Trial By Error: Study Finds “Elevated Brain Injury Markers and Reduced Grey Matter Volume” a Year After Hospitalization for COVID-19

By David Tuller, DrPH

A British study of neurological sequelae in patients many months after hospitalization for COVID-19 has found that “post acute cognitive deficits…were associated with elevated brain injury markers in serum and reduced grey matter volume,” according to a pre-print posted earlier this week. (A pre-print is a paper that has not yet been peer-reviewed and published by a journal.)

The pre-print is part of the COVID-19 Clinical Neuroscience Study (COVID-CNS), a £2.3 million project funded by UK Research and Innovation, a non-departmental public organization. COVID-CNS, designed to investigate the neurological and neuropsychiatric complications of COVID-19, is led by researchers at the University of Liverpool and King’s College London. In late December, a paper from a different team of COVID-CNS researchers—”Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses”–was published in Nature Communications.

The pre-print study, titled “Post-COVID cognitive deficits at one year are global and associated with elevated brain injury markers and grey matter volume reduction: national prospective study,” is currently under review at Nature Portfolio. (That’s not a single journal but an umbrella for many journals published by Nature.)

The study included 351 patients, whose results were compared to data from almost 3,000 matched controls. Of the patients, 190 had a neurological or psychiatric complication associated with their COVID-19; the others did not. At appointments held a median of just over a year after hospitalization for the acute illness, patients underwent cognitive testing and neuroimaging, provided serum samples and filled out questionnaires for self-reported measures.  

Overall, the objective measures of cognitive deficits corresponded with patients’ subjective complaints. According to the paper, the documented deficits were found in multiple domains of cognitive activity, were “equivalent in magnitude to ageing from 50 to 70 years of age,” and were associated with the “severity of the initial infective insult, post-acute psychiatric symptoms, and a history of encephalopathy.” Early corticosteroid treatment seemed to have a protective effect.

“Together, these findings support the hypothesis that brain injury in moderate to severe COVID-19 is immune-mediated, and should guide the development of therapeutic strategies,” the authors wrote.

In a readable thread, Greta Karen Wood, the paper’s second author and an academic fellow at the University of Liverpool’s Institute of Infection, Veterinary and Ecological Sciences, launched into her discussion with the following: “Do cognitive deficits persist after COVID-19 and, if so, what is their biological basis?”

In subsequent tweets, she proceeded to outline the implications. “The half-lives of the brain injury markers mean that this is objective evidence of *ongoing* brain injury one year after COVID-19…

“Deficits were correlated with symptoms of depression and the anterior cingulate cortex volume, which has functional roles in connecting cognition, attention, and emotion…

“There is growing biochemical evidence that neurological complications in COVID-19, including cognitive impairment, are immune-mediated which is corroborated here by clinical demonstration of the protective effect of acute treatment with corticosteroids…

“Mechanisms underpinning this potentially immune-mediated construct of depression, cognition and brain injury need to be further elucidated, to allow the development of targeted therapeutic interventions.”

The dozens of authors included some leaders in the field of functional neurological disorder (FND). In the domain of FND and the related construct of “medically unexplained symptoms,” depression has been framed as a factor in both precipitating and perpetuating the medical complaints. But a key question is whether one is secondary to the other—is depression leading to or causing cognitive symptoms, or are cognitive symptoms and their associated complications leading to depression?

Chronic illness and depression are frequently found to be associated, and their interactions can run in both directions. Distinguishing cause and effect can be challenging. In this case, however, the study found the following: “Pre-existing depression or a history of antidepressant use were not significantly associated with post-acute cognitive impairment.”

In other words, the study did not support a claim that depression played a causal role in generating the cognitive dysfunctions. That does not mean, of course, that depression should be ignored while clinicians consider treatment options. It is always critical to address depression, whatever its source. But in many or most cases of post-acute infection-related medical complaints, such treatment will not resolve adequately or at all the underlying drivers of illness and disease.