Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment

Abstract

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. 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.

Blood brain barrier disruption and glutamatergic excitotoxicity in post-acute sequelae of SARS COV-2 infection cognitive impairment: potential biomarkers and a window into pathogenesis

“…Our central finding is BBB impairment as assessed by the DCE-derived metric K-trans. To the best of our knowledge, there is only one other study that has used K-trans to measure the BBB integrity in PASC ( 4 ). It also showed diffuse BBB impairment at four months post COVID-19 infection but change over the subsequent months was not examined ( 4 ).…”

“…To the best of our knowledge, there is only one other study that has used K-trans to measure the BBB integrity in PASC ( 4 ). It also showed diffuse BBB impairment at four months post COVID-19 infection but change over the subsequent months was not examined ( 4 ). Subtle BBB disruption cannot be identified on routine MR studies with gadolinium administration.…”

“…The pathogenesis, however, remains unclear with possibilities ranging from immune dysregulation, autoimmunity, microthrombi, and blood–brain barrier (BBB) impairment ( 2 , 3 ). To date, there is only one study which explored the role of BBB disruption using MR imaging, but the study did not have a longitudinal design ( 4 ).…”

“…One volumetric MRI study, which followed 401 COVID-19 patients at the onset of infection and 4 months from the acute phase, demonstrated reduced brain volume in the orbitofrontal and parahippocampal gyrus related to the primary olfactory and gustatory systems ( 7 ). A recent cross-sectional study explored BBB disruption as the cause of CI in PASC patients ( 4 ). This study used dynamic contrast enhanced (DCE) perfusion imaging and demonstrated that BBB impairment correlated with neuroinflammatory markers.…”

The Potential Role of Viral Persistence in the Post-Acute Sequelae of SARS-CoV-2 Infection (PASC)

“…Pertinently, COVID-19, particularly in moderate and severe disease, is associated with thrombosis and thrombolytic events, mainly mediated by neutrophils and monocytes [16]. Dysregulation of the coagulation system has been associated in a transcriptomic analysis with disruption of the blood-brain barrier in individuals with neurological symptoms of PASC, including brain fog and cognitive impairment, in association with systemic inflammation [17]. In addition, it has been observed that even a mild respiratory infection of SARS-CoV-2 can induce a persistent inflammatory response in the brain, supported by the CCL11 cytokine, leading to prolonged activation of microglia in subcortical and hippocampal regions, impairing neurogenesis and myelination [18].…”