Longitudinal Relationships Among Sleep, Cognition and Alzheimer's Disease Biomarkers: Discerning Causal Associations, Mediators and Susceptibility

睡眠、认知和阿尔茨海默病生物标志物之间的纵向关系：辨别因果关系、中介因素和易感性

• 批准号: 10399412
• 负责人: Shaun M Purcell
• 金额: $ 303.98万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10399412
• 关键词: Address; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Ambulatory Blood Pressure Monitoring; American; Amyloid beta-Protein; Architecture; Base of the Brain; Biological Markers; Blood Pressure; Blood Vessels; Brain; Brain imaging; Cerebral small vessel disease; Cerebrovascular Disorders; Cerebrum; Circadian Dysregulation; Circadian Rhythms; Cognition; Cognitive; Cognitive aging; Data; Data Collection; Data Set; Dementia; Disease; Disease Marker; Disease susceptibility; Elderly; Electroencephalography; Environmental Risk Factor; Etiology; Evolution; Family; Gender; Genetic; Health; Health Care Costs; Hippocampus (Brain); Hour; Hypoxia; Impaired cognition; Incidence; Individual; Individual Differences; Intervention; Knowledge; Lead; Link; Literature; Longitudinal cohort; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Mediator of activation protein; Morbidity - disease rate; Multi-Ethnic Study of Atherosclerosis; Multiomic Data; Nerve Degeneration; Neurocognitive; Neurons; Nocturnal Hypertension; Outcome; Participant; Pathologic; Pathway interactions; Pattern; Perfusion; Personal Satisfaction; Persons; Phenotype; Physiology; Pittsburgh Compound-B; Polysomnography; Population; Positron-Emission Tomography; Predisposition; Prevalence; Process; Public Health; Race; Research; Risk; Risk Factors; Role; Sampling; Sleep; Sleep Apnea Syndromes; Sleep disturbances; Source; Thinness; Time; Vascular Diseases; White Matter Disease; Woman; abeta accumulation; abeta deposition; actigraphy; age related; aged; arterial stiffness; blood pressure variability; brain health; brain magnetic resonance imaging; cardiometabolism; cardiovascular disorder risk; circadian; cognitive change; cognitive performance; critical period; dementia risk; ethnic difference; ethnic diversity; human old age (65+); imaging biomarker; imaging study; inter-individual variation; lifestyle factors; men; metabolic phenotype; middle age; mild cognitive impairment; neuropsychiatry; novel; recruit; risk stratification; sex; sleep health; sleep physiology; sleep quality; tau Proteins; temporal measurement; uptake; vascular risk factor; β-amyloid burden

As the population has aged, there has been a staggering increase in the prevalence and morbidity of cognitive impairment and Alzheimer's disease (AD) related dementias (ADRD): by 2050 the number of people in the U.S. with ADRD will triple to 13.8 million, and associated health care costs will exceed $1.1 trillion annually. Combinations of genetic, lifestyle and environmental factors appear to increase risk for ADRD through age- related changes in neuronal processes that lead to progressive accumulation of amyloid-beta (Aß) and tau. While there is growing recognition that disturbed sleep and circadian disturbances may accelerate Aß accumulation and cognitive decline, the literature is inconclusive regarding the causal vs non-causal role of specific sleep disturbances and has not addressed whether nocturnal hypertension (a modifiable target) mediates sleep-related cognitive outcomes. We will exploit the marked inter-individual variability in many sleep measures, as well as substantial intra-individual changes over time to develop a longitudinal framework to better approach questions of causality. We propose to leverage the comprehensive sleep phenotyping performed from 2010-2013 (MESA- SLEEP; Exam 5), along with ongoing and newly proposed data to be collected in the MESA MIND study, which includes state-of-the-art cognitive, neuropsychiatric, and brain imaging studies in a sample of MESA participants studied at 2 time points 2.5 years apart (2019-2023) to efficiently and uniquely address critical research gaps. While the MESA MIND study addresses the role of mid- and later-life vascular disease as a risk factor for ADRD, it does not address the potential contributory or mediating roles of sleep and circadian disorders. We therefore propose to efficiently expand the MESA MIND study second exam (2021-2023) to include overnight state-of-the- art polysomnography, 7-day actigraphy, and for the first time in MESA, 24-hour blood pressure recordings, aiming to recruit 1800 of the 2000 participants targeted for that exam. We will generate advanced quantitative metrics of sleep and circadian rhythm to characterize the evolution of sleep disturbances over critical aging periods. These measurements will be incorporated into longitudinal assessments of cognition in order to define the temporal associations between sleep disturbances and cognitive impairment, and thus define which sleep disturbances and metrics are antecedent factors for cognitive impairment. We will evaluate whether sleep measured 8 years prior to brain imaging, as well as trajectories of sleep change, predict neurodegeneration, cerebral vascular disease and AD brain biomarkers as measured by repeated brain MRI and PET imaging (performed as part of the MESA MIND Study). We also will assess the role of blood pressure variability and nocturnal hypertension as a mediating pathway linking sleep disturbance and cognition/AD susceptibility. We will explore differences in associations between men and women and individuals of different race/ethnic backgrounds. The study has large potential impact given that sleep disturbances and nocturnal hypertension are modifiable targets. The study also will inform gender-appropriate risk stratification approaches.

随着人口老龄化，认知障碍的患病率和发病率急剧增加 损伤和阿尔茨海默病 (AD) 相关痴呆 (ADRD)：到 2050 年，美国的人口数量 ADRD 患者将增加两倍，达到 1380 万人，每年相关的医疗保健费用将超过 1.1 万亿美元。 遗传、生活方式和环境因素的结合似乎会随着年龄的增长而增加 ADRD 的风险。 神经过程的相关变化导致β-淀粉样蛋白 (Aß) 和 tau 蛋白逐渐积累。 人们越来越认识到睡眠紊乱和昼夜节律紊乱可能会加速 Aß 积累 和认知能力下降，关于特定睡眠的因果作用与非因果作用，文献尚无定论 扰，并且尚未解决夜间高血压（可修改的目标）是否介导与睡眠相关的问题 我们将利用许多睡眠测量中显着的个体差异。 随着时间的推移，个人内部发生重大变化，以制定纵向框架来更好地解决问题 我们建议利用 2010 年至 2013 年进行的全面睡眠表型分析 (MESA- SLEEP；考试 5)，以及 MESA MIND 研究中收集的正在进行的和新提出的数据， 包括对 MESA 参与者样本进行的最先进的认知、神经精神和脑成像研究 在相隔 2.5 年的 2 个时间点（2019-2023）进行研究，以有效且独特地解决关键研究空白。 虽然 MESA MIND 研究探讨了中晚年血管疾病作为 ADRD 危险因素的作用， 因此，它没有解决睡眠和昼夜节律紊乱的潜在贡献或中介作用。 建议有效扩展 MESA MIND 研究第二次考试（2021-2023 年），以包括隔夜最新状态 - 艺术多导睡眠图、7 天体动记录仪，以及 MESA 首次的 24 小时血压记录， 目标是招募 2000 名参加该考试的参与者中的 1800 名，我们将生成高级定量结果。 睡眠和昼夜节律指标来表征关键衰老过程中睡眠障碍的演变 这些测量将被纳入认知的纵向评估中，以便定义。 睡眠障碍和认知障碍之间的时间关联，从而定义哪种睡眠 干扰和指标是认知障碍的先决因素，我们将评估睡眠是否存在。 脑成像前 8 年测量，以及睡眠变化轨迹，预测神经退行性变， 通过重复脑 MRI 和 PET 成像测量脑血管疾病和 AD 脑生物标志物 （作为 MESA MIND 研究的一部分进行）我们还将评估血压变异性和的作用。 夜间高血压作为连接睡眠障碍和认知/ AD 易感性的中介途径。 将探讨男性和女性以及不同种族/民族的个人之间的联系差异 考虑到睡眠障碍和夜间高血压，这项研究具有巨大的潜在影响。 该研究还将为适合性别的风险分层方法提供信息。