Contributions of sleep to preclinical and clinical Alzheimer's disease

睡眠对阿尔茨海默病临床前和临床的影响

• 批准号: 10581537
• 负责人: Jayandra Jung Himali
• 金额: $ 74.26万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581537
• 关键词: Abeta synthesis; Acceleration; Accounting; Acute; Age; Alzheimer' s Disease; Amyloid beta-Protein; Atherosclerosis Risk in Communities; Biological; Biological Markers; Biology; Brain; Brain Injuries; Buffers; Clinical; Cluster Analysis; Cognition; Cognitive; Communities; Country; Coupling; Data; Dementia; Development; Diagnosis; Electroencephalography; Enrollment; Ethnic Origin; Event; Flushing; Framingham Heart Study; Genetic Risk; Hippocampus; Home; Hypoxia; Incidence; Individual; Infarction; Intervention; Investigation; Ischemic Brain Injury; Magnetic Resonance Imaging; Measures; Memory; Meta-Analysis; Metabolic; Methodology; Nerve Degeneration; Neurocognitive; Outcome; Participant; Pathway interactions; Phase; Phenotype; Play; Polysomnography; Prevention; REM Sleep; Research; Resources; Risk; Risk Reduction; Role; Sample Size; Sampling; Sleep; Sleep Apnea Syndromes; Sleep Disorders; Sleep Wake Cycle; Slow-Wave Sleep; Subgroup; Synaptic plasticity; Therapeutic; Time; Wakefulness; White Matter Disease; Work; abeta accumulation; age difference; aging brain; blood-brain barrier permeabilization; brain magnetic resonance imaging; brain volume; cardiovascular health; cerebral atrophy; cognitive ability; cognitive function; cognitive performance; cohort; dementia risk; density; endophenotype; executive function; glymphatic flow; high risk; improved; innovation; ischemic injury; memory consolidation; men; neuroinflammation; neurophysiology; non-demented; novel; osteoporosis with pathological fracture; poor sleep; population based; pre-clinical; protein aggregation; rate of change; response; risk stratification; sex; sex risk; sleep quality; sleep spindle; socioeconomic diversity; success; verbal; wasting

Identifying the specific aspects of sleep that relate to incident dementia is the first step towards the development of sleep interventions to reduce dementia risk. Detailed overnight sleep studies, known as polysomnography (PSG), provide the gold-standard assessment of sleep. As obtaining PSG is burdensome, studies with PSG tend to enroll a limited number of participants and consequently have limited statistical power to detect small but potentially important associations between sleep and dementia. We propose to curate data from 5 large population-based cohorts (Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study, Osteoporotic Fractures in Men, and the Study of Osteoporotic Fractures) with methodologically consistent sleep studies and neurocognitive outcomes. By combining study-level data in meta-analysis, we propose the following aims: Aim 1 is to examine the aspects of sleep that relate to a higher risk of incident Alzheimer's disease (AD) dementia (N=2776, 499 incident cases). We will capture 134 sleep metrics, measuring all aspects of sleep neurophysiology. We will then identify clusters and calculate the first principal component from each cluster as the exposers. We will further assess the association between cluster specific sleep metrics and outcomes using least absolute shrinkage and selection operator (LASSO) regression 1.a. We will examine each aspect of sleep neurophysiology with respect to the risk of incident AD dementia, after accounting for known confounders. 1.b. We will leverage our statistical power to explore differences by age decades, sex, and genetic risk (e.g., APOE ε4 positivity). Aim 2 is to examine the aspects of sleep (defined in Aim 1) that relate cross-sectionally to dementia endophenotypes. As poor sleep is potentially modifiable, it is important to know whether poor sleep is related to preclinical phenotypes of dementia—a time when dementia risk may still be malleable. Brain atrophy on MRI and subtle deficits in cognitive ability precede dementia diagnosis by up to a decade. We will relate each sleep marker to general and domain-specific cognitive performance (N=6723) as well as brain volume (total brain and hippocampal) and brain injury (white matter disease, silent infarcts) on MRI (N=1157). Aim 3 is to examine whether changes in sleep neurophysiology over ~6 years predict incident dementia (N=1558, 275 events), cognition (N=3065), or brain volume (N=763). Leveraging repeated PSGs ~6 years apart, we will examine if changes in sleep neurophysiology relate to incident AD dementia, brain volume, or cognitive function. Our large analysis of community-based participants from across the U.S. will provide the most robust evidence yet on the associations between sleep and AD dementia risk. Moreover, leveraging our large pooled sample size to examine subgroup differences (e.g., by age decades, sex and APOE) and the comprehensive investigation of sleep neurophysiology, including innovative sleep measures (e.g., spindle density), may inform therapeutic strategies for dementia prevention by identifying subgroups most at risk, new biomarkers to improve dementia risk stratification, and novel biological pathways.

确定与痴呆症事件有关的睡眠的具体方面是发展的第一步。 睡眠干预以降低痴呆风险。详细的夜间睡眠研究，称为多导睡眠图 (PSG)，提供睡眠的黄金标准评估。由于获得巴黎圣日耳曼的负担很重，对巴黎圣日耳曼的研究倾向于 为了招募有限数量的参与者，并因此具有有限的统计能力来检测小但 睡眠和痴呆症之间潜在的重要联系。我们建议从5个大型数据库中收集数据， 基于人群的队列研究（社区动脉粥样硬化风险，心血管健康研究，FRA） 心脏研究、男性骨质疏松性骨折和骨质疏松性骨折的研究）， 一致的睡眠研究和神经认知结果。通过在荟萃分析中结合研究水平的数据，我们 我提出了以下目标：目标1是检查睡眠的各个方面，这些方面与更高的事件风险有关 阿尔茨海默病（AD）痴呆（N=2776，499例事件病例）。我们将采集134个睡眠指标， 测量睡眠神经生理学的各个方面。然后，我们将识别聚类并计算第一个主项 从每个集群中提取组件作为标记。我们将进一步评估集群特异性 使用最小绝对收缩和选择算子（LASSO）回归的睡眠度量和结果我们 将检查睡眠神经生理学的各个方面与AD痴呆症发病风险的关系， 考虑到已知的混杂因素。1.b.我们将利用我们的统计能力来探索年龄的差异 年龄、性别和遗传风险（例如，APOE ε4阳性）。目的2是检查睡眠的各个方面（定义为 在目的1）中，其在横截面上与痴呆内表型相关。由于睡眠不好是可以改变的， 了解睡眠不好是否与痴呆的临床前表型有关是很重要的， 痴呆症的风险可能仍然是可塑性的。MRI显示的脑萎缩和认知能力的轻微缺陷 痴呆症的诊断。我们将把每个睡眠标记与一般和特定领域的认知功能联系起来， 性能（N=6723）以及脑体积（全脑和海马）和脑损伤（白色物质 疾病，无症状性梗死）（N=1157）。目的3是检查睡眠神经生理学的变化是否 超过6年可预测痴呆（N=1558，275起事件）、认知（N=3065）或脑容量 （N=763）。利用间隔约6年的重复PSG，我们将检查睡眠神经生理学的变化是否与 与AD痴呆、脑容量或认知功能的关系。我们对社区参与者的大量分析 将提供关于睡眠与AD之间联系的最有力的证据。 痴呆风险此外，利用我们的大样本量来检查亚组差异（例如，按年龄 几十年，性别和APOE）和睡眠神经生理学的全面调查，包括创新的 睡眠测量（例如，纺锤体密度），可以通过识别 最危险的亚组，改善痴呆风险分层的新生物标志物和新的生物学途径。

项目成果

Sleep-wake parameters can be detected in patients with chronic stroke using a multisensor accelerometer: a validation study.

使用多传感器加速度计可以检测慢性中风患者的睡眠-觉醒参数：一项验证研究。

• DOI: 10.5664/jcsm.8812
• 发表时间: 2021
• 期刊: Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine
• 作者: Gottlieb,Elie;Churilov,Leonid;Werden,Emilio;Churchward,Thomas;Pase,MatthewP;Egorova,Natalia;Howard,MarkE;Brodtmann,Amy
• 通讯作者: Brodtmann,Amy

Sleep Regularity and Mortality: A Prospective Analysis in the UK Biobank.

睡眠规律和死亡率：英国生物库的前瞻性分析。

• DOI: 10.1101/2023.04.14.23288550
• 发表时间: 2023
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Cribb,Lachlan;Sha,Ramon;Yiallourou,Stephanie;Grima,NatalieA;Cavuoto,Marina;Baril,Andree-Ann;Pase,MatthewP
• 通讯作者: Pase,MatthewP