June 22, 2024

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Breakthrough in Treating Long-COVID “Brain Fog”

Breakthrough in Treating Long-COVID “Brain Fog”: Researchers Identify Key Biological Pathway


Breakthrough in Treating Long-COVID “Brain Fog”: Researchers Identify Key Biological Pathway.

Researchers from the University of New South Wales (UNSW Sydney) and St. Vincent’s Hospital have discovered a critical pathway involved in the inflammatory response that appears to be activated in long-term COVID patients experiencing “brain fog.”

Identifying this metabolic pathway could potentially offer answers and new treatment approaches for those suffering from cognitive issues due to long-term COVID.


Breakthrough in Treating Long-COVID "Brain Fog": Researchers Identify Key Biological Pathway


Scientists from the Schools of Psychology and Medical & Health Sciences found that among a study cohort of 128 individuals, those with long-term activation of the kynurenine pathway were more likely to experience mild cognitive impairment 12 months after contracting COVID-19. Furthermore, they observed that these symptoms were unlikely to improve over time.

The patients involved in this study had experienced mild to moderate acute COVID-19 and participated in a longitudinal study led by Professor Gail Matthews – the St. Vincent’s COVID-19 ADAPT study.

Lucette Cysique, the lead author of the study, commented, “This research, along with a previous study from the ADAPT project, suggests a link between Long-COVID brain fog and immune response dysregulation. The current study specifically identifies a crucial metabolic pathway—the kynurenine pathway—associated with the cognitive changes we observed in this group of patients.”

This study was recently published in the Journal of Clinical and Translational Neurology, contributing to the understanding that the root cause of brain fog in individuals suffering from COVID long-term is a biological change.


Breakthrough in Treating Long-COVID "Brain Fog": Researchers Identify Key Biological Pathway



“I believe that when patients present with brain fog, it might be mistaken for a psychological issue,” Professor Cysique stated. “Our research, on the contrary, demonstrates that there is a genuine biological mechanism behind Long-COVID brain fog. This discovery opens up possibilities for identifying and treating the cognitive effects of long-term chronic hepatitis B and offers potential for using the kynurenine pathway as a diagnostic and monitoring marker as well as a potential therapeutic target.”


Existing evidence compiled by the World Health Organization (WHO) suggests that approximately 10% to 20% of individuals experience various medium to long-term effects after recovering from their initial illness. In fact, over 200 different symptoms have been recorded as part of the Long-COVID spectrum.


“Long-COVID is a multi-organ disease, so various aspects of patients’ physical functions can be affected to varying degrees. This isn’t surprising, as the immune system touches on all bodily functions,” Professor Cysique explained. “However, we now know that, aside from fatigue, cognitive changes are the most common symptoms associated with Long-COVID.”


Cognitive dysfunction in long-term chronic obstructive pulmonary disease patients most commonly manifests as mental fogginess, lack of clarity, or mental fatigue, which is unusually severe compared to their previous abilities, especially after engaging in cognitively demanding tasks like reading complex instructions, participating in meetings requiring high concentration, or watching complex documentaries on novel subjects. This is linked to issues with short-term memory, multitasking difficulties, or prolonged attention lapses.


As Professor Cysique explained, the best description of brain fog is akin to months-long flu-like physical and mental fatigue, albeit with some fluctuations.


“Given a moment’s thought, we can all imagine how such long-lasting flu-like physical and mental fatigue can impact daily functioning. Moreover, we’re talking about people in their working age. So, these types of impairments can have economic implications in the context of a pandemic,” Professor Cysique remarked.

Breakthrough in Treating Long-COVID "Brain Fog": Researchers Identify Key Biological Pathway




Monitoring the Long-Term Effects of COVID

While this study included only unvaccinated patients, the testing was conducted before these individuals received their initial vaccine doses, meaning most of them experienced long-term COVID due to mild infections. “After vaccination, many individuals still experience mild symptoms. Therefore, the study’s findings remain relevant, especially in cases of reinfection,” Professor Cysique noted.


As part of Professor Cysique’s research, these cohorts were tracked at 2 months, 4 months, and 12 months. “At each stage, patients underwent extensive assessments, including assessments of mental health, physical health, and cognitive health, as well as four rounds of various blood biomarker tests.”


The research team decided to study the activation of the kynurenine pathway based on previous research into this pathway in other infectious diseases.

Additionally, a study published last year in Nature Immunology as part of the ADAPT study revealed that immune precursors of the kynurenine pathway were associated with persistent chest and fatigue symptoms.


Professor Cysique stated, “While this latest study is a cohort study with some factors not yet measured, there’s evidence to suggest the importance of the kynurenine pathway in Long-COVID and associated brain fog, and this convergence of evidence is not coincidental.”




Discovering the Underlying Mechanisms

Her team found that at the most active point of kynurenine pathway activation, which occurred at two months, 60% of those displaying mild cognitive impairment (such as attention/concentration and processing speed) showed abnormal activation of the kynurenine pathway—abnormal meaning higher than known abnormal levels in age-matched reference samples.


“With the onset of the immune response, the activation of the kynurenine pathway averaged around four months, significantly longer than the normal time. As the kynurenine pathway has pro-inflammatory effects, the entire body, including the brain, remains inundated with inflammatory products in the long term. We know that the kynurenine pathway affects the central nervous system,” Professor Cysique explained.


It’s worth noting that other blood biomarkers, gender, or clinical factors such as pre-existing or COVID-related mental health conditions, disease severity, respiratory function, and smell, were unrelated to cognitive abilities.




Impacts and Future Directions:

In April 2023, as a result of the Long-COVID parliamentary inquiry, the government announced new research funding for Long-COVID. This indicates recognition by the government that long-term chronic obstructive pulmonary disease is a serious issue requiring urgent attention.


This research opens doors to further investigate potential biomarkers and future treatment approaches to assist those suffering from Long-COVID. Professor Cysique remarked, “Long-COVID clinics are still overwhelmed with patients, and hospitals are still grappling with this issue.” We hope our research can bring some hope to Long-COVID patients.


The research team is eager to continue their work, expanding the study to include vaccinated patients and conducting follow-up investigations within 24 months after the infection date.

Researchers have also reached out to a research group in the Netherlands that has found long-term kynurenine pathway activation linked to brain changes in COVID-19 and are hoping to initiate a trial.




(source:internet, reference only)

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