AUTHOR=Müller Sarah , Kufner Anna , Dell'Orco Andrea , Rackoll Torsten , Mekle Ralf , Piper Sophie K. , Fiebach Jochen B. , Villringer Kersten , Flöel Agnes , Endres Matthias , Ebinger Martin , Nave Alexander H. 

TITLE=Evolution of Blood-Brain Barrier Permeability in Subacute Ischemic Stroke and Associations With Serum Biomarkers and Functional Outcome

JOURNAL=Frontiers in Neurology

VOLUME=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2021.730923

DOI=10.3389/fneur.2021.730923

ISSN=1664-2295

ABSTRACT=Background:In the setting of acute ischemic stroke, increased blood brain barrier permeability (BBBP) as a sign of injury is associated with increased risk of poor outcome. Pre-clinical studies show that selected serum biomarkers including C-reactive protein, interleukin-6, tumor necrosis factor-alpha, matrix metallopeptidases, and vascular endothelial growth factors may play a role in BBBP post-stroke. In the subacute phase, increased BBBP may also be caused by regenerative mechanisms, and therefore may improve functional recovery. Our aim was to investigate the evolution of BBBP in subacute ischemic stroke using contrast-enhanced magnetic resonance imaging and to analyze associations with biomarkers and functional recovery. 

Methods: This is an exploratory analysis of patients enrolled in the BAPTISe study nested within the randomized controlled PHYS-STROKE trial. Patients with at least one contrast-enhanced MRI before (v1) or after (v2) four weeks trial intervention of fitness training were eligible. The prevalence of increased BBBP was visually assessed on T1-weighted MRI based on extent of contrast-agent enhancement within the lesion. The intensity of increased BBBP was semi-quantitatively assessed by normalizing the mean voxel intensity within lesion to the contralateral hemisphere. Serum biomarkers (CRP, interleukin-6, tumor necrosis factor-alpha, matrix metallopeptidases, vascular endothelial growth factor) were assessed at v1. Functional outcome was assessed at six months after stroke via modified Rankin Scale. 
Results: Of 93 patients included into the analyses, 80% had visible increased BBBP on v1. At v2, increased BBBP was still detectable in 74%. The presence of increased BBBP was associated with larger lesion volumes and more severe strokes. Time from stroke onset to MRI was inversely associated with BBBP intensity. Selected serum biomarkers were not associated with presence of increased BBBP. We did not identify occurrence or evolution of increased BBBP as independent predictors of long-term outcome. 

Conclusion: In patients with subacute stroke, three out of four patients demonstrated increased BBB permeability, which decreased over time. Presence of increased BBBP was associated with larger lesion volumes and more severe strokes. We could not detect an association between selected serum biomarkers of inflammation and an increased BBBP in this cohort. No clear association with favorable functional outcome was observed.