Researchers at Trinity College Dublin and FutureNeuro discovered brain fog in Long COVID patients is caused in part by leaky blood vessels in the brain. They published their study, “Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment” in Nature Neuroscience.

“Vascular disruption has been implicated in coronavirus disease 2019 (COVID-19) pathogenesis and may predispose to the neurological sequelae associated with long COVID, yet it is unclear how blood–brain barrier (BBB) function is affected in these conditions,” write the scientists.

“Here we show that BBB disruption is evident during acute infection and in patients with long COVID with cognitive impairment, commonly referred to as brain fog. Using dynamic contrast-enhanced magnetic resonance imaging, we show BBB disruption in patients with long COVID-associated brain fog. Transcriptomic analysis of peripheral blood mononuclear cells revealed dysregulation of the coagulation system and a dampened adaptive immune response in individuals with brain fog.

“Accordingly, peripheral blood mononuclear cells showed increased adhesion to human brain endothelial cells in vitro, while exposure of brain endothelial cells to serum from patients with long COVID induced expression of inflammatory markers. Together, our data suggest that sustained systemic inflammation and persistent localized BBB dysfunction is a key feature of long COVID-associated brain fog.”

Novel technique to study Long COVID

“For the first time, we have been able to show that leaky blood vessels in the human brain, in tandem with a hyperactive immune system may be the key drivers of brain fog associated with Long COVID. This is critically important, as understanding the underlying cause of these conditions will allow us to develop targeted therapies for patients in the future,” said Matthew Campbell, PhD, professor in genetics and head of genetics at Trinity, and PI at FutureNeuro.

The team used a new form of MRI scan, dynamic contrast-enhanced magnetic resonance imaging, to identify the changes to neural vasculature. The data showed that there is reduced integrity of the blood vessels in Long COVID patients with brain fog and other cognitive impairments (memory loss, difficulty focusing, and thinking), compared with Long COVID patients without this suite of symptoms, but they do exhibit general fatigue, shortness of breath, and joint pain. For those who suffer from Long COVID symptoms for more than 12 weeks after a bout of COVID, it’s a challenge to find answers or relief. Researchers and clinicians struggle to identify and treat patients with Long COVID, who can account for up to 10% of patients who contract the SARS-CoV-2 virus.

This team also aimed to examine how COVID’s impact on the blood-brain barrier affects different categories of Long COVID symptoms.

“We investigated the functioning of the blood-brain barrier [and] established the barrier is not functioning normally in these patients,” noted Colin Doherty, PhD, professor of neurology and head of the school of medicine at Trinity, and PI at FutureNeuro in a video interview about the study’s implications. “Now we know there is a definite pathological basis for long COVID. Not only that, we have at least a range of possible treatments now to try to repair the barrier. And so, the next phase of these studies will be really exciting for the potential of a cure in the distance.”

Connecting the dots

This is by far not the first study to explore the root cause of neuropathy in Long COVID patients. Many recent reports have focused on the impacts of the disease on the immune system. Just two weeks ago, another team explored a similar phenomenon of neurological impacts triggered by viral infections. This group identified viral-induced neuropathy caused by Zika virus infection activating a lasting immune response. The common and often lasting neurological symptom of loss of smell was studied two years ago by examining inflammation markers in nasal biopsies, finding increases in those markers, and in number of T cells.

The current study opened a different door looking at the impact of viral infection on the vasculature integrity. The group wanted to examine the effect on the brain if there were disruption in the blood-brain barrier coupled with increased inflammation. This study illuminates an area of neurological research that scientists are beginning to explore. Recent work has concluded that viral infections are likely triggers for several neurological conditions, including Long COVID, multiple sclerosis (MS), and others. This study suggests that leaky blood vessels and a disruption of the blood-brain barrier may be factors in the development of these conditions.

“Our findings have now set the stage for further studies examining the molecular events that lead to post-viral fatigue and brain fog. Without doubt, similar mechanisms are at play across many disparate types of viral infection and we are now tantalizingly close to understanding how and why they cause neurological dysfunction in patients,” added postdoctoral researcher Chris Greene, PhD.