Current Neurology and Neuroscience Reports

, Volume 8, Issue 4, pp 304–309

Neuroprotection in Parkinson’s disease: Myth or reality?



Parkinson’s disease (PD) is a chronic, progressive, neurodegenerative disorder with no cure. Therapies that delay or halt disease progression are urgently needed, but finding such therapies has been difficult. In this article, we review historical and recent clinical trial work in the field of neuroprotection. Several issues have arisen during the search for disease-modifying therapies, including challenges in selecting appropriate therapeutic targets, assessing potential therapies, and selecting the proper patient population to study. Advances in the understanding of PD pathogenesis are presented as they relate to selecting potential therapeutic targets, and issues with preclinical testing are described. We review recent innovations in clinical trial design, including futility studies and delayed-start designs that promise to make clinical testing more efficient. It is hoped that ongoing work in this field will lead to treatments that delay the progression of PD.


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References and Recommended Reading

  1. 1.
    Biglan KM, Ravina B: Neuroprotection in Parkinson’s disease: an elusive goal. Semin Neurol 2007, 2:106–112.CrossRefGoogle Scholar
  2. 2.
    Fahn S, Cohen G: The oxidant stress hypothesis in Parkinson’s disease: evidence supporting it. Ann Neurol 1992, 32:804–812.PubMedCrossRefGoogle Scholar
  3. 3.
    Haas RH, Nasirian F, Nakano K, et al.: Low platelet mitochondrial complex I and complex II/III activity in early untreated Parkinson’s disease. Ann Neurol 1995, 37:714–722.PubMedCrossRefGoogle Scholar
  4. 4.
    Dawson TM, Dawson VL: Molecular pathways of neurodegeneration in Parkinson’s disease. Science 2003, 302:819–822.PubMedCrossRefGoogle Scholar
  5. 5.
    Bonifati V, Rizzu P, van Baren MJ, et al.: Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 2003, 299:256–259.PubMedCrossRefGoogle Scholar
  6. 6.
    Klein C, Schlossmacher MG: Parkinson disease, 10 years after its genetic revolution: multiple clues to a complex disorder. Neurology 2007, 69:2093–2104.PubMedCrossRefGoogle Scholar
  7. 7.
    Abou-Sleiman PM, Muqit MM, Wood NW: Expanding insights of mitochondrial dysfunction in Parkinson’s disease. Nat Rev Neurosci 2006, 7:207–219.PubMedCrossRefGoogle Scholar
  8. 8.
    Ravina BM, Fagan SC, Hart RG, et al.: Neuroprotective agents for clinical trials in Parkinson’s disease: a systematic assessment. Neurology 2003, 60:1234–1240.PubMedGoogle Scholar
  9. 9.
    NINDS NET-PD Investigators: A randomized, double blind, futility clinical trial of creatine and minocycline in early Parkinson disease. Neurology 2006, 66:664–671.CrossRefGoogle Scholar
  10. 10.
    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, 59:1541–1550.PubMedCrossRefGoogle Scholar
  11. 11.
    Braak H, Bohl JR, Muller CM, et al.: Stanley Fahn lecture 2005: The staging procedure for the inclusion body pathology associated with sporadic Parkinson’s disease reconsidered. Mov Disord 2006, 21:2042–2051.PubMedCrossRefGoogle Scholar
  12. 12.
    McNaught KS, Jackson T, Baptiste R, et al.: Proteasomal dysfunction in sporadic Parkinson’s disease. Neurology 2006, 66:S37–S49.PubMedCrossRefGoogle Scholar
  13. 13.
    Goldberg AL: Protein degradation and protection against misfolded or damaged proteins. Nature 2003, 426:895–899.PubMedCrossRefGoogle Scholar
  14. 14.
    McNaught KS, Belizaire R, Isacson O, et al.: Altered proteasomal function in sporadic Parkinson’s disease. Exp Neurol 2003, 179:38–46.PubMedCrossRefGoogle Scholar
  15. 15.
    Olanow CW, Schapira AH, LeWitt PA, et al.: TCH346 as a neuroprotective drug in Parkinson’s disease: a double blind, randomised, controlled trial. Lancet Neurol 2006, 12:1013–1020.CrossRefGoogle Scholar
  16. 16.
    The Parkinson Study Group PRECEPT Investigators: Mixed lineage kinase inhibitor CEP-1347 fails to delay disability in early Parkinson disease. Neurology 2007, 69:1480–1490.CrossRefGoogle Scholar
  17. 17.
    McNaught KS, Perl DP, Brownell AL, Olanow CW: Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson’s disease. Ann Neurol 2004, 56:149–162.PubMedCrossRefGoogle Scholar
  18. 18.
    Beal F, Lang A: The proteasomal inhibition model of Parkinson’s disease: “boon or bust”? Ann Neurol 2006, 60:158–161.PubMedCrossRefGoogle Scholar
  19. 19.
    Hughes AJ, Daniel SE, Lees AJ: Improved accuracy of clinical diagnosis of Lewy body Parkinson’s disease. Neurology 2001, 57:1497–1499.PubMedGoogle Scholar
  20. 20.
    The Parkinson Study Group: Effect of deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 1989, 321:1364–1371.Google Scholar
  21. 21.
    Nasreddine ZS, Phillips NA, Bedirian V, et al.: The Montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005, 53:695–699.PubMedCrossRefGoogle Scholar
  22. 22.
    Pocock SJ, Geller NL, Tsiatis AA: The analysis of multiple endpoints in clinical trials. Biometrics. 1987, 43:487–498.PubMedCrossRefGoogle Scholar
  23. 23.
    Polymeropoulos MH, Lavedan C, Leroy E, et al.: Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 1997, 276:2045–2047.PubMedCrossRefGoogle Scholar
  24. 24.
    Johnson J, Hague SM, Hanson M, et al.: SNCA multiplication is not a common cause of Parkinson disease or dementia with Lewy bodies. Neurology 2004, 63:554–556.PubMedGoogle Scholar
  25. 25.
    El-Agnaf OM, Salem SA, Paleologou KE, et al.: Detection of oligomeric forms of alpha-synuclein protein in human plasma as a potential biomarker for Parkinson’s disease. FASEB J 2006, 20:419–425.PubMedCrossRefGoogle Scholar
  26. 26.
    Tokuda T, Salem SA, Allsop D, et al.: Decreased alpha-synuclein in cerebrospinal fluid of aged individuals and subjects with Parkinson’s disease. Biochem Biophys Res Commun 2006, 349:162–166.PubMedCrossRefGoogle Scholar
  27. 27.
    Siderowf A, Newberg A, Chou KL, et al.: 99mTcTRODAT-1 SPECT imaging correlates with odor identification in early Parkinson disease. Neurology 2005, 64:1716–1720.PubMedCrossRefGoogle Scholar
  28. 28.
    Scherzer CR, Eklund AC, Morse LJ, et al.: Molecular markers of early Parkinson’s disease based on gene expression in blood. Proc Natl Acad Sci U S A 2007, 104:955–960.PubMedCrossRefGoogle Scholar
  29. 29.
    Fahn S, Oakes D, Shoulson I, et al.: Levodopa and the progression of Parkinson’s disease. N Engl J Med 2004, 351:2498–2508.PubMedCrossRefGoogle Scholar
  30. 30.
    Holloway RG, Shoulson I, Fahn S, et al.: Pramipexole versus levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Arch Neurol 2004, 61:1044–1053.PubMedCrossRefGoogle Scholar
  31. 31.
    Parkinson Study Group: Dopamine transporter brain imaging to assess the effects of pramipexole versus levodopa on Parkinson disease progression. JAMA 2002, 287:1653–1661.CrossRefGoogle Scholar
  32. 32.
    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.PubMedCrossRefGoogle Scholar
  33. 33.
    Ravina B, Eidelberg D, Ahlskog JE, et al.: The role of radiotracer imaging in Parkinson disease. Neurology 2005, 64:208–215.PubMedGoogle Scholar
  34. 34.
    Kieburtz K: Issues in neuroprotection clinical trials in Parkinson’s disease. Neurology 2006, 66:S50–S57.PubMedGoogle Scholar
  35. 35.
    Parkinson Study Group: A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol 2004, 61:561–566.CrossRefGoogle Scholar
  36. 36.
    Rascol O, Olanow W: ADAGIO: a prospective double-blind delayed-start study to examine potential disease-modifying effect of rasagiline in Parkinson’s disease. Mov Disord 2006, 21(Suppl 15):P888.Google Scholar
  37. 37.
    Schapira AH, Obeso J: Timing of treatment initiation in Parkinson’s disease: a need for reappraisal? Ann Neurol 2006, 59:559–562.PubMedCrossRefGoogle Scholar
  38. 38.
    Hauser RA, Zesiewicz TA: Clinical trials aimed at detecting neuroprotection in Parkinson’s disease. Neurology 2006, 66:S58–S68.PubMedCrossRefGoogle Scholar
  39. 39.
    Siderowf A, Eberly S, Oakes D, Shoulson I, for the Parkinson Study Group TEMPO Steering Committee: Reexamination of the TEMPO study—reply. Arch Neurol 2005, 62:1321a.CrossRefGoogle Scholar
  40. 40.
    Tilley BC, Palesch YY, Kieburtz K, et al.: Optimizing the ongoing search for new treatments for Parkinson disease: using futility designs. Neurology 2006, 66:628–633.PubMedCrossRefGoogle Scholar
  41. 41.
    Elm JJ, Goetz CG, Ravina B, et al.: A responsive outcome for Parkinson’s disease neuroprotection futility studies. Ann Neurol 2005, 57:197–203.PubMedCrossRefGoogle Scholar
  42. 42.
    Levy G, Kaufmann P, Buchsbaum R, et al.: A two-stage design for a phase II clinical trial of coenzyme Q10 in ALS. Neurology 2006, 66:660–663.PubMedCrossRefGoogle Scholar

Copyright information

© Current Medicine Group LLC 2008

Authors and Affiliations

  1. 1.Department of NeurologyUniversity of Rochester School of Medicine and Dentistry, Movement and Inherited Neurological Disorders UnitRochesterUSA

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