Abstract
CSF from unique groups of Parkinson’s disease (PD) patients was biochemically profiled to identify previously unreported metabolic pathways linked to PD pathogenesis, and novel biochemical biomarkers of the disease were characterized. Utilizing both 1H NMR and DI-LC-MS/MS we quantitatively profiled CSF from patients with sporadic PD (n = 20) and those who are genetically predisposed (LRRK2) to the disease (n = 20), and compared those results with age and gender-matched controls (n = 20). Further, we systematically evaluated the utility of several machine learning techniques for the diagnosis of PD. 1H NMR and mass spectrometry-based metabolomics, in combination with bioinformatic analyses, provided useful information highlighting previously unreported biochemical pathways and CSF-based biomarkers associated with both sporadic PD (sPD) and LRRK2 PD. Results of this metabolomics study further support our group’s previous findings identifying bile acid metabolism as one of the major aberrant biochemical pathways in PD patients. This study demonstrates that a combination of two complimentary techniques can provide a much more holistic view of the CSF metabolome, and by association, the brain metabolome. Future studies for the prediction of those at risk of developing PD should investigate the clinical utility of these CSF-based biomarkers in more accessible biomatrices. Further, it is essential that we determine whether the biochemical pathways highlighted here are recapitulated in the brains of PD patients with the aim of identifying potential therapeutic targets.
Highlights
Parkinson’s disease (PD) is a progressive, adult-onset neurodegenerative disorder associated with the degeneration of dopaminergic (DAergic) neurons and the presence of proteinaceous inclusions such as α-synuclein [1]
A total of 80 subjects with no known history of liver dysfunction were enrolled in this study; CSF specimens were obtained via lumbar puncture from participants suffering from sporadic PD (sPD) (n = 20), those genetically predisposed to the disease (LRRK2 acquired PD) (n = 20), and age and gender-matched controls for each group to include patients with the G2019S mutation in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene (n = 20) and those without (n = 20)
Statistical and Metabolite Pathway Enrichment Analysis. Using both 1 H NMR (Supplementary Figure S1) and targeted mass spectrometry we accurately identified and quantified 162 metabolites in CSF to include an additional 12 bile acids
Summary
Parkinson’s disease (PD) is a progressive, adult-onset neurodegenerative disorder associated with the degeneration of dopaminergic (DAergic) neurons and the presence of proteinaceous inclusions such as α-synuclein [1]. PD is the second most common neurodegenerative disorder after Alzheimer’s disease with a prevalence of 1% in people over 60 years of age [2]. The etiology of PD is thought to be multifunctional in that genetic factors, environmental exposures, and aging contribute to disease. The exact underlying mechanism for selective DAergic cell loss in PD remains elusive [5]. The accuracy of such diagnostic criteria is low, as 40% to 50% of DAergic neurons have already degenerated by the time a clinical diagnosis is made [7]. Premotor symptoms, including olfactory deficiency, obstipation, sleep disorders, and depression are very unspecific to PD, further complicating early diagnosis [8]
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