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.

标题：创伤暴露和认知障碍：了解多基因责任及其因果关系 WTC 急救人员中暴露、创伤后应激障碍 (PTSD) 和精神共病的调节作用 摘要：阿尔茨海默病是一种最终致命的神经退行性疾病。前驱期 该疾病始于认知能力逐渐下降，当这些能力逐渐下降时，死亡风险就会增加 损伤影响日常生活的基本活动。该提案响应 FOA 编号 RFA-OH-21-004 （与世界贸易中心健康计划相关的探索性/发展赠款）通过描述遗传 以及导致世贸中心认知障碍和精神共病的环境交易 响应者。该提案的研究活动在全球大流行期间是可行的，建立在 团队在定量和分子遗传学、纵向建模、认知衰老和 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， 将分析世界贸易中心 (WTC) 健康计划的纵向数据，以提高 准确地估计世贸中心响应者的暴露影响，并更好地了解遗传因素 和导致认知障碍、抑郁及其纵向协同的环境交易 发生。世贸中心响应者的认知障碍发生率高于一般人群， PTSD 和抑郁症状的纵向增加促成了这一结果。此外，之间的联系 WTC 应答者的暴露严重程度和认知障碍在 APOE-ε4 中尤其明显 载体9，与基因与环境的相互作用一致。拟议的数据分析通过以下方式扩展了这项工作 解决（1）暴露严重程度与认知障碍之间是否存在关联，以及 PTSD和认知障碍具有因果关系； (2) 暴露严重程度是否 PTSD 和抑郁症状会影响 WTC 应答者认知障碍的多基因责任， 同时还（3）支持性别、种族和族裔群体纵向变化差异的比较 认知健康。了解导致和加剧的致病因素和调节因素 阿尔茨海默病的前驱症状，包括认知障碍，对于理解这一症状至关重要 发病机制以及有效治疗和干预策略的制定。