Associations of Preoperative Cerebrospinal Fluid Acetylcholine, BDNF, and IL-1β with Acute Postoperative Pain Across Educational Strata

Xiaoyu Yang,1,* Lidong Su,2,* Tiantian Kong,3,* Ruyue Li,4 Han Wang,4 Ligang Shan,5 Yanlong Liu,6 Fan Wang71Department of Anesthesiology, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, People’s Republic of China; 2Department of Anesthesiology, the Third Affiliated Hospital of Inner Mongolia Medical University, BaoGang Hospital, Baotou, 014010, People’s Republic of China; 3Development and Reform Division, Xinjiang Medical University, Urumqi, 830017, People’s Republic of China; 4Medical Neurobiology Lab, Inner Mongolia Medical University, Huhhot, 010110, People’s Republic of China; 5Department of Anesthesiology, The Second Affiliated Hospital of Xiamen Medical College, Xiamen, 361021, People’s Republic of China; 6School of Mental Health, Wenzhou Medical University, Wenzhou, 325035, People’s Republic of China; 7Beijing Hui-Long-Guan Hospital, Capital Medical University, Beijing, 100096, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fan Wang, Beijing Hui-Long-Guan Hospital, Peking University, Beijing, 100096, People’s Republic of China, Tel +86 10 83024429, Fax +86 10 62716285, Email fanwang@bjmu.edu.cn Yanlong Liu, School of Mental Health, Medical University, Wenzhou, 325035, People’s Republic of China, Tel +86 577-86689983, Fax, +86 577-86689983, Email benjaminlyl@wmu.edu.cnPurpose: Educational attainment is commonly used as a proxy for cognitive reserve, but whether associations between central pain-related biomarkers and acute postoperative pain differ across educational strata remains unclear. We examined associations of preoperative cerebrospinal fluid (CSF) acetylcholine (ACh), brain-derived neurotrophic factor (BDNF), and interleukin-1 beta (IL-1β) with postoperative pain and explored whether their shapes differed by educational attainment.Patients and Methods: This cross-sectional study included 160 adult male participants in China who underwent anterior cruciate ligament reconstruction between September 2014 and January 2016. Educational attainment was categorized as < 15 or ≥ 15 years. Acute postoperative pain was assessed using a visual analog scale (VAS). CSF ACh, BDNF, and IL-1β were quantified by ELISA. Associations with VAS scores were examined using multivariable linear regression, generalized additive models (GAMs), and exploratory two-piecewise linear regression.Results: Eighty participants were included in each educational stratum. Linear regression identified an association between IL-1β and VAS scores (P=0.003), but not ACh (P=0.313) or BDNF (P=0.086). GAMs showed significant smooth-term associations for ACh (edf=1.017, P=0.015), BDNF (edf=2.000, P=0.023), and IL-1β (edf=4.454, P=0.004). The ACh function was essentially linear, whereas BDNF and IL-1β showed greater curvature. Education-stratified curves appeared flatter in the higher-education group. Two-piecewise models did not significantly improve model fit over standard linear models within educational strata (all likelihood-ratio P> 0.05), providing no robust evidence of discrete thresholds.Conclusion: Preoperative CSF ACh, BDNF, and IL-1β were associated with postoperative pain patterns that differed in shape, with the clearest nonlinearity observed for BDNF and IL-1β. Differences across educational strata should be considered exploratory and require confirmation in larger, prospectively powered studies.Keywords: cerebrospinal fluid, acetylcholine, BDNF, interleukin-1 beta, cognitive reserve, generalized additive model, postoperative pain