Perioperative Neurocognitive Disorders Research Articles

The influence of dexmedetomidine added to ropivacaine for transversus abdominis plane block on perioperative neurocognitive disorders after radical colorectal cancer surgery: randomized, double-blind, controlled trial

ObjectivePerioperative Neurocognitive Disorders (PND) is a common neurological complication after radical colorectal cancer surgery, which increases adverse outcomes. So, our objective is to explore the influence of dexmedetomidine added to ropivacaine for transversus abdominis plane block (TAPB) on perioperative neurocognitive disorders, and to provide a new way to reduce the incidence of PND.MethodsOne hundred and eighty patients submitted to radical laparoscopic colorectal cancer surgery were randomly divided into Control group and Dex group. Ultrasound guided TAPB was performed after anesthesia induction: 0.5% ropivacaine 20 ml was injected into each transversus abdominis plane in Control group, 0.5% ropivacaine + 1 μg/kg dexmedetomidine (amounting to 20 ml) in Dex group. We observed the incidence of PND within 30 days after surgery.ResultsOne hundred and sixty-nine cases were finally analyzed, including 84 cases in Control group and 85 cases in Dex group. Compared with Control group, there was no significant difference in terms of the incidence of PND on the 3rd day and the 7th day (P > 0.05), but the incidence significantly decreased at the 6th hour, at the 24th hour and on the 30th day after surgery (P < 0.05) in Dex group.ConclusionDexmedetomidine added to ropivacaine for TAPB can reduce the incidence of PND in the first 24 h after surgery and on the 30th postoperative day, which may be related to reduce the consumption of general anesthetics and provide satisfactory postoperative analgesia.Trial registration29 /05/ 2021, ChiCTR2100046876.

The Role of the Glymphatic System in Perioperative Neurocognitive Disorders.

The glymphatic system plays a crucial role in clearing metabolic waste from the central nervous system and is most active during sleep. Patients with obstructive sleep apnea (OSA) have a dysfunctional glymphatic system that correlates with disease severity. In addition, these patients have worse outcomes after surgery. The status of the glymphatic system during the perioperative period is unclear and can be examined with magnetic resonance imaging (MRI)-based diffusion tensor imaging (DTI). This study assessed perioperative glymphatic system changes in OSA surgical patients and possible relationships with perioperative neurocognitive disorders. DTI data from 13 OSA patients having laparoscopic abdominal surgery with general anesthesia were acquired and analyzed using a 3.0-T MRI scanner. Diffusivity maps in the x-axis (Dxx), y-axis (Dyy), z-axis (Dzz), x-y axis (Dxy), y-z axis (Dyz), and x-z axis (Dxz) were calculated. Diffusion values for the projection and association fibers were extracted, and DTI analysis along the perivascular space (ALPS) was performed. The patients' cognition was assessed using the Montreal Cognitive Assessment tool. Evaluations were carried out within 5 days before surgery and within the first 48 hours after surgery. The ALPS index decreased after surgery, and this correlated with a decrease in general cognition scores and specific memory domains, including visuospatial and delayed recall. The glymphatic system in OSA patients is worsened after surgery and this may contribute to an increased risk for long-term postoperative cognitive disorders. This study suggest that the glymphatic system might play a role in the pathophysiology of perioperative neurocognitive disorders and be a potential therapeutic target.

Exploring the Impact of Preoperative Sleep Fragmentation on Cognitive Function in Mice: The Role of Microglial Activation and Iron Metabolism

Background. Perioperative neurocognitive disorders (PND) are a significant concern, particularly for aged individuals. Sleep fragmentation (SF), a common condition in older adults, is considered a risk factor for PND. The present study explored the impact of SF on cognitive function and its association with microglial activation and iron metabolism. Methods. Adult and aged C57BL/6J mice were subjected to tibial fracture surgery (TFS) and varying durations of SF. Cognitive function was assessed using the Morris water maze and fear conditioning experiments. Microglial activation was evaluated by measuring CD68 protein expression and inflammatory cytokine levels. Iron metabolism and ferroptosis-related proteins were also examined. Results. SF significantly impacted spatial memory and conditioned fear responses in mice, with aged mice showing greater susceptibility. Microglial activation, indicated by changes in CD68 protein expression and inflammatory cytokine levels, was observed in mice exposed to SF. Alterations in iron metabolism, as evidenced by changes in hippocampal iron content and expression of ferroptosis-related proteins, were also observed in these mice. Conclusion. SF can lead to significant cognitive impairment, particularly in aged mice, likely mediated through microglial activation and dysregulated iron metabolism. These findings provide novel insights into the pathogenesis of PND and suggest potential targets for intervention. Significance. This study illuminates the complex interactions between SF, microglial activation, and cognitive function. It highlights the importance of sleep quality for cognitive health in older adults and points to potential therapeutic strategies for preventing PND, including targeting microglial activation and iron metabolism.

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

BackgroundPostoperative 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. MethodsWe 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. ResultsIn 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 Aβ42 (proportion = 17.56 %), T-tau (proportion = 19.64 %), Aβ42/T-tau (proportion = 29.67 %), and Aβ42/P-tau (proportion = 12.26 %). ConclusionsCOVID-19 vaccine is a protective factor for POD in old patients, which is associated with CSF biomarkers.

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

Our study aimed to investigate the correlation between intraoperative hypothermia and postoperative delirium (POD) in patients undergoing general anesthesia for gastrointestinal surgery. 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 48h post-surgeries. The receiver-operating characteristic (ROC) was utilized to evaluate the effectiveness of intraoperative hypothermia in predicting POD. 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 24h 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. Intraoperative hypothermia may increase the risk of POD, and this association may be partially mediated by NRS scores 24h after surgery.

Upconversion-Mediated Optogenetics for the Treatment of Surgery-Induced Postoperative Neurocognitive Dysfunction.

Perioperative neurocognitive disorder (PND) is a common complication in surgical patients. While many interventions to prevent PND have been studied, the availability of treatment methods is limited. Thus, it is crucial to delve into the mechanisms of PND, pinpoint therapeutic targets, and develop effective treatment approaches. In this study, reduced dorsal tenia tecta (DTT) neuronal activity was found to be associated with tibial fracture surgery-induced PND, indicating that a neuronal excitation-inhibition (E-I) imbalance could contribute to PND. Optogenetics in the DTT brain region was conducted using upconversion nanoparticles (UCNPs) with the ability to convert 808 nm near-infrared light to visible wavelengths, which triggered the activation of excitatory neurons with minimal damage in the DTT brain region, thus improving cognitive impairment symptoms in the PND model. Moreover, this noninvasive intervention to modulate E-I imbalance showed a positive influence on mouse behavior in the Morris water maze test, which demonstrates that UCNP-mediated optogenetics is a promising tool for the treatment of neurological imbalance disorders.

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

This study aims to explore the relationship between physical activity (PA) and postoperative delirium (POD). 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 β plaque 42 (Aβ42), 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. 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 Aβ42 (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 Aβ42 (proportion: 11%, P < 0.05), T-tau (proportion: 13%, P < 0.05), and P-tau (proportion: 12%, P < 0.05). Physical activity is probably a protective factor for POD and may exert a mediating effect through CSF biomarkers.

Correlation between heart rate variability and perioperative neurocognitive disorders in patients undergoing non-cardiac surgery: A retrospective cohort study.

With the improvement of medical level, the number of elderly patients is increasing, and the postoperative outcome of the patients cannot be ignored. However, there have been no studies on the relationship between preoperative heart rate variability (HRV) and Perioperative Neurocognitive Disorders (PND). The purpose of this study was to explore the correlation between (HRV) and (PND), postoperative intensive care unit (ICU), and hospital stay in patients undergoing non-cardiac surgery. This retrospective analysis included 687 inpatients who underwent 24-hour dynamic electrocardiogram examination in our six departments from January 2021 to January 2022. Patients were divided into two groups based on heart rate variability (HRV): high and low. Possible risk factors of perioperative outcomes were screened using univariate analysis, and risk factors were included in multivariate logistic regression to screen for independent risk factors. The subgroup analysis was carried out to evaluate the robustness of the results. The nomogram of PND multi-factor logistic prediction model was constructed. The receiver operating characteristic (ROC) curve was drawn, and the calibration curve was drawn by bootstrap resampling 1000 times for internal verification to evaluate the prediction ability of nomogram. A total of 687 eligible patients were included. The incidence of low HRV was 36.7% and the incidence of PND was 7.6%. The incidence of PND in the low HRV group was higher than that in the high HRV group (11.8% vs 5.2%), the postoperative ICU transfer rate was higher (15.9% than 9.3%P = 0.009), and the hospital stay was longer [15 (11, 19) vs (13), 0.015]. The multivariable logistic regression analysis showed that after adjusting for other factors, decreased low HRV was identified as an independent risk factor for the occurrence of PND (Adjusted Odds Ratio = 2.095; 95% Confidence Interval: 1.160-3.784; P = 0.014) and postoperative ICU admission (Adjusted Odds Ratio = 1.925; 95% Confidence Interval: 1.128-3.286; P = 0.016). This study drew a nomogram column chart for a multivariate logistic regression model, incorporating age and HRV. The calibration curve shows that the predicted value of the model for the occurrence of cardio-cerebrovascular events is in good agreement with the actual observed value, with C-index of 0.696 (95% CI: 0.626 ~ 0.766). Subgroup analysis showed that low HRV was an independent risk factor for PND in patients with gastrointestinal surgery and ASA Ⅲ, aged ≥ 65 years. In patients undergoing non-cardiac surgery, the low HRV was an independent risk factor for PND and postoperative transfer to the ICU, and the hospitalization time of patients with low HRV was prolonged. Through establishing a risk prediction model for the occurrence of PND, high-risk patients can be identified during the perioperative period for early intervention.

Knowledge mapping and research trends on perioperative neurocognitive disorder from 1990 to 2022: a bibliometric analysis.

Perioperative neurocognitive disorder (PND) has attracted consistently increasing attention worldwide. However, there are few bibliometric studies that systematically evaluate this field. This study aimed to visualize the knowledge structure and research trends in PND through bibliometrics to help understand the future development of basic and clinical research. Literature related to PND in Web of Science and PubMed from 1990 to 2022 were collected through keywords retrospectively. Additionally, the source information, citation information, etc. of these publications were extracted. Finally, bibliometric analysis was performed by visualization software and statistical software. There were 2837 articles and reviews in total. An exponential rise in PND-related publications was observed. China had the most publication, followed by the US and Germany. The institution with the most output and citations was Harvard University (149 papers, 8966 citations). The most prominent author was Marcantonio Edward R with 66 publications and 5721 citations. The journal with the highest productivity for PND research was Frontiers in Aging Neuroscience followed by Anesthesia and Analgesia. Keywords were identified as six topics, including postoperative delirium, postoperative neurocognitive disorder, cardiac surgery, anaesthesia, orthopedic surgery, and dementia. According to keyword analysis, the most recent popular keywords in PND research were prevention, older patients, emergence delirium, orthopedic surgery, and dexmedetomidine. Publications on PND are increasing at an alarming rate from 1990 to 2022. Current research and future trends will concentrate on the prevention and treatment of PND, as well as PND associated with orthopedic surgery in older adults.

Propionic acid ameliorates cognitive function through immunomodulatory effects on Th17 cells in perioperative neurocognitive disorders

BackgroundElderly patients undergoing surgery are prone to cognitive decline known as perioperative neurocognitive disorders (PND). Several studies have shown that the microglial activation and the decrease of short-chain fatty acids (SCFAs) in gut induced by surgery may be related to the pathogenesis of PND. The purpose of this study was to determine whether microglia and short-chain fatty acids were involved in cognitive dysfunction in aged rats. MethodsMale wild-type Wistar rats aged 11–12 months were randomly divided into control group (Ctrl: Veh group), propionic acid group (Ctrl: PA group), exploratory laparotomy group (LP: Veh group) and propionic acid + exploratory laparotomy group (LP: PA group) according to whether exploratory laparotomy (LP) or PA pretreatment for 21 days was performed. The motor ability of the rats was evaluated by open field test on postoperative day 3 (POD3), and then the cognitive function was evaluated by Y-maze test and fear conditioning test. The expression of IL-1β, IL-6, RORγt and IL-17A mRNA in hippocampus was detected by RT-qPCR, the expression of IL-17A and IL-17RA in hippocampus was detected by Western blot, and the activation of microglia was detected by immunofluorescence. ResultsThe PND rat model was successfully established by laparotomy. Compared with Ctrl: Veh group, the body weight of LP: Veh group decreased, the percentage of spontaneous alternations in Y maze decreased (P < 0.001), and the percentage of freezing time in contextual fear test decreased (P < 0.001). Surgery triggers neuroinflammation, manifested as the elevated levels of the inflammatory cytokines IL-1β (P < 0.001) and IL-6 (P < 0.001), the increased expression of the transcription factor RORγt (P = 0.0181, POD1; P = 0.0073, POD5)and major inflammatory cytokines IL-17A (P = 0.0215, POD1; P = 0.0071, POD5), and the increased average fluorescence intensity of Iba1 (P < 0.001, POD1; P < 0.001, POD5). After PA preconditioning, the recovery of rats in LP: PA group was faster than that in LP: Veh group as the body weight lost on POD1 (P = 0.0148) was close to the baseline level on POD5 (P = 0.1846), and they performed better in behavioral tests. The levels of IL-1β (P < 0.001) and IL-6 (P = 0.0035) inflammatory factors in hippocampus decreased on POD1 and the average fluorescence intensity of Iba1 decreased (P = 0.0024, POD1; P < 0.001, POD5), representing the neuroinflammation was significantly improved. Besides, the levels of RORγt mRNA (P = 0.0231, POD1; P = 0.0251, POD5) and IL-17A mRNA (P = 0.0208, POD1; P = 0.0071, POD5) in hippocampus as well as the expression of IL-17A (P = 0.0057, POD1; P < 0.001, POD5) and IL-17RA (P = 0.0388) decreased. ConclusionPA pretreatment results in reduced postoperative neuroinflammation and improved cognitive function, potentially attributed to the regulatory effects of PA on Th17-mediated immune responses.

Preoperative cognitive impairment and postoperative delirium among Holocaust survivors who achieved longevity.

Holocaust survivors (HS) experience higher rates of physiological and psychological morbidities, increasing their vulnerability to perioperative complications. Limited information exists regarding their perioperative neurocognitive disorders. This study aimed to assess the rates of preoperative cognitive impairment, postoperative delirium, and other complications among HS aged 75+ undergoing elective surgery. This is a single-center retrospective cohort study that analyzed prospectively collected data. All surgical patients born before 1945 who underwent elective noncardiac surgery at a tertiary hospital in Israel during 2020-2021 were included. The HS group was identified through the hospital's information system. Preoperative cognitive impairment was assessed using the Mini-Cog test. Postoperative delirium was defined as a combined outcome, which included a positive 4A's-Test (4AT) result during the postanesthesia care unit stay up to the second postoperative day, a positive 3-Minute Diagnostic Confusion Assessment Method (3D-CAM) test administered by the geriatric team, and identification through the medical records using the Chart-based Delirium Identification Instrument (CHART-DEL). We used multivariable regression to assess the risk factors for postoperative delirium. Out of 1332 eligible patients, 422 (32%) were HS, while the others served as controls. Both groups had a similar rate of preoperative cognitive impairment (24%, p = 0.89) and postoperative delirium (16%, p = 0.95). HS exhibited a higher risk of the composite adverse events (24% vs. 20%, p = 0.05, aOR [95% CI] 1.3 [1.0-1.7]), driven mainly by falls during hospitalization (4% vs. 2%, p = 0.03, aOR 2.1 [1.1-4.1]). HS patients were more likely to be childless (33% vs. 11%, p = 0.001) and had higher rates of chronic antidepressant and benzodiazepine use. HS achieving longevity do not face increased risks of preoperative cognitive impairment and postoperative delirium. However, special care is still warranted due to their elevated rate of other complications during hospitalization.

A commentary on "Association between cerebrovascular disease and perioperative neurocognitive disorders: a retrospective cohort study".

A commentary on "Association between cerebrovascular disease and perioperative neurocognitive disorders: a retrospective cohort study".

Long-term isoflurane anesthesia induces cognitive deficits via AQP4 depolarization mediated blunted glymphatic inflammatory proteins clearance.

Perioperative neurocognitive disorders (PND) refer to cognitive deterioration that occurs after surgery or anesthesia. Prolonged isoflurane exposure has potential neurotoxicity and induces PND, but the mechanism is unclear. The glymphatic system clears harmful metabolic waste from the brain. This study sought to unveil the functions of glymphatic system in PND and explore the underlying molecular mechanisms. The PND mice model was established by long term isoflurane anesthesia. The glymphatic function was assessed by multiple in vitro and in vivo methods. An adeno-associated virus was used to overexpress AQP4 and TGN-020 was used to inhibit its function. This research revealed that the glymphatic system was impaired in PND mice and the blunted glymphatic transport was closely associated with the accumulation of inflammatory proteins in the hippocampus. Increasing AQP4 polarization could enhance glymphatic transport and suppresses neuroinflammation, thereby improve cognitive function in the PND model mice. However, a marked impaired glymphatic inflammatory proteins clearance and the more severe cognitive dysfunction were observed when decreasing AQP4 polarization. Therefore, long-term isoflurane anesthesia causes blunted glymphatic system by inducing AQP4 depolarization, enhanced the AQP4 polarization can alleviate the glymphatic system malfunction and reduce the neuroinflammatory response, which may be a potential treatment strategy for PND.

Echinatin mitigates sevoflurane-induced neurotoxicity through regulation of ferroptosis and iron homeostasis.

Surgery and anesthesia are vital medical interventions, but concerns over their potential cognitive side effects, particularly with the use of inhalational anesthetics like sevoflurane, have surfaced. This study delves into the neuroprotective potential of Echinatin against sevoflurane-induced neurotoxicity and the underlying mechanisms. Echinatin, a natural compound, has exhibited anti-inflammatory, antioxidant, and anticancer properties. Sevoflurane, while a popular anesthetic, is associated with perioperative neurocognitive disorders (PND) and neurotoxicity. Our investigation began with cellular models, where Echinatin demonstrated a significant reduction in sevoflurane-induced apoptosis. Mechanistically, we identified ferroptosis, a novel form of programmed cell death characterized by iron accumulation and lipid peroxidation, as a key player in sevoflurane-induced neuronal injury. Echinatin notably suppressed ferroptosis in sevoflurane-exposed cells, suggesting a pivotal role in neuroprotection. Expanding our research to a murine model, we observed perturbations in iron homeostasis, inflammatory cytokines, and antioxidants due to sevoflurane exposure. Echinatin treatment effectively restored iron balance, mitigated inflammation, and preserved antioxidant levels in vivo. Behavioral assessments using the Morris water maze further confirmed Echinatin's neuroprotective potential, as it ameliorated sevoflurane-induced spatial learning and memory impairments. In conclusion, our study unveils Echinatin as a promising candidate for mitigating sevoflurane-induced neurotoxicity. Through the regulation of ferroptosis, iron homeostasis, and inflammation, Echinatin demonstrates significant neuroprotection both in vitro and in vivo. These findings illuminate the potential for Echinatin to enhance the safety of surgical procedures involving sevoflurane anesthesia, minimizing the risk of cognitive deficits and neurotoxicity.

Association between cerebrovascular disease and perioperative neurocognitive disorders: a retrospective cohort study: Erratum.

Association between cerebrovascular disease and perioperative neurocognitive disorders: a retrospective cohort study: Erratum.

The Association of Plasma Leptin, Soluble Leptin Receptor and Total and High-Molecular Weight Adiponectin With the Risk of Perioperative Neurocognitive Disorders

BackgroundPerioperative neurocognitive disorders (NCD) are poorly characterized in terms of their risk factor profiles. Leptin and adiponectin are adipose-tissue-derived hormones with a role in inflammation and atherosclerosis whose function in perioperative NCD is unclear. Here, we used a cohort of older adults to examine the association of preoperative plasma concentrations of these biomarkers with the risk of perioperative NCD. MethodsProspective analysis of 768 participants aged ≥ 65 years of the BioCog study. Blood was collected before surgery for measurement of plasma total and high-molecular-weight (hmw) adiponectin, leptin, and soluble leptin receptor (sOB-R). The free leptin index (FLI, leptin:sOB-R) was calculated. Postoperative delirium (POD) was assessed twice daily until postoperative day 7/discharge. Five hundred twenty-six patients (68.5%) returned for 3-month follow-up and provided data on postoperative cognitive dysfunction (POCD). POCD was defined as a decline on six neuropsychological tests that exceeded that of a nonsurgical control group. Logistic regression analyses examined the associations of each exposure with POD and POCD risk, in separate models adjusted for age, sex, fasting, surgery type, and body mass index (BMI). ResultsOf 768 patients, 152 (19.8%) developed POD. Of 526 attendants of the follow-up, 54 (10.3%) had developed POCD. Leptin, sOB-R, and total and hmw adiponectin were each not associated with POD. For POCD, we observed reduced risk in patients in FLI quartile 4 compared with quartile 1 (odds ratio, 0.26; 95% CI 0.08, 0.89). Sensitivity analyses for the outcome POD revealed statistically significant interaction terms of sOB-R and total adiponectin with obesity (BMI≥30kg/m2 versus BMI<30kg/m2). For the outcome POCD, a higher sOB-R was associated with an increased risk in the obese subgroup (odds ratio, 4.00; 95% CI 1.01, 15.86). ConclusionsWe did not find consistent evidence for the role of leptin, its receptor, and total and hmw adiponectin in POD and POCD risk. Future research should be used to support or refute our findings and to fully characterize any differences in the associations of these hormones with POD/POCD between obese and nonobese individuals.

Exercise attenuates the perioperative neurocognitive disorder induced by hyperhomocysteinemia in mice

The perioperative neurocognitive disorder (PND) is a severe complication that affects millions of surgical patients each year. Homocysteine (Hcy) is known to increase the risk of developing PND in both young and elderly mice. However, whether Hcy alone can induce cognitive deficits in middle-aged mice (12-month-old), whether exercise can attenuate Hcy-induced hippocampus-related cognitive deficits after surgery through suppressing neuroinflammation, synaptic elimination, and the level of Hcy remains unknown. The present study aimed to answer these questions through testing the possibility of establishing a PND model using 12-month-old mice which received homocysteine injections before exploratory laparotomy and the therapeutic mechanism of exercise. In the present study, it was found that levels of serum homocysteine were age-dependently increased in mice with a significant difference between that of 18-month-old mice and 6-week, 6-month, and 12-month-old mice. PND occurred in 18-month but not in 12-month-old mice after exploratory laparotomy under isoflurane anesthesia. Intraperitoneal injection of Hcy for 3 consecutive days before surgery rendered 12-month-old mice to develop PND after abdominal laparotomy under isoflurane anesthesia at a minimal dosage of 20mg/kg. Neuroinflammation and synaptic elimination was present in 12-month-old preoperative Hcy-injected mice. Preoperative voluntary wheel exercise could prevent PND in 12-month-old mice that have received Hcy injection before surgery, which might be related to the decreased level of serum Hcy. Activation of glial cells, proinflammatory phenotype markers and synaptic elimination were attenuated in the hippocampus of 12-month-old preoperative Hcy-injected mice by this exercise. These results provide direct evidence that hyperhomocysteinemia can induce postoperative cognitive deficits in middle-aged mice. Pre-surgery exercise can effectively prevent Hcy-precipitated postoperative cognitive dysfunction.

Research Progress of Hippocampal Dopamine System Changes in Perioperative Neurocognitive Disorders.

Perioperative neurocognitive disorders (PND) are a cognitive impairment that occurs after anesthesia, especially in elderly patients and significantly affects their quality of life. The hippocampus, as a critical region for cognitive function and an important location in PND research, has recently attracted increasing attention. However, in the hippocampus the impact of anesthesia and its underlying mechanisms remain unclear. This review focuses on investigation of the effects of anesthesia on the hippocampal dopamine (DA) system and explores its potential association with PND. Through comprehensive review of existing studies, it was found that anesthesia affects the hippocampus through various pathways involved in metabolism, synaptic plasticity and oxygenation. Anesthesia may also influence the DA neurotransmitter system in the brain which plays a role in emotions, rewards, learning and memory functions. Specifically, anesthesia may participate in the pathogenesis of PND by affecting the DA system within the hippocampus. Future studies should explore the molecular mechanisms of these effects through techniques such as neuroimaging to study real-time effects to improve animal models to better simulate clinical observations. For clinical application, it is recommended that physicians exercise caution when selecting and managing anesthetic drugs by adopting comprehensive cognitive assessment methods to reduce post-anesthesia cognitive risk. Overall, this review provides a better understanding of the relationship between the hippocampal DA system and perioperative neurocognitive function and provides valuable guidance for prevention and treatment strategies for PND.

Dysregulation of iron homeostasis and ferroptosis in sevoflurane and isoflurane associated perioperative neurocognitive disorders.

In recent years, sevoflurane and isoflurane are the most popular anesthetics in general anesthesia for their safe, rapid onset, and well tolerant. Nevertheless, many studies reported their neurotoxicity among pediatric and aged populations. This effect is usually manifested as cognitive impairment such as perioperative neurocognitive disorders. The wide application of sevoflurane and isoflurane during general anesthesia makes their safety a major health concern. Evidence indicates that iron dyshomeostasis and ferroptosis may establish a role in neurotoxicity of sevoflurane and isoflurane. However, the mechanisms of sevoflurane- and isoflurane-induced neuronal injury were not fully understood, which poses a barrier to the treatment of its neurotoxicity. We, therefore, reviewed the current knowledge on mechanisms of iron dyshomeostasis and ferroptosis and aimed to promote a better understanding of their roles in sevoflurane- and isoflurane-induced neurotoxicity.

Oral administration of ellagic acid mitigates perioperative neurocognitive disorders, hippocampal oxidative stress, and neuroinflammation in aged mice by restoring IGF-1 signaling

This study investigates the potential of ellagic acid (EA), a phytochemical with antioxidant and anti-inflammatory properties, in managing perioperative neurocognitive disorders (PND). PND, which represents a spectrum of cognitive impairments often faced by elderly patients, is principally linked to surgical and anesthesia procedures, and heavily impacted by oxidative stress in the hippocampus and microglia-induced neuroinflammation. Employing an aged mice model subjected to abdominal surgery, we delve into EA's ability to counteract postoperative oxidative stress and cerebral inflammation by engaging the Insulin-like growth factor-1 (IGF-1) pathway. Our findings revealed that administering EA orally notably alleviated post-surgical cognitive decline in older mice, a fact that was manifested in improved performance during maze tests. This enhancement in the behavioral performance of the EA-treated mice corresponded with the rejuvenation of IGF-1 signaling, a decrease in oxidative stress markers in the hippocampus (like MDA and carbonylated protein), and an increase in the activity of antioxidant enzymes such as SOD and CAT. Alongside these, we observed a decrease in microglia-driven neuroinflammation in the hippocampus, thus underscoring the antioxidant and anti-inflammatory roles of EA. Interestingly, when EA was given in conjunction with an IGF1R inhibitor, these benefits were annulled, accentuating the pivotal role that the IGF-1 pathway plays in the neuroprotective potential of EA. Hence, EA could serve as a potent candidate for safeguarding against PND in older patients by curbing oxidative stress and neuroinflammation through the activation of the IGF-1 pathway.