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Newly Identified Pathway Provides Insight Into Long COVID Brain Fog

A new study has identified a key metabolic pathway that is abnormally activated in people with brain fog, a common symptom of long COVID. The discovery opens the door to developing a way of diagnosing, monitoring and treating people with the condition.

Long COVID can lead to cognitive deficits such as poor concentration, impaired thinking, forgetfulness, and mental fatigue, commonly called brain fog. Researchers from the University of New South Wales Sydney and St Vincent’s Hospital have now identified a biological pathway linked to the condition.

“Long COVID is a multi-organ disease, so people are differently affected across several of their body functions,” said Lucette Cysique, the study’s lead author. “This is not surprising as the immune system is involved across all body functions. However, we know that besides fatigue, cognitive changes are the most common symptoms associated with long COVID.”

The researchers recruited 128 unvaccinated participants with confirmed mild-to-moderate SARS-CoV-2 infection through the Sydney St Vincent’s Hospital COVID-19 ADAPT study. Participants were followed up at two, four, and 12 months.

“At each of these points, the patients went through lots of tests, including on their mental health, physical health and cognitive health, and patients also had tests for various blood biomarkers on four occasions,” Cysique said.

Based on their knowledge of a particular pro-inflammatory biological pathway, the kynurenine pathway, in other infectious diseases, the researchers investigated its involvement in long COVID. They noticed that, at two months, when the kynurenine pathway was the most activated, 60% of those with mild cognitive deficits, such as inattention and poor concentration, showed an abnormal activation of the pathway.

“As the immune response takes place, it activates the kynurenine pathway across a period of four months on average – this is much longer than it should be,” Cysique said. “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-related mental health, disease severity, smell or respiratory function, were associated with the changes in cognition.

While the study only included unvaccinated participants, because the testing was conducted before they’d received their first vaccine, most people had long COVID resulting from mild COVID-19 infection.

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

Given that a study published last year found that the immune precursor of the kynurenine pathway was associated with persistent chest and fatigue symptoms, the researchers say the current findings linking the pathway to cognitive deficits are unlikely to be coincidental.

“While this latest study is a cohort study with factors that remain unmeasured, the convergence of evidence for the importance of the kynurenine pathway in long COVID, and the associated brain fog, is not by chance,” said Cysique.

The researchers say their discovery may help identify and treat patients with long-COVID-related brain fog.

“These findings lay the foundation for the kynurenine pathway as a potential diagnostic and monitoring marker, as well as a possible therapeutic target,” Cysique said.

The researchers plan to expand the study cohort to include vaccinated participants and to continue follow-up for up to 24 months after the infection date.

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