Presynaptic dopamine depletion determines the timing of levodopa-induced dyskinesia onset in Parkinson’s disease

  • Han Soo Yoo
  • Seok Jong Chung
  • Su Jin Chung
  • Hyojeong Moon
  • Jung Su Oh
  • Jae Seung Kim
  • Jin Yong Hong
  • Byoung Seok Ye
  • Young Ho Sohn
  • Phil Hyu LeeEmail author
Original Article



Reduced presynaptic dopaminergic activity plays an important role in the development of levodopa-induced dyskinesia (LID) in Parkinson’s disease (PD). In this study, we investigated whether dopaminergic function in the nigrostriatal system is associated with the timing of LID onset.


From among 412 drug-naive PD patients who underwent a dopamine transporter (DAT) PET scan during their baseline evaluation, we enrolled 65 patients who developed LID during a follow-up period of >2 years. Based on the time from PD onset, LID was classified as early, intermediate or late onset. We then compared DAT availability in the striatal subregions of the patients in the three groups.


The demographic characteristics did not differ among the three patient groups except for earlier intervention of levodopa therapy in the early LID onset group (p = 0.001). After adjusting for age at PD onset, gender, timing of levodopa therapy from PD onset, and the severity of PD motor symptoms, DAT activity in the posterior putamen was found to be significantly lower in the early LID onset group than in the late LID onset group (p = 0.017). Multivariate linear regression analysis showed that low DAT activity in the posterior putamen was significantly associated with the early appearance of LID in the early LID onset group (β = 16.039, p = 0.033).


This study demonstrated that low DAT activity in the posterior putamen at baseline is a major risk factor for the early onset of LID in patients with PD, suggesting that the degree of presynaptic dopaminergic denervation plays an important role in determining the timing of LID onset.


Dopamine transporter PET Parkinson’s disease Levodopa-induced dyskinesia 



This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and welfare, Republic of Korea (grant number: HI16C1118).

Compliance with ethical standards

Conflicts of interest


Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the principles of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Supplementary material

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  1. 1.
    Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F. Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci. 1973;20(4):415–55.CrossRefPubMedGoogle Scholar
  2. 2.
    Nutt JG. Levodopa-induced dyskinesia: review, observations, and speculations. Neurology. 1990;40(2):340–5.CrossRefPubMedGoogle Scholar
  3. 3.
    Pechevis M, Clarke CE, Vieregge P, Khoshnood B, Deschaseaux-Voinet C, Berdeaux G, et al. Effects of dyskinesias in Parkinson’s disease on quality of life and health-related costs: a prospective European study. Eur J Neurol. 2005;12(12):956–63.CrossRefPubMedGoogle Scholar
  4. 4.
    Bezard E, Brotchie JM, Gross CE. Pathophysiology of levodopa-induced dyskinesia: potential for new therapies. Nat Rev Neurosci. 2001;2(8):577–88.CrossRefPubMedGoogle Scholar
  5. 5.
    Cenci MA, Lundblad M. Post- versus presynaptic plasticity in L-DOPA-induced dyskinesia. J Neurochem. 2006;99(2):381–92.CrossRefPubMedGoogle Scholar
  6. 6.
    Calabresi P, Di Filippo M, Ghiglieri V, Picconi B. Molecular mechanisms underlying levodopa-induced dyskinesia. Mov Disord. 2008;23(Suppl 3):S570–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Schneider JS. Levodopa-induced dyskinesias in parkinsonian monkeys: relationship to extent of nigrostriatal damage. Pharmacol Biochem Behav. 1989;34(1):193–6.CrossRefPubMedGoogle Scholar
  8. 8.
    Boyce S, Rupniak NM, Steventon MJ, Iversen SD. Nigrostriatal damage is required for induction of dyskinesias by L-DOPA in squirrel monkeys. Clin Neuropharmacol. 1990;13(5):448–58.CrossRefPubMedGoogle Scholar
  9. 9.
    de la Fuente-Fernandez R, Pal PK, Vingerhoets FJ, Kishore A, Schulzer M, Mak EK, et al. Evidence for impaired presynaptic dopamine function in parkinsonian patients with motor fluctuations. J Neural Transm. 2000;107(1):49–57.CrossRefPubMedGoogle Scholar
  10. 10.
    Chase TN. Levodopa therapy: consequences of the nonphysiologic replacement of dopamine. Neurology. 1998;50(5 Suppl 5):S17–25.CrossRefPubMedGoogle Scholar
  11. 11.
    Hong JY, Oh JS, Lee I, Sunwoo MK, Ham JH, Lee JE, et al. Presynaptic dopamine depletion predicts levodopa-induced dyskinesia in de novo Parkinson disease. Neurology. 2014;82(18):1597–604.CrossRefPubMedGoogle Scholar
  12. 12.
    Huot P. L-DOPA-induced dyskinesia, is striatal dopamine depletion a requisite? J Neurol Sci. 2015;351(1-2):9–12.CrossRefPubMedGoogle Scholar
  13. 13.
    Sunwoo MK, Kim KM, Hong JY, Sohn YH, Lee PH. Levodopa-induced dyskinesia in a patient who has normal presynaptic dopaminergic neurons. Mov Disord. 2013;28(8):1152–3.CrossRefPubMedGoogle Scholar
  14. 14.
    Bedard PJ, Blanchet PJ, Levesque D, Soghomonian JJ, Grondin R, Morissette M, et al. Pathophysiology of L-dopa-induced dyskinesias. Mov Disord. 1999;14(Suppl 1):4–8.PubMedGoogle Scholar
  15. 15.
    Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE. A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. N Engl J Med. 2000;342(20):1484–91.CrossRefPubMedGoogle Scholar
  16. 16.
    Gibb WR, Lees AJ. The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry. 1988;51(6):745–52.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Tinazzi M, Ottaviani S, Isaias IU, Pasquin I, Steinmayr M, Vampini C, et al. [123I]FP-CIT SPET imaging in drug-induced Parkinsonism. Mov Disord. 2008;23(13):1825–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Oh M, Kim JS, Kim JY, Shin KH, Park SH, Kim HO, et al. Subregional patterns of preferential striatal dopamine transporter loss differ in Parkinson disease, progressive supranuclear palsy, and multiple-system atrophy. J Nucl Med. 2012;53(3):399–406.CrossRefPubMedGoogle Scholar
  19. 19.
    Hong JY, Sunwoo MK, Oh JS, Kim JS, Sohn YH, Lee PH. Persistent drug-induced parkinsonism in patients with normal dopamine transporter imaging. PLoS One. 2016;11(6):e0157410.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Wenning GK, Litvan I, Tolosa E. Milestones in atypical and secondary parkinsonisms. Mov Disord. 2011;26(6):1083–95.CrossRefPubMedGoogle Scholar
  21. 21.
    Tomlinson CL, Stowe R, Patel S, Rick C, Gray R, Clarke CE. Systematic review of levodopa dose equivalency reporting in Parkinson’s disease. Mov Disord. 2010;25(15):2649–53.CrossRefPubMedGoogle Scholar
  22. 22.
    Eggers C, Kahraman D, Fink GR, Schmidt M, Timmermann L. Akinetic-rigid and tremor-dominant Parkinson’s disease patients show different patterns of FP-CIT single photon emission computed tomography. Mov Disord. 2011;26(3):416–23.CrossRefPubMedGoogle Scholar
  23. 23.
    Mawlawi O, Martinez D, Slifstein M, Broft A, Chatterjee R, Hwang DR, et al. Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and precision of D(2) receptor parameter measurements in ventral striatum. J Cereb Blood Flow Metab. 2001;21(9):1034–57.CrossRefPubMedGoogle Scholar
  24. 24.
    Oh JS, Oh M, Chung SJ, Kim JS. Cerebellum-specific 18F-FDG PET analysis for the detection of subregional glucose metabolism changes in spinocerebellar ataxia. Neuroreport. 2014;25(15):1198–202.CrossRefPubMedGoogle Scholar
  25. 25.
    Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab. 2007;27(9):1533–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Schrag A, Hovris A, Morley D, Quinn N, Jahanshahi M. Young- versus older-onset Parkinson’s disease: impact of disease and psychosocial consequences. Mov Disord. 2003;18(11):1250–6.CrossRefPubMedGoogle Scholar
  27. 27.
    Lyons KE, Hubble JP, Troster AI, Pahwa R, Koller WC. Gender differences in Parkinson’s disease. Clin Neuropharmacol. 1998;21(2):118–21.PubMedGoogle Scholar
  28. 28.
    Zappia M, Annesi G, Nicoletti G, Arabia G, Annesi F, Messina D, et al. Sex differences in clinical and genetic determinants of levodopa peak-dose dyskinesias in Parkinson disease: an exploratory study. Arch Neurol. 2005;62(4):601–5.CrossRefPubMedGoogle Scholar
  29. 29.
    Parkinson study group. Impact of deprenyl and tocopherol treatment on Parkinson’s disease in DATATOP subjects not requiring levodopa. Ann Neurol. 1996;39(1):29–36.CrossRefGoogle Scholar
  30. 30.
    Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE, et al. Development of dyskinesias in a 5-year trial of ropinirole and L-dopa. Mov Disord. 2006;21(11):1844–50.CrossRefPubMedGoogle Scholar
  31. 31.
    Fabbrini G, Brotchie JM, Grandas F, Nomoto M, Goetz CG. Levodopa-induced dyskinesias. Mov Disord. 2007;22(10):1379–89.CrossRefPubMedGoogle Scholar
  32. 32.
    Schrag A, Quinn N. Dyskinesias and motor fluctuations in Parkinson’s disease. A community-based study. Brain. 2000;123:2297–305.CrossRefPubMedGoogle Scholar
  33. 33.
    Denny AP, Behari M. Motor fluctuations in Parkinson’s disease. J Neurol Sci. 1999;165(1):18–23.CrossRefPubMedGoogle Scholar
  34. 34.
    Yahalom G, Cohen OS, Warmann-Alaluf N, Shabat C, Strauss H, Elincx-Benizri S, et al. The impact of early versus late levodopa administration. J Neural Transm. 2017;124(4):471–6.CrossRefPubMedGoogle Scholar
  35. 35.
    Nadjar A, Gerfen CR, Bezard E. Priming for L-dopa-induced dyskinesia in Parkinson’s disease: a feature inherent to the treatment or the disease? Prog Neurobiol. 2009;87(1):1–9.CrossRefPubMedGoogle Scholar
  36. 36.
    Brotchie JM, Lee J, Venderova K. Levodopa-induced dyskinesia in Parkinson’s disease. J Neural Transm. 2005;112(3):359–91.CrossRefPubMedGoogle Scholar
  37. 37.
    Jenner P. Factors influencing the onset and persistence of dyskinesia in MPTP-treated primates. Ann Neurol. 2000;47(4 Suppl 1):S90–9.PubMedGoogle Scholar
  38. 38.
    Lundblad M, Picconi B, Lindgren H, Cenci MA. A model of L-DOPA-induced dyskinesia in 6-hydroxydopamine lesioned mice: relation to motor and cellular parameters of nigrostriatal function. Neurobiol Dis. 2004;16(1):110–23.CrossRefPubMedGoogle Scholar
  39. 39.
    Scholz B, Svensson M, Alm H, Skold K, Falth M, Kultima K, et al. Striatal proteomic analysis suggests that first L-dopa dose equates to chronic exposure. PLoS One. 2008;3(2):e1589.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Winkler C, Kirik D, Bjorklund A, Cenci MA. L-DOPA-induced dyskinesia in the intrastriatal 6-hydroxydopamine model of parkinson’s disease: relation to motor and cellular parameters of nigrostriatal function. Neurobiol Dis. 2002;10(2):165–86.CrossRefPubMedGoogle Scholar
  41. 41.
    Iravani MM, McCreary AC, Jenner P. Striatal plasticity in Parkinson’s disease and L-dopa induced dyskinesia. Parkinsonism Relat Disord. 2012;18(Suppl 1):S123–5.CrossRefPubMedGoogle Scholar
  42. 42.
    Zesiewicz TA, Sullivan KL, Hauser RA. Levodopa-induced dyskinesia in Parkinson’s disease: epidemiology, etiology, and treatment. Curr Neurol Neurosci Rep. 2007;7(4):302–10.CrossRefPubMedGoogle Scholar
  43. 43.
    Quinn N, Critchley P, Marsden CD. Young onset Parkinson’s disease. Mov Disord. 1987;2(2):73–91.CrossRefPubMedGoogle Scholar
  44. 44.
    Hauser RA, McDermott MP, Messing S. Factors associated with the development of motor fluctuations and dyskinesias in Parkinson disease. Arch Neurol. 2006;63(12):1756–60.CrossRefPubMedGoogle Scholar
  45. 45.
    Onofrj M, Paci C, Thomas A. Sudden appearance of invalidating dyskinesia-dystonia and off fluctuations after the introduction of levodopa in two dopaminomimetic drug naive patients with stage IV Parkinson’s disease. J Neurol Neurosurg Psychiatry. 1998;65(4):605–6.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Mouradian MM, Juncos JL, Fabbrini G, Schlegel J, Bartko JJ, Chase TN. Motor fluctuations in Parkinson’s disease: central pathophysiological mechanisms, Part II. Ann Neurol. 1988;24(3):372–8.CrossRefPubMedGoogle Scholar
  47. 47.
    Cenci MA. Presynaptic mechanisms of L-DOPA-induced dyskinesia: the findings, the debate, and the therapeutic implications. Front Neurol. 2014;5:242.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Di Monte DA, McCormack A, Petzinger G, Janson AM, Quik M, Langston WJ. Relationship among nigrostriatal denervation, parkinsonism, and dyskinesias in the MPTP primate model. Mov Disord. 2000;15(3):459–66.CrossRefPubMedGoogle Scholar
  49. 49.
    Hilker R, Schweitzer K, Coburger S, Ghaemi M, Weisenbach S, Jacobs AH, et al. Nonlinear progression of Parkinson disease as determined by serial positron emission tomographic imaging of striatal fluorodopa F 18 activity. Arch Neurol. 2005;62(3):378–82.CrossRefPubMedGoogle Scholar
  50. 50.
    Bruck A, Aalto S, Rauhala E, Bergman J, Marttila R, Rinne JO. A follow-up study on 6-[18F]fluoro-L-dopa uptake in early Parkinson’s disease shows nonlinear progression in the putamen. Mov Disord. 2009;24(7):1009–15.CrossRefPubMedGoogle Scholar
  51. 51.
    Kuriakose R, Stoessl AJ. Imaging the nigrostriatal system to monitor disease progression and treatment-induced complications. Prog Brain Res. 2010;184:177–92.CrossRefPubMedGoogle Scholar
  52. 52.
    Volkow ND, Ding YS, Fowler JS, Wang GJ, Logan J, Gatley SJ, et al. Dopamine transporters decrease with age. J Nucl Med. 1996;37(4):554–9.PubMedGoogle Scholar
  53. 53.
    Kaasinen V, Joutsa J, Noponen T, Johansson J, Seppanen M. Effects of aging and gender on striatal and extrastriatal [123I]FP-CIT binding in Parkinson’s disease. Neurobiol Aging. 2015;36(4):1757–63.CrossRefPubMedGoogle Scholar
  54. 54.
    Lee JJ, Oh JS, Ham JH, Lee DH, Lee I, Sohn YH, et al. Association of body mass index and the depletion of nigrostriatal dopamine in Parkinson’s disease. Neurobiol Aging. 2016;38:197–204.CrossRefPubMedGoogle Scholar
  55. 55.
    Maeda T, Nagata K, Yoshida Y, Kannari K. Serotonergic hyperinnervation into the dopaminergic denervated striatum compensates for dopamine conversion from exogenously administered l-DOPA. Brain Res. 2005;1046(1-2):230–3.CrossRefPubMedGoogle Scholar
  56. 56.
    Ballanger B, Beaudoin-Gobert M, Neumane S, Epinat J, Metereau E, Duperrier S, et al. Imaging dopamine and serotonin systems on MPTP monkeys: a longitudinal PET investigation of compensatory mechanisms. J Neurosci. 2016;36(5):1577–89.CrossRefPubMedGoogle Scholar
  57. 57.
    Nevalainen N, Af Bjerken S, Gerhardt GA, Stromberg I. Serotonergic nerve fibers in L-DOPA-derived dopamine release and dyskinesia. Neuroscience. 2014;260:73–86.CrossRefPubMedGoogle Scholar
  58. 58.
    Scheffel U, Lever JR, Abraham P, Parham KR, Mathews WB, Kopajtic T, et al. N-substituted phenyltropanes as in vivo binding ligands for rapid imaging studies of the dopamine transporter. Synapse. 1997;25(4):345–9.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Han Soo Yoo
    • 1
  • Seok Jong Chung
    • 1
  • Su Jin Chung
    • 1
  • Hyojeong Moon
    • 2
  • Jung Su Oh
    • 2
  • Jae Seung Kim
    • 2
  • Jin Yong Hong
    • 3
  • Byoung Seok Ye
    • 1
  • Young Ho Sohn
    • 1
  • Phil Hyu Lee
    • 1
    Email author
  1. 1.Department of NeurologyYonsei University College of MedicineSeoulSouth Korea
  2. 2.Department of Nuclear Medicine, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulSouth Korea
  3. 3.Yonsei University Wonju College of MedicineWonjuSouth Korea

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