Untargeted Serum Metabolomics And Lipidomic Revealed Potential Biomarkers For Diagnosing Parkinson’s Disease And Monitoring Its Progression

• By: DAHABIYEH, Lina (The University of Jordan, Jordan)
• Co-author(s): Dr Lina Dahabiyeh (School of Pharmacy/ The University of Jordan, Amman, Jordan)
  
• Abstract:

  Untargeted Serum Metabolomics and Lipidomic Revealed Potential Biomarkers for Diagnosing Parkinson’s Disease and Monitoring its Progression
  
  Lina A. Dahabiyeh*1, Refat M. Nimer2, Jeremiah D. Wells3, Oliver Fiehn3
  
  1 Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, 11942 Amman, Jordan
  2Department of Medical Laboratory Sciences, Jordan University of Science and Technology, Irbid, Jordan
  3 West Coast Metabolomics Center, University of California, Davis, Sacramento, California, USA
  
  Introduction: Parkinson’s disease (PD) stands as the second most prevalent neurodegenerative disorder, and it is the most common age-related ailment. Despite its prevalence, the underlying causes of PD remain largely elusive, with around 95% of cases being idiopathic. Furthermore, accurate diagnosis is challenging, and current medications only improve motor function without slowing down or reversing the disease progression. Therefore, there is an urgent need to provide a better understanding of the underlying pathophysiology of PD, identify new potential diagnostic and prognostic biomarkers and discover promising therapeutic targets for drug development.
  Methods: Serum samples from 50 patients with different stages of idiopathic PD (early, mid and advanced) and 45 age-matched controls were subjected to biphasic liquid extraction. Moderate-to-highly polar metabolites were profiled using hydrophilic interaction liquid chromatography–mass spectrometry (HILIC-MS/MS) and gas chromatography-mass spectrometry (GC-TOF MS) based metabolomics approaches. Non-polar metabolites and lipids were profiled using reversed phase LC-MS lipidomics. Annotated metabolites and lipids were analyzed using MetaboAnalyst and Simca P+14. Metabolites and lipids with variable importance in projection (VIP) score > 1 and P-value <0.05 were considered significant.
  Results: A total of 169 lipids and 212 metabolites were significantly altered (in both univariate analysis and multivariate partial least square-discriminant analysis (PLS-DA)) in patients with PD compared to controls. Among the upregulated metabolites and lipids in PD are cysteine-S-sulfate, N-acetyl tryptophan and saturated lysophosphatidylcholines (LPC 17:0, 16:0, 15:0). Lower levels of N-acetylaspartic acid, phosphatidyserines (e.g. PS 40:4, PS 16:0_22:4), sphingomyelins (SM 42:1) and ceramides (e.g. Cer 40:0, 42:0) were detected in PD patients compared to controls. Set enrichment analysis revealed a decrease in xanthines, including caffeine and its downstream metabolites, in patients with PD relative to controls and in advanced PD versus early stage PD. This suggests that caffeine and its metabolites might have a potential role in protecting against neuronal damage and decelerating PD progression among early stage PD patients. Furthermore, PD progressed from early to advanced stages with decreasing level of lysophosphatidylinositols LPI 20:4. Conversely, cysteine-S-sulfate, LPC-O 20:0 showed an increase in their levels with disease progression. A panel of seven metabolites resulted in a strong receiver-operator curve (ROC) with high classification accuracy (AUC = 0.977) suggesting it could be useful for diagnosing idiopathic PD.
  Conclusion: The study shows an intriguing number of robust changes in specific serum lipids and metabolites that may become useful for diagnosing PD and its progression, once panels have been validated in larger clinical trials and prospective studies. Unusual metabolites like cysteine-S-sulfate and LPI 20:4 might point to therapeutic targets that could enhance the development of novel PD treatments, such as N-methyl-D-aspartate (NMDA) antagonists and GPR55 agonism, respectively.