Trauma Exposure and Cognitive Impairment: Understanding Polygenic Liability and the Causative and Moderating Effects of Exposure, PTSD, and Psychiatric Comorbidity in WTC Responders

创伤暴露和认知障碍：了解 WTC 急救人员中的多基因责任以及暴露、创伤后应激障碍 (PTSD) 和精神共病的因果效应和调节作用

• 批准号: 10314406
• 负责人: Frank D Mann
• 金额: $ 35.37万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10314406
• 关键词: Accounting; Activities of Daily Living; Address; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Area; Clinical; Cognitive; Cognitive aging; Complex; Data; Data Analyses; Development; Disasters; Disease; Education; Enrollment; Environmental Exposure; Environmental Impact; Environmental Risk Factor; Epidemiologist; Ethnic group; Etiology; Exploratory/Developmental Grant; Exposure to; Gender; General Population; Genetic; Genetic Predisposition to Disease; Genetic Risk; Health; Impaired cognition; Impairment; Incidence; Individual; Intervention; Light; Link; Major Depressive Disorder; Mediating; Mendelian randomization; Mental Depression; Mental Health; Modeling; Molecular Genetics; Nerve Degeneration; Neurodegenerative Disorders; Pathogenesis; Pathway interactions; Phase; Phenotype; Population; Post-Traumatic Stress Disorders; Psychiatrist; Quantitative Genetics; Race; Research; Research Activity; Risk; Risk Factors; Role; Severities; Symptoms; Transact; Trauma; Variant; Work; apolipoprotein E-4; cognitive ability; cohort; comorbidity; depressive symptoms; effective therapy; gene environment interaction; genetic architecture; genome-wide; hazard; human disease; innovation; interest; middle age; mild cognitive impairment; mortality risk; pandemic disease; pleiotropism; post-traumatic symptoms; programs; protective factors; trauma exposure; treatment strategy

Title: Trauma Exposure and Cognitive Impairment: Understanding Polygenic Liability and the Causative and Moderating Effects of Exposure, PTSD, and Psychiatric Comorbidity in WTC Responders Abstract: Alzheimer's Disease is a neurodegenerative disorder that is ultimately fatal. The prodromal phase of the disease begins with the gradual decline of cognitive ability, and risk of death increases when these impairments affect basic activities of daily living. This proposal responds to FOA number RFA-OH-21-004 (Exploratory/Developmental Grants Related to the World Trade Center Health Program) by delineating genetic and environmental transactions that undergird cognitive impairment and psychiatric comorbidity in WTC responders. The research activities of this proposal are feasible during a global pandemic, build upon the team's existing expertise in quantitative and molecular genetics, longitudinal modeling, cognitive aging, and the pathogenesis of Alzheimer's Disease and related dementia (ADRD). Specifically, genetically-informative, longitudinal data from the World Trade Center (WTC) Health program will be analyzed to increase the precision with which exposure effects are estimated for WTC responders and better understand the genetic and environmental transactions that contribute to cognitive impairment, depression, and their longitudinal co- occurrence. Incidence of cognitive impairment is higher in WTC responders than in the general population, precipitated by longitudinal increases in PTSD and depressive symptoms. Moreover, the link between exposure severity and cognitive impairment in WTC responders is especially pronounced among APOE-ε4 carriers9, consistent with a gene-by-environment interaction. The proposed data analysis extends this work by addressing (1) whether the association between exposure severity and cognitive impairment, and between PTSD and cognitive impairment are consistent with a cause-effect relation; and (2) whether exposure severity, PTSD, and depressive symptoms moderate polygenic liability for cognitive impairment in WTC responders, while also (3) supporting comparisons of gender, race, and ethnic group differences in longitudinal changes in cognitive health. Understanding the causative and moderating factors that contribute to and exacerbate prodromal symptoms of Alzheimer's Disease, including cognitive impairment, is critical to understanding pathogenesis and the development of effective treatment and intervention strategies.

创伤暴露和认知障碍：了解多基因责任和因果关系， WTC应答者中暴露、PTSD和精神共病的调节作用 翻译后摘要：阿尔茨海默病是一种神经退行性疾病，最终是致命的。的前驱期 这种疾病始于认知能力的逐渐下降，当这些疾病发生时，死亡风险就会增加。 残疾影响基本的日常生活活动。本提案响应FOA编号RFA-OH-21-004 （与世界贸易中心健康计划有关的探索/发展赠款） 以及环境交易加剧了WTC中的认知障碍和精神共病 响应者。本提案的研究活动在全球大流行期间是可行的， 团队现有的定量和分子遗传学，纵向建模，认知老化和 阿尔茨海默病和相关痴呆（ADRD）的发病机制。具体来说，遗传信息， 将分析来自世界贸易中心（WTC）健康计划的纵向数据， 精确估计暴露效应的WTC响应者和更好地了解遗传 和环境交易，有助于认知障碍，抑郁症，和他们的纵向合作， 发生。WTC应答者的认知障碍发生率高于一般人群， 由创伤后应激障碍和抑郁症状的纵向增加所引发。此外， WTC应答者的暴露严重程度和认知障碍在APOE-ε4中尤其明显 携带者9，与基因与环境的相互作用一致。拟议的数据分析扩展了这项工作， 解决（1）暴露严重程度与认知障碍之间的关联，以及 创伤后应激障碍和认知障碍符合因果关系;（2）暴露的严重程度， 创伤后应激障碍和抑郁症状中度多基因倾向的认知障碍的WTC反应， 同时也（3）支持性别，种族和种族群体差异的纵向变化的比较， 认知健康理解导致和加剧 阿尔茨海默病的前驱症状，包括认知障碍，对于理解 发病机制和有效的治疗和干预策略的发展。