The COVID-19 pandemic left a lasting impact not only on society but also on the health of millions of Americans who continue to experience symptoms. Individuals with long COVID-19 display a range of chronic symptoms such as weakness, heart palpitations, fatigue, headaches, and cognitive impairment that can persist for months. Scientists remain perplexed by how long COVID impairs brain function, causing a condition colloquially known as brain fog.
But what causes brain fog in patients with long COVID? Researchers suggest the answer lies in the function or, more aptly, the dysfunction of specialized cells that line blood vessels in the brain, called the blood-brain barrier, or BBB for short. The BBB acts as a filter to prevent toxins, pathogens, and large molecules from entering the brain. Scientists hypothesized a leaky BBB could allow harmful substances to enter the brain, disrupting normal processes and causing brain fog.
To test whether leaks in the BBB cause COVID-related brain fog, researchers led by Dr. Matthew Campbell and Dr. Colin P. Doherty studied the brains of patients previously infected with COVID. The researchers recruited men and women over the age of 18, including 10 individuals who recovered from COVID and 22 individuals who suffered from long COVID for more than 12 weeks. Of these long COVID patients, 11 experienced brain fog, and 11 did not.
The team calculated the ‘leakage rate’ of each patient’s BBB using high-resolution magnetic resonance imaging, or MRIs. First, they injected a contrast agent into each patient’s blood, which allowed the MRI to ‘see’ the blood and track how fast it traveled across the BBB and into the brain. Similar to how your sink drains more quickly when you remove the strainer, blood flows more quickly into the brain if the BBB is leaky. They tracked the blood flow through repeated brain scans of the patients for 20 minutes after each injection, and found patients with brain fog had higher leakage rates than those without. They interpreted this difference to suggest that the BBB indeed played a role in the patients’ sustained brain fog.
Next, the researchers wanted to know how the BBB caused brain fog in these patients. They suggested a leaky BBB could be causing the patients’ brains to swell with inflammation, so they took blood samples from each patient and tested for 50 chemical markers of brain inflammation and BBB dysfunction. They found each group of patients had unique markers in their blood, but patients with long COVID and brain fog all had more markers of inflammation.
They explained that while inflammation is an important part of the body’s immune response, it can damage healthy cells and tissues when sustained for too long. In this case, sustained brain inflammation could cause symptoms of brain fog. They also found patients with brain fog had more of a particular cell signaling protein often found in patients with chronic fatigue syndrome, a condition with similar symptoms.
To further investigate how the immune system was involved in brain inflammation during long COVID, the researchers examined which genes were switched on or off in specific immune cells in the patients’ blood, called white blood cells. They found the white blood cells in long COVID patients with brain fog had 1,078 unique active genes compared to long COVID patients without, many of which related to starting and sustaining the immune response. The researchers interpreted these findings to suggest that a continued active immune response in the brain induced inflammation and swelling, which caused the leaky BBB and brain fog.
Next, the researchers grew brain cells in the lab and tested which genes were switched on and off before and after they mixed them with the patients’ unfiltered blood, simulating the effects of a leaky BBB. They found more genes for inflammation were active in brain cells mixed with long COVID blood and the blood of recovered COVID patients.
Finally, to see the effects of the COVID virus itself leaking directly into the brain, they mixed the brain cells with a protein found on the outside of the COVID virus. After 72 hours, they found brain cells with more COVID proteins also had more active genes for inflammation.
The researchers concluded dysfunction of the BBB during long COVID caused chronic inflammation leading to brain fog. The team suggested their data could help researchers understand other lingering effects of COVID, like loss of smell. They also suggested future researchers investigate how the BBB affects other viral respiratory infections, and develop ways to restore BBB function to treat patients with long COVID.
