Abstract
Throughout the years there has been a longstanding discussion on whether levodopa therapy in Parkinson’s disease should be started in early vs. later stages, in order to prevent or delay motor complications such as fluctuations and dyskinesias. This controversial topic has been extensively debated for decades, and the prevailing view today is that levodopa should not be postponed. However, there is still fear associated with its use in early stages, especially in younger patients, who are more prone to develop dyskinesias. Even though dyskinesias are linked to levodopa use in Parkinson’s disease, it has been shown that starting with a different medication (such as dopamine agonists) will not significantly delay their onset once levodopa is introduced. Since levodopa provides better symptomatic control, and other drugs may be associated with notable side effects, it is our view that there is insufficient evidence to justify levodopa-sparing strategies. The physician should try to assess each patient individually, taking into account motor and non-motor demands, as well as risk factors for potential complications, finding the optimum treatment strategy for each one. The following article provides an historical narrative perspective, as well as a literature review of those intrinsic and modifiable risk factors that have been associated with levodopa-induced dyskinesias, which should be taken into consideration when choosing the therapeutic strategy in individual Parkinson’s disease patients.
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References
Agid Y (1998) Levodopa: is toxicity a myth? Neurology 50:858–863
Ahlskog JE, Muenter MD (2001) Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord 16:448–458
Ahmed I, Bose SK, Pavese N et al (2011) Glutamate NMDA receptor dysregulation in Parkinson’s disease with dyskinesias. Brain 134:979–986. https://doi.org/10.1093/brain/awr028
Antonini A, Leenders KL, Reist H et al (1993) Effect of age on D2 dopamine receptors in normal human brain measured by positron emission tomography and 11C-raclopride. Arch Neurol 50:474–480
Arabia G, Zappia M, Bosco D et al (2002) Body weight, levodopa pharmacokinetics and dyskinesia in Parkinson’s disease. Neurol Sci 23(Suppl 2):S53–S54. https://doi.org/10.1007/s100720200066
Ballard PA, Tetrud JW, Langston JW (1985) Permanent human parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): seven cases. Neurology 35:949–956
Barbeau A (1971) Long-term side-effects of levodopa. Lancet (London, England) 1:395. https://doi.org/10.1016/s0140-6736(71)92226-4
Bibbiani F, Costantini LC, Patel R, Chase TN (2005) Continuous dopaminergic stimulation reduces risk of motor complications in parkinsonian primates. Exp Neurol 192:73–78. https://doi.org/10.1016/j.expneurol.2004.11.013
Biundo R, Weis L, Abbruzzese G et al (2017) Impulse control disorders in advanced Parkinson’s disease with dyskinesia: the ALTHEA study. Mov Disord. https://doi.org/10.1002/mds.27181
Blanchet PJ, Calon F, Martel JC et al (1995) Continuous administration decreases and pulsatile administration increases behavioral sensitivity to a novel dopamine D2 agonist (U-91356A) in MPTP-exposed monkeys. J Pharmacol Exp Ther 272:854–859
Borgohain R, Szasz J, Stanzione P et al (2014) Randomized trial of safinamide add-on to levodopa in Parkinson’s disease with motor fluctuations. Mov Disord 29:229–237. https://doi.org/10.1002/mds.25751
Boyce S, Rupniak NM, Steventon MJ, Iversen SD (1990) Nigrostriatal damage is required for induction of dyskinesias by l-DOPA in squirrel monkeys. Clin Neuropharmacol 13:448–458
Buongiorno M, Antonelli F, Cámara A et al (2015) Long-term response to continuous duodenal infusion of levodopa/carbidopa gel in patients with advanced Parkinson disease: the Barcelona registry. Parkinsonism Relat Disord 21:871–876. https://doi.org/10.1016/j.parkreldis.2015.05.014
Carta M, Carlsson T, Kirik D, Björklund A (2007) Dopamine released from 5-HT terminals is the cause of l-DOPA-induced dyskinesia in parkinsonian rats. Brain 130:1819–1833. https://doi.org/10.1093/brain/awm082
Cheshire P, Bertram K, Ling H et al (2014) Influence of single nucleotide polymorphisms in COMT, MAO-A and BDNF genes on dyskinesias and levodopa use in Parkinson’s disease. Neurodegener Dis 13:24–28. https://doi.org/10.1159/000351097
Cilia R, Akpalu A, Sarfo FS et al (2014) The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa. Brain 137:2731–2742. https://doi.org/10.1093/brain/awu195
Comi C, Ferrari M, Marino F et al (2017) Polymorphisms of dopamine receptor genes and risk of l-Dopa-induced dyskinesia in parkinson’s disease. Int J Mol Sci 18:242. https://doi.org/10.3390/ijms18020242
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
Cotzias GC, Papavasiliou PS, Gellene R (1969) Modification of Parkinsonism—chronic treatment with l-dopa. N Engl J Med 280:337–345. https://doi.org/10.1056/NEJM196902132800701
Datla KP, Blunt SB, Dexter DT (2001) Chronic l-DOPA administration is not toxic to the remaining dopaminergic nigrostriatal neurons, but instead may promote their functional recovery, in rats with partial 6-OHDA or FeCl(3) nigrostriatal lesions. Mov Disord 16:424–434
de la Fuente-Fernández R, Pal PK, Vingerhoets FJ et al (2000) Evidence for impaired presynaptic dopamine function in parkinsonian patients with motor fluctuations. J Neural Transm 107:49–57. https://doi.org/10.1007/s007020050004
de la Fuente-Fernández R, Lu JQ, Sossi V et al (2001) Biochemical variations in the synaptic level of dopamine precede motor fluctuations in Parkinson’s disease: PET evidence of increased dopamine turnover. Ann Neurol 49:298–303
de la Fuente-Fernández R, Sossi V, Huang Z et al (2004) Levodopa-induced changes in synaptic dopamine levels increase with progression of Parkinson’s disease: implications for dyskinesias. Brain 127:2747–2754. https://doi.org/10.1093/brain/awh290
de la Fuente-Fernández R, Schulzer M, Kuramoto L et al (2011) Age-specific progression of nigrostriatal dysfunction in Parkinson’s disease. Ann Neurol 69:803–810. https://doi.org/10.1002/ana.22284
Djaldetti R, Treves TA, Merims D et al (2003) Effect of late initiation of levodopa treatment in patients with long-standing Parkinson’s disease. Clin Neuropharmacol 26:24–27
Doder M, Rabiner EA, Turjanski N et al (2003) Tremor in Parkinson’s disease and serotonergic dysfunction: an 11C-WAY 100635 PET study. Neurology 60:601–605
Dotchin CL, Gray WK, Dewhurst F et al (2015) Parkinson’s disease related dyskinesia in a Tanzanian population. Parkinsonism Relat Disord 21:1109–1110. https://doi.org/10.1016/j.parkreldis.2015.06.021
Eggers C, Kahraman D, Fink GR et al (2011) Akinetic-rigid and tremor-dominant Parkinson’s disease patients show different patterns of FP-CIT single photon emission computed tomography. Mov Disord 26:416–423. https://doi.org/10.1002/mds.23468
Eggers C, Pedrosa DJ, Kahraman D et al (2012) Parkinson subtypes progress differently in clinical course and imaging pattern. PLoS One 7:e46813. https://doi.org/10.1371/journal.pone.0046813
Fahn S (1999) Parkinson disease, the effect of levodopa, and the ELLDOPA trial. Earlier vs later l-DOPA. Arch Neurol 56:529–535. https://doi.org/10.1001/archneur.56.5.529
Fahn S, Oakes D, Shoulson I et al (2004) Levodopa and the progression of Parkinson’s disease. N Engl J Med 351:2498–2508. https://doi.org/10.1056/NEJMoa033447
Falardeau P, Di Paolo T (1987) Regional effect of estradiol on rat caudate-putamen dopamine receptors: lateral–medial differences. Neurosci Lett 74:43–48. https://doi.org/10.1016/0304-3940(87)90048-6
Foltynie T, Cheeran B, Williams-Gray CH et al (2009) BDNF val66met influences time to onset of levodopa induced dyskinesia in Parkinson’s disease. J Neurol Neurosurg Psychiatry 80:141–144. https://doi.org/10.1136/jnnp.2008.154294
Fox SH, Lang AE (2014) “Don’t delay, start today’: delaying levodopa does not delay motor complications. Brain 137:2628–2630. https://doi.org/10.1093/brain/awu212
Giladi N, Mirelman A, Thaler A, Orr-Urtreger A (2016) A personalized approach to Parkinson’s disease patients based on founder mutation analysis. Front Neurol 7:71. https://doi.org/10.3389/fneur.2016.00071
Gomez-Mancilla B, Bédard PJ (1992) Effect of estrogen and progesterone on l-dopa induced dyskinesia in MPTP-treated monkeys. Neurosci Lett 135:129–132. https://doi.org/10.1016/0304-3940(92)90152-W
Goodwin VA, Richards SH, Taylor RS et al (2008) The effectiveness of exercise interventions for people with Parkinson’s disease: a systematic review and meta-analysis. Mov Disord 23:631–640. https://doi.org/10.1002/mds.21922
Grandas F, Galiano ML, Tabernero C (1999) Risk factors for levodopa-induced dyskinesias in Parkinson’s disease. J Neurol 246:1127–1133. https://doi.org/10.1007/s004150050530
Haaxma CA, Bloem BR, Borm GF et al (2007) Gender differences in Parkinson’s disease. J Neurol Neurosurg Psychiatry 78:819–824. https://doi.org/10.1136/jnnp.2006.103788
Hassin-Baer S, Molchadski I, Cohen OS et al (2011) Gender effect on time to levodopa-induced dyskinesias. J Neurol 258:2048–2053. https://doi.org/10.1007/s00415-011-6067-0
Hauser RA, McDermott MP, Messing S (2006) Factors associated with the development of motor fluctuations and dyskinesias in Parkinson disease. Arch Neurol 63:1756–1760. https://doi.org/10.1001/archneur.63.12.1756
Hauser RA, Schapira AHV, Barone P et al (2014) Long-term safety and sustained efficacy of extended-release pramipexole in early and advanced Parkinson’s disease. Eur J Neurol 21:736–743. https://doi.org/10.1111/ene.12375
Havelund JF, Andersen AD, Binzer M et al (2017) Changes in kynurenine pathway metabolism in Parkinson patients with l-DOPA-induced dyskinesia. J Neurochem. https://doi.org/10.1111/jnc.14104
F Hernández L, Castela I, Ruiz-DeDiego I et al (2017) Striatal activation by optogenetics induces dyskinesias in the 6-hydroxydopamine rat model of Parkinson disease. Mov Disord 32:530–537. https://doi.org/10.1002/mds.26947
Herz DM, Haagensen BN, Nielsen SH et al (2016) Resting-state connectivity predicts levodopa-induced dyskinesias in Parkinson’s disease. Mov Disord 31:521–529. https://doi.org/10.1002/mds.26540
Hoehn MM, Yahr MD (1967) Parkinsonism: onset, progression and mortality. Neurology 17:427–442
Holloway RG, Shoulson I, Fahn S et al (2004) Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Arch Neurol 61:1044–1053. https://doi.org/10.1001/archneur.61.7.1044
Hong JY, Oh JS, Lee I et al (2014) Presynaptic dopamine depletion predicts levodopa-induced dyskinesia in de novo Parkinson disease. Neurology 82:1597–1604. https://doi.org/10.1212/WNL.0000000000000385
Hung SW, Adeli GM, Arenovich T et al (2010) Patient perception of dyskinesia in Parkinson’s disease. J Neurol Neurosurg Psychiatry 81:1112–1115. https://doi.org/10.1136/jnnp.2009.173286
Jenner P (2003) Dopamine agonists, receptor selectivity and dyskinesia induction in Parkinson’s disease. Curr Opin Neurol 16(Suppl 1):S3–S7
Jenner P (2008) Molecular mechanisms of l-DOPA-induced dyskinesia. Nat Rev Neurosci 9:665–677. https://doi.org/10.1038/nrn2471
Kaplan N, Vituri A, Korczyn AD et al (2014) Sequence variants in SLC6A3, DRD2, and BDNF genes and time to levodopa-induced dyskinesias in Parkinson’s disease. J Mol Neurosci 53:183–188. https://doi.org/10.1007/s12031-014-0276-9
Katzenschlager R, Lees AJ (2002) Treatment of Parkinson’s disease: levodopa as the first choice. J Neurol 249(Suppl II):19–24. https://doi.org/10.1007/s00415-002-1204-4
Katzenschlager R, Head J, Schrag A et al (2008) Fourteen-year final report of the randomized PDRG-UK trial comparing three initial treatments in PD. Neurology 71:474–480. https://doi.org/10.1212/01.wnl.0000310812.43352.66
Koller WC, Hutton JT, Tolosa E, Capilldeo R (1999) Immediate-release and controlled-release carbidopa/levodopa in PD: a 5-year randomized multicenter study. Carbidopa/Levodopa Study Group. Neurology 53:1012–1019
Kumar N, Van Gerpen JA, Bower JH, Ahlskog JE (2005) Levodopa-dyskinesia incidence by age of Parkinson’s disease onset. Mov Disord 20:342–344. https://doi.org/10.1002/mds.20360
Langston JW, Ballard P (1984) Parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): implications for treatment and the pathogenesis of Parkinson’s disease. Can J Neurol Sci 11:160–165
Lavalaye J, Booij J, Reneman L et al (2000) Effect of age and gender on dopamine transporter imaging with [123I]FP-CIT SPET in healthy volunteers. Eur J Nucl Med 27:867–869
Lee J-Y, Seo S, Lee JS et al (2015) Putaminal serotonergic innervation: monitoring dyskinesia risk in Parkinson disease. Neurology 85:853–860. https://doi.org/10.1212/WNL.0000000000001909
Lees AJ, Ferreira J, Rascol O et al (2017) Opicapone as adjunct to levodopa therapy in patients with Parkinson disease and motor fluctuations: a randomized clinical trial. JAMA Neurol 74:197–206. https://doi.org/10.1001/jamaneurol.2016.4703
Lesser RP, Fahn S, Snider SR et al (1979) Analysis of the clinical problems in parkinsonism and the complications of long-term levodopa therapy. Neurology 29:1253–1260
Lévesque D, Di Paolo T (1989) Chronic estradiol treatment increases ovariectomized rat striatal D-1 dopamine receptors. Life Sci 45:1813–1820
Lévesque D, Di Paolo T (1993) Modulation by estradiol and progesterone of the GTP effect on striatal D-2 dopamine receptors. Biochem Pharmacol 45:723–733. https://doi.org/10.1016/0006-2952(93)90148-P
Lewis MM, Du G, Kidacki M et al (2013) Higher iron in the red nucleus marks Parkinson’s dyskinesia. Neurobiol Aging 34:1497–1503. https://doi.org/10.1016/j.neurobiolaging.2012.10.025
Lindpaintner K (2002) Pharmacogenetics and the future of medical practice. Br J Clin Pharmacol 54:221–230. https://doi.org/10.1046/j.1365-2125.2002.01630.x
Löhle M, Mende J, Wolz M et al (2016) Putaminal dopamine turnover in de novo Parkinson disease predicts later motor complications. Neurology 86:231–240. https://doi.org/10.1212/WNL.0000000000002286
Lyons KE, Hubble JP, Tröster AI et al (1998) Gender differences in Parkinson’s disease. Clin Neuropharmacol 21:118–121
Markham CH, Diamond SG (1981) Evidence to support early levodopa therapy in Parkinson disease. Neurology 31:125–131
Marsden CD, Parkes JD (1976) “On-off” effects in patients with Parkinson’s disease on chronic levodopa therapy. Lancet (London, England) 1:292–296. https://doi.org/10.1016/s0140-6736(76)91416-1
Marsden CD, Parkes JD (1977) Success and problems of long-term levodopa therapy in Parkinson’s disease. Lancet (London, England) 1:345–349
Martin WRW, Wieler M, Stoessl AJ, Schulzer M (2008) Dihydrotetrabenazine positron emission tomography imaging in early, untreated Parkinson’s disease. Ann Neurol 63:388–394. https://doi.org/10.1002/ana.21320
Melamed E (1986) Initiation of levodopa therapy in parkinsonian patients should be delayed until the advanced stages of the disease. Arch Neurol 43:402–405. https://doi.org/10.1001/archneur.1986.00520040080025
Melamed E, Globus M, Friedlender E, Rosenthal J (1983) Chronic l-dopa administration decreases striatal accumulation of dopamine from exogenous l-dopa in rats with intact nigrostriatal projections. Neurology 33:950–953
Mena MA, Davila V, Sulzer D (1997) Neurotrophic effects of l-DOPA in postnatal midbrain dopamine neuron/cortical astrocyte cocultures. J Neurochem 69:1398–1408
Michel PP, Hefti F (1990) Toxicity of 6-hydroxydopamine and dopamine for dopaminergic neurons in culture. J Neurosci Res 26:428–435. https://doi.org/10.1002/jnr.490260405
Molchadski I, Korczyn AD, Cohen OS et al (2011) The role of apolipoprotein E polymorphisms in levodopa-induced dyskinesia. Acta Neurol Scand 123:117–121. https://doi.org/10.1111/j.1600-0404.2010.01352.x
Nicoletti A, Arabia G, Pugliese P et al (2007) Hormonal replacement therapy in women with Parkinson disease and levodopa-induced dyskinesia: a crossover trial. Clin Neuropharmacol 30:276–280. https://doi.org/10.1097/wnf.0b013e318050c9f9
Nicoletti A, Mostile G, Nicoletti G et al (2016) Clinical phenotype and risk of levodopa-induced dyskinesia in Parkinson’s disease. J Neurol 263:888–894. https://doi.org/10.1007/s00415-016-8075-6
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
Obeso JA, Rodriguez-Oroz M, Marin C et al (2004) The origin of motor fluctuations in Parkinson’s disease: importance of dopaminergic innervation and basal ganglia circuits. Neurology 62:S17–S30. https://doi.org/10.1212/WNL.62.1_suppl_1.S17
Oertel WH, Wolters E, Sampaio C et al (2006) Pergolide versus levodopa monotherapy in early Parkinson’s disease patients: the PELMOPET study. Mov Disord 21:343–353. https://doi.org/10.1002/mds.20724
Olanow CW, Obeso JA, Stocchi F (2006) Continuous dopamine-receptor treatment of Parkinson’s disease: scientific rationale and clinical implications. Lancet Neurol 5:677–687. https://doi.org/10.1016/S1474-4422(06)70521-X
Olanow CW, Kieburtz K, Rascol O et al (2013) Factors predictive of the development of Levodopa-induced dyskinesia and wearing-off in Parkinson’s disease. Mov Disord 28:1064–1071. https://doi.org/10.1002/mds.25364
Olanow CW, Kieburtz K, Odin P et al (2014) Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson’s disease: a randomised, controlled, double-blind, double-dummy study. Lancet Neurol 13:141–149. https://doi.org/10.1016/S1474-4422(13)70293-X
Ookubo M, Yokoyama H, Takagi S et al (2008) Effects of estrogens on striatal damage after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in male and female mice. Mol Cell Endocrinol 296:87–93. https://doi.org/10.1016/j.mce.2008.07.019
Payer DE, Guttman M, Kish SJ et al (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
PD Med Collaborative Group, Gray R, Ives N et al (2014) Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson’s disease (PD MED): a large, open-label, pragmatic randomised trial. Lancet London England 384:1196–1205. https://doi.org/10.1016/s0140-6736(14)60683-8
Perez XA, Zhang D, Bordia T, Quik M (2017) Striatal D1 medium spiny neuron activation induces dyskinesias in parkinsonian mice. Mov Disord 32:538–548. https://doi.org/10.1002/mds.26955
Perez-Lloret S, Negre-Pages L, Damier P et al (2017) l-DOPA-induced dyskinesias, motor fluctuations and health-related quality of life: the COPARK survey. Eur J Neurol 24:1532–1538. https://doi.org/10.1111/ene.13466
Petitclerc M, Bédard PJ, Di Paolo T (1995) Progesterone releases dopamine in male and female rat striatum: a behavioral and microdialysis study. Prog Neuropsychopharmacol Biol Psychiatry 19:491–497. https://doi.org/10.1016/0278-5846(95)00029-U
Petzinger GM, Fisher BE, Van Leeuwen J-E et al (2010) Enhancing neuroplasticity in the basal ganglia: the role of exercise in Parkinson’s disease. Mov Disord 25(Suppl 1):S141–S145. https://doi.org/10.1002/mds.22782
Piccini P, Weeks RA, Brooks DJ (1997) Alterations in opioid receptor binding in Parkinson’s disease patients with levodopa-induced dyskinesias. Ann Neurol 42:720–726. https://doi.org/10.1002/ana.410420508
Picconi B, Hernández LF, Obeso JA, Calabresi P (2017) Motor complications in Parkinson’s disease: striatal molecular and electrophysiological mechanisms of dyskinesias. Mov Disord. https://doi.org/10.1002/mds.27261
Politis M, Wu K, Loane C et al (2014) Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients. J Clin Investig 124:1340–1349. https://doi.org/10.1172/JCI71640
Qamhawi Z, Towey D, Shah B et al (2015) Clinical correlates of raphe serotonergic dysfunction in early Parkinson’s disease. Brain 138:2964–2973. https://doi.org/10.1093/brain/awv215
Quinn N, Critchley P, Marsden CD (1987) Young onset Parkinson’s disease. Mov Disord 2:73–91. https://doi.org/10.1002/mds.870020201
Rajput AH, Fenton ME, Birdi S, Macaulay R (1997a) Is levodopa toxic to human substantia nigra? Mov Disord 12:634–638. https://doi.org/10.1002/mds.870120503
Rajput AH, Martin W, Saint-Hilaire MH et al (1997b) Tolcapone improves motor function in parkinsonian patients with the “wearing-off” phenomenon: a double-blind, placebo-controlled, multicenter trial. Neurology 49:1066–1071. https://doi.org/10.1212/WNL.49.4.1066
Ramlackhansingh AF, Bose SK, Ahmed I et al (2011) Adenosine 2A receptor availability in dyskinetic and nondyskinetic patients with Parkinson disease. Neurology 76:1811–1816. https://doi.org/10.1212/WNL.0b013e31821ccce4
Rascol O, Brooks DJ, Korczyn AD et al (2000) 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 342:1484–1491. https://doi.org/10.1056/NEJM200005183422004
Rascol O, Brooks DJ, Melamed E et al (2005) Rasagiline as an adjunct to levodopa in patients with Parkinson’s disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial. Lancet (London, England) 365:947–954. https://doi.org/10.1016/s0140-6736(05)71083-7
Rascol O, Brooks DJ, Korczyn AD et al (2006) Development of dyskinesias in a 5-year trial of ropinirole and l-dopa. Mov Disord 21:1844–1850. https://doi.org/10.1002/mds.20988
Rieck M, Schumacher-Schuh AF, Altmann V et al (2012) DRD2 haplotype is associated with dyskinesia induced by levodopa therapy in Parkinson’s disease patients. Pharmacogenomics 13:1701–1710. https://doi.org/10.2217/pgs.12.149
Riopelle RJ, Gawel MJ, Libman I et al (1988) A double-blind study of bromocriptine and l-dopa in de novo Parkinson’s disease. Short-term results. Eur Neurol 28(Suppl 1):11–14
Roth GS (1997) Age changes in signal transduction and gene expression. Mech Ageing Dev 98:231–238
Roussakis A-A, Politis M, Towey D, Piccini P (2016) Serotonin-to-dopamine transporter ratios in Parkinson disease: relevance for dyskinesias. Neurology. https://doi.org/10.1212/WNL.0000000000002494
Ruggieri S, Stocchi F, Carta A et al (1989) Jejunal delivery of levodopa methyl ester. Lancet (London, England) 2:45–46. https://doi.org/10.1016/s0140-6736(89)90285-7
Schrag A, Quinn N (2000) Dyskinesias and motor fluctuations in Parkinson’s disease. A community-based study. Brain 123(Pt 1):2297–2305. https://doi.org/10.1093/brain/123.11.2297
Sharma JC, Ross IN, Rascol O, Brooks D (2008) Relationship between weight, levodopa and dyskinesia: the significance of levodopa dose per kilogram body weight. Eur J Neurol 15:493–496. https://doi.org/10.1111/j.1468-1331.2008.02106.x
Shoulson I, Oakes D, Fahn S et al (2002) Impact of sustained deprenyl (selegiline) in levodopa-treated Parkinson’s disease: a randomized placebo-controlled extension of the deprenyl and tocopherol antioxidative therapy of parkinsonism trial. Ann Neurol 51:604–612. https://doi.org/10.1002/ana.10191
Simuni T, Stern MB (1999) Does levodopa accelerate Parkinson’s disease? Drugs Aging 14:399–408
Smith LA, Jackson MJ, Al-Barghouthy G et al (2005) Multiple small doses of levodopa plus entacapone produce continuous dopaminergic stimulation and reduce dyskinesia induction in MPTP-treated drug-naive primates. Mov Disord 20:306–314. https://doi.org/10.1002/mds.20317
Sossi V, de la Fuente-Fernández R, Schulzer M et al (2006) Age-related differences in levodopa dynamics in Parkinson’s: implications for motor complications. Brain 129:1050–1058. https://doi.org/10.1093/brain/awl028
Stocchi F, Rascol O, Kieburtz K et al (2010) Initiating levodopa/carbidopa therapy with and without entacapone in early Parkinson disease: the STRIDE-PD study. Ann Neurol 68:18–27. https://doi.org/10.1002/ana.22060
Stoessl AJ (2016) Comment: increased D3 binding-A substrate for levodopa-induced dyskinesias? Neurology 86:228. https://doi.org/10.1212/WNL.0000000000002297
Stowe RL, Ives NJ, Clarke C et al (2008) Dopamine agonist therapy in early Parkinson’s disease. Cochrane Database Syst Rev 2:CD006564. https://doi.org/10.1002/14651858.cd006564.pub2
The Parkinson Study Group (2005) A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations: the PRESTO study. Arch Neurol 62:241–248. https://doi.org/10.1001/archneur.62.2.241
Troiano AR, de la Fuente-Fernández R, Sossi V et al (2009) PET demonstrates reduced dopamine transporter expression in PD with dyskinesias. Neurology 72:1211–1216. https://doi.org/10.1212/01.wnl.0000338631.73211.56
Tsang KL, Ho SL, Lo SK (2000) Estrogen improves motor disability in parkinsonian postmenopausal women with motor fluctuations. Neurology 54:2292–2298. https://doi.org/10.1212/WNL.54.12.2292
Van Laere K, Casteels C, Lunskens S et al (2012) Regional changes in type 1 cannabinoid receptor availability in Parkinson’s disease in vivo. Neurobiol Aging 33:620.e1–8. https://doi.org/10.1016/j.neurobiolaging.2011.02.009
Vingerhoets FJ, Schulzer M, Calne DB, Snow BJ (1997) Which clinical sign of Parkinson’s disease best reflects the nigrostriatal lesion? Ann Neurol 41:58–64. https://doi.org/10.1002/ana.410410111
Weintraub D, Koester J, Potenza MN et al (2010) Impulse control disorders in Parkinson disease: a cross-sectional study of 3090 patients. Arch Neurol 67:589–595. https://doi.org/10.1001/archneurol.2010.65
Zhang Y-H, Tang B-S, Song C-Y et al (2013) The relationship between the phenotype of Parkinson’s disease and levodopa-induced dyskinesia. Neurosci Lett 556:109–112. https://doi.org/10.1016/j.neulet.2013.10.018
Acknowledgements
MM is supported by the Parkinson Canada Clinical Research Fellowship; AJS is supported by the Canada Research Chairs Program.
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Matarazzo, M., Perez-Soriano, A. & Stoessl, A.J. Dyskinesias and levodopa therapy: why wait?. J Neural Transm 125, 1119–1130 (2018). https://doi.org/10.1007/s00702-018-1856-6
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DOI: https://doi.org/10.1007/s00702-018-1856-6