Mild COVID-19 linked to changes in brain structure: study

International researchers have compared brain scans from 785 people aged 51 to 81 in the UK — before and after mostly mild COVID infection (401 people) with brain scans from the remaining non-infected controls.

“Significant, deleterious” long-term effects were seen when comparing the two groups, including changes in parts of the brain that affect memory and smell, and tissue damage in regions linked to smell, according to the study. Also, post-infected people showed larger cognitive decline than controls between scans. The authors say the documented effects were still seen after excluding the 15 people who had been hospitalised with COVID, implying even mild illness may have consequences for the brain.

Long-term effects

Researchers from the University of Oxford, University College London, Imperial College (UK) and National Institutes of Health (US) identified various long-term effects following infection, including a greater reduction in grey matter thickness in the orbitofrontal cortex and parahippocampal gyrus (regions associated with smell and memory of events).

Changes to the human brain, including in areas associated with smell and memory, following SARS-CoV-2 infection are described by Gwenaëlle Douaud and colleagues in a Nature paper. The findings may indicate the degenerative spread of COVID-19, either via smelling pathways, inflammation of the nervous system or a lack of sensory input owing to a loss of smell. The future vulnerability of the brain regions affected in these participants requires further investigation.

Although evidence suggests that COVID-19 may cause brain-related abnormalities, most studies have focused on hospitalised patients with severe disease and have been limited to post-infection imaging data. The effects of SARS-CoV-2 on the brain in milder (and more common) cases remain unknown but investigating these cases could reveal possible mechanisms that contribute to brain disease or damage.

The authors also performed a control analysis on people who developed pneumonia that was not related to COVID-19 to show that the changes were specific to COVID-19, and not due to generic effects of contracting a respiratory illness.

Brain size and cognitive decline

Professor Rob Hester, a researcher in cognitive neuroscience and Head of School in the Melbourne School of Psychological Sciences at the University of Melbourne, said the study is rigorous in its methodology and provides strong evidence of a subtle reduction in brain size (ranging from 0.2 to 2%), particularly in frontal and temporal brain regions important to cognitive abilities such as self-control and memory. For comparison, adults in the sample age range would usually show reductions of 0.2% per year, Hester said.

The subtle brain changes, however, were not associated with declines in cognitive performance overall, although a subtle decline was found in speed of thinking, but are of a level that would be unlikely to affect everyday function (or potentially be noticed), Hester noted.

“The limited period for follow-up makes it unclear whether these changes are recoverable. The study findings also appear to suggest that the brain and cognitive declines were related to the severity of COVID-19 illness, although only a small study sub-group had been hospitalised (15 people). Given the timing of the study, none of the sample are believed to have been infected with the Delta variant,” Hester said.

This “excellent” study of brain scans before and after a COVID-19 infection reveals that the brain is damaged by the infection, even in mild cases, said Professor Ashley Bush, Director of the Melbourne Dementia Research Centre at the Florey Institute of Neuroscience & Mental Health and The University of Melbourne.

“The brain loses some mass, and the shrinkage occurs in areas that are reminiscent of the changes seen in Alzheimer’s disease and Parkinson’s disease. While the changes are not large over the three years of the study, they are accompanied by a loss in cognitive processing. The cognitive losses appear to be similar to accelerated ageing. These are troubling findings, which indicate that the brain is not spared damage in COVID-19, and potentially could be at risk of dementia with time. More work is needed to understand the biological mechanism that damages the brain in COVID-19 to see whether there might be any treatment ideas possible.”

Further research

Professor Anthony J Hannan, an NHMRC Principal Research Fellow from The Florey Institute of Neuroscience and Mental Health, University of Melbourne, said further relevant questions include whether COVID-19 could increase risk of degenerative brain disorders such as Parkinson’s disease, Alzheimer’s disease and other forms of dementia. “It is essential that further research is urgently carried out, regarding our understanding of ‘neuro-COVID’, ‘long COVID’ and other chronic consequences of the global COVID-19 pandemic.”

Dr Susannah Tye is a Senior Research Fellow in the Queensland Brain Institute at The University of Queensland. She said, “The findings from this important study by Douaud and colleagues demonstrate that even mild cases of COVID-19 can have significant effects on brain health, with the authors showing atrophy (shrinking) of brain regions essential for processing smell, memory, cognition and emotion.

“While more research is needed to determine the mechanism through which the virus impacts the brain in this way, it is likely to be via a range of direct (ie, the direct action of the virus on brain cells) and indirect (activation of neuroinflammation) processes. We have long known that inflammation plays a role in neuropsychiatric and neurodegenerative conditions,” Tye said.

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