The most comprehensive molecular study to date of brain tissue from people who died of COVID-19 provides clear evidence that SARS-CoV-2 causes profound molecular changes in the brain, despite no molecular trace of the virus in brain tissue.

"The signature the virus leaves in the brain speaks of strong inflammation and disrupted brain circuits and resembles signatures the field has observed in Alzheimer's or other neurodegenerative diseases," senior author Tony Wyss-Coray, PhD, professor of neurology and neurological sciences, Stanford University School of Medicine, Stanford, California, told Medscape Medical News.

The study was published online June 21 in Nature.

Signs of Distress

"We know that up to a third of SARS-CoV-2-infected people show brain symptoms including brain fog, memory problems, and fatigue, and a growing number of people have such symptoms long after they seemingly recovered from virus infection," said Wyss-Coray.

"However, we have very little understanding of how the virus causes these symptoms and what its effects are on the brain at a molecular level," he added.

Using single-cell RNA sequencing, the researchers studied brain tissue samples from eight patients who died of COVID-19 and 14 controls who died of other causes.

While there was no molecular evidence of SARS-CoV-2 in brain tissue samples from the patients who died of COVID-19, "we were very surprised to learn that no matter which type of cell we studied (different types of nerve cells, immune cells, or different support cells in the brain) there were prominent changes" compared with brain tissue samples from controls who died of other causes, said Wyss-Coray.

The changes in the COVID-19 brains showed signatures of inflammation, abnormal nerve cell communication, and chronic neurodegeneration.

"Across cell types, COVID-19 perturbations overlap with those in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia, and depression," the researchers report.

"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.

The findings may help explain the brain fog, fatigue, and other neurological and psychiatric symptoms of long COVID.

"While we studied only brains from people who died of COVID-19, we believe it is likely that similar, but hopefully weaker, signs of inflammation and chronic neurodegeneration will be found in COVID-19 survivors, especially those with chronic brain symptoms," Wyss-Coray said.