SARS-CoV-2, the infection that triggers COVID-19, most likely does not straight contaminate the brain however can still cause considerable neurological damage, according to a brand-new research study from neuropathologists, neurologists, and neuroradiologists at Columbia University Vagelos College of Physicians and Surgeons.
“There’s been considerable debate about whether this virus infects the brain, but we were unable to find any signs of virus inside brain cells of more than 40 COVID-19 patients,” states James E. Goldman, MD, PhD, teacher of pathology & cell biology (in psychiatry), who led the research study with Peter D. Canoll, MD, PhD, teacher of pathology & cell biology, and Kiran T. Thakur, MD, the Winifred Mercer Pitkin Assistant Professor of Neurology.
“At the same time, we observed many pathological changes in these brains, which could explain why severely ill patients experience confusion and delirium and other serious neurological effects — and why those with mild cases may experience ‘brain fog’ for weeks and months.”
The research study, released in the journal Brain, is the biggest and most comprehensive COVID-19 brain autopsy report released to date, recommends that the neurological modifications typically seen in these clients might arise from swelling activated by the infection in other parts of the body or in the brain’s capillary.
No Virus in Brain Cells
The research study took a look at the brains of 41 clients with COVID-19 who caught the illness throughout their hospitalization. The clients varied in age from 38 to 97; about half had actually been intubated and all had actually lung damage triggered by the infection. Many of the clients were of Hispanic ethnic background. There was a wide variety of healthcare facility length with some clients passing away not long after arrival to the emergency clinic while others stayed in the healthcare facility for months. All of the clients had substantial scientific and laboratory examinations, and some had brain MRI and CT scans.
To find any infection in the nerve cells and glia cells of the brain, the scientists utilized several techniques consisting of RNA in situ hybridization, which can find viral RNA within undamaged cells; antibodies that can find viral proteins within cells; and RT-PCR, a delicate method for spotting viral RNA.
Despite their extensive search, the scientists discovered no proof of the infection in the clients’ brain cells. Though they did find extremely low levels of viral RNA by RT-PCR, this was likely due to infection in capillary or leptomeninges covering the brain.
“We’ve looked at more brains than other studies, and we’ve used more techniques to search for the virus. The bottom line is that we find no evidence of viral RNA or protein in brain cells,” Goldman states. “Though there are some papers that claim to have found virus in neurons or glia, we think that those result from contamination, and any virus in the brain is contained within the brain’s blood vessels.” “If there’s any virus present in the brain tissue, it has to be in very small amounts and does not correlate with the distribution or abundance of neuropathological findings,” Canoll states.
The tests were carried out on more than 2 lots brain areas, consisting of the olfactory bulb, which was browsed since some reports have actually hypothesized that the coronavirus can take a trip from the nasal cavity into the brain through the olfactory nerve. “Even there, we didn’t find any viral protein or RNA,” Goldman states, “though we found viral RNA and protein in the patients’ nasal mucosa and in the olfactory mucosa high in the nasal cavity.” (The latter finding appears in an unpublished research study, presently on BioRxiv, led by Jonathan Overdevest, MD, PhD, assistant teacher of otolaryngology, and Stavros Lomvardas, PhD, teacher of biochemistry & molecular biophysics and neuroscience.)
Hypoxic Damage and Signs of Neuronal Death
Despite the lack of infection in the brain, in every client the scientists discovered considerable brain pathology, which primarily fell under 2 classifications.
“The first thing we noticed was a lot of areas with damage from a lack of oxygen,” Goldman states. “They all had severe lung disease, so it’s not surprising that there’s hypoxic damage in the brain.”
Some of these were big locations triggered by strokes, however many were extremely little and just noticeable with a microscopic lense. Based on other functions, the scientists think these little locations of hypoxic damage were triggered by embolism, typical in clients with extreme COVID-19, that momentarily stopped the supply of oxygen to that location.
A more unexpected finding, Goldman states, was the a great deal of triggered microglia they discovered in the brains of many clients. Microglia are immune cells that live in the brain and can be triggered by pathogens.
“We found clusters of microglia attacking neurons, a process called ‘neuronophagia,’” states Canoll. Since no infection was discovered in the brain, it’s possible the microglia might have been triggered by inflammatory cytokines, such as Interleukin-6, connected with SARS-CoV-2 infection.
“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 states, “so even without directly infecting brain cells, COVID-19 can cause damage to the brain.”
The group discovered this pattern of pathology in among their very first autopsies, explained by Osama Al-Dalahmah, MD, PhD, trainer in pathology & cell biology, in a case report released last March in Acta Neuropathologica Communications. Over the next couple of months, as the neuropathologists did a lot more COVID brain autopsies, they saw comparable findings over and over once again and understood that this is a popular and typical neuropathological finding in clients who pass away of COVID.
The triggered microglia were discovered mainly in the lower brain stem, which manages heart and breathing rhythms, along with levels of awareness, and in the hippocampus, which is associated with memory and state of mind.
“We know the microglia activity will lead to loss of neurons, and that loss is permanent,” Goldman states. “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 at this point.”
Persistent Neurological Problems in Survivors
Goldman states that more research study is required to comprehend the reasons some post-COVID-19 clients continue to experience signs.
The scientists are now analyzing autopsies on clients who passed away a number of months after recuperating from COVID-19 to read more.
They are likewise analyzing the brains from clients who were seriously ill with severe breathing distress syndrome (ARDS) prior to the COVID-19 pandemic to see just how much of COVID-19 brain pathology is an outcome of the extreme lung illness.
Reference: “COVID-19 neuropathology at Columbia University Irving Medical Center/New York Presbyterian Hospital” by Kiran T Thakur, Emily Happy Miller, Michael D Glendinning, Osama Al-Dalahmah, Matei A Banu, Amelia K Boehme, Alexandra L Boubour, Samuel S Bruce, Alexander M Chong, Jan Claassen, Phyllis L Faust, Gunnar Hargus, Richard A Hickman, Sachin Jambawalikar, Alexander G Khandji, Carla Y Kim, Robyn S Klein, Angela Lignelli-Dipple, Chun-Chieh Lin, Yang Liu, Michael L Miller, Gul Moonis, Anna S Nordvig, Jonathan B Overdevest, Morgan L Prust, Serge Przedborski, William H Roth, Allison Soung, Kurenai Tanji, Andrew F Teich, Dritan Agalliu, Anne-Catrin Uhlemann, James E Goldman and Peter Canoll, 15 April 2021, Brain.
DOI: 10.1093/brain/awab148
Other factors (all at Columbia unless otherwise kept in mind): 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 (Washington University School of Medicine), Angela Lignelli-Dipple, Chun-Chieh Lin (Dartmouth-Hitchcock Medical Center), Yang Liu, Michael L. Miller, Gul Moonis, Anna S. Nordvig, Serge Przedborski, Morgan L. Prust, William H. Roth, Allison Soung (Washington University School of Medicine), Kurenai Tanji, Andrew F. Teich, Dritan Agalliu, and Anne-Catrin Uhlemann.
The research study was supported by an Encephalitis and COVID-19 Seed Funding Award supplied by the Encephalitis Society, a grant from the U.S. National Institutes of Health (1K23NS105935-01), and the Department of Pathology & Cell Biology at Columbia University Vagelos College of Physicians and Surgeons.
