Neurocognitive Recovery After Liver Transplantation Is Driven by Metabolite-mediated Reactivation of Cortical Networks

BACKGROUND: Liver transplantation (LT) is a life-saving therapy for end-stage liver disease, but postoperative neurocognitive recovery and mechanisms remain unclear. Although liver-brain crosstalk is known, whether LT restores neurological dysfunction is uncertain. METHODS: Twenty-one patients undergoing LT were prospectively evaluated within 1-3 d before transplantation and 21 d postoperatively. Cognitive function was assessed using the Montreal Cognitive Assessment and the Psychometric Hepatic Encephalopathy Score, and resting-state electroencephalography (EEG) was analyzed for power spectral density, functional connectivity, and microstate dynamics. Paired plasma samples underwent nontargeted metabolomics, and candidate metabolites were further examined using in vitro inflammatory injury models, patch-clamp electrophysiology, ex vivo brain slices, and in vivo behavioral testing. RESULTS: Montreal Cognitive Assessment scores increased from 23.14 ± 2.46 to 24.67 ± 1.88 (P = 0.0002), and Psychometric Hepatic Encephalopathy Scores improved from -11.28 ± 2.42 to -6.11 ± 2.89 (P < 0.0001) after LT. EEG analyses showed increased alpha1 and beta power, enhanced functional connectivity, and altered microstate dynamics after transplantation. Plasma glial fibrillary acidic protein decreased postoperatively, suggesting reduced neuroinflammatory injury. Nontargeted metabolomics identified postoperative elevation of S-methyl-5'-thioadenosine (MTA), and experimental validation showed that MTA attenuated inflammatory neurotoxicity, reduced reactive oxygen species production, and preserved neuronal excitability and synaptic transmission. CONCLUSIONS: LT was associated with early improvement in neurocognitive function in patients with end-stage liver disease. Integrated EEG and metabolomic analyses suggest that posttransplant cognitive recovery may involve restoration of cortical network activity and systemic metabolic remodeling. MTA emerged as a candidate recovery-associated biomarker and functional metabolite that may contribute to neuroprotection by modulating neuroinflammation.