Altered blood-brain barrier permeability is associated with abnormal distant connectivity and regional homogeneity in covert hepatic encephalopathy – a cross sectional study

Covert hepatic encephalopathy (CHE) is clinically underrecognized. Using MRI, we explored the relationship between functional connectivity as a marker of executive dysfunction and the blood-brain barrier permeability marker KTRANS in a cross-sectional cohort of covert HE (CHE), no HE (NHE), and healthy controls (HC). This study was a single-center prospective cohort study conducted between 2018 and 2021. CHE was diagnosed using the Psychometric Hepatic Encephalopathy Score (PHES) with an abnormality threshold of <-4. Blood brain barrier permeability was determined using MRI KTRANS, based on cerebral efflux of gadolinium from blood plasma to the extravascular space. Resting-state fMRI determined the intrinsic dynamics of regions of the brain. Three cohorts were recruited: cirrhosis and CHE (n=17); cirrhosis with no HE (NHE; n=13); and healthy controls (n=10). There was a significant negative correlation (r=-0.59, p=0.003) between KTRANS and components of the Default Mode Network (DMN). Group-level ANOVA (F-test) revealed a significant difference between groups in functional connectivity within the Salience Network (SN) (Cluster level significance, F(4,62)=8.45, pcorrected=0.000005) and the DMN (Cluster level significance, F(4,62)=6.20, pcorrected=0.0004). The analysis revealed significant differences in regional homogeneity between the CHE and Health Controls. There was a strong association between disrupted blood-brain barrier (BBB) integrity and attenuated functional connectivity, with reductions in functional connectivity within the DMN and Frontoparietal Network (FPN), circuits closely linked to executive control. This attenuation was evident both in local regional and in distant connectivity within these networks.