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: 10583493
• 负责人: Shaun M Purcell
• 金额: $ 232.25万
• 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/10583493
• 关键词: Acceleration; 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; 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; Ethnic Origin; Etiology; Evolution; Family; Gender; Genetic; Health; Health Care Costs; Hippocampus; Hour; Hypoxia; Impaired cognition; Incidence; Individual; Individual Differences; Intervention; Knowledge; Link; Literature; Longitudinal cohort; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Mediator; 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; Sex Differences; 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 based; 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; racial difference; recruit; risk mitigation; risk stratification; 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.

随着人口的年龄，认知的患病率和发病率惊人地增加 障碍和阿尔茨海默氏病（AD）相关痴呆症（ADRD）：到2050年，美国的人数 随着ADRD的影响，每年将三倍至1,380万，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组合似乎会增加ADRD的风险。 神经元过程的相关变化导致淀粉样蛋白β（Aß）和tau的逐步积累。尽管 人们越来越认识到会影响睡眠和昼夜节律障碍可能加速Aß的积累 和认知能力下降，文献在特定睡眠的因果与非因果的作用方面尚无定论 干扰，尚未解决夜间高血压（可修改的目标）是否介导与睡眠有关 认知结果。我们将利用许多睡眠措施中的明显个体间变异性以及 随着时间的流逝，实质性的内部变化，以开发一个纵向框架以更好地解决问题 因果关系。我们建议利用2010 - 2013年进行的全面睡眠表型（Mesa- 睡觉;考试5），以及持续的和新提出的数据将在梅萨心理研究中收集，这是 包括最先进的认知，神经精神病学和脑成像研究 在相距2。5年（2019 - 2023年）的2个时间点上进行了研究，以有效地解决关键的研究差距。 尽管MESA思维研究将中后期血管疾病作为ADRD的危险因素的作用，但 它无法解决睡眠和昼夜节律疾病的潜在促成或中介作用。因此，我们 提出有效扩大台面研究第二考试（2021-2023）的建议，包括一夜之间 ART多摄影术，7天的摄影术，这是梅萨第一次，24小时的血压记录， 旨在招募针对该考试的2000名参与者中的1800名。我们将产生高级定量 睡眠和昼夜节律的指标以表征临界衰老的睡眠障碍的演变 时期。这些测量将纳入认知的纵向评估，以定义 睡眠障碍与认知障碍之间的临时关联，从而定义了哪个睡眠 扰动和指标是认知障碍的前提因素。我们将评估是否睡眠 在大脑成像之前8年以及睡眠变化的轨迹，预测神经退行性的轨迹， 通过反复的脑MRI和PET成像测量的脑血管疾病和AD脑生物标志物 （作为MESA思维研究的一部分进行）。我们还将评估血压变异性的作用和 夜间高血压是将睡眠障碍和认知/AD敏感性联系起来的介导途径。我们 将探索男女之间的联想差异，不同种族/种族的个人 背景。鉴于睡眠障碍和夜间高血压是 可修改目标。该研究还将为适当的性别风险分层方法提供信息。