3-hydroxykynurenine and other Parkinson's disease biomarkers discovered by metabolomic analysis

Peter A. Lewitt, Jia Li, Mei Lu, Thomas G. Beach, Charles H. Adler, Lining Guo

Research output: Contribution to journalArticle

73 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1653-1660
Number of pages8
JournalMovement Disorders
Volume28
Issue number12
DOIs
StatePublished - Oct 1 2013

Keywords

  • Biomarker
  • Cerebrospinal fluid
  • Metabolomics
  • Parkinson's disease

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Fingerprint Dive into the research topics of '3-hydroxykynurenine and other Parkinson's disease biomarkers discovered by metabolomic analysis'. Together they form a unique fingerprint.

  • Cite this