Structural and Functional Differences in the Brains of Individuals with Post-Acute Sequelae of COVID-19: A Systematic Review of Neuroimaging Findings

Abstract Post-acute sequelae of SARS-CoV-2 infection (PASC) is a heterogeneous condition characterized by a panoply of symptoms presenting after a SARS-CoV-2 infection and persisting for months or years, with no alternative explanation. Many symptoms of PASC, such as fatigue or cognitive complaints, are neurological in nature, and various changes in the brain associated with COVID-19 have been proposed as plausible mechanisms. This systematic review summarizes structural and functional brain magnetic resonance imaging (MRI) and positron emission tomography (PET) findings in adults with PASC. Three databases (PubMed, Scopus, and Europe PMC) were searched, and 34 studies met eligibility criteria and were included in the review. Most PASC patients were female and had a history of mild to moderate acute COVID-19 on average three to thirty months prior to image acquisition, with common symptoms including fatigue, cognitive impairment, and olfactory dysfunction. Included studies varied widely in imaging modality, control group characterization, sample size, and time since infection, but were largely cross-sectional in design. Significant differences in PASC compared with controls were reported for grey and white matter volume, cortical thickness, white matter microstructure, functional connectivity, cerebral perfusion, blood-brain barrier permeability and cerebral gliosis, and glucose metabolism, among other measures, and many of these outcomes correlated with symptom burden and clinical measures. The most consistent findings were cerebral hypometabolism (especially frontotemporal) and hypoperfusion, blood-brain barrier disruption, alterations in white matter microstructure, and changes in multiple metrics in the cerebellum. Findings for volume and cortical thickness in most regions and connectivity alterations were bidirectional and inconsistent. Because most data are cross-sectional, longitudinal, multimodal studies are needed to establish whether these brain changes contribute causally to PASC symptoms.