Low blood S-methyl-5-thioadenosine is associated with postoperative delayed neurocognitive recovery

Abstract

Abstract Background Elderly individuals display metabolite alterations that may contribute to development of cognitive impairment following surgery and exposure to anesthesia. However, these relationships remain largely unexplored. We assessed altered metabolites following anesthesia/surgery in both mouse models and human patients to identify blood biomarkers of delayed neurocognitive recovery (dNCR). Methods We used metabolomics to evaluate metabolite levels in the brains of mice following exposure to anesthesia. We also clinically evaluated 67 elderly patients who had neck and maxillofacial tumor resection under general anesthesia. Presence of dNCR was assessed with the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Preoperative and postoperative plasma metabolites were determined by widely targeted metabolomics. Results The brains of mice with anesthesia/surgery-induced cognitive dysfunction showed decreased S-methyl-5-thioadenosine (MTA) levels and activated MTA phosphorylase (MTAP). Mouse models also showed that preoperative administration of MTA could prevent inflammation and cognitive decline. In clinical patients, we detected lower preoperative serum MTA levels (adjusted OR: 0.094; 95% CI: 0.014–0.477; P = 0.008, per ng/mL) in those who developed dNCR following anesthesia/surgery. Further, anesthesia/surgery decreased serum MTA levels compared to preoperative levels (adjusted OR: 0.057; 95% CI: 0.005–0.376; P = 0.008, per ng/mL). Both low preoperative and postoperative blood MTA levels were associated with increased risk of postoperative dNCR. Conclusions These results suggest that anesthesia/surgery induces cognitive decline through pathways involving inflammation and methionine synthesis and that MTA could be a perioperative predictor of dNCR as well as a potential therapeutic target. Trial registration: This prospective observational cohort study was registered with clinicaltrials.gov (No. NCT05105451; May 28, 2021; Hong Jiang). The study was performed in 2021 to 2022 at the Shanghai Ninth People’s Hospital at Shanghai Jiao Tong University School of Medicine in Shanghai, China. Ethics approval was obtained from the Ethics Committee of Shanghai Ninth People’s Hospital (SH9H-2021-T120).