The association between physical activity and delayed neurocognitive recovery in elderly patients: a mediation analysis of pro-inflammatory cytokines.

BACKGROUND: Delayed neurocognitive recovery (dNCR) can result in unfavorable outcomes in elderly surgical patients. Physical activity (PA) has been shown to improve cognitive function, potentially by reducing systemic inflammatory responses. However, there is a lack of supportive data indicating whether PA has a protective effect against dNCR. AIMS: To examine the correlation between dNCR and PA, and to further analyze if pro-inflammatory cytokines mediate this relationship. METHODS: This study is a prospective nested case-control investigation of elderly patients who had knee replacement surgery. dNCR was defined as a decline in cognitive function compared with baseline by using a battery of neuropsychological tests. PA was assessed with the Physical Activity Scale for the Elderly (PASE). Enzyme-linked immunosorbent assay (ELISA) was used to measure the serum concentrations of IL-6, IL-1ß, and TNF-α. Multivariable logistic regression analysis was conducted to assess the association between PA and dNCR. Mediation analysis was employed to evaluate whether pro-inflammatory cytokines mediate the relationship between them. RESULTS: A cohort of 152 patients was included, resulting in an incidence rate of dNCR of 23.68%. PA was associated with dNCR after full adjustment [OR = 0.199, (95% CI, 0.061; 0.649), P = 0.007]. Mediation analysis showed that the IL-6 mediated the statistical association between PA and dNCR, with mediation proportions (%) of 77.68 (postoperative concentration of IL-6) or 27.58 (the absolute change in IL-6 before and after surgery). CONCLUSIONS: PA serves as a protective factor against dNCR, possibly through the reduction of pro-inflammatory cytokine concentrations. THE CHINESE CLINICAL TRAIL REGISTRY: : www.http://chictr.org.cn , Registration No. ChiCTR2300070834, Registration date: April 24, 2023.

Cognitive impairment induced by sevoflurane anesthesia is mediated by the cholinergic system after gastrointestinal surgery in older patients: A randomized, controlled trial.

Delayed neurocognitive recovery after surgery is associated with increased morbidity and mortality. However, its mechanism of action remains controversial and complex. A prospective, double-blind, randomized controlled trial was performed at the Affiliated Hospital of Zunyi Medical University. Older patients (aged 65 years and older) who underwent gastrointestinal surgery were randomly divided into sevoflurane-based or propofol-based anesthesia groups. The Mini-Mental State Examination was performed to evaluate cognitive function. Peripheral venous blood was collected to test the levels of choline acetyltransferase and acetylcholinesterase. A total of 75 patients were enrolled and 30 patients in each group completed the study. On Day 1 postoperation, patients in the sevoflurane group showed worse performance on the Mini-Mental State Examination than patients in the propofol group. Lower blood choline acetyltransferase concentrations and higher acetylcholinesterase concentrations were observed in patients who had sevoflurane anesthesia than in patients who had propofol anesthesia 1 day postoperative. At 3 days postoperation, patients with sevoflurane- or propofol-based general anesthesia did not differ regardless of Mini-Mental State Examination score or choline acetyltransferase and acetylcholinesterase levels. Sevoflurane-based anesthesia has short-term delayed neurocognitive recovery in older surgical patients, which may be related to central cholinergic system degeneration.

Desflurane versus sevoflurane anesthesia and postoperative recovery in older adults undergoing minor- to moderate-risk noncardiac surgery - A prospective, randomized, observer-blinded, clinical trial.

STUDY OBJECTIVE: The effect of volatile anesthetics on postoperative recovery in older adults is still not entirely clear. Thus, we evaluated the effect of desflurane versus sevoflurane anesthesia on speed of postoperative recovery in older adults eligible for same-day discharge. We further evaluated the incidence of postoperative nausea and vomiting (PONV), bispectral index (BIS) values, and S100B concentrations. DESIGN: Single-center, prospective, observer-blinded, randomized clinical trial. SETTING: Operating room. PATIENTS: 190 patients ≥65 years of age and scheduled for minor- to moderate-risk noncardiac surgeries. INTERVENTIONS: Goal-directed administration of desflurane versus sevoflurane for maintenance of anesthesia with an intraoperative goal of BIS 50 ± 5. MEASUREMENTS: The primary outcome was the time to anesthesia recovery, which was defined as the time between arrival at the post-anesthesia care unit (PACU) and reaching criteria for discharge from PACU, based on modified Aldrete score ≥ 12 points. Modified Aldrete scores were assessed at PACU arrival and thereafter in five-minute intervals. PONV was evaluated during PACU stay and the first three postoperative days, BIS values were recorded during PACU stay, and S100B values were measured before and after surgery, and on the second postoperative day. MAIN RESULTS: 95 patients were randomized to receive desflurane, and 95 patients to receive sevoflurane. We did not observe a significant difference in median duration of postoperative recovery between the groups (desflurane: 0 min [0;0]; sevoflurane: 0 min [0;0]; p = 0.245). 77 patients (81.1%) in the desflurane group and 84 patients (88.4%) in the sevoflurane group already had Aldrete scores ≥12 points upon arrival at PACU (p = 0.277). There was also no significant difference in the incidences of PONV (p = 0.606), postoperative BIS values (p = 0.197), and postoperative maximum S100B concentrations (p = 0.821) between the groups. CONCLUSIONS: Despite previous reports, we did not observe significant faster recovery times after desflurane anesthesia. Both volatile anesthetics may be appropriate for same-day discharge in older adults.

Postoperative Delirium and Neurocognitive Disorders: Updates for Providers Caring for Cancer Patients.

PURPOSE OF REVIEW: To provide up to date information on postoperative delirium and neurocognitive disorders in surgical cancer patients. RECENT FINDINGS: Established risk factors such as age, psychosocial factors, comorbidities, frailty and preexisting cognitive decline continue to exhibit associations with perioperative neurocognitive disorders (PND); novel risk factors identified recently include microbiome composition and vitamin D deficiency. Prevention measures include cognitive prehabilitation, perioperative geriatric assessment and multidisciplinary care, dexmedetomidine and multimodal analgesic techniques. Studies investigating ciprofol, remimazolam, esketamine, ramelteon and suvorexant have shown encouraging results. Controversy remains regarding the use of inhalational versus intravenous general anesthesia. Innovative approaches to address PND are a rapidly developing area of research, but more studies are needed to identify effective prevention and management interventions. Despite challenges and controversy in the field, implementation of best practice can reduce the detrimental impact of PND on patients, caregivers, and society at large.

Establishment and validation of a risk prediction model for delayed neurocognitive recovery associated with cerebral oxygen saturation monitoring.

BACKGROUND: Delayed neurocognitive recovery (DNR) is a common complication in patients undergoing laparoscopic surgery, and there are currently no effective therapies. It is vital to provide a reliable basis for clinical prediction. This study tried to analyse the risk factors for DNR in patients undergoing laparoscopic colorectal surgery and to establish a risk prediction model. METHODS: A retrospective analysis of the clinical data and DNR status of patients undergoing laparoscopic colorectal surgery at Xiangya Hospital of Central South University from March 2018 to July 2020 was conducted. Logistic regression was performed to analyse the related risk factors for DNR post-operatively, and the predictive model of DNR post-operatively was constructed and validated internally. Patients who underwent laparoscopic colorectal surgery between January and July 2021 were also selected for external validation of the predictive model, to ultimately investigate the risk factors for DNR in patients undergoing laparoscopic colorectal surgery. RESULTS: The incidence of DNR in patients undergoing laparoscopic colorectal surgery was 15.2% (31/204). The maximum variability of cerebral oxygen, age, education, and pre-existing diabetes was related to the incidence of DNR (p < 0.05). The risk prediction model of DNR after laparoscopic colorectal surgery was established. The internal and external validation showed that the discrimination was good (the AUCs were 0.751 and 0.694, respectively). CONCLUSIONS: The risk prediction model of DNR related to cerebral oxygen saturation monitoring shows good predictive performance and clinical value, providing a basis for postoperative DNR prevention.

Effect of prophylactic corticosteroids on postoperative neurocognitive dysfunction in the adult population: An updated systematic review, meta-analysis, and trial sequential analysis of randomised controlled trials.

Background and Aims: Postoperative neurocognitive dysfunction (PNCD) commonly occurs after surgery and prolongs hospital stays. Both direct noxious stimuli to the central nervous system and systemic inflammation have been implicated. Due to their potent anti-inflammatory effects, corticosteroids have been utilised to attenuate the incidence and severity of PNCD. This systematic review and meta-analysis strived to evaluate the prophylactic role of perioperative corticosteroids for PNCD. Methods: A search was run in pre-defined databases for randomised controlled trials (RCTs) assessing the role of corticosteroids in preventing PNCD. The incidence of PNCD within 1 month was the primary outcome. Secondary outcomes included the use of antipsychotic medications for the treatment, postoperative infection, and hospital length of stay. The results are exhibited as odds ratio (OR) and the mean difference (MD) with 95% confidence interval (CI). Results: Fifteen RCTs comprising 15,398 patients were included. The incidence of PNCD was significantly lower in the corticosteroid group than in the control group, with a pooled OR of 0.75 (95% CI 0.58, 0.96; P = 0.02; I2 = 66%). Trial sequential analysis showed the clinical benefit of corticosteroids in preventing PNCD; however, the requisite information size is still inadequate. The sub-group analysis supported the prophylactic effect of corticosteroids on delirium prevention but not on delayed neurocognitive recovery. Conclusions: Our meta-analysis revealed statistically significant protective effects of corticosteroids on the incidence of PNCD. However, further studies are still needed to confirm the protective role of this commonly used and relatively safe strategy for preventing PNCD.

Preoperative ketamine administration for prevention of postoperative neurocognitive disorders after major orthopedic surgery in elderly patients: A multicenter randomized blinded placebo-controlled trial.

BACKGROUND: Preventive anesthetic impact on the high rates of postoperative neurocognitive disorders in elderly patients is debated. The Prevention of postOperative Cognitive dysfunction by Ketamine (POCK) study aimed to assess the effect of ketamine on this condition. METHODS: This is a multicenter, randomized, double-blind, interventional study. Patients ≥60 years undergoing major orthopedic surgery were randomly assigned in a 1:1 ratio to receive preoperative ketamine 0.5 mg/kg as an intravenous bolus (n = 152) or placebo (n = 149) in random blocks stratified according to the study site, preoperative cognitive status and age. The primary outcome was the proportion of objective delayed neurocognitive recovery (dNR) defined as a decline of one or more neuropsychological assessment standard deviations on postoperative day 7. Secondary outcomes included a three-month incidence of objective postoperative neurocognitive disorder (POND), as well as delirium, anxiety, and symptoms of depression seven days and three months after surgery. RESULTS: Among 301 patients included, 292 (97%) completed the trial. Objective dNR occurred in 50 (38.8%) patients in the ketamine group and 54 (40.9%) patients in the placebo group (OR [95% CI] 0.92 [0.56; 1.51], p = 0.73) on postoperative day 7. Incidence of objective POND three months after surgery did not differ significantly between the two groups nor did incidence of delirium, anxiety, apathy, and fatigue. Symptoms of depression were less frequent in the ketamine group three months after surgery (OR [95% CI] 0.34 [0.13-0.86]). CONCLUSIONS: A single preoperative bolus of intravenous ketamine does not prevent the occurrence of dNR or POND in elderly patients scheduled for major orthopedic surgery. (Clinicaltrials.gov NCT02892916).

A53T α-synuclein mutation increases susceptibility to postoperative delayed neurocognitive recovery via hippocampal Ang-(1-7)/MasR axis.

Delayed neurocognitive recovery (dNCR) is a common complication in geriatric surgical patients. The impact of anesthesia and surgery on patients with neurodegenerative diseases, such as Parkinson's disease (PD) or prion disease, has not yet been reported. In this study, we aimed to determine the association between a pre-existing A53T genetic background, which involves a PD-related point mutation, and the development of postoperative dNCR. We observed that partial hepatectomy induced hippocampus-dependent cognitive deficits in 5-month-old A53T transgenic mice, a model of early-stage PD without cognitive deficits, unlike in age-matched wild-type (WT) mice. We respectively examined molecular changes at 6 h, 1 day, and 2 days after partial hepatectomy and observed that cognitive changes were accompanied by weakened angiotensin-(1-7)/Mas receptor [Ang-(1-7)/MasR] axis, increased alpha-synuclein (α-syn) expression and phosphorylation, decreased methylated protein phosphatase-2A (Me-PP2A), and prompted microglia M1 polarization and neuronal apoptosis in the hippocampus at 1 day after surgery. Nevertheless, no changes in blood-brain barrier (BBB) integrity or plasma α-syn levels in either A53T or WT mice. Furthermore, intranasal administration of selective MasR agonist AVE 0991, reversed the mentioned cognitive deficits in A53T mice, enhanced MasR expression, reduced α-syn accumulation and phosphorylation, and attenuated microglia activation and apoptotic response. Our findings suggest that individuals with the A53T genetic background may be more susceptible to developing postoperative dNCR. This susceptibility could be linked to central α-syn accumulation mediated by the weakened Ang-(1-7)/MasR/methyl-PP2A signaling pathway in the hippocampus following surgery, independent of plasma α-syn level and BBB.

Neuropsychiatric Symptoms of Moyamoya Disease: Considerations for the Clinician.

Neurocognitive impairment in moyamoya disease is common, under recognized, and potentially devastating. The purpose of this paper is to provide an updated overview on this topic for the practicing clinician. We searched PubMed for keywords including cognitive impairment, neurocognitive dysfunction, and neuropsychological recovery in moyamoya disease. We summarized the literature to provide a concise review of the treatment and management of neuropsychiatric symptoms associated with moyamoya disease. Neuropsychiatric sequelae have conventionally been attributed to chronic cerebral hypoperfusion and/or stroke. Cognitive dysfunction in adults with moyamoya disease is most commonly in the form of impaired executive function, whereas intelligence is the predominant impairment in children with moyamoya disease. Pharmacotherapy for treatment of the neuropsychiatric symptoms associated with moyamoya disease is appropriate and can improve quality of life; however, careful consideration is needed to avoid adverse cerebrovascular events. It remains unclear as to whether surgical revascularization improves or stabilizes cognitive performance and outcomes. Additional prospective studies are warranted to better understand the long-term impact of revascularization on cognitive functioning in moyamoya disease.

The impact of cognitive reserve on delayed neurocognitive recovery after major non-cardiac surgery: an exploratory substudy.

Introduction: Delayed neurocognitive recovery is a common and severe complication after surgery and anesthesia with an adverse impact on daily living, morbidity, and mortality. High cognitive reserve may mitigate the development of delayed neurocognitive recovery, however, supporting data is lacking. We aimed to assess the association between cognitive reserve and delayed neurocognitive recovery in the early postoperative period. Methods: This is a substudy of two prospective observational studies. Adult patients undergoing elective major non-cardiac surgery, who were fluent in German, were eligible for study participation. Patients with any pre-existing central nervous system disorders were excluded. Cognitive reserve was assessed using the Cognitive Reserve Index questionnaire. Delayed neurocognitive recovery was defined as a decline in cognitive function compared with baseline assessments and was evaluated with a battery of neuropsychological tests on the day of hospital admission and between day three post procedure and before hospital discharge. Results: A total of 67 patients with a median age of 67 [IQR: (63-73)] years were included in our analysis. We found delayed neurocognitive recovery in 22.4% of patients. There was a significant association between Cognitive Reserve Index questionnaire total score and the occurrence of delayed neurocognitive recovery in the early postoperative period [OR = 0.938, (95% CI, 0.891; 0.988), p = 0.015]. Conclusion: Higher cognitive reserve in elderly patients undergoing major non-cardiac surgery decreases the risk for subsequent delayed neurocognitive recovery in the early postoperative period.

Impact of paravertebral block on perioperative neurocognitive disorder: a systematic review and meta-analysis of randomized controlled trials.

Objective: To investigate whether paravertebral block reduces postoperative delirium (POD)/delayed neurocognitive recovery (DNR) in adults after major surgery with general anesthesia. Methods: For this systematic review and meta-analysis, we searched online databases PubMed, EMBASE, CENTRAL, and Web of Science till March 19th, 2023 to examine studies which use paravertebral block (PVB) for perioperative neurocognitive disorder. Primary and secondary outcomes were identified for the incidence of perioperative neurocognitive disorder. We did not restrict the follow-up duration of the included studies. Statistical analysis was performed to calculate mean difference (MD), Odd ratios (OR) and CI between RCTs. The quality of the evidence was assessed with the Cochrane risk of bias tool. The registration number of the study in PROSPERO is CRD42023409502. PROSPERO is an international database of prospectively registered systematic reviews. Registration provides transparency in the review process and it helps counter publication bias. Results: Total 1,225 patients from 9 RCTs were analyzed. The incidence of POD [Odds Ratio (OR) = 0.48, 95% CI 0.32, 0.72; p = 0.0004; I2 = 0%] and DNR [OR = 0.32, 95% CI 0.13, 0.80; p = 0.01; I2 = 0%] were significantly reduced in PVB group. The analysis showed no significant differences in postoperative MMSE scores [MD = 0.50, 95% CI -2.14, 3.15; p = 0.71; I2 = 98%]. Paravertebral block analgesia reduces pain scores and/or opioid use after surgery. Additionally, blood pressure was significantly lower in the PVB group, intraoperatively [MD = -15.50, 95% CI -20.71, -10.28; p < 0.001; I2 = 12%] and postoperatively [MD = -5.34, 95% CI -10.65, -0.03 p = 0.05; I2 = 36%]. Finally, PVB group had significantly shorter hospital stays [MD = -0.86, 95% CI -1.13, -0.59; p < 0.001; I2 = 0%]. Conclusion: Paravertebral block analgesia may prevent perioperative POD/DNR in patients undergoing major surgery. Further research with large sample sizes is required to confirm its effectiveness.

Neurocognitive Recovery in Abstinent Patients with Alcohol Use Disorder: A Scoping Review for Associated Factors.

Objective: Studies have reported inconsistent results regarding the extent to which neurocognitive recovery occurs in abstinent patients with alcohol use disorder (AUD). In addition to abstinence, other factors may have influenced this process and contributed to the inconsistencies. This review examines the factors investigated in this regard and describes the possible influence of each factor based on the evidence collected. Methodology: PubMed was systematically searched for articles published between January 2000 and July 2023. Longitudinal humane studies investigating neurocognitive recovery in abstinent adult AUD patients were included. Studies with a cross-sectional design were excluded, as were studies that did not classify AUD according to the DSM-IV or 5 criteria, only examined binge use, did not report neuropsychological outcomes or duration of abstinence, or where neurological disorders were present. Results: Sixteen categories of factors were distinguished from 31 full-text articles. Consistent patterns were found, indicating an association between neurocognitive recovery and the "smoking" and 'brain volume" factors. Consistent patterns were also found indicating that there is no relationship with "quantities of alcohol used" and "education level." A similar consistent pattern was also found for "polysubstance use", "gender" and "verbal reading", but the number of studies is considered limited. The association with "age" is studied frequently but with inconsistent findings. The remaining eight factors were regarded as understudied. Conclusion: The clearest patterns emerging from the evidence are a predominantly negative influence of smoking on neurocognitive recovery, associations between changes in brain area volume and neurocognitive recovery, and no association between neurocognitive recovery and the amount of alcohol consumed, as measured by self-report, nor with educational attainment. Future research on the understudied factors and factors with inconsistent evidence is needed, preferably through longitudinal designs with multiple assessment periods starting after at least two weeks of abstinence.

Postoperative cognitive recovery and prevention of postoperative cognitive complications in the elderly patient.

Elderly patients undergoing surgery are at higher risk of life-altering and costly complications. This challenge is increasingly recognized with the growing geriatric surgical population. Advanced age and comorbid conditions, such as disability and frailty that often develop with age, are all independent risk factors of postoperative morbidity and mortality. A common factor in this age group is cognitive impairment, which poses a challenge for the patient and clinician in the perioperative setting. It affects the capacity for informed consent and limits optimization before surgery; furthermore, an existing impairment may progress in severity during the perioperative period, and new onset of signs of delirium or postoperative cognitive dysfunction may arise during postoperative recovery. In this article, we aim to review the current literature examining the latest definitions, diagnostic criteria, and preventive strategies that may ameliorate postoperative cognitive complications.

The relationship between longer leukocyte telomeres and dNCR in non-cardiac surgery patients: a retrospective analysis.

BACKGROUND: Cognitive decline following surgery is a common concern among elderly individuals. Leukocyte telomere length (LTL) can be assessed as a biological clock connected to an individual lifespan. However, the mechanisms causing this inference are still not fully understood. As a result of this, LTL has the potential to be useful as an aging-related biomarker for assessing delayed neurocognitive recovery (dNCR) and related diseases. METHODS: For this study, 196 individuals over 60 who were scheduled due to major non-cardiac surgical operations attended neuropsychological testing before surgery, followed by additional testing one week later. The finding of dNCR was based on a measured Z-score ≤ -1.96 on two or more separate tests. The frequency of dNCR was presented as the primary outcome of the study. Secondly, we evaluated the association between dNCR and preoperative LTL. RESULTS: Overall, 20.4% [40/196; 95% confidence interval (CI), 14.7-26.1%] of patients exhibited dNCR 1-week post-surgery. Longer LTL was identified as a predictor for the onset of early cognitive impairment resulting in postoperative cognitive decline [odds ratio (OR), 14.82; 95% CI, 4.01-54.84; P < 0.001], following adjustment of age (OR, 12.33; 95% CI, 3.29-46.24; P < 0.001). The dNCR incidence based on LTL values of these patients, the area under the receiver operating characteristic (ROC) curve was 0.79 (95% CI, 0.722-0.859; P < 0.001). At an optimal cut-off value of 0.959, LTL values offered respective specificity and sensitivity values of 64.7% and 87.5%. CONCLUSIONS: In summary, the current study revealed that the incidence of dNCR was strongly associated with prolonged LTL. Furthermore, this biomarker could help identify high-risk patients and offer insight into the pathophysiology of dNCR.

Plasma lipidomics reveals potential lipid markers for the prediction of delayed neurocognitive recovery after cardiac surgery with cardiopulmonary bypass.

BACKGROUND: Delayed neurocognitive recovery (DNR) is a cognitive change that affects patients after anesthesia and surgery, with a high incidence, severely impairing their quality of life. We identified relevant metabolic pathways to determine predictive lipid markers and understand the pathogenesis of DNR. METHODS: A non-targeted lipidomic strategy using Waters Acquity I Class UPLC-Xevo G2-S QTOF UPLC-MS was employed to identify different lipids in the 24 h postoperative plasma of patients whose cognitive function was assessed 7-14 days after surgery. Principal component analysis, orthogonal partial least squares discriminant analysis, and receiver operating characteristic (ROC) curves were used to identify potential biomarkers for predicting DNR. Metabolic pathway analysis was performed using the online platform MetaboAnalyst 5.0. RESULTS: Pre-operative hemoglobin was identified as an independent risk factor for DNR. The individual areas under the ROC curves (AUC) of the 5 representative lipids were all > 0.6, and the AUC of the combined predictor was 0.912. Glycerophospholipid metabolic pathway was dysregulated in patients with subsequent DNR. CONCLUSION: This study identified a series of potential predictive biomarkers for DNR. These data suggested that glycerophospholipid metabolism may be the mechanism underlying the occurrence and progression of DNR.

High preoperative blood oxaloacetate and 2-aminoadipic acid levels are associated with postoperative delayed neurocognitive recovery.

Introduction: This study aimed to identify preoperative blood biomarkers related to development of delayed neurocognitive recovery (dNCR) following surgery. Methods: A total of 67 patients (≥65 years old) who underwent head and neck tumor resection under general anesthesia were assessed using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Preoperative serum metabolomics were determined using widely targeted metabolomics technology. Results: Of the 67 patients, 25 developed dNCR and were matched to 25 randomly selected patients from the remaining 42 without dNCR. Differential metabolites were selected using the criteria of variable importance in projection > 1.0 in orthogonal partial least squares discrimination analysis, false discovery rate <0.05, and fold-change >1.2 or <0.83 to minimize false positives. Preoperative serum levels of oxaloacetate (OR: 1.054, 95% CI: 1.027-1.095, P = 0.001) and 2-aminoadipic acid (2-AAA) (OR: 1.181, 95% CI: 1.087-1.334, P = 0.001) were associated with postoperative dNCR after adjusting for anesthesia duration, education, and age. Areas under the curve for oxaloacetate and 2-AAA were 0.86 (sensitivity: 0.84, specificity: 0.88) and 0.86 (sensitivity: 0.84, specificity: 0.84), respectively. High levels of preoperative oxaloacetate and 2-AAA also were associated with postoperative decreased MoCA (ß: 0.022, 95% CI: 0.005-0.04, P = 0.013 for oxaloacetate; ß: 0.077, 95%CI: 0.016-0.137, P = 0.014 for 2-AAA) and MMSE (ß: 0.024, 95% CI: 0.009-0.039, P = 0.002 for oxaloacetate; ß: 0.083, 95% CI: 0.032-0.135, P = 0.002 for 2-AAA) scores after adjusting for age, education level, and operation time. Conclusion: High preoperative blood levels of oxaloacetate and 2-AAA were associated with increased risk of postoperative dNCR. Clinical trial registration: https://classic.clinicaltrials.gov/ct2/show/NCT05105451, identifier NCT05105451.

Predicative factors and development of a nomogram for postoperative delayed neurocognitive recovery in elderly patients with gastric cancer.

BACKGROUND: Delayed neurocognitive recovery (DNR) is a common complication after radical gastrectomy and closely associated with poor outcomes. This study aimed to investigate predictors and develop a nomogram prediction model for DNR. METHODS: Elderly gastric cancer (GC) patients (≥ 65 years) undergoing elective laparoscopic radical gastrectomy between 2018 and 2022 were prospectively included in this study. DNR was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V, 2013). Independent risk factors for DNR were screened by the multivariate logistic regression analysis. Based on these factors, the nomogram model was established and validated by R. RESULTS: A total of 312 elderly GC patients were enrolled in the training set, with an incidence of DNR within postoperative 1 month of 23.4% (73/312). Multivariate logistic regression analysis indicated that age (OR: 1.207, 95%CI: 1.113-1.309, P < 0.001), nutritional risk screening 2002 (NRS2002) score (OR: 1.716, 95%CI: 1.211-2.433, P = 0.002), neutrophil-to-lymphocyte ratio (NLR) (OR: 1.976, 95%CI: 1.099-3.552, P = 0.023), albumin-to-fibrinogen ratio (AFR) (OR: 0.774, 95%CI: 0.620-0.966, P = 0.024), and prognostic nutritional index (PNI) (OR: 0.768, 95%CI: 0.706-0.835, P < 0.001) were five independent factors for DNR in elderly GC patients. The constructed nomogram model based on these five factors has a good predictive value for DNR with an area under the curve (AUC) of 0.863. CONCLUSIONS: In conclusions, the established nomogram model based on age, NRS-2002, NLR, AFR, and PNI has a well predictive value for postoperative DNR in elderly GC patients.

Reciprocal interaction between mitochondrial fission and mitophagy in postoperative delayed neurocognitive recovery in aged rats.

INTRODUCTION: Emerging evidence suggests that mitochondrial dysfunction plays a crucial role in the pathogenesis of postoperative delayed neurocognitive recovery (dNCR). Mitochondria exist in a dynamic equilibrium that involves fission and fusion to regulate morphology and maintains normal cell function via the removal of damaged mitochondria through mitophagy. Nonetheless, the relationship between mitochondrial morphology and mitophagy, and how they influence mitochondrial function in the development of postoperative dNCR, remains poorly understood. Here, we observed morphological alterations of mitochondria and mitophagy activity in hippocampal neurons and assessed the involvement of their interaction in dNCR following general anesthesia and surgical stress in aged rats. METHODS: Firstly, we evaluated the spatial learning and memory ability of the aged rats after anesthesia/surgery. Hippocampal mitochondrial function and mitochondrial morphology were detected. Afterwards, mitochondrial fission was inhibited by Mdivi-1 and siDrp1 in vivo and in vitro separately. We then detected mitophagy and mitochondrial function. Finally, we used rapamycin to activate mitophagy and observed mitochondrial morphology and mitochondrial function. RESULTS: Surgery impaired hippocampal-dependent spatial learning and memory ability and caused mitochondrial dysfunction. It also increased mitochondrial fission and inhibited mitophagy in hippocampal neurons. Mdivi-1 improved mitophagy and learning and memory ability of aged rats by inhibiting mitochondrial fission. Knocking down Drp1 by siDrp1 also improved mitophagy and mitochondrial function. Meanwhile, rapamycin inhibited excessive mitochondrial fission and improved mitochondrial function. CONCLUSION: Surgery simultaneously increases mitochondrial fission and inhibits mitophagy activity. Mechanistically, mitochondrial fission/fusion and mitophagy activity interact reciprocally with each other and are both involved in postoperative dNCR. These mitochondrial events after surgical stress may provide novel targets and modalities for therapeutic intervention in postoperative dNCR.

Rapamycin Affects the Hippocampal SNARE Complex to Alleviate Cognitive Dysfunction Induced by Surgery in Aged Rats.

Delayed neurocognitive recovery (dNCR) is a common complication that occurs post-surgery, especially in elderly individuals. The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex plays an essential role in various membrane fusion events, such as synaptic vesicle exocytosis and autophagosome-lysosome fusion. Although SNARE complex dysfunction has been observed in several neurodegenerative disorders, the causal link between SNARE-mediated membrane fusion and dNCR remains unclear. We previously demonstrated that surgical stimuli caused cognitive impairment in aged rats by inducing α-synuclein accumulation, inhibiting autophagy, and disrupting neurotransmitter release in hippocampal synaptosomes. Here, we evaluated the effects of propofol anesthesia plus surgery on learning and memory and investigated levels of SNARE proteins and chaperones in hippocampal synaptosomes. Aged rats that received propofol anesthesia and surgery exhibited learning and memory impairments in a Morris water maze test and decreased levels of synaptosome-associated protein 25, synaptobrevin/vesicle-associated membrane protein 2, and syntaxin 1. Levels of SNARE chaperones, including mammalian uncoordinated-18, complexins 1 and 2, cysteine string protein-α, and N-ethylmaleimide-sensitive factor, were all significantly decreased following anesthesia with surgical stress. However, the synaptic vesicle marker synaptophysin was unaffected. The autophagy-enhancer rapamycin attenuated structural and functional disturbances of the SNARE complex and ameliorated disrupted neurotransmitter release. Our results indicate that perturbations of SNARE proteins in hippocampal synaptosomes may underlie the occurrence of dNCR. Moreover, the protective effect of rapamycin may partially occur through recovery of SNARE structural and functional abnormalities. Our findings provide insight into the molecular mechanisms underlying dNCR.

Low-Intensity Pulsed Ultrasound Attenuates Postoperative Neurocognitive Impairment and Salvages Hippocampal Synaptogenesis in Aged Mice.

Postoperative neurocognitive impairment is an urgent problem with global aging accelerating. The prevention and treatment of postoperative neurocognitive impairment have been widely investigated but lack effective strategies. Low-intensity pulsed ultrasound (LIPUS), a non-invasive tool, has shown an effect on neuroprotection, but whether it could attenuate the postoperative neurocognitive impairment and the underlying mechanisms remains unknown. An experimental setup for LIPUS stimulation of the hippocampus was well established. A laparotomy model in aged mice was applied, and a Morris water maze was used to assess cognitive function. RT-qPCR and western blotting were used to detect levels of Piezo1, synapse-associated proteins in the hippocampus, respectively. Immunofluorescent staining was also used to determine the neural activation and Piezo1 expression. The results showed that LIPUS increased synapse-related proteins of the hippocampus and attenuated cognitive impairment in aged mice. Meanwhile, LIPUS suppressed the overexpression of Piezo1 in the hippocampus. We further found that LIPUS promoted Calpain1 activity and increased extracellular regulated protein kinases (Erk) phosphorylation. Our results suggested that LIPUS could improve cognitive impairment and increase hippocampal synaptogenesis through the Piezo1-mediated Calpain1/ Erk pathway. LIPUS could be used as an effective physical intervention to alleviate postoperative cognitive dysfunction in the aged population.