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

Vascular disruption has been implicated in COVID-19 pathogenesis, and may predispose to the neurological sequelae associated with the condition (known as Long COVID), yet it remains 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 Long COVID patients with cognitive impairment, commonly referred to as brain fog. Using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), we show BBB disruption correlated with brain volume changes. Transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) revealed dysregulation of the coagulation system and a dampened adaptive immune response in individuals with brain fog. Accordingly, PBMCs showed increased adhesion to human brain endothelial cells in vitro, while exposure of endothelial cells to serum from Long COVID patients induced expression of inflammatory markers. Together, our data suggest that sustained systemic inflammation and persistent localised BBB dysfunction is a key feature of Long COVID-associated brain fog. To investigate the role of systemic inflammation in Long COVID we performed RNA seq on peripheral blood mononuclear cells from unaffected controls, patients recovered from SARS-CoV-2 infection and Long COVID patients with or without cognitive impairment, also known as brain fog.