Hostname: page-component-78c5997874-mlc7c Total loading time: 0 Render date: 2024-11-05T05:06:56.325Z Has data issue: false hasContentIssue false
  • English
  • Français

Progress in Clinical Neurosciences: A Forum on the Early Management of Parkinson's Disease

Published online by Cambridge University Press:  02 December 2014

Anthony E. Lang ,
Janis Miyasaki ,
C. Warren Olanow ,
A. Jon Stoessl  and
Oksana Suchowersky
Anthony E. Lang*
Affiliation:
Division of Neurology, Department of Medicine, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada
Janis Miyasaki
Affiliation:
Division of Neurology, Department of Medicine, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada
C. Warren Olanow
Affiliation:
Department of Neurology, Mount Sinai School of Medicine, Toronto, Ontario, Canada
A. Jon Stoessl
Affiliation:
Pacific Parkinson's Research Center, University of British Columbia, Vancouver, British Columbia, Canada
Oksana Suchowersky
Affiliation:
Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
*
Movement Disorders Center, TorontoWestern Hospital, 399 Bathurst St.,7McL, Toronto, ON M5T 2S8 Canada
Rights & Permissions [Opens in a new window]

Abstract:

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

There are numerous concerns related to treatment choices involving early dopaminergic therapy in Parkinson's disease. These include the effect on the underlying progression of the neurodegenerative process as well as the development of motor complications such as fluctuations and dyskinesias. A number of recent basic and clinical studies have provided new insights but have also added confusion and controversy. This report summarizes presentations and discussion dealing with these issues from a one-day symposium involving Canadian Movement Disorders neurologists.

Résumé:

RÉSUMÉ:

Le traitement précoce de la maladie de Parkinson au moyen d’agents dopaminergiques soulève plusieurs questions, entre autres son effet sur la progression du processus neurodégénératif et sur le développement de complications motrices telles les fluctuations et les dyskinésies. Des études fondamentales et cliniques récentes ont fourni de nouvelles avenues de réflexion, mais elles ont également suscité la confusion et la controverse. Cet article résume les présentations et les discussions sur le sujet lors d’un symposium d’une journée tenue par des neurologues intéressés par les troubles du movement (Canadian Movement Disorders Group).

Type
Review Article
Information
Canadian Journal of Neurological Sciences , Volume 32 , Issue 3 , August 2005 , pp. 277 - 286
Copyright
Copyright © The Canadian Journal of Neurological 2005

References

Reference List

1. Lang, AE, Lozano, AM. Parkinson’s disease – First of two parts. NEngl J Med 1998; 339:1044–1053.CrossRefGoogle ScholarPubMed
2. Olanow, CW, Obeso, JA. Preventing levodopa-induced dyskinesias. Ann Neurol 2000; 47:S167-S178.Google ScholarPubMed
3. Grace, AA, Bunney, BS. The control of firing pattern in nigraldopamine neurons: single spike firing. J Neurosci 1984; 4:2866–2876.CrossRefGoogle ScholarPubMed
4. Schultz, W. Behavior-related activity of primate dopamine neurons. Rev Neurol (Paris) 1994; 150:634–639.Google ScholarPubMed
5. Fahn, S, Oakes, D, Shoulson, I, et al. Levodopa and the progressionof Parkinson’s disease. N Engl J Med 2004; 351:2498–2508.Google Scholar
6. Obeso, JA, Rodriguez-Oroz, MC, Rodriguez, M, DeLong, MR, Olanow, CW. Pathophysiology of levodopa-induced dyskinesias in Parkinson’s disease: problems with the current model. Ann Neurol 2000; 47:S22-S34.Google ScholarPubMed
7. Bedard, PJ, DiPaolo, T, Falardeau, P, Coucher, R. Chronic treatmentwith L-Dopa, but not bromocriptine induces dyskinesia in MPTP-Parkinsonian monkeys. Correlation with [3H] spiperone binding. Brain Res 1986; 379:294–299.CrossRefGoogle Scholar
8. Pearce, RK, Banerji, T, Jenner, P, Marsden, CD. De novoadministration of ropinirole and bromocriptine induces less dyskinesia than L-dopa in the MPTP-treated marmoset. Mov Disord 1998; 13:234–241.CrossRefGoogle ScholarPubMed
9. Blanchet, PJ, Calon, F, Martel, JC, et al. Continuous administrationdecreases and pulsatile administration increases behavioral sensitivity to a novel dopamine D2 agonist (U-91356A) inMPTP-exposed monkeys. J Pharmacol Exp Ther 1995; 272:854–859.Google ScholarPubMed
10. Rascol, O, Brooks, DJ, Korczyn, AD, et al. A five-year study of theincidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. N Engl J Med 2000; 342:1484–1491.CrossRefGoogle ScholarPubMed
11. Holloway, R, Shoulson, I, Kieburtz, K, et al. Pramipexole vs levodopaas initial treatment for Parkinson disease – A randomized controlled trial. JAMA 2000; 284:1931–1938.Google Scholar
12. Sage, JI, Trooskin, S, Sonsalla, PK, Heikkila, R, Duvoisin, RC. Long-term duodenal infusion of levodopa for motor fluctuations in parkinsonism. Ann Neurol 1988; 24:87–89.CrossRefGoogle ScholarPubMed
13. Ruggieri, S, Stocchi, F, Carta, A, Catarci, M, Agnoli, A. Jejunaldelivery of levodopa methyl ester. Lancet 1989; 2:45–46.CrossRefGoogle ScholarPubMed
14. Salarian, A, Russmann, H, Vingerhoets, FJG, et al. Gait assessment inParkinson’s disease: toward an ambulatory system for long-term monitoring. IEEE Trans Biomed Eng 2004; 51(8):1434–1443.CrossRefGoogle ScholarPubMed
15. Kurlan, R, Rubin, AJ, Miller, C, et al. Duodenal delivery of levodopafor on-off fluctuations in parkinsonism: preliminary observations. Ann Neurol 1986; 20:262–265.CrossRefGoogle ScholarPubMed
16. Kurth, MC, Tetrud, JW, Tanner, CM, et al. Double-blind, placebo-controlled, crossover study of duodenal infusion of levodopa/carbidopa in Parkinson’s disease patients with ’on-off’ fluctuations. Neurology 1993; 43:1698–1703.CrossRefGoogle ScholarPubMed
17. Nutt, JG, Carter, JH, Lea, ES, Woodward, WR. Motor fluctuationsduring continuous levodopa infusions in patients with Parkinson’sdisease. Mov Disord 1997; 12:285–292.CrossRefGoogle Scholar
18. Nilsson, D, Hansson, LE, Johansson, K, et al. Long-termintraduodenal infusion of a water based levodopa-carbidopa dispersion in very advanced Parkinson’s disease. Acta Neurol Scand 1998; 97:175–183.CrossRefGoogle ScholarPubMed
19. Syed, N, Murphy, J, Zimmerman, T Jr., Mark, MH, Sage, JI. Ten years’experience with enteral levodopa infusions for motor fluctuations in Parkinson’s disease. Mov Disord 1998; 13:336–338.CrossRefGoogle ScholarPubMed
20. Stocchi, F, Vacca, L, Ruggieri, S, Olanow, CW. Infusion of levodopamethyl ester in patients with advanced PD: a clinical and pharmacokinetic study. Arch Neurol 2004; in press.Google Scholar
21. Olanow, CW, Stocchi, F. COMT inhibitors in Parkinson’s disease -Can they prevent and/or reverse levodopa-induced motor complications? Neurology 2004; 62:S72-S81.CrossRefGoogle ScholarPubMed
22. Nutt, JG, Woodward, WR, Beckner, RM, et al. Effect of peripheralcatechol-O-methyltransferase inhibition on the pharmacokinetics and pharmacodynamics of levodopa in parkinsonian patients. Neurology 1994; 44:913–919.CrossRefGoogle ScholarPubMed
23. Smith, LA, Jackson, MJ, Al-Barghouthy, G, et al. Multiple smalldosses of levodopa plus entacapone produces continuous dopaminergic stimulation and reduces dyskinesia induction in MPTP-treated drug naive primates. Mov Disord 2004; in press.Google Scholar
24. Barbeau, A, Roy, M. Six-year results of treatment with levodopa plusbenzerazide in Parkinson’s disease. Neurology 1976; 26:399–404.CrossRefGoogle ScholarPubMed
25. Koller, WC, Hubble, JP. Levodopa therapy in Parkinson’s disease. Neurology 1990; 40(10 Suppl 3):S7.Google ScholarPubMed
26. Hoehn, MM, Yahr, DM. Parkinsonism: Onset, progression andmortality. Neurology 1967; 17:427–442.CrossRefGoogle Scholar
27. Bennett, DA, Beckett, LA, Murray, AM, et al. Prevalence ofParkinsonian signs and associated mortality in a communitypopulation of older people. N Engl J Med 1996; 334(2):71–76.CrossRefGoogle Scholar
28. Yahr, M. Evaluation of long-term therapy in Parkinson’s disease:mortality and therapeutic efficacy. In: Birkmayer, W, Hornykiewicz, O, (Eds). Advances In Parkinsonism: Biochemistry, Physiology, Treatment. Basle: Editiones Roche, 1976: 435–444.Google Scholar
29. Rajput, AH, Uitti, RJ, Offord, KP. Timely levodopa (LD)administration prolongs survival in Parkinson’s disease. Parkinsonism & Rel Disord 1997; 3:159–165.CrossRefGoogle ScholarPubMed
30. Goetz, CG, Tanner, CM, Shannon, KM. Progression of Parkinson’sdisease without levodopa. Neurology 1987; 37:695–698.CrossRefGoogle Scholar
31. Parkinson Study Group. DATATOP: A Multicenter ControlledClinical Trial in Early Parkinson’s Disease. Arch Neurol 1989; 46:1052–1060.CrossRefGoogle Scholar
32. Koller, WC, Hutton, JT, Tolosa, E, Capilldeo, R. Carbidopa LSGImmediate-release and controlled-release carbidopa/levodopa in PD - A 5-year randomized multicenter study. Neurology 1999; 53:1012–1019.CrossRefGoogle ScholarPubMed
33. Rinne, UK, Bracco, F, Chouza, C, et al. Early treatment of Parkinson’sdisease with cabergoline delays the onset of motor complications – results of a double-blind levodopa controlled trial. Drugs 1998; 55:23–30.CrossRefGoogle Scholar
34. Rajput, AH, Stern, W, Laverty, WH. Chronic low-dose levodopatherapy in Parkinson’s disease: an argument for delaying levodopa therapy. Neurology 1984; 34:991–996.CrossRefGoogle Scholar
35. Lesser, RP, Fahn, S, Snider, SR, et al. Analysis of the clinicalproblems in parkinsonism and the complications of long-term levodopa therapy. Neurology 1979; 29:1253–1260.CrossRefGoogle Scholar
36. Markham, CH, Diamond, SG. Evidence to support early levodopatherapy in Parkinson disease. Neurology 1981; 31:125–131.CrossRefGoogle Scholar
37. Cedarbaum, JM, Gandy, SE, McDowell, FH. “Early” initiation oflevodopa treatment does not promote the development of motor response fluctuations, dyskinesias, or dementia in Parkinson’sdisease. Neurology 1991; 41:622–629.CrossRefGoogle Scholar
38. Caraceni, T, Scigliano, G, Musicco, M. The occurrence of motorfluctuations in parkinsonian patients treated long term with levodopa: role of early treatment and disease progression. Neurology 1991; 41:380–384.CrossRefGoogle Scholar
39. Horstink, MW, Zijlmans, JC, Pasman, JW, Berger, HJ, Van’t Hof, MA. Severity of Parkinson’s disease is a risk factor for peak-dose dyskinesia. J Neurol Neurosurg Psychiatry 1990; 53:224–226.CrossRefGoogle ScholarPubMed
40. Miyasaki, JM, Martin, W, Suchowersky, O, Weiner, WJ, Lang, AE. Practice parameter: initiation of treatment for Parkinson’s disease: An evidence-based review – report of the quality standards subcommittee of the American Academy of Neurology. Neurology 2002; 58:11–17.CrossRefGoogle Scholar
41. Poewe, WH. Clinical aspects of motor fluctuations in Parkinson’sdisease. Neurology 1994; 44 (Suppl. 6):S6-S9.Google Scholar
42. Parkinson Study Group. Impact of Deprenyl and Tocopheroltreatment on Parkinson’s Disease in DATATOP subjects not requiring Levodopa. Ann Neurol 1996; 39:29–36.CrossRefGoogle Scholar
43. Dupont, E, Andersen, A, Boas, J, et al. Sustained-release Madopar HBS compared with standard Madopar in the long-term treatment of de novo parkinsonian patients. Acta Neurol Scand 1996; 93:14–20.CrossRefGoogle ScholarPubMed
44. Ruottinen, HM, Rinne, UK. Entacapone prolongs levodopa responsein a one month double blind study in parkinsonian patients with levodopa related fluctuations. J Neurol Neurosurg Psychiatry 1996; 60:36–40.CrossRefGoogle Scholar
45. Brooks, DJ, Sagar, H, UK-Irish Entacapone Study Group.Entacapone is beneficial in both fluctuating and non-fluctuating patients with Parkinson’s disease: a randomized, placebo controlled, double blind, six month study. J Neurol Neurosurg Psychiatry 2003; 74:1071–1079.CrossRefGoogle ScholarPubMed
46. Poewe, WH, Deuschl, G, Gordin, A, Kultalahti, ER, Leinonen, M. Efficacy and safety of entacapone in Parkinson’s disease patients with suboptimal levodopa response: a 6-month randomized placebo-controlled double-blind study in Germany and Austria (Celomen study). Acta Neurol Scand 2002; 105:245–255.CrossRefGoogle ScholarPubMed
47. Olanow, CW, Kieburtz, K, Stern, M, et al. Double-blind, placebo-controlled study of entacapone in levodopa-treated patients with stable Parkinson disease. Arch Neurol 2004; 61:1563–1568.CrossRefGoogle ScholarPubMed
48. Uitti, RJ, Ahlskog, JE, Maraganore, DM, et al. Levodopa therapy andsurvival in idiopathic Parkinson’s disease: Olmsted County project. Neurology 1993; 43:1918–1926.CrossRefGoogle Scholar
49. Ahlskog, JE, Muenter, MD. Frequency of levodopa-relateddyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord 2001; 16:448–458.CrossRefGoogle ScholarPubMed
50. Marras, C, Lang, A, Krahn, M, et al. Quality of life in earlyParkinson’s disease: Impact ofdyskinesias and motorfluctuations. Mov Disord 2004; 19:22–28.CrossRefGoogle Scholar
51. Lozano, AM. Surgery for Parkinson’s disease, the five W’s: why,who, what, where, and when. Adv Neurol 2003; 91:303–307.Google ScholarPubMed
52. Juncos, JL, Engber, TM, Susel, Z, et al. Continuous and intermittentlevodopa administration differentially affectbasal gangliafunction. Ann Neurol 1989; 25:473–478.CrossRefGoogle Scholar
53. Chase, TN, Oh, JD. Striatal mechanisms and pathogenesis ofparkinsonian signs and motor complications. Ann Neurol 2000; 47:S122-S130.Google Scholar
54. Papa, SM, Engber, TM, Kask, AM, Chase, TN. Motor fluctuations inlevodopa treated parkinsonian rats: relation to lesion extent and treatment duration. Brain Res 1994; 662:69–74.CrossRefGoogle ScholarPubMed
55. Mytilineou, C, Walker, RH, JnoBaptiste, R, Olanow, CW. Levodopa istoxic to dopamine neurons in an in vitro but not an in vivo modelof oxidative stress. J Pharmacol Exp Ther 2003; 304:792–800.CrossRefGoogle Scholar
56. Nishibayashi, S, Asanuma, M, Kohno, M, Gomez-Vargas, M, Ogawa, N. Scavenging effects of dopamine agonists on nitric oxideradicals. J Neurochem 1996; 67:2208–2211.CrossRefGoogle Scholar
57. Diguet, E, Gross, CE, Bezard, E, et al. Neuroprotective agents forclinical trials in Parkinson’s disease: A systematic assessment. Neurology 2004; 62:158.CrossRefGoogle Scholar
58. Holloway, RG, Shoulson, I, Kieburtz, K, et al. Pramipexole vslevodopa as initial treatment for Parkinson disease – a 4-year randomized controlled trial. Arch Neurol 2004; 61:1044–1053.Google ScholarPubMed
59. Marek, K, Seibyl, J, Shoulson, I, et al. Dopamine transporter brainimaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 2002; 287:1653–1661.Google Scholar
60. Frucht, S, Rogers, JD, Greene, PE, Gordon, MF, Fahn, S. Falling asleepat the wheel: motor vehicle mishaps in persons taking pramipexole and ropinirole. Neurology 1999; 52:1908–1910.CrossRefGoogle ScholarPubMed
61. Olanow, CW, Schapira, AHV, Roth, T. Waking up to sleep episodes inParkinson’s disease. Mov Disord 2000; 15:212–215.3.0.CO;2-6>CrossRefGoogle ScholarPubMed
62. Arnulf, I, Konofal, E, Merino-Andreu, M, et al. Parkinson’s diseaseand sleepiness – an integral part of PD. Neurology 2002; 58:1019–1024.CrossRefGoogle Scholar
63. Tracik, F, Ebersbach, G. Sudden daytime sleep onset in Parkinson’sdisease: polysomnographic recordings. Mov Disord 2001; 16:500–506.CrossRefGoogle Scholar
64. Van Camp, G, Flamez, A, Cosyns, B, et al. Treatment of Parkinson’sdisease with pergolide and relation to restrictive valvular heart disease. Lancet 2004; 363:1179–1183.CrossRefGoogle Scholar
65. Horvath, J, Fross, RD, Kleiner-Fisman, G, et al. Severe multivalvularheart disease: a new complication of the ergot derivative dopamine agonists. Mov Disord 2004; 19:656–662.CrossRefGoogle ScholarPubMed
66. Noyes, K, Dick, A, Holloway, RG, and the Parkinson Study Group.Pramipexole vs levodopa as initial treatment for Parkinson’s disease. A randomized clinical-economic trail. Med Decis Making 2004; 24: 472–485.CrossRefGoogle Scholar
67. Fernandez, HH, Friedman, JH. Punding on l-dopa. Mov Disord 1999; 14:836–838.3.0.CO;2-0>CrossRefGoogle ScholarPubMed
68. Evans, AH, Katzenschlager, R, Paviour, D, et al. Punding inParkinson’s disease: its relation to the dopamine dysregulation syndrome. Mov Disord 2004; 19:397–405.CrossRefGoogle Scholar
69. Kurlan, R. Disabling repetitive behaviors in Parkinson’s disease. Mov Disord 2004; 19:433–437.CrossRefGoogle ScholarPubMed
70. Voon, V. Repetition, repetition, and repetition: compulsive andpunding behaviors in Parkinson’s disease. Mov Disord 2004; 19:367–370.CrossRefGoogle ScholarPubMed
71. Gschwandtner, U, Aston, J, Renaud, S, Fuhr, P. Pathologic gamblingin patients with Parkinson’s disease. Clin Neuropharmacol 2001; 24:170–172.CrossRefGoogle ScholarPubMed
72. Snow, BJ, Tooyama, I, McGeer, EG, et al. Human positron emissiontomographic [18F]fluorodopa studies correlate with dopaminecell counts and levels. Ann Neurol 1993; 34:324–330.CrossRefGoogle Scholar
73. Pate, BD, Kawamata, T, Yamada, T, et al. Correlation of striatalfluorodopa uptake in the MPTP monkey with dopaminergic indices. Ann Neurol 1993; 34:331–338.CrossRefGoogle ScholarPubMed
74. Volkow, ND, Ding, YS, Fowler, JS, et al. A new PET ligand for thedopamine transporter: studies in the human brain. J Nucl Med 1995; 36:2162–2168.Google ScholarPubMed
75. Kilbourn, MR. In vivo radiotracers for vesicular neurotransmittertransporters. Nucl Med Biol 1997; 24:615–619.CrossRefGoogle Scholar
76. Brooks, DJ, Ibanez, V, Sawle, GV, et al. Differing Patterns of Striatal 18F-Dopa Uptake in Parkinson’s Disease, Multiple System Atrophy, and Progressive Supranuclear Palsy. Ann Neurol 1990; 28:547–555.CrossRefGoogle ScholarPubMed
77. Antonini, A, Leenders, KL, Vontobel, P, et al. Complementary PETstudies of striatal neuronal function in the differential diagnosis between multiple system atrophy and Parkinson’s disease. Brain 1997; 120:2187–2195.CrossRefGoogle Scholar
78. Lin, SK, Vingerhoets, FJG, Snow, B, Schulzer, M, Wai, YY. Isolatedinvolvement of substantia nigra in acute transient parkinsonism: MRI and PET observations. Parkinsonism & Rel Disord 1995; 1:67–73.CrossRefGoogle ScholarPubMed
79. Furtado, S, Farrer, M, Tsuboi, Y, et al. SCA-2 presenting asparkinsonism in an Alberta family – clinical, genetic, and PET findings. Neurology 2002; 59:1625–1627.CrossRefGoogle Scholar
80. Calne, DB, Langston, JW, Martin, WRW, et al. Positron emissiontomography after MPTP: observations relating to the cause of Parkinson’s disease. Nature 1985; 317:246–248.CrossRefGoogle Scholar
81. Piccini, P, Burn, DJ, Ceravolo, R, Maraganore, D, Brooks, DJ. The roleof inheritance in sporadic Parkinson’s disease: evidence from a longitudinal study of dopaminergic function in twins. Ann Neurol 1999; 45:577–582.3.0.CO;2-O>CrossRefGoogle Scholar
82. Frost, JJ, Rosier, AJ, Reich, SG, et al. Positron emission tomographicimaging of the dopamine transporter with 11C-WIN 35,428 reveals marked declines in mild Parkinson’s disease. Ann Neurol 1993; 34:423–431.CrossRefGoogle Scholar
83. Marek, KL, Seibyl, JP, Zoghbi, SS, et al. [123I] b-CIT/SPECT imagingdemonstrates bilateral loss of dopamine transporters in hemi-Parkinson’s disease. Neurology 1996; 46:231–237.CrossRefGoogle Scholar
84. Guttman, M, Burkholder, J, Kish, SJ, et al. [11C]RTI-32 PET studiesof the dopamine transporter in early dopa-naive Parkinson’s disease: Implications for the symptomatic threshold. Neurology 1997; 48:1578–1583.CrossRefGoogle Scholar
85. Lee, CS, Samii, A, Sossi, V, et al. In vivo positron emissiontomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson’s disease. Ann Neurol 2000; 47:493–503.3.0.CO;2-4>CrossRefGoogle Scholar
86. Eidelberg, D, Moeller, JR, Ishikawa, T, et al. Early differentialdiagnosis of Parkinson’s disease with 18F- fluorodeoxyglucose and positron emission tomography. Neurology 1995; 45:1995–2004.CrossRefGoogle Scholar
87. Parkinson Study Group. Effect of deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 1989; 321:1364–1371.CrossRefGoogle Scholar
88. The Parkinson Study Group. Effects of Tocopherol and Deprenyl onthe Progression of Disability in Early Parkinson’s Disease. N Engl J Med 1993; 328:176–183.CrossRefGoogle Scholar
89. Schulzer, M, Mak, E, Calne, DB. The antiparkinson efficacy of deprenyl derives from transient improvement that is likely to besymptomatic. Ann Neurol 1992; 32:795–798.CrossRefGoogle Scholar
90. De la Fuente-Fernàndez, R, Stoessl, AJ. The placebo effect inParkinson’s disease. Trends Neuro 2002; 25:302–306.CrossRefGoogle ScholarPubMed
91. Whone, AL, Watts, RL, Stoessl, AJ, et al. Slower progression of Parkinson’s disease with ropinirole versus levodopa: The REAL-PET study. Ann Neurol 2003; 54:93–101.CrossRefGoogle ScholarPubMed
92. Ahlskog, JE. Slowing Parkinson’s disease progression - recentdopamine agonist trials. Neurology 2003; 60:381–389.CrossRefGoogle ScholarPubMed
93. Albin, RL, Frey, KA. Initial agonist treatment of Parkinson disease a critique. Neurology 2003; 60:390–394.CrossRefGoogle Scholar
94. Freed, CR, Greene, PE, Breeze, RE, et al. Transplantation ofembryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med 2001; 344:710–719.CrossRefGoogle ScholarPubMed
95. Olanow, CW, Goetz, CG, Kordower, JH, et al. A double-blindcontrolled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann Neurol 2003; 54:403–414.CrossRefGoogle ScholarPubMed
96. Doder, M, Rabiner, EA, Turjanski, N, Lees, AJ, Brooks, DJ. Tremor inParkinson’s disease and serotonergic dysfunction - An 11C-WAY 100635 PET study. Neurology 2003; 60:601–605.CrossRefGoogle ScholarPubMed
97. Brooks, DJ, Frey, KA, Marek, KL, et al. Assessment of neuroimagingtechniques as biomarkers of the progression of Parkinson’sdisease. Exp Neurol 2003; 184:S68-S79.CrossRefGoogle Scholar
98. DeKosky, ST, Marek, K. Looking backward to move forward: earlydetection of neurodegenerative disorders. Science 2003; 302:830–834.CrossRefGoogle Scholar
99. Guttman, M, Stewart, D, Hussey, D, et al. Influence of L-dopa andpramipexole on striatal dopamine transporter in early PD. Neurology 2001; 56:1559–1564.CrossRefGoogle ScholarPubMed
100. Ahlskog, JE, Uitti, RJ, O’Connor, MK, et al. The effect of dopamineagonist therapy on dopamine transporter imaging in Parkinson’sdisease. Mov Disord 1999; 14:940–946.3.0.CO;2-Y>CrossRefGoogle Scholar
101. Ceravolo, R, Piccini, P, Bailey, DL, et al. 18F-dopa PET evidence thattolcapone acts as a central COMT inhibitor in Parkinson’s disease. Synapse 2002; 43:201–207.CrossRefGoogle ScholarPubMed
102. Vander, BT, Kilbourn, M, Desmond, T, Kuhl, D, Frey, K. The vesicularmonoamine transporter is not regulated by dopaminergic drugtreatments. Eur J Pharmacol 1995; 294:577–583.Google Scholar
103. Wilson, JM, Kish, SJ. The vesicular monoamine transporter, incontrast to the dopamine transporter, is not altered by chronic cocaine self-administration in the rat. J Neurosci 1996; 16:3507–3510.CrossRefGoogle Scholar
104. Kemmerer, ES, Desmond, TJ, Albin, RL, Kilbourn, MR, Frey, KA. Treatment effects on nigrostriatal projection integrity in partial 6-OHDA lesions: comparison of L-DOPA and pramipexole. Exp Neurol 2003; 183:81–86.CrossRefGoogle ScholarPubMed
105. Vingerhoets, FJG, Schulzer, M, Caine, DB, Snow, BJ. Which clinicalsign of Parkinson’s disease best reflects the nigrostriatal lesion? Ann Neurol 1997; 41:58–64.CrossRefGoogle Scholar