Gender-associated differences in serum metabolite profiles among patients with Parkinson’s Disease

Parkinson’s disease (PD) is increasingly recognized as a multisystem disorder associated with peripheral metabolic abnormalities. However, the extent to which sex and genetic background influence circulating metabolomic alterations remains unclear. Using ¹ H-Nuclear Magnetic Resonance (NMR)-based metabolomics, we profiled serum metabolites from 245 clinically and genetically characterized patients with PD and 137 sex-matched healthy controls (HCs). The PD cohort comprised 121 patients with idiopathic PD and 124 patients carrying at least one pathogenic variant in LRRK2 , TMEM175 , PARK2 , PINK1 , PARK7 , or GBA1 .

NMR profiling revealed marked metabolic differences between cases and controls, identifying sex as a major determinant of the circulating metabolic signature. Compared with HCs, male patients exhibited prominent alterations in amino acid metabolism, characterized by reduced glutamate and increased tryptophan levels, together with changes in metabolites related to energy homeostasis. By contrast, female patients displayed a distinct metabolic profile characterized by altered threonine and choline levels, together with perturbations in phosphatidylethanolamine, fatty acids, and ketone bodies.

Notably, despite PD subtype-specific metabolic differences relative to sex-matched controls, multivariate analyses did not discriminate idiopathic from genetic PD in either sex, suggesting that shared disease-related metabolic alterations predominate within the resolution and metabolite coverage of the NMR platform.

Overall, our findings identify biological sex as a major determinant of circulating metabolomic alterations in PD, whereas idiopathic and genetic forms largely converge towards a common systemic metabolic phenotype.