Dysregulation of NMDAR-related amino acids in the serum samples of Parkinson disease

Introduction: Emerging evidence suggests that dysregulation of NMDAR-related amino acids may contribute to the pathophysiology of Parkinson’s disease (PD). We recently described increased D- and L-serine concentrations in the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, the post-mortem caudate-putamen of human PD brains and the cerebrospinal fluid (CSF) of living PD patients. Objectives: In the present study, we extended these observations by quantifying serum concentrations of neuroactive amino acids in a clinically well-characterized cohort of PD patients and healthy controls (HC), with specific attention to sex- and genotype- related differences. Methods: Firstly, we investigated serum samples from 83 PD patients and 41 (HC), then we recruited another well-characterized cohort of 245 PD patients and 203 HC and they were all analyzed using high-performance liquid chromatography (HPLC). PD cases in the second cohort were stratified by sex and genotype: idiopathic (n = 121) and genetic (n = 124). Results and discussion: we demonstrated that D-serine and the D-/total serine ratio positively correlated with age in PD but not in HC and further associated with age at disease onset. Moreover, higher levodopa equivalent daily dose (LEDD) correlated with reduced levels of D-serine and other excitatory amino acids. In addition, we identified striking sex-specific alterations in the amino acid profile. Male patients with idiopathic PD exhibited broad reductions in NMDAR-related amino acids and their precursors, including L-glutamate, L-aspartate, glycine, D-serine, L-serine, L-glutamine, and L-asparagine, compared with HC. In contrast, male patients with genetic PD showed a selective reduction in L-aspartate. Notably, female PD patients did not display significant amino acid decreases. Conclusion: These findings uncover a previously unrecognized interplay between sex and genotype in shaping the serum amino acid profile in PD. They underscore the necessity of accounting for these biological variables in biomarker discovery and suggest that precision medicine strategies targeting glutamatergic signaling may benefit from sex- and genotype- specific tailoring.