Long COVID Blood-Brain Barrier Disruption

In a recent study published on Research Square* preprint servers, researchers examined the destruction of the blood-brain barrier (BBB) due to cognitive impairment associated with ongoing coronavirus disease (COVID). background

Studies have demonstrated the microvascular injury observed in the brains of deceased patients with acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including thinning of the laminae of endothelial cells in the olfactory bulb and leakage of fibrinogen. BBB-related changes and responses after exposure to SARS-CoV-2 have also been studied. In addition, evidence suggests that the SARS-CoV-2 spike protein can effectively cross the rodent BBB, which can lead to cognitive changes as well as inflammation. However, cerebrovascular pathology in patients and related mechanisms require further research, particularly in long-standing COVID patients. The impact of COVID-19 on BBB changes also remains to be explored.

About research

In this study, researchers assessed the neurobiological effects of COVID-19 in patients diagnosed with acute SARS-CoV-2 infection and in patients with ongoing, long-term COVID with the presence or absence of cognitive impairment.

Eligible participants include recovered COVID-19 patients, including those aged 18 and over who may or may not have neurological symptoms. Long-standing COVID patients who report persistent symptoms for more than 12 weeks since infection are also eligible. The team collected serological samples from 76 acute COVID-19 hospitalized patients. In addition, 25 unaffected control samples were obtained before the COVID-19 pandemic. In addition, serum samples are screened for BBB dysfunction and inflammatory markers.

Eligible participants were then assessed through smell testing, a rapid olfactory identification test (Q-SIT), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and an assessment of the lung imaging and hematological features observed when the patient was diagnosed with COVID-19. The olfactory function was assessed using the Q-SIT. In addition, candidates have screened an average of 146 days after SARS-CoV-2 infection.


The mean age of the COVID-19 samples and controls was 44.7 and 44 years, respectively. The most frequently observed symptoms were loss of taste and smell, dyspnoea, fatigue, cough, and fever. In addition, more men than women report severe COVID-19 infections, while more men require supplemental oxygen.

The severity of COVID-19, assessed according to the World Health Organization (WHO) severity guidelines, revealed 25 unaffected patients, as well as 10 moderate cases, 43 mild cases, and 23 severe cases. A notable increase in interleukin (IL)-8 levels has been noted in moderate cases. Also, in severe cases of COVID-19, there was a significant increase in IL-6, IL-8, and tumor necrosis factor (TNF) levels. Stratification of patients based on the absence or presence of brain fog revealed significant increases in serum levels of IL6, IL8, TNF, and S100β in brain fog cases after adjustment for age, sex, and severity of infection.

The mean duration of symptoms in Brain Fog cases was 222.75 days and in non-Brain Fog, patients were 170.55 days. Remarkably, 50% of the participants suffered from anosmia, as indicated by the Q-SIT test performed during the study. Nearly six participants presented with mild to moderate cognitive dysfunction, executive function deficits, memory deficits, and word search deficits on the Montreal Cognitive Assessment (MoCA) test.

The study found that standard diagnostic MRI scans showed no pathological changes in any of the candidates. On the other hand, DCE-MRI imaging found significantly increased whole-brain leakage in COVID-19 patients diagnosed with brain fog. The team found an increased percentage of brain volume with leaky blood vessels in the Brain Fog group compared to the non-Brain Fog group. When the cohort was grouped into recovered, long COVID with brain fog, and long COVID without brain fog, patients with brain fog showed significantly higher BBB permeability compared to patients who had recovered and who had long COVID without brain fog. In addition, when assessing the area of interest, significantly higher levels of leakage were found in the left and right temporal lobes and the left and right frontal cortex.

Comparing individuals with a history of COVID-19 to unaffected individuals revealed volumetric deficits mainly in the temporal and frontal lobes and enlargement of the occipital lobes and lateral ventricles. In addition, a comparison of macrostructures within cohorts showed reduced global brain volume in brain fog patients and markedly reduced white matter volume in both hemispheres in brain fog patients and recovered patients. The team also found decreased cerebellar white matter volume in long-standing, recovering COVID-19 patients and brain fog. There was also a marked increase in cerebrospinal fluid (CSF) volume in the brain fog alone group.


Study results suggest that prolonged COVID “brain fog” is associated with BBB dysfunction and increased expression of markers of BBB dysfunction and systemic inflammation. This study also highlights that BBB dysfunction is specific to brain fog patients with persistent dysfunction observed up to one year after recovery from COVID-19 infection.