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Special Communication | Clinician's Corner

Neuroprotection in Parkinson Disease:  Mysteries, Myths, and Misconceptions

Anthony H. V. Schapira, DSc, MD; C. Warren Olanow, MD, FRCPC
JAMA. 2004;291(3):358-364. doi:10.1001/jama.291.3.358.
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Parkinson disease is an age-related neurodegenerative disease that affects approximately 1 million persons in the United States. Current therapies provide effective control of symptoms, particularly in the early stages of the disease, but most patients develop motor complications with long-term treatment, and features develop such as postural instability, falling, and dementia that are not adequately controlled with existing medications. Accordingly, neuroprotective therapy that might slow, stop, or reverse disease progression is urgently needed. While many agents appear to be promising based on laboratory studies, selecting clinical end points for clinical trials that are not confounded by symptomatic effects of the study intervention has been difficult. More recently, neuroimaging end points have been used as biomarkers of disease progression, but again there are concerns that they may be influenced by regulatory effects of the drugs used. We review clinical trials aimed at detecting neuroprotection in Parkinson disease and address the controversies surrounding the interpretation of these studies.

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Figure 1. Schema of Etiologic and Pathogenetic Factors That Have Been Implicated in Cell Death in Parkinson Disease and Possible Neuroprotective Approaches
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COX-2 indicates cyclooxygenase 2; GDNF, glial-derived neurotrophic factor.
Figure 2. Neuroimaging Scans in Normal Controls and Patients With Parkinson Disease
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Top, fluorodopa with positron emission tomography in healthy controls and patients with Parkinson disease (provided courtesy of and with permission from David Brooks, MD). Bottom, 2β-carbomethoxy-3β-[4-iodophenyl]tropane (β-CIT) with single-photon emission computed tomography uptake in healthy controls and patients with Parkinson disease (provided courtesy of and with permission from Ken Marek, MD). Note that in Parkinson disease, striatal uptake of these markers is asymmetrically reduced, more so in the posterior portion of the putamen. Note also that with advancing disease, uptake of these indices is further reduced, which can be quantified and serve as a surrogate marker of disease progression.
Figure 3. Imaging Results of the REAL-PET and CALM-PD-CIT Studies
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At each time point in both studies, the rate of decline in the surrogate imaging marker of nigrostriatal function is greater in patients treated with levodopa compared with those treated with the dopamine agonist. REAL-PET indicates Requip as Early Therapy versus L-dopa25; CALM-PD, parallel-group, double-blind comparison study of pramipexole and carbidopa/levodopa in the treatment of PD24; and CIT, 2β-carbomethoxy-3β-(4-iodophenyl)tropane.

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