Higher Plasma Kynurenine to Tryptophan Correlates with Increased Incidence of Mild Cognitive Impairment in Treated Metabolic Syndrome Patients

An increase in cognitive impairment has been observed in metabolic syndrome (MetS) patients. Although alterations in metabolomic profiles have been identified as potential plasma/serum biomarkers of mild cognitive impairment (MCI) and MetS, findings remain inconsistent— likely due to the heterogeneity among MetS patients and the lack of subsequent validation using targeted analysis after initial untargeted analysis. In this study, we validated mass spectrometry-based quantitation methods and quantified amino acids, fatty acids, and tryptophan metabolites in the kynurenine pathway in plasma of ninety-five treated MetS patients with and without MCI assessed by Montreal cognitive assessment. We found that MCI was positively associated with kynurenine to tryptophan ratio (KTR) after the adjustment for age, gender, and BMI, as well as were negatively associated with C20:3 [all-Z-8,11,14] and lysine. One-unit increase in KTR resulted in increased probability of developing MCI by 371%. In contrast, one-unit increases in C20:3 and lysine were associated with decreased odds of developing MCI by 81% and 78%, respectively. Our finding underscores the prominent neuroinflammation, beyond normal aging, in MetS patients, even under ongoing clinical treatment. It also points to the potential of KTR as a risk marker for MCI, offering a valuable complement to the existing cognitive assessments that may be influenced by educational background. In addition, the validated metabolite data is an useful resource for future research. It can facilitate comparisons across different studies, contribute to large-scale analyses, and be used in machine learning models for discovering and validating new biomarkers.