Perioperative neurocognitive disorders as a neuroimmune landscape disorder: microglial priming, state heterogeneity, and time-dependent neuroinflammation

Abstract

Perioperative neurocognitive disorders (PND) are common and highly heterogeneous neurological complications in older and otherwise vulnerable surgical patients, with clinical manifestations ranging from delayed cognitive recovery to persistent postoperative cognitive decline. Although neuroinflammation is closely associated with the development of PND, an integrative framework is still lacking to explain how perioperative systemic immune activation leads to sustained central immune imbalance and cognitive dysfunction. Here, we propose that the brain immune landscape is a key determinant of susceptibility to PND. This landscape represents a baseline phenotype defined by central immune cell states, inflammatory activation thresholds, and resolution capacity. Within this microglia-centered framework, multiple perioperative factors may jointly drive maladaptive transitions in microglial states. We further discuss mitochondrial stress, glycolytic bias, epigenetic remodeling, non-coding RNA regulation, and trained immunity-like mechanisms, suggesting that these processes may serve as important drivers of sustained neuroimmune imbalance. This perspective supports time- and state-dependent, biomarker-guided intervention strategies aimed at preserving inflammatory resolution and enhancing perioperative cognitive resilience.