Editorial: Neuroinflammation in postoperative cognitive dysfunction and related disorders

Postoperative neurocognitive dysfunction (PND) describes a clinical condition in which patients undergoing general anesthesia experience declines in memory, loss of vigilance, alterations in personality, and abnormalities in social functioning. In severe cases, PND may induce neurological or psychiatric symptoms such as postoperative delirium or hallucinations. Traditional anesthetic management has mainly focused on stabilizing intraoperative vital signs with little attention to cognitive protection and the lack of effective prevention standards. Recent studies have increasingly focused on pathogenesis, risk factors, and interventions for PND. Within our research topic, four studies further elucidate the central roles of inflammation, preoperative cognitive status, anesthetic optimization, and intranasal insulin intervention in PND occurrence and prevention. In this editorial we summarize these studies, highlight their interrelationships, thereby providing references for the clinical prevention and management of PND as well as the advancement of related research.Two comprehensive reviews have demonstrated that inflammation is the core and unifying mechanism underlying the development and progression of PND. Peripheral inflammation triggered by surgical trauma and anesthetic stimulation might serve as an initiating factor of PND.Proinflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor- (TNF-) can cross the blood-brain barrier and activate the polarization of central microglia toward the proinflammatory phenotype, thereby inducing neuroinflammation, further disrupting neurotransmitter balance, damaging neurons, and ultimately leading to cognitive decline [1].Inhalational anesthetics may exacerbate the condition by damaging the blood-brain barrier and aggravating neuroinflammation, while intravenous anesthetics such as propofol exhibit potential anti-inflammatory and neuroprotective effects. The study showed that Patients receiving inhalational anesthetics have 1.49 times higher risk of delayed neurocognitive recovery compared with those receiving intravenous anesthetics [2,3]. Those research findings provide promising clues for understanding the pathogenesis of PND and key information for its prevention and treatment.Preoperative cognitive status was considered as an individual risk factor affecting susceptibility to PND [4]. A clinical study on elderly male patients undergoing laparoscopic radical prostatectomy revealed that those with preoperative cognitive impairment measured by the Montreal Cognitive Assessment (MoCA) lower than 26 exhibited significantly heightened sensitivity to propofol. Specifically, to reach the same anesthetic depth, these patients required a lower dose of propofol compared to cognitively intact individuals. Additionally, their bispectral index values were higher when the eyelash reflex disappeared. This evidence indicates that preoperative cognitive decline might be positively correlated with changes in neurotransmitter receptor function, which in turn affects the pharmacodynamic response to anesthetics. Clinically, MoCA scoring might be incorporated into the pre-anesthetic evaluation of elderly patients to identify high-risk groups and achieve precise, individualized medication utilization.Based on current research findings on the pathogenesis of PND and understanding of its risk factors, anesthetic optimization might serve as a feasible preventive strategy for PND. Due to the antiinflammatory properties of intravenous anesthetics and the anesthetic sensitivity of patients with cognitive impairment, elderly patients with preoperative cognitive impairment may benefit from the preferential use of intravenous anesthetics such as propofol and dexmedetomidine, with appropriate reduction in induction and maintenance doses to avoid cognitive damage caused by excessive anesthetic depth. Propofol attenuates inflammation by inhibiting the NF-κB signaling pathway, thereby reducing the production of pro-inflammatory cytokines. Dexmedetomidine, an α 2adrenergic receptor agonist, exerts anti-inflammatory effects by inhibiting microglial polarization toward the M1 phenotype and downregulating pro-inflammatory mediators, thereby reducing the risk of neuronal injury and contributing to the prevention and mitigation of PND [5]. In addition, ultrasound-guided regional nerve block combined with multimodal analgesia can also reduce the dosage of general anesthetics and opioids, indirectly alleviating the inflammatory response and anesthesia-related neurotoxicity. Although the protective effect of regional anesthesia on PND still requires investigations, its advantages of minimal invasiveness and effective analgesia have made it an alternative of perioperative cognitive protection.Intranasal insulin intervention is a novel and safe pharmacological prevention method for PND, and its effectiveness has been confirmed by relevant clinical studies [6]. A randomized, double-blind pilot study on elderly patients undergoing laparoscopic radical resection of colorectal cancer found that intranasal insulin administration from 2 days before surgery to 1 hour before surgery could significantly reduce the incidence of PND evaluated at 7 days after surgery (13.3% vs 38.7%). At Secondly, the consistency of action in humans, applicability to different surgical types, and longterm safety of various potential drugs targeting PND pathological pathways such as Morin targeting ferroptosis and palmitoylethanolamide (PEA) targeting inflammation, still require further investigation [7,8]. Moreover, key details of interventions remain unclear, such as the specific adjustment ratio of propofol dose for patients with different degrees of cognitive impairment, and the optimal dose and administration duration of intranasal insulin. Dose-gradient studies are needed to improve clinical practice guidelines. Thirdly, the synergistic effect of multiple intervention strategies has not been explored. For example, the combined application of intranasal insulin with anesthetic optimization and multimodal analgesia may achieve better protective effects by targeting different links of PND pathogenesis, which awaits clinical validation. Fourthly, most existing studies focus on short-term cognitive outcomes within 7 days after surgery, lacking long-term follow-up data. Longitudinal studies are carried out to evaluate the long-term value of interventions and their potential impact on chronic neurodegenerative diseases such as Alzheimer's disease.Finally, it is necessary to develop a PND risk prediction model that integrates factors such as preoperative cognitive status, inflammatory markers, and surgical invasiveness to create practical tools for early identification and precise intervention of high-risk patients.In conclusion, the latest studies have significantly advanced our understanding of the mechanisms, risk factors, and interventions for perioperative neurocognitive disorders (PND). Future research should address existing limitations, focus on large-sample verification, optimization of intervention details, exploration of synergistic effects, long-term follow-up, and precise prediction, and translate research findings into standardized and individualized guidelines for the prevention and treatment of PND. Such efforts will not only enhance postoperative quality of life in elderly surgical patients but also drive progress in perioperative medicine and neuroanesthesiology, ultimately advancing toward precision medicine in perioperative cognitive protection.