Neuroprotective therapy for Parkinson disease
- Daniel Tarsy, MD
Daniel Tarsy, MD
- Professor of Neurology
- Harvard Medical School
The pharmacologic treatment of Parkinson disease (PD) can be divided into neuroprotective and symptomatic therapy. In practice, however, nearly all of the available treatments are symptomatic in nature and do not appear to slow or reverse the natural course of the disease.
This topic will review potential neuroprotective therapies for PD. Other aspects of PD are discussed separately. (See "Etiology and pathogenesis of Parkinson disease" and "Clinical manifestations of Parkinson disease" and "Diagnosis and differential diagnosis of Parkinson disease" and "Pharmacologic treatment of Parkinson disease".)
Neuroprotective therapy of PD is still theoretical, but it is based on the concept that the three to four hundred thousand at-risk dopaminergic neurons in the human substantia nigra can somehow be protected from the complex degenerative process that causes premature cell death and depletion of dopamine. Once identified and shown to be effective, neuroprotective drugs could be used in patients with early clinical signs of disease or potentially even prior to the appearance of disease in those shown to be at genetic risk. Several potential neuroprotective agents for PD have shown some promise in animals and/or humans, including selegiline and rasagiline (both monoamine oxidase inhibitors), and the natural substance coenzyme Q10. However, no treatment to date has proven to be effective for neuroprotection in PD.
Our suggested approach for patients with newly diagnosed PD is to make them aware that most of the current therapeutic research in PD involves a search for neuroprotective agents ; this gives them hope. To date, however, only weak signals have emerged for a few agents.
Accumulating clinical trial data suggest that levodopa either slows the progression of PD or has a prolonged benefit even after the drug has been stopped. These data are presented separately. (See "Pharmacologic treatment of Parkinson disease", section on 'Levodopa'.)
- Schapira AH, Olanow CW, Greenamyre JT, Bezard E. Slowing of neurodegeneration in Parkinson's disease and Huntington's disease: future therapeutic perspectives. Lancet 2014; 384:545.
- Suchowersky O, Gronseth G, Perlmutter J, et al. Practice Parameter: neuroprotective strategies and alternative therapies for Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006; 66:976.
- Jenner P. Preclinical evidence for neuroprotection with monoamine oxidase-B inhibitors in Parkinson's disease. Neurology 2004; 63:S13.
- Parkinson Study Group. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol 2004; 61:561.
- 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.
- Schapira AH, Obeso J. Timing of treatment initiation in Parkinson's disease: a need for reappraisal? Ann Neurol 2006; 59:559.
- 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.
- Rascol O, Fitzer-Attas CJ, Hauser R, et al. A double-blind, delayed-start trial of rasagiline in Parkinson's disease (the ADAGIO study): prespecified and post-hoc analyses of the need for additional therapies, changes in UPDRS scores, and non-motor outcomes. Lancet Neurol 2011; 10:415.
- 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.
- Olanow CW, Hauser RA, Gauger L, et al. The effect of deprenyl and levodopa on the progression of Parkinson's disease. Ann Neurol 1995; 38:771.
- Giladi N, McDermott MP, Fahn S, et al. Freezing of gait in PD: prospective assessment in the DATATOP cohort. Neurology 2001; 56:1712.
- Impact of deprenyl and tocopherol treatment on Parkinson's disease in DATATOP patients requiring levodopa. Parkinson Study Group. Ann Neurol 1996; 39:37.
- Miyasaki JM, Martin W, Suchowersky O, et al. 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.
- Schapira AH, Olanow CW. Neuroprotection in Parkinson disease: mysteries, myths, and misconceptions. JAMA 2004; 291:358.
- Olanow CW. A rationale for using dopamine agonists as primary symptomatic therapy in Parkinson's disease. In: Dopamine Agonists in Early Parkinson's Disease, Olanow CW, Obeso JA (Eds), Wells Medical, Kent, UK 1997. p.37.
- International symposium on early dopamine agonist therapy of Parkinson's disease. Arch Neurol 1988; 45:204.
- Parkinson Study Group. Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 2002; 287:1653.
- 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.
- Rakshi JS, Pavese N, Uema T, et al. A comparison of the progression of early Parkinson's disease in patients started on ropinirole or L-dopa: an 18F-dopa PET study. J Neural Transm (Vienna) 2002; 109:1433.
- Ahlskog JE. Slowing Parkinson's disease progression: recent dopamine agonist trials. Neurology 2003; 60:381.
- Schapira AH, McDermott MP, Barone P, et al. Pramipexole in patients with early Parkinson's disease (PROUD): a randomised delayed-start trial. Lancet Neurol 2013; 12:747.
- Weiner WJ, Reich SG. Agonist or levodopa for Parkinson disease?: ultimately, it doesn't matter; neither is good enough. Neurology 2008; 71:470.
- Katzenschlager R, Head J, Schrag A, et al. Fourteen-year final report of the randomized PDRG-UK trial comparing three initial treatments in PD. Neurology 2008; 71:474.
- Hely MA, Morris JG, Reid WG, Trafficante R. Sydney Multicenter Study of Parkinson's disease: non-L-dopa-responsive problems dominate at 15 years. Mov Disord 2005; 20:190.
- 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.
- Horstink MW, van Engelen BG. The effect of coenzyme Q10 therapy in Parkinson disease could be symptomatic. Arch Neurol 2003; 60:1170.
- Storch A, Jost WH, Vieregge P, et al. Randomized, double-blind, placebo-controlled trial on symptomatic effects of coenzyme Q(10) in Parkinson disease. Arch Neurol 2007; 64:938.
- Parkinson Study Group QE3 Investigators, Beal MF, Oakes D, et al. A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit. JAMA Neurol 2014; 71:543.
- 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.
- 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.
- Gao X, Chen H, Choi HK, et al. Diet, urate, and Parkinson's disease risk in men. Am J Epidemiol 2008; 167:831.
- Alonso A, Rodríguez LA, Logroscino G, Hernán MA. Gout and risk of Parkinson disease: a prospective study. Neurology 2007; 69:1696.
- Parkinson Study Group SURE-PD Investigators, Schwarzschild MA, Ascherio A, et al. Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial. JAMA Neurol 2014; 71:141.
- Schwarzschild MA, Macklin EA, Ascherio A, Parkinson Study Group SURE-PD Investigators. Urate and neuroprotection trials. Lancet Neurol 2014; 13:758.
- Ilijic E, Guzman JN, Surmeier DJ. The L-type channel antagonist isradipine is neuroprotective in a mouse model of Parkinson's disease. Neurobiol Dis 2011; 43:364.
- Parkinson Study Group. Phase II safety, tolerability, and dose selection study of isradipine as a potential disease-modifying intervention in early Parkinson's disease (STEADY-PD). Mov Disord 2013; 28:1823.
- Wyse RK, Brundin P, Sherer TB. Nilotinib - Differentiating the Hope from the Hype. J Parkinsons Dis 2016; 6:519.
- Pagan F, Hebron M, Valadez EH, et al. Nilotinib Effects in Parkinson's disease and Dementia with Lewy bodies. J Parkinsons Dis 2016; 6:503.