title: 3-hydroxykynurenine and other Parkinson's disease biomarkers discovered by metabolomic analysis.
abstract: Parkinson's disease (PD) biomarkers are needed to enhance therapeutics research and to understand PD pathogenesis. Methods that simultaneously measure hundreds of small molecular-weight compounds-metabolomic analysis-"fingerprint" disease-specific alterations in individual compounds or metabolic pathways. Beyond a nontargeted search for PD biomarkers, we hypothesized that PD cerebrospinal fluid would show increased formation of the excitotoxin 3-hydroxykynurenine and diminished concentration of the antioxidant glutathione. Cerebrospinal fluid was collected at <4 hours postmortem from 48 pathologically-verified PD subjects and 57 comparably-aged controls. Assays involved ultra-high-performance liquid and gas chromatography linked to mass spectrometry. We used univariate techniques to determine fold-changes in concentrations of biochemicals; false-discovery rates were calculated to exclude spurious findings. Data was modeled using a Support Vector Machine for analyzing compounds selected by Welch's t test. Classification accuracy was determined by cross-validation. Of 243 structurally-identified biochemicals,19 compounds differentiated PD from controls at a 20% false-discovery level. In PD, mean 3-hydroxykynurenine concentration was increased by one-third, and mean oxidized glutathione was decreased by 40% (for each, P < .01). Four of the 19 compounds differentiating PD from controls were N-acetylated amino acids, suggesting a generalized alteration in N-acetylation activity. The Support Vector Machine classification model distinguished between groups at 83% sensitivity and 91% specificity for the learning data, and at 65% and 79% from cross-validation. In this study, the first for metabolomic profiling of PD cerebrospinal fluid, we found several novel biomarkers and offer new directions for recognizing disease-specific biochemical indicators. The findings support involvement of excitotoxicity and oxidative stress in the pathogenesis of PD.
authors.affiliation: Department of Neurology, Henry Ford Hospital, West Bloomfield, Michigan, USA; School of Medicine, Wayne State University, Detroit, Michigan, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Lewitt
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Mei
authors.initials: M
authors.lastname: Lu
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Beach
authors.forename: Charles H
authors.initials: CH
authors.lastname: Adler
authors.forename: Lining
authors.initials: L
authors.lastname: Guo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000134:cerebrospinal fluid; D005260:Female; D005978:Glutathione / Q000134:cerebrospinal fluid; D006801:Humans; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000134:cerebrospinal fluid; D008297:Male; D013058:Mass Spectrometry; D055432:Metabolomics; D008875:Middle Aged; D018384:Oxidative Stress / Q000502:physiology*; D010300:Parkinson Disease / Q000134:cerebrospinal fluid*; D012680:Sensitivity and Specificity
chemical_list: D015415:Biomarkers; C005045:3-hydroxykynurenine; D007737:Kynurenine; D005978:Glutathione
keywords: Parkinson's disease; biomarker; cerebrospinal fluid; metabolomics