Abstract Although severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) is considered a respiratory pathogen, myriad neurologic complications including confusion, stroke, and neuromuscular disorders manifest during acute COVID-19. Furthermore, maladies such as impaired concentration, headache, sensory disturbances, depression, and even psychosis may persist for months following infection, as part of a constellation of symptoms now called Post Acute Sequelae of COVID-19 (PASC). The pathophysiological mechanisms of nervous system PASC (NS-PASC) are not well understood, although evidence to date implicates immune dysfunction, including non-specific neuroinflammation and anti-neural autoimmune dysregulation1. With millions of individuals affected, nervous system complications pose public health challenges for rehabilitation and recovery and major disruptions in the workforce. There is an urgent need to understand the pathophysiology of these disorders and develop disease modifying therapies. Through the COVID Mind Study at Yale, we have initiated a longitudinal study to investigate the pathogenic mechanisms of NS-PASC through examination of cerebrospinal fluid (CSF), blood, and magnetic resonance imaging (MRI), alongside detailed clinical data in individuals with NS-PASC. In Aim 1, we will define the clinical and immunological features through deep immunophenotyping of the CSF and blood, including assessment of brain autoimmunity and altered T cell function. In Aim 2, we will assess for SARS-CoV-2 persistence in the CSF and blood through single copy PCR and highly sensitive viral antigen detection assays. In Aim 3, we will measure objective markers of nervous system dysfunction through brain MRI, neurocognitive testing, and CSF and blood markers of neuronal injury, and will perform multivariate analysis to assess for the relationship between immune perturbations, viral persistence, and objective measures of neurologic injury.