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.
