Summary: Adults who developed cognitive symptoms—commonly called “brain fog”—after mild COVID-19 infection showed abnormalities in their cerebrospinal fluid. Researchers suggest an overactive immune response triggered by SARS-CoV-2 may underlie these cognitive problems.
Source: UCSF
New cognitive symptoms following otherwise mild COVID-19 were linked to measurable abnormalities in cerebrospinal fluid, offering clues about how SARS-CoV-2 may affect the brain.
In a focused observational study of 32 adults who previously tested positive for SARS-CoV-2 but did not require hospitalization, researchers from the UC San Francisco Memory and Aging Center and Weill Cornell Medicine examined neurological changes in people who reported new cognitive difficulties after infection. Of the 32 participants, 22 reported cognitive symptoms and 10 served as controls. Seventeen participants consented to lumbar puncture for cerebrospinal fluid (CSF) analysis.
Among those who underwent lumbar puncture, 10 of 13 participants with post-COVID cognitive complaints had abnormalities in their CSF. In contrast, all four samples from participants who did not report cognitive symptoms were within normal limits. The full results were published on Jan. 18, 2022 in Annals of Clinical and Translational Neurology.
Participants with cognitive symptoms were, on average, older (mean age 48) than the control group (mean age 39). The cognitive complaints centered on executive function: difficulties remembering recent events, retrieving names or words, sustaining attention, holding and manipulating information, and slowed processing speed, according to senior author Joanna Hellmuth, MD, MHS, of UCSF. These complaints are often described by patients as “brain fog.”
Brain fog is a common complaint after COVID-19 infection. In other clinic-based series, a large share of post-COVID patients report similar symptoms. In this study, participants were enrolled through the Long-term Impact of Infection with Novel Coronavirus (LIINC) cohort, which follows adults recovering from confirmed SARS-CoV-2 infection.
Laboratory analysis of CSF showed signs consistent with inflammation: elevated protein levels and the presence of antibodies not typically expected in the CSF. Some antibodies were detected in both blood and CSF, indicating a systemic inflammatory reaction; others appeared only in CSF, which suggests localized immune activation in the central nervous system. The precise targets of these antibodies remain unknown, but researchers note the possibility these could be autoreactive antibodies that mistakenly target the body’s own tissues.
Immune dysregulation months after initial infection
The investigators observed these immune changes even though none of the participants were actively infected at the time of testing. Lumbar punctures were performed on average about 10 months after participants’ first COVID-19 symptoms. “It’s possible that the immune system, stimulated by the virus, may be functioning in an unintended pathological way,” said Hellmuth, who leads the UCSF Coronavirus Neurocognitive Study and is affiliated with the UCSF Weill Institute for Neurosciences.
Beyond CSF findings, participants who reported cognitive trouble tended to have more preexisting cognitive risk factors. On average they had 2.5 such risk factors, compared with fewer than one risk factor in controls. These included conditions known to affect brain health—diabetes and hypertension, which raise the risk for vascular cognitive impairment; prior attention-deficit/hyperactivity disorder (ADHD), which can increase vulnerability to executive dysfunction; and histories of anxiety, depression, heavy alcohol use, stimulant use, or learning disabilities.
Standard cognitive tests may miss meaningful decline
All participants completed in-person neuropsychological testing using assessment criteria adapted from HIV-associated neurocognitive disorder (HAND). Interestingly, 13 of the 22 participants who reported cognitive symptoms (59 percent) met HAND criteria, while seven of 10 control participants (70 percent) also met those criteria. The team cautions that relying only on comparisons to normative test references can fail to detect true cognitive decline—particularly for people whose pre-COVID baseline was high. A person might experience a substantial drop in function that nevertheless remains within population norms.
“If people tell us they have new thinking and memory issues, I think we should believe them rather than require that they meet certain severity criteria,” Hellmuth said, emphasizing the importance of listening to patients and considering both subjective reports and objective testing.
Cognitive impairment following infection is not unique to COVID-19. Prior research has documented similar sequelae after infections with other viruses, including SARS, MERS, hepatitis C and Epstein-Barr virus. These patterns underscore how infectious triggers and subsequent immune responses can influence brain function.
Authors and funding
The study’s first author is Alexandra C. Apple, PhD, of the UCSF Memory and Aging Center and the Weill Institute for Neurosciences. The research received support from grants from the National Institutes of Health (NIMH K23MH114724 and NINDS R01NS118995-14S). For a complete list of co-authors and disclosures, please consult the published paper.
About this COVID-19 and cognition research news
Author: Suzanne Leigh
Source: UCSF
Contact: Suzanne Leigh – UCSF
Image: The image is in the public domain
Original Research: The findings will appear in Annals of Clinical and Translational Neurology