Stress Mental Disorders Accelerated Aging and Dementia a 35 year Cohort Study

 描述（由申请人提供）：许多研究表明抑郁症状或障碍与认知和功能结果不良之间存在联系。焦虑症状和障碍、睡眠不佳以及压力性生活事件很常见，并与抑郁症相关，但对它们与认知和功能下降的关系知之甚少，例如 如阿尔茨海默病（AD）中发生的。这些与压力相关的暴露也与医疗发病率和残疾有关，但将其与不良健康结果联系起来的机制尚不清楚。横断面研究表明，这些暴露可能通过加速细胞衰老（通过缩短端粒来衡量）导致这些结果。需要对具有良好特征的应激相关暴露史和重复测量细胞衰老的队列进行前瞻性研究，以调查这种可能性。我们建议使用已经收集的数据分析这些问题，在巴尔的摩流行病学流域（ECA）随访研究队列，增加另一波数据收集。1981年，巴尔的摩ECA研究开始收集东巴尔的摩居民的代表性样本中有关抑郁症和焦虑症的结构化诊断访谈数据，并进行了三次额外的调查，最近一次是在2004年（第4次调查）。除了焦虑和抑郁症状和障碍的测量外，多元化（35%非裔美国人）ECA队列还完成了对睡眠不良、生活压力源、创伤暴露、认知和功能障碍的重复测量。2004年，当所有参与者年龄≥40岁时，他们捐献了血液和口腔样本。所有ECA受试者的年龄均≥50岁（估计平均值= 68，范围52-96）。我们将找到并采访来自第4波的约601名参与者，重复对精神障碍的结构化诊断访谈评估，并通过自我报告和腕关节活动记录仪测量生活压力源、创伤暴露和睡眠不良。参与者将完成神经心理学测试和功能测量，并将再次捐献血液和口腔样本。这将使我们能够确定从中年到晚年的35年压力相关暴露史与认知和功能下降、裁定的轻度认知障碍和痴呆诊断（包括可能和可能的AD）以及细胞衰老的生物标志物（端粒缩短和2004年至2016年p16 ink 4a水平增加）的关联。我们还将确定这些暴露是否与ECA中基因的表观遗传修饰相关，我们基于新的全基因组关联和甲基化分析选择ECA，我们将在巴尔的摩老龄化纵向研究（BLSA）和InCHIANTI队列的现有数据中进行分析。我们将检查这些候选位点的甲基化以及ECA中的炎症指标（2004年和2016年在血液中测量）是否介导ECA队列中假设的预测关联。研究结果将澄清从中年到晚年的压力相关暴露与衰老相关结果之间的联系，推进将这些暴露与疾病和残疾联系起来的机制的知识，并为预防这些结果的途径提供线索。

 DESCRIPTION (provided by applicant): Numerous studies demonstrate links between depressive symptoms or disorders and poor cognitive and functional outcomes. Anxiety symptoms and disorders, poor sleep, and stressful life events are common and correlated with depression, but little is known about their association with cognitive and functional decline, such as occurs in Alzheimer's disease (AD). These stress-related exposures are also associated with medical morbidity and disability, but the mechanisms linking them to poor health outcomes are unclear. Cross-sectional studies suggest that these exposures might lead to these outcomes by hastening cellular aging, measured by shortening of telomeres. Prospective studies in cohorts with well-characterized histories of stress-related exposures and repeated measures of cellular aging are needed to investigate this possibility. We propose to analyze these issues using data already collected in the Baltimore Epidemiologic Catchment Area (ECA) Followup Study cohort, adding another wave of data collection. The Baltimore ECA Study began collecting structured diagnostic interview data on depressive and anxiety disorders in 1981 in a representative sample of East Baltimore residents, and did so over three additional waves, most recently in 2004 (Wave 4). In addition to measures of anxiety and depressive symptoms and disorders, the diverse (35% African American) ECA cohort has completed repeated measures of poor sleep, life stressors, trauma exposure, cognition, and functional impairment. In 2004, when all participants were aged ≥40 years, they donated blood and buccal samples. All ECA subjects are now aged ≥50 (estimated mean = 68, range 52-96). We will locate and interview an estimated 601 participants from Wave 4, repeating structured diagnostic interview assessment of mental disorders, and measuring life stressors, trauma exposure, and poor sleep by both self-report and wrist actigraphy. Participants will complete neuropsychological tests and functional measures, and will again donate blood and buccal samples. This will enable us to determine the association of 35-year histories of stress- related exposures, from mid to later life, with cognitie and functional decline, adjudicated mild cognitive impairment and dementia diagnoses, including probable and possible AD, and biomarkers of cellular aging: shortening of telomeres and increases in p16ink4a levels from 2004 to 2016. We will also determine if these exposures are associated with epigenetic modification of genes in the ECA that we select based on novel genome-wide association and methylation analyses we will conduct in existing data from the Baltimore Longitudinal Study of Aging (BLSA) and the InCHIANTI cohorts. We will examine whether methylation of these candidate sites, and measures of inflammation (measured in blood in 2004 and 2016) in the ECA, mediate hypothesized predictive associations in the ECA cohort. Results will clarify the link between stress-related exposures from mid to later life and aging-related outcomes, advance knowledge of mechanisms linking these exposures to disease and disability, and provide clues to avenues for preventing these outcomes.