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

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

Research output: Contribution to journalArticle

63 Citations (Scopus)

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 2013

Fingerprint

Metabolomics
Parkinson Disease
Biomarkers
Cerebrospinal Fluid
3-hydroxykynurenine
Therapeutic Human Experimentation
Glutathione Disulfide
Neurotoxins
Dermatoglyphics
Acetylation
Metabolic Networks and Pathways
Glutathione
Mass Spectrometry
Oxidative Stress
Antioxidants
Molecular Weight
Gases
High Pressure Liquid Chromatography
Learning
Amino Acids

Keywords

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

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

Cite this

3-hydroxykynurenine and other Parkinson's disease biomarkers discovered by metabolomic analysis. / Lewitt, Peter A.; Li, Jia; Lu, Mei; Beach, Thomas G.; Adler, Charles Howard; Guo, Lining.

In: Movement Disorders, Vol. 28, No. 12, 10.2013, p. 1653-1660.

Research output: Contribution to journalArticle

Lewitt, Peter A. ; Li, Jia ; Lu, Mei ; Beach, Thomas G. ; Adler, Charles Howard ; Guo, Lining. / 3-hydroxykynurenine and other Parkinson's disease biomarkers discovered by metabolomic analysis. In: Movement Disorders. 2013 ; Vol. 28, No. 12. pp. 1653-1660.
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