Cerebrum Spring 2021

“A large proportion of our patients here were never hospitalized, yet still have pretty debilitating symptoms.” access. Using an animal model, one showed the spike protein—the projection by which Covid latches onto and attacks cells—crossing the blood-brain barrier to be taken up by brain tissue. In the other , post-mortem analysis found the virus in the mucosa of the nose and throat, and along the olfactory nerve, and in a path through the brain. At Yale, Song was also the first author of a recent paper that explores neuroinvasion using an organoid—a three-dimensional neural tissue culture—a mouse model, and brain autopsy of people who had died of Covid. “Every model has its limitations; we used all three to see what they had in common,” he says. Besides the presence of virus, “we found metabolic changes and vascular remodeling, and we think long-term changes in the CNS might have to do with destruction of vasculature.” His own findings notwithstanding, Song sees a multifactorial picture. “The field as a whole has been approaching [mechanisms] in multiple avenues—there’s the direct neuroinvasion portion, and how systemic inflammation and hypoxemia are affecting the brain. I think it’s hard to call the neurological sequelae of Covid a single disease. You have to keep an open mind.” Some researchers, like Frontera, lean toward a systemic explanation. In the NYU series of hospitalized Covid-19 patients, “we did not detect meningitis or encephalitis due to direct invasion by SARS-CoV-2,” she explains. “Our paper highlighted the idea that most neurological manifestations were secondary effects of the virus, related to being hypoxic, uremic, or in sepsis.” A key to Covid injury, she speculates, may be microvascular damage. “Small vessels become leaky, prone to bleeding. We have patients with multifocal hemorrhages.” Other researchers agree. “The SARS-COV-2 (Covid’s formal title) virus has a special predilection for the ACE2 receptors, which is expressed in [the lining of blood vessels] all across the body,” says Batra. “Pulmonary symptoms are what got all the attention early on, but it’s not surprising to see neurological symptoms as well, there’s such a vast network of blood vessels in both the lung and brain.” A post-mortem study of 13 patients who had died of Covid-19 found signs of microvascular injury in brain tissue, thinning of the cells lining blood vessels, and signs of congested blood vessels. There were indications of microhemorrhages in the olfactory bulb and other areas. “Quite possibly, the virus first attacks endothelial cells,” says Nath, an author of the study. “Then the immune system targets those cells, leading to blood vessel damage. There is a hypercoagulable state which leads to occlusions, and some patients develop hemorrhages, too. I suspect that’s the major initial pathophysiology.”

rate of mental maladies was 5.8 percent—double what it was in the comparison groups. Post-traumatic stress disorder is not rare: A paper reported that one-third of 381 patients who had come to a hospital emergency department with Covid-19 were diagnosed with post-traumatic stress disorder when evaluated one to three months later. Parsing biological, situational, and psychological factors in mental disorders can be daunting in the best of times, but all the more so in a year when psychosocial stressors and mental health problems constitute a pandemic of their own. Although definitive conclusions in some cases aren’t yet possible pending the gathering of additional data, speculation by scientists who have studied Covid and brain patterns for months have led to some well-honed observations. In February, for example, “just after the second surge,” Frontera’s group at NYU compared individuals (999 in all) who had been diagnosed with Covid-19, but not hospitalized, with those who had not had the disease. “We’re examining the question, ‘What is the additive effect of Covid on top of the fatigue and the mood and cognitive insults of being socially isolated, under financial stress, and threatened by serious disease?'” he says. “We asked about stuff like financial insecurity, food insecurity, homelessness, childcare, relationship problems,” Frontera says. “There was a lot of political conflict—with family, friends and colleagues.” The survey explored the place of pre-existing psychiatric, neurological, and medical conditions. “We asked about fear of illness and about personal illness as a stressor.” The participants self-tested with a battery that evaluated anxiety, depression, fatigue, sleep, and cognitive dysfunction—“how they feel about their thinking processes,” Frontera says. Because the paper is still under review for publication, she could not disclose findings. The Enemy Within Research into neural effects of Covid-19 began in the earliest days of the pandemic and has accelerated ever since. “The pace has been exponential,” says Batra at Northwestern. “There’s been a lot of fantastic scientific work worldwide, and it’s been stunning to see the rate of progress… a heroic and unprecedented achievement.” Much of this work has sought to clarify the underlying mechanisms by which Covid-19 wreaks its havoc in the CNS. But though much has been learned, answers to perhaps the most fundamental question—does the virus attack the brain directly?—are elusive. “Viral invasion? I think everyone agrees this remains controversial,” says Nath. Although some researchers have found signs of infection in neural tissue, “there’s no evidence of overwhelming virus in the brain. I don’t think that alone explains all this.” Two recent papers suggested how the virus might gain


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