Researchers from the University of NSW and St. Vincent’s Hospital have identified a key pathway involved in inflammation, which appears to be activated in people with long COVID who have symptoms of ‘brain fog’. This could lead to answers and new treatments.

Patients who participated in this study had mild to moderate acute COVID-19 and were enrolled in the St Vincent's COVID-19 ADAPT study, a longitudinal study led by Professor Gail Matthews. 

Scientists from the School of Psychology and Faculty of Medicine & Health found that of the study cohort of 128 people, those with prolonged activation of the kynurenine pathway were more likely to have mild cognitive deficits 12 months after developing COVID-19. They also found that these symptoms were less likely to improve over time. The study helps demonstrate that there is a biological change underlying brain fog in people who have long COVID as a result of mild acute COVID-19 infection.  

“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 Associate Professor Lucette Cysique, lead author of the study. “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.” 

A/Prof. Cysique says, “I think when patients go to the doctor 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.”

The discovery opens up possibilities for identifying and treating people experiencing the cognitive effects of long COVID and perhaps long COVID in general. “These findings lay the foundation for the kynurenine pathway as a potential diagnostic and monitoring marker, as well as a possible therapeutic target,” A/Prof. Cysique says. 

Current evidence compiled by the World Health Organisation (WHO) suggests approximately 10–20 per cent of people experience a variety of mid and long-term effects after they recover from their initial illness. In fact, up to 100 different symptoms have been recorded as part of the long COVID disease profile.  

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

The cognitive dysfunctions experienced by those with long COVID manifest most often as a lack of mental focus, clarity or mental fatigue that is unusual compared to one’s previous capacity. Especially after a cognitively demanding task (for example, reading complex instructions, participating in a meeting that demands a high concentration level, or watching a documentary on a topic that is new and complex). This is associated with short-term memory problems, difficulty in multi-tasking or concentration over long periods of time. 

“With a little introspection, we can all imagine how long-term flu-like physical and mental fatigue would impact everyday function,” says A/Prof. Cysique. “And we are talking of mostly working-age people. Hence, these types of deficits can affect work efficiency to some degree and probably contribute to the economic impact of the pandemic.”

While this study included only unvaccinated patients, because the testing was conducted before patients received their first vaccine, the majority of people in the study had long COVID due to mild COVID-19 infection.

“With vaccination, many of us will still experience mostly mild symptoms. Hence the results are still relevant, especially in the context of reinfection,” says A/Prof. Cysique.  

In April 2023, the government announced new research funding for long COVID due to the long COVID parliamentary enquiry, showing that the government recognises long COVID as a serious issue that demands urgent solutions. 

The team are keen to continue building on their research by extending the study cohort to vaccinated patients and to continue the investigation up to 24 months after the infection date.  

“We are also in contact with a Dutch research group who also find that a prolonged activation of the KP is involved in COVID-19 brain changes and want to start a trial,” says A/Prof. Cysique.