Long COVID brain fog linked to immune response

Australian researchers have identified a biological pathway that appears to be activated in people with long COVID who suffer from ‘brain fog’ giving heart to people who fear their issues are being dismissed as “all in the mind.”

In the medium-sized study of 128 people, those who had prolonged activation of the kynurenine pathway – which is involved in inflammation – were more likely to have mild cognitive deficits 12 months after developing COVID-19.

The patients had mild to moderate acute COVID-19 and were enrolled in the St Vincent’s COVID-19 ADAPT study prior to COVID-19 vaccination availability, so the findings can’t be generalised to vaccinated populations.

“Together, this study and a previous study in the ADAPT program show that long COVID brain fog is associated with a dysregulation of the immune response,” says Lucette Cysique, associate professor and neuropsychologistat the University of New South Wales.

“The current study specifically found that an important metabolic pathway – the kynurenine pathway – is linked to the cognitive changes we’re seeing in this group of patients,” says Cysique, who is lead author of the study in Annals of Clinical and Translational Neurology.

“I think when patients go to the doctor’s with brain fog, it may be dismissed as a psychological problem. Our study speaks to the contrary, that there is a real biological mechanism behind long COVID brain fog.”

According to Cysique the findings “lay the foundation for the kynurenine pathway as a potential diagnostic and monitoring marker, as well as a possible therapeutic target” for people who are experiencing the cognitive effects of long COVID.

The majority of people enrolled in this study had long COVID as a result of mild COVID-19 infection. But Cysique says: “With vaccination, many of us will still experience mostly mild symptoms. Hence the results are still relevant, especially in the context of reinfection.”

The cohort was followed up at 2, 4, and 12 months after infection. And at 2 months, when the kynurenine pathway was the most activated, 60% of those who showed mild cognitive deficits also showed an abnormal activation of the kynurenine pathway. This abnormality was above the known abnormal level in reference samples of the same age. 

“As the immune response takes place, it activates the kynurenine pathway across a period of four months in average – this is much longer than it should be,” says Cysique.

“Because the kynurenine pathway is pro-inflammatory, the entire body, including the brain, is flooded by inflammatory products over a prolonged period. And we know that the kynurenine pathway impacts the central nervous system.”

No other blood biomarkers, sex, or clinical factors – such as pre-existing or COVID-associated mental health, disease severity or respiratory function, and olfaction – were associated with cognition. 

Current evidence compiled by the World Health Organization (WHO) suggests that approximately 10–20% of people experience a variety of mid and long-term effects after they recover from their initial COVID-19 illness.

“Long COVID is a multi-organ disease, so people are differently affected across several of their body functions. This is not surprising as the immune system is involved across all body functions,” says Cysique.

“However, we now know that besides fatigue, cognitive changes are the most common symptoms associated with long COVID.” 

“We hope that our study can provide some hope to people who are suffering from long COVID.”

The authors also acknowledge several limitations to the study, including a medium sample size and that it was restricted to “the socio-economically advantaged parts of Sydney and with relatively high education, optimal care access, and management of medical comorbidities.”

To build upon the research, the team plan to extend the study cohort to vaccinated patients, and up to 24 months after the infection date.