JAMA. Published online March 23, 2022. doi:10.1001/jama.2022.4507
A large study comparing brain scans from the same individuals before and after SARS-CoV-2 infection suggests that brain changes could be a lingering outcome of even mild COVID-19. Writing in Nature, researchers at Oxford University’s Wellcome Centre for Integrative Neuroimaging reported that several months after study participants had SARS-CoV-2 infections, they had more gray matter loss and tissue abnormalities, mainly in the areas of the brain associated with smell, and more brain size shrinkage than participants who hadn’t been infected with the virus.
Why It’s Important
Researchers, clinicians, and the public all are eager to learn more about COVID-19’s outcomes after the initial infection, especially for individuals with mild or asymptomatic disease, which represents most people with SARS-CoV-2 infection. Of particular interest are brain-related changes that could help explain commonly reported long-term symptoms including loss of smell and taste, headaches, and memory problems.
With nearly 800 volunteers, the new study is the largest COVID-19 brain imaging analyses to date. It’s also the first to focus on patients with mostly nonsevere illness and to include preinfection data from the same people. “The fact that we have the pre-infection scan helps us distinguish brain changes related to the infection from differences that may have pre-existed in their brains,” Stephen Smith, DPhil, the study’s senior author and a professor of biomedical engineering at the Nuffield Department of Clinical Neurosciences (NDCN) at Oxford, said in a statement.
In an email, JAMA Neurology Editor S. Andrew Josephson, MD, who was not involved with the work, called the report “an intriguing study that furthers our understanding of COVID-19 and the brain.”
The scans came from the UK Biobank—a research resource with data from half a million volunteers—where Smith is scientific lead for brain imaging. The baseline magnetic resonance imaging took place from 2014 through early March of 2020. For the UK Biobank COVID-19 Repeat Imaging study, the researchers invited hundreds of original volunteers aged 51 to 81 years back for a second round of scans between February and May of 2021. The current reimaging study analysis included:
401 cases—volunteers infected with SARS-CoV-2 between March 2020 and April 2021. Of this group, 15 people, or 4%, were hospitalized and 2 received critical care. The group underwent reimaging an average of 3 years after their baseline scans and 4.5 months after their COVID-19 diagnoses.
384 controls—volunteers without SARS-CoV-2 infection who were matched with the COVID-19 group for age, sex, ethnicity, the amount of time elapsed between scans, and risk factors such as blood pressure, obesity, smoking, socioeconomic status, and diabetes.
The researchers first estimated brain changes over time in each group and then looked for differences in these changes between the groups. They also compared the groups’ changes in cognitive decline based on differences in cognitive task scores. To investigate if other respiratory infections are associated with brain changes, the team compared imaging from separate groups of UK Biobank volunteers who had influenza or pneumonia not related to COVID-19.
What We’ve Learned
The brain scans and cognitive scores of participants who had been infected with SARS-CoV-2 showed changes between the 2 time points that differed from those seen in the control group, with greater differences among older participants. Although not everyone who became infected with SARS-CoV-2 had these differences, the prior-infection group on average had:
greater loss of gray matter thickness in the orbitofrontal cortex and parahippocampal gyrus, areas associated with the sense of smell
greater tissue damage in areas connected with the primary olfactory cortex, also linked with smell
greater decrease in whole-brain volume and increase in cerebrospinal fluid volume
greater decline in the ability to perform complex tasks, which on brain scans was associated with atrophy in crus II, an area of the cerebellum associated with cognition
Compared with the control group, volunteers with a prior SARS-CoV-2 infection had an additional 0.2% to 2% gray matter loss or tissue damage on average between their 2 sets of scans. For context, adults lose about 0.2% to 0.3% of gray matter in memory-related brain regions per year, according to Gwenaëlle Douaud, PhD, the study’s lead author and an associate professor at the NDCN.
The findings remained statistically significant when the patients hospitalized with COVID-19 were removed from the analysis.
Too few influenza cases occurred to draw comparisons, but brain differences among 11 volunteers who developed non–COVID-19 pneumonia between imaging sessions did not substantially overlap with brain regions implicated in the COVID-19 analysis. This could indicate that the study’s findings are specific to SARS-CoV-2 infection, not respiratory infection in general.
In their article, Douaud’s team offered several potential mechanisms by which SARS-CoV-2 infection might directly or indirectly alter brain structure, including
reduced sensory input related to loss of smell
neuroinflammation or immune reactions
direct viral infection of brain cells
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