White matter microstructural abnormalities in neurological poste-acute sequelae of coronavirus disease: Imaging signatures consistent with persistent neuroinflammation

Background: Essential workers, many of whom were infected with coronavirus disease (COVID-19) at work before vaccination, developed Neurological Post-Acute Sequelae of COVID-19 (N-PASC) at high rates. Method: To characterize white matter abnormalities associated with N-PASC and to examine correlates of symptomatology, we recruited 54 participants with N-PASC and compared them to 26 participants with no COVID-19 history or who recovered from acute COVID-19 without PASC into a neuroimaging study to profile the cerebral connectome starting from 1/1/2021-12/31/2024. Diffusion parameters from whole-brain white matter and cortical gray matter analyses were examined with multi-shell diffusion MRI data. Correlational tractography was used to examine the nature and extent of white matter changes. Results: Participants with N-PASC lasting, on average, 2.7 years had global and tract-specific white matter alterations after adjusting for demographics across measures of white matter health. Correlational tractography located pronounced bilateral changes to the fornix and minor forceps, possibly providing indirect evidence of axonal injury or demyelination in these regions. But diffusion measures alone cannot determine the specific underlying biological process. Diffusion measures were associated with the presence of fatigue, executive impairment, anosmia and mood disorders, but not brain fog. Conclusions: Results identify changes in N-PASC consistent with neuroinflammation that help explain cognitive dysfunction, providing insights into the long-term cerebral implications of COVID-19 and suggesting that symptoms may reflect evidence of a cerebral changes persisting years after symptom onset.