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

阿尔茨海默病和 PSP 睡眠觉醒行为的临床特征和神经病理学基础

• 批准号: 10589765
• 负责人: Lea Tenenholz Grinberg
• 金额: $ 80.51万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589765
• 关键词: Accounting; Alzheimer' s Disease; Alzheimer' s disease patient; Amyloid beta-Protein; Anatomy; Area; Autopsy; Behavior; Biological Specimen Banks; Brain; Brain Stem; Cell Nucleus; Cessation of life; Clinical; Collection; Deposition; Dimensions; Disease; Drowsiness; Future; Glutamates; Hypothalamic structure; Institutionalization; Lesion; Maps; Measures; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Neurotransmitters; Parvalbumins; Patients; Pattern; Population; Preoptic Areas; Progressive Supranuclear Palsy; REM Sleep; Regulation; Residual state; Reticular Formation; Rodent; Sleep; Sleep Disorders; Sleep Fragmentations; Sleep disturbances; Slow-Wave Sleep; Synapses; Tauopathies; Testing; Time; Wakefulness; abeta deposition; actigraphy; aged; analog; basal forebrain; brain cell; calbindin; cholinergic; design; experience; hypocretin; interest; neuron loss; neuronal patterning; neuropathology; non rapid eye movement; noradrenergic; novel; parvocellular; preoptic nucleus; segregation; sleep pattern; sleep regulation; tau Proteins; tau mutation; therapeutic target

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.

项目摘要/摘要 睡眠障碍经常发生在神经退行性疾病中，并且是神经退行性疾病最常见的原因。 制度化。睡眠中断也被认为是导致β淀粉样蛋白增加的原因 （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， 但其与其他主要AD神经病理学的关系-致病性tau蛋白相关的累积 神经纤维缠结-未知。在AD中，睡眠功能障碍包括睡眠片段化、日落和睡眠障碍。 白天嗜睡，通过多次睡眠潜伏期测试（MPEST）的短睡眠潜伏期来测量。与此相反， 我们发现进行性核上性麻痹（PSP），一种与Aβ沉积无关的不同tau蛋白病， 快速眼动（REM）睡眠和非快速眼动（NREM）睡眠的持续时间显著减少 睡眠，以及MSLT观察到的睡眠潜伏期延长。AD和PSP的tau神经病理学都开始于 皮质下脑干和下丘脑。他们不同的睡眠-觉醒行为模式-在PSP中， 与AD相比，总睡眠时间显著减少，白天睡眠不足，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-沿着睡眠和觉醒相关的对比tau负荷 脑干核团（brainstem nucleus，BRN）Res.），提供了一个新的机会，发现他们的神经生物学基础， 睡眠-觉醒节律紊乱我们将测试新的假设，不同的脆弱性的核， 唤醒促进（AD > PSP中的损失）和睡眠促进（PSP > AD中的损失）神经元决定了不同的 这两种对比鲜明的tau蛋白病的睡眠-觉醒障碍模式。 该建议的前提是：1）睡眠-觉醒障碍是这两种tau蛋白病共同的; 2） 利用在PSP和AD早期观察到的皮质下解剖学上不同的神经变性灶， 在AD中以觉醒为主的功能和在PSP中以睡眠为主的核团，作为自然病变，将揭示 他们的睡眠和觉醒被干扰的差异概况的机制;和3）有效的， PSP和AD睡眠的具体治疗需要了解其各自的机制。 我们将通过确定PSP和AD受试者与健康受试者的睡眠-觉醒行为是否存在差异来验证我们的想法。 对照组（HC）在定量上归因于相应的病理解剖学指标（包括总的 神经元和特定神经元亚群的数量，和hp-tau负荷）在涉及觉醒的核中 NREM睡眠调节我们将评估定量临床神经组织病理学相关性， PSP、AD和对照受试者的子样本，这些受试者在死亡和尸检前完成了睡眠测量。的 项目代表了一个独特的合作/跨学科的机会，高度专业化的大脑集合 和睡眠分析，其结果可能会产生一个前所未有的疾病特异性机制的理由， 在AD和PSP中，治疗靶向促睡眠回路与觉醒抑制方法。

项目成果

Association of Sleep and β-Amyloid Pathology Among Older Cognitively Unimpaired Adults.

• DOI: 10.1001/jamanetworkopen.2021.17573
• 发表时间: 2021-07-01
• 期刊: JAMA network open
• 影响因子: 13.8
• 作者: Insel PS;Mohlenhoff BS;Neylan TC;Krystal AD;Mackin RS
• 通讯作者: Mackin RS

Proof-of-concept for characterization of neurodegenerative disorders utilizing two non-REM sleep biomarkers.

• DOI: 10.3389/fneur.2023.1272369
• 发表时间: 2023
• 期刊: Frontiers in neurology
• 影响因子: 3.4

Sleep disruption is not observed with brain-responsive neurostimulation for epilepsy.

大脑反应性神经刺激治疗癫痫未观察到睡眠中断。

• DOI: 10.1002/epi4.12382
• 发表时间: 2020
• 期刊: Epilepsia open
• 影响因子: 3
• 作者: Ruoff,Leslie;Jarosiewicz,Beata;Zak,Rochelle;Tcheng,ThomasK;Neylan,ThomasC;Rao,VikramR
• 通讯作者: Rao,VikramR