D-amino Acids as Novel Blood-based Biomarkers

Background: D-amino acids are present in the human body originating from diet, bacterial flora, and endogenous synthesis (at least for D-serine and, probably, D-aspartate). D-amino acids are involved in important physiological processes (e.g., D-serine and D-aspartate act on the N-methyl-D-aspartate receptor as co-agonist and agonist, respectively) and increasing evidence links D-amino acids to different pathological states. Methods: Determination of D-amino acids levels in blood is mainly based on enantiomeric separations by high performance liquid chromatography. Because of the low amount of D-enantiomers compared to the corresponding L-amino acids and the high background noise associated with biological matrices, positive and negative controls are absolutely required to obtain reliable values. Results: Altered levels of D-serine in blood have been reported in several neurological and psychiatric disorders: it has been proposed as promising biomarker in schizophrenia, Alzheimer's disease, and amyotrophic lateral sclerosis. Indeed, D-serine levels seem an appropriate predictor of anti-depressant response in major depressive disorder and post- traumatic stress disorder, as well as a prognostic biomarker of early cognitive decline, especially when considering D-serine and D-proline levels simultaneously. Furthermore, D-amino acids seem useful biomarkers for pathologies not related to the central nervous system, such as pancreatic cancer and chronic kidney diseases. Conclusion: This is the first review focusing on the determination of blood levels of D-amino acids as diagnostic and prognostic biomarkers. The experimental evidence of involvement of D-amino acids in various physiological pathways suggest investigating their levels in additional pathologies too, such as diabetes mellitus. In conclusion, the levels of D-amino acids in blood may represent novel diagnostic peripheral biomarkers for various disorders. Further studies are required to standardize/automatize the determinations and for confirming their clinical effectiveness.