PREDICTION OF POSTOPERATIVE DELIRIUM BY BLOOD METABOLOME

Abstract Background Delirium is a notable risk factor for cognitive dysfunction and poor prognosis. Despite its importance, there is currently no established blood marker that can predict postoperative delirium in the preoperative period. Aims & Objectives We aimed to examine that water-soluble metabolites, lipids, and cytokines in peripheral blood could uniquely classify postoperative delirium. In addition, we investigated whether changes in neuroinflammation-related and water-soluble metabolites in the indoleamine 2,3-dioxygenase (IDO) pathway could predict postoperative delirium. Method We designed a prospective cohort study of postoperative delirium and received approval from the Keio University School of Medicine Ethics Committee in December 2017. We used a comprehensive metabolomics and cytokine panel analysis involving 18 subjects in the delirium group and 24 subjects in the non-delirium group to determine whether preoperative blood metabolites, lipids, and cytokines could predict postoperative delirium. We also performed non-targeted metabolomics to investigate unanticipated small molecular weight metabolites in addition to IDO pathway metabolites and their correlations with cytokines indicative of an activated immune state. In addition, we conducted an in vitro experiment to test secretion with T-cell receptor stimulation on T cells. Results & Discussion We found that preoperative levels of amino acid catabolites, especially tryptophan catabolites produced via the IDO pathway, were higher in the delirium group than in the non-delirium group. These catabolites were validated as reliable predictors of postoperative delirium. Interestingly, the delirium group had elevated levels of tryptophan catabolites even before surgery, but only a limited increase in these levels was observed postoperatively. This suggests that the tryptophan catabolic pathway may be activated preoperatively in patients at high risk for developing delirium. In addition, our non-targeted metabolomic analysis identified a set of preoperatively elevated gamma-glutamyl dipeptides as significant discriminators of postoperative delirium. In vitro experiments showed that T- cell receptor stimulation resulted in increased tryptophan metabolism and specific gamma-glutamyl dipeptide secretion, which may explain increased metabolic byproducts in postoperative delirium. Conclusion Our study highlights the potential of blood concentrations of amino acid catabolites and dipeptides, including those secreted extracellularly upon T-cell activation, as reliable predictors of postoperative delirium.