Characteristics and Determinants of Post-COVID Neurocognitive Dysfunction

Neurologic symptoms are among the most common post-acute sequelae of COVID-19 (PASC). Recent studies show that there is a very high rate of neurocognitive changes among Veterans surviving acute COVID- 19 infection. The long-term neurocognitive changes of this infection could be even worse and remains incompletely characterized. Moreover, neurological sequelae have been considered the most disabling of the long-term complications. Possible mechanisms of neuronal damage from SARS CoV-2 infection include direct viral CNS invasion through the cribriform plate or hematogenous route, or retrograde neuronal dissemination, or indirect injury mediated by systemic inflammation, and secondary degenerative mechanisms. Whether neurocognitive changes can be predicted by biomarkers - or imaging evidence of - inflammation, neuronal damage or disruption of blood brain barrier has never been evaluated in a well-characterized cohort. Furthermore, no treatment strategies exist at present, but preliminary data suggests that antivirals may prevent the occurrence of cognitive impairment in PASC. VHA has established a nationwide COVID-19 cohort early in the pandemic. This objective of this cohort - called Epidemiology, Immunology and Clinical Characteristics of COVID-19 (EPIC3) - is to characterize the natural history, clinical outcomes, and the development of immunity while also gathering biospecimens for future study as questions emerge about this new pathogen. We will leverage the data and samples from this study to compare participants who received antivirals during their acute COVID-19 illness with those who did not, by 1) conducting longitudinal cognitive assessments of participants of EPIC3 and characterize trajectories of cognitive changes, using a novel tablet-based tool; 2) carrying out detailed longitudinal analyses of biomarkers of neuronal damage, neurodegeneration and blood-brain barrier disruption or participants with and without COVID-19, and 3) performing advanced structural and functional imaging of a subset of these participants. We will then correlate biomarkers and imaging findings to the presence, degree and trajectories of neurocognitive changes in COVID-19 patients who did and did not receive antivirals. We have assembled a multidisciplinary team with expertise critical to answering the challenging questions posed by neurocognitive changes of PASC. Expected findings of our study will have immediate clinical impact: 1) they will establish whether PASC is an additional goal for antiviral therapy, 2) they will establish a benchmark for standardized, validated assessment of possible neurocognitive changes in patients with COVID-19; this will provide a basis for future interventions and management guidelines; 2) determine whether these cognitive changes could be predicted or monitored using well validated biomarkers of neuronal damage and/or blood-brain barrier disruption; 3) determine whether structural and function brain imaging could assist in further studies of mechanisms of neuronal damage and/or neurocognitive dysfunction from COVID-19 infection. Here we propose addressing current gaps in our understanding of cognitive function in PASC by following the trajectories of cognitive function over three years using validated, tablet-based neuropsychological tests, analyzing the relationship between co-morbidities prevalent amongst veterans such as PTSD and depressive disorders and cognitive impairment following COVID-19. This study will link key neurological and immunological markers, clinical outcomes, and imaging of cerebral blood flow and demyelination, thereby contributing a cohesive understanding of the mechanisms of neurological injury.