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Original Contribution |

Urate as a Predictor of the Rate of Clinical Decline in Parkinson Disease FREE

Alberto Ascherio, MD, DrPH; Peter A. LeWitt, MD; Kui Xu, MD, PhD; Shirley Eberly, MS; Arthur Watts, BS; Wayne R. Matson, PhD; Connie Marras, MD; Karl Kieburtz, MD; Alice Rudolph, PhD; Mikhail B. Bogdanov, PhD; Steven R. Schwid, MD; Marsha Tennis, RN; Caroline M. Tanner, MD, PhD; M. Flint Beal, MD; Anthony E. Lang, MD; David Oakes, PhD; Stanley Fahn, MD; Ira Shoulson, MD; Michael A. Schwarzschild, MD, PhD; Parkinson Study Group DATATOP Investigators
[+] Author Affiliations

Author Affiliations: Departments of Nutrition and Epidemiology, Harvard School of Public Health (Dr Ascherio), Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School (Dr Ascherio), and Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital (Drs Xu and Schwarzschild and Ms Tennis), Boston, and Bedford Veterans Administration Medical Center, Bedford (Drs Matson and Bogdanov); Department of Neurology, Henry Ford Hospital and Wayne State University School of Medicine, Detroit, Michigan (Dr LeWitt); Departments of Biostatistics (Ms Eberly, Mr Watts, and Dr Oakes) and Neurology (Drs Kieburtz, Rudolph, Schwid, and Shoulson), University of Rochester, Rochester, and Department of Neurology and Neuroscience, Cornell University (Dr Beal) and Department of Neurology, Columbia University (Dr Fahn), New York, New York; The Morton and Gloria Shulman Movement Disorders Centre, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada (Drs Marras and Lang); and Department of Clinical Research, Parkinson's Institute, Sunnyvale, California (Dr Tanner). †Deceased.Group Information: A list of the Parkinson Study Group DATATOP Investigators was published in N Engl J Med. 1993;328(3):176-183.


Arch Neurol. 2009;66(12):1460-1468. doi:10.1001/archneurol.2009.247.
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Published online

Background  The risk of Parkinson disease (PD) and its rate of progression may decline with increasing concentration of blood urate, a major antioxidant.

Objective  To determine whether serum and cerebrospinal fluid concentrations of urate predict clinical progression in patients with PD.

Design, Setting, and Participants  Eight hundred subjects with early PD enrolled in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial. The pretreatment urate concentration was measured in serum for 774 subjects and in cerebrospinal fluid for 713 subjects.

Main Outcome Measures  Treatment-, age-, and sex-adjusted hazard ratios (HRs) for clinical disability requiring levodopa therapy, the prespecified primary end point of the original DATATOP trial.

Results  The HR of progressing to the primary end point decreased with increasing serum urate concentrations (HR for highest vs lowest quintile = 0.64; 95% confidence interval [CI], 0.44-0.94; HR for a 1-SD increase = 0.82; 95% CI, 0.73-0.93). In analyses stratified by α-tocopherol treatment (2000 IU/d), a decrease in the HR for the primary end point was seen only among subjects not treated with α-tocopherol (HR for a 1-SD increase = 0.75; 95% CI, 0.62-0.89; vs HR for those treated = 0.90; 95% CI, 0.75-1.08). Results were similar for the rate of change in the Unified Parkinson's Disease Rating Scale score. Cerebrospinal fluid urate concentration was also inversely related to both the primary end point (HR for highest vs lowest quintile = 0.65; 95% CI, 0.44-0.96; HR for a 1-SD increase = 0.89; 95% CI, 0.79-1.02) and the rate of change in the Unified Parkinson's Disease Rating Scale score. As with serum urate concentration, these associations were present only among subjects not treated with α-tocopherol.

Conclusions  Higher serum and cerebrospinal fluid urate concentrations at baseline were associated with slower rates of clinical decline. The findings strengthen the link between urate concentration and PD and the rationale for considering central nervous system urate concentration elevation as a potential strategy to slow PD progression.Published online October 12, 2009 (doi:10.1001/archneurol.2009.247).

Figures in this Article

In humans, urate is a major antioxidant as well as the end product of purine metabolism.1,2 Its high concentrations in cerebrospinal fluid (CSF) and blood have been attributed to a mutation in the urate oxidase gene occurring late in hominid evolution.3 Oxidative damage is suspected to contribute to the neurodegenerative process in Parkinson disease (PD),4,5 and antioxidants like urate may provide an endogenous defense against the development and progression of PD.

Prospective epidemiological studies have demonstrated that healthy individuals with higher blood urate concentrations are at reduced risk for developing PD.69 Similarly, a lower risk of PD has also been reported among individuals consuming diets that increase serum urate concentration10 and among those with a history of gout.11,12 Recently, we found that higher urate blood concentrations in patients in the early stages of PD predict a slower rate of disease progression, assessed by both clinical and neuroimaging measures.13 These studies suggest that urate concentration measured systemically may serve as a robust predictor of the brain neurodegeneration that leads to the initiation and progression of PD.

The studies also raise the possibility that central nervous system urate directly protects against the neuronal degeneration underlying clinical deterioration in PD. Cerebrospinal fluid may more closely reflect the microenvironment of degenerating neurons than does blood.14 Accordingly, we used the clinical database from a completed multicenter, randomized, placebo-controlled trial (the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism [DATATOP] trial)15,16 to test the hypothesis that higher urate concentrations in both CSF and blood specimens from patients with PD predict a slower rate of clinical disease progression.

STUDY DESIGN

The DATATOP study was a 2-year, double-blind, randomized trial originally designed to test the hypothesis that long-term treatment of early PD with the monoamine oxidase type B inhibitor deprenyl (selegiline hydrochloride) and/or the antioxidant α-tocopherol would extend the time until the emergence of disability requiring therapy with levodopa.15 The 800 participants were enrolled between September 1987 and November 1988 at 28 sites across the United States and Canada.

STUDY POPULATION

Subjects enrolled in the study had typical and early PD (Hoehn and Yahr stages 1 and 2) of less than 5 years' duration and were excluded if they used symptomatic PD medication or had severe tremor, serious dementia (Mini-Mental State Examination score ≤22), or depression (Hamilton Scale for Depression score ≥16). Subjects were reviewed and examined by neurologists who were PD specialists. After baseline evaluation, study participants were randomized according to a 2 × 2 factorial design to 1 of 4 treatment assignments: deprenyl (10 mg/d) and α-tocopherol placebo, α-tocopherol (2000 IU/d) and deprenyl placebo, active deprenyl and active α-tocopherol, or double placebo.17

SERUM AND CSF URATE CONCENTRATIONS AND COVARIATES

Urate concentration was measured in serum samples collected at the baseline visit prior to treatment assignment. Serum was shipped without freezing to a central commercial clinical laboratory (SciCor, Indianapolis, Indiana) for immediate enzymatic assay of urate concentrations, which were available for 774 of the 800 enrolled subjects. Values maintained in a digitized database were not analyzed with respect to disease progression outcome measures until their retrieval in May 2006 specifically for this purpose.

Cerebrospinal fluid was collected at baseline after overnight bed rest from 730 subjects (ie, 91.2% of enrollees, with technical difficulties in performing lumbar punctures precluding the collection from the others)18 and at the end of the study in 486 subjects. Specimens were rapidly frozen for storage at −70°C after first splitting all CSF collection tubes into aliquots with or without metabisulfite preservative added.18 Baseline and final CSF urate concentrations were measured in 1991 by high-performance liquid chromatography with electrochemical detection from collection tubes containing the 18th to 20th milliliter of lumbar CSF flow in 2 selected subsets totaling 290 subjects who had provided both baseline and final CSF collections.19 The values of CSF urate concentrations at baseline correlated well with those at the end of treatment or follow-up in both subsets (Spearman coefficient = 0.69; P < .001), a result that supports the reproducibility of the assay as well as relatively stable within-person CSF urate concentrations. For the present analyses, in 2008 we obtained CSF aliquots from the same collection tubes (containing no metabisulfite preservative) and repeated the measurement of urate concentrations by high-performance liquid chromatography with electrochemical detection. For these assays, 50μM α-methyldopa served as an internal standard. Baseline CSF urate concentrations could be determined in 713 participants (ie, 97.7% of those from whom a baseline CSF sample was obtained and stored). Although mean CSF urate concentrations were lower than those measured in 1991, a good correlation was found between original urate concentrations and those measured in 2008 among the 277 individuals in both sets (Spearman coefficient = 0.72; P < .001). Furthermore, baseline serum urate concentrations correlated more strongly with baseline CSF urate concentrations measured in 2008 (r = 0.73) than in 1991 (r = 0.58). These results provide evidence of the stability of urate in these samples and of the accuracy of CSF urate concentration measurements.

CLINICAL EVALUATION AND OUTCOMES

Following the baseline visit and initiation of study drugs, subjects were scheduled for visits every 3 months until 24 months had elapsed.17 At each visit the site investigator evaluated the subject for disability sufficient to require dopaminergic therapy, the primary end point for the study, and for the secondary response variables, including the Unified Parkinson's Disease Rating Scale (UPDRS) score (sum of the motor, cognitive, and activity of daily living subscale scores).17 Because the UPDRS score is modified by the dopaminergic treatment instituted at the primary end point, the annualized rate of change in the UPDRS score was determined based on change from baseline to the primary end point (or the final visit if the primary end point was not reached) for each subject and was calculated as follows: [(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 d/y. The vital status and date of death of participants in the DATATOP trial were collected in 2001 to 2002 as previously described.20 The shortest time elapsed between enrollment and vital status update was 13 years. Information was available for 768 subjects with baseline serum urate concentration measurement.

STATISTICAL ANALYSIS

In the original trial, the hazard ratios (HRs) for the primary end point were 0.50 (95% confidence interval [CI], 0.41-0.62) among patients assigned to deprenyl and 0.91 (95% CI, 0.74-1.12) among patients assigned to α-tocopherol.17 Accordingly, all of the analyses were adjusted for assignment to deprenyl vs placebo.

Cox proportional hazards models were used to estimate the HRs of reaching the primary end point according to quintiles of baseline serum urate concentration, adjusting for sex, age (in 5-year groups), and treatment assignment (deprenyl vs placebo). Initial analyses were conducted using quintiles based on the combined urate concentration distribution in men and women. However, because this categorization resulted in a markedly skewed distribution within sex as expected, we also conducted analyses based on sex-specific quintiles. Tests for trend were conducted by including serum urate concentration as a continuous variable in the proportional hazards models. Potential confounding was assessed by adjusting the regression analyses for body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) and use of antihypertensive drugs or nonsteroidal anti-inflammatory drugs (use vs no use). With the exception of BMI, these adjustments did not affect the results. Therefore, only the treatment-, age-, and sex-adjusted results or the treatment-, age-, sex-, and BMI-adjusted results are presented. Possible interactions were explored by including the cross-product of serum urate concentration (continuous variable) with age (continuous in years), sex, or deprenyl and α-tocopherol treatments in the proportional hazards model. No interaction terms were significant, and only results that do not include these terms are reported. The results of these exploratory analyses, however, suggested a possible interaction between α-tocopherol treatment and serum urate concentration. Because both α-tocopherol and urate have antioxidant properties, this interaction has some biological plausibility. This interaction was examined further by estimating the HRs for the primary outcome in groups of subjects classified according to both their serum urate concentration and treatment group. The relationship between serum urate concentration and rate of change in the UPDRS score (between baseline and the last visit before reaching the primary end point) was assessed by linear regression with adjustment for treatment, age, and sex using both common quintiles of serum urate concentration and sex-specific quintiles. This analysis was complemented by a repeated-measures analysis using all available UPDRS score determinations. This analysis was conducted by fitting a linear mixed model with random intercept and slope and fixed effects for treatment, age, sex, urate concentration, and the interaction between urate concentration and α-tocopherol treatment. The association between serum urate concentration and time from study enrollment until death was investigated using Cox proportional hazards models adjusted for treatment, age, sex, and smoking history (pack-years), with or without further adjustment for cardiac morbidity at baseline. Analyses for CSF urate concentration were conducted in the same manner.

SERUM URATE CONCENTRATION

Serum urate concentration at baseline was available for 774 of the 800 subjects (96.8%; 510 men and 264 women) enrolled in the trial. Selected characteristics of these subjects are shown in Table 1. As expected, serum urate concentrations correlated positively with being male, BMI, use of thiazide diuretics, and hypertension. Use of calcium channel blockers was reported by only 17 patients and showed no relationship to serum urate concentration.

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

Overall, 369 (47.7%) of these participants progressed to disability sufficient to require levodopa therapy during follow-up. The HR of reaching this primary end point declined with increasing concentrations of serum urate (P for trend = .002) and was 36% lower among subjects in the top quintile as compared with those in the bottom quintile of serum urate concentration (HR = 0.64; 95% CI, 0.44-0.94) (Table 2). This association was stronger in men than in women, although a test for interaction of urate concentration with sex was not significant (P = .54). Further, in both sexes, the HR for reaching the primary end point decreased with increasing BMI (P for trend = .05 in men, P for trend = .02 in women). After adjustment for BMI, the association between serum urate concentration and the primary clinical end point was partially attenuated; the HRs for a 1-SD increase in serum urate concentration were 0.89 in all subjects (P = .07), 0.85 in men (P = .04), and 1.01 in women (P = .94).

Table Graphic Jump LocationTable 2. Hazard Ratios for Reaching the Primary End Point According to Common Quintiles of Baseline Serum Urate Concentration or Corresponding to a 1-SD Increase in Serum Urate Concentrationa

When subjects were classified simultaneously according to serum urate concentration and α-tocopherol treatment, a decreasing HR for reaching the primary end point with increasing serum urate concentration was observed among untreated subjects (HR = 0.75; 95% CI, 0.62-0.89; P = .001) but not among those treated (HR = 0.90; 95% CI, 0.75-1.08; P = .24), consistent with comparisons of baseline urate concentration quintiles (Figure 1A) and unadjusted Kaplan-Meier analyses (eFigure) in subgroups without or with α-tocopherol treatment. Conversely, randomization to α-tocopherol treatment appeared to lower the HR of reaching the primary end point among subjects in the lowest quintile of serum urate concentration (HR = 0.59; 95% CI, 0.36-0.97) but not among those with a higher serum urate concentration (Figure 1A). Further analyses were conducted within sex. In men, the HRs for a 1-SD increase in serum urate concentration were 0.74 (95% CI, 0.59-0.92; P = .008) among subjects not receiving α-tocopherol and 0.88 (95% CI, 0.71-1.08; P = .21) among subjects receiving α-tocopherol. In women, the corresponding HRs were 0.73 (95% CI, 0.52-1.02; P = .06) for subjects not receiving α-tocopherol and 1.04 (95% CI, 0.69-1.59; P = .84) for subjects receiving α-tocopherol. The interaction between α-tocopherol and serum urate concentration was nonsignificant for men and for women (P for interaction = .55 in men, and P for interaction = .06 in women). No significant interaction was found between serum urate concentration and deprenyl treatment; a decreasing HR with increasing serum urate concentration was found in the placebo-placebo and deprenyl-placebo groups but not in the placebo–α-tocopherol and deprenyl–α-tocopherol groups (eTable 1).

Place holder to copy figure label and caption
Figure 1.

Hazard ratio for reaching the primary end point according to assignment to α-tocopherol (vitamin E) and quintile of baseline serum (A) or cerebrospinal fluid (CSF) (B) urate concentration (referenced to placebo-treated subjects in the lowest quintile). Error bars indicate 95% confidence intervals for hazard ratios adjusted for age, sex, and treatment group (deprenyl or placebo).

Graphic Jump Location

The change in UPDRS score between baseline and either the time of reaching the primary end point or the end of follow-up was available for 760 of the 774 subjects with baseline serum urate concentrations. Overall, the rate of UPDRS score change declined with increasing serum urate concentration (P for trend = .03). As observed previously for the primary end point, results were more robust in men, although there was no statistically significant interaction with sex. Among men, the adjusted rate of UPDRS score change declined from 14.8 points per year for subjects in the lowest quintile of serum urate concentration to 8.9 points per year for those in the highest quintile (P for trend = .03); comparable results among women were 11.0 and 8.2 points per year, respectively (P for trend = .35). The relationship between serum urate concentration and the rate of UPDRS score change was modified by α-tocopherol treatment (P for interaction = .009) (Figure 2A). In separate models, among subjects not assigned to receive α-tocopherol, the rate of UPDRS score change was 9.8 points per year lower in the highest serum urate concentration quintile than in the lowest quintile (P = .003), whereas no difference was observed for subjects assigned to receive α-tocopherol (0.5 points per year higher in the highest quintile as compared with the lowest quintile; P = .89). In analyses based on repeated measures, the overall association between higher urate levels at baseline and a slower rate of UPDRS score increase was even stronger (P = .001). There was also a significant interaction between urate concentration and α-tocopherol treatment (P = .003), and consistent with results observed in the primary analyses, higher levels of serum urate were strongly associated with a slower rate of UPDRS score increase among patients not treated with α-tocopherol (P = .001) but not in those treated with α-tocopherol (P = .37). No significant interaction was found between serum urate concentration and deprenyl treatment (eTable 2).

Place holder to copy figure label and caption
Figure 2.

Mean annualized rate of Unified Parkinson's Disease Rating Scale (UPDRS) score change according to assignment to α-tocopherol (vitamin E) and quintile of baseline serum (A) or cerebrospinal fluid (CSF) (B) urate concentration. Error bars indicate standard errors of the mean adjusted for age, sex, and treatment group (deprenyl or placebo). *Significantly different from the placebo-treated subjects in the lowest quintile (P < .001). †Significantly different from the placebo-treated subjects in the lowest quintile (P < .01). ‡Significantly different from the placebo-treated subjects in the lowest quintile (P < .05).

Graphic Jump Location

Two hundred eleven men (41.4%) and 81 women (30.7%) were identified as having died after 13 years of follow-up. In men and women combined, after adjustment for deprenyl treatment, age, sex, and pack-years of smoking (Table 3) and after adjustment for deprenyl treatment, age, sex, pack-years of smoking, and cardiac comorbidity at baseline (Table 4), serum urate concentration was not significantly associated with mortality. In men, however, the relationship between serum urate concentration and mortality was a U-shaped curve, with the lowest mortality in the fourth quintile of urate concentration. In women, a suggestion of increased mortality at any urate concentration higher than that in the lowest quintile was not substantiated statistically. No significant interactions between serum urate concentration and α-tocopherol were found in analyses on mortality.

Table Graphic Jump LocationTable 3. Hazard Ratios for Death From Any Cause According to Common Quintiles of Baseline Serum Urate Concentration, Adjusted for Age, Sex, Treatment Group (Deprenyl or Placebo), and Pack-years of Smoking
Table Graphic Jump LocationTable 4. Hazard Ratios for Death From Any Cause According to Common Quintiles of Baseline Serum Urate Concentration, Adjusted for Age, Sex, Treatment Group (Deprenyl or Placebo), Pack-years of Smoking, and Cardiac Comorbidity at Baseline
CSF URATE CONCENTRATION

Mean urate concentrations in CSF collected at baseline were higher in men (0.42 mg/dL) than in women (0.28 mg/dL) and, as expected, were substantially lower than in serum.21 Despite the lower concentrations of CSF urate, a strong correlation was found between CSF and serum urate concentrations (r = 0.73; P < .001).

The primary clinical end point of disability was reached by 342 of the 713 subjects (48%) for whom CSF urate concentrations were available. Overall, the HR of reaching the primary end point of disability was significantly lower among individuals with higher concentrations of CSF urate. The HR comparing subjects in the highest quintile of CSF urate concentration with those in the lowest quintile was 0.65 (95% CI, 0.44-0.96; P = .03); the HR associated with a 1-SD increase in CSF urate concentration was 0.89 (95% CI, 0.79-1.02; P = .09) (Table 5). Results were not significantly different by sex, although a strong interaction was found between α-tocopherol assignment and CSF urate concentration (P for interaction = .009) (Figure 1B). As for serum urate concentration, a significant decrease in the HRs for the primary end point with increasing CSF urate concentration was observed only among subjects not receiving α-tocopherol. The HR corresponding to a 1-SD increase in CSF urate concentration was 0.77 (95% CI, 0.62-0.96; P = .02) among men not treated with α-tocopherol and 1.10 (95% CI, 0.90-1.34; P = .34) among those receiving α-tocopherol. In women, the corresponding HRs were 0.64 (95% CI, 0.40-1.03; P = .07) for subjects not assigned to α-tocopherol and 0.77 (95% CI, 0.43-1.37; P = .37) for subjects treated with α-tocopherol. No significant interaction was found between CSF urate concentration and deprenyl treatment (eTable 3).

Table Graphic Jump LocationTable 5. Hazard Ratios for Reaching the Primary End Point According to Common Quintiles of Baseline Cerebrospinal Fluid Urate Concentration or Corresponding to a 1-SD Increase in Cerebrospinal Fluid Urate Concentrationa

The change in UPDRS score between baseline and either the time of reaching the primary end point or the end of follow-up was available for 702 of the 713 subjects with baseline CSF urate concentrations. Overall, the rate of UPDRS score change was not related significantly to CSF urate concentration. As observed for serum urate concentration, however, the relationship between CSF urate concentration and the rate of UPDRS score change was modified by α-tocopherol treatment (P for interaction = .04) (Figure 2B). Among subjects not treated with α-tocopherol, the rate of UPDRS score change declined with increasing CSF urate concentrations (P for trend = .05). Conversely, randomization to α-tocopherol treatment appeared to lower the rate of UPDRS score change among subjects in the lowest quintile of urate concentration measured either in CSF (Figure 2B) or in serum (Figure 2A) but not among those with higher urate concentrations. No significant interaction was found between CSF urate concentration and deprenyl treatment (eTable 4).

Among subjects with early PD participating in a large randomized trial, we found that both serum and CSF urate concentrations measured at baseline were inversely related to clinical progression of PD. The internal consistency of the results across the primary and secondary end points supports their validity. These findings, like data from a similar early PD trial (the Parkinson Research Examination of CEP-1347 Trial [PRECEPT] study),13 demonstrate a robust link between blood urate concentrations and the rate of clinical progression in PD. In addition, the association of CSF urate concentration with disease progression strengthens the possibility that brain urate concentration (or its determinants) might protect against the neurodegeneration of PD. Taken together, these data establish urate as the first molecular predictor of clinical progression in PD and provide a rationale for investigating the possibility that a therapeutic increase of urate in patients with PD might act favorably to slow the disease course. Interestingly, the inverse relationship between urate concentration and clinical progression was not observed among patients randomized to α-tocopherol at a dosage of 2000 IU/d, suggesting that there may be an interaction between these antioxidants.

There is strong evidence that oxidative stress and nitrative stress are major pathogenetic mechanisms in PD.13,22,23 Urate is an effective antioxidant,1 peroxynitrite scavenger,2427 iron chelator,28 and ascorbate stabilizer.29 In cellular models of PD neurodegeneration, urate can reduce oxidative stress, mitochondrial dysfunction, and cell death occurring spontaneously in culture or induced by the pesticide rotenone, 1-methyl-4-phenylpyridinium, glutamate, and iron ions.3032 Although urate appears to have the potential for neuroprotection, it is possible that the predictive association between urate concentration and PD progression reflects instead the effect of a urate precursor, such as adenosine or inosine, or another determinant of systemic and CSF urate concentrations.

As compared with serum urate concentration, the weaker association of CSF urate concentration to clinical progression of PD may seem at odds with the hypothesis that urate (or its metabolic precursors) exerts a beneficial effect through presence in the central nervous system. The CSF urate concentrations, however, display a strong caudorostral gradient from the lumbar space, with lumbar region values approximately 50% higher than those arising at the cisterna magna (brainstem) level.33,34 Although we consistently used CSF aliquots obtained from the 18th to 20th milliliter of CSF flow, variations in CSF circulation patterns between patients35—along with freezer storage for 20 years—may have contributed to a reduction of the accuracy of this measure compared with assays of freshly collected serum samples. In addition to technical variability, substantial biological differences between the urate in CSF sampled from the subarachnoid space and that in the degenerating neurons themselves may lessen the strength of a CSF urate concentration–clinical progression correlation in PD.

The finding that the inverse relationship between urate concentration and clinical progression of PD was modified by α-tocopherol treatment was unforeseen because, as originally reported, no favorable effect of α-tocopherol on PD progression was found among study participants in the DATATOP trial.16 The mechanisms for a possible interaction between urate and α-tocopherol remain uncertain. Although hydrophilic (eg, urate) and hydrophobic (eg, α-tocopherol) antioxidants target different subcellular compartments, their functional interactions have been described.36,37 Further, α-tocopherol at doses commonly used in vitamin supplements may reduce concentrations of other endogenous antioxidants,38,39 and α-tocopherol at high doses may have pro-oxidant rather than antioxidant effects.40,41 Alternatively, a simple competitive interaction or “ceiling effect” may have contributed to the observed lack of α-tocopherol benefits among patients with PD with higher urate concentrations as well as to the loss of the inverse association between urate concentration and PD progression among those receiving supplemental α-tocopherol. Regardless of the mechanism for a possible interaction between α-tocopherol and urate, our results raise the possibility that such an interaction may have obscured a protective effect of α-tocopherol among those subjects with low baseline concentrations of urate in the DATATOP trial. Further investigations are therefore needed to consider the possibility that α-tocopherol supplementation may be beneficial in individuals with low urate concentrations.

Serum urate may also affect the progression of cognitive impairment in that higher concentrations seem to be associated with slower rates of cognitive decline and lower risk of dementia.4244 As in the present study, among participants in a randomized trial, this association was observed in patients treated with placebo but not in those treated with α-tocopherol.43 Higher serum urate concentration has also been linked to a lower rate of worsening in Huntington disease.45 Although each of these neurodegenerative disorders manifests differently from PD, the relationships between urate concentration and these disorders may be indicative of a more general influence of urate (or its precursors) on neuronal cell death.

The main results of this study are strikingly consistent with those recently reported from the PRECEPT study.13 Although the overall inverse relationship between serum urate concentration and the clinical progression of PD was greater in the PRECEPT study than in the DATATOP study, results among subjects in the DATATOP study not assigned to α-tocopherol were virtually identical to those observed in the PRECEPT study (which did not include an α-tocopherol treatment arm). In both trials, HRs for risk of disability progression showed a decline in patients whose values were higher than the median concentration but still within the normal range of serum urate concentrations. Moreover, in both trials, the concentration-dependent inverse relationship was robust in men but weak and nonsignificant among women. This consistent difference between men and women could result in part from a biological effect of sex on urate mechanisms in PD46 or could simply reflect the small number of women with urate concentrations high enough to slow disease progression if urate were protective.

A potentially therapeutic effect of elevating serum urate concentration warrants consideration. Urate levels can be elevated by dietary means, including increased intake of fructose4749 or purines,50 or by pharmacological means. The latter may include administration of the purine metabolite and urate precursor inosine, which is being investigated as a therapy for multiple sclerosis.26,27 The potential benefit of elevating urate concentration in individuals with PD, however, has to be weighed against possible adverse effects, which may include an increased risk of hypertension, coronary heart disease, and stroke6,5153 in addition to the known risks of gout and urolithiasis. Available data are therefore insufficient to support a therapeutic recommendation.

The discovery of a urate link to PD progression was achieved through additional analyses of 2 rigorously conducted clinical trials whose databases were made available to test an unforeseen hypothesis months54 or decades18,19 after conclusion of the primary investigations. These latent insights highlight a broader opportunity to achieve further advances through explorations of the growing repository of high-quality data collected from neuroprotection trials of PD and other neurodegenerative disorders.

Correspondence: Michael A. Schwarzschild, MD, PhD, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, 114 16th St, Boston, MA 02129 (michaels@helix.mgh.harvard.edu).

Accepted for Publication: May 27, 2009.

Published Online: October 12, 2009 (doi:10.1001/archneurol.2009.247).

Author Contributions: Dr Schwarzschild had full access to all of 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: Ascherio, Kieburtz, Shoulson, and Schwarzschild. Acquisition of data: LeWitt, Xu, Matson, Marras, Rudolph, Schwid, Tennis, Tanner, Beal, Lang, Fahn, Shoulson, and Schwarzschild. Analysis and interpretation of data: Ascherio, LeWitt, Xu, Eberly, Watts, Marras, Kieburtz, Bogdanov, Tennis, Tanner, Lang, Oakes, Fahn, Shoulson, and Schwarzschild. Drafting of the manuscript: LeWitt, Oakes, and Schwarzschild. Critical revision of the manuscript for important intellectual content: Ascherio, LeWitt, Xu, Eberly, Watts, Matson, Marras, Kieburtz, Rudolph, Bogdanov, Tennis, Tanner, Beal, Lang, Oakes, Fahn, Shoulson, and Schwarzschild. Statistical analysis: Eberly and Oakes. Obtained funding: Ascherio, LeWitt, Shoulson, and Schwarzschild. Administrative, technical, and material support: LeWitt, Xu, Watts, Matson, Kieburtz, Rudolph, Schwid, Fahn, Shoulson, and Schwarzschild. Study supervision: Beal and Schwarzschild.

Financial Disclosure: Dr LeWitt reports receiving lecture fees from Allergan, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Schwarz Pharma (now UCB), Solstice Neurosciences, and Vernalis (now Ipsen), consulting fees from Asubio Pharmaceuticals, Boehringer Ingelheim, Brittania Pharmaceuticals, Eisai, Neurologix, Novartis, Orion, Prestwick Pharmaceuticals (now Biovail), Santhera Pharmaceuticals, Schering-Plough, Schwarz Pharma, Solvay, Spherics, Supernus Pharmaceuticals, Valeant Pharmaceuticals International, Vernalis, and XenoPort, and grant support from Boehringer Ingelheim, Chelsea Therapeutics, Novartis, Santhera Pharmaceuticals, Schering-Plough, and Schwarz Pharma.

Funding/Support: This work was supported by grants NS24778, NS27892, NS048517, NS054978, and NS060991 from the National Institutes of Health, by grant W81XWH-04-1-0881 from the US Department of Defense, and by the RJG Foundation, the Beeson Scholars/Hartford Collaborative Research program of the American Federation for Aging Research, and a data-mining research award from the Parkinson Disease Foundation and the Parkinson Study Group.

Role of the Sponsors: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Additional Contributions: Eilis O’Reilly, ScD, conducted an expert secondary review of statistical programs and reported results, Andrew McAleavey, AB, provided excellent technical assistance in neurochemical analyses, and Leslie Unger, BA, provided technical assistance in preparing the manuscript.

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
Alho  HLeinonen  JSErhola  MLonnrot  KAejmelaeus  R Assay of antioxidant capacity of human plasma and CSF in aging and disease. Restor Neurol Neurosci 1998;12 (2-3) 159- 165
PubMed
Johnson  RJTitte  SCade  JRRideout  BAOliver  WJ Uric acid, evolution and primitive cultures. Semin Nephrol 2005;25 (1) 3- 8
PubMed
Burkhardt  CRWeber  HK Parkinson's disease: a chronic, low-grade antioxidant deficiency? Med Hypotheses 1994;43 (2) 111- 114
PubMed
Beal  MF Mitochondria take center stage in aging and neurodegeneration. Ann Neurol 2005;58 (4) 495- 505
PubMed
Davis  JWGrandinetti  AWaslien  CIRoss  GWWhite  LRMorens  DM Observations on serum uric acid levels and the risk of idiopathic Parkinson's disease. Am J Epidemiol 1996;144 (5) 480- 484
PubMed
de Lau  LMKoudstaal  PJHofman  ABreteler  MM Serum uric acid levels and the risk of Parkinson disease. Ann Neurol 2005;58 (5) 797- 800
PubMed
Weisskopf  MGO'Reilly  EChen  HSchwarzschild  MAAscherio  A Plasma urate and risk of Parkinson's disease. Am J Epidemiol 2007;166 (5) 561- 567
PubMed
Chen  HMosley  THAlonso  AHuang  X Plasma urate and Parkinson's disease in the Atherosclerosis Risk in Communities (ARIC) study. Am J Epidemiol 2009;169 (9) 1064- 1069
PubMed
Gao  XChen  HChoi  HKCurhan  GSchwarzschild  MAAscherio  A Diet, urate, and Parkinson's disease risk in men. Am J Epidemiol 2008;167 (7) 831- 838
PubMed
Alonso  ARodriguez  LALogroscino  GHernan  MA Gout and risk of Parkinson disease: a prospective study. Neurology 2007;69 (17) 1696- 1700
PubMed
De Vera  MRahman  MMRankin  JKopec  JGao  XChoi  H Gout and the risk of Parkinson's disease: a cohort study. Arthritis Rheum 2008;59 (11) 1549- 1554
PubMed
Schwarzschild  MASchwid  SRMarek  K  et al. Parkinson Study Group PRECEPT Investigators, Serum urate as a predictor of clinical and radiographic progression in Parkinson's disease. Arch Neurol 2008;65 (6) 716- 723
PubMed
Blennow  K Cerebrospinal fluid protein biomarkers for Alzheimer's disease. NeuroRx 2004;1 (2) 213- 225
PubMed
Parkinson Study Group, DATATOP: a multicenter controlled clinical trial in early Parkinson's disease. Arch Neurol 1989;46 (10) 1052- 1060
PubMed
Parkinson Study Group, Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. N Engl J Med 1993;328 (3) 176- 183
PubMed
Parkinson Study Group, Effect of deprenyl on the progression of disability in early Parkinson's disease. N Engl J Med 1989;321 (20) 1364- 1371
PubMed
Parkinson Study Group, Cerebrospinal fluid homovanillic acid in the DATATOP study on Parkinson's disease. Arch Neurol 1995;52 (3) 237- 245
PubMed
LeWitt  PAGalloway  MPMatson  W  et al. Parkinson Study Group, Markers of dopamine metabolism in Parkinson's disease. Neurology 1992;42 (11) 2111- 2117
PubMed
Marras  CMcDermott  MPRochon  PA  et al. Parkinson Study Group, Survival in Parkinson disease: thirteen-year follow-up of the DATATOP cohort. Neurology 2005;64 (1) 87- 93
PubMed
Niklasson  FAgren  H Brain energy metabolism and blood-brain barrier permeability in depressive patients: analyses of creatine, creatinine, urate, and albumin in CSF and blood. Biol Psychiatry 1984;19 (8) 1183- 1206
PubMed
Moore  DJWest  ABDawson  VLDawson  TM Molecular pathophysiology of Parkinson's disease. Annu Rev Neurosci 2005;2857- 87
PubMed
Danielson  SRAndersen  JK Oxidative and nitrative protein modifications in Parkinson's disease. Free Radic Biol Med 2008;44 (10) 1787- 1794
PubMed
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
Whiteman  MKetsawatsakul  UHalliwell  B A reassessment of the peroxynitrite scavenging activity of uric acid. Ann N Y Acad Sci 2002;962242- 259
PubMed
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
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
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
Stocker  RFrei  B Endogenous antioxidant defences in human blood plasma. Sies  HOxidative Stress Oxidants and Antioxidants San Diego, CA Academic Press1991;213- 243
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
Haberman  FTang  SCArumugam  TV  et al.  Soluble neuroprotective antioxidant uric acid analogs ameliorate ischemic brain injury in mice. Neuromolecular Med 2007;9 (4) 315- 323
PubMed
Guerreiro  SPonceau  AToulorge  D  et al.  Protection of midbrain dopaminergic neurons by the end-product of purine metabolism uric acid: potentiation by low-level depolarization. J Neurochem 2009;109 (4) 1118- 1128
PubMed
Niklasson  FHetta  JDegrell  I Hypoxanthine, xanthine, urate and creatinine concentration gradients in cerebrospinal fluid. Ups J Med Sci 1988;93 (3) 225- 232
PubMed
Degrell  INagy  E Concentration gradients for HVA, 5-HIAA, ascorbic acid, and uric acid in cerebrospinal fluid. Biol Psychiatry 1990;27 (8) 891- 896
PubMed
Quencer  RMPost  MJHinks  RS Cine MR in the evaluation of normal and abnormal CSF flow: intracranial and intraspinal studies. Neuroradiology 1990;32 (5) 371- 391
PubMed
Yeum  KJRussell  RMKrinsky  NIAldini  G Biomarkers of antioxidant capacity in the hydrophilic and lipophilic compartments of human plasma. Arch Biochem Biophys 2004;430 (1) 97- 103
PubMed
Niki  ENoguchi  NTsuchihashi  HGotoh  N Interaction among vitamin C, vitamin E, and beta-carotene. Am J Clin Nutr 1995;62 (6) ((suppl)) 1322S- 1326S
PubMed
Jiang  QChristen  SShigenaga  MKAmes  BN Gamma-tocopherol, the major form of vitamin E in the US diet, deserves more attention. Am J Clin Nutr 2001;74 (6) 714- 722
PubMed
Huang  HYAppel  LJ Supplementation of diets with alpha-tocopherol reduces serum concentrations of gamma- and delta-tocopherol in humans. J Nutr 2003;133 (10) 3137- 3140
PubMed
Bowry  VWStocker  R Tocopherol-mediated peroxidation: the prooxidant effect of vitamin E on the radical-initiated oxidation of human low-density lipoprotein. J Am Chem Soc 1993;115 (14) 6029- 604410.1021/ja00067a019
Abudu  NMiller  JJAttaelmannan  MLevinson  SS Vitamins in human arteriosclerosis with emphasis on vitamin C and vitamin E. Clin Chim Acta 2004;339 (1-2) 11- 25
PubMed
Petersen  RCThomas  RGGrundman  M  et al. Alzheimer's Disease Cooperative Study Group, Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005;352 (23) 2379- 2388
PubMed
Irizarry  MCRaman  RSchwarzschild  MA  et al.  Plasma urate and progression of mild cognitive impairment. Neurodegener Dis 2009;6 (1-2) 23- 28
PubMed
Euser  SMHofman  AWestendorp  RGBreteler  MM Serum uric acid and cognitive function and dementia. Brain 2009;132 (pt 2) 377- 382
PubMed
Auinger  PKieburtz  KMcDermott  MP The relationship between uric acid levels and Huntington's disease progression [abstract]. Mov Disord 2008;23 ((suppl 1)) S187
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
Hallfrisch  J Metabolic effects of dietary fructose. FASEB J 1990;4 (9) 2652- 2660
PubMed
Gao  XQi  LQiao  N  et al.  Intake of added sugar and sugar-sweetened drink and serum uric acid concentration in US men and women. Hypertension 2007;50 (2) 306- 312
PubMed
Choi  JWFord  ESGao  XChoi  HK Sugar-sweetened soft drinks, diet soft drinks, and serum uric acid level: the Third National Health and Nutrition Examination Survey. Arthritis Rheum 2008;59 (1) 109- 116
PubMed
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
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
Wheeler  JGJuzwishin  KDEiriksdottir  GGudnason  VDanesh  J Serum uric acid and coronary heart disease in 9458 incident cases and 155 084 controls: prospective study and meta-analysis. PLoS Med 2005;2 (3) e76
PubMed10.1371/journal.pmed.0020076
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
Parkinson Study Group PRECEPT Investigators, Mixed lineage kinase inhibitor CEP-1347 fails to delay disability in early Parkinson disease. Neurology 2007;69 (15) 1480- 1490
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Hazard ratio for reaching the primary end point according to assignment to α-tocopherol (vitamin E) and quintile of baseline serum (A) or cerebrospinal fluid (CSF) (B) urate concentration (referenced to placebo-treated subjects in the lowest quintile). Error bars indicate 95% confidence intervals for hazard ratios adjusted for age, sex, and treatment group (deprenyl or placebo).

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

Mean annualized rate of Unified Parkinson's Disease Rating Scale (UPDRS) score change according to assignment to α-tocopherol (vitamin E) and quintile of baseline serum (A) or cerebrospinal fluid (CSF) (B) urate concentration. Error bars indicate standard errors of the mean adjusted for age, sex, and treatment group (deprenyl or placebo). *Significantly different from the placebo-treated subjects in the lowest quintile (P < .001). †Significantly different from the placebo-treated subjects in the lowest quintile (P < .01). ‡Significantly different from the placebo-treated subjects in the lowest quintile (P < .05).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics of Study Participants According to Quintiles of Baseline Serum Urate Concentration
Table Graphic Jump LocationTable 2. Hazard Ratios for Reaching the Primary End Point According to Common Quintiles of Baseline Serum Urate Concentration or Corresponding to a 1-SD Increase in Serum Urate Concentrationa
Table Graphic Jump LocationTable 3. Hazard Ratios for Death From Any Cause According to Common Quintiles of Baseline Serum Urate Concentration, Adjusted for Age, Sex, Treatment Group (Deprenyl or Placebo), and Pack-years of Smoking
Table Graphic Jump LocationTable 4. Hazard Ratios for Death From Any Cause According to Common Quintiles of Baseline Serum Urate Concentration, Adjusted for Age, Sex, Treatment Group (Deprenyl or Placebo), Pack-years of Smoking, and Cardiac Comorbidity at Baseline
Table Graphic Jump LocationTable 5. Hazard Ratios for Reaching the Primary End Point According to Common Quintiles of Baseline Cerebrospinal Fluid Urate Concentration or Corresponding to a 1-SD Increase in Cerebrospinal Fluid Urate Concentrationa

References

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
Alho  HLeinonen  JSErhola  MLonnrot  KAejmelaeus  R Assay of antioxidant capacity of human plasma and CSF in aging and disease. Restor Neurol Neurosci 1998;12 (2-3) 159- 165
PubMed
Johnson  RJTitte  SCade  JRRideout  BAOliver  WJ Uric acid, evolution and primitive cultures. Semin Nephrol 2005;25 (1) 3- 8
PubMed
Burkhardt  CRWeber  HK Parkinson's disease: a chronic, low-grade antioxidant deficiency? Med Hypotheses 1994;43 (2) 111- 114
PubMed
Beal  MF Mitochondria take center stage in aging and neurodegeneration. Ann Neurol 2005;58 (4) 495- 505
PubMed
Davis  JWGrandinetti  AWaslien  CIRoss  GWWhite  LRMorens  DM Observations on serum uric acid levels and the risk of idiopathic Parkinson's disease. Am J Epidemiol 1996;144 (5) 480- 484
PubMed
de Lau  LMKoudstaal  PJHofman  ABreteler  MM Serum uric acid levels and the risk of Parkinson disease. Ann Neurol 2005;58 (5) 797- 800
PubMed
Weisskopf  MGO'Reilly  EChen  HSchwarzschild  MAAscherio  A Plasma urate and risk of Parkinson's disease. Am J Epidemiol 2007;166 (5) 561- 567
PubMed
Chen  HMosley  THAlonso  AHuang  X Plasma urate and Parkinson's disease in the Atherosclerosis Risk in Communities (ARIC) study. Am J Epidemiol 2009;169 (9) 1064- 1069
PubMed
Gao  XChen  HChoi  HKCurhan  GSchwarzschild  MAAscherio  A Diet, urate, and Parkinson's disease risk in men. Am J Epidemiol 2008;167 (7) 831- 838
PubMed
Alonso  ARodriguez  LALogroscino  GHernan  MA Gout and risk of Parkinson disease: a prospective study. Neurology 2007;69 (17) 1696- 1700
PubMed
De Vera  MRahman  MMRankin  JKopec  JGao  XChoi  H Gout and the risk of Parkinson's disease: a cohort study. Arthritis Rheum 2008;59 (11) 1549- 1554
PubMed
Schwarzschild  MASchwid  SRMarek  K  et al. Parkinson Study Group PRECEPT Investigators, Serum urate as a predictor of clinical and radiographic progression in Parkinson's disease. Arch Neurol 2008;65 (6) 716- 723
PubMed
Blennow  K Cerebrospinal fluid protein biomarkers for Alzheimer's disease. NeuroRx 2004;1 (2) 213- 225
PubMed
Parkinson Study Group, DATATOP: a multicenter controlled clinical trial in early Parkinson's disease. Arch Neurol 1989;46 (10) 1052- 1060
PubMed
Parkinson Study Group, Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. N Engl J Med 1993;328 (3) 176- 183
PubMed
Parkinson Study Group, Effect of deprenyl on the progression of disability in early Parkinson's disease. N Engl J Med 1989;321 (20) 1364- 1371
PubMed
Parkinson Study Group, Cerebrospinal fluid homovanillic acid in the DATATOP study on Parkinson's disease. Arch Neurol 1995;52 (3) 237- 245
PubMed
LeWitt  PAGalloway  MPMatson  W  et al. Parkinson Study Group, Markers of dopamine metabolism in Parkinson's disease. Neurology 1992;42 (11) 2111- 2117
PubMed
Marras  CMcDermott  MPRochon  PA  et al. Parkinson Study Group, Survival in Parkinson disease: thirteen-year follow-up of the DATATOP cohort. Neurology 2005;64 (1) 87- 93
PubMed
Niklasson  FAgren  H Brain energy metabolism and blood-brain barrier permeability in depressive patients: analyses of creatine, creatinine, urate, and albumin in CSF and blood. Biol Psychiatry 1984;19 (8) 1183- 1206
PubMed
Moore  DJWest  ABDawson  VLDawson  TM Molecular pathophysiology of Parkinson's disease. Annu Rev Neurosci 2005;2857- 87
PubMed
Danielson  SRAndersen  JK Oxidative and nitrative protein modifications in Parkinson's disease. Free Radic Biol Med 2008;44 (10) 1787- 1794
PubMed
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
Whiteman  MKetsawatsakul  UHalliwell  B A reassessment of the peroxynitrite scavenging activity of uric acid. Ann N Y Acad Sci 2002;962242- 259
PubMed
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
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
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
Stocker  RFrei  B Endogenous antioxidant defences in human blood plasma. Sies  HOxidative Stress Oxidants and Antioxidants San Diego, CA Academic Press1991;213- 243
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
Haberman  FTang  SCArumugam  TV  et al.  Soluble neuroprotective antioxidant uric acid analogs ameliorate ischemic brain injury in mice. Neuromolecular Med 2007;9 (4) 315- 323
PubMed
Guerreiro  SPonceau  AToulorge  D  et al.  Protection of midbrain dopaminergic neurons by the end-product of purine metabolism uric acid: potentiation by low-level depolarization. J Neurochem 2009;109 (4) 1118- 1128
PubMed
Niklasson  FHetta  JDegrell  I Hypoxanthine, xanthine, urate and creatinine concentration gradients in cerebrospinal fluid. Ups J Med Sci 1988;93 (3) 225- 232
PubMed
Degrell  INagy  E Concentration gradients for HVA, 5-HIAA, ascorbic acid, and uric acid in cerebrospinal fluid. Biol Psychiatry 1990;27 (8) 891- 896
PubMed
Quencer  RMPost  MJHinks  RS Cine MR in the evaluation of normal and abnormal CSF flow: intracranial and intraspinal studies. Neuroradiology 1990;32 (5) 371- 391
PubMed
Yeum  KJRussell  RMKrinsky  NIAldini  G Biomarkers of antioxidant capacity in the hydrophilic and lipophilic compartments of human plasma. Arch Biochem Biophys 2004;430 (1) 97- 103
PubMed
Niki  ENoguchi  NTsuchihashi  HGotoh  N Interaction among vitamin C, vitamin E, and beta-carotene. Am J Clin Nutr 1995;62 (6) ((suppl)) 1322S- 1326S
PubMed
Jiang  QChristen  SShigenaga  MKAmes  BN Gamma-tocopherol, the major form of vitamin E in the US diet, deserves more attention. Am J Clin Nutr 2001;74 (6) 714- 722
PubMed
Huang  HYAppel  LJ Supplementation of diets with alpha-tocopherol reduces serum concentrations of gamma- and delta-tocopherol in humans. J Nutr 2003;133 (10) 3137- 3140
PubMed
Bowry  VWStocker  R Tocopherol-mediated peroxidation: the prooxidant effect of vitamin E on the radical-initiated oxidation of human low-density lipoprotein. J Am Chem Soc 1993;115 (14) 6029- 604410.1021/ja00067a019
Abudu  NMiller  JJAttaelmannan  MLevinson  SS Vitamins in human arteriosclerosis with emphasis on vitamin C and vitamin E. Clin Chim Acta 2004;339 (1-2) 11- 25
PubMed
Petersen  RCThomas  RGGrundman  M  et al. Alzheimer's Disease Cooperative Study Group, Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005;352 (23) 2379- 2388
PubMed
Irizarry  MCRaman  RSchwarzschild  MA  et al.  Plasma urate and progression of mild cognitive impairment. Neurodegener Dis 2009;6 (1-2) 23- 28
PubMed
Euser  SMHofman  AWestendorp  RGBreteler  MM Serum uric acid and cognitive function and dementia. Brain 2009;132 (pt 2) 377- 382
PubMed
Auinger  PKieburtz  KMcDermott  MP The relationship between uric acid levels and Huntington's disease progression [abstract]. Mov Disord 2008;23 ((suppl 1)) S187
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
Hallfrisch  J Metabolic effects of dietary fructose. FASEB J 1990;4 (9) 2652- 2660
PubMed
Gao  XQi  LQiao  N  et al.  Intake of added sugar and sugar-sweetened drink and serum uric acid concentration in US men and women. Hypertension 2007;50 (2) 306- 312
PubMed
Choi  JWFord  ESGao  XChoi  HK Sugar-sweetened soft drinks, diet soft drinks, and serum uric acid level: the Third National Health and Nutrition Examination Survey. Arthritis Rheum 2008;59 (1) 109- 116
PubMed
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
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
Wheeler  JGJuzwishin  KDEiriksdottir  GGudnason  VDanesh  J Serum uric acid and coronary heart disease in 9458 incident cases and 155 084 controls: prospective study and meta-analysis. PLoS Med 2005;2 (3) e76
PubMed10.1371/journal.pmed.0020076
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
Parkinson Study Group PRECEPT Investigators, Mixed lineage kinase inhibitor CEP-1347 fails to delay disability in early Parkinson disease. Neurology 2007;69 (15) 1480- 1490
PubMed

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For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
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