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An integrative model of Parkinson’s disease treatment including levodopa pharmacokinetics, dopamine kinetics, basal ganglia neurotransmission and motor action throughout disease progression

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Abstract

Levodopa is considered the gold standard treatment of Parkinson’s disease. Although very effective in alleviating symptoms at their onset, its chronic use with the progressive neuronal denervation in the basal ganglia leads to a decrease in levodopa’s effect duration and to the appearance of motor complications. This evolution challenges the establishment of optimal regimens to manage the symptoms as the disease progresses. Based on up-to-date pathophysiological and pharmacological knowledge, we developed an integrative model for Parkinson’s disease to evaluate motor function in response to levodopa treatment as the disease progresses. We combined a pharmacokinetic model of levodopa to a model of dopamine’s kinetics and a neurocomputational model of basal ganglia. The parameter values were either measured directly or estimated from human and animal data. The concentrations and behaviors predicted by our model were compared to available information and data. Using this model, we were able to predict levodopa plasma concentration, its related dopamine concentration in the brain and the response performance of a motor task for different stages of disease.

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References

  1. Adamiak U, Kaldonska M, Klodowska-Duda G, Wyska E, Safranow K, Bialecka M, Gawronska-Szklarz B (2010) Pharmacokinetic-pharmacodynamic modeling of levodopa in patients with advanced Parkinson disease. Clin Neuropharmacol 33:135–141. https://doi.org/10.1097/WNF.0b013e3181d47849

    Article  CAS  PubMed  Google Scholar 

  2. Agid Y (1991) Parkinson’s disease: pathophysiology. Lancet 337:1321–1324. https://doi.org/10.1016/0140-6736(91)92989-f

    Article  CAS  PubMed  Google Scholar 

  3. Albin RL, Young AB, Penney JB (1989) The functional anatomy of basal ganglia disorders. Trends Neurosci 12:366–375

    Article  CAS  Google Scholar 

  4. Aquilonius SM, Nyholm D (2017) Development of new levodopa treatment strategies in Parkinson’s disease-from bedside to bench to bedside. Upps J Med Sci 122:71–77. https://doi.org/10.1080/03009734.2017.1285374

    Article  Google Scholar 

  5. Ashby FG, Crossley MJ (2011) A computational model of how cholinergic interneurons protect striatal-dependent learning. J Cogn Neurosci 23(6):1549–1566. https://doi.org/10.1162/jocn.2010.21523

    Article  PubMed  Google Scholar 

  6. Baston C, Contin M, Buonaura GC, Cortelli P, Ursino M (2016) A mathematical model of levodopa medication effect on basal ganglia in Parkinson’s disease: an application to the alternate finger tapping task. Front Hum Neurosci 10:280. https://doi.org/10.3389/fnhum.2016.00280

    Article  PubMed  PubMed Central  Google Scholar 

  7. Baston C, Ursino M (2015) A biologically inspired computational model of basal ganglia in action selection. Comput Intell Neurosci 2015:1–24. https://doi.org/10.1155/2015/187417

    Article  Google Scholar 

  8. Bergstrom BP, Garris PA (2003) “Passive stabilization” of striatal extracellular dopamine across the lesion spectrum encompassing the presymptomatic phase of Parkinson’s disease: a voltammetric study in the 6-ohda-lesioned rat. J Neurochem 87:1224–1236. https://doi.org/10.1046/j.1471-4159.2003.02104.x

    Article  CAS  PubMed  Google Scholar 

  9. Best JA, Nijhout HF, Reed MC (2009) Homeostatic mechanisms in dopamine synthesis and release: a mathematical model. Theor Biol Med Model 6:1. https://doi.org/10.1186/1742-4682-6-21

    Article  CAS  Google Scholar 

  10. Bezard E, Dovero S, Prunier C, Ravenscroft P, Chalon S, Guilloteau D, Crossman AR, Bioulac B, Brotchie JM, Gross CE (2001) Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson’s disease. J Neurosci 21:6853–6861

    Article  CAS  Google Scholar 

  11. Black KJ, Acevedo HK, Koller JM (2020) Dopamine buffering capacity imaging: a pharmacodynamic fmri method for staging Parkinson disease. Front Neurol 11:370. https://doi.org/10.3389/fneur.2020.00370

    Article  PubMed  PubMed Central  Google Scholar 

  12. Boileau I, Guttman M, Rusjan P, Adams JR, Houle S, Tong J, Hornykiewicz O, Furukawa Y, Wilson AA, Kapur S, Kish SJ (2009) Decreased binding of the d3 dopamine receptor-preferring ligand [11c]-(+)-phno in drug-naive Parkinson’s disease. Brain 132:1366–1375. https://doi.org/10.1093/brain/awn337

    Article  PubMed  Google Scholar 

  13. Budygin EA, John CE, Mateo Y, Jones SR (2002) Lack of cocaine effect on dopamine clearance in the core and shell of the nucleus accumbens of dopamine transporter knock-out mice. J Neurosci 22(RC222):20026389

    Google Scholar 

  14. Cavanagh JF, Wiecki TV, Cohen MX, Figueroa CM, Samanta J, Sherman SJ, Frank MJ (2011) Subthalamic nucleus stimulation reverses mediofrontal influence over decision threshold. Nat Neurosci 14(11):1462–1467. https://doi.org/10.1038/nn.2925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chan PLS, Nutt JG, Holford NHG (2004) Modeling the short- and long-duration responses to exogenous levodopa and to endogenous levodopa production in Parkinson’s disease. J Pharmacokinet Pharmacodyn 31:243–268

    Article  CAS  Google Scholar 

  16. Chan PLS, Nutt JG, Holford NHG (2005) Pharmacokinetic and pharmacodynamic changes during the first four years of levodopa treatment in Parkinson’s disease. J Pharmacokinet Pharmacodyn 32:459–484. https://doi.org/10.1007/s10928-005-0055-x

    Article  CAS  PubMed  Google Scholar 

  17. Chou YH, Karlsson P, Halldin C, Olsson H, Farde L (1999) A pet study of d(1)-like dopamine receptor ligand binding during altered endogenous dopamine levels in the primate brain. Psychopharmacology 146:220–227. https://doi.org/10.1007/s002130051110

    Article  CAS  PubMed  Google Scholar 

  18. Contin M, Riva R, Martinelli P, Albani F, Avoni P, Baruzzi A (2001) Levodopa therapy monitoring in patients with Parkinson disease: a kinetic-dynamic approach. Ther Drug Monit 23:621–629

    Article  CAS  Google Scholar 

  19. Cotzias GC, Van Woert MH, Schiffer LM (1967) Aromatic amino acids and modification of parkinsonism. N Engl J Med 276:374–379. https://doi.org/10.1056/NEJM196702162760703

    Article  CAS  PubMed  Google Scholar 

  20. Crossman AR, Clarke CE, Boyce S, Robertson RG, Sambrook MA (1987) Mptp-induced parkinsonism in the monkey: neurochemical pathology, complications of treatment and pathophysiological mechanisms. Can J Neurol Sci 14:428–435. https://doi.org/10.1017/s0317167100037859

    Article  CAS  PubMed  Google Scholar 

  21. Cutsuridis V, Perantonis S (2006) A neural network model of Parkinson’s disease bradykinesia. Neural Netw 19:354–374. https://doi.org/10.1016/j.neunet.2005.08.016

    Article  PubMed  Google Scholar 

  22. DeLong MR (1990) Primate models of movement disorders of basal ganglia origin. Trends Neurosci 13:281–285

    Article  CAS  Google Scholar 

  23. Dentresangle C, Le Cavorsin M, Savasta M, Leviel V (2001) Increased extracellular da and normal evoked da release in the rat striatum after a partial lesion of the Substantia nigra. Brain Res 893:178–185. https://doi.org/10.1016/s0006-8993(00)03311-4

    Article  CAS  PubMed  Google Scholar 

  24. Dietz M, Harder S, Graff J, Künig G, Vontobel P, Leenders KL, Baas H (2001) Levodopa pharmacokinetic-pharmacodynamic modeling and 6-[18f]levodopa positron emission tomography in patients with Parkinson’s disease. Clin Pharmacol Ther 70:33–41. https://doi.org/10.1067/mcp.2001.116328

    Article  CAS  PubMed  Google Scholar 

  25. Dreyer JK (2014) Three mechanisms by which striatal denervation causes breakdown of dopamine signaling. J Neurosci 34(37):12444–12456. https://doi.org/10.1523/jneurosci.1458-14.2014

    Article  PubMed  PubMed Central  Google Scholar 

  26. Dreyer JK, Herrik KF, Berg RW, Hounsgaard JD (2010) Influence of phasic and tonic dopamine release on receptor activation. J Neurosci 30(42):14273–14283. https://doi.org/10.1523/JNEUROSCI.1894-10.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Fabbrini G, Juncos J, Mouradian MM, Serrati C, Chase TN (1987) Levodopa pharmacokinetic mechanisms and motor fluctuations in Parkinson’s disease. Ann Neurol 21:370–376. https://doi.org/10.1002/ana.410210409

    Article  CAS  PubMed  Google Scholar 

  28. Frank MJ (2005) Dynamic dopamine modulation in the basal ganglia: a neurocomputational account of cognitive deficits in medicated and nonmedicated parkinsonism. J Cognit Neurosci 17(1):51–72. https://doi.org/10.1162/0898929052880093

    Article  Google Scholar 

  29. Gangadhar G, Joseph D, Srinivasan AV, Subramanian D, Shivakeshavan RG, Shobana N, Chakravarthy VS (2009) A computational model of parkinsonian handwriting that highlights the role of the indirect pathway in the basal ganglia. Hum Mov Sci 28:602–618. https://doi.org/10.1016/j.humov.2009.07.008

    Article  CAS  PubMed  Google Scholar 

  30. Gerfen CR, Engber TM, Mahan LC, Susel Z, Chase TN, Monsma FJ, Sibley DR (1990) D1 and d2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 250:1429–1432. https://doi.org/10.1126/science.2147780

    Article  CAS  PubMed  Google Scholar 

  31. Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, Poewe W, Sampaio C, Stern MB, Dodel R, Dubois B, Holloway R, Jankovic J, Kulisevsky J, Lang AE, Lees A, Leurgans S, LeWitt PA, Nyenhuis D, Olanow CW, Rascol O, Schrag A, Teresi JA, van Hilten JJ, LaPelle N, Force MDSURT (2008) Movement disorder society-sponsored revision of the unified Parkinson’s disease rating scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord 23:2129–2170. https://doi.org/10.1002/mds.22340

    Article  PubMed  Google Scholar 

  32. Gomez G, Escande MV, Suarez LM, Rela L, Belforte JE, Moratalla R, Murer MG, Gershanik OS, Taravini IRE (2019) Changes in dendritic spine density and inhibitory perisomatic connectivity onto medium spiny neurons in l-dopa-induced dyskinesia. Mol Neurobiol 56:6261–6275. https://doi.org/10.1007/s12035-019-1515-4

    Article  CAS  PubMed  Google Scholar 

  33. Greffard S, Verny M, Bonnet AM, Beinis JY, Gallinari C, Meaume S, Piette F, Hauw JJ, Duyckaerts C (2006) Motor score of the unified Parkinson disease rating scale as a good predictor of lewy body–associated neuronal loss in the substantia nigra. Arch Neurol 63(4):584. https://doi.org/10.1001/archneur.63.4.584

    Article  PubMed  Google Scholar 

  34. Group PS (2002) Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 287:1653–1661. https://doi.org/10.1001/jama.287.13.1653

    Article  Google Scholar 

  35. Guthrie M, Myers CE, Gluck MA (2009) A neurocomputational model of tonic and phasic dopamine in action selection: a comparison with cognitive deficits in Parkinson’s disease. Behav Brain Res 200:48–59. https://doi.org/10.1016/j.bbr.2008.12.036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Guttman M, Seeman P (1985) L-dopa reverses the elevated density of d2 dopamine receptors in Parkinson’s diseased striatum. J Neural Transm 64:93–103. https://doi.org/10.1007/bf01245971

    Article  CAS  PubMed  Google Scholar 

  37. Haeri M, Sarbaz Y, Gharibzadeh S (2005) Modeling the Parkinson’s tremor and its treatments. J Theor Biol 236(3):311–322. https://doi.org/10.1016/j.jtbi.2005.03.014

    Article  PubMed  Google Scholar 

  38. Harder S, Baas H (1998) Concentration-response relationship of levodopa in patients at different stages of Parkinson’s disease. Clin Pharmacol Ther 64:183–191. https://doi.org/10.1016/S0009-9236(98)90152-7

    Article  CAS  PubMed  Google Scholar 

  39. Hille B (1992) G protein-coupled mechanisms and nervous signaling. Neuron 9(2):187–195. https://doi.org/10.1016/0896-6273(92)90158-a

    Article  CAS  PubMed  Google Scholar 

  40. Hisahara S, Shimohama S (2011) Dopamine receptors and Parkinson’s disease. Int J Med Chem 2011:403039. https://doi.org/10.1155/2011/403039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Holford N, Nutt JG (2008) Disease progression, drug action and Parkinson’s disease: why time cannot be ignored. Eur J Clin Pharmacol 64:207–216. https://doi.org/10.1007/s00228-007-0427-9

    Article  PubMed  Google Scholar 

  42. Holford NHG, Chan PLS, Nutt JG, Kieburtz K, Shoulson I, Group PS (2006) Disease progression and pharmacodynamics in Parkinson disease–evidence for functional protection with levodopa and other treatments. J Pharmacokinet Pharmacodyn 33:281–311. https://doi.org/10.1007/s10928-006-9012-6

    Article  CAS  Google Scholar 

  43. Homann CN, Suppan K, Wenzel K, Giovannoni G, Ivanic G, Horner S, Ott E, Hartung HP (2000) The bradykinesia akinesia incoordination test (brain test), an objective and user-friendly means to evaluate patients with parkinsonism. Mov Disord 15:641–647

    Article  CAS  Google Scholar 

  44. Hunger L, Kumar A, Schmidt R (2020) Abundance compensates kinetics: Similar effect of dopamine signals on d1 and d2 receptor populations. J Neurosci 40(14):2868–2881. https://doi.org/10.1523/JNEUROSCI.1951-19.2019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kuwabara H, McCaul ME, Wand GS, Earley CJ, Allen RP, Weerts EM, Dannals RF, Wong DF (2012) Dissociative changes in the bmax and kd of dopamine d2/d3 receptors with aging observed in functional subdivisions of the striatum: a revisit with an improved data analysis method. J Nucl Med 53:805–812. https://doi.org/10.2967/jnumed.111.098186

    Article  PubMed  PubMed Central  Google Scholar 

  46. Lee T, Seeman P, Rajput A, Farley IJ, Hornykiewicz O (1978) Receptor basis for dopaminergic supersensitivity in Parkinson’s disease. Nature 273:59–61. https://doi.org/10.1038/273059a0

    Article  CAS  PubMed  Google Scholar 

  47. Lopez A, Muũoz A, Guerra MJ, Labandeira-Garcia JL (2001) Mechanisms of the effects of exogenous levodopa on the dopamine-denervated striatum. Neuroscience 103:639–651. https://doi.org/10.1016/s0306-4522(00)00588-1

    Article  CAS  PubMed  Google Scholar 

  48. May T (1992) Striatal dopamine d1-like receptors have higher affinity for dopamine in ethanol-treated rats. Eur J Pharmacol 215(2–3):313–316. https://doi.org/10.1016/0014-2999(92)90047-8

    Article  CAS  PubMed  Google Scholar 

  49. Mink JW (1996) The basal ganglia: Focused selection and inhibition of competing motor programs. Prog Neurobiol 50(4):381–425. https://doi.org/10.1016/S0301-0082(96)00042-1

    Article  CAS  PubMed  Google Scholar 

  50. Moustafa AA, Gluck MA (2011) A neurocomputational model of dopamine and prefrontal-striatal interactions during multicue category learning by Parkinson patients. J Cogn Neurosci 23(1):151–167. https://doi.org/10.1162/jocn.2010.21420

    Article  PubMed  Google Scholar 

  51. Neve KA, Neve RL (1997) Molecular biology of dopamine receptors. Humana Press, Totowa, pp 27–76. https://doi.org/10.1007/978-1-4757-2635-0

    Book  Google Scholar 

  52. Nord M, Zsigmond P, Kullman A, Dizdar N (2017) Levodopa pharmacokinetics in brain after both oral and intravenous levodopa in one patient with advanced Parkinson’s disease. Adv Parkinson’s Dis 6(2):52–66. https://doi.org/10.4236/apd.2017.62006

    Article  CAS  Google Scholar 

  53. Nutt JG, Holford NH (1996) The response to levodopa in Parkinson’s disease: imposing pharmacological law and order. Ann Neurol 39:561–573. https://doi.org/10.1002/ana.410390504

    Article  CAS  PubMed  Google Scholar 

  54. Nutt JG, Woodward WR, Carter JH, Gancher ST (1992) Effect of long-term therapy on the pharmacodynamics of levodopa. Relation to on-off phenomenon. Arch Neurol 49:1123–1130. https://doi.org/10.1001/archneur.1992.00530350037016

    Article  CAS  PubMed  Google Scholar 

  55. Olanow CW, Agid Y, Mizuno Y, Albanese A, Bonuccelli U, Bonucelli U, Damier P, De Yebenes J, Gershanik O, Guttman M, Grandas F, Hallett M, Hornykiewicz O, Jenner P, Katzenschlager R, Langston WJ, LeWitt P, Melamed E, Mena MA, Michel PP, Mytilineou C, Obeso JA, Poewe W, Quinn N, Raisman-Vozari R, Rajput AH, Rascol O, Sampaio C, Stocchi F (2004) Levodopa in the treatment of Parkinson’s disease: current controversies. Mov Disord 19:997–1005. https://doi.org/10.1002/mds.20243

    Article  PubMed  Google Scholar 

  56. Olanow W, Schapira AH, Rascol O (2000) Continuous dopamine-receptor stimulation in early Parkinson’s disease. Trends Neurosci 23:S117–S126. https://doi.org/10.1016/s1471-1931(00)00030-6

    Article  CAS  PubMed  Google Scholar 

  57. Pal PK, Lee CS, Samii A, Schulzer M, Stoessl AJ, Mak EK, Wudel J, Dobko T, Tsui JK (2001) Alternating two finger tapping with contralateral activation is an objective measure of clinical severity in Parkinson’s disease and correlates with pet. Parkinsonism Relat Disord 7:305–309. https://doi.org/10.1016/s1353-8020(00)00048-1

    Article  PubMed  Google Scholar 

  58. Payer DE, Guttman M, Kish SJ, Tong J, Adams JR, Rusjan P, Houle S, Furukawa Y, Wilson AA, Boileau I (2016) D3 dopamine receptor-preferring [11c]phno pet imaging in Parkinson patients with dyskinesia. Neurology 86:224–230. https://doi.org/10.1212/WNL.0000000000002285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Poewe W, Antonini A, Zijlmans JC, Burkhard PR, Vingerhoets F (2010) Levodopa in the treatment of parkinson’s disease: an old drug still going strong. Clin Interv Aging 5:229–238

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Reed MC, Best J, Nijhout HF (2009) Passive and active stabilization of dopamine in the striatum. Biosci Hypotheses 2(4):240–244. https://doi.org/10.1016/j.bihy.2009.03.008

    Article  Google Scholar 

  61. Reed MC, Nijhout HF, Best JA (2012) Mathematical insights into the effects of levodopa. Front Integr Neurosci 6:21. https://doi.org/10.3389/fnint.2012.00021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Richfield E, Penney J, Young A (1989) Anatomical and affinity state comparisons between dopamine d1 and d2 receptors in the rat central nervous system. Neuroscience 30(3):767–777. https://doi.org/10.1016/0306-4522(89)90168-1

    Article  CAS  PubMed  Google Scholar 

  63. Rinne JO, Laihinen A, Ruottinen H, Ruotsalainen U, Någren K, Lehikoinen P, Oikonen V, Rinne UK (1995) Increased density of dopamine d2 receptors in the putamen, but not in the caudate nucleus in early parkinson’s disease: a pet study with [11c]raclopride. J Neurol Sci 132:156–161. https://doi.org/10.1016/0022-510x(95)00137-q

    Article  CAS  PubMed  Google Scholar 

  64. Salamon A, Zádori D, Szpisjak L, Klivényi P, Vécsei L (2019) Neuroprotection in parkinson’s disease: facts and hopes. J Neural Transm 127(5):821–829. https://doi.org/10.1007/s00702-019-02115-8

    Article  PubMed  Google Scholar 

  65. Schroll H, Vitay J, Hamker FH (2012) Working memory and response selection: a computational account of interactions among cortico-basalganglio-thalamic loops. Neural Netw 26:59–74. https://doi.org/10.1016/j.neunet.2011.10.008

    Article  PubMed  Google Scholar 

  66. Seeman P, Niznik HB (1990) Dopamine receptors and transporters in parkinson’s disease and schizophrenia. FASEB J 4:2737–2744. https://doi.org/10.1096/fasebj.4.10.2197154

    Article  CAS  PubMed  Google Scholar 

  67. Senek M, Nyholm D, Nielsen EI (2018) Population pharmacokinetics of levodopa/carbidopa microtablets in healthy subjects and Parkinson’s disease patients. Eur J Clin Pharmacol 74:1299–1307. https://doi.org/10.1007/s00228-018-2497-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Sharma S, Moon CS, Khogali A, Haidous A, Chabenne A, Ojo C, Jelebinkov M, Kurdi Y, Ebadi M (2013) Biomarkers in Parkinson’s disease (recent update). Neurochem Int 63:201–229. https://doi.org/10.1016/j.neuint.2013.06.005

    Article  CAS  PubMed  Google Scholar 

  69. Skorvanek M, Martinez-Martin P, Kovacs N, Rodriguez-Violante M, Corvol JC, Taba P, Seppi K, Levin O, Schrag A, Foltynie T, Alvarez-Sanchez M, Arakaki T, Aschermann Z, Aviles-Olmos I, Benchetrit E, Benoit C, Bergareche-Yarza A, Cervantes-Arriaga A, Chade A, Cormier F, Datieva V, Gallagher DA, Garretto N, Gdovinova Z, Gershanik O, Grofik M, Han V, Huang J, Kadastik-Eerme L, Kurtis MM, Mangone G, Martinez-Castrillo JC, Mendoza-Rodriguez A, Minar M, Moore HP, Muldmaa M, Mueller C, Pinter B, Poewe W, Rallmann K, Reiter E, Rodriguez-Blazquez C, Singer C, Tilley BC, Valkovic P, Goetz CG, Stebbins GT (2017) Differences in MDS-UPDRS scores based on hoehn and yahr stage and disease duration. Mov Disord Clin Pract 4:536–544. https://doi.org/10.1002/mdc3.12476

    Article  PubMed  PubMed Central  Google Scholar 

  70. Smith LA, Jackson MJ, Hansard MJ, Maratos E, Jenner P (2003) Effect of pulsatile administration of levodopa on dyskinesia induction in drug-naïve mptp-treated common marmosets: effect of dose, frequency of administration, and brain exposure. Mov Disord 18:487–495. https://doi.org/10.1002/mds.10394

    Article  PubMed  Google Scholar 

  71. Sulzer D, Cragg SJ, Rice ME (2016) Striatal dopamine neurotransmission: regulation of release and uptake. Basal Ganglia 6(3):123–148. https://doi.org/10.1016/j.baga.2016.02.001

    Article  PubMed  PubMed Central  Google Scholar 

  72. Taylor Tavares AL, Jefferis GSXE, Koop M, Hill BC, Hastie T, Heit G, Bronte-Stewart HM (2005) Quantitative measurements of alternating finger tapping in Parkinson’s disease correlate with UPDRS motor disability and reveal the improvement in fine motor control from medication and deep brain stimulation. Mov Disord 20:1286–1298. https://doi.org/10.1002/mds.20556

    Article  PubMed  Google Scholar 

  73. Thanvi BR, Lo TCN (2004) Long term motor complications of levodopa: clinical features, mechanisms, and management strategies. Postgrad Med J 80(946):452–458. https://doi.org/10.1136/pgmj.2003.013912

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Triggs EJ, Charles BG, Contin M, Martinelli P, Cortelli P, Riva R, Albani F, Baruzzi A (1996) Population pharmacokinetics and pharmacodynamics of oral levodopa in parkinsonian patients. Eur J Clin Pharmacol 51:59–67. https://doi.org/10.1007/s002280050161

    Article  CAS  PubMed  Google Scholar 

  75. Ursino M, Baston C (2018) Aberrant learning in Parkinson’s disease: a neurocomputational study on bradykinesia. Eur J Neurosci 47:1563–1582. https://doi.org/10.1111/ejn.13960

    Article  PubMed  Google Scholar 

  76. Ursino M, Magosso E, Lopane G, Calandra-Buonaura G, Cortelli P, Contin M (2020) Mathematical modeling and parameter estimation of levodopa motor response in patients with Parkinson disease. PLoS ONE 15(3):1–20. https://doi.org/10.1371/journal.pone.0229729

    Article  CAS  Google Scholar 

  77. Venton BJ, Zhang H, Garris PA, Phillips PEM, Sulzer D, Wightman RM (2003) Real-time decoding of dopamine concentration changes in the caudate-putamen during tonic and phasic firing. J Neurochem 87:1284–1295. https://doi.org/10.1046/j.1471-4159.2003.02109.x

    Article  CAS  PubMed  Google Scholar 

  78. Wiecki TV, Frank MJ (2010) Neurocomputational models of motor and cognitive deficits in Parkinson’s disease. Prog Brain Res 183:275–297. https://doi.org/10.1016/S0079-6123(10)83014-6

    Article  CAS  PubMed  Google Scholar 

  79. Zigmond MJ, Abercrombie ED, Berger TW, Grace AA, Stricker EM (1990) Compensations after lesions of central dopaminergic neurons: some clinical and basic implications. Trends Neurosci 13:290–296

    Article  CAS  Google Scholar 

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Acknowledgements

F.V.-V. received a scholarship from the Natural Sciences and Engineering Research Council (NSERC), Canada through the PGS-D program. Support was also provided by NSERC -Industrial Chair in Pharmacometrics funded by Novartis, Pfizer and Syneos, as well as FRQNT Projet d’équipe (F.N.).

Funding

Funding was provided by Natural Sciences and Engineering Research Council of Canada (Grant Numbers PGSD3, 462059-12), Fonds de Recherche du Québec - Nature et Technologies (Grant Number 2016-PR-192198).

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Authors and Affiliations

  1. Faculté de Pharmacie, Université de Montréal, Montréal, QC, Canada

    Florence Véronneau-Veilleux & Fahima Nekka

  2. Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada

    Mauro Ursino

  3. Department of Electrical, Electronic and Information Engineering “Guglielmo Marconi”, University of Bologna, Bologna, 40136, Italy

    Philippe Robaey

  4. Centre de Recherches Mathématiques, Université de Montréal, Montréal, QC, Canada

    Fahima Nekka

  5. Centre for Applied Mathematics in Bioscience and Medicine (CAMBAM), McGill University, Montréal, QC, Canada

    Fahima Nekka

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  1. Florence Véronneau-Veilleux
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  4. Fahima Nekka
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Correspondence to Florence Véronneau-Veilleux.

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Véronneau-Veilleux, F., Robaey, P., Ursino, M. et al. An integrative model of Parkinson’s disease treatment including levodopa pharmacokinetics, dopamine kinetics, basal ganglia neurotransmission and motor action throughout disease progression. J Pharmacokinet Pharmacodyn 48, 133–148 (2021). https://doi.org/10.1007/s10928-020-09723-y

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