Neurobiological mechanisms of postoperative delirium at neural molecular and cellular levels

Postoperative delirium (POD) is an acute neuropsychiatric syndrome predominantly affecting older adults after surgery, characterized by disturbances in attention, awareness, and cognition. Its incidence ranges from 10% to over 70%, depending on patient vulnerability and surgical type. POD is independently associated with prolonged hospital stays, increased morbidity and mortality, and long-term cognitive decline. The pathophysiology is multifactorial and involves dysregulation at neural, molecular, and cellular levels. Neurotransmitter imbalances, especially acetylcholine deficiency and dopaminergic excess, play a central role. Glutamate excitotoxicity and disrupted GABAergic tone further impair synaptic function. Neuroimaging and EEG reveal disrupted functional connectivity within key networks such as the Default Mode Network (DMN) and Central Executive Network (CEN), alongside cortical slowing and reduced EEG complexity. Molecularly, systemic inflammation triggered by surgery—marked by elevated IL-6, TNF-α, and IL-1β—activates microglia and astrocytes, propagating central neuroinflammation. Concurrent blood–brain barrier (BBB) dysfunction, driven by cytokine-induced tight junction degradation and endothelial apoptosis, permits peripheral immune mediators to enter the CNS, exacerbating damage. Oxidative stress and mitochondrial dysfunction further disrupt energy metabolism and amplify neuronal vulnerability. At the cellular level, microglia adopt a pro-inflammatory M1 phenotype, releasing neurotoxic cytokines and glutamate, while astrocyte dysfunction impairs glutamate clearance, water homeostasis, and BBB support. Neuronal apoptosis, synaptic loss, and increased tau pathology suggest that POD may unmask or accelerate neurodegeneration. Understanding these interconnected pathways offers opportunities for mechanism-based prevention, including cholinergic support, anti-inflammatory strategies, and perioperative biomarker-guided risk stratification.