P: 15 Functional MRI: Evidence of a Treatment Effect of LOLA

BACKGROUND: Minimal hepatic encephalopathy (MHE) is associated with structural and functional connectivity abnormalities in the brain which correlate with cognitive dysfunction. The default mode network (DMN) comprises functionally interconnected brain regions responsible for attention and may explain cognitive deficits in MHE. While L-ornithine L-aspartate (LOLA) may improve MHE, its mechanism of action is not well characterised in controlled studies. METHODS: We performed a double-blind, randomised trial comparing the impact of oral L-ornithine L-aspartate (LOLA) 6g three times per day with placebo on 34 individuals with MHE (defined by PHES) for 12 weeks. Fourteen subjects received LOLA, 20 patients received placebo for the study duration. Subjects underwent functional MRI (fMRI) of the brain while performing motor and cognitive tasks and resting state studies at baseline (before starting on LOLA) or placebo, and at 12 weeks. The motor and cognitive task data in the LOLA arm (vs placebo) were analysed by comparing the sum total of fMRI activation at baseline with data collected at 12 weeks. For resting state data, the level of functional connectivity within a network was compared between baseline and 12 weeks for LOLA against placebo. Results: Groups were matched for age, sex, baseline educational level, weekly alcohol consumption, baseline PHES score, CogstateTM computerised psychometric testing, WTAR and SF36 scores. Color-naming subtest of the Stroop task was significantly impaired at baseline in LOLA receivers (P = 0.0179) For group averaged whole-brain data, there was no significant difference in activation for both motor and cognitive tasks or in resting state in all 34 patients at baseline and 12 weeks. Group differences by region of interest (see Table 1 below): the choice reaction time task in the default mode network (DMN) demonstrated significant treatment (P = 0.026) advantage after 12 weeks of LOLA. Of the 12 resting state networks studied, visual area 2 showed a significant treatment (P = 0.021) benefit after 12 weeks of LOLA.Conclusion: In the first RCT of LOLA combined with modern brain imaging analysis, a significant treatment benefit with LOLA on task activation was noted in the DMN. A significant treatment advantage of LOLA on resting-state fMRI in the visual network is consistent with this, this may be a compensatory mechanism in early MHE. Future studies could stratify patients who may benefit from LOLA based on base-line fMRI characterisation.