Even a mild case of Covid-19 can damage the brain and addle thinking, scientists found in a study that highlights the illness's alarming impact on mental function.
Researchers identified Covid-associated brain damage months after infection, including in the region linked to smell, and shrinkage in size equivalent to as much as a decade of normal aging. The changes were linked to cognitive decline in the study, which was published Monday in the journal Nature.
The findings represent striking evidence of the virus's impact on the central nervous system. More research will be required to understand whether the evidence from the Wellcome Centre for Integrative Neuroimaging at the University of Oxford means Covid-19 will exacerbate the global burden of dementia -- which cost an estimated $1.3 trillion in the year the pandemic began -- and other neurodegenerative conditions.
"It is a very novel study with conclusive data," said Avindra Nath, clinical director of the U.S. National Institute of Neurological Disorders and Stroke, who wasn't involved in the research. "The findings are very intriguing, with important implications for the population at large."
The SARS-CoV-2 virus is widely considered a respiratory pathogen that attacks the lungs. Taking a narrow view of it, however, misses myriad neurologic complications -- including confusion, stroke, and neuromuscular disorders -- that manifest during the acute phase of the illness. Other effects like impaired concentration, headache, sensory disturbances, depression, and even psychosis may persist for months as part of a constellation of symptoms termed long Covid.
To investigate changes in the brain, neuroscientist Gwenaelle Douaud and colleagues leveraged the world's largest magnetic resonance imaging database. Initial MRI scans of the brains of 785 volunteers were taken before the pandemic began as part of U.K. Biobank research, which marries large-scale genomic and detailed clinical data for half a million people.
A subsequent scan was taken an average of 38 months later. By then, 401 participants had tested positive for Covid. The uninfected remainder served as a control group that was similar to the survivors in age, sex, and many risk factors, including blood pressure, obesity, smoking, socio-economic status and diabetes. The participants in the study, aged 51 to 81, were mostly Caucasian.
'Quite Surprised'
"We were quite surprised to see some clear differences in how the brain had changed in the participants who have become infected," Douaud said in an interview. Whether the effects persist, or can be partially reversed as neuronal networks repair, requires further investigation, she said. "The brain is 'plastic' and can heal itself."
Among those infected an average of 4.5 months prior to their second scan, the researchers found a greater reduction in grey matter thickness in the regions of the brain associated with smell, known as the orbitofrontal cortex and parahippocampal gyrus. The finding may help explain the impaired olfaction many Covid patients experience, as a result of either direct viral damage or inflammation spurred by the body's immune response to the virus.
A loss of grey matter, which makes up the outer most layer of the brain, represents degeneration, said Leah Beauchamp, a neuropharmacologist at the Florey Institute of Neuroscience and Mental Health in Melbourne. "This is really concerning," she said.
The infected group also displayed a 0.2%-to-2% greater reduction in brain size compared with those who hadn't been infected and showed greater cognitive decline based on their performance undertaking complex tasks. This was associated with atrophy, or shrinkage, in a specific part of the cerebellum -- an area at the back and bottom of the brain -- linked to cognition. Differences between infected and non-infected participants was more marked in older people.
'Identify the Mechanisms'
"What is going to be pertinent now is to identify the mechanisms that are leading to this degeneration in the acute phase of disease so that we can attempt to intervene," Beauchamp said.
Studies of blood and central nervous system samples from patients are needed to tease out the mechanisms that result in these brain changes, said Serena Spudich, the Gilbert H. Glaser professor of neurology at Yale School of Medicine in New Haven, Connecticut.
Recent research revealed the plasticity of brain connectivity and structure, she said. The findings suggest there may be renewal of damaged neuronal pathways that could ultimately result in full recovery for affected patients, she said.
"We are fortunate to have extremely resilient brains that can function with many potential insults without experiencing any impairment," she said in an email. "Hopefully, these neuroimaging findings equate to few clinical consequences in most people who are infected with SARS-CoV-2."
Study participants weren't selected because they were experiencing long Covid symptoms. It's possible some of the findings were incidental and have no impact. Still, both Nath and Beauchamp said it will be important to identify whether long Covid symptoms correlate with brain abnormalities or the results of any other pathology tests.
Subtle Changes
The size of the changes on individual scans were "subtle" and not visible to the naked eye, Douaud said. A 0.2% reduction in grey matter represents about a year of normal aging in an older person's brain. A 2% reduction represents about 10 years of aging.
Almost all of the infected participants recovered at home, which suggests the findings might be relevant for the majority of Covid survivors worldwide. Among the 15 who were hospitalized for Covid, there were hints of even stronger and more widely distributed effects in the brain, Douaud said.
The research supports growing evidence that brain-based changes can occur following a SARS-CoV-2 infection, even in people who didn't need hospitalization, said Joanna Hellmuth, a neurologist and assistant professor at the University of California, San Francisco's Memory and Aging Center. "Future research efforts can help us understand if these brain changes are clinically relevant, and if they associate with specific neurological issues after Covid," she said.
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