SARS-CoV-2, the virus that causes COVID-19, likely does not directly infect the brain but can still inflict significant neurological damage, according to a new study by neuropathologists, neurologists and neuroradiologists in the United States. Columbia University Vagelos College of Physicians and Surgeons.
“There has been considerable debate over whether this virus infects the brain, but we have not been able to find any signs of the virus inside the brain cells of more than 40 COVID-19 patients,” explains James E. Goldman, MD, PhD, professor of pathology and cell biology (in psychiatry), who led the study with Peter D. Canoll, MD, PhD, professor of pathology and cell biology, and Kiran T. Thakur, MD , Assistant Professor of Neurology Winifred Mercer Pitkin.
“At the same time, we have observed many pathological changes in these brains, which could explain why critically ill patients suffer from confusion, delirium and other serious neurological effects – and why those with mild cases may experience a “brain fog” for weeks and months. “
The study, published in the journal Brain, is the largest and most detailed COVID-19 brain autopsy report released to date, suggests that the neurological changes often seen in these patients may result from virus-triggered inflammation in other parts of the body or in the blood vessels of the brain.
No virus in brain cells
The study examined the brains of 41 patients with COVID-19 who succumbed to the disease while in hospital. The patients were between 38 and 97 years old; about half had been intubated and all had lung damage caused by the virus. Many of the patients were of Hispanic ethnicity. There was a wide range of hospital stays, with some patients dying soon after arriving in the emergency room while others remained in the hospital for months. All patients underwent extensive clinical and laboratory examinations, and some underwent brain MRI and CT scans.
To detect any virus in neurons and glial cells in the brain, the researchers used several methods, including in situ hybridization of RNA, which can detect viral RNA in intact cells; antibodies capable of detecting viral proteins in cells; and RT-PCR, a sensitive technique for detecting viral RNA.
Despite their intensive research, the researchers found no evidence of the virus in patients’ brain cells. Although they detected very low levels of viral RNA by RT-PCR, this was likely due to a virus in the blood vessels or leptomeninges lining the brain.
“We looked at more brains than other studies, and we used more techniques to look for the virus. The bottom line is that we can’t find any evidence of viral RNA or protein in brain cells,” Goldman says. . “Although some papers claim to have found viruses in neurons or glia, we believe these are the result of contamination and that any virus in the brain is contained in the blood vessels of the brain.” “If there is a virus present in brain tissue, it must be in very small amounts and does not correlate with the distribution or abundance of neuropathological findings,” Canoll says.
The tests were conducted on more than two dozen regions of the brain, including the olfactory bulb, which was excavated because some reports have speculated that the coronavirus can travel from the nasal cavity to the brain via the olfactory nerve. “Even there, we didn’t find any viral proteins or RNAs,” Goldman says, “although we did find viral RNA and proteins in the nasal lining of patients and in the olfactory lining at the level of the skin. nasal cavity. (This latest finding appears in an unpublished study, currently on BioRxiv, led by Jonathan Overdevest, MD, PhD, assistant professor of otolaryngology, and Stavros Lomvardas, PhD, professor of biochemistry and molecular biophysics and neuroscience.)
Hypoxic damage and signs of neuronal death
Despite the absence of the virus in the brain, the researchers found in each patient significant brain pathology, which fell mainly into two categories.
“The first thing we noticed was that a lot of areas are damaged by a lack of oxygen,” says Goldman. “They all had severe lung disease, so it’s no surprise that there is hypoxic damage to the brain.”
Some of them were large areas caused by strokes, but most were very small and only detectable under a microscope. Based on other characteristics, the researchers believe that these small areas of hypoxic damage were caused by blood clots, common in patients with severe COVID-19, which temporarily stopped the supply of oxygen to this area. .
A more surprising finding, Goldman says, was the large number of activated microglia they found in the brains of most patients. Microglia are immune cells that reside in the brain and can be activated by pathogens.
“We found clumps of microglia attacking neurons, a process called ‘neuronophagy’,” Canoll explains. Since no viruses were found in the brain, it is possible that the microglia were activated by inflammatory cytokines, such as interleukin-6, associated with infection with SARS-CoV-2.
“At the same time, hypoxia can induce the expression of ‘eat me’ signals on the surface of neurons, making hypoxic neurons more vulnerable to activated microglia,” Canoll says, “so even without directly infecting cells brain damage, COVID-19 can cause brain damage. “
The group found this pattern of pathology in one of their first autopsies, described by Osama Al-Dalahmah, MD, PhD, instructor in pathology and cell biology, in a case report published last March in Acta Neuropathologica Communications. Over the next several months, as neuropathologists performed numerous more COVID brain autopsies, they repeatedly saw similar results and realized that this was an important and common neuropathological finding in deceased patients. of COVID.
Activated microglia have been found primarily in the lower brainstem, which regulates heart and respiratory rhythms, as well as levels of consciousness, and in the hippocampus, which is involved in memory and mood.
“We know that the activity of the microglia will cause the loss of neurons, and that loss is permanent,” Goldman says. “Is there enough loss of neurons in the hippocampus to cause memory problems? Or in other parts of the brain that help direct our attention? It’s possible, but we really don’t know how to this stage. “
Persistent neurological problems in survivors
Goldman says more research is needed to understand why some post-COVID-19 patients continue to show symptoms.
Researchers are currently reviewing autopsies of patients who died several months after recovering from COVID-19 to find out more.
They are also examining the brains of patients with severe acute respiratory distress syndrome (ARDS) before the COVID-19 pandemic to see to what extent COVID-19 brain pathology is the result of severe lung disease.
The study, titled “COVID-19 Neuropathology at Columbia University Irving Medical Center / New York Presbyterian Hospital”, was published on April 15, 2021 in Brain.
Other contributors (all at Columbia, unless otherwise noted): Emily Happy Miller, Michael D. Glendinning, Osama Al-Dalahmah, Matei A. Banu, Amelia K. Boehme, Alexandra L. Boubour, Samuel L. Bruce, Alexander M. Chong , Jan Claassen, Phyllis L. Faust, Gunnar Hargus, Richard Hickman, Sachin Jambawalikar, Alexander G. Khandji, Carla Y. Kim, Robyn S. Klein (University of Washington School of Medicine), Angela Lignelli-Dipple, Chun -Chieh Lin (Dartmouth -Hitchcock Medical Center), Yang Liu, Michael L. Miller, Gul Moonis, Anna S. Nordvig, Serge Przedbourski, Morgan L. Prust, William H. Roth, Allison Soung (University School of Medicine of Washington), Kurenai Tanji, Andrew F Teich, Dritan Agalliu and Anne-Catrin Uhlemann.
The study was supported by an encephalitis award and COVID-19 seed funding provided by the Encephalitis Society, a grant from the United States National Institutes of Health (1K23NS105935-01) and the Department of Pathology and Columbia University cell biology Vagelos College of Physicians and Surgeons.