"Leaky brain": Lifting the fog behind this long COVID symptom could generate treatment

For many people, COVID-19 can be a relatively mild infection. For many others, it is not. For someone who is living with so-called long COVID, in which the symptoms last for months or even years, it can contain a litany of debilitating symptoms from extreme fatigue to heart problems. For Angela Meriquez Vázquez, a long COVID patient and advocate, "brain fog" is “one of the most disabling symptoms.” The condition is exactly what it sounds like: a cloudy feeling in the mind that can make it difficult to focus or remember. It's one of many ways in which the SARS-CoV-2 virus responsible for COVID can impact the brain and alter perception.

Prior to getting infected with COVID-19 in March 2020, Vázquez said she was decent at multitasking. For example, she could write an email about one topic and engage in a verbal conversation about another topic at the same time. But today, she struggles to maintain focus and attention on phone calls. She tells Salon she is now bad at multitasking. And on days where she is really struggling, she has to turn on closed captioning on Zoom to follow along with the conversation.

“While I don’t think my performance has suffered appreciably, I now spend a majority of my daily energy managing my executive function and pacing my cognitive exertion,”Vázquez told Salon via email. “Things that my brain used to do automatically and with ease.”

Brain fog is a term used to describe a range of neurocognitive symptoms, which can include forgetfulness and difficulties focusing, and paying attention — like what Vázquez described. While it’s been reported to be a symptom during an acute COVID-19 infection, an estimated 50 percent of patients who experience long COVID experience brain fog, which is so insidious in part due to the broad range of symptoms it encompasses. For this reason, it can often be a symptom that’s not taken seriously by doctors or others. But as Vázquez explained, it can affect life on a daily basis and be one of the most difficult parts of living with long-COVID. 

Recent research in the journal Nature Neuroscience suggests we're one step closer to the cause behind brain fog in long COVID patients, specifically "leakiness" of the blood-brain barrier in conjunction with an overactive immune system. It is the first time scientists have found evidence that this debilitating symptom is due to underlying changes in the brain. It could also be the first step to a possible treatment. 

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“We and others have been searching for a possible remedy for the leaky blood-brain barrier,” Dr. Colin Doherty, one of the study’s coauthors, who is a neurology professor and head of the school of medicine at Trinity College, told Salon via email. “One target is a protein called Claudin-5 which makes up the most important element of the glue or scaffolding that keeps the barrier together.” 

Prior research indicated that blood-brain barrier disruption could be causing brain fog. But this provides the first biological evidence. In the study, researchers analyzed blood samples to identify biomarker differences between those who did and didn't report brain fog. Specifically, they took blood samples from 76 patients who were hospitalized with acute COVID in 2020. They found that those who reported having brain fog had higher levels of a protein called S100 beta, which is produced by brain cells — but is not normally found in the blood, hence suggesting a leaky barrier in the brain.

In the second part of their study, researchers scanned the brains of 11 people who recovered from COVID and 22 people who had long COVID — half of which reported having brain fog. By examining brain circulation, they found that long COVID patients with brain fog had a leaky blood-brain barrier when compared to other long COVID patients who had recovered.

“When we scanned these patients and measured the levels of a molecule called s-100Beta — a brain-derived molecule that can only get into the blood if the barrier is damaged — and compared the scans and S100beta levels to patients who had had acute COVID but had fully recovered,” Doherty said. “The barrier was very leaky and obviously damaged, especially in areas like the temporal lobe which is essential for learning and memory.”

Doherty emphasized that by identifying this biomarker in blood, it could help pave the way for testing and treating brain fog in long-COVID patients. 

“It’s an important finding because the medical community has been split between those who did not believe that long COVID was a ‘real’ disorder and those who were desperate to find a reliable biomarker,” he said. “We believe this could be that biomarker.”

Matthew Campbell, co-author of the study and a professor in genetics and head of genetics at Trinity College Dublin, told Salon via email that “therapies aimed at regulating the integrity of the blood-brain barrier” should be considered and tested as a potential treatment. 

“There are some drugs such as steroids and losartan that have the capacity to do this,” he said. “But newer, more ‘targeted’ developmental drugs might have better efficacy.”

In regards to next steps, he said researchers need to increase the numbers of people involved in this work and keep testing.

“The MRI study we reported was small, but suggestive that if we expand to larger numbers of patients we will see the same signals,” he said. “So, the biomarker that we have identified will have use for diagnosis but also for clinical trials as we can use it as an indicator that a potential drug has biological efficacy.”