ABSTRACT
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.
ABSTRACT
Parkinson's disease (PD) is a highly prevalent neurodegenerative movement disorder with an unclear etiology and a lack of definite diagnostic tests and effective treatments. About 95% of PD cases are idiopathic, in which none of the well-known genes underlying familial parkinsonism are mutated. We used untargeted liquid chromatography-mass spectrometry (LC-MS/MS) to profile the serum lipidome of 50 patients with different stages of idiopathic PD (early, mid, or advanced) and 45 age-matched controls. When comparing the PD patients to the control subjects, 169 lipids were significantly altered in both a univariate analysis and a multivariate partial least-squares discriminant analysis (PLS-DA). Compared to the controls, the patients with PD had higher levels of unsaturated triacylglycerides (e.g., TG O-56:9 and TG 52:3), saturated lysophosphatidylcholines (LPC 17:0, 16:0, and 15:0), and hydroxyeicosatetraenoic acid (12-HETE), while lower levels of phosphatidylserines (e.g., PS 40:4 and PS 16:0_22:4), sphingomyelins (SM 42:1), and ceramides (e.g., Cer 40:0 and 42:0) were found between the PD patients and the controls. A panel of 10 significantly altered lipids (PS 40:0, Cer 40:0, Cer 42:0, LPC 17:0, LPC 15:0, PC 37:7, PE O-40:8, PC O-42:4, FA 23:0, and SM 42:1) resulted in a strong receiver operating characteristic curve with an AUC = 0.974. This panel may, therefore, be useful for diagnosing PD. In addition, lipid panels may prove useful for distinguishing among the progression stages of PD. Using one-way ANOVA, 155 lipid species were significantly altered among the PD stages. Parkinson's disease progressed from the early to advanced stages with decreasing levels of PC 31:1, PC 38:4, and LPE 22:5. Conversely, LPC-O 20:0, PC O-42:3, FA 19:0, and FA 22:2 showed an increase in their levels with disease progression. Overall, this study shows an intriguing number of robust changes in specific serum lipids that may become useful for diagnosing PD and its progression, once panels have been validated in larger clinical trials and prospective studies.
