SARS-CoV-2 Associated With Brain-Related Abnormalities, Even for Mild Cases

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Researchers sought to investigate the effects of COVID-19 infection by assessing brain changes in individuals who underwent brain scans twice who tested positive between scans or were COVID-19-free.

SARS-CoV-2 was associated with a consistent spatial pattern of limbic brain region abnormalities, mainly in the olfactory network, according to a study published in Nature.

Patients with COVID-19 have been observed to develop neurologic manifestations and for those with severe disease, as many as 80% exhibit neurological symptoms. Brain imaging studies have found a broad range of gross cerebral abnormalities such as white matter hyperintensities, signs of ischemic events, and hypoperfusion. Most studies have focused on acute COVID-19, and it remains unclear whether mild symptoms may also be associated with changes to brain structures.

To explore potential brain effects of COVID-19 infection, data were sourced from the United Kingdom Biobank. Individuals who underwent 2 brain scans were assessed for brain-related changes between scans. Participants were subdivided by whether they tested positive for COVID-19 between scans (n=401) or remained COVID-19-free (n=384).

Cases and control individuals were aged mean 58.9±7.0 and 60.2±7.4 years at scan 1 and 62.1±6.7 and 63.3±7.1 years at scan 2, 42.9% and 42.7% were men, 96.8% and 97.1% were White, respectively.

Among the COVID-19 cohort, 15 were hospitalized, 2 were transferred to the intensive care unit, and 1 received invasive ventilation.

Using the hypothesis that COVID-19 is likely to affect olfactory networks, a total of 68 of the 297 olfactory-related cerebral imaging-derived phenotypes were significant after correcting for multiple testing. The most significant changes for patients who had COVID-19 were observed in the temporal piriform cortex functional network orientation dispersion (0.34%; P =.0068), olfactory tubercle function network isotropic volume fraction (1.22%; P =.028), frontal piriform cortex functional network mean diffusivity (0.39%; P =.0386), temporal piriform cortex functional network mean diffusivity (0.38%; P =.0396), olfactory tubercle functional network mean diffusivity (0.39%; P =.0446), and left lateral orbitofrontal cortex thickness (-0.76%; P =.0449).

Using an exploratory approach, 65 out of 2047 longitudinal imaging-derived phenotypes were found to differ between cases and control individuals. The most significant COVID-19-related changes were in the ratio of brain volumes to total intracranial volume (-0.29%; P =.0083), normalized cerebrospinal fluid volume (1.52%; P =.0277), right lateral ventricle volume (1.7%; P =.0329), temporal piriform cortex function network orientation dispersion (0.34%; P =.0405), and superior fronto-occipital fasciculus intra-cellular volume fraction (-0.79%; P =.0431).

Stratified by hospitalization, significant group differences were observed for cortical thicknesses of the prefrontal, parietal, and temporal lobes.

There was also evidence of cognitive effects. After infection with COVID-19, individuals took longer to complete the numeric task (7.8%; P =.005) and alphanumeric task (12.2%; P =.002) of the Trail Making Test.

Overall, cognitive scores were correlated with the volume of the lobule crus II of the cerebellum (r, -0.19, P =.020).

This study was limited by not having access to clinical information beyond whether the individual was hospitalized.

“By using automated, objective, and quantitative methods, we uncovered a consistent spatial pattern of longitudinal abnormalities in limbic brain regions forming a mainly olfactory network,” the researchers stated. “Whether these abnormal changes are the hallmark of the spread of the pathogenic effects, or of the virus itself in the brain, and whether these may prefigure a future vulnerability of the limbic system in particular, including memory, for these participants, remains to be investigated.”


Douaud G, Lee S, Alfaro-Almagro F, et al. SARS-CoV-2 is associated with changes in brain structure in UK Biobank. Nature. Published online March 7, 2022. doi:10.1038/s41586-022-04569-5