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.

Neutrophil extracellular traps and long COVID

“…Indicators of glial cell reactivity are elevated amongst LC patients with persistent depressive symptoms ( 253 ). A study of 76 LC patients experiencing “brain fog” (encompassing headache, fatigue, malaise, and altered level of consciousness) was the first to objectively demonstrate COVID-19-associated BBB disruption by utilizing neurological biomarkers and dynamic contrast-enhanced magnetic resonance imaging ( 254 ). Sustained elevations in S100β, IL-8, TGF-β, and GFAP were observed in brain fog LC patients, indicating persistent inflammation.…”

“…Sustained elevations in S100β, IL-8, TGF-β, and GFAP were observed in brain fog LC patients, indicating persistent inflammation. Importantly, the adhesion of peripheral blood mononuclear cells to brain microvascular endothelial cells was enhanced in patients with brain fog, and exposing endothelial cells to the serum of these patients triggered endothelial cell activation ( 254 ).…”

Long COVID: Molecular Mechanisms and Detection Techniques

“…Neurological manifestations of long COVID are associated with neuroinflammation and suspected blood-brain barrier disruption, where systemic inflammatory responses may affect CNS-resident cells [ 127 ]. Despite the absence of direct viral invasion, the role of systemic inflammation, in which NETs may participate, is evident in neurological symptoms post-COVID-19 [ 128 ].…”