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Published: October 12, 2009 Reviewed by Zalman S. Agus, MD; Emeritus Professor University of Pennsylvania School of Medicine. A High serum and cerebrospinal fluid concentrations of urate were associated with slower rates of clinical decline among patients with Parkinson's disease, analysis of data from a randomized trial revealed. The hazard ratio of reaching the endpoint -- disability requiring levodopa treatment -- declined with higher serum urate concentrations (P for trend=0.002), according to Alberto Ascherio, MD, of Harvard Medical School, and colleagues. The likelihood of progressing to that level of disability over two years was 36% lower among patients in the top quintile of serum urate concentration, compared with those in the bottom quintile (HR 0.64, 95% CI 0.44 to 0.94, P=0.02), the investigators reported online in the Archives of Neurology. Previous studies had shown that healthy subjects with higher levels of urate are at lower risk for Parkinson's disease, and that higher levels in patients with early Parkinson's disease appear to predict slower disease progression. These findings suggested that urate, a powerful antioxidant, may serve as an endogenous defense against the neuronal degeneration of Parkinson's disease, which researchers believe to be influenced by oxidative damage. To more fully explore the association, Ascherio and colleagues analyzed data from a completed trial known as DATATOP, for Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism. This was was a two-year multicenter study that evaluated whether treatment with Deprenyl (selegiline) and/or α-tocopherol in early disease would delay the time until levodopa was needed. Among the 800 patients enrolled in DATATOP during 1987 and 1988, levels of urate in serum were available for 774 and levels in cerebrospinal fluid were available for 713. A total of 369 (47.7%) patients progressed to a level of disability requiring levodopa therapy during the course of the trial. The association between urate level and progression was greater in men, and in both sexes the hazard ratio for disability decreased with higher body mass index (P=0.05 for trend among men, P=0.02 for trend in women). After adjustment for body mass index, the hazard ratios for a 1-SD increase in serum urate concentration were 0.89 among all patients (P=0.07), 0.85 among men (P=0.04), and 1.01 among women (P=0.94). In the original analysis of DATATOP, the hazard ratios for reaching the primary endpoint of disability requiring levodopa was 0.50 among those who had been randomized to selegiline and 0.91 in those assigned to α-tocopherol. In the present study, decreasing hazard ratios for reaching the endpoint of disability with increased serum urate were found only among patients not receiving α-tocopherol (HR 0.75, 95% CI 0.62 to 0.89, P=0.001). On the secondary response variable, the Unified Parkinson's Disease Rating Scale score (which combines motor, cognitive, and activities of daily living subscores), the rate of change in score fell with higher serum urate levels (P for trend=0.03). Mean urate concentrations in cerebrospinal fluid were lower than in serum, and analysis of these urate levels found that patients in the highest quintile had a hazard ratio of 0.65 (95% CI 0.44 to 0.96, P=0.03) for disability compared with those in the lowest quintile. The hazard ratio associated with a 1-SD increase in cerebrospinal fluid urate level was 0.89 (95% CI 0.79 to 1.02, P=0.09). As with serum urate, the associations were seen only among patients not receiving α-tocopherol, which suggests that there may be a competitive interaction between the two antioxidants. During 13 years of follow-up, 41.4% of men and 30.7% of women had died. After adjusting for factors including age, sex, smoking, and cardiac comorbidities, no significant association was seen between serum urate and mortality. Nonetheless, the results of this analysis, according to the investigators, "establish urate as the first molecular predictor of clinical progression in [Parkinson's disease] and provide a rationale for investigating the possibility that a therapeutic increase of urate in patients ... might act favorably to slow the disease course." That could happen through diet, such as increased intake of fructose or purines, or pharmacologically by administration of the urate precursor inosine. But the researchers said the potential benefits must be weighed against potential risks, such as gout, coronary artery disease, hypertension, stroke and nephrolithiasis. At present there are insufficient data for therapeutic recommendations to be made, they cautioned. New insights, such as the link between urate and disease progression, have been made possible "through explorations of the growing repository of high- quality data collected from neuroprotection trials of [Parkinson's disease] and other neurodegenerative disorders," the investigators wrote. The study was funded by the National Institutes of Health, the U.S. Department of Defense, the RJG Foundation, the American Federation for Aging Research, the Parkinson Disease Foundation, and the Parkinson Study Group. Co-author Peter LeWitt reported lecture and lecture fees and grant support from multiple pharmaceutical companies, including Allergan, Boehringer Ingelheim, GlaxoSmithKline, Schering-Plough, and Novartis. Primary source: Archives of Neurology Source reference: Ascherio A, et al "Urate as a predictor of the rate of clinical decline in Parkinson disease" Arch Neurol 2009; 66. DOI:10.1001/archneurol.2009.247. ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn