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Early this year, leading researchers discussed what we knew -- and didn't know -- about COVID-19 and the brain. Since then, new findings have emerged about SARS-CoV-2 and the nervous system, including the results of an autopsy study that showed the presence of the virus throughout the body and brain.

How can a respiratory pathogen like SARS-CoV-2 cause the nervous system to go haywire? That's the question researchers posed in January, and it's still being asked nearly a year later.

Neurologic complications of COVID are diverse and can be long-lasting, noted Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke, at the time. "They are largely immune-mediated, the brain endothelial cells being a major target," he told 麻豆传媒.

Research throughout the year supported this view. In July, an autopsy study of nine COVID patients showed vascular damage with serum proteins leaking into the brain parenchyma, accompanied by widespread endothelial cell activation. Consistent with other studies, SARS-CoV-2 virus was not detected in the brain.

But in December, an who died with COVID-19 in the first year of the pandemic showed that SARS-CoV-2 virus had spread throughout the body -- including the brain -- and persisted in tissue for months.

Despite this, there was little evidence of inflammation or direct viral cytopathology outside the respiratory tract, reported Daniel Chertow, MD, MPH, of the NIH Clinical Center and the National Institute of Allergy and Infectious Diseases, and co-authors in Nature.

"We did a total of 44 autopsies and in 11 of those, we were able to do a detailed evaluation of the brain," Chertow told 麻豆传媒. "In most of those individuals where we had brain [samples], we did find evidence of viral RNA and protein across multiple regions we sampled."

"And in one of those patients, using a modified Vero cell line that expresses the human ACE2 and TMPRSS2 receptors, we actually were able to culture virus from the brain," he continued. "So we were able to show not just the presence of viral components -- RNA and protein -- but also live, replication-competent virus."

Several factors set this autopsy study apart from others, Chertow pointed out. The postmortem interval was short, a median of 22 hours, he said.

"In addition, at the time of autopsy, we freshly dissected brain tissue," he added. "We collected tissue from 10 different regions of the brain, and from each of those regions, we preserved tissues in different ways that were amenable for the types of downstream analyses we did."

The findings may not be generalizable, Chertow cautioned. "Everybody in our cohort was unvaccinated because the study was done during the first year of the pandemic, before the vaccine was available," he said. "And most of the people were older and had significant comorbidities." The cohort included predominantly severe and ultimately fatal COVID cases, and results might not apply to younger, healthier, or vaccinated individuals.

Despite its limitations, the study showed that SARS-CoV-2 has the potential to disseminate to cells and tissues throughout the body and the brain, though it leaves important questions unanswered.

"This is a meticulously done detailed study showing that SARS-CoV-2 infection is indeed systemic and involves many organ systems, including the brain," observed Ziyad Al-Aly, MD, of Washington University in St. Louis, who wasn't involved with the research.

"What the study doesn't show is the presence of inflammation, cytopathology, or a clear mechanistic explanation of the neurologic complications of SARS-CoV-2 infection," Al-Aly told 麻豆传媒.

"Much more needs to be done to help us understand the mechanisms underpinning the neurologic injury we see so vividly in people with COVID-19 both in the acute and the long COVID phase of the disease," he added.

Also contributing to the knowledge of COVID and the brain in 2022 was the who recovered from COVID without respiratory compromise.

Extracellular vesicles isolated from her brain biopsy tissue showed the presence of viral nucleocapsid protein, which was associated with endothelial cell activation, fibrinogen leakage, and immune cell infiltration, reported Nath and co-authors in Neurology.

"We never found the virus," Nath told 麻豆传媒. "We found the viral protein, but no RNA."

Few researchers have found the virus, Nath noted. And when they do find it, "it's not like they're finding overwhelming amounts of virus in the brain," he pointed out. "They find very small amounts of it."

"The question is, really, how significant is it?" he added. "Is it driving the pathology or is it just sitting there? That still remains to be understood."

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