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，这是最常见的原因 制度化。不幸的是，还建议睡眠中断为增加淀粉样蛋白β （Aβ）沉积，这引起了对睡眠与阿尔茨海默氏病（AD）的双向关系的兴趣 但是它与其他主要AD神经病理学的关系 - 致病性TAU相关的积累 神经纤维缠结 - 未知。在AD中，睡眠功能障碍包括睡眠破碎，日落和 白天嗜睡，通过在多个睡眠潜伏期测试（MSLT）上的短睡眠潜伏期来衡量。相比之下， 我们发现渐进性闭核麻痹（PSP）是与Aβ沉积无关的不同tauopathy， 快速眼动（REM）睡眠和非REM（NREM）的持续时间的特征是明显减少的特征 MSLT看到的睡眠和长时间的睡眠潜伏期。 AD和PSP的TAU神经病理学都开始 从下属中，在脑干和下丘脑中。他们发散的睡眠唤醒行为曲线 - 在PSP中， 急剧改善了总睡眠时间，缺少白天睡眠，与广告中的睡眠，夜间重新分配 时期，总睡眠时间几乎减少 - 以及与睡眠和唤醒有关的对比的Tau Burnen 脑干核（PRELIM。RES。）提供了一个新的机会来发现其神经生物学基础 干扰的睡眠节奏。我们将检验一个新的假设，即核的差异漏洞 启动唤醒（AD> PSP中的损失）和促进睡眠（PSP> AD中的损失）神经元决定不同 在这两种对比鲜明的tauopathies中，睡眠效果的模式。 该提议的前提是：1）这两种tauopathies都常见，睡眠效果是共同的； 2） 利用皮层下解剖上不同的神经退行性焦点，请参见PSP＆AD的早期，该焦点是分离的 在功能上，作为自然病变的AD和PSP中唤醒核主导的核位 他们的睡眠和清醒的差异谱的机制； 3）未来的高效设计， PSP和AD中睡眠的特定治疗方法将需要了解其各自的机制。 我们将通过确定PSP和AD受试者的睡眠效果行为的差异与健康的差异来测试我们的想法 对照（HC）在定量上归因于相应改变的途径措施（包括总计 核涉及的核中神经元和特定神经元亚群的数量和HP-TAU负担） 和NREM睡眠调节。我们将评估相对的定量临床神经组织病理学相关性 PSP，AD和控制受试者的子样本在死亡和尸检之前完成睡眠措施。这 项目代表了一个独特的协作/跨学科机会，并具有高度专业的大脑收集 和睡眠分析，其结果可能会产生前所未有的疾病特异性机械原理 在AD和PSP中，在治疗上靶向前静脉电路。

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