Diagnosing Parkinson's disease and monitoring its progression: Biomarkers from combined GC-TOF MS and LC-MS/MS untargeted metabolomics.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder with a poorly understood etiology. An accurate diagnosis of idiopathic PD remains challenging as misdiagnosis is common in routine clinical practice. Moreover, current therapeutics focus on symptomatic management rather than curing or slowing down disease progression. Therefore, identification of potential PD biomarkers and providing a better understanding of the underlying disease pathophysiology are urgent. Herein, hydrophilic interaction liquid chromatography-mass spectrometry (LC-MS/MS) and gas chromatography-mass spectrometry (GC-TOF MS) based metabolomics approaches were used to profile the serum metabolome of 50 patients with different stages of idiopathic PD (early, mid and advanced) and 45 age-matched controls. Levels of 57 metabolites including cysteine-S-sulfate and N-acetyl tryptophan were significantly higher in patients with PD compared to controls, with lower amounts of additional 51 metabolites including vanillic acid, and N-acetylaspartic acid. Xanthines, including caffeine and its downstream metabolites, were lowered in patients with PD relative to controls indicating a potential role caffeine and its metabolites against neuronal damage. Seven metabolites, namely cysteine-S-sulfate, 1-methylxanthine, vanillic acid, N-acetylaspartic acid, 3-N-acetyl tryptophan, 5-methoxytryptophol, and 13-HODE yielded a ROC curve with a high classification accuracy (AUC 0.977). Comparison between different PD stages showed that cysteine-S-sulfate levels were significantly increasing with the advancement of PD stages while LPI 20:4 was significantly decreasing with disease progression. Our findings provide new biomarker candidates to assist in the diagnosis of PD and monitor its progression. Unusual metabolites like cysteine-S-sulfate might point to therapeutic targets that could enhance the development of novel PD treatments, such as NMDA antagonists.