Postoperative Cognitive Dysfunction Research Articles

Effects of intraoperative body temperature, blood pressure, cerebral tissue oxygenation, and anesthesia type on postoperative cognitive functions in geriatric arthroplasty surgery for hip fracture.

This study aimed to explore the effects of cerebral oxygenation, body temperature, hemodynamic changes, and anesthesia type on postoperative cognitive dysfunction (POCD) in geriatric patients undergoing hip fracture surgery. One hundred five elderly patients (59 males, 46 females; mean age: 76.7±8.8 years; range, 65 to 95 years) who were scheduled for hip fracture surgery under general or spinal anesthesia between March 2021 and March 2023 were enrolled in the prospective observational study. The cognitive functions were evaluated using the Mini-Mental State Examination (MMSE). Postoperative MMSE values <24 were considered indicative of POCD. Cerebral oxygenation was evaluated before and during the operation using near-infrared spectroscopy (NIRS), and body temperature was measured using a tympanic thermometer, with values <36℃ considered hypothermia. The relationship between decreases in blood pressure ≥30% and POCD was investigated. The relationship between decreases in NIRS of 25% and POCD was also investigated. Postoperative cognitive dysfunction was observed in 29 (27.25%) of the 105 patients. The MMSE value was 24 in 67.06% of 29 patients, and all these patients developed POCD. The incidence of POCD in patients with a preoperative MMSE1 score of 30 was 12.30% (p=0.001). No relationship was identified between MMSE changes and anesthesia type, hypotension, and decreases in the NIRS (p=0.439, p=0.399). Hypothermia was found to be significantly related to POCD (p=0.013). The degree of hypothermia decreased the postoperative MMSE value at different rates. A 1°C body temperature decrease caused a 16.7%, 44.4%, and 50% decrease in MMSE scores of one, one, and two patients, respectively. Hypothermia was found to be significantly related to POCD. The same degree of hypothermia caused different MMSE changes. Since the number of patients with POCD was very low, the effect of amounts of body temperature changes on clinically significant MMSE changes could not be supported by logistic regression. The preoperative MMSE values, MMSE change rates, and age were found to be effective in POCD. Maintaining the body temperature throughout the operation will ensure the preservation of postoperative cognitive functions.

Vagus nerve stimulation (VNS) preventing postoperative cognitive dysfunction (POCD): two potential mechanisms in cognitive function.

Postoperative cognitive dysfunction (POCD) impacts a significant number of patients annually, frequently impairing their cognitive abilities and resulting in unfavorable clinical outcomes. Aimed at addressing cognitive impairment, vagus nerve stimulation (VNS) is a therapeutic approach, which was used in many mental disordered diseases, through the modulation of vagus nerve activity. In POCD model, the enhancement of cognition function provided by VNS was shown, demonstrating VNS effect on cognition in POCD. In the present study, we primarily concentrates on elucidating the role of the VNS improving the cognitive function in POCD, via two potential mechanisms: the inflammatory microenvironment and epigenetics. This study provided a theoretical support for the feasibility that VNS can be a potential method to enhance cognition function in POCD.

The effect of pre-operative exercise training on post-operative cognitive function: a systematic review.

With population aging and advances in surgical and anesthetic procedures, the incidence of surgery in patients over the age of 65 years is increasing. One post-operative complication often encountered by older surgical patients is post-operative cognitive dysfunction (POCD). Preoperative exercise training can improve the overall physiological resilience of older surgical patients, yet its impact on post-operative cognition is less well-established. Six databases (Medline (OVID); EMBASE (OVID); EMCARE (OVID); CINAHL (EBSCOHost), the Cochrane Library, and PubMed) were searched for studies reporting the effect of pre-operative physical training on post-operative cognition. The quality of evidence was assessed using the Mixed Methods Assessment Tool. A total of 3983 studies were initially identified, three of which met the inclusion criteria for this review. Two studies were pilot randomized trials, and one was a prospective randomized trial. Two of the studies were high-quality. Each study used a different type of physical exercise and cognition assessment tool. Across the studies, post-operative cognition (p = 0.005) and attention (p = 0.04) were found to be better in the intervention groups compared to control, with one study reporting no difference between the groups. Preoperative physical training may improve post-operative cognitive function, although more research with a consistent endpoint is required. Future studies should focus on patients at high risk of POCD, such as older adults, and explore the impact of different exercise regimes, including frequency, intensity, time, and type.

Role of Microglial Mitophagy in Alleviating Postoperative Cognitive Dysfunction: a Mechanistic Study.

Postoperative cognitive dysfunction (POCD), a common complication following anesthesia and surgery, is influenced by hippocampal neuroinflammation and microglial activation. Mitophagy, a process regulating inflammatory responses by limiting the accumulation of damaged mitochondria, plays a significant role. This study aimed to determine whether regulating microglial mitophagy and the cGAS-STING pathway could alleviate cognitive decline after surgery. Exploratory laparotomy was performed to establish a POCD model using mice. Western blotting, immunofluorescence staining, transmission electron microscopy, and mt-Keima assays were used to examine microglial mitophagy and the cGAS-STING pathway. Quantitative polymerase chain reaction (qPCR) was used to detect inflammatory mediators and cytosolic mitochondrial DNA (mtDNA) levels in BV2 cells. Exploratory laparotomy triggered mitophagy and enhanced the cGAS-STING pathway in mice hippocampi. Pharmacological treatment reduced microglial activation, neuroinflammation, and cognitive impairment after surgery. Mitophagy suppressed the cGAS-STING pathway in mice hippocampi. In vitro, microglia-induced inflammation was mediated by mitophagy and the cGAS-STING pathway. Small interfering RNA (siRNA) of PINK1 hindered mitophagy activation and facilitated the cytosolic release of mtDNA, resulting in the initiation of the cGAS-STING pathway and innate immune response. Microglial mitophagy inhibited inflammatory responses via the mtDNA-cGAS-STING pathway inducing microglial mitophagy and inhibiting the mtDNA-cGAS-STING pathway may be an effective therapeutic approach for patients with POCD.

Red light-induced localized release of carbon monoxide for alleviating postoperative cognitive dysfunction

Inflammation within the central nervous system (CNS), which may be triggered by surgical trauma, has been implicated as a significant factor contributing to postoperative cognitive dysfunction (POCD). The relationship between mitigating inflammation at peripheral surgical sites and its potential to attenuate the CNS inflammatory response, thereby easing POCD symptoms, remains uncertain. Notably, carbon monoxide (CO), a gasotransmitter, exhibits pronounced anti-inflammatory effects. Herein, we have developed carbon monoxide-releasing micelles (CORMs), a nanoparticle that safely and locally liberates CO upon exposure to 650 nm light irradiation. In a POCD mouse model, treatment with CORMs activated by light (CORMs + hv) markedly reduced the concentrations of interleukin (IL)-6, IL-1β, and tumor necrosis factor-alpha (TNF-α) in both the peripheral blood and the hippocampus, alongside a decrease in ionized calcium-binding adapter molecule 1 in the hippocampal CA1 region. Furthermore, CORMs + hv treatment diminished Evans blue extravasation, augmented the expression of tight junction proteins zonula occludens-1 and occludin, enhanced neurocognitive functions, and fostered fracture healing. Bioinformatics analysis and experimental validation has identified Htr1b and Trhr as potential key regulators in the neuroactive ligand-receptor interaction signaling pathway implicated in POCD. This work offers new perspectives on the mechanisms driving POCD and avenues for therapeutic intervention.

Exploring the Potential Role of Dexmedetomidine in Reducing Postoperative Cognitive Dysfunction in Elderly Hip Fracture Patients.

Hip fractures are prevalent in the elderly; however, Postoperative Cognitive Dysfunction (POCD) is a possible complication of hip fracture surgery in elderly patients. This study examines the influence and the underlying mechanism of dexmedetomidine on POCD in elderly patients following hip fracture surgery. The retrospective study involved elderly patients with hip fracture who were treated at the Fifth Affiliated Hospital of Xinjiang Medical University from October 2021 to August 2022. During the surgery procedures, dexmedetomidine was administrated and the peripheral blood samples were collected from the patients. Inflammatory factors were measured using Enzyme-linked immunosorbent assay (ELISA), while pyroptosis-related proteins were detected through quantitative reverse transcription PCR (RT-qPCR) and western blot. Additionally, the levels of CD4+T and CD8+T cells were assessed using flow cytometry. An aged rats hip fracture model was established to further investigate the impact of dexmedetomidine on postoperative mobility, cognition function, pyroptosis and immune cells in rats. Postoperative cognitive function in patients did not show significant alteration when compared with pre-operation levels (p > 0.05). There were notable reduction in the levels of interleukin-18 (IL-18), Caspase-3, Gasdermin-D (GSDMD) and NLR Family Pyrin Domain Containing 3 (NLRP3) (p < 0.001), accompanied by an increase in the proportion of CD4+T cells and an decrease in CD8+T cells after operation (p < 0.01). In aged rats, postoperative exploratory activities increased compared to their preoperative state. Compared with preoperative levels, the levels of interleukin-1β (IL-1β), IL-18, Caspase-3, GSDMD, and NLRP3 were significantly decreased (p < 0.001), the proportion of CD4+T cells was increased, and the proportion of CD8+T cells was decreased postoperatively (p < 0.01). Although there was no significant alteration in postoperative cognitive function in patients, dexmedetomidine may still play a role in mitigating POCD potentially due to its effects on reducing immune inflammation and pyroptosis markers. Further research is needed to fully understand the underlying mechanisms and its clinical implications.

Acute changes in hippocampal metabolism after anesthesia and surgery: Implications for perioperative neurocognitive disorder

BackgroundThe risk of developing dementia is higher in individuals who suffer from perioperative neurocognitive disorder (PND), including postoperative cognitive dysfunction (POCD) and delirium. Recent studies have indicated correlations between anesthesia, surgery and PND. Acute metabolic changes induced by anesthesia and surgery may be related to cognitive impairments. Despite a paucity of research on acute metabolic changes in the hippocampus during surgery, there are conflicting about specific metabolites. MethodsWe developed a mouse model of cognitive impairment induced by isoflurane anesthesia and unilateral nephrectomy. Cognition was evaluated by Y maze and fear conditioning test (FCT). The hippocampus was harvested after the surgery. LC-MS (liquid chromatography-mass spectrometry) was performed. The differential metabolites involved in lipid, amino acid, nucleotide, carbohydrate metabolism were analyzed. ResultsAnesthesia and surgery exposure induced cognition decline. A total of 49 metabolites were significantly up-regulated and 122 down-regulated. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway of the metabolites identified purine, glutathione, nicotinate and nicotinamide metabolism. Metabolites involved in lipid, amino acid, nucleotide, carbohydrate metabolism were identified including nicotinamide adenine dinucleotide (NAD), 1-Methylnicotinamide, propionic acid, histidine, adenosine, and guanosine cyclic monophosphate. Some metabolites exhibited a consistent change trend in the hippocampus of aging mice. ConclusionsThe study indicates that anesthesia and surgery can induce acute alterations in hippocampal metabolomics, including metabolites involved in lipid, amino acid, nucleotide, and carbohydrate metabolism. These metabolites may play a role in modulating PND through the regulation of neuroinflammation, oxidative stress, blood-brain barrier (BBB) permeability.

Gut microbiota-derived metabolite trimethylamine N-oxide aggravates cognitive dysfunction induced by femoral fracture operation in mice.

An increasing number of elderly individuals are experiencing postoperative cognitive dysfunction (POCD) problems after undergoing hip replacement surgery, with gut microbiota metabolites playing a role in its pathogenesis. Among these, the specific effects of trimethylamine N-oxide (TMAO) on POCD are still unclear. This study aimed to explore the role of TMAO on cognitive dysfunction and underlying mechanisms in mice. The POCD model was created through femoral fracture surgery in elderly mice, followed by cognitive function assessments using the Morris Water Maze and Novel Object Recognition tests. The gut microbiota depletion and fecal microbiota transplantation were performed to examine the relationship between TMAO levels and cognitive outcomes. The effects of TMAO treatment on cognitive dysfunction, microglial activation, and inflammatory cytokine levels in the brain were also evaluated, with additional assessment of the role of microglial ablation in reducing TMAO-induced cognitive impairment. Elevated TMAO levels were found to be associated with cognitive decline in mice following femoral fracture surgery, with gut microbiota depletion mitigating both TMAO elevation and cognitive dysfunction. In contrast, fecal microbiota transplantation from postoperative mice resulted in accelerated cognitive dysfunction and TMAO accumulation in germ-free mice. Furthermore, TMAO treatment worsened cognitive deficits, neuroinflammation, and promoted microglial activation, which were reversed through the ablation of microglia. TMAO exacerbates cognitive dysfunction and neuroinflammation in POCD mice, with microglial activation playing a crucial role in this process. Our findings may provide new therapeutic strategies for managing TMAO-related POCD and improving the quality of life for elderly patients.

Modulating neuroinflammation and cognitive function in postoperative cognitive dysfunction via CCR5-GPCRs-Ras-MAPK pathway targeting with microglial EVs.

Postoperative cognitive dysfunction (POCD) is prevalent among the elderly, characterized primarily by cognitive decline after surgery. This study aims to explore how extracellular vesicles (EVs) derived from BV2 microglial cells, with and without the C-C chemokine receptor type 5 (CCR5), affect neuroinflammation, neuronal integrity, and cognitive function in a POCD mouse model. We collected EVs from LPS-stimulated BV2 cells expressing CCR5 (EVsM1) and from BV2 cells with CCR5 knockdown (EVsM1-CCR5). These were administered to POCD-induced mice. Protein interactions between CCR5, G-protein-coupled receptors (GPCRs), and Ras were analyzed using structure-based docking and co-immunoprecipitation (Co-IP). We assessed the phosphorylation of p38 and Erk, the expression of synaptic proteins PSD95 and MAP2, and conducted Morris Water Maze tests to evaluate cognitive function. Structure-based docking and Co-IP confirmed interactions between CCR5, GPR, and Ras, suggesting a CCR5-GPCRs-Ras-MAPK pathway involvement in neuroinflammation. EVsM1 heightened neuroinflammation, reduced synaptic integrity, and impaired cognitive function in POCD mice. In contrast, EVsM1-CCR5 reduced neuroinflammatory markers, preserved synaptic proteins, enhanced dendritic spine structure, and improved cognitive outcomes. EVsM1 induced neuroinflammation via the CCR5-GPCRs-Ras-MAPK pathway, with EVsM1-CCR5 showing protective effects on POCD progression, suggesting a new therapeutic strategy for POCD management via targeted modification of microglial EVs.

Postoperative Cognitive Dysfunction: A Review.

Elderly patients are more vulnerable to cognitive dysfunction in the postoperative period. Patients who are apparently well in cognitive functions in the preoperative period after undergoing anesthesia in noncardiac surgery will develop symptoms of cognitive dysfunction. Postoperative cognitive dysfunction (POCD) doesn't continue for a long duration and usually undergoes self-resolution. Proper definitions and congruous tests for diagnosis are absent. Rigorous preoperative assessment of cognitive function and distinguishing risk factors are indispensable for recognizing the range of POCD and its association with surgery and anesthesia. Recent studies haven't revealed any anesthesia technique or drug which can significantly reduce the incidence of POCD. Therefore, giving accurate information to patients can be challenging.

Exploring Cognitive Changes in High-Risk Cardiac Patients Receiving Dexmedetomidine and Evaluating the Correlation between Different Cognitive Tools: A Cohort Study.

Mini-mental State Examination (MMSE) is widely accepted clinically for postoperative cognitive dysfunction (POCD) assessment. This study aims to investigate the post-operative cognitive changes among high-risk cardiothoracic patients and establish a standardised approach to post-surgery cognitive assessment. This is a prospective cohort study, where cognitive assessments were done 1-day before surgery, at discharge, and during 6 weeks of follow-up. Sample size calculation, accounting for an estimated 20% dropout rate, determined a minimum of 170 subjects were required for the study. Reduction of MMSE score of more than 2.5 was considered as having POCD. Score differences between groups were analysed using T-test and analysis of variance (ANOVA), while consistency between tools was analysed using correlation and regression. A total of 188 patients completed the study, with a POCD prevalence of 20.2% and 6.9% at discharge and at the 6 week follow up, respectively. All cognitive tools show a significant difference between preoperative and postoperative scores. All tests show a significant moderate correlation with MMSE. In conclusion, it is imperative to employ a battery of cognitive assessments to evaluate cognitive changes comprehensively.

CD33 Ameliorates Surgery-Induced Spatial Learning and Memory Impairments Through TREM2.

Neuroinflammation is implicated in the onset of postoperative cognitive dysfunction (POCD), with CD33 and triggering receptor expressed on myeloid cells 2 (TREM2) playing crucial roles in immune response modulation and neuroinflammatory processes. A total of 96 aged male C57/BL6 mice (9-12 months) were randomly assigned to one of four groups, each receiving an siRNA injection into the lateral ventricle. Subsequently, the mice underwent partial hepatectomy under general anesthesia. To assess cognitive function, the Morris water maze tests were conducted both pre- and post-surgery. Following behavioral assessments, hippocampal tissues were swiftly harvested. The regulation of CD33 and TREM2 expression was achieved through siRNA in the BV2 microglia cell line. Expression levels of CD33 and TREM2 were evaluated both in vitro and in vivo using quantitative RT-PCR and western blot analyses. This study explored the impact of CD33 and TREM2 on POCD in aged mice and revealed that surgery and anesthesia increased CD33 expression, leading to spatial learning and memory impairments. Inhibiting CD33 expression via siRNA administration ameliorated cognitive deficits and mitigated the neuroinflammatory response triggered by surgery. Additionally, CD33 inhibition reversed the surgery-induced decrease in synaptic-related proteins, highlighting its role in preserving synaptic integrity. Moreover, our experiments suggest that CD33 may influence neuroinflammation and cognitive function through mechanisms involving TREM2. This is evidenced by the suppression of pro-inflammatory cytokines following CD33 knockdown in microglia and the reversal of these effects when both CD33 and TREM2 are concurrently knocked down. These findings imply that CD33 might promote neuroinflammation by inhibiting TREM2. This study highlights the potential of targeting CD33 as a promising therapeutic strategy for preventing and treating POCD. It provides valuable insights into the intricate mechanisms underlying cognitive dysfunction following surgical procedures.

Cognitive dysfunction in older patients undergoing non-neurosurgery in the immediate postoperative period: A systematic review.

To explore the risk factors associated with postoperative cognitive dysfunction in older patients within the first 7 days after non-neurosurgical surgery and anaesthesia. A systematic review. Following, PRISMA 2020 (Preferred Reporting Items for Systematic Reviews and Meta-analyses). Checklist, a systematic review of studies published from January 2018 to January 2024. The literature search was conducted across six electronic online databases, including PubMed, EMBASE, Scopus, Ovid, MEDLINE and Science Direct, and the Johns Hopkins Nursing Evidence-Based Practice Evidence Rating Scale was used for study appraisal. The initial search yielded 1750 studies. The review included 19 studies which comprised prospective observational, case-control and retrospective studies. The prevalence of postoperative cognitive dysfunction ranged from 19% to 64% among older adults undergoing non-neurosurgery. The identified risk factors were classified into three phases including preoperative, intraoperative and postoperative. Preoperative risk factors were found in age, educational attainment, malnutrition, preoperative biomarkers and co-morbidities. Intraoperative risk factors were the duration of the operation, blood loss during the operation and anaesthesia used. Postoperative risk factors consisted of postoperative biomarkers and postoperative pain. The result from this review may assist researchers and healthcare providers in assessing the underlying causes and risk factors of postoperative cognitive dysfunction, and in formulating suitable preventative and therapeutic strategies for older adults with non-neurosurgery during the short-term postoperative period.

Ginsenoside Rg1 protects the blood-brain barrier and myelin sheath to prevent postoperative cognitive dysfunction in aged mice.

In this study, the postoperative cognitive dysfunction (POCD) mouse model was established to observe the changes in inflammation, blood-brain barrier permeability, and myelin sheath, and we explore the effect of ginsenoside Rg1 pretreatment on improving POCD syndrome. The POCD model of 15- to 18-month-old mice was carried out with internal fixation of tibial fractures under isoflurane anesthesia. Pretreatment was performed by continuous intraperitoneal injection of ginsenoside Rg1(40 mg/kg/day) for 14 days before surgery. The cognitive function was detected by the Morris water maze. The contents of interleukin-1β and tumor necrosis factor-α in the hippocampus, cortex, and serum were detected by ELISA. The permeability of blood-brain barrier was observed by Evans blue. The mRNA levels and protein expression levels of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase), myelin basic protein (MBP), beta-catenin, and cyclin D1 in the hippocampus were analyzed by quantitative PCR and western blotting. The protein expression levels of ZO-1 and Wnt1 in the hippocampus were analyzed by western blotting. Finally, the localizations of CNPase and MBP in the hippocampus were detected by immunofluorescence. Ginsenoside Rg1 can prevent POCD, peripheral and central inflammation, and blood-brain barrier leakage, and reverse the downregulation of ZO-1, CNPase, MBP, and Wnt pathway-related molecules in aged mice. Preclinical studies suggest that ginsenoside Rg1 improves postoperative cognitive function in aged mice by protecting the blood-brain barrier and myelin sheath, and its specific mechanism may be related to the Wnt/β-catenin pathway.

Mdivi-1 alleviates ferroptosis induced by hypoxia combined with propofol in HT22 cells by inhibiting excessive mitophagy.

Pediatric postoperative cognitive dysfunction (POCD) is a prevalent complication following anesthesia and surgery. Hypoxia and propofol are the primary risk factors contributing to pediatric POCD. Our previous in vivo animal research has demonstrated that cognitive dysfunction in immature Sprague-Dawley (SD) rats, induced by hypoxia combined with propofol (HCWP), is closely associated with hippocampal neuron ferroptosis. In vivo transcriptome sequencing and KEGG functional analysis revealed significant enrichment of the mitophagy pathway. To further elucidate the relationship between mitophagy and ferroptosis, HT22 cells were selected to construct an in vitro HCWP model. Our findings indicate that HCWP activates excessive mitophagy in HT22 cells, leading to decreased mitochondrial membrane potential (ΔΨm), reactive oxygen species (ROS) burst, mitochondrial fragmentation, and the induction of ferroptosis. To explore this causal relationship further, we employed Mdivi-1, a mitophagy inhibitor. Notably, low-dose Mdivi-1 (10 µM) effectively suppressed excessive mitophagy in HT22 cells, improved mitochondrial function and morphology, and mitigated markers associated with ferroptosis. The mechanism by which Mdivi-1 alleviates HCWP-induced ferroptosis in HT22 cells is likely due to its inhibition of excessive mitophagy, thereby promoting mitochondrial homeostasis. Our study suggests that mitophagy may be an upstream event in HCWP-induced ferroptosis in HT22 cells. Consequently, targeted regulation of mitophagy by Mdivi-1 may represent a promising approach to prevent cognitive dysfunction following HCWP exposure.

Involvement of selected circulating ncRNAs in the regulation of cognitive dysfunction induced by anesthesia

Post-operative cognitive dysfunction (POCD) refers to the functional impairment of the nervous system caused by prolonged exposure to anesthetics. It is known that prolonged exposure to anesthetics may increase the risk for the development of several cognitive impairments. The drugs used to induce general anesthesia are generally safe, owing to the CNS’s direct and/or indirect self-protective activity against drug-induced damages. Non-coding RNAs have recently started to gain attention to better understand the mechanism of gene regulation correlated to cellular physiology and pathology. In order to provide new insights for the neuroprotective function of highly expressed ncRNAs in the central nervous system, we investigated their expression profile in the circulating exosomes of patients exposed to anesthesia vs healthy controls. The experimental design envisaged the recruitment of 30 adult patients undergoing general anesthesia and healthy controls. The effects of anesthetics have been evaluated on miR-34a and miR-124, on the lncRNAs MALAT-1, HOTAIR, GAS5, BLACAT1, HULC, PANDA, and on YRNAs. NcRNAs miR-34a, miR-124, MALAT-1, HOTAIR, GAS5, BLACAT1, and YRNA1 are significantly overexpressed following anesthesia, while YRNA5 is significantly down regulated. Some of them have neuroprotective function, while other correlate with neurological dysfunctions. Our data suggests that, during anesthesia, the toxic action of some non-coding RNAs could be compensated by other non-coding RNAs, both synthesized by the CNS or also transported into neurons from other tissues. It is reasonable to suppose a mutual action of these molecules likely to secure the CNS from anesthetics, that drive a convoluted cascade of ncRNA-dependent biological counter-responses. Our findings are novel in the field of brain dysfunction, indicating that some of the analyzed ncRNAs, although several of their functions still need to be addressed, could be suggested as potential biomarkers and therapeutic targets in post-operative cognitive dysfunction-related processes.

Foxq1 activates CB2R with oleamide to alleviate POCD.

Postoperative cognitive dysfunction (POCD) is a major concern, particularly among older adults. This study used social isolation (ISO) and multiomics analyses in aged mice to investigate potential mechanisms underlying POCD development. Aged mice were divided into two groups: ISO and paired housing (PH). Oleamide and the cannabinoid receptor type 2 (CB2R) antagonist AM630 were administered intraperitoneally, while Foxq1 adeno-associated viral (AAV) vector was injected directly into the hippocampus. Intramedullary tibial surgeries were subsequently performed to establish the POCD models. Behavioral tests comprising the Y-maze, open field test, and novel object recognition were conducted 2 days after surgery. Hippocampal and serum inflammatory cytokines were assessed. Following surgery, ISO mice demonstrated intensified cognitive impairments and escalated inflammatory markers. Integrative transcriptomic and metabolomic analysis revealed elevated oleamide concentrations in the hippocampus and serum of PH mice, with associative investigations indicating a close relationship between the Foxq1 gene and oleamide levels. While oleamide administration and Foxq1 gene overexpression substantially ameliorated postoperative cognitive performance and systemic inflammation in mice, CB2R antagonist AM630 impeded these enhancements. The Foxq1 gene and oleamide may be crucial in alleviating POCD. While potentially acting through CB2R-mediated pathways, these factors may modulate neuroinflammation and attenuate proinflammatory cytokine levels within the hippocampus, substantially improving cognitive performance postsurgery. This study lays the groundwork for future research into therapeutic approaches targeting the Foxq1-oleamide-CB2R axis, with the ultimate goal of preventing or mitigating POCD.

Macrophage-derived exosomes exacerbate postoperative cognitive dysfunction in mice through inflammation

This study investigated the impact of two-hit inflammation on postoperative cognitive dysfunction (POCD) in mice and the role of macrophage-derived exosomes in regulating this process. Mice models were used to mimic the state of two-hit inflammation, and cognitive function was assessed through behavioral experiments. Proinflammatory cytokine expression levels and blood-brain barrier (BBB)-associated functional proteins were measured using ELISA and Western blot, respectively. An in vitro macrophage inflammation two-hit model was created, and the role of exosomes was examined using the previously mentioned assays. Additionally, exosomes were injected into mice to further understand their impact in the two-hit inflammation model. Mice exposed to two-hit inflammation experienced impaired cognitive function, increased BBB permeability, and elevated levels of proinflammatory cytokines. Macrophages subjected to two-hit inflammation released higher levels of proinflammatory cytokines compared to the control group and other treatment groups. Treatment with an exosome inhibitor GW4869 effectively reduced the expression levels of proinflammatory cytokines in macrophages exposed to two-hit inflammation. Moreover, injection of macrophage-released exosomes into healthy mice induced inflammation, hippocampal damage, and cognitive disorders, which were mitigated by treatment with GW4869. In mice with two-hit inflammation, macrophage-released exosomes worsened cognitive disorders by promoting inflammation in the peripheral blood and central nervous system. However, treatment with GW4869 protected cognitive function by suppressing exosome release. These findings highlight the importance of two-hit inflammation in POCD and emphasize the critical role of exosomes as regulatory factors. This research provides valuable insights into the pathogenesis of POCD and potential intervention strategies.

The Role of Cerebral Oximetry in Predicting and Preventing Postoperative Cognitive Dysfunction

Postoperative Cognitive Dysfunction (POCD) is a serious problem that is frequently seen especially in elderly patients and can cause permanent cognitive decline, prolonged hospital stay, loss of independence, decreased quality of life and even mortality. Identifying individuals at risk of developing POCD can prevent this condition by enabling the development of early interventions. POCD has a multifactorial etiology, and intraoperative cerebral perfusion disorder is considered to be one of these mechanisms. Near-infrared Spectroscopy (NIRS) device provides monitoring of regional brain oxygenation. There are studies on the predictability and preventability of cognitive disorders that may develop after surgery with the use of NIRS. In this article, it is aimed to present the study results and inferences regarding the relationships between the areas of use of NIRS and the pathogenesis of POCD.

Recombinant chitinase-3-like protein 1 alleviates learning and memory impairments via M2 microglia polarization in postoperative cognitive dysfunction mice.

Postoperative cognitive dysfunction is a severe complication of the central nervous system that occurs after anesthesia and surgery, and has received attention for its high incidence and effect on the quality of life of patients. To date, there are no viable treatment options for postoperative cognitive dysfunction. The identification of postoperative cognitive dysfunction hub genes could provide new research directions and therapeutic targets for future research. To identify the signaling mechanisms contributing to postoperative cognitive dysfunction, we first conducted Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of the Gene Expression Omnibus GSE95426 dataset, which consists of mRNAs and long non-coding RNAs differentially expressed in mouse hippocampus 3 days after tibial fracture. The dataset was enriched in genes associated with the biological process "regulation of immune cells," of which Chill was identified as a hub gene. Therefore, we investigated the contribution of chitinase-3-like protein 1 protein expression changes to postoperative cognitive dysfunction in the mouse model of tibial fracture surgery. Mice were intraperitoneally injected with vehicle or recombinant chitinase-3-like protein 1 24 hours post-surgery, and the injection groups were compared with untreated control mice for learning and memory capacities using the Y-maze and fear conditioning tests. In addition, protein expression levels of proinflammatory factors (interleukin-1β and inducible nitric oxide synthase), M2-type macrophage markers (CD206 and arginase-1), and cognition-related proteins (brain-derived neurotropic factor and phosphorylated NMDA receptor subunit NR2B) were measured in hippocampus by western blotting. Treatment with recombinant chitinase-3-like protein 1 prevented surgery-induced cognitive impairment, downregulated interleukin-1β and nducible nitric oxide synthase expression, and upregulated CD206, arginase-1, pNR2B, and brain-derived neurotropic factor expression compared with vehicle treatment. Intraperitoneal administration of the specific ERK inhibitor PD98059 diminished the effects of recombinant chitinase-3-like protein 1. Collectively, our findings suggest that recombinant chitinase-3-like protein 1 ameliorates surgery-induced cognitive decline by attenuating neuroinflammation via M2 microglial polarization in the hippocampus. Therefore, recombinant chitinase-3-like protein 1 may have therapeutic potential for postoperative cognitive dysfunction.