Disruption of the blood-brain barrier due to long COVID

Bhavana Kunkalikar Jan 27 2023 Reviewed by Aimee Molineux, https://doi.org/10.21203/rs.3.rs-2069710/v2

In a recent study posted to the Research Square* preprint server, researchers explored the destruction of the blood-brain barrier (BBB) due to cognitive impairment associated with long coronavirus disease (COVID).


Studies have demonstrated microvascular injuries observed in the brains of deceased severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients, including thinning of the laminae of the endothelial cells in the olfactory bulb and fibrinogen leakage. BBB-related alterations and responses after SARS-CoV-2 exposure have also been examined. Furthermore, evidence has shown that the SARS-CoV-2 spike protein can effectively cross rodent BBB, which can result in cognitive changes as well as inflammation. Yet, cerebrovascular pathology among patients and the associated mechanisms need extension research, particularly in long COVID patients. Also, the impact of COVID-19 on BBB alterations is yet to be studied.

About the study

In the present study, researchers assessed the neurobiological impact of COVID-19 on patients diagnosed with acute SARS-CoV-2 infection and those experiencing persistent long COVID in the presence or absence of cognitive impairment.

Eligible participants involved recovered COVID-19 patients, including persons aged 18 years and above who did or did not present neurological symptoms. Long COVID patients who reported the persistence of symptoms for over 12 weeks since infection were also eligible. The team collected serological specimens from 76 acute COVID-19 in-patients. Furthermore, 25 unaffected control specimens were obtained before the COVID-19 pandemic. Additionally, serum specimens were screened for BBB dysfunction as well as inflammation markers.

Eligible participants were subsequently assessed with quick smell identification test (Q-SIT) olfactory testing, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) imaging, and an evaluation of pulmonary imaging as well as hematological characteristics observed when the patient was diagnosed with COVID-19. Olfactory function was assessed using the Q-SIT. Furthermore, the candidates were screened for a mean of 146 days after SARS-CoV-2 infection.


The average age of COVID-19 and control specimens was 44.7 and 44 years, respectively. The most frequently observed symptoms included loss of taste and smell, dyspnoea, fatigue, cough, and fever. Also, more men than women reported severe COVID-19 infection, while more men needed supplemental oxygen.

COVID-19 severity which was assessed based on the World Health Organization (WHO) Severity Guidelines revealed 25 unaffected patients along with ten moderate, 43 mild, and 23 severe cases. A remarkable increase in interleukin (IL)-8 levels was noted in moderate cases. Also, there was a considerable elevation in IL-6, IL-8, and tumor necrosis factor (TNF) levels in severe COVID-19 cases. Stratifying patients based on the absence or presence of brain fog showed a significant rise in serum levels of IL6, IL8, TNF, and S100β among brain fog cases after adjusting for age, gender, and infection severity.

The average symptom duration displayed by brain fog cases was 222.75 days, and for non-brain fog patients was 170.55 days. Notably, 50% of the participants had anosmia, which was verified by Q-SIT testing performed during screening. Almost six participants exhibited mild to moderate cognitive dysfunction on the Montreal Cognitive Assessment (MoCA) test as well as deficits in executive function, recall, and word finding.

The study revealed that standard diagnostic MRI scans found no pathological changes in any candidate. On the other hand, DCE-MRI imaging noted significantly elevated whole-brain leakage among COVID-19 patients diagnosed with brain fog. The team found increased brain volume percentage with leaky blood vessels among the brain fog group in comparison to those without brain fog. When the cohorts were stratified into recovered, long COVID with brain fog and long COVID without brain fog showed remarkably elevated BBB permeability within the brain fog patients in comparison to patients who had recovered and who had long COVID without brain fog. Furthermore, a region of interest assessment detected significantly higher leakage in the left and right temporal lobes and left and right frontal cortex.

A comparison of individuals having a history of COVID-19 to unaffected individuals showed volumetric deficits primarily in the temporal and frontal lobes along with elevations in the occipital lobes and lateral ventricles. Additionally, cohort-wise comparisons of macrostructures showed reduced global brain volume among brain fog patients and a considerably decreased volume of cerebral white matter in both hemispheres within the brain fog and recovered patients. The team also noted the decreased volume of cerebellar white matter in long COVID, recovered, and brain fog patients. There was also a noticeable increase in the cerebrospinal fluid (CSF) volume within the brain fog group only.


The study findings showed that long COVID “brain fog” was related to BBB dysfunction and the elevated expression of markers of BBB dysfunction and systemic inflammation. The study also highlighted that BBB dysfunction was specific to the brain fog patients with persistent dysfunction observed up to one year after recovery from COVID-19 infection.

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