Potential value of serum prealbumin and serum albumin in the identification of postoperative delirium in patients undergoing knee/hip replacement: an observational study and internal validation study.

Background: Postoperative delirium (POD) is a common postoperative neurological complication that can lead to a variety of postoperative complications. At present, the pathogenesis of POD is unclear. This study aims to explore the relationship between serum prealbumin and serum albumin and POD and whether serum prealbumin and serum albumin influence POD through POD core pathology. Objective: We enrolled 500 Chinese Han patients between September 2020 to January 2023. We analyzed the risk and protective factors of POD using the multivariate logistic regression. We also assessed the predictive power of serum prealbumin, serum albumin, and both in combination with CSF POD biomarkers. We used Stata MP16.0. to examine whether the association between serum prealbumin and serum albumin and POD was mediated by CSF POD biomarkers, and conducted an internal validation study to verify the accuracy of the combination of serum prealbumin + serum albumin + CSF POD biomarkers for predicting POD. The model was visualized using ROC curve and decision curve analysis (DCA). DynNom and Shiny packages were used to create an online calculator. Ten patients who had POD occurring from February 2023 to October 2023 were selected for internal verification. Results: Finally, a total of 364 patients were included in our study. Levels of serum prealbumin, serum albumin in the POD group were lower than those in the NPOD group. The lever of serum prealbumin, serum albumin were protective factors for POD. The relationship between serum prealbumin, serum albumin and POD was partially mediated by T-tau (12.28%) and P-tau (20.61%). The model combining serum prealbumin and serum albumin and POD biomarkers exhibited a relatively better discriminatory ability to predict POD. DCA also showed that the combination of serum prealbumin and serum albumin and POD biomarkers brought high predictive benefits to patients. The dynamic online calculator can accurately predict the occurrence of POD in the internal validation study. Conclusion: Preoperative low serum prealbumin and serum albumin levels were the preoperative risk factors for POD, which is partly mediated by T-tau and P-tau. The model combining serum prealbumin and serum albumin and CSF POD biomarkers can accurately predict the occurrence of POD. Clinical trial registration: http://www.clinicaltrials.gov, identifier ChiCTR2000033439.

The relationship between intraoperative hypothermia and postoperative delirium: The PNDRFAP study.

OBJECTIVE: Our study aimed to investigate the correlation between intraoperative hypothermia and postoperative delirium (POD) in patients undergoing general anesthesia for gastrointestinal surgery. METHODS: The study comprised 750 participants from the Perioperative Neurocognitive Disorder Risk Factor and Prognosis (PNDRFAP) study database, which ultimately screened 510 individuals in the final analysis. Preoperative cognitive function was evaluated using the Mini-Mental State Examination (MMSE). The occurrence of POD was determined using the Confusion Assessment Method, and the severity of POD was evaluated using the Memorial Delirium Assessment Scale. Logistic regression was employed to scrutinize the association between intraoperative hypothermia and the incidence of POD, and the sensitivity analysis was conducted by introducing adjusted confounding variables. Decision curves and a nomogram model were utilized to assess the predictive efficacy of intraoperative hypothermia for POD. Mediation analysis involving 10,000 bootstrapped iterations was employed to appraise the suggested mediating effect of numeric rating scale (NRS) scores at 24 and 48 h post-surgeries. The receiver-operating characteristic (ROC) was utilized to evaluate the effectiveness of intraoperative hypothermia in predicting POD. RESULTS: In the PNDRFAP study, the occurrence of POD was notably higher in the intraoperative hypothermia group (62.2%) compared to the intraoperative normal body temperature group (9.8%), with an overall POD incidence of 17.6%. Logistic regression analysis, adjusted for various confounding factors (age [40-90], gender, education, MMSE, smoking history, drinking history, hypertension, diabetes, and the presence of cardiovascular heart disease), demonstrated that intraoperative hypothermia significantly increased the risk of POD (OR = 4.879, 95% CI = 3.020-7.882, p < .001). Mediation analyses revealed that the relationship between intraoperative hypothermia and POD was partially mediated by NRS 24 h after surgery, accounting for 14.09% of the association (p = .002). The area under the curve of the ROC curve was 0.685, which confirmed that intraoperative hypothermia could predict POD occurrence to a certain extent. Decision curve and nomogram analyses, conducted using the R package, further substantiated the predictive efficacy of intraoperative hypothermia on POD. CONCLUSION: Intraoperative hypothermia may increase the risk of POD, and this association may be partially mediated by NRS scores 24 h after surgery.

COVID-19 vaccination may prevent postoperative delirium in elderly patients undergoing elective non-cardiac surgery: The PNDRFAP and PNDABLE studies.

Background: Postoperative delirium (POD) often occurs in elderly patients after surgery. We conducted two clinical studies to determine whether COVID-19 vaccination has a protective effect on POD and to explore the role of CSF biomarkers in this process. Methods: We conducted two clinical studies, Perioperative Neurocognitive Disorder Risk Factor and Prognosis (PNDRFAP) and Perioperative Neurocognitive Disorder and Biomarker Lifestyle (PNDABLE), in which patients more than or equal to 65 years old who have had elective non-cardiac surgery were enrolled. The preoperative cognitive status of patients were evaluated by Mini-Mental State Examination (MMSE) one day preoperatively. Confusion Assessment Method (CAM) was used to diagnose POD. We used the mediation model to analyze the relationship between CSF biomarkers, COVID-19 vaccination and POD, as well as Dynamic Nomogram to calculate the incidence of Non-Postoperative Delirium (NPOD). The main outcome of these studies was the incidence of POD during seven days postoperatively or before discharge, which was assessed by CAM. Results: In the final, 705 participants were enrolled in the PNDRFAP study, and 638 patients in the PNDABLE. In both studies, we found that the occurrence of POD was lower in patients who had injected COVID-19 vaccination before surgery compared with those without vaccination (PNDRFAP: 10.20 % [21/205] vs 25.80 % [129/500], P < 0.001; PNDABLE: 2.40 % [4/164] vs 34.60 % [164/474], P < 0.001). Mediation analysis showed that the protective effect of preoperative COVID-19 vaccine on POD was significantly mediated by CSF Aß42 (proportion = 17.56 %), T-tau (proportion = 19.64 %), Aß42/T-tau (proportion = 29.67 %), and Aß42/P-tau (proportion = 12.26 %). Conclusions: COVID-19 vaccine is a protective factor for POD in old patients, which is associated with CSF biomarkers.

Echocardiographic measures of the left heart and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact adults: The CABLE study.

INTRODUCTION: This study delineated the interrelationships between subclinical alterations in the left heart, cerebrospinal fluid (CSF), Alzheimer's disease (AD) biomarkers, and cognition. METHODS: Multiple linear regressions were conducted in 1244 cognitively normal participants (mean age = 65.5; 43% female) who underwent echocardiography (left atrial [LA] and left ventricular [LV] morphologic or functional parameters) and CSF AD biomarkers measurements. Mediating effects of AD pathologies were examined. Differences in cardiac parameters across ATN categories were tested using analysis of variance (ANOVA) and logistic regressions. RESULTS: LA or LV enlargement (characterized by increased diameters and volumes) and LV hypertrophy (increased interventricular septal or posterior wall thickness and ventricular mass) were associated with higher CSF phosphorylated (p)-tau and total (t)-tau levels, and poorer cognition. Tau pathologies mediated the heart-cognition relationships. Cardiac parameters were higher in stage 2 and suspected non-Alzheimer's pathology groups than controls. DISCUSSION: These findings suggested close associations of subclinical cardiac changes with tau pathologies and cognition. HIGHLIGHTS: Various subclinical alterations in the left heart related to poorer cognition. Subclinical cardiac changes related to tau pathologies in cognitively normal adults. Tau pathologies mediated the heart-cognition relationships. Subclinical cardiac changes related to the AD continuum, especially to stage 2. The accumulation of cardiac alterations magnified their damage to the brain.

Physical activity may a probably protective factor for postoperative delirium: the PNDABLE study.

Objective: This study aims to explore the relationship between physical activity (PA) and postoperative delirium (POD). Methods: We selected 400 patients from the Perioperative Neurocognitive Disorder and Biomarkers Lifestyle (PNDABLE) database, and the patients in the PNDABLE database were sampled and tested Alzheimer's biomarkers. The diagnosis of POD was made using the Confusion Assessment Scale (CAM) and the severity was assessed using Memorial Delirium Assessment Scale (MDAS). Mini-Mental State Examination (MMSE) scale was used to detect the mental state of the patients. Enzyme-linked immunosorbent assay (ELISA) was used to detect the level of preoperative cerebrospinal fluid (CSF) biomarkers, such as amyloid ß plaque 42 (Aß42), total tau protein (T-tau), and phosphorylated tau protein (P-tau). Logistic regression, sensitivity analysis, and post hoc analysis were used to explore the relationship between risk and protective factors on POD. We used the mediating effect to explore whether PA mediates the occurrence of POD through CSF biomarkers. Results: The incidence of POD was 17.5%. According to our research, the consequence prompted that PA might be the protective factor for POD [odds ratio (OR): 0.336, 95% confidence interval (95 CI) 0.206-0.548, P < 0.001]. The result of logistic regression revealed that CSF biomarker Aß42 (OR: 0.997, 95 CI 0.996-0.999, P < 0.001) might be a protective factor against POD, and the T-tau (OR: 1.006, 95 CI 1.003-1.009, P = 0.001) and P-tau (OR: 1.039, 95 CI 1.018-1.059, P < 0.001) might risk factors for POD. Sensitivity analysis confirmed the correlation between PA and CSF biomarkers in the patients with POD. Mediation effect analysis showed that PA may reduce the occurrence of POD partly through CSF biomarkers, such as Aß42 (proportion: 11%, P < 0.05), T-tau (proportion: 13%, P < 0.05), and P-tau (proportion: 12%, P < 0.05). Conclusion: Physical activity is probably a protective factor for POD and may exert a mediating effect through CSF biomarkers.

Daytime dysfunction may be associated with postoperative delirium in patients undergoing total hip/knee replacement: The PNDABLE study.

PURPOSE: Postoperative delirium (POD) is a usual complication after total hip/knee replacement, which may be affected by sleep characteristics. However, up to now, preoperative sleep characteristics have not been evaluated as risk factors of POD. The relationship between self-reported sleep characteristics and POD in patients has been investigated in this study. PATIENTS AND METHODS: We recruited 495 cognitively intact individuals in the final analysis from the Perioperative Neurocognitive Disorder and Biomarker Lifestyle study. Sleep characteristics were tested by the Pittsburgh Sleep Quality Index (PSQI). Mini-mental state examination was applied to assess preoperative mental status of patients. Postoperatively, we used confusion assessment method and memorial delirium assessment scale to evaluate the incidence of POD and POD severity, respectively. The cerebrospinal fluid (CSF) levels of T-tau, P-tau, Aß40, and Aß42 were detected by enzyme-linked immune-sorbent assay before the operation. Logistic regression, multiple linear regression, and mediation effects were performed to analyze the relationship between self-reported sleep characteristics and POD. RESULTS: POD was detected in 11.31% (56/495) of the patients, with logistic regression analysis showing that daytime dysfunction, P-tau, and T-tau were risk factors of POD, and Aß42 was a protective factor of POD. Multiple linear regression analysis confirmed that daytime dysfunction was positively correlated with P-tau in patients with POD. Meanwhile, compared to the patients with no postoperative delirium, the CSF levels of P- and T-tau were higher in patients with POD. Furthermore, mediation analysis showed that it was probable that daytime dysfunction mediated POD through P-tau (proportion: 12.90%) partially. CONCLUSION: Daytime dysfunction is a risk factor of POD preoperatively. To sum up, CSF P-tau protein might partially mediate the influence of daytime dysfunction on POD. CLINICAL TRIAL REGISTRATION: This study was registered at Chinese Clinical Trial Registry (ChiCTR2000033439).

Relationship between preoperative neutrophil-to-lymphocyte ratio and postoperative delirium: The PNDABLE and the PNDRFAP cohort studies.

OBJECTIVES: In this study, the relationship between preoperative neutrophil-to-lymphocyte ratio (NLR) and Alzheimer-related biomarkers in cerebrospinal fluid (CSF) was investigated to determine whether high NLR is a potential risk factor for postoperative delirium (POD) and to evaluate its predictive efficacy. METHODS: We selected 1000 patients from the perioperative neurocognitive disorder risk factor and prognosis (PNDRFAP) database and 999 patients from the perioperative neurocognitive disorder and biomarker lifestyle (PNDABLE) database. Patients in the PNDABLE database have been measured for Alzheimer-related biomarkers in CSF (Aß40 , Aß42 , P-tau, and tau protein). Mini-mental state examination was used to assess the preoperative mental status of patients. POD was diagnosed using the confusion assessment method and assessed for severity using the memorial delirium assessment scale. Logistic regression analysis was utilized to explore the association of preoperative NLR with POD. What's more, we also performed sensitivity analysis by adding corrected confounders, and the results were almost unchanged. Spearman's rank correlation was used to determine the associations between NLR and Alzheimer-related biomarkers. Mediation analyses with 10,000 bootstrapped iterations were used to explore the mediation effects. Finally, we use decision curves and the nomogram model to evaluate the efficacy of preoperative NLR in predicting POD; we also performed external validation using data from Qilu Hospital. RESULT: Logistic regression results showed that an elevated preoperative NLR was a risk factor for the development of POD in patients (PNDRFAP: OR = 1.067, 95% CI 1.020-1.116; PNDABLE: OR = 1.182, 95% CI 1.048-1.335, p < .05). Spearman's rank correlation analysis showed a positive but weak correlation between NLR and P-tau/T-tau (R = .065). The mediating effect results indicate that NLR likely mediates the occurrence of POD through elevated tau protein levels (proportion: 47.47%). The results of the box plots showed statistically significant NLR and CSF biomarkers between the POD and non-POD (NPOD) groups (p < .05), with higher NLR, P-tau, and T-tau in the POD group than in the NPOD group. In contrast, the NPOD group had higher Aß42 levels compared to the POD group. In addition, we used R package to plot the decision curve and nomogram both suggesting a good predictive effect of preoperative NLR on the occurrence of POD. CONCLUSION: Elevated preoperative NLR levels may be a risk factor for POD and likely mediate the development of POD through elevated P-tau/T-tau levels.

Alcohol consumption may be associated with postoperative delirium in the elderly: the PNDABLE study.

OBJECTIVES: This study aimed to reveal the relationship between alcohol consumption and Postoperative delirium (POD) in the elderly. METHODS: We selected 252 patients from the Perioperative Neurocognitive Disorder And Biomarker Lifestyle (PNDABLE ) study. Patients in the PNDABLE database have been measured for Alzheimer-related biomarkers in CSF (Aß40, Aß42, P-tau, and tau protein). Mini-Mental State Examination (MMSE) was used to assess the preoperative mental status of patients. POD was diagnosed using the Confusion Assessment Method (CAM) and assessed for severity using the Memorial Delirium Assessment Scale (MDAS). Logistic regression analysis was utilized to explore the association of alcohol consumption with POD. Linear regression analysis was used to study the relationship between alcohol consumption and CSF biomarkers. Mediation analyses with 10,000 bootstrapped iterations were used to explore the mediation effects. Finally, we constructed the receiver operating characteristic (ROC) curve and the nomogram model to evaluate the efficacy of alcohol consumption and CSF biomarkers in predicting POD.  RESULT: The incidence of POD was 17.5%. Logistic regression showed that alcohol consumption (OR = 1.016, 95%CI 1.009-1.024, P < 0.001) is a risk factor for POD. What's more, Aß42 is a protective factor for POD (OR = 0.993, 95%CI 0.989-0.997, P < 0.05), and P-Tau was a risk factor for POD (OR = 1.093, 95%CI 1.022-1.168, P < 0.05). Linear regression analysis revealed that alcohol consumption was negatively associated with CSF Aß42 (ß = -0.638, P < 0.001) in POD patients. Mediation analyses showed that alcohol consumption is likely to partially mediate POD through Aß42 (proportion:14.21%). ROC curve showed that alcohol consumption (AUC = 0.904; P < 0.001) exhibited a relatively better discriminatory ability in POD prediction compared to Aß42 (AUC = 0.798; P < 0.001). The calibration curve indicated a good nomogram prediction (P = 0.797). CONCLUSION: Alcohol consumption is a risk factor for POD (particularly for those with > 24 g a day on average) in the elderly, and contributes to POD through the mediation of Aß42.

Preoperative cerebrospinal fluid biomarkers may be associated with postoperative delirium in patients undergoing knee/hip arthroplasty: the PNDABLE study.

BACKGROUND: In the global aging population, the incidence of postoperative delirium (POD) is increasing. Therefore, finding its effective predictive tools becomes crucial. We aimed to identify potential Cerebrospinal fluid (CSF)biomarkers for POD. METHODS: A total of 825 patients undergoing knee/hip arthroplasty under combined spinal-epidural anesthesia were selected. The patients were aged 40 to 90 years with American Society of Anesthesiologists physical status I~II. The Mini-Mental State Examination was completed 1 day before the operation. CSF was extracted after successful spinal-epidural combined puncture, and α-synuclein (α-syn), amyloid beta40 (Aß40), amyloid beta42 (Aß42), t-Tau, phosphorylated Tau (p-Tau), progranulin (PGRN) and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in the CSF were measured by enzyme-linked immunosorbent assays (ELISA). The patient's operation time, anesthesia time, intraoperative blood loss and fluid input were also recorded. After the operation, the occurrence rate and severity of POD were determined by the Confusion Assessment Method and the Memorial Delirium Assessment Scale (MDAS), respectively. Patients were categorized into POD group and non-POD group. Logistic regression analysis was performed on the indicators with statistically significant differences, and the area under the ROC curve (AUC) was used to estimate the predictive accuracy of the biomarkers for POD. RESULTS: A total of 92 patients developed POD and the incidence of POD was 11.15%. The results of the multivariable logistic regression showed that CSF t-Tau (P = 0.004, OR = 1.006, 95%CI 1.002~1.009) and α-syn (P = 0.004, OR = 1.001, 95%CI 1.000~1.001) were positively associated with the occurrence rate of POD, while Aß42 (P < 0.001, OR = 0.989, 95%CI 0.986~0.993), CSF PGRN (P = 0.002, OR = 0.999, 95%CI 0.999~1.000), Aß42/ t-Tau (P < 0.001, OR = 0.181, 95%CI 0.102~0.319) and Aß42/p-Tau (P < 0.001, OR = 0.617, 95%CI 0.526~0.725) were inversely proportional to the occurrence of POD. ROC curve analysis indicated that Aß42/t-Tau (AUC = 0.823), CSF Aß42 (AUC = 0.813), Aß42/p-Tau (AUC = 0.810), α-syn (AUC = 0.644) and PGRN (AUC = 0.638) could predict the occurrence rate of POD. The combination of all these biomarkers showed a greater AUC(0.896) than using any of them alone. CONCLUSIONS: CSF Aß42, PGRN, α-syn, Aß42/t-Tau and Aß42/p-Tau might be associated with the occurrence rate of POD in patients undergoing knee/hip arthroplasty. TRIAL REGISTRATION: Clinical Registration No. ChiCTR2000033439.

Subjective cognitive decline may mediate the occurrence of postoperative delirium by P-tau undergoing total hip replacement: The PNDABLE study.

Objective: We again investigated the relationship between subjective cognitive decline (SCD) and postoperative delirium (POD) with a larger sample queue. We also determined whether SCD could cause the occurrence of POD through cerebrospinal fluid (CSF) biomarkers. Methods: A prospective, observational cohort study was implemented in the Qingdao Municipal Hospital Affiliated with Qingdao University. This study recruited 1,471 qualified patients affiliated with the Perioperative Neurocognitive Disorder And Biomarker Lifestyle (PNDABLE) study scheduled for total hip replacement under combined spinal and epidural anesthesia from June 2020 to May 2022. The Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) were used to assess the cognitive level of the patients the day before surgery. Pittsburgh sleeps quality index (PSQI) scale was used to assess sleep status. Patients were divided into the SCD group and the non-SCD (NSCD) group based on the Subjective Cognitive Decline Scale (SCDS). CSF was collected after a successful spinal-epidural combined puncture, and amyloid-ß40 (Aß40), amyloid-ß42 (Aß42), total tau (T-tau), and phosphorylated tau (P-Tau) in CSF were analyzed by enzyme-linked immunosorbent assays. After the surgery, the incidence of POD was determined by the Confusion Assessment Scale (CAM), and Memorial Delirium Assessment Scale (MDAS) score was used to determine the severity of POD. Logistic regression and sensitivity analyses were performed to determine the relationship between CSF biomarkers, SCD, and POD. The mediating effect was used to analyze the function of specific CSF biomarkers in the relationship between SCD and POD. The risk factors of SCD were also separately verified by logistic regression and sensitivity analysis models. Results: The total incidence rate of POD was 19.60% (n = 225/1148), which was 29.3% (n = 120/409) in the SCD group and 14.2% (n = 105/739) in the NSCD group. We comprehensively considered the effect of covariates such as age, hypertension, and diabetes. Multivariate logistic regression analysis showed that SCD (OR = 1.467, 95%CI: 1.015-2.120, p = 0.042) and P-tau (OR = 1.046, 95%CI: 1.028-1.063, p < 0.001) were risk factors for POD. The sensitivity analysis results were consistent with the above results. Mediation analysis showed that the relationship between SCD and POD was partially mediated by P-tau, which accounted for 31.25% (P-tau, IE = 4.279 × 10-2, p < 0.001). For SCD, the results of logistic regression analysis models showed that age (OR = 1.035, 95% CI: 1.020-1.049, p < 0.001), higher preoperative PSQI score (OR = 1.047, 95%CI: 1.014-1.080, p = 0.005), and P-tau (OR = 1.015, 95%CI: 1.002-1.028, p = 0.021) were risk factors for SCD, and subsequent sensitivity analysis confirmed this result after adjustment for ASA grade, height, and weight. Conclusion: Patients with SCD are more likely to develop POD undergoing total hip replacement, and SCD can mediate the occurrence of POD via P-tau. Clinical trial registration: This study was registered at China Clinical Trial Registry (Chictr2000033439).

Potential value of cerebrospinal fluid α-synuclein in the identification of postoperative delirium undergoing knee/hip arthroplasty: The perioperative neurocognitive disorder and biomarker lifestyle study.

Objective: Postoperative delirium (POD) is a common postoperative complication, which may be associated with α-synuclein (α-syn). The purpose of this study was to explore the association between the expression level of α-syn in cerebrospinal fluid (CSF) and POD. Methods: We conducted a prospective observational cohort study, which involved in 740 participants (mean age of 61.86 years, range 40-90 years; 40% female) from the Perioperative Neurocognitive Disorder And Biomarker Lifestyle (PNDABLE) study in the final analysis. POD was diagnosed using the Confusion Assessment Scale (CAM), and its severity was measured using the Memorial Delirium Assessment Scale (MDAS). Enzyme-linked immune-sorbent assay (ELISA) was used to detect the concentrations of α-syn, Aß40, Aß42, T-tau, and P-tau in CSF. Results: The incidence of POD was 11.22% (83/740). The logistic regression analysis showed that the increased concentrations of CSF α-syn (OR = 1.005, 95%CI 1.004-1.006, P < 0.001), P-tau (OR = 1.093, 95%CI 1.071-1.115, P < 0.001), and T-tau (OR = 1.008, 95%CI 1.006-1.009, P < 0.001) were risk factors of POD. Linear regression showed that CSF α-syn had positive correlations with P-tau (ß = 0.480, P < 0.001), T-tau (ß = 0.334, P < 0.001), while negative correlations with Aß40 (ß = -0.378 P < 0.001), Aß42 (ß = -0.800, P = 0.001) in POD patients. Mediation analyses showed the association between α-syn and POD was partially mediated by tau pathologies (proportion: 16-17%). Conclusion: CSF α-syn is one of the preoperative risk factors for POD, which may be mediated through tau pathologies. Clinical trial registration: [www.ClinicalTrials.gov], identifier [ChiCTR20 00033439].

The relationship between mild cognitive impairment and postoperative delirium undergoing total knee arthroplasty: The PNDABLE study.

Background: Patients undergoing surgery are at a higher risk of developing postoperative delirium (POD) as a result of anesthesia and surgical procedures. This study examined the association between POD and mild cognitive impairment (MCI) and whether MCI influences POD through the core pathology of POD. Methods: We enrolled Chinese Han patients undergoing unilateral total knee arthroplasty (aged 50-90, weighing 50-80 kg, and using ASAI-II), combined with epidural anesthesia between October 2020 and June 2021. All the participants were assessed using Winblad's criteria for diagnosing MCI on pre-operation and using the Confusion Assessment Method (CAM) and the Memorial Delirium Assessment Scale (MDAS) postoperative 1-7 days (or before discharge) for diagnosing POD by an anesthesiologist. Cerebrospinal fluid (CSF) biomarkers of POD were measured by enzyme-linked immunosorbent assay (ELISA). To examine the mechanism by which POD pathologies affect cognition, causal mediation analyses were performed. Results: POD incidence was 20.2%, including 32.5% in the MCI group and 12.4% in the non-mild cognitive impairment (NMCI) group. The MCI and CSF levels of T-tau and P-tau were risk factors, and the CSF levels of Aß42, Aß42/ T-tau, and Aß42/ P-tau were protective factors in POD (p < 0.05). Part of the effects of MCI on cognition can be attributed to amyloid pathology and tau. Conclusion: MCI may be a reasonably good prognostic factor in POD development. Overall, amyloid pathology and tau protein might partially mediate the influence of MCI on POD. Clinical trial registration: www.clinicaltrials.gov, identifier: ChiCTR2000033439.

Potential value of preoperative fasting blood glucose levels in the identification of postoperative delirium in non-diabetic older patients undergoing total hip replacement: The perioperative neurocognitive disorder and biomarker lifestyle study.

Background: Postoperative delirium (POD) is a common complication after total hip replacement. This study aims to explore the relationship between preoperative fasting blood glucose (FBG) levels and POD in non-diabetic older patients undergoing total hip replacement. Materials and methods: This study included a total of 625 patients undergoing elective total hip replacement under combined spinal and epidural anesthesia from the PNDABLE study. The relationship between POD and preoperative FBG was analyzed by using the logistic regression model. The associations of FBG with individual cerebrospinal fluid (CSF) biomarkers were detected by using the multivariable linear regression model controlling for age, gender, and education level. The mediation effects were explored by mediation analyses with 5,000 bootstrap iterations, while sensitivity analysis was used to test the reliability and stability of the results. The receiver operating characteristic (ROC) curve and the nomogram model were applied to evaluate the efficacy of FBG and POD-related CSF biomarkers in predicting POD. POD assessment was performed two times daily by a trained anesthesiologist at 9:00-10:00 am and 2:00-3:00 pm on postoperative days 1-7 or before the patients were discharged from the hospital. POD was defined by the Confusion Assessment Method (CAM), and POD severity was measured using the Memorial Delirium Assessment Scale (MDAS). Enzyme-linked immunosorbent assay (ELISA) was used to measure CSF Aß40, Aß42, T-tau, and P-tau levels. Results: POD was detected in 10.2% (60/588) of the patients. Logistic regression analysis showed that after adjusting for age and education level, the increased levels of FBG (OR 1.427, 95% CI 1.117-1.824, P = 0.004), CSF P-tau (OR 1.039, 95% CI 1.019-1.060, P < 0.001), and CSF T-tau (OR 1.013, 95% CI 1.009-1.018, P < 0.001) were risk factors for POD, and the increased level of CSF Aß42 (OR 0.996, 95% CI 0.994-0.998, P = 0.001) was a protective factor for POD. Multivariable linear regression models showed that when adjusting for age, gender, and education level, in the POD group, higher preoperative FBG levels were negatively correlated with the CSF Aß42 level (ß = -0.290, P = 0.028) and positively correlated with CSF P-tau (ß = 0.384, P = 0.004) and T-tau (ß = 0.447, P < 0.001). In the non-POD group, a higher preoperative FBG was not related to CSF biomarkers. Mediated effect analysis showed that CSF T-tau (proportion = 17.1%) had an apparent mediation effect on the relationship between FBG and POD. Sensitivity analysis revealed that the results from the logistic regression and multivariable linear regression models were consistent with previous results. Conclusion: Increased preoperative FBG was a risk factor for POD in older patients without T2DM, and T-tau might mediate the relationship between FBG and POD.

Potential Value of Serum Uric Acid in the Identification of Postoperative Delirium in Geriatric Patients Undergoing Knee Replacement.

Objectives: The relationship between preoperative serum uric acid (SUA) and cerebrospinal fluid (CSF) Alzheimer-related biomarkers were investigated to determine whether high SUA is a potential risk factor for postoperative delirium (POD) and to evaluate its predictive efficacy. Methods: The participants were selected from the Perioperative Neurocognitive Disorder Risk Factor and Prognosis (PNDRFAP) study and the Perioperative Neurocognitive Disorder and Biomarker Lifestyle (PNDABLE) study. The logistic regression equation was used to analyze the risk factors and protective factors of POD. The interaction term (SUA × Sex) was introduced into the linear model to explore the potential modification effects of sex on the identified correlations. We analyzed the mediating effects of Alzheimer-related biomarkers. Finally, we constructed the receiver operating characteristic (ROC) curve and the nomogram model to evaluate the efficacy of SUA and Alzheimer-related biomarkers in predicting POD. Results: Patients with POD had elevated SUA level (PNDRFAP: p = 0.002, PNDABLE: p < 0.001). Preoperative SUA level was positively correlated with CSF phosphorylated tau (P-tau) (p = 0.027) and ß-amyloid42 (Aß42)/P-tau (p = 0.023). Interaction analysis did not find any modification effect of sex. The relationship between SUA and POD was partially mediated by CSF P-tau (15.3%). ROC curve showed that the model combining SUA and Alzheimer-related biomarkers had better performance in predicting POD [area under the curve (AUC) = 0.880; p < 0.001], and the predictive model is accurate. Conclusions: High SUA may enhance CSF P-tau level, thus increasing the risk of POD, and the model combining SUA and Alzheimer-related biomarkers can accurately predict the occurrence of POD.

The effect of neostigmine on postoperative delirium after colon carcinoma surgery: a randomized, double-blind, controlled trial.

BACKGROUND: Postoperative delirium (POD) is a critical complication in patients accepting colon carcinoma surgery. Neostigmine, as a cholinesterase inhibitor, can enhance the transmission of cholinergic transmitters in synaptic space, and play an important role in maintaining the normal level of cognition, attention and consciousness. The objective of this study was to investigate the effect of neostigmine on POD and clinical prognosis. METHODS: A randomized, double-blind controlled trial was implemented in Qingdao Municipal Hospital Affiliated to Qingdao University. A total of 454 patients aged 40 to 90 years old accepted colon carcinoma surgery were enrolled between June 7, 2020, and June 7, 2021, with final follow-up on December 8, 2021. Patients were randomly assigned to two groups: the neostigmine group (group N) and the placebo group (group P), the patients in group N were injected with 0.04 mg/kg neostigmine and 0.02 mg/kg atropine intravenously. The primary endpoint was the incidence of POD, researchers evaluated the occurrence of POD by the Confusion Assessment Method (CAM) twice daily (at 10 a.m. and 2 p.m.) during the first 7 postoperative days, POD severity was assessed by the Memorial Delirium Assessment Scale (MDAS). The secondary endpoints were the extubating time, postanesthesia care unit (PACU) time, the incidence of various postoperative complications, length of hospital stays, and 6 months postoperative mortality. RESULTS: The incidence of POD was 20.20% (81/401), including 19.39% (38/196) in group N and 20.98% (43/205) in group P. There was no significant statistical significance in the incidence of POD between group N and group P (P > 0.05); Compared to group P, the extubating time and PACU time in group N were significantly reduced (P < 0.001), the incidence of postoperative pulmonary complications (POPCs) decreased significantly in group N (P < 0.05), while no significant differences were observed in postoperative hospital stay and mortality in 6 months between the two groups (P > 0.05). CONCLUSION: For patients accepted colon carcinoma surgery, neostigmine did not significantly reduce the incidence of POD, postoperative mortality and postoperative hospital stay, while it indeed reduced the extubating time, PACU time and the incidence of POPCs. TRIAL REGISTRATION: The randomized, double-blind, controlled trial was registered retrospectively at www.chictr.org.cn on 07/06/2020 (ChiCTR2000033639).

The Relationship Between Cardiovascular Disease Risk Score and Postoperative Delirium: The PNDABLE Study.

Objective: We aimed to investigate the relationship between Framingham Heart Study general cardiovascular disease risk score (FHS-CVD risk score) and postoperative delirium (POD) among patients who had unilateral total knee arthroplasty performed under epidural anesthesia. Furthermore, we examined whether such a hypothesized relationship was mediated by the cerebrospinal fluid (CSF) biomarkers. Methods: A total of 750 participants were included in the current study. And the data were drawn from the database obtained from the Perioperative Neurocognitive Disorder And Biomarker Lifestyle (PNDABLE) study. The preoperative cognitive function of participants was measured by using Mini-Mental State Examination (MMSE). The incidence of POD was assessed using the Confusion Assessment Method (CAM). The POD severity was measured using the Memorial Delirium Assessment Scale (MDAS). The POD CSF biomarkers included in the current study were: Aß42, T-tau, P-tau, Aß42/T-tau, and Aß42/P-tau. The level of the CSF biomarkers was measured using the enzyme-linked immune-sorbent assay (ELISA) in the PNDABLE study. Linear regression analysis was performed to examine the relationship between the FHS-CVD risk score and the POD CSF biomarkers. Logistic regression was used to analyze the relationship between FHS-CVD risk score, POD CSF biomarkers, and POD incidence. The proposed mediating effect of CSF biomarkers was evaluated using Mediation Analysis with 10,000 bootstrapped iterations. The receiver operating characteristic (ROC) curve is chosen as the evaluation metric for assessing the efficacy of the FHS-CVD risk score in predicting POD. Results: In the PNDABLE study, the overall incidence of POD was 22.9% with 37.2% in the higher vascular risk group and 7.9% in the lower vascular risk group. Multiple linear regression models showed that a higher preoperative FHS-CVD risk score was positively correlated with CSF T-tau (ß = 0.218, P = 0.015) and P-tau level (ß = 0.309, P < 0.001) in the higher vascular risk group. After adjusting for age (40-90 years), gender, education, MMSE, smoking history, drinking history, hypertension, diabetes, and the presence of CHD (cardiovascular heart disease), the results of the logistic regression analysis demonstrated the effect of Aß42 (OR = 0.994, 95% CI 0.992-0.996, P < 0.001), Aß42/T-tau (OR = 0.353, 95% CI 0.254-0.491, P < 0.001), and Aß42/P-tau (OR = 0.744, 95% CI 0.684-0.809, P < 0.001) in protecting patients against POD. However, the FHS-CVD risk score (OR = 1.142, 95% CI 1.017-1.282, P = 0.025) and the remaining two biomarkers: T-tau (OR = 1.005, 95% CI 1.004-1.007, P < 0.001) and P-tau (OR = 1.045, 95%CI 1.029-1.062, P < 0.001) were identified as the risk factors. Mediation analyses revealed that the association between FHS-CVD risk score and POD was partially mediated by T-tau (proportion: 31.6%) and P-tau (proportion: 23.6%). The predictive power of the FHS-CVD risk score was validated by the ROC curve with an AUC of 0.7364. Conclusion: Higher vascular risk score is one of the preoperative risk factors for POD, which is partly mediated by CSF biomarker tau protein. Clinical Trial Registration: [www.clinicaltrials.gov], identifier [ChiCTR2000033439].

Application of the Amyloid/Tau/Neurodegeneration Framework in Cognitively Intact Adults: The CABLE Study.

OBJECTIVES: The amyloid/tau/neurodegeneration (AT[N]) framework has conceptualized the Alzheimer's disease (AD) continuum as a continuum of disease with evidence of amyloid-related pathologies independent of clinical manifestation. Based on this framework, it is necessary to reveal the distribution and risk factors of AD continuum in the cognitively intact population among different cohorts and races, including the northern Chinese Han population. METHODS: This study classified cognitively intact Chinese Alzheimer's Biomarker and LifestylE (CABLE) participants through the AT(N) scheme. Gaussian mixture models were used to identify the cutoff values of cerebrospinal fluid biomarkers, which distinguished AD continuum ( A + T-N-, A + T + N-, A + T-N + and A + T + N +) from 1,005 participants (mean age 61 years; 40% female). Multivariable logistic regressions and Cochran-Armitage trend tests were used to test neuropsychological performance and risk factors for AD continuum. RESULTS: Approximately one-third of individuals (33.7%) belonged to the AD continuum. Four potential modifiable risk factors, including hypertension, thyroid diseases, social isolation, and minimal depression symptoms, were identified for the AD continuum (OR ranging 1.68-6.90). A trend toward higher prevalence of the AD continuum was associated with a larger number of risk factors (p for trend <0.0001). The risk of AD continuum increased by approximately twofold for each additional modifiable risk factor (OR 1.9, 95% CI 1.65-2.24, p < 0.0001). INTERPRETATION: This study revealed the distribution and potential risk factors of the AD continuum in a cognitively intact Han population in northern China, which filled the gap in the area about the performance of the AT(N) framework in the Asian population. ANN NEUROL 2022;92:439-450.

The Relationship Between Suboptimal Social Networks and Postoperative Delirium: The PNDABLE Study.

Background: Although it has been proven that social networks are related to cognition, studies are conducted to characterize the correlation between social networks and postoperative delirium (POD). Objective: We investigated whether suboptimal social networks are a risk factor for POD, and to verify whether different levels of intimacy in the same social relationship can affect the concentration of cerebrospinal fluid (CSF) biomarkers, such as amyloid-ß (Aß42), total tau (T-tau), and phosphorylated tau (P-tau), and the mediating role of CSF biomarkers between social network and POD in middle-aged and elderly Han people. Methods: Our study recruited 743 participants from The Perioperative Neurocognitive Disorder and Biomarker Lifestyle (PNDABLE) study. Confusion Assessment Method (CAM) was used to evaluate the incidence of POD and its severity was measured using the Memorial Delirium Assessment Scale (MDAS). The social networks were measured using self-reported questionnaires about social ties. Mann-Whitney U test, Logistic Regression and Independent-samples test were used for Statistical Analysis. Results: The incidence of POD was 20.7%. Mann-Whitney U test showed that the total score of the social network was associated with POD (P < 0.001). Independent-samples test showed that different levels of intimacy in the same social relationship were significantly associated with CSF POD biomarkers, and mediation analyses revealed that the association between suboptimal social networks and POD was partially mediated by T-tau (proportion: 20%), P-tau (proportion: 33%), Aß42/T-tau (proportion: 14%), and Aß42/P-tau (proportion: 15%). Conclusion: Having suboptimal social networks is a risk factor for POD in middle-aged and elderly Han people. CSF POD biomarkers can mediate the correlation between suboptimal social networks and POD, which is mainly mediated by tau protein. Clinical Trial Registration: www.chictr.org.cn, identifier ChiCTR2000033439.

Association between Life's Simple 7 and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact adults: the CABLE study.

INTRODUCTION: This study sought to explore the association between Life's Simple 7 (LS7) and cerebrospinal fluid (CSF) Alzheimer's disease (AD) pathological biomarkers in the cognitively normal northern Chinese population. METHODS: From the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study, 1106 cognitively normal participants were enrolled. The mean age was 62.34 years, and 39.6% were female. LS7 scores were summed with each metric assigned 0, 1, or 2 scores. The multiple linear regression models were used to investigate the association between LS7 scores and CSF AD biomarkers. RESULTS: We found that LS7 scores were significantly associated with CSF AD pathologies, including Aß42/40 (ß = 0.034, P = .041), p-tau181 (ß = - 0.043, P = .006), and t-tau (ß = - 0.044, P = .003). In subscales, the biological metrics (blood pressure, cholesterol, glucose) were significantly related to CSF tau-related biomarkers. These associations were observed in the APOE ε4 allele non-carriers, yet not in carriers. The relationship of behavior metrics was found in the middle age and males. CONCLUSION: Improving LS7 scores might do a favor to alleviate the pathology of AD in the preclinical stage, especially among the APOE ε4 allele non-carriers.

Habitual tea consumption and postoperative delirium after total hip/knee arthroplasty in elderly patients: The PNDABLE study.

PURPOSE: To clarify the effects of habitual tea consumption on postoperative delirium (POD) in elderly patients undergoing total hip/knee arthroplasty. PATIENTS AND METHODS: A prospective cohort study was carried out at Qingdao Municipal Hospital Affiliated to Qingdao University between June 2020 and June 2021. A total of 332 patients aged 65-85 years undergoing total hip/knee arthroplasty under combined spinal and epidural anesthesia were enrolled from the Perioperative Neurocognitive Disorder and Biomarker Lifestyle (PNDABLE) study in the final analysis, consisting of 168 patients with habitual tea consumption and 164 patients with infrequent tea consumption. The primary endpoint was the effects of habitual tea consumption on POD and the incidence of POD, which was assessed by the Confusion Assessment Method (CAM) twice daily during the first 7 postoperative days, and POD severity was measured by the Memorial Delirium Assessment Scale (MDAS). The secondary endpoints were the concentrations of caffeine and tea polyphenols in plasma and cerebrospinal fluid (CSF), which were detected by the enzyme-linked immunosorbent assay. RESULTS: POD occurred in 61 of 332 patients (18.37%), among whom 19 had habitual tea consumption (5.72%) and 42 had infrequent tea consumption (12.65%). Habitual tea consumption (odds ratio [OR] = 0.370, 95% confidence interval [CI]: 0.205-0.670, P = .001) was significantly associated with POD in the logistic analysis, and then after adjusting for age and American Society of Anesthesiologists (ASA) physical status (OR = 0.353, 95% CI: 0.190-0.655, P = .001). Furthermore, caffeine in T0 plasma (OR = 0.834, 95% CI: 0.752-0.924, P = .001), T1 plasma (OR = 0.818, 95% CI: 0.738-0.908, P < .001), and CSF (OR = 0.899, 95% CI: 0.820-0.984, P = .022) and tea polyphenols in T0 plasma (OR = 0.541, 95% CI: 0.416-0.704, P < .001), T1 plasma (OR = 0.477, 95% CI: 0.359-0.633, P < .001), and CSF (OR = 0.526, 95% CI: 0.397-0.696, P < .001) were associated with POD after adjusting for age and ASA physical status. CONCLUSION: Habitual tea consumption may be associated with a lower incidence of POD in elderly patients.