Total Knee Arthroplasty (TKA) is widely regarded as the most effective surgical intervention for managing end-stage knee osteoarthritis (KOA), offering significant pain relief and functional restoration (1, 2). Despite advancements in surgical techniques, prosthetic knee designs (3), and postoperative rehabilitation protocols, approximately 10–40% of patients may still develop postoperative cognitive dysfunction (POCD) (4, 5). POCD is a common postoperative syndrome characterized by cognitive impairments, including deficits in memory, intellectual ability, and executive function (6). This complex condition often persists beyond the expected recovery period from anesthesia, contributing to prolonged hospital stays, increased healthcare costs, greater care requirements, as well as elevated morbidity and mortality (7–9).

The precise mechanisms underlying POCD remain poorly understood, emerging evidence points to a potential role of central sensitization (CS) in its pathogenesis (10). CS, a pathological condition frequently observed in chronic pain patients, is marked by a heightened excitability of the central nervous system (CNS) triggered by persistent peripheral nociceptive stimuli, leading to exaggerated pain responses even from subthreshold or normal sensory input (11). CS has been shown to a significant risk factor for persistent pain and patient dissatisfaction after TKA (12, 13). However, CS not only intensifies pain perception in patients undergoing TKA, but also potentially compromises cognitive function through a cascade of neuroinflammatory processes (14, 15). Studies suggest that patients with CS exhibit a significantly lowered pain threshold, a phenomenon closely linked to microglial activation and the release of pro-inflammatory cytokines such as IL-6 and TNF-α within the CNS (16–18). These inflammatory mediators are thought to be key drivers of cognitive decline (19, 20). This suggests that CS is not only a primary mechanism responsible for chronic postoperative pain but also a contributor to POCD through sustained neuroinflammation and altered neuroplasticity.

Notably, the presence of CS in TKA patients is often accompanied by preoperative chronic pain and psychosocial factors, such as anxiety, depression, and sleep disturbances, all of which are themselves closely linked to the occurrence of POCD (21, 22). As such, CS is considered to be a critical risk factor for POCD following TKA. Although previous studies have explored the impact of CS on postoperative pain and functional recovery, systematic research into its relationship with POCD remains very limited.

Given this, the study aims to conduct a retrospective analysis to investigate the impact of preoperative CS on POCD in TKA patients. Patients will be stratified based on their preoperative Central Sensitization Inventory (CSI) scores, and the correlation between CS and POCD will be assessed. The findings from this study are expected to offer new insights for preoperative screening, and postoperative management, ultimately reducing the incidence of POCD and improving patient outcomes.

This study demonstrates that CS is a significant risk factor for POCD following TKA. A retrospective analysis of 142 patients revealed that 30.91% of the CS group experienced POCD, compared to 12.64% in the non-CS group. Additionally, the CS group exhibited lower MMSE scores at multiple postoperative time points, along with lower pain and quality of life scores in the KOOS subdomains compared to the non-sensitized group. Logistic regression analysis further indicated that even after accounting for potential confounders, a higher CSI score (≥40) remained an independent risk factor for POCD. This finding clearly underscores the critical role of CS in impairing neurocognitive recovery following TKA.

TKA is one of the most cost-effective surgeries in orthopedics. Despite its high success rate, postoperative complications, especially POCD, are increasingly concerning, with rates reported to range from 19.4 to 72.0% 1 week postoperatively (4). Although the precise mechanisms underlying POCD remain unclear, several risk factors are known to be closely associated, including lower educational level (29), older age (30), alcohol use disorder (31, 32), preexisting cognitive impairment (33, 34). This study is the first to reveal a close link between CS and POCD, suggesting that CS not only affects postoperative pain management but may also exacerbate cognitive decline following TKA.

CS refers to a persistent and exaggerated response of the central nervous system to painful stimuli, characterized by a lowered pain threshold and abnormal pain perception. Recent studies have demonstrated that CS not only alters pain perception but may also impair cognitive function through various mechanisms (10). Neuroinflammation is considered a key pathophysiological foundation of CS. In chronic pain conditions, pro-inflammatory signals released from peripheral tissues can penetrate the blood–brain barrier, activating microglia and astrocytes, which in turn heightens neuronal excitability, leading to neuronal damage and apoptosis, potentially affecting cognitive function (35, 36). TKA is a highly invasive procedure often accompanied by severe postoperative pain and inflammation. During this process, the release of pro-inflammatory cytokines, such as IL-6, TNF-α, and IL-1β, exacerbates the effects of CS, potentially contributing to the development of POCD (37, 38). This mechanism may explain the occurrence of POCD in TKA patients, and the impact is likely to be more pronounced in those with CS. The results of this study’s MMSE assessments further support this hypothesis, indicating that CS may negatively affect postoperative cognitive recovery through similar mechanisms. We observed significant declines in MMSE scores on postoperative days 1and 3 compared to preoperative scores in both the CS and control groups, suggesting marked cognitive deterioration in the acute phase of TKA, which aligns with previous research. Additionally, MMSE scores in the CS group were significantly lower than those in the control group on postoperative days 1, 3, and 7, indicating a notable delay in cognitive recovery during the acute postoperative period among CS patients. This trend persisted through postoperative day 30, suggesting that CS has a sustained negative impact on long-term cognitive recovery. However, the potential impact of the learning effect could not be ignored. Conducting the MMSE assessment five times within 1 month might have led to patients becoming familiar with the test, artificially improving scores without truly reflecting cognitive recovery. Although we implemented standardized testing procedures and multidimensional data analyses to minimize the learning effect, it is not entirely possible to rule out its influence on the results. Furthermore, as this is a retrospective study, we were unable to directly verify or quantify the existence of the learning effect through experimental design. Future research should consider longer intervals between assessments or incorporate more complex cognitive tests to reduce the impact of the learning effect.

The KOOS results further demonstrated the negative impact of CS on postoperative recovery following TKA. Repeated measures ANOVA revealed that the CS group had significantly lower pain and quality of life scores compared to the non-sensitized group, while no significant differences were observed in the subdomains of symptoms, daily living activities, or sports/recreation. This suggests that CS primarily affects pain perception and quality of life, rather than other functional domains of the knee. Moreover, time had a significant main effect across all KOOS subdomains, indicating that overall knee function improved postoperatively for all patients. However, the interaction between time and group was significant for pain and quality of life scores, indicating that the trajectories of postoperative pain relief and quality of life recovery differed significantly between the high-sensitization and low-sensitization groups. Notably, by postoperative days 7 and 30, the CS group showed a marked delay in pain perception relief and quality of life improvement. This suggests that CS not only exacerbates postoperative pain perception but may also hinder the recovery of knee function by affecting patients’ psychological states and fear of physical activity, thereby exerting a prolonged negative effect on long-term quality of life. Consequently, during postoperative recovery in CS patients, greater emphasis should be placed on pain management and quality of life enhancement.

Notably, in the univariate and multivariate logistic regression analyses, even after adjusting for multiple confounding factors, central sensitization (CSI score ≥ 40) was identified as a significant risk factor for POCD following TKA, further emphasizing the critical role of CS in the development of POCD. Additionally, patients with cerebrovascular disease, intraoperative hemorrhage exceeding 200 mL and preoperative MMSE scores below 27 were significantly associated with an increased risk of POCD, suggesting that underlying cerebrovascular conditions, physiological stressors (such as intraoperative blood loss) and baseline cognitive function are key contributors to the occurrence of POCD. Consistent with previous research (2, 39), we speculate that patients with central sensitization may experience a heightened stress response during surgery, potentially leading to increased blood loss and a compounded neurocognitive burden. This finding also underscores the necessity of a thorough preoperative assessment, including screening for cognitive impairment, and cerebrovascular health, as well as meticulous intraoperative management for patients at risk of central sensitization to mitigate these adverse outcomes.

Although this study provides new evidence for understanding the association between CS and POCD, several limitations should be acknowledged. First, as a retrospective study, this research can only reveal correlations between patients with more pronounced CS symptoms and POCD, without establishing causality. Second, although multiple potential confounding factors were adjusted for, other factors not accounted for in the study-such as postoperative infections, preoperative and intraoperative drug use, emotional disorders like depression and anxiety, and sleep disturbances-may also influence the occurrence of POCD. Third, conducting the MMSE assessment five times within 1 month may have introduced a learning effect, where patients’ familiarity with the test could artificially improve scores rather than reflect true cognitive recovery. Moreover, the MMSE may lack the sensitivity required to identify nuanced cognitive changes, potentially affecting the accuracy of POCD evaluation. Future studies should consider adopting more detailed neuropsychological assessment tools to comprehensively evaluate specific cognitive domains. Fourth, the sample size of this study was relatively small, and the follow-up points were limited to postoperative days 1, 3, 7, and 30. The short follow-up duration and small sample size may introduce bias, and the findings should therefore be interpreted with caution. Finally, the study did not utilize imaging techniques, such as structural MRI, FDG-PET, or resting-state fMRI, nor were biomarkers employed to explore the impact of CS on patients (40). This limits the understanding of the neural mechanisms underlying POCD and hinders the development of personalized treatment strategies.

This study suggests that CS may be a novel risk factor for POCD following TKA, and may adversely affect postoperative recovery in terms of cognitive function, pain, and quality of life. Preoperative assessment of CS, particularly through individualized management of patients with chronic pain, may help reduce the incidence of POCD and improve overall postoperative outcomes after TKA. Future prospective, multicenter studies are needed to validate these findings and explore additional interventions to mitigate the negative impact of CS on postoperative cognitive function.