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.