Blood brain barrier integrity and immune dynamics contributing to neuropsychiatric sequela in COVID long-haulers

PROJECT SUMMARY/ABSTRACT A substantial (>35%) proportion of patients acutely infected with SARS-CoV-2 demonstrate neurological symptoms ranging from serious headaches to encephalopathy, stroke, seizure, and acute neuropathies. However, some patients experience lingering or emergent neuropsychiatric symptoms within weeks to months following acute infection. The neuropsychiatric burden among COVID long-haulers is a major issue; and yet the underlying pathophysiology of these conditions remains elusive. SARS-Cov-2 infection results in increased levels of circulating proinflammatory cytokines/chemokines and elevation of intermediate monocyte (CD14+CD16+) subsets in blood. Trafficking of these proinflammatory monocytes into the brain of individuals with other chronic viral infections (eg. HIV) has emerged a putative contributor to neuroinflammation, blood brain barrier (BBB) disruption and may explain the ongoing neurological sequalae in COVID long-haulers. We propose to test our hypothesis that COVID long-haulers will have BBB disruption mechanistically linked to targeted, circulating proinflammatory cytokines/chemokines and elevation of intermediate monocytes that traffic to the brain. Monocyte infiltration in response to infection is a hallmark of CNS inflammation and occurs consistently in chronic conditions. Thus, we further hypothesize that disruption in BBB integrity by intermediate monocyte activation and diapedesis promotes persistent neuroinflammation and altered neuronal activity, contributing to neuropsychiatric sequela COVID-19 long-haulers. To this end, we propose cross-sectional imaging to assess BBB integrity, with neuropsychiatric assessments, and immunophenotyping in 100 COVID long-haulers and 100 individuals who have recovered from acute COVID (control group). First, we aim to assess BBB integrity in COVID long-haulers (vs. control) and its contribution to neuropsychiatric conditions. We will assess BBB integrity using a novel, non-contrast magnetic resonance imaging technique that uses water-extraction-with-phase- contrast-arterial-spin-tagging (WEPCAST), to determine BBB permeability to small molecules. We have shown this to be sensitive to BBB change in mild cognitive impairment, a precursor to Alzheimer's disease, and are currently using this technique in other neuro-infectious diseases. Second, we aim to assess the link between circulating soluble markers, PBMC-associated markers, and BBB permeability to small molecules, which collectively may promote diapedesis into brain. We target factors implicated in transmigration of activated PBMCs across the BBB into brain, where they may contribute to neuronal damage and neuropsychiatric burden in COVID long-haulers. After 3 years of funding, this R01 will advance our understanding of BBB integrity and related PBMC migration into the brains of COVID long-haulers, which may contribute to neuroinflammation and related neuropsychiatric burden. Findings will inform next steps in the development of therapeutic approaches to minimize PBMC contribution to neuroinflammation in COVID long-haulers.