Untargeted 1H NMR-based metabolomics reveal sex-based differences in blood metabolome profiles among patients with Parkinson's disease, regardless of their idiopathic or genetic subtype.

Emerging findings indicate systemic metabolic dysregulations linked to Parkinsons disease (PD) pathophysiology. However, the specific effects of sex and subtype differences on blood metabolomic abnormalities in patients compared with controls remain elusive. Here, we conducted an untargeted 1H NMR-based analysis to characterize serum metabolome variations in a large cohort of clinically and genetically characterized PD patients (N = 245), compared to sex-matched healthy controls (HCs) (N = 140). The cohort included patients with idiopathic conditions (iPD; N = 121) and cases carrying at least a pathogenic mutation in the LRRK2, TMEM175, PARK2, PINK1, PARK7, or GBA1 genes (gPD; N = 124). The same cohort was also analyzed using gene-targed association studies with a comprehensive panel of markers for key enzymes involved in glycine and serine metabolism. By integrating NMR analysis with genetic, demographic, and clinical data, we identified a striking sexual dimorphism in blood metabolomic variations found in both iPD and gPD patients compared to matched controls. Accordingly, the Robust Volcano plot showed that, regardless of PD subtype, only men had substantial decreases in L-glutamic acid, accompanied by increases in L-tryptophan concentrations. Conversely, women with either idiopathic conditions or mutations in PD-linked genes exhibited a selective increase in threonine and 3-hydroxybutyric acid, along with significant reductions in choline. Pathway enrichment analysis consequently revealed more pronounced disruptions in amino acid homeostasis, glutathione biosynthesis, and energy-related processes in male individuals with PD. In contrast, female patients showed more selective biochemical alterations in methionine, betaine, and lipid-related pathways than sex-matched HCs. Besides sex influences, current metabolomic findings also highlighted an impact of genetic status on determining the unique serum biochemical abnormalities observed in patients with distinct subtypes. Since the LEDD values and MS-UPDRS part III scores are similar in both men and women with the same subtype, our study suggests that antiparkinsonian treatments and the severity of motor symptoms do not mainly affect the metabolomic features observed between the sexes. Lastly, consistent with biochemical results indicating substantial alterations in glycine-serine metabolism in PD, we identified significant associations between sex, subtype, and variants in PHGDH, DAO, SRR, and GCSH genes. Our study highlights the importance of accounting for sex and genetic status to identify reliable metabolic biomarkers and develop targeted therapies for PD.