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

 描述(由申请人提供)：大量研究表明抑郁症状或障碍与认知和功能结果差之间存在联系。焦虑症状和障碍、睡眠不佳和应激性生活事件是常见的，并与抑郁症相关，但对它们与认知和功能衰退的关系知之甚少，如 就像在阿尔茨海默病(AD)中发生的那样。这些与压力相关的暴露也与医疗发病率和残疾有关，但将它们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而导致这些结果，端粒缩短是衡量这一结果的指标。需要对有明确的应激相关暴露史和反复测量细胞老化的队列进行前瞻性研究，以探讨这种可能性。我们建议使用巴尔的摩流行病学集水区(ECA)后续研究队列中已经收集的数据来分析这些问题，增加另一波数据收集。巴尔的摩ECA的研究于1981年开始收集具有代表性的东巴尔的摩居民样本中关于抑郁和焦虑障碍的结构化诊断性访谈数据，并在另外三次浪潮中收集数据，最近一次是在2004年(浪潮4)。除了焦虑和抑郁症状和障碍的测量外，多样化的ECA队列(35%的非裔美国人)已经完成了对睡眠质量差、生活压力、创伤暴露、认知和功能损害的重复测量。2004年，当所有参与者都是40岁的≥时，他们捐献了血液和口腔样本。所有的非洲经委会受试者现在都是≥50岁(估计平均值为68岁，范围52-96)。我们将从第四波中找到并采访大约601名参与者，重复对精神障碍的结构化诊断性访谈评估，并通过自我报告和手腕动作记录仪测量生活应激源、创伤暴露和睡眠不良。参与者将完成神经心理测试和功能测量，并将再次献血和口腔样本。这将使我们能够确定从中年到晚年与压力相关的35年暴露历史与认知和功能衰退的关系，判定轻度认知障碍和痴呆症诊断，包括可能和可能的AD，以及细胞老化的生物标记物：2004年至2016年端粒缩短和p16INK4a水平上升。我们还将确定这些暴露是否与ECA中基因的表观遗传修饰有关，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新的全基因组关联和甲基化分析。我们将检验ECA中这些候选位点的甲基化以及炎症测量(2004年和2016年用血液测量)是否在ECA队列中中介假想预测关联。结果将澄清中老年压力相关暴露与衰老相关结果之间的联系，促进对这些暴露与疾病和残疾之间联系的机制的了解，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.