Alternations of Metabolic Profile and Kynurenine Metabolism in the Plasma of Parkinson’s Disease
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The pathogenesis of Parkinson’s disease (PD) remains to be elucidated. Metabolomic analysis has the potential to identify biochemical pathways and metabolic profiles that are involved in PD pathogenesis. Here, we performed a targeted metabolomics to quantify the plasma levels of 184 metabolites in a discovery cohort including 82 PD patients and 82 normal controls (NCs) and found two up-regulated (dopamine, putrescine/ornithine ratio) and four down-regulated (octadecadienylcarnitine C18:2, asymmetric dimethylarginine, tryptophan, and kynurenine (KYN)) metabolites in the plasma of PD patients. We then measured the plasma levels of a panel of metabolic products of KYN pathway in an independent validation cohort including 118 PD patients, 22 Huntington’s disease (HD) patients, and 37 NCs. Lower kynurenic acid (KA)/KYN ratio, higher quinolinic acid (QA) level, and QA/KA ratio were observed in PD patients compared to HD patients and NCs. PD patients at advanced stage (Hoehn-Yahr stage > 2) showed lower KA and KA/KYN ratio, as well as higher QA and QA/KA ratio compared to PD patients at early stage (Hoehn-Yahr stage ≤ 2) and NCs. Levels of KA and QA, as well as the ratios of KA/KYN and QA/KA between PD patients with and without psychiatric symptoms, dementia, or levodopa-induced dyskinesia in the advanced PD were similar. This metabolomic analyses demonstrate a number of plasma biomarker candidates for PD, suggesting a shift toward neurotoxic QA synthesis and away from neuroprotective KA production in KYN pathway.
KeywordsParkinson’s disease Biomarker Metabolomics Kynurenine pathway Kynurenic acid Quinolinic acid
false discovery rate
gas chromatography-time-of-flight mass spectrometry
high-performance liquid chromatography/mass spectrometry
liquid chromatography time-of-flight mass spectrometry
liquid chromatography coupled with electrochemical coulometric array detection
levodopa equivalent daily dose
orthogonal projection to latent structure discriminant analysis
receiver operating characteristic
ultrahigh-performance liquid chromatography/tandem mass spectrometry
The authors would like to thank the patients and controls for participating in this study. We also thank for the technical support from Metabolomics Core laboratory, Chang Gung University.
Conceived and designed the experiments: K-HC, M-LC, and C-MC. Performed the experiments: H-YT and C-YH. Analyzed the data: K-HC, M-LC, and C-MC. Contributed reagents/materials/analysis tools: K-HC, Y-RW, and C-MC. Wrote the paper: K-HC, M-LC and C-MC.
This work was supported by CMRPG 3E142 and CMRPG 3F136 from Chang Gung Memorial Hospital, Taoyuan, Taiwan.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no competing interests.
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