Brain signature of SARS-CoV-2 Infection and its impact on long-term cognitive functioning in older adults

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Several reports have highlighted the presence of cognitive and psychiatric manifestation associated with severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) infection. Autopsy and CSF studies suggest that COVID-19 associated injury of the central nervous system derives from a combination of coagulopathy, endothelial injury with subsequent alteration of the blood brain barrier, infection and activation of microglia and macrophages followed by release of cytokines. The neurocognitive symptoms may persist in the subacute phase of the recovery while it remains to be determined what the long-term effects will be. The documented involvement of the brain microcirculation by SARS-CoV-2 infection, is likely to contribute to cerebral small vessel disease (CSVD). CSVD pathogenesis is not fully understood and is likely multifactorial. Among the factors that may link COVID-19 to CSVD are direct injury to endothelial cells, platelets and leukocyte activation. These processes can then lead to an altered blood brain barrier (BBB) with increased crossing of activated monocytes into the brain parenchyma. CSVD is clinically quite relevant since it is a leading cause of cognitive impairment and dementia. There are several unknowns that justify the implementation of this proposal. We do not know whether there is an increased burden of CSVD in those older adults who have been infected by SARS-CoV-2 and whether there will be an accelerated progression of CSVD in this population. It is also unclear whether the initial endothelial dysfunction induced by the infection may persist in a milder form that is sufficient to maintain a chronically altered cerebral microcirculation. If this occurs, it will contribute to several neurodegenerative disorders including vascular dementia and Alzheimer disease. In this proposal, we will focus on older individuals aged between ≥65 and 80, who were infected with SARS- CoV-2 at least six months prior to study enrolment, who were hospitalized but not admitted to a critical care unit and did not have a significant neurological history prior to SARS-CoV-2 infection. We will match by age and sex, 150 COVID-19 patients with 150 controls who will be followed for two years. CSVD will be assessed via state- of the-art magnetic resonance multimodality imaging. We will address the specific aims listed below. AIM 1: To assess the severity and progression of CSVD in individuals previously infected by SARS-CoV-2 compared to age and sex matched controls. Sub-AIM 1: To assess the impact of SARS-CoV-2 on brain microstructure integrity. AIM 2: To assess in individuals previously infected by SARS-CoV-2, compared to controls, changes in cerebrovascular function and its association to peripheral makers of endothelial function and altered blood brain barrier. AIM 3: To assess changes in cognitive performance and its relation to imaging metrics in individuals previously infected by SARS-CoV-2 compared to controls.