Association Between MRI-Assessed Patterns of Connectome Gradient and Gene-Expression Profiles in Two Independent Patient Cohorts With Hepatitis B Virus-Related Cirrhosis

Abstract

Background: Patients with hepatitis B virus-related cirrhosis (HBV-RC) exhibit progressive neurologic dysfunction from primary sensorimotor to high-order cognition, as their disease advances. However, the exact neurobiologic mechanisms and the potential association with gene-expression profiles are not fully understood.

Purpose: To explore the hierarchical disorganization in the large-scale functional connectomes in HBV-RC patients and to investigate its potential underlying molecular basis.

Study type: Prospective.

Population: Fifty HBV-RC patients and 40 controls (Cohort 1) and 30 HBV-RC patients and 38 controls (Cohort 2).

Field strength/sequence: Gradient-echo echo-planar and fast field echo sequences at 3.0 T (Cohort 1) and 1.5 T (Cohort 2).

Assessment: Data were processed with Dpabi and the BrainSpace package. Gradient scores were evaluated from global to voxel level. Cognitive measurement and patients grouping were based on psychometric hepatic encephalopathy scores. The whole-brain microarray-based gene-expression data were obtained from the AIBS website.

Statistical tests: One-way ANOVA, chi-square test, two-sample t-test, Kruskal-Wallis test, Spearman's correlation coefficient (r), the gaussian random field correction, false discovery rate (FDR) correction and the Bonferroni correction. Significance level: P < 0.05.

Results: HBV-RC patients exhibited a robust and replicable connectome gradient dysfunction, which was significantly associated with the gene-expression profiles in both cohorts (r = 0.52 and r = 0.56, respectively). The most correlated genes were enriched in γ-aminobutyric acid (GABA) and GABA-related receptor genes (FDR q value <0.05). Moreover, the connectome gradient dysfunction at network level observed in HBV-RC patients correlated with their poor cognitive performance (Cohort 2: visual network, r = -0.56; subcortical network, r = 0.66; frontoparietal network, r = 0.51).

Data conclusion: HBV-RC patients had hierarchical disorganization in the large-scale functional connectomes, which may underly their cognitive impairment. In addition, we showed the potential molecular mechanism of the connectome gradient dysfunction, which suggested the importance of GABA and GABA-related receptor genes.

Evidence level: 2 TECHNICAL EFFICACY: Stage 2.

Keywords: BOLD; HBV-RC; connectome gradient; fMRI; transcriptomics.