Persistent Brain Fog After Mild COVID Infection Tied to CSF Markers

People with persistent cognitive changes after mild COVID had elevated levels of immune activation and immunovascular markers in their cerebrospinal fluid (CSF) 10 months after acute SARS-CoV-2 infection, a small study showed.

In a late-breaking abstract presented at the American Academy of Neurology (AAN) annual meeting, Joanna Hellmuth, MD, MHS, of the University of California San Francisco, reported higher median CSF levels of C-reactive protein (P=0.004) and serum amyloid A (P=0.001) in long COVID patients with cognitive symptoms compared with COVID patients who experienced no cognitive changes after infection.

CSF immune activation markers interferon-gamma-inducible protein (IP-10, P=0.059), interleukin (IL)-8 (P=0.059), and immunovascular markers vascular endothelial growth factor-C (VEGF-C, P=0.095) and VEGFR-1 (the soluble receptor for VEGFs, P=0.059) also trended higher in people with post-COVID cognitive changes, the researchers said.

“In this group of 13 participants with cognitive issues and five controls with no cognitive symptoms after COVID, the median age was 40 years old and the cerebrospinal fluid was collected a median of 10 months after the first COVID symptoms,” Hellmuth said at an AAN press briefing.

Some CSF markers showed specificity for COVID patients who had early-onset cognitive changes, Hellmuth added.

“If true, these findings imply that inflammation within the brain may contribute to these cognitive changes after COVID, and also that SARS-CoV-2 could trigger an immunovascular dysregulation via endothelial dysfunction and activation,” she said. “And in those with early onset cognitive issues after COVID, this homeostasis was not regained 10 months later.”

This information is important, noted Avindra Nath, MD, clinical director of the National Institute of Neurological Disorders and Stroke at the NIH, who wasn’t involved with the study.

“It’s consistent with the observation that there’s a fair bit of vascular injury and repair taking place,” Nath told MedPage Today. “In our COVID pathology research, we found there is disruption of small blood vessels in the brain: they leak a lot of protein into the brain and that sets up the inflammation.”

The new findings build on previous research from Hellmuth and colleagues that reported test abnormalities among people with post-COVID cognitive problems.

“What we found on neuropsychological testing was really similar to what other groups have found, which is that this is universally an executive function disorder,” Hellmuth pointed out. “People have difficulty retrieving names and words or holding onto and manipulating information, or difficulties with slow processing speed.”

With this CSF analysis, Hellmuth and colleagues are “making some first definitive steps toward understanding what seems to be one of the greatest questions of our times related to the post-acute sequelae of COVID,” noted AAN Science Committee Chair Natalia Rost, MD, of Massachusetts General Hospital in Boston, who also wasn’t involved with the study. “I think this is going to be an issue of tremendous proportion for us to address in the coming years and decades.”