Investigating the Contribution of Peripheral versus Central Nervous System Immune Dysfunction to Cognitive Aging

项目摘要/摘要 冠状病毒病2019年的暴发(新冠肺炎)对老年人的影响不成比例 并对新型SARS-CoV-2病毒的长期后遗症提出了许多问题 晚年临床结局。病理性的衰老环境的特征是一种“启动”的炎症状态， 增加阿尔茨海默病相关蛋白沉积的风险，并更容易受到系统性疾病的影响 感染。我们认为，与SARS-CoV-2暴露相关的临床结果的异质性可能源于 从宿主免疫环境的可变性和AD相关病理的存在，这可能与 对认知轨迹产生负面影响。因此，我们行政部门的总体假设 补充说，接触SARS-CoV-2病毒的老年人将会有更强的认知能力 下降，在AD相关病理程度更高和水平更高的人中注意到更差的结果 全身炎症标志物。父R01的现有基础架构提供了一个关键平台 评估SARS-CoV-2对老龄化结局的影响，因为我们的获奖资金用于确定 生物质谱学[血液；脑脊液]，阿尔茨海默病相关病理分析(即A？1-42；磷酸化 Tau；神经丝轻链[NFL])和180例两次以上老年人炎症标志物的分析 积分。在这项行政补充资料中，我们建议评估抗体水平(即存在或不存在)，以 基线时的血清SARS-CoV-2和父母R01队列中的2年随访。SARS-CoV-2暴露于 与有症状和无症状的疾病有关；以丰富父母R01队列的可能性 对于SARS-CoV-2接触，我们将优先招募20名有确诊病史的年长人士 (即RT-PCR法)新冠肺炎病。我们将解决以下目标：确定是否暴露于 SARS-CoV-2加剧社区老年人的记忆衰退(目标1)；并阐明 SARS-CoV-2暴露与记忆结果之间的关系是否受存在的影响 阿尔茨海默病病理和基线免疫状态的评估(目标2)。我们相信拟议的研究是 对免疫老化的认知神经科学的重要意义；通过阐明病毒暴露对认知的作用 在晚年的结局，我们将准备好了解SARS-CoV-2对神经系统的长期影响 社区老年人的认知和阿尔茨海默病病理，这可能最终指导 针对弱势群体的干预措施。

Project Summary/Abstract The insurgence of coronavirus disease 2019 (COVID-19) has disproportionately affected the older adult population and raised numerous questions regarding long-term sequalae of the novel SARS-CoV-2 virus on late life clinical outcomes. The pathological aging milieu is characterized by a ‘primed’ inflammatory state, increased risk of Alzheimer’s disease-related protein deposition, and greater vulnerability to systemic infections. We propose that the heterogeneity of clinical outcomes related to SARS-CoV-2 exposure may stem from variability in the “host” immune milieu and the presence of AD-related pathology, which may interface to negatively impact cognitive trajectories. As such, the overarching hypothesis of our administrative supplement is that older adults who are exposed to SARS-CoV-2 virus will experience greater cognitive decline, with worse outcomes noted in individuals with greater AD-related pathology and higher levels of systemic inflammatory markers. The existing infrastructure of the parent R01 provides a critical platform to appraise the effect of SARS-CoV-2 on aging outcomes, as our awarded grant funds the ascertainment of biospecimens [blood; CSF], analyses of Alzheimer’s Disease-related pathology (i.e., Aß1-42; phosphorylated tau; neurofilament light chain [NfL]) and analyses of inflammatory markers in 180 older adults over two time points. In this administrative supplement, we propose to evaluate antibody levels (i.e., presence or absence) to SARS-CoV-2 in serum at baseline and 2-year follow-up in the parent R01 cohort. SARS-CoV-2 exposure is associated with both symptomatic and asymptomatic disease; to enrich the parent R01 cohort for the likelihood of SARS-CoV-2 exposure, we will preferentially recruit 20 additional older adults with a history of confirmed (i.e., RT-PCR test) COVID-19 disease. We will address the following Aims: to determine whether exposure to SARS-CoV-2 exacerbates memory decline in community-dwelling older adults (Aim 1); and to elucidate whether associations between SARS-CoV-2 exposure and memory outcomes are influenced by the presence of Alzheimer’s Disease pathology and baseline immune status (Aim 2). We believe that the proposed study is significant to the cognitive neuroscience of immune aging; by clarifying the role of virus exposure on cognitive outcomes in late life, we will be poised to understand long-term neurological implications of SARS-CoV-2 on cognition and Alzheimer’s disease pathology in community-dwelling older adults, which may ultimately guide interventions for vulnerable populations.