Blood-brain barrier disruption in Long COVID-associated cognitive impairment

Abstract Vascular disruption has been heavily implicated in COVID-19 pathogenesis and may predispose the neurological sequelae associated with the condition now known as long COVID. To date, no studies have objectively assessed blood-brain barrier (BBB) function in individuals with neurological complications stemming from prior SARS-CoV-2 infection. Here, we explored the neurobiological effects of SARS-CoV-2 infection in humans with acute infection (n = 76) and those with persistent long COVID with and without neurological impairment. Following acute infection, patients with neurological impairment had increased serum S100β, indicative of BBB disruption. Furthermore, using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in long COVID patients (n = 32), we observed elevated BBB permeability in distinct neuroanatomical regions including the frontal cortex, occipital lobe and temporal lobes which correlated with global brain volume and white matter volume deficits in patients with neurological impairment. Patients with neurological impairment had increased levels of blood-based biomarkers including GFAP, TGFβ and IL8 with levels of TGFβ that correlated with BBB permeability and structural brain changes. Peripheral blood mononuclear cells isolated from unaffected and long COVID patients had persistent upregulation of inflammatory markers including IFNA/G and showed increased adhesion to human brain endothelial cells in vitro . Finally, exposure of endothelial cells to serum from long COVID patients induced increases in ICAM-1, VCAM-1 and TNF irrespective of neurological sequelae. Together, these data suggest that sustained systemic inflammation and persistent localised BBB dysfunction is a feature of long COVID-associated neurological impairment. Importantly, this may also be therapeutically relevant in the treatment and clinical management of this patient group.