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Discovery of Long COVID Brain Fog Cause Hints at Future Treatments

MRI scans of the human brain
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Brain fog is often described as a feeling of fatigue, forgetfulness and reduced cognitive ability. After the outbreak of the COVID-19 pandemic, patients began to report symptoms such as brain fog months after initially contracting the SARS-CoV-2 virus, a syndrome that came to be termed long COVID.

Now, results from a study into long COVID brain fog suggest that leaky blood vessels in the brains of patients may be the underlying cause of the malady. These findings are likely to change the landscape of how post-viral neurological conditions are treated. The findings were published in Nature Neuroscience.

Long COVID induces an array of neurological symptoms

The World Health Organization estimates that 10-20% of people continue to have, or develop, at least one symptom more than three months after SARS-CoV-2 infection. While common symptoms among patients reporting long COVID can include fatigue, shortness of breath and cognitive dysfunction, over 200 different symptoms have been reported that can have an impact on everyday functioning.

Long COVID has now become a major public health issue with symptoms of long COVID sometimes lasting for years. According to the United Kingdom’s Office of National Statistics Coronavirus (COVID-19) Infection Survey from March 2023, 41% of patients with self-reported long COVID were still experiencing symptoms 2 years after initial infection with SARS-CoV-2.

Neurological symptoms of long COVID are increasingly being reported. One 2021 study found that, among 236,379 patients diagnosed with COVID-19, 33.62% had demonstrated clinically important neurological or psychiatric dysfunction.

Neurological problems have also been reported in other respiratory viral infections. Evidence also suggests that many neurological conditions can be triggered by viral infections. For example, the Epstein-Barr virus (EBV) has been identified as a leading risk factor for developing multiple sclerosis (MS). Despite this, there is still little understanding of the long-term outcome of neurological problems after SARS-CoV-2 infection.

Determining the cause of post-viral brain fog

To determine the cause of neurological problems resulting from SARS-CoV-2 infection, researchers at Trinity College Dublin and investigators from FutureNeuro examined the integrity of blood vessels in the brains of patients reporting long COVID and those reporting long COVID with brain fog.

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Investigating the function of the blood–brain barrier (BBB) in these patients, the researchers established that BBB disruption is evident during acute infection and in patients with long COVID brain fog. To investigate this BBB disruption, the researchers used a novel form of magnetic resonance imaging.

“Prior to our work, it has been difficult to use objective imaging-based methods to observe damage in the brain in patients with post-viral neurological conditions. We now believe that imaging the blood–brain barrier may be useful for a whole range of post-viral conditions,” Matthew Campbell, a professor in genetics and head of genetics at Trinity College Dublin and principal investigator at FutureNeuro, told Technology Networks.

Conducting transcriptomic analysis also revealed dysregulation of the coagulation system and a dampened adaptive immune response in individuals with brain fog. Additionally, expression of inflammatory markers was induced when brain endothelial cells were exposed to serum from patients with long COVID. The researchers suggest that sustained systemic inflammation and persistent localized BBB dysfunction are key features of long COVID associated brain fog.

The results provide a definite pathological basis for long COVID and demonstrate that the neurological symptoms of long COVID are measurable with real and verifiable metabolic and vascular changes in the brain.

“Future studies should be focused on examining in greater detail if BBB restoration aligns with the improvement of clinical symptoms. At present, we don’t know if this is the case. We also don’t know how the BBB changes in other post-viral illnesses and that remains to be elucidated,” said Campbell.

Treatments for long COVID brain fog

Measuring blood vessel integrity is already a clinically useful measurement applied to people suffering from neurological disorders. The researchers at Trinity College Dublin now want to use this measurement to identify those who are at risk of developing neurological symptoms because of post-viral illnesses such as long COVID. 

By understanding the underlying cause of long COVID brain fog researchers hope to develop targeted therapies to try and repair the integrity of these vessels in the brain. “There are emerging drugs that may be able to restore blood–brain barrier integrity and therefore they may have utility in treating brain fog or indeed other post-viral associated neurological conditions,” said Campbell.

“Long COVID is still such a new disease and we’re only now getting to grips with its long-term effects. We still need a much clearer understanding of how BBB changes align with the clinical progress of long COVID. Aligned with this, we also need to identify a solid panel of biomarkers that can be used in tandem with any imaging approach so that we can accurately predict how patients are faring with/without any potential therapies that emerge in the years to come,” Campbell summarizes.

Prof. Matthew Campbell was speaking to Blake Forman, Senior Science Writer & Editor for Technology Networks.

About the interviewee:  Matthew Campbell is a professor in genetics and head of department at the Smurfit Institute of Genetics in Trinity College Dublin as well as a principal investigator at FutureNeuro. He graduated with a degree in Biochemistry from University College Dublin in 2002 and went on to complete his PhD in 2006 at the same institution. His current research focuses on understanding the role of the bloodbrain barrier in healthy and diseased states.


Reference: Greene C, Connolly R, Brennan D, et al. Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. Nat Neurosci. 2024. doi: 10.1038/s41593-024-01576-9