Serum urate as a predictor of clinical and radiographic progression in Parkinson disease

Abstract

Objective: To determine whether concentration of serum urate, a purine metabolite and potent antioxidant that has been linked to a reduced risk of Parkinson disease (PD), predicts prognosis in PD.

Design: Prospective study.

Setting: The Parkinson Research Examination of CEP-1347 Trial (PRECEPT) study, which investigated the effects of a potential neuroprotectant on rates of PD progression, was conducted between April 2002 and August 2005 (average follow-up time 21.4 months).

Participants: Eight hundred four subjects with early PD enrolled in the PRECEPT study.

Main outcome measures: The primary study end point was progression to clinical disability sufficient to warrant dopaminergic therapy. Cox proportional hazards models were used to estimate the hazard ratio (HR) of reaching end point according to quintiles of baseline serum urate concentration, adjusting for sex, age, and other potential covariates. Change in striatal uptake of iodine I 123-labeled 2-beta-carbomethoxy-3-beta-(4-iodophenyl)tropane ([(123)I]beta-CIT), a marker for the presynaptic dopamine transporter, was assessed with linear regression for a subset of 399 subjects.

Results: The adjusted HR of reaching end point declined with increasing baseline concentrations of urate; subjects in the top quintile reached the end point at only half the rate of subjects in the bottom quintile (HR, 0.51; 95% confidence interval [CI], 0.37-0.72; P for trend < .001). This association was markedly stronger in men (HR, 0.39; 95% CI, 0.26-0.60; P for trend < .001) than in women (HR, 0.77; 95% CI, 0.39-1.50; P for trend = .33). The percentage of loss in striatal [(123)I]beta-CIT uptake also improved with increasing serum urate concentrations (overall P for trend = .002; men, P = .001; women, P = .43).

Conclusions: These findings identify serum urate as the first molecular factor directly linked to the progression of typical PD and suggest that targeting urate or its determinants could be an effective disease-modifying therapy in PD. Trial Registration clinicaltrials.gov Identifier: NCT00040404.

Figure 1

Kaplan-Meier estimates of the cumulative probability of reaching the end point by 24 months of follow-up, according to gender-specific quintiles of baseline serum urate. A. Men; B. Women. Log-rank tests: p=0.0011 in men, p=0.47 in women. At 24 months sample size was 46 in men and 21 in women.

Figure 1

Kaplan-Meier estimates of the cumulative probability of reaching the end point by 24 months of follow-up, according to gender-specific quintiles of baseline serum urate. A. Men; B. Women. Log-rank tests: p=0.0011 in men, p=0.47 in women. At 24 months sample size was 46 in men and 21 in women.

Figure 2

Age-adjusted percent change in striatal ^[123I^]β-CIT uptake according to overall and gender-specific quintiles of baseline serum urate. Median serum urate by quintiles (1 to 5) mg/dL: All: 3.8, 4.8, 5.5, 6.3, 7.5; Men: 4.4, 5.3, 6.0, 6.6, 7.8; Women: 3.1, 4.0, 4.5, 5.2, 6.6. * p < 0.05; ** p < 0.001 compared to corresponding quintile 1. P for linear trend: all, p= 0.002; men, p=0.0008; women, p=0.4.