Drugs & Aging

, Volume 28, Issue 8, pp 605–615

Disease Modification in Parkinson’s Disease

Leading Article

Abstract

Parkinson’s disease (PD) is an age-related, progressive, multisystem neurodegenerative disorder resulting in significant morbidity and mortality, as well as a growing social and financial burden in an aging population. The hallmark of PD is loss of dopaminergic neurons of the substantia nigra pars compacta, leading to bradykinesia, rigidity and tremor. Current pharmacological treatment is therefore centred upon dopamine replacement to alleviate symptoms. However, two major problems complicate this approach: (i) motor symptoms continue to progress, requiring increasing doses of medication, which result in both short-term adverse effects and intermediate- to long-term motor complications; (ii) dopamine replacement does little to treat non-dopaminergic motor and non-motor symptoms, which are an important source of morbidity, including dementia, sleep disturbances, depression, orthostatic hypotension, and postural instability leading to falls. It is critical, therefore, to develop a broader and more fundamental therapeutic approach to PD, and major research efforts have focused upon developing neuroprotective interventions.

Despite many encouraging preclinical data suggesting the possibility of addressing the underlying pathophysiology by slowing cell loss, efforts to translate this into the clinical realm have largely proved disappointing in the past. Barriers to finding neuroprotective or disease-modifying drugs in PD include a lack of validated biomarkers of progression, which hampers clinical trial design and interpretation; difficulties separating symptomatic and neuroprotective effects of candidate neuroprotective therapies; and possibly fundamental flaws in some of the basic preclinical models and testing.

However, three recent clinical trials have used a novel delayed-start design in an attempt to overcome some of these roadblocks. While not examining markers of cell loss and function, which would determine neuroprotective effects, this trial design pragmatically tests whether earlier versus later intervention is beneficial. If positive (i.e. if an earlier intervention proves more effective), this demonstrates disease modification, which could result from neuroprotection or from other mechanisms. This strategy therefore provides a first step towards supporting neuroprotection in PD. Of the three delayed-start design clinical trials, two have investigated early versus later start of rasagiline, a specific irreversible monoamine oxidase B inhibitor. Each trial has supported, although not proven, disease-modifying effects. A third delayed-start-design clinical trial examining potential disease-modifying effects of pramipexole has unfortunately reportedly been negative according to preliminary presentations. The suggestion that rasagiline is disease modifying is made all the more compelling by in vitro and PD animal-model studies in which rasagiline was shown to have neuroprotective effects.

In this review, we examine efforts to demonstrate neuroprotection in PD to date, describe ongoing neuroprotection trials, and critically discuss the results of the most recent delayed-start clinical trials that test possible disease-modifying activities of rasagiline and pramipexole in PD.

References

  1. 1.
    Fahn S, Elton RL, UPDRS program members. Unified Parkinson’s Disease Rating Scale. Florham Park (NJ): Macmillan Healthcare Information, 1987Google Scholar
  2. 2.
    Fahn S, Oakes D, Shoulson I, et al. Levodopa and the progression of Parkinson’s disease. N Engl J Med 2004; 351: 2498–508PubMedCrossRefGoogle Scholar
  3. 3.
    Goetz CG, Tilley BC, Shaftman SR, et al. Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord 2008; 23: 2129–70PubMedCrossRefGoogle Scholar
  4. 4.
    Hart RG, Pearce LA, Ravina BM, et al. Neuroprotection trials in Parkinson’s disease: systematic review. Mov Disord 2009; 24: 647–54PubMedCrossRefGoogle Scholar
  5. 5.
    Shults CW, Oakes D, Kieburtz K, et al. Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol 2002; 59: 1541–50PubMedCrossRefGoogle Scholar
  6. 6.
    Castagnoli K, Palmer S, Castagnoli Jr N. Neuroprotection by (R)-deprenyl and 7-nitroindazole in the MPTP C57BL/6 mouse model of neurotoxicity. Neurobiology (Bp) 1999; 7: 135–49Google Scholar
  7. 7.
    Muralikrishnan D, Samantaray S, Mohanakumar KP. D-deprenyl protects nigrostriatal neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurotoxicity. Synapse 2003; 50: 7–13PubMedCrossRefGoogle Scholar
  8. 8.
    Miyake Y, Fukushima W, Tanaka K, et al. Dietary intake of antioxidant vitamins and risk of Parkinson’s disease: a case-control study in Japan. Eur J Neurol 2011; 18: 106–13PubMedCrossRefGoogle Scholar
  9. 9.
    Etminan M, Gill SS, Samii A. Intake of vitamin E, vitamin C, and carotenoids and the risk of Parkinson’s disease: a meta-analysis. Lancet Neurol 2005; 4: 362–5PubMedCrossRefGoogle Scholar
  10. 10.
    Birkmayer W, Knoll J, Riederer P, et al. Increased life expectancy resulting from addition of L-deprenyl to Mado-par treatment in Parkinson’s disease: a long term study. J Neural Transm 1985; 64: 113–27PubMedCrossRefGoogle Scholar
  11. 11.
    Tetrud JW, Langston JW. The effect of deprenyl (selegiline) on the natural history of Parkinson’s disease. Science 1989; 245: 519–22PubMedCrossRefGoogle Scholar
  12. 12.
    Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. The Parkinson Study Group. N Engl J Med 1993; 328: 176–83Google Scholar
  13. 13.
    Shoulson I, Oakes D, Fahn S, et al. Impact of sustained deprenyl (selegiline) in levodopa-treated Parkinson’s disease: a randomized placebo-controlled extension of the deprenyl and tocopherol antioxidative therapy of parkin-sonism trial. Ann Neurol 2002; 51: 604–12PubMedCrossRefGoogle Scholar
  14. 14.
    Palhagen S, Heinonen EH, Hagglund J, et al. Selegiline delays the onset of disability in de novo parkinsonian patients. Swedish Parkinson Study Group. Neurology 1998; 51: 520–5PubMedCrossRefGoogle Scholar
  15. 15.
    Pramipexole vs levodopa as initial treatment for Parkinson disease: a randomized controlled trial. Parkinson Study Group. JAMA 2000; 284: 1931–8Google Scholar
  16. 16.
    Long-term effect of initiating pramipexole vs levodopa in early Parkinson disease. Parkinson Study Group CALM Cohort Investigators. Arch Neurol 2009; 66: 563–70Google Scholar
  17. 17.
    Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. Parkinson Study Group. JAMA 2002; 287: 1653–61Google Scholar
  18. 18.
    Albrecht S, Buerger E. Potential neuroprotection mechanisms in PD: focus on dopamine agonist pramipexole. Curr Med Res Opin 2009; 25: 2977–87PubMedCrossRefGoogle Scholar
  19. 19.
    Li C, Guo Y, Xie W, et al. Neuroprotection of pramipexole in UPS impairment induced animal model of Parkinson’s disease. Neurochem Res 2010; 35: 1546–56PubMedCrossRefGoogle Scholar
  20. 20.
    Du F, Li R, Huang Y, et al. Dopamine D3 receptor-preferring agonists induce neurotrophic effects on mesencephalic dop-amine neurons. Eur J Neurosci 2005; 22: 2422–30PubMedCrossRefGoogle Scholar
  21. 21.
    Ling ZD, Robie HC, Tong CW, et al. Both the antioxidant and D3 agonist actions of pramipexole mediate its neuroprotective actions in mesencephalic cultures. J Pharmacol Exp Ther 1999; 289: 202–10PubMedGoogle Scholar
  22. 22.
    Iida M, Miyazaki I, Tanaka K, et al. Dopamine D2 receptor-mediated antioxidant and neuroprotective effects of ropinirole, a dopamine agonist. Brain Res 1999; 838: 51–9PubMedCrossRefGoogle Scholar
  23. 23.
    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: 93–101PubMedCrossRefGoogle Scholar
  24. 24.
    Pavese N, Kiferle L, Piccini P. Neuroprotection and imaging studies in Parkinson’s disease. Parkinsonism Relat Disord 2009; 15Suppl. 4: S33–7PubMedCrossRefGoogle Scholar
  25. 25.
    Guttman M, Stewart D, Hussey D, et al. Influence of L-dopa and pramipexole on striatal dopamine transporter in early PD. Neurology 2001; 56: 1559–64PubMedCrossRefGoogle Scholar
  26. 26.
    Jennings DL, Tabama R, Seibyl JP, et al. Investigating the effect of short term treatment with pramipexole or levodopa on [123I]-beta-CIT-SPECT imaging. Mov Dis 2007; 22 Suppl.: S143Google Scholar
  27. 27.
    Fahn S. Parkinson disease, the effect of levodopa, and the ELLDOPA trial: earlier vs later L-DOPA. Arch Neurol 1999; 56: 529–35PubMedCrossRefGoogle Scholar
  28. 28.
    Fernagut PO, Li Q, Dovero S, et al. Dopamine transporter binding is unaffected by L-DOPA administration in normal and MPTP-treated monkeys. PLoS One 2010 Nov 22; 5(11): e14053PubMedCrossRefGoogle Scholar
  29. 29.
    Olanow CW, Rascol O, Hauser R, et al. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med 2009; 361: 1268–78PubMedCrossRefGoogle Scholar
  30. 30.
    D’Agostino Sr RB. The delayed-start study design. N Engl J Med 2009; 361: 1304–6PubMedCrossRefGoogle Scholar
  31. 31.
    Freedman NM, Mishani E, Krausz Y, et al. In vivo measurement of brain monoamine oxidase B occupancy by rasagiline, using(11)C-l-deprenyl and PET. JNucl Med 2005; 46:1618–24Google Scholar
  32. 32.
    Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study. Arch Neurol 2002; 59: 1937–43CrossRefGoogle Scholar
  33. 33.
    Parkinson Study Group. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol 2004; 61: 561–6CrossRefGoogle Scholar
  34. 34.
    Hauser RA, Lew MF, Hurtig HI, et al. Long-term outcome of early versus delayed rasagiline treatment in early Parkinson’s disease. Mov Disord 2009; 24: 564–73PubMedCrossRefGoogle Scholar
  35. 35.
    Finberg JP, Takeshima T, Johnston JM, et al. Increased survival of dopaminergic neurons by rasagiline, a mono-amine oxidase B inhibitor. Neuroreport 1998; 9: 703–7PubMedCrossRefGoogle Scholar
  36. 36.
    Heikkila RE, Duvoisin RC, Finberg JP, et al. Prevention of MPTP-induced neurotoxicity by AGN-1133 and AGN-1135, selective inhibitors of monoamine oxidase-B. Eur J Pharmacol 1985; 116: 313–7PubMedCrossRefGoogle Scholar
  37. 37.
    Akao Y, Maruyama W, Yi H, et al. An anti-Parkinson’s disease drug, N-propargyl-1(R)-aminoindan (rasagiline), enhances expression of anti-apoptotic bc1-2 in human dopaminergic SH-SY5Y cells. Neurosci Lett 2002; 326: 105–8PubMedCrossRefGoogle Scholar
  38. 38.
    Maruyama W, Akao Y, Carrillo MC, et al. Neuroprotection by propargylamines in Parkinson’s disease: suppression of apoptosis and induction of prosurvival genes. Neurotox-icol Teratol 2002; 24: 675–82CrossRefGoogle Scholar
  39. 39.
    Chau KY, Cooper JM, Schapira AH. Rasagiline protects against alpha-synuclein induced sensitivity to oxidative stress in dopaminergic cells. Neurochem Int 2010; 57: 525–9PubMedCrossRefGoogle Scholar
  40. 40.
    Weinreb O, Amit T, Bar-Am O, et al. Rasagiline: a novel anti-Parkinsonian monoamine oxidase-B inhibitor with neuroprotective activity. Prog Neurobiol 2010; 92: 330–44PubMedCrossRefGoogle Scholar
  41. 41.
    Weinreb O, Amit T, Bar-Am O, et al. Induction of neuro-trophic factors GDNF and BDNF associated with the mechanism of neurorescue action of rasagiline and lados-tigil: new insights and implications for therapy. Ann N Y Acad Sci 2007; 1122: 155–68PubMedCrossRefGoogle Scholar
  42. 42.
    Carrillo MC, Minami C, Kitani K, et al. Enhancing effect of rasagiline on superoxide dismutase and catalase activities in the dopaminergic system in the rat. Life Sci 2000; 67: 577–85PubMedCrossRefGoogle Scholar
  43. 43.
    Youdim MB, Wadia A, Tatton W, et al. The anti-Parkinson drug rasagiline and its cholinesterase inhibitor derivatives exert neuroprotection unrelated to MAO inhibition in cell culture and in vivo. Ann N Y Acad Sci 2001; 939: 450–8PubMedCrossRefGoogle Scholar
  44. 44.
    Schapira AH, Barone P, Comella C, et al. Immediate vs. delayed-start pramipexole in early Parkinson’s disease: the PROUD study [abstract]. Parkinsonism Relat Disord 2009; 15: S81CrossRefGoogle Scholar
  45. 45.
    Schapira AH, Albrecht S, Barone P, et al. Rationale for delayed-start study of pramipexole in Parkinson’s disease: The PROUD study. Mov Disord 2010; 25: 1627–32PubMedCrossRefGoogle Scholar
  46. 46.
    A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease. NINDS NET-PD Investigators. Neurology 2006; 66: 664–71Google Scholar
  47. 47.
    Surmeier DJ. Calcium, ageing, and neuronal vulnerability in Parkinson’s disease. Lancet Neurol 2007; 6: 933–8PubMedCrossRefGoogle Scholar
  48. 48.
    Weisskopf MG, O’Reilly E, Chen H, et al. Plasma urate and risk of Parkinson’s disease. Am J Epidemiol 2007; 166: 561–7PubMedCrossRefGoogle Scholar
  49. 49.
    Ascherio A, LeWitt PA, Xu K, et al. Urate as a predictor of the rate of clinical decline in Parkinson disease. Arch Neurol 2009; 66: 1460–8PubMedCrossRefGoogle Scholar
  50. 50.
    Peterson AL, Nutt JG. Treatment of Parkinson’s disease with trophic factors. Neurotherapeutics 2008; 5: 270–80PubMedCrossRefGoogle Scholar
  51. 51.
    Kaplitt MG. Parkinson disease: another player in gene therapy for Parkinson disease. Nat Rev Neurol 2010; 6: 7–8PubMedCrossRefGoogle Scholar
  52. 52.
    Ahlskog JE, Uitti RJ. Rasagiline, Parkinson neuroprotection, and delayed-start trials: still no satisfaction? Neurology 2010; 74: 1143–8PubMedCrossRefGoogle Scholar
  53. 53.
    Olanow CW, Rascol O. The delayed-start study in Parkinson disease: can’t satisfy everyone. Neurology 2010; 74: 1149–50PubMedCrossRefGoogle Scholar
  54. 54.
    Clarke CE. Are delayed-start design trials to show neuroprotection in Parkinson’s disease fundamentally flawed? Mov Disord 2008; 23: 784–9PubMedCrossRefGoogle Scholar
  55. 55.
    Schrag A, Sampaio C, Counsell N, et al. Minimal clinically important change on the Unified Parkinson’s Disease Rating Scale. Mov Disord 2006; 21: 1200–7PubMedCrossRefGoogle Scholar
  56. 56.
    Schapira AH, Obeso J. Timing of treatment initiation in Parkinson’s disease: a need for reappraisal? Ann Neurol 2006; 59: 559–62PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2011

Authors and Affiliations

  1. 1.Department of Neurology and NeuroscienceWeill Medical College of Cornell UniversityNew YorkUSA
  2. 2.Beth Israel Mirken Department of NeurologyBeth Israel Medical CenterNew YorkUSA

Personalised recommendations