SARS-CoV-2, the virus that causes COVID-19, probably doesn’t straight infect the mind but can nonetheless inflict vital neurological harm, in line with a brand new research from neuropathologists, neurologists, and neuroradiologists at Columbia College Vagelos Faculty of Physicians and Surgeons.
“There’s been appreciable debate about whether or not this virus infects the mind, but we have been unable to search out any indicators of virus inside mind cells of greater than 40 COVID-19 sufferers,” says James E. Goldman, MD, PhD, professor of pathology & cell biology (in psychiatry), who led the research with Peter D. Canoll, MD, PhD, professor of pathology & cell biology, and Kiran T. Thakur, MD, the Winifred Mercer Pitkin Assistant Professor of Neurology.
“At the similar time, we noticed many pathological adjustments in these brains, which may clarify why severely ailing sufferers expertise confusion and delirium and different severe neurological results — and why these with delicate circumstances could expertise ‘mind fog’ for weeks and months.”
The research, revealed in the journal Mind, is the largest and most detailed COVID-19 mind post-mortem report revealed up to now, means that the neurological adjustments typically seen in these sufferers could end result from irritation triggered by the virus in different elements of the physique or in the mind’s blood vessels.
The research examined the brains of 41 sufferers with COVID-19 who succumbed to the illness throughout their hospitalization. The sufferers ranged in age from 38 to 97; about half had been intubated and all had lung harm attributable to the virus. Lots of the sufferers have been of Hispanic ethnicity. There was a variety of hospital size with some sufferers dying quickly after arrival to the emergency room whereas others remained in the hospital for months. All of the sufferers had intensive scientific and laboratory investigations, and a few had mind MRI and CT scans.
To detect any virus in the neurons and glia cells of the mind, the researchers used a number of strategies together with RNA in situ hybridization, which might detect viral RNA inside intact cells; antibodies that may detect viral proteins inside cells; and RT-PCR, a delicate method for detecting viral RNA.
Regardless of their intensive search, the researchers discovered no proof of the virus in the sufferers’ mind cells. Although they did detect very low ranges of viral RNA by RT-PCR, this was probably because of virus in blood vessels or leptomeninges overlaying the mind.
“We’ve checked out extra brains than different research, and we’ve used extra methods to seek for the virus. The underside line is that we discover no proof of viral RNA or protein in mind cells,” Goldman says. “Although there are some papers that declare to have discovered virus in neurons or glia, we predict that these end result from contamination, and any virus in the mind is contained inside the mind’s blood vessels.” “If there’s any virus current in the mind tissue, it needs to be in very small quantities and doesn’t correlate with the distribution or abundance of neuropathological findings,” Canoll says.
The exams have been carried out on greater than two dozen mind areas, together with the olfactory bulb, which was searched as a result of some reviews have speculated that the coronavirus can journey from the nasal cavity into the mind by way of the olfactory nerve. “Even there, we didn’t discover any viral protein or RNA,” Goldman says, “although we discovered viral RNA and protein in the sufferers’ nasal mucosa and in the olfactory mucosa excessive in the nasal cavity.” (The latter discovering seems in an unpublished research, presently on BioRxiv, led by Jonathan Overdevest, MD, PhD, assistant professor of otolaryngology, and Stavros Lomvardas, PhD, professor of biochemistry & molecular biophysics and neuroscience.)
Regardless of the absence of virus in the mind, in each affected person the researchers discovered vital mind pathology, which largely fell into two classes.
“The very first thing we observed was a whole lot of areas with harm from a scarcity of oxygen,” Goldman says. “All of them had extreme lung illness, so it’s not stunning that there’s hypoxic harm in the mind.”
A few of these have been giant areas attributable to strokes, but most have been very small and solely detectable with a microscope. Based mostly on different options, the researchers consider these small areas of hypoxic harm have been attributable to blood clots, frequent in sufferers with extreme COVID-19, that briefly stopped the provide of oxygen to that space.
A extra stunning discovering, Goldman says, was the giant variety of activated microglia they present in the brains of most sufferers. Microglia are immune cells that reside in the mind and may be activated by pathogens.
“We discovered clusters of microglia attacking neurons, a course of known as ‘neuronophagia,’” says Canoll. Since no virus was present in the mind, it’s doable the microglia could have been activated by inflammatory cytokines, equivalent to Interleukin-6, related to SARS-CoV-2 an infection.
“At the similar time, hypoxia can induce the expression of ‘eat me’ indicators on the floor of neurons, making hypoxic neurons extra susceptible to activated microglia,” Canoll says, “so even with out straight infecting mind cells, COVID-19 may cause harm to the mind.”
The group discovered this sample of pathology in one among their first autopsies, described by Osama Al-Dalahmah, MD, PhD, teacher in pathology & cell biology, in a case report revealed final March in Acta Neuropathologica Communications. Over the subsequent few months, as the neuropathologists did many extra COVID mind autopsies, they noticed comparable findings time and again and realized that it is a distinguished and customary neuropathological discovering in sufferers who die of COVID.
The activated microglia have been discovered predominantly in the decrease mind stem, which regulates coronary heart and respiratory rhythms, in addition to ranges of consciousness, and in the hippocampus, which is concerned in reminiscence and temper.
“We all know the microglia exercise will result in lack of neurons, and that loss is everlasting,” Goldman says. “Is there sufficient lack of neurons in the hippocampus to trigger reminiscence issues? Or in different elements of the mind that assist direct our consideration? It’s doable, but we actually don’t know at this level.”
Goldman says that extra analysis is required to grasp the the reason why some post-COVID-19 sufferers proceed to expertise signs.
The researchers are actually inspecting autopsies on sufferers who died a number of months after recovering from COVID-19 to study extra.
They’re additionally inspecting the brains from sufferers who have been critically ailing with acute respiratory misery syndrome (ARDS) earlier than the COVID-19 pandemic to see how a lot of COVID-19 mind pathology is a results of the extreme lung illness.
Reference: “COVID-19 neuropathology at Columbia College Irving Medical Heart/New York Presbyterian Hospital” by Kiran T Thakur, Emily Glad Miller, Michael D Glendinning, Osama Al-Dalahmah, Matei A Banu, Amelia Okay 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, Mind.
Different contributors (all at Columbia until in any other case famous): Emily Glad Miller, Michael D. Glendinning, Osama Al-Dalahmah, Matei A. Banu, Amelia Okay. 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 College College of Drugs), Angela Lignelli-Dipple, Chun-Chieh Lin (Dartmouth-Hitchcock Medical Heart), Yang Liu, Michael L. Miller, Gul Moonis, Anna S. Nordvig, Serge Przedborski, Morgan L. Prust, William H. Roth, Allison Soung (Washington College College of Drugs), Kurenai Tanji, Andrew F. Teich, Dritan Agalliu, and Anne-Catrin Uhlemann.
The research was supported by an Encephalitis and COVID-19 Seed Funding Award offered by the Encephalitis Society, a grant from the U.S. Nationwide Institutes of Well being (1K23NS105935-01), and the Division of Pathology & Cell Biology at Columbia College Vagelos Faculty of Physicians and Surgeons.