Cognitive sequelae of cerebrovascular and gut dysfunction in post-acute COVID-19 syndrome. - ABSTRACT: Approximately one third of non-hospitalized coronavirus disease of 2019 (COVID-19) patients report chronic symptoms after recovering from the acute stage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Some of the most persistent and common complaints of this post-acute COVID-19 syndrome (PACS) are cognitive in nature, described subjectively as “brain fog” and also objectively measured as deficits in executive function, working memory, attention, processing speed. The mechanisms of these chronic cognitive sequelae are currently not understood. Most studies to-date have focused on direct SARS-CoV-2 infection of the brain; however, while direct viral brain infection is plausible in acute cases of severe and fatal COVID-19, it is of interest to examine indirect mechanisms of chronic cognitive dysfunction that follow mild and asymptomatic disease cases. SARS-CoV-2 inflicts damage to cerebral blood vessels and the intestinal wall by binding to angiotensin-converting enzyme 2 (ACE2) receptors and also by producing high levels of systemic cytokines, compromising the brain’s neurovascular unit and degrading the intestinal barrier, potentially increasing the permeability of both to harmful substances. Such substances are hypothesized to be produced by pathogenic microbiota in the gut that, given the profound effects COVID-19 has on the gastrointestinal system, may flourish via intestinal dysbiosis. COVID-19 may therefore create a scenario in which neurotoxic and neuroinflammatory substances readily proliferate from the gut lumen and encounter a weakened neurovascular unit, gaining access to the brain and subsequently producing cognitive deficits. We intend to examine such effects of SARS-CoV-2 in PACS patients longitudinally over the course of 3 study visits (baseline, 4 months, and 8 months). The impairments of cerebrovascular function and intestinal barrier, as well as their effects on cognitive symptomology, will be examined in 80 former COVID-19 patients who recovered from non-hospitalized acute phases of COVID-19, yet report persistent cognitive symptoms (PACS+). These patients will be compared with 80 former similar COVID-19 patients without such symptoms (PACS-). Forty healthy control participants will also be recruited to establish general neurovascular, intestinal, and cognitive effects of COVID-19 history. Cerebrovascular function will be quantified via innovative functional magnetic resonance imaging of cerebrovascular reactivity (CVR) to respiration of CO2 gas, while the intestinal barrier will be assessed via concentrations of intestinal wall biomarkers in blood plasma such as fatty acid-binding protein 2 (FABP-2) and zonulin. Gut dysbiosis will be established via lactulose breath testing, and levels of subsequently produced and systemically released lipopolysaccharide (LPS), peptidoglycan (PGN) and pro-inflammatory cytokines will also be quantified. Impairments in the neurovascular unit and intestinal barrier in the context of gut dysbiosis are expected to be associated with greater cognitive deficits in PACS+ patients. This work may reveal immediate recourses for resolving PACS cognitive effects via existing treatments for vascular dysfunction and gut health.
