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Clinical Trials |

Serum Urate as a Predictor of Clinical and Radiographic Progression in Parkinson Disease FREE

Michael A. Schwarzschild, MD, PhD; Steven R. Schwid, MD; Kenneth Marek, MD; Arthur Watts, MS; Anthony E. Lang, MD; David Oakes, PhD; Ira Shoulson, MD; Alberto Ascherio, MD; Parkinson Study Group PRECEPT Investigators
[+] Author Affiliations

Author Affiliations:MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital (Dr Schwarzschild), and Departments of Nutrition and Epidemiology, Harvard School of Public Health, and Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston (Dr Ascherio); Departments of Neurology and Biostatistics, University of Rochester, Rochester, New York (Drs Schwid, Oakes, and Shoulson and Mr Watts); Institute for Neurodegenerative Disorders, New Haven, Connecticut (Dr Marek); and Toronto Western Hospital, Toronto, Ontario, Canada (Dr Lang).


Section Editor: Ira Shoulson, MD

More Author Information
Arch Neurol. 2008;65(6):716-723. doi:10.1001/archneur.2008.65.6.nct70003.
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Published online

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 ([123I]β-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; Pfor trend < .001). This association was markedly stronger in men (HR, 0.39; 95% CI, 0.26-0.60; Pfor trend < .001) than in women (HR, 0.77; 95% CI, 0.39-1.50; Pfor trend = .33). The percentage of loss in striatal [123I]β-CIT uptake also improved with increasing serum urate concentrations (overall Pfor 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.

Figures in this Article

As a consequence of mutations in the urate oxidase gene early in primate evolution,1urate in humans circulates at high concentrations near the limits of its solubility and constitutes the main end product of purine metabolism. Urate has an antioxidant efficacy comparable with that of ascorbate, and thus, its high level may serve as one of our major defenses against oxidative damage caused by reactive nitrogen and oxygen species.2Because oxidative stress may contribute to the loss of dopaminergic neurons in the substantia nigra of individuals with Parkinson disease (PD)3and to the pathophysiology of other neurodegenerative diseases,4blood urate concentration could be an important determinant of disease susceptibility and progression.

Supporting this notion, the results of prospective epidemiological studies consistently indicate that among healthy people the risk of PD declines with increasing uricemia.57Whether uricemia also predicts a better prognosis in established PD has not, to our knowledge, been investigated. To address this question efficiently, we sought completed, rigorously conducted clinical studies of PD progression in which prospectively determined (baseline) levels of urate were available. We identified a large randomized clinical trial entitled Parkinson Research Examination of CEP-1347 Trial (PRECEPT), which was originally designed to investigate a candidate neuroprotectant in PD using clinical and imaging assessments of neurodegeneration,8as an ideal opportunity to evaluate the potential association between serum urate concentration and subsequent rates of PD progression.

STUDY DESIGN

We conducted a longitudinal cohort investigation among participants in the PRECEPT study, a 2-year, double-blind, randomized trial of oral CEP-1347, an antiapoptotic mixed lineage kinase inhibitor that has been found to be neuroprotective in animal models of PD.8The PRECEPT study was designed to determine whether this drug could slow the progression of early PD. It was carried out by the Parkinson Study Group and sponsored by Cephalon, Inc and H. Lundbeck A/S. The participants (n = 806) were enrolled between April 2002 and April 2004 at 65 sites across the United States and Canada. All participating sites obtained approval of the protocol by their institutional review boards, and all subjects gave written consent for study participation.

STUDY POPULATION

Subjects to be enrolled in the study had to have early PD (modified Hoehn and Yahr stage of ≤ 2.5 with 2 of the cardinal signs: resting tremor, bradykinesia, or rigidity), not require the use of dopaminergic therapy, and be 30 years or older at diagnosis.8Exclusion criteria included atypical parkinsonism, a diagnosis of PD of 5 or more years' duration, a tremor score of 3 or higher, a Mini-Mental Status Examination score of 26 or lower, a Beck Depression Inventory score of 15 or higher, the use of symptomatic therapy within 6 months prior to randomization, or an expectation that dopaminergic therapy would be required within 3 months of study enrollment. Subjects were randomly assigned to receive placebo or 10, 25, or 50 mg of CEP-1347 twice daily. The PRECEPT study was stopped early following a prespecified interim analysis for futility.8

SERUM URATE CONCENTRATION AND COVARIATES

Serum urate concentration was measured at screening as well as the subsequent baseline visit (on average 4 weeks apart) as one component of the routine safety monitoring performed. The correlation between the screening and baseline serum urate concentration was high (r = 0.88; P < .001), and only baseline values, which were available for 99.8% of patients enrolled in the trial, have been used in the present analyses. Serum urate levels were determined using an enzymatic assay on nonfasting blood, performed at a central commercial clinical laboratory (Covance, Indianapolis, Indianapolis). Information on medical history and regular use of medications was collected at the screening visit.

CLINICAL EVALUATION

Following the initial screening and baseline visits, subjects were seen 1 month after starting the study drug and then every 3 months until 24 months had elapsed. At each visit, the site investigator conducted a clinical assessment and evaluated the subject for disability sufficient to require dopaminergic therapy, the primary end point for the study. A follow-up visit was performed 1 month after discontinuing the study medication. Of the 806 randomized patients, 95 (11.8%) were censored, 48 because of withdrawal and 47 because they requested dopaminergic treatment before this was considered required by the investigators. The average follow-up time was 21.4 months.8

OUTCOME

The primary end point was time to disability requiring dopaminergic therapy,8,9determined by individual investigators masked to treatment assignment. Secondary end points included changes in the Unified Parkinson's Disease Rating Scale (UPDRS) (sum of the motor, mentation, and activity of daily living subscales, termed totalin this study) score and 2-beta-carbomethoxy-3-beta-(4-iodophenyl)tropane (β-CIT) single-photon emission computed tomography (SPECT) imaging of ligand binding to striatal dopamine transporter, a marker for nigrostriatal dopaminergic nerve terminals. Because the UPDRS score was modified by the dopaminergic treatment instituted at end point, the annualized rate of change in UPDRS score was determined based on change from baseline to end point for each subject and was calculated as

[(total UPDRS score at the last assessment before initiation of dopaminergic treatment − total UPDRS score at baseline)/number of days between the 2 assessments] × [365 days/y].

NEUROIMAGING SUBSTUDY

Single-photon emission computed tomography of iodine I 123–labeled ([123I]) β-CIT uptake was used at baseline to measure striatal dopamine transporter density among all subjects in the trial; imaging was carried out at the Institute for Neurodegenerative Disorders in New Haven, Connecticut, with methods as described previously.10All subjects were invited to repeat the SPECT at the end of the follow-up. The 399 subjects with repeated SPECT imaging completed as of May 2005 and with baseline serum urate concentration were included in a subanalysis on the relation between baseline serum urate level and percentage of change in the ratio of the specific striatal [123I]β-CIT uptake to the nondisplaceable striatal [123I]β-CIT uptake between the 2 images. Mean interval between the 2 SPECT scans was 22 months.

STATISTICAL ANALYSIS

Cox proportional hazards models were used to estimate the hazard ratios (HRs) of reaching the end point according to quintiles of baseline serum urate concentration, adjusting for sex and age (5-year groups). Initial analyses were conducted using quintiles based on the combined urate distribution in men and women (“common quintiles”). An important advantage of using common quintiles is that the HRs in men and women estimate the effects of similar levels of serum urate. However, because of the expected higher level of urate in men, this categorization resulted in a markedly skewed distribution within sex, with most men in the top quintiles and most women in the bottom quintiles of serum urate level, and thus in a loss of power of analyses within sex. These analyses were therefore complemented by estimating HRs for sex-specific quintiles. In these analyses, the advantage of a more balanced distribution of subjects across quintiles was in part offset by the lack of comparability of the HRs; for example, in men the cutoffs for lowest and highest quintiles were less than 4.9 and more than 7.0 mg/dL vs less than 3.7 and more than 5.6 mg/dL in women. Tests for trend were conducted by including serum urate level as a continuous variable in the proportional hazard models (Wald test). Potential confounding was assessed by adjusting the regression analyses for cigarette smoking (never, past, or current), body mass index (calculated as weight in kilograms divided by height in meters squared) (quintiles), serum cholesterol level (continuous), and use of antihypertensive drugs or nonsteroidal anti-inflammatory drugs (use vs no use). Because the adjusted results were not materially different from the unadjusted and none of these covariates was significantly related to PD progression, only the age- and sex-adjusted results have been included in this report. Possible interactions between serum urate level and age, sex, and treatment group were explored by including in the proportional hazard model the cross-product of serum urate level as a continuous variable with the corresponding covariates (age, continuous in years; sex, 0 or 1; treatment, 0, 1, 2, or 3 for placebo and each of the CEP-1347 doses). None of the interaction terms was significant, and only results not including these terms are reported. There was no significant deviation from the proportional hazard assumption, tested by adding the cross-product of urate level (continuous) with time of follow-up (0 for first year, 1 thereafter) to the Cox model.

The relation between serum urate level and rate of change in UPDRS score or percentage of change in striatal [123I]β-CIT uptake was assessed by linear regression. For each of these outcomes, we fitted regression models including age, sex (for analyses including men and women combined), and either common quintiles of serum urate level or sex-specific quintiles, as outlined earlier. Because of the skewed distribution of UPDRS rates, analyses for this outcome were also conducted using Spearman correlation. All the Pvalues presented are for 2-tailed tests with levels <.05 defined as significant.

Serum urate concentration at baseline was available for 804 (517 men and 287 women) of the 806 subjects enrolled in the trial. Selected characteristics of these subjects are shown in Table 1. As expected, serum urate concentrations were positively correlated with male sex, body mass index, use of thiazide diuretics, and history of gout and hypertension (Table 1).

Table Graphic Jump LocationTable 1. Characteristics of 804 Study Participants According to Quintiles of Baseline Serum Urate Level

Overall, 493 participants (61%) reached the end point of disability sufficient to require dopaminergic therapy during follow-up. The hazard ratio of reaching the end point declined with increasing concentrations of serum urate; subjects in the top common quintile reached end point at approximately half the rate of subjects in the bottom quintile (HR, 0.51; 95% confidence interval, 0.37-0.72; P < .001) (Table 2). This association was markedly stronger in men than in women, although a test for interaction of urate level with sex was not significant (Table 2). Results of analyses based on sex-specific quintiles were similar and are summarized in Kaplan-Meier curves (Figure 1).

Place holder to copy figure label and caption
Figure 1.

Kaplan-Meier estimates of the cumulative probability of reaching the end point by 24 months of follow-up according to sex-specific quintiles of baseline serum urate level. A, Men. B, Women. Log-rank tests: P = .001 in men; P = .47 in women. At 24 months, the sample size was 46 men and 21 women.

Graphic Jump Location
Table Graphic Jump LocationTable 2. HRs for Reaching the End Point According to Common Quintiles of Baseline Serum Urate Level

The rate of change in UPDRS score (points per year) in men and women combined was 16.9 among patients in the lowest quintile of baseline urate level and 14.3 among those in the highest quintile (Pfor trend = .09). Among men, there was a modest but significant inverse association between baseline serum urate level and rate of UPDRS score change (Spearman correlation coefficient = −0.10; P = .02). A significantly lower rate of change in UPDRS score was observed among patients in the highest as compared with those in the lowest sex-specific quintile of serum urate level (adjusted difference = 7.0; P = .02). In contrast, no significant association was found in women (Spearman r = −0.03; P = .52).

The percentage of change in striatal [123I]β-CIT uptake also declined with increasing serum urate concentrations (Pfor trend = .002), although the trend was largely driven by a lower percentage of change among subjects in the top quintile of serum urate level, with little or no differences between quintiles 1 through 4 (Figure 2). Because there were only 4 women in the top quintile of serum urate level when the cutoffs for quintiles were generated from men and women combined, stratified analyses were only conducted using sex-specific quintiles. As in the end point analyses, a significant association was only seen in men (Figure 2).

Place holder to copy figure label and caption
Figure 2.

Age-adjusted percentage of change in striatal iodine I 123–labeled 2-beta-carbomethoxy-3-beta-(4-iodophenyl)tropane ([123I]β-CIT) uptake according to overall and sex-specific quintiles of baseline serum urate level. Median serum urate level by quintiles (1-5) in milligrams per deciliter: all: 3.8, 4.8, 5.5, 6.3, and 7.5; men: 4.4, 5.3, 6.0, 6.6, and 7.8; and women: 3.1, 4.0, 4.5, 5.2, and 6.6. *P < .05; †P < .001 compared with corresponding quintile 1. Pfor linear trend: all, P = .002; men, P = .001; and women, P = .43. Error bars represent the standard error of the mean.

Graphic Jump Location

In this large prospective investigation among subjects in the early stages of PD enrolled in a randomized clinical trial, we found that the rate of progression to the primary clinical end point declined with increasing levels of baseline serum urate. There was a clear dose-response relationship, with a 35% reduction in rate of progression among patients in the fourth quintile of serum urate level and a 49% reduction among those in the highest quintile, as compared with those in the lowest quintile. These associations were highly significant and corroborated by the finding that patients with a higher urate concentration also had a lower percentage of loss of striatal [123I]β-CIT uptake during the follow-up.

Strengths of this study include the longitudinal design, the measurement of serum urate level at baseline and before starting any antiparkinsonian treatment, the large number of participants, and the rigorous clinical assessment of all patients. We specifically examined the relation between serum urate level and PD progression because of the strong a priori evidence that individuals with high levels of serum urate have a markedly reduced risk of developing PD.57The convergence between the results of previous epidemiological studies and those of the present investigation is striking. Combined, these results support the continuity of the neurodegenerative process before and after the onset of the first motor symptoms that lead to the diagnosis of PD and imply that either a higher serum urate level itself is neuroprotective or it serves as an indirect marker of protection of the dopaminergic neurons that are lost in PD.

The inverse association between uricemia and PD progression could be explained if both were affected by a common factor or, in epidemiological lexicon, a confounder. In subjects without PD, the strongest correlates of serum urate level are male sex, obesity, and arterial hypertension.11Further, use of thiazide diuretics is known to increase urate levels.12These correlations were also found among participants in our study, suggesting that the main determinants of serum urate level are the same in individuals with or without PD. However, the relation between serum urate level and PD progression in our study was independent from these factors. Also, adjustment for cigarette smoking and use of nonsteroidal anti-inflammatory drugs, which have been related to PD risk, did not appreciably change the results. Genetic factors could also affect both serum urate level and PD progression and thus act as confounders. Heritability of serum urate level is estimated to range from 25% to 70%,13and several genetic mutations that affect uricemia have been identified.1416Known mutations with marked effects on uricemia, however, are rare and seem unlikely to fully explain the strong inverse associations between uricemia and both PD risk and PD progression. Finally, dietary factors should also be considered. High dairy consumption has been associated with an increased risk of PD1719and with decreased serum urate concentration,20but the latter association is weak and unlikely to account for much variation in urate levels. On the other hand, high alcohol consumption increases serum urate concentration,21but in longitudinal studies, alcohol consumption was not consistently related to PD risk.22Purine20and fructose23intakes also increase serum urate level, but these effects are modest and there is no evidence that these nutrients would affect PD risk or progression independently from their effects on uricemia. Overall, it seems therefore unlikely that the inverse relation between uricemia and PD progression is due to confounding by known factors. As in all observational studies, however, a role for unknown factors cannot be excluded.

Although several clinical features of PD (eg, prominent asymmetry, rest tremor predominance, absence of early cognitive or gait dysfunction) have been identified previously as predictors of a slower rate of clinical progression,24,25these are complex behavioral characteristics of the disease and are thus likely to result from, rather than influence, pathogenic mechanisms. By contrast, as an antioxidant with peroxynitrite scavenging and metal chelating26properties, urate is well positioned to serve as a neuroprotectant against the underlying neurodegeneration of PD. Considerable evidence from genetic as well as idiopathic forms of PD has implicated oxidative and nitrative stress as central pathogentic mechanisms.27,28Urate at physiological concentrations is as effective an antioxidant as ascorbate.2It also stabilizes ascorbate,29possibly by forming complexes with iron ions,26and scavenges nitrogen radicals.30,31Further, administration of urate reduced the exacerbation of the oxidative stress and mitochondrial dysfunction in human dopaminergic cells exposed to the pesticide rotenone or to iron ions.32

Alternatively, the predictive association between urate concentration and PD progression could reflect a neuroprotective effect of a urate precursor, rather than urate itself. For example, adenosine and its deaminated metabolite inosine (which is in turn deribosylated and oxidized to urate) both modulate neuronal death on their own. Adenosine can have either neuroprotective or neurotoxic effects on dopaminergic neurons via adenosine A1and A2Areceptors, respectively.33,34Inosine has also shown potential as a neuroprotectant in models of stroke and multiple sclerosis.35,36Whether urate, its metabolic precursors, or other determinants modulate neurodegeneration in PD, their potential is supported by lower levels of urate in cerebrospinal fluid37and postmortem substantia nigra38of patients with PD.

Whereas the concentration-dependent inverse relationship was robust and highly significant statistically in men, it appeared as a weak nonsignificant trend among women. This difference between men and women (also noted for the association between urate level and [123I]β-CIT uptake neuroimaging) could result in part from a biological effect of sex on urate mechanisms in PD.39Alternatively, it may reflect the substantially lower average urate concentrations in women, who account for only 16% of the subjects in the 2 uppermost quintiles in which the substantially slower rates of disease progression were observed.

That urate and its metabolic pathway are particularly amenable to existing pharmacological and dietary manipulations enhances the potential therapeutic significance of the present findings. A purine-rich diet can elevate serum urate concentration, and the purine supplement inosine, used as a potential therapy for multiple sclerosis in a phase 2 randomized clinical trial, markedly raised urate concentrations in the long-term without inducing gout or other adverse effects.40,41It is also well known that thiazide diuretics even at low doses elevate urate concentration by reducing its renal clearance.12Individuals with a higher serum urate level, however, have an increased risk of hypertension, coronary heart disease, and stroke.5,42Although these associations may in part be confounded by obesity and other risk factors,43,44a long-term neuroprotective effect of urate or its precursors would have to be weighed against potential adverse cardiovascular effects.

Measurement of urate on its own in patients with newly diagnosed PD as an indicator of an individual patient's future rate of progression is likely to be of modest clinical utility.45On the other hand, urate testing may aid the rational design of neuroprotective trials in PD, particularly those targeting mechanisms (antioxidant chelating or purinergic) that are potentially shared with urate. For example, coenzyme Q10, creatine, and rasagiline—potential neuroprotectants targeting oxidative stress pathways in planned neuroprotection trials—might be most effective in patients with PD whose endogenous antioxidant pool (including urate) is lowest at baseline; thus, controlling for an interaction with or stratifying by urate levels at baseline may improve the power of such trials.

The present discovery of a urate concentration link to PD progression was achieved through additional analyses of a rigorously conducted clinical trial whose database was made available to test unforeseen hypotheses on conclusion of the primary investigation.8The findings thus reflect a broader opportunity to retrospectively explore a growing repository of high-quality data from neuroprotection trials for PD, Alzheimer disease, and other progressive degenerative disorders.

Correspondence:Alberto Ascherio, MD, Harvard School of Public Health, 665 Huntington Ave, Bldg 2, Boston, MA 02115 (aascheri@hsph.harvard.edu).

Accepted for Publication: July 26, 2007.

Author Contributions:Dr Ascherio had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Schwarzschild, Marek, Oakes, Shoulson, and Ascherio. Acquisition of data: Schwarzschild, Schwid, Marek, and Shoulson. Analysis and interpretation of data: Schwarzschild, Schwid, Marek, Watts, Lang, Oakes, Shoulson, and Ascherio. Drafting of the manuscript: Schwarzschild, Oakes, and Ascherio. Critical revision of the manuscript for important intellectual content: Schwarzschild, Schwid, Marek, Watts, Lang, Oakes, Shoulson, and Ascherio. Statistical analysis: Watts, Oakes, and Ascherio. Obtained funding: Schwarzschild, Marek, and Shoulson. Administrative, technical, and material support: Schwarzschild, Schwid, Marek, Watts, and Shoulson. Study supervision: Schwarzschild and Schwid.

Financial Disclosure:None reported.

Funding/Support:This work was supported by National Institutes of Health grants NS048517 and ES010804 and the Beeson Scholars Program of the American Federation for Aging Research. The PRECEPT study was supported by Cephalon, Inc and H. Lundbeck A/S. The analyses of the fully accessible PRECEPT database were carried out independently by the Parkinson Study Group Biostatistics Center in Rochester, NY.

Additional Contributions:Emily Gorbold, BA, helped coordinate this collaborative project, Leslie Unger, BA, helped prepare the manuscript, and John Ondrasik, PhD, conducted a secondary review of statistical programs and reported results.

Box Section Ref ID

Additional Authors/Parkinson Study Group PRECEPT Investigators and Steering Committee

The following members of the Parkinson Study Group were investigators in PRECEPT (Parkinson Research Examination of CEP-1347 Trial) and authored this report:

Rajeev Kumar, MD, Colorado Neurological Institute, Englewood; Mandar Jog, MD, and Cheryl Horn, RN, London Health Sciences Center, London, Ontario, Canada; Kathleen Shannon, MD, Rush-Presbyterian–St Luke's Medical Center, Chicago, Illinois; Maureen Leehey, MD, and Teresa Derian, RN, University of Colorado Health Sciences Center, Denver; David Grimes, MD, and Melodie Mortensen, BSCN, Ottawa Hospital Civic Site, Ottawa, Ontario, Canada; Paul Tuite, MD, University of Minnesota/Minnesota VA Medical Center, Minneapolis; Neal Hermanowicz, MD, and Shari Niswonger, RN, University of California, Irvine; Roger Kurlan, MD, and Irenita Gardiner, RN, CCRC, University of Rochester, Rochester, New York; Janis Miyasaki, MD, FRCPC, and Lisa Johnston, RN, BSCN, CNN, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada; James Tetrud, MD, The Parkinson's Institute, Sunnyvale, California; Joseph Friedman, MD, and Hubert Fernandez, MD, NeuroHealth Parkinson's Disease Movement Disorders Center, Warwick, Rhode Island; Robert Rodnitzky, MD, and Judith Dobson, RN, CCRC, University of Iowa, Iowa City; Virgilio Evidente, MD, and Marlene Lind, RN, Mayo Clinic Arizona, Scottsdale; Pamela Andrews, BS, Oregon Health and Science University, Portland; Michel Panisset, MD, Centre Hospitalier de l'Université de Montréal (CHUM)–Hotel Dieu Hospital/McGill Center for Studies in Aging, Montreal, Quebec, Canada; Brad Racette, MD, and Patricia Deppen, RN, Washington University School of Medicine, St Louis, Missouri; Joseph Jankovic, MD, and Christine Hunter, RN, CCRC, Baylor College of Medicine, Houston, Texas; Eric Molho, MD, and Stewart Factor, MD, Albany Medical College, Albany, New York; Joanne Wojcieszek, MD, Indiana University School of Medicine, Indianapolis; Burton Scott, MD, Duke University Medical Center, Durham, North Carolina; Thyagarajan Subramanian, MD, and Ruth Kolb, CCRP, Cleveland Clinic, Cleveland, Ohio; Andrew Siderowf, MD, University of Pennsylvania, Philadelphia; Robert Hauser, MD, University of South Florida, Tampa; Joseph Savitt, MD, PhD, and Melissa Gerstenhaber, RNC, MSN, Johns Hopkins University, Baltimore, Maryland; Alok Sahay, MD, and Maureen Gartner, RN, University of Cincinnati/Cincinnati Children's Hospital, Cincinnati, Ohio; Margaret Turk, RN, Mayo Clinic Jacksonville, Jacksonville, Florida; Jean Rivest, MD, University of Sherbrooke, Sherbrooke, Quebec, Canada; Frederick Wooten, MD, University of Virginia, Charlottesville; Michael Schwarzschild, MD, PhD, and Marsha Tennis, RN, Massachusetts General Hospital, Boston; Kapil Sethi, MD, and Lisa Hatch, RN, BSN, Medical College of Georgia, Augusta; Ronald Pfeiffer, MD, and Brenda Pfeiffer, RN, BSN, University of Tennessee, Memphis; Andrew Feigin, MD, North Shore–LIJ Health System, Manhasset, New York; Tanya Simuni, MD, and Karen Williams, BA, Northwestern University, Chicago; Lawrence Elmer, MD, PhD, Medical University of Ohio, Toledo; Antonelle deMarcaida, MD, and Sheila Thurlow, RN, University of Connecticut, Glastonbury; Sylvain Chouinard, MD, and Hubert Poiffaut, RN, Hotel Dieu Hospital–CHUM, Montreal; Holly Shill, MD, and Mark Stacy, MD, Barrow Neurological Institute, Phoenix, Arizona; Richard Zweig, MD, and Rhonda Feldt, RN, Louisiana State University Health Science Center, Shreveport; Cheryl Waters, MD, Columbia University Medical Center, New York, New York; Rajesh Pahwa, MD, and Amy Parsons, RN, BSN, University of Kansas Medical Center, Kansas City; Jennifer Hui, MD, and Allan Wu, MD, University of Southern California, Los Angeles; Richard Camicioli, MD, and Pamela King, BSCN, RN, University of Alberta, Edmonton, Alberta, Canada; Arif Dalvi, MD, and Un Jung Kang, MD, University of Chicago, Chicago; Stephen Reich, MD, and Lisa Shulman, MD, University of Maryland School of Medicine, Baltimore; Margery Mark, MD, University of Medicine and Dentistry, New Jersey/Robert Wood Johnson Medical School, New Brunswick; Ali Rajput, MD, Saskatoon District Health Board Royal University Hospital, Saskatoon, Saskatchewan, Canada; David Song, MD, University of California San Diego, La Jolla; John M. Bertoni, MD, and Carolyn Peterson, RN, Creighton University, Omaha, Nebraska; Karen Blindauer, MD, and Jeanine Petit, ANP, Medical College of Wisconsin, Milwaukee; Bala Manyam, MD, Scott and White Hospital/Texas A & M University, Temple; Oksana Suchowersky, MD, University of Calgary, Calgary, Alberta, Canada; Lewis Sudarsky, MD, Brigham and Women's Hospital, Boston; Daniel Tarsy, MD, Beth Israel Deaconess Medical Center, Boston; Mark Forrest Gordon, MD, Long Island Jewish Medical Center, New Hyde Park, New York; Alessandro DiRocco, MD, Beth Israel Medical Center, New York; Amy Andrzejewski, BS, Stanford University Medical Center, Stanford, California; Nestor Galvez-Jimenez, MD, Cleveland Clinic Florida, Weston; and Sami Harik, MD, and Samer Tabbal, MD, University of Arkansas for Medical Sciences, Little Rock.

The following members of the PRECEPT Steering Committee authored this report:

Christopher Hyson, MD (medical monitor), Emily Gorbold, BA (project coordinator), Alice Rudolph, PhD (project coordinator), and Karl Kieburtz, MD, MPH (director, Clinical Trials Coordination Center), University of Rochester, Rochester; Stanley Fahn, MD, Columbia University Medical Center, New York; Lisa Gauger, BA, Duke University Medical Center, Durham; Christopher Goetz, MD, Rush University Medical Center, Chicago; John Seibyl, MD, Institute for Neurodegenerative Disorders, New Haven, Connecticut; Misser Forrest, MD, H. Lundbeck A/S, Copenhagen, Denmark; and John Ondrasik, PhD, Cephalon, Inc, Fraser, Pennsylvania.

A complete list of PRECEPT Investigators, steering committee members, sponsors, and data monitoring committee members was published in Neurology. 2007;69(15):1480-1490.

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Marek  KInnis  Rvan Dyck  C  et al.  [123I]beta-CIT SPECT imaging assessment of the rate of Parkinson's disease progression. Neurology 2001;57 (11) 2089- 2094
PubMed Link to Article
Roubenoff  RKlag  MJMead  LALiang  KYSeidler  AJHochberg  MC Incidence and risk factors for gout in white men. JAMA 1991;266 (21) 3004- 3007
PubMed Link to Article
Reyes  AJ Cardiovascular drugs and serum uric acid. Cardiovasc Drugs Ther 2003;17 (5-6) 397- 414
PubMed Link to Article
Yang  QGuo  CYCupples  LALevy  DWilson  PWFox  CS Genome-wide search for genes affecting serum uric acid levels: the Framingham Heart Study. Metabolism 2005;54 (11) 1435- 1441
PubMed Link to Article
Enomoto  AKimura  HChairoungdua  A  et al.  Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature 2002;417 (6887) 447- 452
PubMed
Graessler  JGraessler  AUnger  S  et al.  Association of the human urate transporter 1 with reduced renal uric acid excretion and hyperuricemia in a German Caucasian population. Arthritis Rheum 2006;54 (1) 292- 300
PubMed Link to Article
Berry  CEHare  JM Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications. J Physiol 2004;555 (pt 3) 589- 606
PubMed Link to Article
Chen  HZhang  SMHernan  MAWillett  WCAscherio  A Diet and Parkinson's disease: a potential role of dairy products in men. Ann Neurol 2002;52 (6) 793- 801
PubMed Link to Article
Park  MRoss  GWPetrovitch  H  et al.  Consumption of milk and calcium in midlife and the future risk of Parkinson disease. Neurology 2005;64 (6) 1047- 1051
PubMed Link to Article
Chen  HO'Reilly  EMcCullough  ML  et al.  Consumption of dairy products and risk of Parkinson's disease. Am J Epidemiol 2007;165 (9) 998- 1006
PubMed Link to Article
Choi  HKLiu  SCurhan  G Intake of purine-rich foods, protein, and dairy products and relationship to serum levels of uric acid: the Third National Health and Nutrition Examination Survey. Arthritis Rheum 2005;52 (1) 283- 289
PubMed Link to Article
Yamamoto  TMoriwaki  YTakahashi  S Effect of ethanol on metabolism of purine bases (hypoxanthine, xanthine, and uric acid). Clin Chim Acta 2005;356 (1-2) 35- 57
PubMed Link to Article
Hernán  MAChen  HSchwarzschild  MAAscherio  A Alcohol consumption and the incidence of Parkinson's disease. Ann Neurol 2003;54 (2) 170- 175
PubMed Link to Article
Mayes  PA Intermediary metabolism of fructose. Am J Clin Nutr 1993;58 (5) ((suppl)) 754S- 765S
PubMed
Marras  CRochon  PLang  AE Predicting motor decline and disability in Parkinson disease: a systematic review. Arch Neurol 2002;59 (11) 1724- 1728
PubMed Link to Article
Gasparoli  EDelibori  DPolesello  G  et al.  Clinical predictors in Parkinson's disease. Neurol Sci 2002;23 ((suppl 2)) S77- S78
PubMed Link to Article
Davies  KJSevanian  AMuakkassah-Kelly  SFHochstein  P Uric acid-iron ion complexes: a new aspect of the antioxidant functions of uric acid. Biochem J 1986;235 (3) 747- 754
PubMed
Moore  DJWest  ABDawson  VLDawson  TM Molecular pathophysiology of Parkinson's disease. Annu Rev Neurosci 2005;2857- 87
PubMed Link to Article
Jenner  POlanow  CW The pathogenesis of cell death in Parkinson's disease. Neurology 2006;66 (10) ((suppl 4)) S24- S36
PubMed Link to Article
Stocker  RFrei  B Endogenous antioxidant defences in human blood plasma. Sies  HOxidative Stress Oxidants and Antioxidants. San Diego, CA Academic Press1991;213- 243
Squadrito  GLCueto  RSplenser  AE  et al.  Reaction of uric acid with peroxynitrite and implications for the mechanism of neuroprotection by uric acid. Arch Biochem Biophys 2000;376 (2) 333- 337
PubMed Link to Article
Whiteman  MKetsawatsakul  UHalliwell  B A reassessment of the peroxynitrite scavenging activity of uric acid. Ann N Y Acad Sci 2002;962242- 259
PubMed Link to Article
Duan  WLadenheim  BCutler  RGKruman  IICadet  JLMattson  MP Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson's disease. J Neurochem 2002;80 (1) 101- 110
PubMed Link to Article
Delle Donne  KTSonsalla  PK Protection against methamphetamine-induced neurotoxicity to neostriatal dopaminergic neurons by adenosine receptor activation. J Pharmacol Exp Ther 1994;271 (3) 1320- 1326
PubMed
Xu  KBastia  ESchwarzschild  M Therapeutic potential of adenosine A(2A) receptor antagonists in Parkinson's disease. Pharmacol Ther 2005;105 (3) 267- 310
PubMed Link to Article
Scott  GSSpitsin  SVKean  RBMikheeva  TKoprowski  HHooper  DC Therapeutic intervention in experimental allergic encephalomyelitis by administration of uric acid precursors. Proc Natl Acad Sci U S A 2002;99 (25) 16303- 16308
PubMed Link to Article
Shen  HChen  GJHarvey  BKBickford  PCWang  Y Inosine reduces ischemic brain injury in rats [published correction appears in Stroke. 2005;36(5):1112]. Stroke 2005;36 (3) 654- 659
PubMed Link to Article
Tohgi  HAbe  TTakahashi  SKikuchi  T The urate and xanthine concentrations in the cerebrospinal fluid in patients with vascular dementia of the Binswanger type, Alzheimer type dementia, and Parkinson's disease. J Neural Transm Park Dis Dement Sect 1993;6 (2) 119- 126
PubMed Link to Article
Church  WHWard  VL Uric acid is reduced in the substantia nigra in Parkinson's disease: effect on dopamine oxidation. Brain Res Bull 1994;33 (4) 419- 425
PubMed Link to Article
Nilsen  JBrinton  RD Mitochondria as therapeutic targets of estrogen action in the central nervous system. Curr Drug Targets CNS Neurol Disord 2004;3 (4) 297- 313
PubMed Link to Article
Spitsin  SHooper  DCLeist  TStreletz  LJMikheeva  TKoprowskil  H Inactivation of peroxynitrite in multiple sclerosis patients after oral administration of inosine may suggest possible approaches to therapy of the disease. Mult Scler 2001;7 (5) 313- 319
PubMed Link to Article
Koprowski  HSpitsin  SVHooper  DC Prospects for the treatment of multiple sclerosis by raising serum levels of uric acid, a scavenger of peroxynitrite. Ann Neurol 2001;49 (1) 139
PubMed Link to Article
Bos  MJKoudstaal  PJHofman  AWitteman  JCBreteler  MM Uric acid is a risk factor for myocardial infarction and stroke: the Rotterdam Study. Stroke 2006;37 (6) 1503- 1507
PubMed Link to Article
Wheeler  JGJuzwishin  KDEiriksdottir  GGudnason  VDanesh  J Serum uric acid and coronary heart disease in 9,458 incident cases and 155,084 controls: prospective study and meta-analysis. PLoS Med 2005;2 (3) e76
PubMed Link to Article
Forman  JPChoi  HCurhan  GC Plasma uric acid level and risk for incident hypertension among men. J Am Soc Nephrol 2007;18 (1) 287- 292
PubMed Link to Article
Ware  JH The limitations of risk factors as prognostic tools. N Engl J Med 2006;355 (25) 2615- 2617
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Kaplan-Meier estimates of the cumulative probability of reaching the end point by 24 months of follow-up according to sex-specific quintiles of baseline serum urate level. A, Men. B, Women. Log-rank tests: P = .001 in men; P = .47 in women. At 24 months, the sample size was 46 men and 21 women.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Age-adjusted percentage of change in striatal iodine I 123–labeled 2-beta-carbomethoxy-3-beta-(4-iodophenyl)tropane ([123I]β-CIT) uptake according to overall and sex-specific quintiles of baseline serum urate level. Median serum urate level by quintiles (1-5) in milligrams per deciliter: all: 3.8, 4.8, 5.5, 6.3, and 7.5; men: 4.4, 5.3, 6.0, 6.6, and 7.8; and women: 3.1, 4.0, 4.5, 5.2, and 6.6. *P < .05; †P < .001 compared with corresponding quintile 1. Pfor linear trend: all, P = .002; men, P = .001; and women, P = .43. Error bars represent the standard error of the mean.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Characteristics of 804 Study Participants According to Quintiles of Baseline Serum Urate Level
Table Graphic Jump LocationTable 2. HRs for Reaching the End Point According to Common Quintiles of Baseline Serum Urate Level

References

Oda  MSatta  YTakenaka  OTakahata  N Loss of urate oxidase activity in hominoids and its evolutionary implications. Mol Biol Evol 2002;19 (5) 640- 653
PubMed Link to Article
Ames  BNCathcart  RSchwiers  EHochstein  P Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A 1981;78 (11) 6858- 6862
PubMed Link to Article
Jenner  P Oxidative stress in Parkinson's disease. Ann Neurol 2003;53 ((suppl 3)) S26- S36, discussion S36-S28
PubMed Link to Article
Beal  MF Mitochondria take center stage in aging and neurodegeneration. Ann Neurol 2005;58 (4) 495- 505
PubMed Link to Article
Davis  JWGrandinetti  AWaslien  CIRoss  GWWhite  LRMorens  DM Observations on serum uric acid and the risk of idiopathic Parkinson's disease. Am J Epidemiol 1996;144 (5) 480- 484
PubMed Link to Article
de Lau  LMKoudstaal  PJHofman  ABreteler  MM Serum uric acid levels and the risk of Parkinson disease. Ann Neurol 2005;58 (5) 797- 800
PubMed Link to Article
Weisskopf  MGO'Reilly  EChen  HSchwarzschild  MAAscherio  A Plasma urate and risk of Parkinson's disease. Am J Epidemiol 2007;166 (5) 561- 567
PubMed Link to Article
The Parkinson Study Group PRECEPT Investigators, Mixed lineage kinase inhibitor CEP-1347 fails to delay disability in early Parkinson's disease [published online ahead of print September 19, 2007]. Neurology 2007;69 (15) 1480- 1490
PubMed Link to Article
Parkinson Study Group, DATATOP: a multicenter controlled clinical trial in early Parkinson's disease. Arch Neurol 1989;46 (10) 1052- 1060
PubMed Link to Article
Marek  KInnis  Rvan Dyck  C  et al.  [123I]beta-CIT SPECT imaging assessment of the rate of Parkinson's disease progression. Neurology 2001;57 (11) 2089- 2094
PubMed Link to Article
Roubenoff  RKlag  MJMead  LALiang  KYSeidler  AJHochberg  MC Incidence and risk factors for gout in white men. JAMA 1991;266 (21) 3004- 3007
PubMed Link to Article
Reyes  AJ Cardiovascular drugs and serum uric acid. Cardiovasc Drugs Ther 2003;17 (5-6) 397- 414
PubMed Link to Article
Yang  QGuo  CYCupples  LALevy  DWilson  PWFox  CS Genome-wide search for genes affecting serum uric acid levels: the Framingham Heart Study. Metabolism 2005;54 (11) 1435- 1441
PubMed Link to Article
Enomoto  AKimura  HChairoungdua  A  et al.  Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature 2002;417 (6887) 447- 452
PubMed
Graessler  JGraessler  AUnger  S  et al.  Association of the human urate transporter 1 with reduced renal uric acid excretion and hyperuricemia in a German Caucasian population. Arthritis Rheum 2006;54 (1) 292- 300
PubMed Link to Article
Berry  CEHare  JM Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications. J Physiol 2004;555 (pt 3) 589- 606
PubMed Link to Article
Chen  HZhang  SMHernan  MAWillett  WCAscherio  A Diet and Parkinson's disease: a potential role of dairy products in men. Ann Neurol 2002;52 (6) 793- 801
PubMed Link to Article
Park  MRoss  GWPetrovitch  H  et al.  Consumption of milk and calcium in midlife and the future risk of Parkinson disease. Neurology 2005;64 (6) 1047- 1051
PubMed Link to Article
Chen  HO'Reilly  EMcCullough  ML  et al.  Consumption of dairy products and risk of Parkinson's disease. Am J Epidemiol 2007;165 (9) 998- 1006
PubMed Link to Article
Choi  HKLiu  SCurhan  G Intake of purine-rich foods, protein, and dairy products and relationship to serum levels of uric acid: the Third National Health and Nutrition Examination Survey. Arthritis Rheum 2005;52 (1) 283- 289
PubMed Link to Article
Yamamoto  TMoriwaki  YTakahashi  S Effect of ethanol on metabolism of purine bases (hypoxanthine, xanthine, and uric acid). Clin Chim Acta 2005;356 (1-2) 35- 57
PubMed Link to Article
Hernán  MAChen  HSchwarzschild  MAAscherio  A Alcohol consumption and the incidence of Parkinson's disease. Ann Neurol 2003;54 (2) 170- 175
PubMed Link to Article
Mayes  PA Intermediary metabolism of fructose. Am J Clin Nutr 1993;58 (5) ((suppl)) 754S- 765S
PubMed
Marras  CRochon  PLang  AE Predicting motor decline and disability in Parkinson disease: a systematic review. Arch Neurol 2002;59 (11) 1724- 1728
PubMed Link to Article
Gasparoli  EDelibori  DPolesello  G  et al.  Clinical predictors in Parkinson's disease. Neurol Sci 2002;23 ((suppl 2)) S77- S78
PubMed Link to Article
Davies  KJSevanian  AMuakkassah-Kelly  SFHochstein  P Uric acid-iron ion complexes: a new aspect of the antioxidant functions of uric acid. Biochem J 1986;235 (3) 747- 754
PubMed
Moore  DJWest  ABDawson  VLDawson  TM Molecular pathophysiology of Parkinson's disease. Annu Rev Neurosci 2005;2857- 87
PubMed Link to Article
Jenner  POlanow  CW The pathogenesis of cell death in Parkinson's disease. Neurology 2006;66 (10) ((suppl 4)) S24- S36
PubMed Link to Article
Stocker  RFrei  B Endogenous antioxidant defences in human blood plasma. Sies  HOxidative Stress Oxidants and Antioxidants. San Diego, CA Academic Press1991;213- 243
Squadrito  GLCueto  RSplenser  AE  et al.  Reaction of uric acid with peroxynitrite and implications for the mechanism of neuroprotection by uric acid. Arch Biochem Biophys 2000;376 (2) 333- 337
PubMed Link to Article
Whiteman  MKetsawatsakul  UHalliwell  B A reassessment of the peroxynitrite scavenging activity of uric acid. Ann N Y Acad Sci 2002;962242- 259
PubMed Link to Article
Duan  WLadenheim  BCutler  RGKruman  IICadet  JLMattson  MP Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson's disease. J Neurochem 2002;80 (1) 101- 110
PubMed Link to Article
Delle Donne  KTSonsalla  PK Protection against methamphetamine-induced neurotoxicity to neostriatal dopaminergic neurons by adenosine receptor activation. J Pharmacol Exp Ther 1994;271 (3) 1320- 1326
PubMed
Xu  KBastia  ESchwarzschild  M Therapeutic potential of adenosine A(2A) receptor antagonists in Parkinson's disease. Pharmacol Ther 2005;105 (3) 267- 310
PubMed Link to Article
Scott  GSSpitsin  SVKean  RBMikheeva  TKoprowski  HHooper  DC Therapeutic intervention in experimental allergic encephalomyelitis by administration of uric acid precursors. Proc Natl Acad Sci U S A 2002;99 (25) 16303- 16308
PubMed Link to Article
Shen  HChen  GJHarvey  BKBickford  PCWang  Y Inosine reduces ischemic brain injury in rats [published correction appears in Stroke. 2005;36(5):1112]. Stroke 2005;36 (3) 654- 659
PubMed Link to Article
Tohgi  HAbe  TTakahashi  SKikuchi  T The urate and xanthine concentrations in the cerebrospinal fluid in patients with vascular dementia of the Binswanger type, Alzheimer type dementia, and Parkinson's disease. J Neural Transm Park Dis Dement Sect 1993;6 (2) 119- 126
PubMed Link to Article
Church  WHWard  VL Uric acid is reduced in the substantia nigra in Parkinson's disease: effect on dopamine oxidation. Brain Res Bull 1994;33 (4) 419- 425
PubMed Link to Article
Nilsen  JBrinton  RD Mitochondria as therapeutic targets of estrogen action in the central nervous system. Curr Drug Targets CNS Neurol Disord 2004;3 (4) 297- 313
PubMed Link to Article
Spitsin  SHooper  DCLeist  TStreletz  LJMikheeva  TKoprowskil  H Inactivation of peroxynitrite in multiple sclerosis patients after oral administration of inosine may suggest possible approaches to therapy of the disease. Mult Scler 2001;7 (5) 313- 319
PubMed Link to Article
Koprowski  HSpitsin  SVHooper  DC Prospects for the treatment of multiple sclerosis by raising serum levels of uric acid, a scavenger of peroxynitrite. Ann Neurol 2001;49 (1) 139
PubMed Link to Article
Bos  MJKoudstaal  PJHofman  AWitteman  JCBreteler  MM Uric acid is a risk factor for myocardial infarction and stroke: the Rotterdam Study. Stroke 2006;37 (6) 1503- 1507
PubMed Link to Article
Wheeler  JGJuzwishin  KDEiriksdottir  GGudnason  VDanesh  J Serum uric acid and coronary heart disease in 9,458 incident cases and 155,084 controls: prospective study and meta-analysis. PLoS Med 2005;2 (3) e76
PubMed Link to Article
Forman  JPChoi  HCurhan  GC Plasma uric acid level and risk for incident hypertension among men. J Am Soc Nephrol 2007;18 (1) 287- 292
PubMed Link to Article
Ware  JH The limitations of risk factors as prognostic tools. N Engl J Med 2006;355 (25) 2615- 2617
PubMed Link to Article

Correspondence

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