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An Oxford University study of 785 UK Biobank subjects found those who had been infected with Covid-19 had a 1.3-1.8 per cent loss of grey matter compared to an estimated 0.2 to 0.3 per cent loss of brain volume a year in normal middle-aged individuals. Photo: Shutterstock

Coronavirus: even mild cases may change the brain and shrink grey matter, finds Oxford study

  • Researchers tap into British biobank data to assess brain health before and after coronavirus infection
  • Data shows significant impact associated with the virus, mainly in areas responsible for emotions, memory and smell
Even a mild Covid-19 infection may cause the structure of the brain to change in areas associated with smell, memory, cognition and emotions, a study by Oxford University has found.

Gwenaelle Douaud, associate professor with the Nuffield Department of Clinical Neurosciences, and her colleagues based the assessment on a study of brain scan data from UK Biobank, a large databank of in-depth health information from more than half a million adults in Britain. The study was published in the journal Nature on Tuesday.

From the UK Biobank records, researchers identified 401 participants who had brain MRI scans an average 38 months apart and whose health records showed they were infected with Sars-CoV-2, the virus that causes Covid-19.

Researchers included a control group of 384 participants who were slightly older, underwent the same MRI protocol but tested negative for Covid-19. The study participants were between 51 and 81 years old and the vast majority of the infected participants had not been admitted to hospital, or even showed symptoms.


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The study revealed a “significant, deleterious” impact associated with Sars-CoV-2, mainly in the limbic and olfactory cortical system – areas generally responsible for emotions, memory and smell.

The group that had been infected with Sars-CoV-2 had a 1.3 to 1.8 per cent loss of grey matter in the brain, compared to an estimated 0.2 to 0.3 per cent loss of brain volume per year in normal middle-aged individuals.

They also identified that the overall size of the cerebellum, a brain region linked to cognition, had shrunk more in the infected participants.

These changes are associated with decline in cognition, which might lead to individuals taking longer to answer questions in standard cognitive tests.

The researchers also used people who developed pneumonia as a control group and concluded the brain change was specific to Covid-19 survivors.

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Douaud said the abnormalities might be caused by a loss of smell in the infected participants.

“Repeated olfactory loss has been shown in previous studies to lead to loss of grey matter in brain regions related to olfaction,” Douaud said in a statement, adding that the study did not have information about infected participants’ symptoms, such as loss of smell.

“Another explanation could be the effect of the virus itself, either because it invades the brain, or because it causes inflammation or immune reactions. It is still unclear why such invasion or inflammatory or immune reactions should be mainly seen in specific regions of the brain, but not others.”

She said it was possible these brain abnormalities might become less marked over time if the sense of smell was recovered.

“It is likely that the harmful effects of the virus, whether direct, or indirect via inflammation or immune reaction, decrease over time after infection. There is some indication, from small previous studies, that issues seen in functional brain imaging may improve in part more than six months after infection,” she said.


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Anthony Hannan, professor at the Florey Institute of Neuroscience and Mental Health, University of Melbourne, said there were other potential causes of these brain changes in the infected participants.

“Covid-19 can be highly stressful, and we know that chronic stress can cause reduction in volume of some brain regions. There may have been other shared aspects of experience in those infected with Sars-CoV-2, such as reduced physical activity during and after illness, which has also been associated with decreases in specific brain regions.”

The overlapping smell and memory-related functions of the regions shown to alter significantly over time in Sars-CoV-2 raise the possibility that longer-term effects of Sars-CoV-2 infection might in time contribute to Alzheimer’s disease or other forms of dementia.

But the Oxford study, which involves subjects with mainly mild symptoms, did not show signs of memory impairment. The memory-related region in the brain did not show any change at a functional level.

“It remains to be determined whether the loss of grey matter and increased tissue damage seen in these specific limbic regions may in turn increase the risk for these participants developing memory problems,” the study authors wrote.

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The participants were infected between March 2020 and April 2021, when different variants were dominant in Britain.

Researchers said they believed a minority of the subjects were likely infected with the original virus, and most with the variants of concern present in Britain from October 2020 – Alpha, Beta and Gamma.

The researchers presumed very few participants, if any, were infected with the Delta variant, which only appeared in Britain in April 2021.

The authors said it would be valuable to follow up with the cohort, increasing the number of cases infected for six months or longer and including Delta variant infections, to determine “the longer-term effects of infection on these limbic structures, as well as possible differential effects between the various strains”.