Gene-Specific DNA Methylation Linked to Postoperative Cognitive Dysfunction in Apolipoprotein E3 and E4 Mice

Background: Geriatric surgical patients are at higher risk of developing postoperative neurocognitive disorders (NCD) than younger patients. The specific mechanisms underlying postoperative NCD remain unknown, but they have been linked to genetic risk factors, such as the presence of APOE4, compared to APOE3, and epigenetic modifications caused by exposure to anesthesia and surgery. Objective: To test the hypothesis that compared to E3 mice, E4 mice exhibit a more pronounced postoperative cognitive impairment associated with differential DNA methylation in brain regions linked to learning and memory. Methods: 16-month-old humanized apolipoprotein-E targeted replacement mice bearing E3 or E4 were subjected to surgery (laparotomy) under general isoflurane anesthesia or sham. Postoperative behavioral testing and genome-wide DNA methylation were performed. Results: Exposure to surgery and anesthesia impaired cognition in aged E3, but not E4 mice, likely due to the already lower cognitive performance of E4 prior to surgery. Cognitive impairment in E3 mice was associated with hypermethylation of specific genes, including genes in the Ephrin pathway implicated in synaptic plasticity and learning in adults and has been linked to Alzheimer’s disease. Other genes, such as the Scratch Family Transcriptional Repressor 2, were altered after surgery and anesthesia in both the E3 and E4 mice. Conclusion: Our findings suggest that the neurocognitive and behavioral effects of surgery and anesthesia depend on baseline neurocognitive status and are associated with APOE isoform-dependent epigenetic modifications of specific genes and pathways involved in memory and learning.

The correlation of intraoperative hypotension and postoperative cognitive impairment: a meta-analysis of randomized controlled trials

Background: There is no consensus on whether intraoperative hypotension is associated with postoperative cognitive impairment. Hence, we performed a meta-analysis to evaluate the correlation of intraoperative hypotension and the incidence of postoperative delirium (POD) or postoperative cognitive dysfunction (POCD).Methods: We searched PubMed, Embase, and Cochrane Library databases to find randomized controlled trials (RCTs) in which reported the relationship between intraoperative hypotension and POD or POCD. The retrieval time is up to January 2020, without language restrictions. Quality assessment of the eligible studies was conducted by two researchers independently with the Cochrane evaluation system.Results: We analyzed five eligible RCTs. Based on the relative mean arterial pressure (MAP), participants were divided into low-target and high-target groups. For the incidence of POD, there were two studies with 99 participants in the low-target group and 94 participants in the high-target pressure group. For the incidence of POCD, there were four studies involved 360 participants in the low-target group and 341 participants in the high-target group, with a study assessed both POD and POCD. No significant difference between the low-target and the high-target group was observed in the incidence of POD (RR = 3.30, 95% CI 0.80 to 13.54, P = 0.10), or POCD (RR = 1.26, 95% CI 0.76 to 2.08, P = 0.37). Furthermore, it also demonstrates that intraoperative hypotension prolonged the length of ICU stay, but did not increased the mortality, the length of hospital stay, and mechanical ventilation (MV) time.Conclusions: There is no significant correlation between intraoperative hypotension and the incidence of POD or POCD. Keywords: Intraoperative hypotension, Postoperative delirium, Postoperative cognitive dysfunction, Meta-analysis

High-Pressure Pneumoperitoneum Aggravates Surgery-Induced Neuroinflammation and Cognitive Dysfunction in Aged Mice

Postoperative cognitive dysfunction (POCD) is a common complication after surgery, especially in aged patients. Neuroinflammation has been closely associated with the development of POCD. While the contribution of pneumoperitoneum to the systemic inflammation has been well documented, the effect of pneumoperitoneal pressure on neuroinflammation and postoperative cognitive function remains unclear. In this study, we showed that high-pressure pneumoperitoneum promoted the postoperative neuroinflammation and microglial activation in the hippocampus and aggravated the postoperative cognitive impairment in aged mice. These results support the requirement to implement interventions with lower intra-abdominal pressure, which allows for adequate exposure of the operative field rather than a routine pressure.

Presurgical Identification of Patients With Glioblastoma at Risk for Cognitive Impairment at 3-Month Follow-up

BACKGROUND Pre- and postoperative cognitive deficits have repeatedly been demonstrated in patients with glioblastoma (GBM). OBJECTIVE To identify presurgical risk factors that facilitate the identification of GBM patients at risk for postoperative cognitive impairment. METHODS Patients underwent neuropsychological assessment using Central Nervous System Vital Signs 1 d before (T0) and 3 mo after surgery (T3). Patients’ standardized scores on 7 cognitive domains were compared to a normative sample using one-sample z tests. Reliable change indices with correction for practice effects were calculated to assess cognitive changes in individual patients over time. Logistic regression models were performed to assess presurgical sociodemographic, clinical, psychological, and cognitive risk factors for postoperative cognitive impairments. RESULTS At T0, 208 patients were assessed, and 136 patients were retested at T3. Patients showed significantly lower performance both prior to and 3 mo after surgery on all cognitive domains compared to healthy controls. Improvements and declines over time occurred respectively in 11% to 32% and 6% to 26% of the GBM patients over the domains. The regression models showed that low preoperative cognitive performance posits a significant risk factor for postoperative cognitive impairment on all domains, and female sex was a risk factor for postoperative impairments in Visual Memory. CONCLUSION We demonstrated preoperative cognitive risk factors that enable the identification of GBM patients who are at risk for cognitive impairment 3 mo after surgery. This information can help to inform patients and clinicians at an early stage, and emphasizes the importance of recognizing, assessing, and actively dealing with cognitive functioning in the clinical management of GBM patients.

The correlation of intraoperative hypotension and postoperative cognitive impairment: a meta-analysis of randomized controlled trials

Background There is no consensus on whether intraoperative hypotension is associated with postoperative cognitive impairment. Hence, we performed a meta-analysis to evaluate the correlation of intraoperative hypotension and the incidence of postoperative delirium (POD) or postoperative cognitive dysfunction (POCD).Methods We searched PubMed, Embase, and Cochrane library databases to find randomized controlled trials (RCTs) in which reported the relationship of intraoperative hypotension and POD or POCD. The retrieval time is up to January 2020, without language restrictions. Quality assessment of the eligible studies was conducted by two researchers independently using the Cochrane evaluation system.Results Five RCTs were included. For the incidence of POD, there are two studies with 99 participants in the low-blood pressure (LP) group and 94 participants in the high-blood pressure (HP) group. For the incidence of POCD, there are four studies with 360 participants in the LP group and 341 participants in the HP group, with a study contains both POD and POCD. No significant difference between the LP and the HP group was observed in the incidence of POD (RR = 3.30, 95% CI 0.80 to 13.54, P = 0.10), or POCD (RR = 1.26, 95% CI 0.76 to 2.08, P = 0.37). Furthermore, it also demonstrated that intraoperative hypotension prolonged the length of ICU stay, but did not increased the mortality, the length of hospital stay, and mechanical ventilation (MV) time.Conclusions There is no significant correlation between intraoperative hypotension and the incidence of POD or POCD.