Mechanisms underlying COVID-19 induced Neurocognitive Dysfunction

项目总结/摘要 严重急性呼吸道综合征冠状病毒2型（SARS-CoV-2）感染，导致冠状病毒疾病 2019年（COVID-19），已成为全球健康危机。迄今为止，已有超过650万人死于COVID-19， 在全球范围内报道。在幸存者中，神经认知功能障碍和神经精神障碍，如 如焦虑和抑郁，越来越多地被认识到，并可能持续数月，甚至数年。这种持久 神经认知和神经精神痛苦迫使我们解决关键问题，他们的持续时间，风险 因素和潜在机制。该项目的目标是检验SARS-CoV-2促进 通过刺激炎症通路，以前正常的受试者认知能力下降， 最大的风险是老年人，女性和那些代表性不足的群体。我们建议利用 我们的生物储存库中因SARS-CoV-2感染住院的患者，以实现三个具体目标： (1)确定神经认知功能障碍的类型和持续时间;（2）确定 持续的认知能力下降，包括性别、年龄、人种/种族和合并症;以及，（3）验证持续的 神经炎症是认知能力下降的基础为了实现这些目标，我们的团队建立了一个精心策划， 超过650名因COVID-19住院的患者的高度多样化的生物储存库。大约15%的人 与COVID相关的疾病;然而，37%的人在3-6和12个月后继续返回进行检测 住院初步数据表明，30%的受试者在一年后返回， 认知能力下降，这与炎症和神经元应激标志物升高有关。这里我们 建议跟踪这些患者，进行详细的认知测试，并评估他们血液中的生物标志物- 血清、脊髓液和影像学检查，以说明存在的认知变化的类型和时间过程， 与认知功能障碍相关的因素，以及炎症诱导的神经元窘迫是否是 进行性神经认知障碍这项建议是创新的，因为我们正在评估长期的 严重COVID-19的神经认知后果来自我们自发病以来一直跟踪的队列， 大流行病，它提供了支持我们的目标的初步数据。此外，我们还召集了 研究人员在认知评估和治疗，以及基础和转化研究，所有在 建立强有力的体制基础设施。我们的工作意义重大，因为了解 COVID-19引起的认知功能障碍中的持续神经炎症将大大增强我们的能力， 合理地测试免疫抑制剂对这种非常衰弱的疾病。

PROJECT SUMMARY/ABSTRACT Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, which causes Coronavirus Disease 2019 (COVID-19), has become a global health crisis. To date, more than 6.5 million deaths from COVID-19 have been reported worldwide. Amongst survivors, neurocognitive dysfunction and neuropsychiatric disorders, such as anxiety and depression, are increasingly recognized and can persist for months, or even years. This enduring neurocognitive and neuropsychiatric distress obligates us to address critical questions about their duration, risk factors, and underlying mechanisms. The goal of this project is to test the hypothesis that SARS-CoV-2 promotes cognitive decline in subjects who were previously normal via stimulating inflammatory pathways, with the greatest risk being in older adults, females, and those from underrepresented groups. We propose to utilize patients in our biorepository, who were hospitalized with SARS-CoV-2 infection, to achieve three Specific Aims: (1) to determine the type and duration of neurocognitive dysfunction present; (2) to ascertain risk factors for ongoing cognitive decline, including sex, age, race/ethnicity and comorbidities; and, (3) to verify that persistent neuroinflammation underlies cognitive decline. To achieve these Aims, our team has established a well-curated, highly diverse biorepository of more than 650 patients hospitalized with COVID-19. About 15% have succumbed to COVID-related illnesses; however, 37% have continued to return for testing at 3-6 and 12-months post hospitalization. Preliminary data demonstrates that 30% of subjects returning at one year show progressive cognitive decline, which is associated with elevated markers of inflammation and neuronal stress. Here we propose to follow these patients and perform detailed cognitive testing and assess biomarkers from their blood- serum, spinal fluid, and imaging to explicate the type and time course of cognitive changes present, the risk factors associated with cognitive dysfunction, and whether inflammation-induced neuronal distress underlies progressive neurocognitive impairment. This proposal is innovative because we are evaluating the long-term neurocognitive consequences of severe COVID-19 from a cohort that we have followed since the onset of the pandemic, which has provided preliminary data supporting our Aims. Moreover, we have brought together investigators with expertise in cognitive assessment and treatment, and basic and translational research, all in the setting of a strong institutional infrastructure. Our work is significant because understanding the role of persistent neuroinflammation in COVID-19-induced cognitive dysfunction will greatly enhance our ability to rationally test immunosuppressants for this very debilitating disorder.