The Association Between Cerebrospinal Fluid α-synuclein And Postoperative Delirium In Patients Undergoing Knee/Hip Arthroplasty

Objective Postoperative delirium(POD)is frequently accompanied by decreased level of consciousness,emotional changes,with acute onset and usually occurring 1-7days after operation(or before discharge),which is one of the common complications in perioperative period.The occurrence of POD can lead to the increase of hospital stays and the growing of the cost of diagnosis and treatment,which affects the prognosis of patients.However,the pathophysiological mechanism of POD is not clear for now,so it becomes very important to explore the biomarkers of POD for its early detection and prevention.The purpose of this study was to investigate the association between the expression level of α-synuclein(α-syn)in cerebrospinal fluid(CSF)and POD in patients undergoing knee/ hip arthroplasty.Methods This was an observational cohort study.We recruited 833 patients who underwent knee / hip arthroplasty under combined lumbar and epidural anesthesia from the Perioperative Neurocognitive Disorder and Biomarker Lifestyl E(PNDABLE)study.One day before operation,the baseline characteristics of the patients,such as age,body weight,education level,hypertension and other complications,were collected according to the electronic medical record system and visits.All subjects were assessed by neuropsychological tests.CSF 2 ml was extracted during the puncture of combined spinal-epidural anesthesia.The concentrations of α-syn,phosphorylated tau protein(Ptau),β-amyloid protein(Aβ,Aβ40,Aβ42)and total tau(T-tau)in CSF of patients were detected by enzyme-linked immune-sorbent assay(ELISA).The incidence of POD was evaluated by Confusion Assessment Scale(CAM),and the severity of POD was evaluated by Memorial Delirium Assessment Scale(MDAS).After excluding the patients who refused to participate,changed the method of anesthesia and lost follow-up after operation,the study finally included 740 participants who met the criteria(the average age was61.86 years old,ranging from 40 to 90 years old,with 40% of women).Binary logistic regression was used to analyze the relationships between α-syn,CSF biomarkers(Aβ40,Aβ42,T-tau,P-tau)and POD.Multiple linear regression was used to analyze the relationships between α-syn and CSF biomarkers.The mediating effect analysis of 5000 bootstrap iterations was used to explore whether CSF biomarkers mediate the relationship between α-syn and POD.Results The incidence of POD was 11.22%(83/740).Compared with non-POD group,the concentrations of α-syn,T-tau and P-tau in CSF of POD group were higher,while the concentration of Aβ40 and Aβ42 were lower(P <0.001).In the whole population,after the stratification analysis,the concentration of α-syn in CSF was not related to gender(P=0.593).After adjusting blood loss and other factors,multi-factor logistic regression analysis showed that the increased concentrations of CSF α-syn(adjusted OR=1.005,95%CI 1.004-1.006,P <0.001),P-tau(adjusted OR=1.095,95%CI 1.069-1.122,P <0.001)and T-tau(adjusted OR=1.007,95%CI 1.005-1.009,P <0.001)were risk factors of POD.The increased concentration of Aβ42(adjusted OR=0.982,95%CI 0.971-0.994,P=0.003)was the protective factor of POD.By adding more correction variables,the results of sensitivity analysis showed that the increased concentrations of CSF α-syn(adjusted OR=1.006,95%CI 1.004-1.007,P <0.001),P-tau(adjusted OR=1.103,95%CI1.075-1.133,P <0.001)and T-tau(adjusted OR=1.008,95%CI 1.006-1.010,P <0.001)were still risk factors of POD.Similarly,the increased concentration of Aβ42(adjusted OR=0.982,95%CI 0.970-0.993,P =0.002)was still the protective factor of POD.The results of multiple linear regression showed that the concentration of CSF α-syn in POD group was positively correlated with the concentrations of P-tau(β = 0.445,P =0.001)and T-tau(β = 0.318,P <0.001).It was negatively correlated with the concentrations of Aβ40(β =-0.355,P <0.001),while had no significant correlation with Aβ42(β =-0.466,P =0.103).In non-POD group,there was no significant correlations among the concentrations of α-syn with Aβ40(β=-0.012,P=0.638),Aβ42(β=-0.028,P=0.354),Ptau(β=-0.064,P=0.190)and T-tau(β=-0.022,P=0.406).Subsequently,to further explore whether the association between α-syn and POD in CSF was mediated by CSF biomarkers,we conducted an intermediary effect analysis,and the results suggested the association between α-syn and POD in CSF may be mediated by tau pathology(proportion: 16-17%),rather than Aβ pathology(ratio: 2-6%).Conclusion The increase of α-syn concentration in CSF may be associated with POD in patients undergoing knee / hip arthroplasty,and the specific mechanism may be partly related to the participation of tau pathology.