Researchers find signs of brain inflammation in COVID-19 patients

A comprehensive molecular study of the brains of people who died of the novel coronavirus (COVID-19) found clear signs of inflammation and impaired brain circuits, according to a new study published in the journal Nature.

For the study, investigators at the Stanford School of Medicine in California, United States and Saarland University in Saarbrücken, Germany used an approach called single-cell RNA sequencing, logging the activation levels of thousands of genes in each of 65,309 individual cells taken from brain-tissue samples from COVID-19 patients and controls. While a systematic analysis yielded no molecular traces of SARS-CoV-2, the virus that causes COVID-19, in the brain, the researchers said that what they saw looks a lot like what's observed in the brains of people who died of neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease.

The findings may help explain why many COVID-19 patients report neurological problems, the researchers said. These complaints increase with the severity of infection with SARS-CoV-2, and they can persist as an aspect of "long COVID," a long-lasting disorder that sometimes arises following infection.

About one-third of individuals hospitalized for COVID-19 report symptoms of fuzzy thinking, forgetfulness, difficulty concentrating and depression, said Tony Wyss-Coray, PhD, professor of neurology and neurological sciences at Stanford. However, the researchers couldn't find any signs of SARS-CoV-2 in brain tissue they obtained from eight individuals who died of the disease. Brain samples from 14 people who died of other causes were used as controls for the study. Scientists disagree about whether SARS-CoV-2 is present in COVID-19 patients' brains. 

The blood-brain barrier, which consists in part of blood-vessel cells that are tightly stitched together, and blob-like abutments created by brain cells' projections squishing up against the vessels, has until recently been thought to be exquisitely selective in granting access to cells and molecules produced outside the brain, the researchers said.

Previous work by Wyss-Coray's group and by others has shown that bloodborne factors outside the brain can signal through the blood-brain barrier to ignite inflammatory responses inside the brain. This could explain why factors in young mice's blood can rejuvenate older mice's cognitive performance, whereas blood from old mice can detrimentally affect their younger peers' mental ability.

On hearing reports of enduring neurological symptoms among some COVID-19 patients, Wyss-Coray became interested in how SARS-CoV-2 infection might cause such problems, which resemble those that occur due to aging as well as to various neurodegenerative diseases. Having also seen conflicting reports of the virus's presence in brain tissue in other studies, he said he wanted to know whether the virus does indeed penetrate the brain.

Brain tissue from COVID-19 patients is hard to find, Wyss-Coray said. Neuropathologists are reluctant to take the steps required to excise it because of potential exposure to SARS-CoV-2 and because regulations often prohibit such procedures to prevent viral transmission. The researchers were able to access COVID-19 brain-tissue samples from autopsies conducted at the hospital that's associated with Saarland University.

Activation levels of hundreds of genes in all major cell types in the brain differed in the COVID-19 patients' brains versus the control group's brains. Many of these genes are associated with inflammatory processes.

There were also signs of distress in neurons in the cerebral cortex, the brain region that plays a key role in decision-making, memory, and mathematical reasoning, the researchers said. These neurons, which are mostly of two types, excitatory and inhibitory, form complex logic circuits that perform those higher brain functions, they said.

The outermost layers of the cerebral cortex of patients who died of COVID-19 showed molecular changes suggesting suppressed signaling by excitatory neurons, along with heightened signaling by inhibitory neurons, which act like brakes on excitatory neurons. This kind of signaling imbalance has been associated with cognitive deficits and neurodegenerative conditions such as Alzheimer's disease.

An additional finding was that peripheral immune cells called T cells, immune cells that prowl for pathogens, were significantly more abundant in brain tissue from dead COVID-19 patients. In healthy brains, these immune cells are few and far between, the researchers said.

"Viral infection appears to trigger inflammatory responses throughout the body that may cause inflammatory signaling across the blood-brain barrier, which in turn could trip off neuroinflammation in the brain," Wyss-Coray said in a statement. "It's likely that many COVID-19 patients, especially those reporting or exhibiting neurological problems or those who are hospitalized, have these neuroinflammatory markers we saw in the people we looked at who had died from the disease, It may be possible to find out by analyzing these patients' cerebrospinal fluid, whose contents to some extent mirror those of the living brain. "Our findings may help explain the brain fog, fatigue, and other neurological and psychiatric symptoms of long COVID," he said.

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