COVID-19 is associated with loss of grey matter and increased tissue damage in regions linked to cognition and smell, a large study comparing brain scans of patients before and after being infected with COVID-19 has revealed.

Appearing in the journal Nature, the investigation provides strong evidence for these deleterious effects, even in patients who were not hospitalized by the virus.

“There is strong evidence for brain-related abnormalities in COVID-19,” state the authors, before going on to explain that “it remains unknown however whether the impact of SARS-CoV-2 infection can be detected in milder cases.”

The team examined brain scans of 785 people between the ages of 51 and 81, each of whom was scanned before and during the pandemic as part of the UK Biobank study.

Of these, 401 had tested positive for COVID-19 at some point between their first and second scan, enabling the researchers to analyze how their brains changed in the months after infection. The remaining 384 individuals who did not catch the virus provided a control group.

When comparing the two groups, researchers found that those who had been infected displayed a greater reduction in grey matter thickness within the orbitofrontal cortex and parahippocampal gyrus, both playing a key role in memory function. Increased tissue damage was also seen within the olfactory cortex, which coordinates smell, while a greater reduction in overall brain size was observed as well.

In addition, participants who had caught the virus showed “significantly greater cognitive decline,” as evidenced by their scores on a range of cognitive tests. These reductions in mental capacity were associated with tissue loss in a part of the cerebellum known as crus II.

Keen not to cause too much alarm, the study authors insist that “these structural and microstructural longitudinal significant differences are modest in size,” while also stressing that their findings “represent an average effect,” and that “not every infected participant will display brain longitudinal abnormalities.”

Overall, the scans showed an average grey matter loss of 0.7 percent within olfactory-related brain regions in those who had tested positive for COVID-19, while parahippocampal volume decreased by 1.3 to 1.8 percent. For comparison, the hippocampus typically shrinks by around 0.2 percent a year in healthy middle-aged individuals, and by roughly 0.3 percent per year in old age.

Overall, these COVID-19-related changes were more pronounced in older individuals and in those who were hospitalized, yet were still observable even in those who did not require medical attention. Such a finding implies that even mild cases may still result in an accelerated loss of grey matter.

In spite of these results, the researchers insist that the observational nature of their study makes it impossible to confirm a causal link between the virus and negative brain changes. However, the fact that they examined brain scans from before and after infection makes it highly unlikely that any of the observed alterations were caused by pre-existing risk factors.

The mechanism by which the virus causes these effects is beyond the scope of this study. The authors speculate that the observed damage may be caused by SARS-CoV-2 directly harming olfactory pathways, or by an increase in neuroinflammation following infection. Alternatively, a lack of sensory input resulting from the temporary loss of smell may result in tissue damage and cell atrophy.

Amidst this uncertainty, it's also important to note that these scans were performed between March 2020 and April 2021, when neither the Delta nor the Omicron variant had become prevalent in the UK. As such, it is unknown whether more recent strains of the virus would produce similar effects.

Finally, the researchers state that “whether this deleterious impact can be partially reversed, or whether these effects will persist in the long term, remains to be investigated with additional follow up.”