The link between the early surgery-induced inflammatory response and postoperative cognitive dysfunction in older patients.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common complication in older patients with cancer and is associated with decreased quality of life and increased disability and mortality rates. Systemic inflammation resulting in neuroinflammation is considered important in the pathogenesis of POCD. The aim of this study was to explore the association between the early surgery-induced inflammatory response and POCD within 3 months after surgery in older cancer patients. METHODS: Patients ≥65 years in need of surgery for a solid tumor were included in a prospective cohort study. Plasma levels of C-reactive protein (CRP), interleukin-1 beta (IL-1ß), IL-6, IL-10, and Neutrophil gelatinase-associated lipocalin (NGAL) were measured perioperatively. Cognitive performance was assessed preoperatively and 3 months after surgery. POCD was defined as a decline in cognitive test scores of ≥25% on ≥2 of five tests within the different cognitive domains of memory, executive functioning, and information processing speed. Logistic regression analysis was performed. RESULTS: POCD was observed in 44 (17.7%) of 248 included patients. Age >75, preoperative Mini-Mental State Examination (MMSE) score ≤26 and major surgery were independent significant predictors for POCD. In multivariate logistic regression analysis, no significant associations were shown between the early surgery-induced inflammatory response and either POCD or decline within the different cognitive domains. CONCLUSIONS: This study shows that one out of six older patients with cancer developed POCD within 3 months after surgery. The early surgery-induced inflammatory response was neither associated with POCD, nor with decline in the separate cognitive domains. Further research is necessary for better understanding of the complex etiology of POCD.

Effect of Dexmedetomidine on The Neuroglobin Expression in Elderly Patients With Minimally Invasive Coronary Artery Bypass Graft Surgery.

BACKGROUND: To study the effect of dexmedetomidine (Dex) on the expression of Neuroglobin (Ngb) and postoperative cognitive function in elderly patients undergoing minimally invasive coronary artery bypass surgery. METHODS: Forty patients, who underwent elective minimally invasive off-pump coronary artery bypass grafting in our hospital from January 2018 to December 2019, were randomly divided into the Dex group (N = 20) and control group (N = 20). Venous blood samples were taken to determine the expression level of Ngb in both groups. Mini mental status examination (MMSE) was used to detect the cognitive function of patients. RESULTS: The expression level of Ngb in the Dex group was significantly higher than that in the control group at 6h after one-lung ventilation and postoperative 24h (P < .01). The MMSE score of the Dex group was significantly higher than the control group at postoperative 7 days and postoperative 30 days (P < .01). Although with no statistical significance, the MMSE score of the Dex group was higher than the control group at postoperative 90 days (P > .05). The incidence of postoperative cognitive dysfunction (POCD) in the Dex group was significantly lower than that in the control group at postoperative 7 days and postoperative 30 days (P < .05). CONCLUSION: Dex used in elderly patients undergoing minimally invasive coronary artery bypass graft surgery can effectively increase the expression level of Ngb and reduce the incidence of POCD.

Intravenous versus Volatile Anesthetic Effects on Postoperative Cognition in Elderly Patients Undergoing Laparoscopic Abdominal Surgery.

BACKGROUND: Delayed neurocognitive recovery after surgery is associated with poor outcome. Most surgeries require general anesthesia, of which sevoflurane and propofol are the most commonly used inhalational and intravenous anesthetics. The authors tested the primary hypothesis that patients with laparoscopic abdominal surgery under propofol-based anesthesia have a lower incidence of delayed neurocognitive recovery than patients under sevoflurane-based anesthesia. A second hypothesis is that there were blood biomarkers for predicting delayed neurocognitive recovery to occur. METHODS: A randomized, double-blind, parallel, controlled study was performed at four hospitals in China. Elderly patients (60 yr and older) undergoing laparoscopic abdominal surgery that was likely longer than 2 h were randomized to a propofol- or sevoflurane-based regimen to maintain general anesthesia. A minimum of 221 patients was planned for each group to detect a one-third decrease in delayed neurocognitive recovery incidence in propofol group compared with sevoflurane group. The primary outcome was delayed neurocognitive recovery incidence 5 to 7 days after surgery. RESULTS: A total of 544 patients were enrolled, with 272 patients in each group. Of these patients, 226 in the propofol group and 221 in the sevoflurane group completed the needed neuropsychological tests for diagnosing delayed neurocognitive recovery, and 46 (20.8%) in the sevoflurane group and 38 (16.8%) in the propofol group met the criteria for delayed neurocognitive recovery (odds ratio, 0.77; 95% CI, 0.48 to 1.24; P = 0.279). A high blood interleukin-6 concentration at 1 h after skin incision was associated with an increased likelihood of delayed neurocognitive recovery (odds ratio, 1.04; 95% CI, 1.01 to 1.07; P = 0.007). Adverse event incidences were similar in both groups. CONCLUSIONS: Anesthetic choice between propofol and sevoflurane did not appear to affect the incidence of delayed neurocognitive recovery 5 to 7 days after laparoscopic abdominal surgery. A high blood interleukin-6 concentration after surgical incision may be an independent risk factor for delayed neurocognitive recovery.

S100B protein and neuron-specific enolase as predictors of postoperative cognitive dysfunction in aged dogs: a case-control study.

OBJECTIVE: Postoperative cognitive dysfunction (POCD) may be related to brain injury. S100B protein and neuron-specific enolase (NSE) have been investigated as potential biochemical markers of neural cell injury in animals and humans. This study aimed to investigate the association between POCD, brain injury and serum concentrations of S100B and NSE after periodontal surgery in aged dogs. STUDY DESIGN: Prospective observational animal study. ANIMALS: A total of 24 male and female dogs undergoing periodontal surgery. METHODS: Dogs were separated into two groups based on age: control group, 10 dogs ≤ 8 years and aged group, 14 dogs > 8 years. Cognitive function was measured preoperatively and on the seventh postoperative day using the Canine Cognitive Dysfunction Rating scale and the Age-Related Cognitive and Affective Disorders scale. S100B protein and NSE serum concentrations were measured before and immediately after the surgery. RESULTS: POCD was not observed after surgery in the present study. Serum concentrations of S100B and NSE were increased postoperatively in the control group but not in the aged group (p = 0.04 and 0.03, respectively). Preoperative S100B serum concentrations were significantly higher in the aged group (p = 0.01). CONCLUSIONS: There was no association between POCD and high concentrations of S100B and NSE in dogs. However, increased postoperative serum concentrations of S100B and NSE were found in the control group after surgery, an effect that may indicate neural damage. CLINICAL RELEVANCE: The results suggest that anesthesia and oral surgery are associated with higher postoperative serum concentrations of S100B and NSE in dogs ≤ 8 years old, which may indicate neural damage. Serum concentrations of S100B were elevated in aged dogs before anesthesia, a finding that might be related to chronic preoperative brain damage.

Hippocampal complement C3 might contribute to cognitive impairment induced by anesthesia and surgery.

Postoperative cognitive dysfunction is a well-recognized complication after major surgery in the elderly, but its pathophysiological mechanism is not fully understood. In the present study, we used liquid chromatography-tandem mass spectrometry combined with tandem mass tags to identify differentially expressed proteins and perform further functional studies on protein of interest. Here, we showed that hippocampal complement C3 was significantly upregulated after surgery, which was accompanied by marked decreases in synaptic related proteins and density. In aged patients undergoing gastrointestinal surgery, we also found significantly increased plasma level of C3b postoperatively and were negatively associated with cognitive performance. Notably, selective inhibition of complement C3 by compstatin was able to rescue synaptic and cognitive impairments induced by surgery in aged mice. Collectively, our study confirms that surgery can induce cognitive impairments, and the possible mechanisms might be related to abnormal complement signaling and synaptic disruption.

Serum Metabolomics of Early Postoperative Cognitive Dysfunction in Elderly Patients Using Liquid Chromatography and Q-TOF Mass Spectrometry.

Postoperative cognitive dysfunction (POCD) is a common postoperative complication observed in elderly patients. However, the diagnosis of POCD is not very satisfactory as no specific biomarkers have been classified. It is necessary to identify new diagnostic markers to better understand the pathogenesis of POCD. We performed liquid chromatography with a time-of-flight mass spectrometer- (LC/Q-TOF-MS-) based metabolomics study to investigate POCD. A total of 40 metabolites were differentially expressed between POCD and non-POCD patients. In this study, we investigated whether phosphatidylserine (PS) (17:2/0:0), with an area under the curve value of 0.966, was a potential sensitive and specific biomarker for the diagnosis and prognosis of POCD. Pathway analysis showed that fatty acid metabolism, lipid metabolism, and carnitine metabolism were significantly altered in POCD. Network analysis indicated that nitric oxide signaling, PI3K-AKT signaling, mTOR signaling, and mitochondrial dysfunction were related to the pathogenesis of POCD. This study showed that metabolic profiling was meaningful when studying the diagnosis and pathogenesis of POCD.

Neuroinflammatory markers associate with cognitive decline after major surgery: Findings of an explorative study.

OBJECTIVE: Long-term cognitive decline is an adverse outcome after major surgery associated with increased risk for mortality and morbidity. We studied the cerebrospinal fluid (CSF) and serum biochemical inflammatory response to a standardized orthopedic surgical procedure and the possible association with long-term changes in cognitive function. We hypothesized that the CSF inflammatory response pattern after surgery would differ in patients having long-term cognitive decline defined as a composite cognitive z score of ≥1.0 compared to patients without long-term cognitive decline at 3 months postsurgery. METHODS: Serum and CSF biomarkers of inflammation and blood-brain barrier (BBB) integrity were measured preoperatively and up to 48 hours postoperatively, and cognitive function was assessed preoperatively and at 2 to 5 days and 3 months postoperatively. RESULTS: Surgery was associated with a pronounced increase in inflammatory biomarkers in both CSF and blood throughout the 48-hour study period. A principal component (PC) analysis was performed on 52 inflammatory biomarkers. The 2 first PC (PC1 and PC2) construct outcome variables on CSF biomarkers were significantly associated with long-term cognitive decline at 3 months, but none of the PC construct serum variables showed a significant association with long-term cognitive decline at 3 months. Patients both with and patients without long-term cognitive decline showed early transient increases of the astroglial biomarkers S-100B and glial fibrillary acidic protein in CSF, and in BBB permeability (CSF/serum albumin ratio). INTERPRETATION: Surgery rapidly triggers a temporal neuroinflammatory response closely associated with long-term cognitive outcome postsurgery. The findings of this explorative study require validation in a larger surgical patient cohort. Ann Neurol 2020;87:370-382.

Malondialdehyde on postoperative day 1 predicts postoperative cognitive dysfunction in elderly patients after hip fracture surgery.

Background: Postoperative cognitive dysfunction (POCD) is a great problem for anesthetized subjects and is associated with poor short- and long-term outcomes. We explored promising predictors for POCD in elderly patients after hip fracture surgery.Methods: Elderly subjects (aged ≥65 years) undergoing surgery for hip fracture were consecutively recruited. Neuropsychological assessments were performed 1 day preoperatively (baseline) and 7 days postoperatively, and POCD was defined using the 'Z scores' method. Clinical data and laboratory tests were compared between patients with and without POCD development. Binary univariate and multivariate logistic regression analyses were conducted for risk factor assessment. Receiver operating characteristic (ROC) curve analysis was performed to investigate the predictive value of malondialdehyde (MDA) on postoperative day 1 (POD1) for POCD.Results: A total of 198 patients were finally enrolled in the analysis and 51 patients exhibited POCD within 7 postoperative days, with an incidence rate of 25.8%. MDA expression on POD1 (OR: 1.12, 95%CI: 1.03-1.23, P=0.017) was the only independent risk factor for POCD according to the final multivariate logistic regression analysis. ROC curve analysis indicated that MDA on POD1 was a predictor for POCD, with an area under the curve (AUC) of 0.683 and 95%CI of 0.590-0.775 (P<0.001).Conclusions: In conclusion, we demonstrated that MDA on POD1 was an independent risk factor for POCD in elderly subjects undergoing hip fracture surgery.

Serum Phosphorylated Neurofilament Heavy Subunit-H, a Potential Predictive Biomarker for Postoperative Cognitive Dysfunction in Elderly Subjects Undergoing Hip Joint Arthroplasty.

BACKGROUND: Postoperative cognitive dysfunction (POCD), which refers to a cognitive impairment subsequent to surgical procedures, is a common complication in the elderly subjects. This study aimed to investigate potential risk factors for POCD in elderly subjects undergoing hip joint arthroplasty. METHODS: Consecutive elderly osteoarthritis patients who were scheduled to undergo hip arthroplasty under epidural anesthesia were enrolled into this single-center, prospective observational study. Serum phosphorylated neurofilament heavy subunit-H (pNF-H) was measured by the enzyme-linked immunosorbent assay method. A level of >70.5 pg/mL was accepted as pNF-H positivity. Neuropsychological assessment at baseline (1 day before the surgery) and postoperative day 7 was conducted. POCD was defined according to the calculated Z scores. Risk factors for POCD were evaluated by univariate and multivariate logistic regression analyses. RESULTS: In final, 287 patients were enrolled, and 55 had suffered POCD within postoperative 7 days with an incidence of 19.2%. The final multiple logistic regression analysis revealed a higher pNF-H positivity was the only independent risk factor for POCD (odds ratio: 2.03, 95% confidence interval: 1.21-3.29, P = .012). CONCLUSIONS: Our results revealed an increased preoperative serum pNF-H expression was an independent risk factor for POCD development in elderly subjects undergoing hip joint arthroplasty, suggesting the close association between anatomical damage in central nervous system and POCD.

The presence of elevated circulating trimethylamine N-oxide exaggerates postoperative cognitive dysfunction in aged rats.

Surgical trauma can cause brain oxidative stress and neuroinflammation, leading to postoperative cognitive dysfunction (POCD), especially in the elderly. Additionally, the pre-existing risk factors may enhance POCD. Gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) has recently been shown to contribute to the pathogenesis of many diseases by increasing oxidative stress and inflammation in the peripheral tissues. Here we examined whether the presence of elevated circulating TMAO would influence surgery-induced cognitive decline. Aged rats were treated with vehicle or TMAO for 3 weeks. After two weeks of treatment, these rats underwent sham-operation or laparotomy. One week after surgery, rats underwent laparotomy exhibited hippocampal-dependent cognitive dysfunction as evidenced by reduced contextual freezing time, which was associated with elevated plasma proinflammatory cytokine levels, increased microglia-mediated neuroinflammation and reactive oxygen species (ROS) production in the hippocampus. Treatment with TMAO, which elevated plasma TMAO before and 1 week after surgery, further increased microglia-mediated neuroinflammation and ROS production in the hippocampus, resulting in exaggerated cognitive dysfunction in laparotomy group but not in sham-operation group. Moreover, TMAO treatment decreased expression of antioxidant enzyme methionine sulfoxide reductase (Msr) A in both groups. The results suggest that the presence of elevated circulating TMAO downregulates antioxidant enzyme MsrA in the hippocampus, which may increase the susceptibility to surgery-induced oxidative stress, contributing to exaggerations of neuroinflammation and cognitive decline in aged rats following surgery. Interventions to reduce circulating TMAO in the perioperative period may be a novel strategy to prevent the exaggeration of cognitive decline in elderly patients with high circulating TMAO.