Skip to main content
SpringerLink
Log in

Alternations of Metabolic Profile and Kynurenine Metabolism in the Plasma of Parkinson’s Disease

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

AD:

Alzheimer’s disease

CSF:

cerebrospinal fluid

DAergic:

dopaminergic

FDR:

false discovery rate

GC-TOFMS:

gas chromatography-time-of-flight mass spectrometry

HD:

Huntington’s disease

HPLC/MS:

high-performance liquid chromatography/mass spectrometry

KA:

kynurenic acid

KYN:

kynurenine

LC-TOFMS:

liquid chromatography time-of-flight mass spectrometry

LCECA:

liquid chromatography coupled with electrochemical coulometric array detection

LEDD:

levodopa equivalent daily dose

LID:

levodopa-induced dyskinesia

NC:

normal control

OPLS-DA:

orthogonal projection to latent structure discriminant analysis

PD:

Parkinson’s disease

QA:

quinolinic acid

ROC:

receiver operating characteristic

UPLC/MS/MS:

ultrahigh-performance liquid chromatography/tandem mass spectrometry

References

  1. Lang AE, Lozano AM (1998) Parkinson’s disease. N Engl J Med 339(15):1044–1053. https://doi.org/10.1056/NEJM199810083391506

    Article  PubMed  CAS  Google Scholar 

  2. Halbach OB, Schober A, Krieglstein K (2004) Genes, proteins, and neurotoxins involved in Parkinson’s disease. Prog Neurobiol 73(3):151–177. https://doi.org/10.1016/j.pneurobio.2004.05.002

    Article  CAS  Google Scholar 

  3. Dexter DT, Jenner P (2013) Parkinson disease: from pathology to molecular disease mechanisms. Free Radic Biol Med 62:132–144. https://doi.org/10.1016/j.freeradbiomed.2013.01.018

    Article  PubMed  CAS  Google Scholar 

  4. Ahmed SS, Santosh W, Kumar S, Christlet HTT (2009) Metabolic profiling of Parkinson’s disease: evidence of biomarker from gene expression analysis and rapid neural network detection. J Biomed Sci 16(1):1–12. https://doi.org/10.1186/1423-0127-16-63

    Article  CAS  Google Scholar 

  5. Bogdanov M, Matson WR, Wang L, Matson T, Saunders-Pullman R, Bressman SS, Flint Beal M (2008) Metabolomic profiling to develop blood biomarkers for Parkinson’s disease. Brain 131(2):389–396. https://doi.org/10.1093/brain/awm304

    Article  PubMed  Google Scholar 

  6. Chan RB, Perotte AJ, Zhou B, Liong C, Shorr EJ, Marder KS, Kang UJ, Waters CH et al (2017) Elevated GM3 plasma concentration in idiopathic Parkinson’s disease: a lipidomic analysis. PLoS One 12(2):e0172348. https://doi.org/10.1371/journal.pone.0172348

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Hatano T, Saiki S, Okuzumi A, Mohney RP, Hattori N (2016) Identification of novel biomarkers for Parkinson’s disease by metabolomic technologies. J Neurol Neurosurg Psychiatry 87(3):295–301. https://doi.org/10.1136/jnnp-2014-309676

    Article  PubMed  Google Scholar 

  8. Havelund JF, Andersen AD, Binzer M, Blaabjerg M, Heegaard NHH, Stenager E, Faergeman NJ, Gramsbergen JB (2017) Changes in kynurenine pathway metabolism in Parkinson patients with L-DOPA-induced dyskinesia. J Neurochem 142(5):756–766. https://doi.org/10.1111/jnc.14104

    Article  PubMed  CAS  Google Scholar 

  9. Johansen KK, Wang L, Aasly JO, White LR, Matson WR, Henchcliffe C, Beal MF, Bogdanov M (2009) Metabolomic profiling in LRRK2-related Parkinson’s disease. PLoS One 4(10):e7551. https://doi.org/10.1371/journal.pone.0007551

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Roede JR, Uppal K, Park Y, Lee K, Tran V, Walker D, Strobel FH, Rhodes SL et al (2013) Serum metabolomics of slow vs. rapid motor progression Parkinson’s disease: a pilot study. PLoS One 8(10):e77629. https://doi.org/10.1371/journal.pone.0077629

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Trupp M, Jonsson P, Ohrfelt A, Zetterberg H, Obudulu O, Malm L, Wuolikainen A, Linder J et al (2014) Metabolite and peptide levels in plasma and CSF differentiating healthy controls from patients with newly diagnosed Parkinson’s disease. J Parkinsons Dis 4(3):549–560. https://doi.org/10.3233/JPD-140389

    Article  PubMed  CAS  Google Scholar 

  12. Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55(3):181–184. https://doi.org/10.1136/jnnp.55.3.181

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Hoehn MM, Yahr MD (1967) Parkinsonism: onset, progression and mortality. Neurology 17(5):427–442. https://doi.org/10.1212/WNL.17.5.427

    Article  PubMed  CAS  Google Scholar 

  14. Tomlinson CL, Stowe R, Patel S, Rick C, Gray R, Clarke CE (2010) Systematic review of levodopa dose equivalency reporting in Parkinson’s disease. Mov Disord 25(15):2649–2653. https://doi.org/10.1002/mds.23429

    Article  PubMed  Google Scholar 

  15. Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12(3):189–198. https://doi.org/10.1016/0022-3956(75)90026-6

    Article  PubMed  CAS  Google Scholar 

  16. Morris JC (1993) The clinical dementia rating (CDR): current version and scoring rules. Neurology 43(11):2412–2414. https://doi.org/10.1212/WNL.43.11.2412-a

    Article  PubMed  CAS  Google Scholar 

  17. MacDonald ME, Ambrose CM, Duyao MP, Myers RH, Lin C, Srinidhi L, Barnes G, Taylor SA et al (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72(6):971–983. https://doi.org/10.1016/0092-8674(93)90585-E

    Article  Google Scholar 

  18. Burté F, Houghton D, Lowes H, Pyle A, Nesbitt S, Yarnall A, Yu-Wai-Man P, Burn DJ et al (2017) Metabolic profiling of Parkinson’s disease and mild cognitive impairment. Mov Disord 32(6):927–932. https://doi.org/10.1002/mds.26992

    Article  PubMed  PubMed Central  Google Scholar 

  19. Cheng ML, Chang KH, Wu YR, Chen CM (2016) Metabolic disturbances in plasma as biomarkers for Huntington’s disease. J Nutr Biochem 31:38–44. https://doi.org/10.1016/j.jnutbio.2015.12.001

    Article  PubMed  CAS  Google Scholar 

  20. Gulaj E, Pawlak K, Bien B, Pawlak D (2010) Kynurenine and its metabolites in Alzheimer’s disease patients. Adv Med Sci 55(2):204–211. https://doi.org/10.2478/v10039-010-0023-6

    Article  PubMed  CAS  Google Scholar 

  21. Myint AM (2012) Kynurenines: from the perspective of major psychiatric disorders. FEBS J 279(8):1375–1385. https://doi.org/10.1111/j.1742-4658.2012.08551.x

    Article  PubMed  CAS  Google Scholar 

  22. Grégoire L, Rassoulpour A, Guidetti P, Samadi P, Bédard PJ, Izzo E, Schwarcz R, Di Paolo T (2008) Prolonged kynurenine 3-hydroxylase inhibition reduces development of levodopa-induced dyskinesias in parkinsonian monkeys. Behav Brain Res 186(2):161–167. https://doi.org/10.1016/j.bbr.2007.08.007

    Article  PubMed  CAS  Google Scholar 

  23. Guidetti P, Luthi-Carter RE, Augood SJ, Schwarcz R (2004) Neostriatal and cortical quinolinate levels are increased in early grade Huntington’s disease. Neurobiol Dis 17(3):455–461. https://doi.org/10.1016/j.nbd.2004.07.006

    Article  PubMed  CAS  Google Scholar 

  24. Jauch D, Urbańska EM, Guidetti P, Bird ED, Vonsattel JPG, Whetsell WO Jr, Schwarcz R (1995) Dysfunction of brain kynurenic acid metabolism in Huntington’s disease: focus on kynurenine aminotransferases. J Neurol Sci 130(1):39–47. https://doi.org/10.1016/0022-510X(94)00280-2

    Article  PubMed  CAS  Google Scholar 

  25. Ilzecka J, Kocki T, Stelmasiak Z, Turski WA (2003) Endogenous protectant kynurenic acid in amyotrophic lateral sclerosis. Acta Neurol Scand 107(6):412–418. https://doi.org/10.1034/j.1600-0404.2003.00076.x

    Article  PubMed  CAS  Google Scholar 

  26. Ogawa T, Matson WR, Beal MF, Myers RH, Bird ED, Milbury P, Saso S (1992) Kynurenine pathway abnormalities in Parkinson’s disease. Neurology 42(9):1702–1706. https://doi.org/10.1212/WNL.42.9.1702

    Article  PubMed  CAS  Google Scholar 

  27. Lewitt PA, Li J, Lu M, Beach TG, Adler CH, Guo L, Arizona Parkinson's Disease C (2013) 3-Hydroxykynurenine and other Parkinson’s disease biomarkers discovered by metabolomic analysis. Mov Disord 28(12):1653–1660. https://doi.org/10.1002/mds.25555

    Article  PubMed  CAS  Google Scholar 

  28. Hartai Z, Klivenyi P, Janaky T, Penke B, Dux L, Vecsei L (2005) Kynurenine metabolism in plasma and in red blood cells in Parkinson’s disease. J Neurol Sci 239(1):31–35. https://doi.org/10.1016/j.jns.2005.07.006

    Article  PubMed  CAS  Google Scholar 

  29. Stone TW, Perkins MN (1981) Quinolinic acid: a potent endogenous excitant at amino acid receptors in CNS. Eur J Pharmacol 72(4):411–412. https://doi.org/10.1016/s0014-2999(81)90587-2

    Article  PubMed  CAS  Google Scholar 

  30. Schwarcz R, Whetsell WO Jr, Mangano RM (1983) Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain. Science 219(4582):316–318. https://doi.org/10.1126/science.6849138

    Article  PubMed  CAS  Google Scholar 

  31. Sˇtípek S, Sˇtastný FE, Pláteník J, Crkovská JI, Zima T (1997) The effect of quinolinate on rat brain lipid peroxidation is dependent on iron. Neurochem Int 30(2):233–237. https://doi.org/10.1016/S0197-0186(97)90002-4

    Article  Google Scholar 

  32. Pláteník J, Stopka P, Vejražka M, Štípek S (2001) Quinolinic acid—iron(II) complexes: slow autoxidation, but enhanced hydroxyl radical production in the Fenton reaction. Free Radic Res 34(5):445–459. https://doi.org/10.1080/10715760100300391

    Article  PubMed  Google Scholar 

  33. Braidy N, Grant R, Adams S, Brew BJ, Guillemin GJ (2009) Mechanism for quinolinic acid cytotoxicity in human astrocytes and neurons. Neurotox Res 16(1):77–86. https://doi.org/10.1007/s12640-009-9051-z

    Article  PubMed  CAS  Google Scholar 

  34. Maddison DC, Giorgini F (2015) The kynurenine pathway and neurodegenerative disease. Semin Cell Dev Biol 40:134–141. https://doi.org/10.1016/j.semcdb.2015.03.002

    Article  PubMed  CAS  Google Scholar 

  35. Lugo-Huitrón R, Blanco-Ayala T, Ugalde-Muñiz P, Carrillo-Mora P, Pedraza-Chaverrí J, Silva-Adaya D, Maldonado PD, Torres I et al (2011) On the antioxidant properties of kynurenic acid: free radical scavenging activity and inhibition of oxidative stress. Neurotoxicol Teratol 33(5):538–547. https://doi.org/10.1016/j.ntt.2011.07.002

    Article  PubMed  CAS  Google Scholar 

  36. Hilmas C, Pereira EFR, Alkondon M, Rassoulpour A, Schwarcz R, Albuquerque EX (2001) The brain metabolite kynurenic acid inhibits α7 nicotinic receptor activity and increases non-α7 nicotinic receptor expression: physiopathological implications. J Neurosci 21(19):7463–7473

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  37. Perkins MN, Stone TW (1982) An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acid. Brain Res 247(1):184–187. https://doi.org/10.1016/0006-8993(82)91048-4

    Article  PubMed  CAS  Google Scholar 

  38. Rebouche CJ (2004) Kinetics, pharmacokinetics, and regulation of L-carnitine and acetyl-L-carnitine metabolism. Ann N Y Acad Sci 1033(1):30–41. https://doi.org/10.1196/annals.1320.003

    Article  PubMed  CAS  Google Scholar 

  39. Hagen TM, Liu J, Lykkesfeldt J, Wehr CM, Ingersoll RT, Vinarsky V, Bartholomew JC, Ames BN (2002) Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc Natl Acad Sci U S A 99(4):1870–1875. https://doi.org/10.1073/pnas.261708898

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Fritz IB, Arrigoni-Martelli E (1993) Sites of action of carnitine and its derivatives on the cardiovascular system: interactions with membranes. Trends Pharmacol Sci 14(10):355–360. https://doi.org/10.1016/0165-6147(93)90093-Y

    Article  PubMed  CAS  Google Scholar 

  41. Hauser DN, Hastings TG (2013) Mitochondrial dysfunction and oxidative stress in Parkinson’s disease and monogenic parkinsonism. Neurobiol Dis 51:35–42. https://doi.org/10.1016/j.nbd.2012.10.011

    Article  PubMed  CAS  Google Scholar 

  42. Tang XQ, Fang HR, Li YJ, Zhou CF, Ren YK, Chen RQ, Wang CY, Hu B (2011) Endogenous hydrogen sulfide is involved in asymmetric dimethylarginine-induced protection against neurotoxicity of 1-methyl-4-phenyl-pyridinium ion. Neurochem Res 36(11):2176–2185. https://doi.org/10.1007/s11064-011-0542-y

    Article  PubMed  CAS  Google Scholar 

  43. Paschen W (1992) Polyamine metabolism in different pathological states of the brain. Mol Chem Neuropathol 16(3):241–271. https://doi.org/10.1007/BF03159973

    Article  PubMed  CAS  Google Scholar 

  44. Morrison LD, Cao XC, Kish SJ (1998) Ornithine decarboxylase in human brain: influence of aging, regional distribution, and Alzheimer’s disease. J Neurochem 71(1):288–294. https://doi.org/10.1046/j.1471-4159.1998.71010288.x

    Article  PubMed  CAS  Google Scholar 

  45. Rassoulpour A, Wu H-Q, Poeggeler B, Schwarcz R (1998) Systemic d-amphetamine administration causes a reduction of kynurenic acid levels in rat brain. Brain Res 802(1–2):111–118. https://doi.org/10.1016/S0006-8993(98)00577-0

    Article  PubMed  CAS  Google Scholar 

  46. Wu HQ, Rassoulpour A, Schwarcz R (2002) Effect of systemic L-DOPA administration on extracellular kynurenate levels in the rat striatum. J Neural Transm 109(3):239–249. https://doi.org/10.1007/s007020200020

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

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.

Funding

This work was supported by CMRPG 3E142 and CMRPG 3F136 from Chang Gung Memorial Hospital, Taoyuan, Taiwan.

Author information

Author notes

  1. Kuo-Hsuan Chang and Mei-Ling Cheng contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Chang Gung Memorial Hospital Linkou Medical Center and College of Medicine, Chang Gung University, Taoyuan, Taiwan

    Kuo-Hsuan Chang, Yih-Ru Wu & Chiung-Mei Chen

  2. Department of Biomedical Sciences, Chang Gung University, Tao-Yuan, Taiwan

    Mei-Ling Cheng

  3. Metabolomics Core Laboratory, Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan

    Mei-Ling Cheng, Hsiang-Yu Tang & Cheng-Yu Huang

  4. Clinical Phenome Center, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan

    Mei-Ling Cheng

Authors
  1. Kuo-Hsuan Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mei-Ling Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hsiang-Yu Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cheng-Yu Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yih-Ru Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chiung-Mei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Chiung-Mei Chen.

Ethics declarations

Conflict of Interest

The authors declare that they have no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chang, KH., Cheng, ML., Tang, HY. et al. Alternations of Metabolic Profile and Kynurenine Metabolism in the Plasma of Parkinson’s Disease. Mol Neurobiol 55, 6319–6328 (2018). https://doi.org/10.1007/s12035-017-0845-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-017-0845-3

Keywords

Search

Navigation