Post-Acute Sequelae of SARS-CoV-2 Infection and Subsequent Disease Progression in Individuals with AD/ADRD: Influence of the Social and Environmental Determinants of Health

项目摘要 二零一九年新型冠状病毒病（COVID-19）全球大流行带来严重后果。最近 研究表明，COVID-19患者发生一系列急性期后神经系统事件的风险增加， 在COVID-19诊断后12个月内出现后遗症，包括认知和记忆障碍。尽管 在一般人群中观察到COVID-19急性期后神经系统结局的风险升高， 已知认知受损个体中SARS-CoV-2感染后急性后遗症（PASC）（例如， 轻度认知障碍[MCI]和阿尔茨海默病[AD]/AD相关痴呆[ADRD]患者）， 它如何影响他们随后的疾病进展。快速采用电子健康记录（EHR） 系统已经为研究提供了纵向临床数据，特别是对于MCI患者或 AD/ADRD患者需要频繁的常规护理。然而，现有的基于EHR的大型COVID-19队列并不 特别关注有几个关键限制的认知受损个体，包括（1）缺失或 关于认知障碍的信息不准确，（2）表征疾病进展的挑战， MCI或AD/ADRD患者，以及（3）可以解释MCI或AD/ADRD的可靠因果建模方法。 观察性RWD中的复杂混杂和选择偏倚。更重要的是， 导致PASC和随后的疾病进展的因素 新冠肺炎。长期以来，人们认识到，健康的社会和环境决定因素（SEDH） 在认知健康中的重要作用。暴露于多种SEDH与MCI相关， AD/ADRD。我们最近的研究（R21 ES 032762和RECOVER Initiative）也发现SEDH是 与普通人群中COVID-19的发病率、严重程度、死亡率和PASC相关。个人 同时暴露于多个SEDH，并且该问题是一个理想的框架，可以严格检查如何 SEDH影响认知受损个体对PASC的易感性和随后的疾病进展。 基于我们之前和正在进行的关于COVID-19和PASC在普通人群中的工作， RECOVER Initiative，亚表型和疾病进展建模，以及多个SEDH，我们将（1） 了解MCI或AD/ADRD患者中PASC的流行病学， 推理方法，（2）检查COVID-19和PASC对随后疾病进展的影响， 个体MCI或AD/ADRD与新的动态主题建模方法，和（3）评估如何SEDH 导致MCI或AD/ADRD患者的PASC和随后的疾病进展 令人困惑的概念框架。该项目将填补我们对以下方面的重要知识空白， 特别是SEDH对PASC风险和随后疾病进展的贡献， 认知障碍

PROJECT SUMMARY The global pandemic of the 2019 novel coronavirus disease (COVID-19) has severe consequences. Recent studies showed that individuals with COVID-19 had increased risk of an array of postacute incident neurologic sequelae, including cognition and memory disorders, in 12 months after COVID-19 diagnosis. Despite elevated risks of postacute neurologic outcomes of COVID-19 observed in the general population, little is known about Post-Acute Sequelae of SARS-CoV-2 Infection (PASC) in cognitively impaired individuals (e.g., those with mild cognitive impairment [MCI] and Alzheimer’s disease [AD]/AD-related dementias [ADRD]) and how it may impact their subsequent disease progression. The rapid adoption of electronic health record (EHR) systems has made longitudinal clinical data available for research, especially for individuals with MCI or AD/ADRD who engage in frequent routine care. However, existing large EHR-based COVID-19 cohorts do not specifically focus on cognitively impaired individuals have several key limitations, including (1) missing or inaccurate information on cognitive impairment, (2) challenges to characterize disease progression in individuals with MCI or AD/ADRD, and (3) robust causal modeling approaches that can account for the complex confounding and selection biases in observational RWD. More importantly, little is known about factors contributing to PASC and subsequent disease progression in cognitively impaired individuals with COVID-19. It has long been recognized that social and environmental determinants of health (SEDH) play important roles in cognitive health. Exposures to multiple SEDH have been associated with MCI and AD/ADRD. Our recent studies (R21ES032762 and the RECOVER Initiative) also found that SEDH are associated with COVID-19 incidence, severity, mortality, and PASC in the general population. Individuals are exposed to multiple SEDH simultaneously, and the exposome is an ideal framework to rigorously examine how SEDH impacts cognitively impaired individuals’ susceptibility to PASC and subsequent disease progression. Building upon our prior and ongoing work on COVID-19 and PASC in the general population with the RECOVER Initiative, sub-phenotyping and disease progression modeling, and multiple SEDH, we will (1) understand the epidemiology of PASC in individuals with MCI or AD/ADRD with high-throughput causal inference approaches, (2) examine the impacts of COVID-19 and PASC on subsequent disease progression in individuals with MCI or AD/ADRD with a novel dynamic topic modeling approach, and (3) assess how SEDH contribute to PASC and subsequent disease progression in individuals with MCI or AD/ADRD with the exposome conceptual framework. This project will fill important knowledge gaps on our understanding of, especially SEDH’s contributions to, risks of PASC and subsequent disease progression in individuals with cognitive impairment.