During at least the first few months following a coronavirus infection, even mild cases of Covid-19 are associated with subtle tissue damage and accelerated losses in brain regions tied to the sense of smell, as well as a small loss in the brain’s overall volume, a new British study finds. Having mild Covid is also associated with a cognitive function deficit.
These are the striking findings of the new study led by University of Oxford investigators, one that leading Covid researchers consider particularly important because it is the first study of the disease’s potential impact on the brain that is based on brain scans taken both before and after participants contracted the coronavirus.
“This study design overcomes some of the major limitations of most brain-related studies of Covid-19 to date, which rely on analysis and interpretation at a single time point in people who had Covid-19,” said Dr. Serena S. Spudich, a neurologist at the Yale University School of Medicine, who was not involved in the research.
The research, which was published Monday in Nature, also stands out because the lion’s share of its participants apparently had mild Covid — by far, the most common outcome of coronavirus infections. Most of the brain-related studies in this field have focused on those with moderate to severe Covid.
Gwenaëlle Douaud, an associate professor at the Nuffield Department of Clinical Neurosciences at Oxford and the paper’s lead author, said that the excess loss of brain volume she and her colleagues observed in brain scans of hundreds of British individuals is equivalent to at least one extra year of normal aging.
“It is brain damage, but it is possible that it is reversible,” she said. “But it is still relatively scary because it was in mildly infected people.”
Douaud and her team relied on a rich data source: the United Kingdom Biobank. Before the Covid pandemic began, this mammoth database already had on hand tens of thousands of brain MRIs of people in Britain, along with responses to surveys about their diets and lifestyles and results from cognitive function tests.
The investigators focused on 401 people between 51 and 81 years old who had tested positive for Covid according to clinical data linked to the Biobank study. They were invited back for a second brain scan, which they received an average of about five months after contracting the coronavirus. Covid was apparently mild in the vast majority of these participants; only 15 of them were hospitalized with the disease.
Between the pairs of MRIs, which were separated by an average of about three years, the researchers observed a striking trend among those who had Covid: a greater loss of what’s known as gray matter in the brain, as well as a higher rate of abnormalities in the brain tissue. Gray matter, which appears gray on certain brain scans, is comprised of various cells, including neurons.
It would be normal for adults within the study’s age range to lose a small amount of brain tissue after three years of aging, the researchers note. But compared with the control group, those who had Covid experienced an additional 0.2 percent to 2 percent loss of brain tissue in regions which are mostly associated with the sense of smell — specifically, in the parahippocampal gyrus, the orbitofrontal cortex and the insula.
The overall brain volume in people with Covid declined by an extra 0.3 percent over those without the disease.
Older participants experienced all these excess brain-related declines more profoundly.
The study offers no indication whether a Covid vaccination would mitigate the risk of such changes. The participants tested positive for the disease between March 2020 and April 2021, before the vaccines were widely available in the U.K.
On cognitive function tests, those who had Covid demonstrated a slower ability to process information and had lower marks on what’s known as executive function, which is an umbrella measure of the brain’s ability to manage complex tasks. Again, these Covid-linked deficits were more pronounced among older individuals.
Dr. Avindra Nath, clinical director of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health, said that these findings “have long-term implications, since we would be concerned about the possibility of similar cognitive dysfunction in a large population worldwide."
"It needs to be determined if these patients could further deteriorate over a period of time," he said.
The investigators had no access to data on any Covid-related symptoms the participants may have experienced. So they don’t know if the participants actually lost their sense of smell or have experienced long-term symptoms in the disease’s wake. Some likely had asymptomatic cases.
That said, the loss of smell was particularly prevalent among those infected with the coronavirus during the first two major waves of the pandemic. And when particular regions of the brain go unused, they are inclined to atrophy. Nevertheless, the study’s authors don’t know whether the coronavirus caused a loss of smell through a nonbrain-based mechanism and this, in turn, prompted the brain damage, or if possibly the brain damage caused the loss of smell.
How long do Covid brain changes last?
A study published in Cell in February found that a coronavirus infection of various cells in the nasal cavity gives rise to inflammation that inhibits the functioning of smell-receptor proteins on nerve cells, leading to smell loss.
Covid’s link to declines in the smell-related brain regions, Douaud said, does not discount the other ways that it might impact the brain in regions unrelated to smell. The disease has proved maddeningly variable from patient to patient, and other studies have identified various means by which severe Covid in particular might damage the brain. What the study revealed is that changes to the smell-related regions were the most consistent brain-related trend tied to Covid in the study cohort.
Whether these changes will persist over the long term remains unknown. Douaud is hoping to conduct a third round of brain scans.
“The brain is plastic, which means it can reorganize and heal itself,” she said. “This is true even in older people.”
Experts in long Covid praised Douaud’s paper.
“This study provides the most definitive clinical data available to date that SARS-CoV-2 directly or indirectly damages nerves and that this, in turn, can have systemic effects, including changes in the brain,” said Dr. Steven Deeks, a veteran HIV researcher at the University of California, San Francisco. “It contributes to an emerging theme that nerve damage was common during the first few waves of the pandemic.”
Deeks, who is directing a major cohort study of people suffering from persistent symptoms following a coronavirus infection, noted a limitation of the new study. Those who got Covid, he pointed out, had some differences in their baseline cognitive function and in some of the initial brain scans compared with those who did not get the disease.
“It is possible, but perhaps unlikely,” he said, “that those who had higher risk for becoming infected were destined to progress more rapidly in the changes in their brain for other unmeasured reasons.”
That said, having the pairs of brain scans before and after an infection provided Douaud and her colleagues with a unique ability to factor out brain abnormalities that might have already been present before individuals developed Covid and therefore were not likely connected to the disease.