Neuroprotection in Parkinson's Disease: An Elusive Goal

 

 Buy Article Permissions and Reprints

ABSTRACT

Despite increases in our understanding of the pathophysiology and environmental and genetic influences of illness in Parkinson's disease, neuroprotection remains an elusive goal. No interventions are widely accepted as disease modifying in Parkinson's disease. Continued research identifying novel therapeutic targets is likely to result in several putative neuroprotective agents. Assimilating lessons from previous neuroprotection trials will be critical in developing future trials aimed at efficiently identifying neuroprotective treatments. Ultimately, overcoming the unique challenges of a heterogenous, slowly progressive disorder with multiple potential outcome measures will be necessary to identify treatments that have meaningful effects.

REFERENCES

• 1 Birkmayer W, Der Hornykiewicz O. L-3,4-dioxyphenylalanin (= DOPA) Effekt bei der Parkinson-Akinese.  Wien Klin Wochenschr. 1961;  73 787-788
  PubMedGoogle Scholar
• 2 Fahn S. Adverse effects of levodopa. In: Olanow CW, Lieberman AN The Scientific Basis for the Treatment of Parkinson's Disease. Carnforth, Lancashire, United Kingdom: Parthenon Publishing Group 1992: 89-112
  Google Scholar
• 3 Aarsland D, Andersen K, Larsen J P et al.. The rate of cognitive decline in Parkinson disease.  Arch Neurol. 2004;  61 1906-1911
  CrossrefPubMedGoogle Scholar
• 4 Aarsland D, Larsen J P, Lim N G et al.. Range of neuropsychiatric disturbances in patients with Parkinson's disease.  J Neurol Neurosurg Psychiatry. 1999;  67 492-496
  CrossrefPubMedGoogle Scholar
• 5 Zesiewicz T A, Baker M J, Wahba M, Hauser R A. Autonomic nervous system dysfunction in Parkinson's disease.  Curr Treat Options Neurol. 2003;  5 149-160
  PubMedGoogle Scholar
• 6 Grimbergen Y AM, Munneke M, Bloem B R. Falls in Parkinson's disease.  Curr Opin Neurol. 2004;  17 405-415
  CrossrefPubMedGoogle Scholar
• 7 Shoulson I. DATATOP: a decade of neuroprotective inquiry. Parkinson Study Group. Deprenyl and tocopherol antioxidative therapy of parkinsonism.  Ann Neurol. 1998;  44(suppl 1) S160-S166
  PubMedGoogle Scholar
• 8 Polymeropoulos M H, Lavedan C, Leroy E et al.. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease.  Science. 1997;  276 2045-2047
  PubMedGoogle Scholar
• 9 Singleton A B, Farrer M, Johnson J et al.. Alpha-synuclein locus triplication causes Parkinson's disease.  Science. 2003;  302 841
  CrossrefPubMedGoogle Scholar
• 10 Dauer W, Kholodilov N, Vila M et al.. From the cover: resistance of alpha -synuclein null mice to the parkinsonian neurotoxin MPTP.  Proc Natl Acad Sci USA. 2002;  99 14524-14529
  CrossrefPubMedGoogle Scholar
• 11 Zhang Y, Gao J, Chung K KK, Huang H, Dawson V L, Dawson T M. Parkin functions as an E2-dependent ubiquitin-protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1.  Proc Natl Acad Sci USA. 2000;  97 13354-13359
  CrossrefPubMedGoogle Scholar
• 12 Leroy E, Boyer R, Polymeropoulos M H. Intron-exon structure of ubiquitin C-terminal hydrolase-L1.  DNA Res. 1998;  5 397-400
  CrossrefPubMedGoogle Scholar
• 13 McNaught K S, Belizaire R, Isacson O, Jenner P, Olanow C W. Altered proteasomal function in sporadic Parkinson's disease.  Exp Neurol. 2003;  179 38-46
  CrossrefPubMedGoogle Scholar
• 14 McNaught K S, Perl D P, Brownell A L, Olanow C W. Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson's disease.  Ann Neurol. 2004;  56 149-162
  CrossrefPubMedGoogle Scholar
• 15 Langston J W, Ballard P, Tetrud J W, Irwin I. Chronic parkinsonism in humans due to a product of meperidine-analog synthesis.  Science. 1983;  219 979-980
  PubMedGoogle Scholar
• 16 Mitsumoto A, Nakagawa Y, Takeuchi A, Okawa K, Iwamatsu A, Takanezawa Y. Oxidized forms of peroxiredoxins and DJ-1 on two-dimensional gels increased in response to sublethal levels of paraquat.  Free Radic Res. 2001;  35 301-310
  CrossrefPubMedGoogle Scholar
• 17 Valente E M, Abou-Sleiman P M, Caputo V et al.. Hereditary early-onset Parkinson's disease caused by mutations in PINK1.  Science. 2004;  304 1158-1160
  CrossrefPubMedGoogle Scholar
• 18 Strauss K M, Martins L M, Plun-Favreau H et al.. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease.  Hum Mol Genet. 2005;  14 2099-2111
  CrossrefPubMedGoogle Scholar
• 19 Abou-Sleiman P M, Muqit M MK, Wood N W. Expanding insights of mitochondrial dysfunction in Parkinson's disease.  Nat Rev Neurosci. 2006;  7 207-219
  CrossrefPubMedGoogle Scholar
• 20 Shults C W, 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
  CrossrefPubMedGoogle Scholar
• 21 Parkinson Study Group . DATATOP: a multicenter controlled clinical trial in early Parkinson's disease.  Arch Neurol. 1989;  46 1052-1060
  PubMedGoogle Scholar
• 22 Parkinson Study Group . Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease.  N Engl J Med. 1993;  328 176-183
  CrossrefPubMedGoogle Scholar
• 23 Leber P. Slowing the progression of Alzheimer disease: methodologic issues.  Alzheimer Dis Assoc Disord. 1997;  11(suppl 5) S10-S21
  PubMedGoogle Scholar
• 24 Parkinson Study Group . A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease.  Arch Neurol. 2004;  61 561-566
  CrossrefPubMedGoogle Scholar
• 25 Parkinson Study Group . Pramipexole vs levodopa as initial treatment for Parkinson disease: a randomized controlled trial.  JAMA. 2000;  284 1931-1938
  CrossrefPubMedGoogle Scholar
• 26 Parkinson Study Group . Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression.  JAMA. 2002;  287 1653-1661
  CrossrefPubMedGoogle Scholar
• 27 The Parkinson Study Group . Levodopa and the progression of Parkinson's disease.  N Engl J Med. 2004;  351 2498-2508
  CrossrefPubMedGoogle Scholar
• 28 Whone A L, Watts R L, Stoessl A J et al.. Slower progression of Parkinson's disease with ropinirole versus levodopa: the REAL-PET study.  Ann Neurol. 2003;  54 93-101
  CrossrefPubMedGoogle Scholar
• 29 Freed C R, Greene P E, Breeze R E et al.. Transplantation of embryonic dopamine neurons for severe Parkinson's disease.  N Engl J Med. 2001;  344 710-719
  CrossrefPubMedGoogle Scholar
• 30 Ravina B M, Fagan S C, Hart R G et al.. Neuroprotective agents for clinical trials in Parkinson's disease: a systematic assessment.  Neurology. 2003;  60 1234-1240
  PubMedGoogle Scholar
• 31 Tilley B C, Palesch Y Y, Kieburtz K et al.. Optimizing the ongoing search for new treatments for Parkinson disease: using futility designs.  Neurology. 2006;  66 628-633
  CrossrefPubMedGoogle Scholar
• 32 The NINDS NET-PD Investigators . A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease.  Neurology. 2006;  66 664-671
  CrossrefPubMedGoogle Scholar
• 33 The NINDS NET-PD Investigators . A randomized clinical trial of coenzyme Q₁₀ and GPI-1485 in early Parkinson's disease.  Neurology. 2007;  68 20-28
  PubMedGoogle Scholar
• 34 Marras C, Rochon P, Lang A E. Predicting motor decline and disability in Parkinson disease: a systematic review.  Arch Neurol. 2002;  59 1724-1728
  CrossrefPubMedGoogle Scholar
• 35 Guimaraes P, Kieburtz K, Goetz C G et al.. Non-linearity of Parkinson's disease progression: implications for sample size calculations in clinical trials.  Clin Trials. 2005;  2 509-518
  CrossrefPubMedGoogle Scholar
• 36 Biglan K M, Holloway R G. Surrogate endpoints in Parkinson's disease research.  Curr Neurol Neurosci Rep. 2003;  3 314-320
  PubMedGoogle Scholar
• 37 Tetrud J W, Langston J W. The effect of deprenyl (selegiline) on the natural history of Parkinson's disease.  Science. 1989;  245 519-522
  CrossrefPubMedGoogle Scholar
• 38 The Parkinson Study Group . Effect of lazabemide on the progression of disability in early Parkinson's disease.  Ann Neurol. 1996;  40 99-107
  CrossrefPubMedGoogle Scholar
• 39 Palhagen S, Heinonen E H, Hagglund J et al.. Selegiline delays the onset of disability in de novo parkinsonian patients. Swedish Parkinson Study Group.  Neurology. 1998;  51 520-525
  PubMedGoogle Scholar
• 40 Parkinson Study Group . A controlled trial of rasagiline in early Parkinson disease.  Arch Neurol. 2002;  59 1937-1943
  CrossrefPubMedGoogle Scholar
• 41 Jankovic J, Hunter C. A double-blind, placebo-controlled and longitudinal study of riluzole in early Parkinson's disease.  Parkinsonism Relat Disord. 2002;  8 271-276
  CrossrefPubMedGoogle Scholar
• 42 Shoulson I. Parkinson Study Group, PRECEPT Investigators . CEP-1347 treatment fails to favorably modify the progression of Parkinson's disease (PRECEPT) study: S61.003.  Neurology. 2006;  67 185
  PubMedGoogle Scholar
• 43 Lang A E, Gill S, Patel N K et al.. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease.  Ann Neurol. 2006;  59 459-466
  CrossrefPubMedGoogle Scholar
• 44 Olanow C W, Hauser R A, Gauger L et al.. The effect of deprenyl and levodopa on the progression of signs and symptoms in Parkinson's disease.  Ann Neurol. 1995;  38 771-777
  CrossrefPubMedGoogle Scholar
• 45 Larsen J P, Boas J, Erdal J E. Does selegiline modify the progression of early Parkinson's disease? Results from a five-year study. The Norwegian-Danish Study Group.  Eur J Neurol. 1999;  6 539-547
  CrossrefPubMedGoogle Scholar
• 46 Gold B G, Nutt J G. Neuroimmunophilin ligands in the treatment of Parkinson's disease.  Curr Opin Pharmacol. 2002;  2 82-86
  PubMedGoogle Scholar
• 47 Rascol O, Olanow W, Brooks D, Koch G, Truffinet P, Bejuit R. Effect of riluzole on parkinson's disease progression: a double-blind placebo-controlled study.  Neurology. 2003;  60(suppl 1) A288
  PubMedGoogle Scholar

Kevin M BiglanM.D. M.P.H. 

Department of Neurology, University of Rochester School of Medicine and Dentistry

1351 Mt. Hope Avenue, Suite 223, Rochester, NY 14620