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: 9887564
• 负责人: Jayandra Jung Himali
• 金额: $ 84.69万
• 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 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9887564
• 关键词: Abeta synthesis; Accounting; Acute; Age; Alzheimer' s Disease; Alzheimer' s disease brain; 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; Event; Flushing; Framingham Heart Study; Genetic Risk; Gold; Hippocampus (Brain); Home environment; 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 stratification; Role; Sample Size; Sampling; Sleep; Sleep Apnea Syndromes; Sleep Disorders; Sleep Wake Cycle; Sleep disturbances; Slow-Wave Sleep; Subgroup; Synaptic plasticity; Therapeutic; Time; Wakefulness; White Matter Disease; Work; abeta accumulation; age difference; aging brain; apolipoprotein E-4; base; blood-brain barrier permeabilization; brain volume; cardiovascular health; cerebral atrophy; cognitive ability; cognitive function; cognitive performance; cohort; dementia risk; density; endophenotype; executive function; glymphatic system; high risk; improved; innovation; ischemic injury; memory consolidation; men; neuroinflammation; neurophysiology; non-demented; novel; osteoporosis with pathological fracture; population based; pre-clinical; protein aggregation; rate of change; response; sex; sex risk; sleep quality; sleep spindle; socioeconomics; success; 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.

确定与痴呆症相关的睡眠的具体方面是发展的第一步 睡眠干预措施可降低痴呆风险。详细的夜间睡眠研究，称为多导睡眠图 （PSG），提供睡眠评估的黄金标准。由于获得 PSG 很麻烦，因此 PSG 的研究倾向于 招募有限数量的参与者，因此检测小而多的统计能力有限 睡眠与痴呆症之间存在潜在的重要关联。我们建议整理 5 个大的数据 基于人群的队列（社区动脉粥样硬化风险、心血管健康研究、弗雷明汉 心脏研究、男性骨质疏松性骨折以及骨质疏松性骨折的研究）方法论 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 提出以下目标： 目标 1 是检查与较高事件风险相关的睡眠方面 阿尔茨海默病 (AD) 痴呆（N=2776，499 例发病病例）。我们将捕获 134 个睡眠指标， 测量睡眠神经生理学的各个方面。然后我们将识别集群并计算第一个本金 每个集群中的组件作为暴露者。我们将进一步评估集群特定之间的关联 使用最小绝对收缩和选择算子 (LASSO) 回归的睡眠指标和结果 1.a.我们 将检查睡眠神经生理学的各个方面，以了解 AD 痴呆症的风险，之后 考虑已知的混杂因素。 1.b.我们将利用我们的统计能力来探索按年龄划分的差异 几十年、性别和遗传风险（例如 APOE ε4 阳性）。目标 2 是检查睡眠的各个方面（定义 目标 1）与痴呆内表型具有横截面相关性。由于睡眠不佳是可以改变的， 重要的是要知道睡眠不佳是否与痴呆症的临床前表型有关，即痴呆症的临床前表型。 痴呆症风险可能仍然具有可塑性。 MRI 上的脑萎缩和认知能力的轻微缺陷先于 痴呆症诊断时间长达十年。我们将把每个睡眠标记与一般和特定领域的认知联系起来 表现（N=6723）以及脑容量（总脑和海马）和脑损伤（白质） 疾病、无症状梗塞）在 MRI 上（N=1157）。目标 3 是检查睡眠神经生理学是否发生变化 超过约 6 年的时间预测痴呆事件（N=1558，275 个事件）、认知（N=3065）或脑容量 （N = 763）。利用相隔约 6 年的重复 PSG，我们将检查睡眠神经生理学的变化是否与其相关 AD 痴呆症、脑容量或认知功能的影响。我们对社区参与者的大量分析 来自美国各地的研究将提供迄今为止关于睡眠与 AD 之间关联的最有力证据 痴呆症风险。此外，利用我们的大量合并样本量来检查亚组差异（例如，按年龄 几十年来，性和 APOE）以及睡眠神经生理学的全面研究，包括创新 睡眠测量（例如纺锤体密度）可以通过识别来为预防痴呆症的治疗策略提供信息 风险最高的亚组、改善痴呆症风险分层的新生物标志物以及新的生物途径。