In one of the most extensive COVID-19 brain imaging studies – published today in Nature – researchers from the University of Oxford have observed changes in parts of the brain that control memory and smell, and more significant cognitive decline in people who recovered from a COVID-19 infection.
While medical research has made a lot of progress in treating severe acute respiratory infection caused by SARS-CoV-2, with new drugs being approved in the past few months, the research focus has increasingly shifted to the effects of mild-to-moderate COVID-19 in the longer term.
Previous studies have demonstrated that brain-related pathologies can result from COVID-19. Some of these pathologies could be a consequence of viral neurotropism – infection of nerve tissue – or virus-induced neuroinflammation.
One study showed that in more than 80% of severe cases patients experienced neurological symptoms. Radiological and post mortem tissue analyses have demonstrated the impact of COVID-19 on the brain and the possible presence of the virus in the central nervous system.
Most studies have focused on hospitalised patients with severe disease and have been limited to post-infection imaging data. The Oxford research team conducted the first longitudinal imaging study where participants were scanned before and after being infected.
This is a unique aspect of the study, says Dr Maithili Sashindranath, a senior research fellow and lead scientist in the Vascular Biology Group, Australian Centre for Blood Diseases, at Monash University.
She explains that comparing brain images of the same individuals before and after the infection eliminates the possibility that any findings could be due to pre-existing brain changes.
The Oxford team compared brain scans from almost 800 people aged 51 to 81 in the UK taken on average 38 months apart. Participants also underwent cognitive tests.
Of all participants, about 400 people did not catch the infection during the study and were used as a control group. A total of 401 participants tested positive for COVID-19 between their two scans. Of these, 15 people required hospitalisation.
Those infected showed a 1.3–1.8% reduction in grey matter thickness in the orbitofrontal cortex and parahippocampal gyrus – regions associated with smell and memory of events – compared to an estimated loss of about 0.2% of brain volume per year in middle-aged people.
They also displayed tissue damage in regions associated with the olfactory cortex – an area linked to smell – and brain size reduction.
On average, the participants who have had COVID-19 also took longer to answer questions in standard cognitive tests.
The authors confirmed that the changes were specific to COVID-19 and not due to generic effects of contracting a respiratory illness. To check this, they performed a control analysis on people who developed pneumonia not related to COVID-19.
They also excluded the 15 people whose symptoms were bad enough to require hospitalisation, yet the brain changes observed in those with mild infection were still relevant.
“This suggests that any episode of SARS-CoV-2 infection, whether resulting in severe disease requiring hospitalisation or not, can cause brain damage,” Sashindranath says.
“The results from this article are unfortunately what we expected,” says Professor James St John, head of the Clem Jones Centre for Neurobiology and Stem Cell Research at Griffith University, Queensland.
“Numerous pathogens are now known to be able to enter the brain using the olfactory nerve within the nasal cavity, and they can contribute to a range of neurological and neurodegenerative conditions including stroke and Alzheimer’s disease.
“It is still not certain whether SARS-CoV-2 can enter the brain, but at a minimum, it certainly can destroy the nerve cells responsible for the sense of smell which may then set off a cascade of events that lead to pathologies further in the brain.”
Professor Trichur Vidyasagar, head of the Visual and Cognitive Neuroscience Laboratory at the University of Melbourne, says the loss of grey matter extends across many critical brain regions responsible for several functions, such as decision making, attention, emotions and empathy.
What remains little understood is whether the most recent variants, Delta and Omicron, might have a similar effect on the brain and whether these changes are permanent.
“We don’t yet know whether the functional effects of the observed anatomical changes will get worse and how much the brain’s capacity for plasticity will help in the recovery,” Vidyasagar says.
St John says results from the study may explain the long-COVID brain fog that many people report even after a mild infection.
“What we still don’t know are the long-term effects such as whether there will be ongoing deficits that lead to chronic illnesses or neurodegeneration – I hope not, but I suspect there will be.”