可以预测过夜的记忆保持。MTL是已知的第一个大脑区域之一 积累tau病理，在阿尔茨海默病发病前出现症状。鉴于这一解剖结构 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，这种由tau引起的干扰 振荡耦合的发生与长期记忆巩固受损有关。通过在体内结合(I) Tau病理的脑成像(18F-AV1451PET)，(Ii)隔夜高密度脑电，(Iii)一周手表 睡眠的活动测量，和(Iv)记忆巩固的敏感测量，这项提议旨在 表征tau与睡眠生理学之间的联系，以及它们对海马体依赖的影响 临床前阿尔茨海默病背景下的记忆。目标1将决定早期tau的积累 In MTL与NREM睡眠振荡的中断有关，如果这种中断导致内存故障 整合。目标2试图确定腕表动作记录仪是否测量多个 夜晚可能是牛磺酸负担的一个敏感而具体的标志。通过阐明tau和Tau之间的关系 病理学和多项睡眠测量，这些实验可能为 开发以睡眠为基础的疗法，以预防和治疗阿尔茨海默病。

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.