Association of global DNA hypomethylation with post‐operative cognitive dysfunction in elderly patients undergoing hip surgery

Abstract

Post-operative cognitive dysfunction (POCD) is a decline in cognitive status after surgery, typically manifesting as alterations in orientation, memory, thinking, attention, insight or other aspects of central nervous system function. 1 POCD can last for a few days to years and is associated with adverse effects, including increased surgical morbidity and mortality, hospitalization and out-of-hospital care costs. For patients older than 60 years-of-age, POCD occurred in 25% to 40% of patients 1 week after non-cardiac surgery. 2-4 Accumulating evidence suggests that anesthetics, surgical stress, hypo-perfusion, and inflammatory responses may contribute to the risk of POCD. 5 Recent studies also indicate that genetic factors contribute to this post-operative neurologic injury. 6,7 However, the traditional explanations are not sufficient to explain the complex interaction between POCD, environment, and genetics.Epigenetic modification emerges as an important mechanism of regulating gene-environment interaction, and its critical function in Background: Post-operative cognitive dysfunction (POCD) is a decline of cognitive status that commonly occurs after surgery in elderly patients. Whether DNA methylation is associated with the development of POCD remains unclear.Methods: Subjects (N = 124) older than 65 years-of-age undergoing hip replacement surgery were enrolled. A battery of neuropsychiatric tests was used to examine the perioperative cognitive function of the patients. Early POCD was analyzed using the reliable change index (RCI), and subjects were diagnosed with POCD if RCI < −1.96.Peripheral leukocyte DNA was isolated, and DNA methylation was measured via 5-methylcytosine (mC) using Elisa. Results:Twenty-four patients (19.4%) developed early POCD. There was no difference in baseline 5-mC levels by POCD status. The 5-mC levels significantly decreased on day 7 after surgery in patients who developed early POCD (P = .004), but did not change in non-POCD patients. Moreover, post-operative 5-mC levels were significantly lower in POCD patients than those in non-POCD patients (P = .003). Bivariate logistic models adjusted for age, gender, BMI, duration of anesthesia, and education level clearly demonstrated an independent association between post-operative 5-mC level and early POCD. Conclusions:Post-operative global hypomethylation of leukocyte DNA was associated with the development of early POCD. Trial registration: ClinicalTrial, NCT02965235. Registered 16 November 2016, https ://www.clini caltr ials.gov/ct2/resul ts?term=NCT02 96523 5&rank=1#rowId0

Post-Operative Cognitive Impairment: A Cognitive Epidemiology Perspective

“…To name one landmark study included in the meta-analysis, the International Study of Post-Operative Cognitive Dysfunction (ISPOCD 1), found that among 1011 older surgical patients recruited in eight European countries and the USA, patients with more than a high school education had even a halved risk of POCD at one week after surgery compared with patients with less than high school education ( Moller et al 1998 ). Studies from various European and Asian countries and the USA that were not included in the 2017 meta-analysis ( Grichnik et al 1999 ) or published thereafter ( Bendikaite and Vimantaite 2020 ; Ehsani et al 2020 ; Huang et al 2020a ; Klinger et al 2019 ; Li et al 2020 ; Wang et al 2018 ; Yuhe et al 2020 ; Zhang et al 2019 ; Zhou et al 2020 ) too, consistently indicate that patients with a lower educational level are at increased POCD risk at discharge ( Zhang et al 2019 ) within days of surgery ( Ehsani et al 2020 ; Li et al 2020 ; Zhao et al 2020 ; Zhou et al 2020 ) but also during six to 12 weeks after surgery ( Grichnik et al 1999 ; Yuhe et al 2020 ). The fact that observations extend to several months after surgery is important because studies on POCD with longer follow-up periods offer preferred scope for conclusions: during shorter follow-up periods immediate effects of surgery on brain function including a potential influence of POD can prevail.…”

Global DNA hypomethylation in hysterectomy: An 8-year follow-up study from Haryana, India

“…Only a few studies thus far have evaluated post-operative acute epigenetic changes for any kind of surgery (except bariatric surgery). [13][14][15] Studies have shown alterations in gene-speci c and global DNA methylation levels during and after the surgery; however, no consistent trend has been reported. [13][14][15] Again, no study has explored long-term and persistent epigenetic changes after the surgery (except in the case of bariatric surgery).…”

A decrease in NR2B expression mediated by DNA hypermethylation induces perioperative neurocognitive disorder in aged mice

“…However, similar results were observed in the processes of aging and carcinogenesis. 9 , 38 Indeed, studies on PND have also observed global DNA hypomethylation, 11 , 39 and DNA hypermethylation of several genes (e.g. glucocorticoid receptor, Arc, Bdnf, Reln, PSD‐95 ), 10 , 40 , 41 indicating that the global DNA methylation status did not necessarily reflect the methylation of specific genes.…”

“…transcription factors) 8 . An imbalance of DNA methylation has been regarded as a valuable biomarker for aging and aging‐related pathologies, including PND 9–11 . Importantly, previous studies have reported that methylation at specific CpG sites around the promoter of NR2B gene will downregulate NR2B transcription 12,13 .…”

“… 8 An imbalance of DNA methylation has been regarded as a valuable biomarker for aging and aging‐related pathologies, including PND. 9 , 10 , 11 Importantly, previous studies have reported that methylation at specific CpG sites around the promoter of NR2B gene will downregulate NR2B transcription. 12 , 13 However, whether DNA methylation is involved in the regulation of NR2B by laparotomy and the associated cellular mechanism is still unknown.…”