Clinical Features and Neuropathological Basis of Sleep Wake Behavior in Alzheimer's and PSP

项目摘要/摘要 睡眠障碍经常发生在神经退行性疾病中，并构成 制度化。睡眠障碍也被认为是导致淀粉样β蛋白增加的原因之一。 (Aβ)沉积，这激发了人们对睡眠和阿尔茨海默病(AD)双向关系的兴趣， 但它与其他主要AD神经病理的关系--与tau相关的致病堆积 神经原纤维缠结--未知。在AD中，睡眠功能障碍包括睡眠碎片、日落和 白天嗜睡，通过多重睡眠潜伏期测试(MSLT)上的短睡眠潜伏期来衡量。相比之下， 我们发现进行性核上性麻痹是一种与Aβ沉积无关的不同的变态反应， 显著缩短快速眼动(REM)睡眠和非快速眼动(NREM)睡眠时间 睡眠，以及MSLT看到的延长的睡眠潜伏期。AD和PSP的tau神经病理均始于 皮质下，在脑干和下丘脑。他们不同的睡眠-觉醒行为特征-在PSP中， 与AD组相比，总睡眠时间显著减少，没有白天睡眠，睡眠在夜间和白天重新分配 周期，总睡眠时间几乎没有减少--以及睡眠和清醒相关的tau负担的对比 脑干核团(Prelim.Res.)，为发现其神经生物学基础提供了一个新的机会 紊乱的睡眠-觉醒节律。我们将测试新的假设，即原子核的不同易损性 促进觉醒(AD&GT；PSP)神经元和睡眠促进(PSP&GT；AD)神经元决定了不同 这两种截然不同的疾病中睡眠-觉醒障碍的模式。 这一建议的前提是：1)睡眠-觉醒障碍是这两种紧张症的共同特征；2) 利用PSP和AD早期出现的皮质下解剖上不同的神经变性灶，分离 在功能上，AD以觉醒为主，PSP以睡眠为主，作为自然损害，将揭示 睡眠紊乱和清醒的不同特征的机制；以及3)未来设计高效、 对PSP和AD的睡眠的具体治疗需要了解它们各自的机制。 我们将通过确定PSP和AD受试者与健康受试者睡眠-觉醒行为的差异来检验我们的想法 对照(HC)在数量上归因于相应的改变的病理解剖措施(包括总 神经元和特定神经元亚群的数量，以及hp-tau负荷)参与觉醒的核团 和NREM睡眠规则。我们将分别评估定量的临床神经组织病理学相关性 在死亡和尸检前完成睡眠测量的PSP、AD和对照组受试者的亚样本。这个 该项目代表了一个独特的协作/跨学科机会，具有高度专业化的大脑集合 和睡眠分析，其结果可能会产生史无前例的疾病特异性机制基础 在阿尔茨海默病和PSP中，以促睡眠回路为治疗靶点与清醒抑制方法相比。

PROJECT SUMMARY / ABSTRACT Sleep disturbances occur frequently in neurodegenerative disease and constitute the most common reason for institutionalization. Sleep disruption has also been proposed to contribute causally to increasing amyloid beta (Aβ) deposition, which has fueled interest in bidirectional relationships of sleep and Alzheimer's Disease (AD), but its relationship to the other major AD neuropathology – accumulation of pathogenic tau-related neurofibrillary tangles – is unknown. In AD, sleep dysfunction includes sleep fragmentation, sundowning, and daytime sleepiness, measured by short sleep latencies on the multiple sleep latency test (MSLT). In contrast, we found that Progressive Supranuclear Palsy (PSP), a different tauopathy not associated with Aβ deposition, features marked reductions in duration of both Rapid Eye Movement (REM) sleep and Non-REM (NREM) sleep, and prolonged sleep latencies seen by MSLT. The tau neuropathologies of AD and PSP both begin subcortically, in brainstem and hypothalamus. Their divergent sleep-wake behavior profiles – in PSP, dramatically decreased total sleep time, absent daytime sleep, vs. in AD, sleep redistributed across night & day periods, with little reduction of total sleep time – along with contrasting tau burden in sleep- and wake-related brainstem nuclei (Prelim. Res.), provides a novel opportunity to discover the neurobiological basis of their disturbed sleep-wake rhythms. We will test the novel hypothesis that differential vulnerabilities of nuclei in wake-promoting (loss in AD > PSP) and sleep-promoting (loss in PSP > AD) neurons determines the different pattern of sleep-wake disturbances in these 2 contrasting tauopathies. The premise of this proposal is that: 1) sleep-wake disturbances are common to both of these tauopathies; 2) leveraging the subcortical anatomically distinct neurodegeneration foci seen early in PSP & AD, that segregate functionally as wake-predominant in AD and sleep-predominant nuclei in PSP, as natural lesions, will uncover mechanisms of their differential profiles of disturbed sleep and wakefulness; and 3) future design of efficient, specific treatments for sleep in PSP and AD will require understanding of their respective mechanisms. We will test our idea by determining if differences in sleep-wake behavior in PSP and AD subjects vs. healthy controls (HC) are quantitatively attributable to corresponding altered pathoanatomical measures (including total numbers of neurons and of specific neuronal subpopulations, and hp-tau burden) in nuclei involved in wake and NREM sleep regulation. We will assess quantitative clinical neurohistopathological correlates in respective subsamples of PSP, AD, and control subjects who completed sleep measures prior to death and autopsy. The project represents a unique collaborative/interdisciplinary opportunity with highly specialized brain collections and sleep analysis, whose results may yield an unprecedented disease-specific mechanistic rationale for therapeutically targeting pro-sleep circuits vs. a wakefulness-inhibition approach in AD and PSP.