Targeting glycolysis and maintaining glucose homeostasis for treating perioperative neurocognitive disorder: a narrative review

Perioperative neurocognitive disorder (PND) is a significant neurological complication in ageing surgical populations. PND is characterised by cognitive decline and associated with prolonged hospitalisation, functional impairment, and increased mortality. Emerging evidence implicates dysregulated cerebral glucose metabolism as a pivotal pathophysiological mechanism of PND. This review synthesises clinical and experimental findings to elucidate the dual role of glycolytic flux in PND pathogenesis. While physiological glycolysis supports neuroenergetics and protection, its aberrant activation during anaesthesia/surgery triggers lactate accumulation, disrupts metabolic homeostasis, and promotes neuroinflammation and oxidative stress. We analysed different effects of anaesthetics and found that intravenous anaesthetics (e.g. propofol) and inhalation anaesthetics (e.g. sevoflurane, isoflurane) differ in their effects on metabolic pathways and their correlation with PND. In addition, surgical trauma further amplifies metabolic reprogramming through mechanisms such as neuroimmune activation. Critically, perturbations in glycolytic-lactic acid dynamics impair synaptic plasticity, neuronal function, and glial responses, establishing a cycle that accelerates cognitive deterioration. By describing the intersection of brain glucose metabolism and neurocognition, this review proposes targeting glycolytic homeostasis as a potential research direction and new strategy to address clinical challenges encountered in PND diagnosis and management.