Serum D-serine to total serine ratio and glycine levels as predictive biomarkers for cognitive dysfunction in frail elderly subjects

Here we report (i) the raw data used to conduct the study analyses; (ii) a list of online-only supplementary tables.

Abstract: Frailty is a common age-related clinical syndrome characterized by a decline in the function of multiple organ systems, increased vulnerability to stressors and huge socio-economic burden on healthcare systems. Despite recent research efforts, the physiopathological mechanisms concurring to determine frailty remain elusive and biomarkers able to predate its occurrence in the early stages are still lacking. Beyond its physical component, cognitive decline represents a crucial domain of frailty associated with higher risk of adverse health outcomes. Previous OMICS studies showed a range of metabolic abnormalities in frail compared to non-frail subjects, such as dysregulation in the blood levels of glutamate, carnitine, urea cycle and kidney markers, as well as of anti-oxidants and pro-inflammatory cytokines.

Here, in a well-characterized cohort of elderly subjects encompassing the entire continuum from fitness to frailty, we measured by High Performance Liquid Chromatography (HPLC) a pool of serum amino acids including L-glutamate, L-aspartate, glycine and D-serine, as well as their precursors L-glutamine, L-asparagine and L-serine. These amino acids are known to orchestrate excitatory and inhibitory neurotransmission the brain, but also play a key role as intermediates of energy metabolism and are critically involved in liver, kidney, muscle and immune system functioning. To comprehensively assess frailty, we employed both the Edmonton Frail Scale (EFS), as a practical and quick tool to capture the multidimensionality of frailty, and the frailty phenotype, as a measure of physical function. We found that D-serine and D-/Total serine ratio were independent predictors of EFS but not of physical frailty. Furthermore, higher glycine levels and D-/Total serine correlated with worse cognition and depressive symptoms in the frail group. Taken together, these findings suggest that altered homeostasis of blood D-serine may represent a biochemical signature of frailty in the elderly, while increased serum glycine and D-/Total serine ratio could be specifically associated with cognitive decline and depression in frail older populations.