Brain shrinkage linked to COVID-19

COVID-19 may shrink the brain's gray matter, primarily in areas of the brain involved in smell and memory processing, a large study suggests.

These distinct changes in brain structure crop up in both people who required hospitalization for COVID-19 and those who had less severe infections, according to the study, published March 7 in the journal Nature. And the tissue loss and damage seen in these study participants was "above and beyond" the structural brain changes that normally occur with age, said Jessica Bernard, a neuroscientist and associate professor at Texas A&M University, who was not involved in the study. 

"This definitely is statistically, reliably, above and beyond that," said Bernard, who studies how normal age-related brain changes affect people's ability to think and move.

Related: Why is gray matter gray? 

The new research included data from 785 people, ages 51 to 81, who previously contributed brain scans to the U.K. Biobank, a repository of brain imaging data from more than 45,000 U.K. residents. Of these participants, 401 had a known COVID-19 infection sometime between March 2020 and April 2021; of these, 15, or about 4%, were hospitalized for their infections. 

The remaining 384 participants had not caught COVID-19 but closely matched the infected participants in terms of age, sex and COVID-19 risk factors, such as whether they smoked or had diabetes, for instance. These participants tested negative for SARS-CoV-2 antibodies and/or had no record of confirmed or suspected COVID-19 from primary care, hospital records or a diagnostic test, and they served as a control group. All the participants underwent a second brain scan for the study, so the researchers could pinpoint how and where their brains differed from their initial Biobank scans, taken around three years prior. 

"The real power of the U.K. Biobank is that they do have pre- and post-infection imaging," meaning they essentially have "before" and "after" snapshots of the participants' brains, said Dr. Jennifer Frontera, a professor in the department of neurology at the NYU Grossman School of Medicine and neurologist at NYU Langone Health, who was not involved in the study.

To peer inside the participants' brains, the team used magnetic resonance imaging (MRI), a technique that uses a strong magnetic field and radio waves to generate images of soft tissues in the body. In the infected group, participants caught COVID-19 about 4.5 months prior to their second scan, on average. These MRI scans revealed distinct patterns of shrinkage in the brains of people who caught COVID-19;  the damage was more extensive and occurred in different regions than the normal changes that show up in people who never caught the virus.

Compared with the control group, the infected group showed greater tissue loss in specific regions of the cerebral cortex, the wrinkled outer surface of the brain. One region, called the orbitofrontal cortex, sits just above the eye sockets, receives signals from brain areas involved in sensation, emotion and memory and plays an important role in decision-making. The other, known as the parahippocampal gyrus, surrounds the hippocampus, a seahorse-shaped structure in the middle of the brain that's important for encoding new memories. 

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Shrinkage was most pronounced in these areas, but the infected group also showed a greater reduction in overall brain size than the control group, the authors reported. The team also uncovered tissue damage in brain areas connected to the primary olfactory cortex, a bulbous structure that receives sensory information from scent-detecting neurons in the nose. 

"Certainly they're showing, particularly, the areas that are involved in memory encoding being affected, and connections to the olfactory cortex and the limbic system being involved," Frontera said; the limbic system is involved in emotional behavior, learning and memory.

On average, the infected group showed 0.2% to 2% greater tissue loss and damage over the course of about three years, compared with the control group. To put that in context, estimates suggest that aging adults lose about 0.2% to 0.3% of their gray matter in regions related to memory each year, according to a 2021 report in the journal Neurobiology of Aging, so additional loss beyond that would be out of the ordinary.

The study participants also completed several cognitive assessments; the study authors repeated some of these tests during their study, to see how the participants' scores had changed. Notably, the infected group performed significantly worse on so-called trail making tests than the controls; these tests are designed to test attention and executive function, Frontera said. 

"I think it's really important also, that they showed that there's a difference in quantitative, cognitive testing, as well as the structural data from the MRIs," she said.

Although it has many strengths, the new study does have a few limitations. For example, while the authors know which participants developed mild or severe COVID-19, they don't catalog exactly what symptoms each person experienced during their infection. It would be interesting to know which participants had symptoms of smell loss or olfactory dysfunction, as that might provide hints as to why damage occurred in brain areas connected to the primary olfactory cortex, Frontera said. A loss of sensory information from the nose could theoretically cause such areas to atrophy, she noted.

The study authors agree that this loss of sensory information could potentially explain the observed damage. Alternatively, it's possible that the coronavirus may directly infect the brain, or that the virus may set off an inflammatory immune response that damages the brain indirectly, they suggested in their report.

"I don't know that there's anything that suggests one way or another at this point," Bernard said. "I think it is completely up in the air." 

"I don't think we know mechanistically, still, what's underpinning this," Frontera agreed. That said, based on recent studies, "I don't think that there's direct invasion involved," meaning the coronavirus isn't necessarily invading these regions of the brain and causing direct damage, she said.

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A recent study, published Feb. 1 in the journal Cell, supports this idea, she said. The research suggests that SARS-CoV-2 doesn't directly infect olfactory neurons in the nose, which could theoretically serve as a highway into the brain. Instead, the virus infects cells that lie near the olfactory neurons, embedded in the lining of the nasal cavity. This infection then triggers inflammation that messes with the function of the neighboring olfactory neurons, causing them to produce fewer scent receptors, for example. This, in turn, causes smell loss, the authors concluded.

Whatever is driving the observed brain shrinkage, it's possible that the mechanism might slightly differ between coronavirus variants, Frontera noted. The study only included individuals infected between March 2020 and April 2021, who most likely caught the original strain of SARS-CoV-2 or the alpha variant, the authors noted. Future studies could zoom in on how more recent variants, such as omicron, affect the brain, and others could focus on whether these findings extend to people with long COVID, many of whom report memory problems and "brain fog," she noted.

And of course, ideally, another study would be conducted with the individuals from the U.K. Biobank, to see how their brains change in the coming months and years, Frontera said.

"What will we see five, 10, 15 years down the road?" Bernard said. Hopefully, the rate of structural change will plateau relatively soon after infection and the participants' cognitive deficits will resolve, she said. But there's a possibility that, down the line, the COVID-related brain damage could accelerate normal processes of aging and cause cognitive decline to occur at a faster rate than would normally be expected.         

"And to be clear, this is entirely speculative," Bernard said. "It's way too early to know." 

Beyond the U.K., many other research groups are tackling these questions. "Certainly, a lot of people have their eyes on this," Frontera said. Frontera and her colleagues at NYU are currently launching a study to assess markers of neurodegenerative disease, namely Alzheimer's, in individuals who recovered from COVID-19; their participants will also undergo MRIs and cognitive assessments.

Originally published on Live Science.