Development of a cognitive function marker based on D-amino acid proportions using new chiral tandem LC-MS/MS systems

The incidence of dementia, a clinical symptom characterized by severe cognitive decline, is increasing worldwide. Predictive biomarkers are therefore required for early identification and management. D-amino acids in the brain contribute to cognitive function and are suggested as useful biomarkers for diagnosing dementia risk. To clarify their relationship with human cognitive decline, we developed an identification method of chiral metabolomics for detecting slight differences in chiral amino acid amounts. Chiral tandem liquid chromatography-tandem mass spectrometry systems were applied for sensitive and selective amino acid species along with chiral species determination based on anion and zwitterion exchange mechanisms. In a comprehensive health cohort (cross-sectional study), we measured blood chiral amino acid levels from 305 women (65-80 years old) classified into Control, Mild-cognitive-Impairment (MCI), and Dementia groups using the Mini-Mental State Examination. MCI exhibited higher D-Pro (D-Pro/(D-Pro+L-Pro)) proportion vs the Control group, suggesting this proportion as a useful biomarker for MCI. Biomarker accuracy was improved in combination with D-Ser proportion. Receiver operating characteristics analysis of the Control vs. MCI proportion obtained area under the curve (0.80) with 70% sensitivity and 84% specificity at the optimal cutoff value (0.30). Thus, dementia monitoring can be improved by including trace D-amino acids measurements.