SEX AND GENOTYPE INFLUENCE THE DISRUPTION OF CIRCULATING NMDAR-RELATED AMINO ACIDS IN PATIENTS WITH PARKINSON'S DISEASE

Sex and genetic factors substantially influence the epidemiology and pathophysiology of Parkinson's disease (PD). However, their specific impact on the modulation of N-methyl-D-aspartate receptor (NMDAR)-related amino acids and their precursors remains largely unexplored. Here, we measured these neuroactive molecules by high-performance liquid chromatography (HPLC) in the serum of a genetically and clinically well-characterized cohort of PD patients (n = 245) and healthy controls (HCs, n = 203), stratified by sex and subtype (idiopathic, n = 121; genetic, n = 124). The genetic subgroup included carriers of at least one pathogenic variant in LRRK2, TMEM175, PARK2, PINK1, PARK7, and GBA1. Distinct sex- and subtype-dependent metabolic signatures emerged.
Idiopathic male patients showed marked reductions in serum D-serine, L-serine, glycine, L-glutamate, L-glutamine, L-aspartate and L-asparagine levels, compared to sex-matched HCs. In contrast, genetic male PD patients displayed only a selective decrease in L-aspartate. Female patients, regardless of subtype, exhibited no significant alterations in NMDAR-related amino acids compared to HCs. Moreover, serum D-serine levels positively correlated with motor symptom severity scores only in genetic PD cases of both sexes. The same cohort was also investigated by targeted association analysis of genetic variants in GRIN1, GRIN2A and GRIN2B genes encoding for NMDAR subunits, which revealed sex- and subtype-specific associations between GRIN2A polymorphisms and PD.
Our findings reveal a previously unrecognized sex- and genotype-dependent regulation of NMDAR-related amino acid homeostasis in PD, highlighting the importance of biological stratification for biomarker discovery and for developing more targeted, personalized therapeutic strategies.