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What causes brain fog in long COVID? New research finds clues in patients’ cerebrospinal fluid. Gillian Vann/Stocksy
  • Researchers do not fully understand the underlying mechanisms and risks factors associated with the occurrence of brain fog, or cognitive symptoms, in individuals with long COVID, or post-COVID conditions.
  • A recent study found that individuals with a higher number of preexisting cognitive risk factors, such as diabetes, anxiety, or depression, were more likely to develop post-COVID cognitive symptoms.
  • The study authors also found an association between the development of post-COVID cognitive symptoms and abnormalities in the cerebrospinal fluid.
  • These abnormalities generally included the presence of antibodies, suggesting that post-COVID cognitive symptoms could be due to an increase in inflammation.

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Brain fog, or cognitive dysfunction, is one of the most common symptoms that health professionals observe in individuals with long COVID, or post-acute COVID-19.

A recent study by researchers at the University of California, San Francisco (UCSF) suggests a link between the presence of persistent cognitive symptoms several months after a SARS-CoV-2 infection and the presence of abnormalities in the cerebrospinal fluid.

The study also found that individuals with persistent cognitive symptoms were likely to have a higher number of preexisting risk factors associated with cognitive dysfunction before the SARS-CoV-2 infection.

These results may provide a clue for understanding the mechanisms and predisposing factors that lead to cognitive dysfunction in individuals with long COVID.

The study appears in the journal Annals of Clinical and Translational Neurology.

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A substantial minority of individuals with SARS-CoV-2 infection continue to experience symptoms beyond the initial 3–4 weeks after contracting the virus. Health experts describe these persistent COVID-19 symptoms as long COVID or post-acute COVID syndrome.

Cognitive symptoms — such as difficulty maintaining attention, as well as deficits in memory and executive function — are some of the most common symptoms individuals experience beyond the acute phase of the infection.

The researchers conducted the present study to better understand the mechanisms behind and risk factors for post-COVID cognitive symptoms.

This small study was a part of the Long-term Impact of Infection with Novel Coronavirus (LIINC) study, which is a collaboration among researchers at UCSF to understand the long-term effects of a SARS-CoV-2 infection.

The present study involved 32 participants who had experienced mild COVID-19 symptoms during the acute phase of the infection. A cognitive neurologist interviewed them using a standardized questionnaire to determine whether they had developed cognitive deficits after contracting SARS-CoV-2.

Based on the interviews, the researchers determined that 22 participants had experienced cognitive symptoms after the acute phase of the SARS-CoV-2 infection. The remaining 10 participants were in the control group.

The questionnaire also helped determine the presence of risk factors, such as a history of anxiety, depression, high blood pressure, or diabetes, before the infection that would predispose the participants to cognitive dysfunction.

The time between the SARS-CoV-2 infection and the interview was about 9 months for the individuals with cognitive symptoms, and 15 months for those in the control group.

The researchers found that more than 2 in 5 individuals who experienced post-COVID cognitive symptoms had an onset of symptoms at least 1 month after contracting SARS-CoV-2. The participants experiencing a delayed onset of cognitive symptoms were likely to be younger than those who developed the symptoms during the acute phase.

The high proportion of the participants with a delayed onset of cognitive symptoms may allow for the use of early mental health interventions to prevent these symptoms.

Notably, the average number of preexisting cognitive risk factors was higher in the individuals with post-COVID cognitive symptoms than in those in the control group.

A neuropsychologist also evaluated various aspects of the participants’ cognitive function using multiple tests.

The majority of the individuals who experienced post-COVID cognitive symptoms (59%) and the control group participants (70%) met the predefined criteria for cognitive impairment. In other words, there was a difference between the results from the interview and the neuropsychological tests.

The authors note that this discrepancy could be due to the neuropsychological tests failing to capture the changes in cognitive function following the SARS-CoV-2 infection.

This would be especially relevant for the people with preexisting cognitive deficits. It is also possible that the participants did not observe any changes in their cognitive functioning, whereas the neuropsychological tests successfully gauged these cognitive deficits.

Previous studies have observed that individuals with cognitive symptoms during the post-acute phase of COVID-19 show elevated levels of markers associated with brain inflammation and injury in the plasma.

To further investigate the link between cognitive symptoms and brain inflammation, the researchers used cerebrospinal fluid samples obtained from consenting participants. They were able to obtain samples from 13 participants with cognitive symptoms and from 4 individuals from the control group.

They found that more than 3 in 4 individuals with post-COVID cognitive symptoms had abnormalities in their cerebrospinal fluid and that such abnormalities were absent in the control group.

Most of the people with cerebrospinal abnormalities had an abnormal presence of antibodies in their cerebrospinal fluid and serum samples.

The presence of antibodies in the cerebrospinal fluid indicates activation of the immune system and inflammation in the brain. Furthermore, the co-occurrence of these proteins in the serum samples suggests that these abnormalities could potentially be due to an inflammatory response in the entire body.

Dr. Joanna Helmuth, a neurologist at UCSF and lead author of the study, says: “It’s possible that the immune system, stimulated by the virus, may be functioning in an unintended pathological way. This would be the case even though the individuals did not have the virus in their bodies [several months after the SARS-CoV-2 infection].”

Medical News Today spoke with Dr. Elizabeta Mukaetova-Ladinska, a professor of psychiatry at the University of Leicester in the United Kingdom.

Dr. Mukaetova-Ladinska noted that the presence of antibodies in the cerebrospinal fluid and serum in individuals with post-COVID cognitive symptoms was similar to that in HIV-positive individuals.

However, she cautioned that these phenomena may or may not be mechanistically similar.

Dr. Mukaetova-Ladinska did add that the presence of antibodies “may indicate persistent, albeit mild, infection in these patients, that in some COVID-19 patients, especially those with premorbid higher cognitive function, can also manifest with cognitive complaints and impairment.”

Dr. Mukaetova-Ladinska also noted that psychological stress could be another mechanism, besides the SARS-CoV2 infection, contributing to the increased inflammation observed in individuals with post-COVID cognitive symptoms.

She said:

“Psychological stress, as a result of the COVID-19 illness per se and living with the pandemic, may worsen the gut permeability, with the latter being associated with a wide range of immune-related diseases, i.e., arthritis, asthma, type 1 diabetes, and multiple sclerosis, and in some animal studies has been shown to precede them, suggesting causation.”

Dr. Mary Olmstead, a professor of psychology at Queen’s University in Kingston, ON, in Canada, told MNT that the cognitive deficits in individuals with post-COVID cognitive symptoms could be explained by the weakening of the blood-brain barrier.

The blood-brain barrier is a semipermeable membrane between the brain and the blood that prevents immune cells and pathogens from entering the brain.

The participants with post-COVID cognitive symptoms in the present study were older than those in the control group, with aging being associated with the weakening of the blood-brain barrier.

Dr. Olmstead said, “Individuals with weaker [blood-brain barrier] would have worse outcomes with influenza or any other infection, not to mention exposure to a physiological or psychological stressor.”

However, “[A]ll of the findings could be explained by stress, which is heightened during the pandemic and presumably higher in anyone experiencing COVID symptoms.”

The authors note that the small size of their study might limit the validity of their results and that the study needs replicating in a larger sample.

They add that the study sample might not represent the broader population experiencing post-COVID symptoms.

The participants in the group with post-COVID cognitive symptoms were, on average, older than those in the control group. This could potentially influence the presence of cognitive risks before the SARS-CoV-2 infection and thus bias the results.

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