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Post-COVID Cognitive Symptoms Are Accompanied by Elevated Immune Markers in CSF

Persistent cognitive symptoms after recovering from COVID-19 are associated with higher levels of immune markers in cerebrospinal fluid (CSF), according to a late-breaking study presented at the AAN Annual Meeting.

“Many millions of people experience persistent cognitive issues after COVID infection, which can affect even young healthy adults with a mild case," said the study leader Joanna Hellmuth, MD, assistant professor of neurology at the University of California, San Francisco. In almost every case, Dr. Hellmuth said, executive function is impaired, manifested by difficulty retrieving words or manipulating information.

“However, there are not yet laboratory tests for COVID-associated cognitive changes, in part because we do not understand the underlying biology. The objective of our study was to determine if there is an inflammatory signature in the CSF of people with persistent cognitive issues after recovering from infection."

The team enrolled 33 participants, with a mean age of 40 years, all of whom had recovered from COVID without hospitalization, including 23 who experienced persistent cognitive post-acute sequelae of SARS-CoV-2 (PASC), and 10 who did not (the controls). All participants underwent a detailed, structured neurocognitive interview. A subgroup consented to lumbar puncture, including 13 patients with PASC and cognitive issues and five controls.

“We found that those with persistent cognitive issues had higher levels of CSF inflammation and immunovascular markers compared with controls," Dr. Hellmuth said, including C-reactive protein (0.007 vs. 0.000 mg/L, p=0.004) and serum amyloid A (0.001 vs 0.000 mg/L, p=0.001), along with trends for higher levels of interferon-gamma-inducible protein 10, interleukin-8, and the immunovascular markers, vascular endothelial growth factor-C and its receptor VEGFR-1.

In previously published work with this cohort in Annals of Clinical and Translational Neurology, Dr. Hellmuth and colleagues reported that cognitive symptoms were delayed in onset in 43 percent of those who experienced them, developing one or more months later than infection. In the new study, several of the measured proteins were more strongly elevated among those whose symptoms began earliest, including VEGF-C.

“Though this is a very small study, we found that people with COVID-associated cognitive changes had higher levels of inflammation and immunovascular markers in CSF compared with those who did not experience cognitive changes," Dr. Hellmuth said. “This may imply that inflammation within the brain may contribute to these cognitive changes."

“This study suggests one potential mechanism for cognitive PASC, and therefore potential avenues for therapy and monitoring therapy," commented William Yong, MD, chief of neuropathology at the University of California, Irvine School of Medicine, who was not involved with the study.

“The findings are intriguing and bear further investigating. However, to better understand their significance, it will be helpful to have a larger cohort and to know more about the patient demographics, including vaccine status, COVID treatment if any, medications at time of the CSF draw, and co-morbidities," which would be important to rule out as a potential contributor to the cognitive symptoms and elevated markers.

“He added, “I would not be surprised if their findings hold up, as inflammation is not uncommon in brain autopsies of COVID patients, and persistence or aggravation of the inflammatory state is a plausible reason for the cognitive PASC."

Drs. Hellmuth and Yong had no disclosures.

AAN Abstract: Oddi A, Peluso M, Asken B, et al. Cognitive symptoms after mild SARS-CoV-2 infection associate with higher levels of CSF immune activation and immunovascular markers.​


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