Researchers have connected long COVID’s cognitive phenomenon known as “brain fog” with the kynurenine pathway, highlighting a biological foundation for the cognitive struggles experienced by sufferers. This discovery may create avenues for future treatments.
The pinpointing of a metabolic pathway could unlock solutions and novel treatments for those who are suffering from brain fog as a result of long COVID.
A key pathway, which plays a role in inflammation, has been identified by researchers from the University of New South Wales (UNSW Sydney) and St. Vincent’s Hospital, and appears to be activated in individuals with long COVID experiencing ‘brain fog.’
A study of 128 participants by scientists from the School of Psychology and Faculty of Medicine & Health revealed that those who endured prolonged activation of the kynurenine pathway were more likely to show mild cognitive impairments a year after COVID-19 onset. Moreover, these symptoms were found less likely to improve as time progressed.
The study included patients with mild to moderate acute COVID-19 symptoms and were part of the St Vincent’s COVID-19 ADAPT study, overseen by Professor Gail Matthews.
“This research, along with a prior study within the ADAPT program, demonstrates that long COVID brain fog correlates with a dysfunction in the immune response,” states Associate Professor Lucette Cysique, the study’s lead author. “This specific research detected that a crucial metabolic pathway – the kynurenine pathway – has a connection to the cognitive variations we observe in this patient group.”
Published in the Annals of Clinical and Translational Neurology, the study proves that a biological alteration underpins the brain fog in individuals who suffer from long COVID after a mild acute COVID-19 infection.
“I believe that when individuals consult a doctor about brain fog, it may be dismissed as merely psychological. Our research provides evidence to the contrary, indicating a genuine biological mechanism behind long COVID brain fog,” says A/Prof. Cysique.
This revelation creates opportunities for the recognition and treatment of those impacted by the cognitive effects of long COVID, possibly extending to long COVID in its entirety. “These findings establish the foundation for the kynurenine pathway as a potential diagnostic and surveillance marker, as well as a plausible therapeutic target,” comments A/Prof. Cysique.
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Understanding Long COVID and ‘Brain Fog’
According to data gathered by the World Health Organisation (WHO), roughly 10–20 percent of people experience various mid and long-term symptoms after recovering from their primary illness. Long COVID’s disease profile has registered over 200 distinct symptoms.
“Long COVID affects multiple organs, so symptoms can vary significantly across various bodily functions. This is expected since the immune system has widespread influence,” explains A/Prof. Cysique. “We now understand that cognitive alterations are among the most common symptoms of long COVID, aside from fatigue.”
Those with long COVID commonly experience cognitive dysfunction as a decreased ability to focus, or an atypical mental fatigue following mentally demanding tasks, such as reading intricate instructions, attending intense meetings, or watching complex documentaries. Symptoms might also include short-term memory issues and difficulties with multi-tasking or concentrating for extended periods.
As A/Prof. Cysique elucidates, the most apt description of brain fog would be a lingering flu-like physical and mental fatigue, although it can vary over time.
“Through introspection, we can comprehend how this enduring flu-like physical and mental fatigue would disrupt daily function,” A/Prof. Cysique remarks. “Mostly affecting working-age individuals, these deficits can impair work efficiency to some extent and likely contribute to the pandemic’s economic toll.”
Monitoring Long-term Effects of COVID
This research only included unvaccinated patients, as the testing occurred before they were vaccinated. The majority of the study participants had long COVID as a result of a mild COVID-19 infection. “Even with vaccination, many will experience mainly mild symptoms, so the findings are still applicable, especially in light of potential reinfection,” notes A/Prof. Cysique.
The participants were followed by A/Prof. Cysique’s team at two, four, and 12-month intervals. “At each juncture, patients underwent extensive testing on their mental, physical, and cognitive health, along with various blood biomarker tests on four occasions.”
Based on prior experiences studying the pathway in other infections, the team chose to investigate the activation of the kynurenine pathway. A previous paper from the ADAPT study, published last year in Nature Immunology, also linked the kynurenine pathway’s immune precursor with persistent chest and fatigue symptoms.
“The convergence of evidence for the kynurenine pathway’s significance in long COVID and associated brain fog is not accidental,” asserts A/Prof. Cysique.
Discovery of an Underlying Mechanism
At the two-month mark, when the kynurenine pathway was most activated, A/Prof. Cysique and her team discovered that 60 percent of those displaying mild cognitive deficits, like attention/concentration and speed processing problems, exhibited an unusual activation of the pathway – abnormal in comparison to age-matched reference samples.
“During the immune response, the kynurenine pathway becomes activated for an average of four months – a significantly extended period. As the pathway is pro-inflammatory, the entire body, including the brain, is exposed to inflammatory products over a prolonged time. We know that the kynurenine pathway affects the central nervous system,” explains A/Prof. Cysique.
Notably, no other blood biomarkers, gender, or clinical factors, such as pre-existing or COVID-related mental health, severity of disease or respiratory function, and olfaction were connected to cognition.
Implications and Future Directions
In April 2023, the government announced additional funding for long COVID research following a parliamentary inquiry into the matter, signifying that long COVID is a grave concern requiring immediate solutions.
This research offers a gateway for more in-depth investigation into potential biomarkers and upcoming therapies for those afflicted with long COVID. “Long COVID clinics are still crowded, and hospitals are grappling with the issue,” shares A/Prof. Cysique. “Our study aims to provide some optimism for those struggling with long COVID.”
The team is keen to expand their research to include vaccinated patients and extend the study to up to 24 months post-infection.
“We are also liaising with a Dutch research group that has also found a prolonged activation of the KP in COVID-19 brain changes, and we plan to start a trial,” states A/Prof. Cysique.
Reference: “The kynurenine pathway relates to post-acute COVID-19 objective cognitive impairment and PASC” by Lucette A. Cysique, David Jakabek, Sophia G. Bracken, Yasmin Allen-Davidian, Benjamin Heng, Sharron Chow, Mona Dehhaghi, Ananda Staats Pires, David R. Darley, Anthony Byrne, Chansavath Phetsouphanh, Anthony Kelleher, Gregory J. Dore, Gail V. Matthews, Gilles J. Guillemin and Bruce J. Brew, 15 June 2023, Annals of Clinical and Translational Neurology.
DOI: 10.1002/acn3.51825
Frequently Asked Questions (FAQs) about kynurenine pathway
What is the key discovery in long COVID’s brain fog treatment?
Researchers at the University of New South Wales and St. Vincent’s Hospital have identified a biological connection to long COVID’s “brain fog” in the kynurenine pathway. This discovery points to a biological basis for the cognitive challenges faced by patients and opens up new opportunities for treatment.
What were the significant findings in the study regarding the kynurenine pathway?
Scientists found that prolonged activation of the kynurenine pathway was more likely to result in mild cognitive deficits 12 months after developing COVID-19. This pathway, involved in inflammation, seems to be activated in people with long COVID exhibiting brain fog symptoms.
Who conducted the study, and where was it published?
The study was conducted by researchers from the University of New South Wales (UNSW Sydney) and St. Vincent’s Hospital. It was published in the Annals of Clinical and Translational Neurology.
What are the implications of these findings?
The discovery of the kynurenine pathway’s link to long COVID brain fog offers potential for diagnostic and monitoring markers, as well as possible therapeutic targets. It represents a critical step towards understanding and treating the cognitive effects of long COVID.
How does the study describe the cognitive dysfunctions related to long COVID?
The cognitive dysfunctions in long COVID often manifest as a lack of mental focus or clarity and unusual mental fatigue, particularly after cognitively demanding tasks. They are associated with short-term memory problems, difficulty in multitasking, or concentration over extended periods.
What is the future direction of this research?
The research team plans to extend the study cohort to vaccinated patients and continue the investigation up to 24 months after infection. Collaboration with other research groups is also planned, indicating ongoing exploration of the kynurenine pathway in COVID-19 related brain changes.
What economic impacts are associated with the cognitive deficits in long COVID?
The cognitive deficits in long COVID can affect work efficiency and may contribute to the broader economic impact of the pandemic, especially since they mainly affect working-age people.
How does this study relate to vaccination and reinfection?
Though the study included only unvaccinated patients, the findings are still relevant, particularly in the context of reinfection. Since many vaccinated individuals may experience mostly mild symptoms, understanding the long-term effects of COVID-19 remains crucial.
More about kynurenine pathway
- Annals of Clinical and Translational Neurology
- University of New South Wales
- St. Vincent’s Hospital
- World Health Organisation on Long COVID
5 comments
Wow this is big news, especially for those suffering from long COVID. Hope this leads to real treatments soon, great progress.
I read this study in the Journal last week; this is a complex issue. There must be more research done to understand it fully, but it’s a start.
So basically, the kynurenine pathwy is a new area of research for COVID. Important discovery indeed!
my brother has long COVID and the brain fog is real, this gives me hope that science is working towards something, thanx for the information
i’m not surprised that they’ve found something biological behind brain fog, it’s about time the medical community takes it seriously. What’s the next step?