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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Mov Disord. Author manuscript; available in PMC Aug 15, 2012.
Published in final edited form as:
PMCID: PMC3150627
NIHMSID: NIHMS280553
Serum urate and probability of dopaminergic deficit in early ‘Parkinson disease’
Michael A. Schwarzschild, M.D., Ph.D.,1 Kenneth Marek, M.D.,2 Shirley Eberly, M.S.,3 David Oakes, Ph.D.,3 Ira Shoulson, M.D.,3 Danna Jennings, MD,2 John Seibyl, MD,2 and Alberto Ascherio, M.D., Dr.P.H.4,5, on behalf of the Parkinson Study Group PRECEPT Investigators
1Department of Neurology, Massachusetts General Hospital, Boston, MA
2Institute for Neurodegenerative Disorders, New Haven, CT
3Departments of Neurology and Biostatistics, University of Rochester, Rochester, NY
4Departments of Epidemiology and Nutrition, Harvard School of Public Health
5Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
Corresponding Author: Alberto Ascherio, 655 Huntington Ave, 3rd Floor, Boston, MA 02115; aascheri/at/hsph.harvard.edu
Objective
Investigate whether higher levels of urate, an antioxidant linked to a lower likelihood of developing Parkinson disease (PD), is also a predictor of having a dopamine transporter brain scan without evidence of dopaminergic deficit (SWEDD).
Methods
In a cross-sectional study of 797 mildly affected, untreated parkinsonian subjects diagnosed with early PD in the Parkinson Research Examination of CEP-1347 Trial (PRECEPT), we investigated the relationship at baseline between serum urate and striatal dopamine transporter density, determined by single-photon emission computed-tomography of iodine-123-labeled 2-β-carboxymethoxy-3-β-(4-iodophenyl)tropane ([123I]β-CIT) uptake. A SWEDD was defined as lowest putamen [123I]β-CIT > 80% age-expected putamen DAT density.
Results
Odds of having a SWEDD rose across increasing quintiles of urate level, with an age- and gender-adjusted odds ratio of 3.2 comparing the highest to the lowest urate quintile; 95% CI: 1.5 to 7.2; p for trend = 0.0003) and remained significant after adjusting for potential confounding factors. The association was significant in men but not women, regardless of whether common or sex-specific quintiles of urate were used.
Conclusions
Higher levels of urate were associated with a greater likelihood of a SWEDD amongst subjects with early untreated parkinsonism in the PRECEPT study. The findings support the diagnostic utility of urate in combination with other determinants.
Keywords: Parkinson disease, urate, dopamine transporter, neuroimaging, diagnosis, biomarker
Urate is a potent antioxidant1 and may reduce the oxidative damage suspected to contribute to the neurodegenerative process in Parkinson disease (PD).2, 3 Consistent with this hypothetical benefit, individuals with higher levels of serum urate have been consistently found to have a decreased risk of PD in several longitudinal studies.47 Similarly, dietary8 and genetic9 determinants of higher serum urate recently have been linked to a reduced risk of PD or a later age at onset. These studies, however, relied on clinical diagnoses of PD, and some level of diagnostic misclassification is likely. Randomized clinical trials targeting early PD and conducting dopaminergic imaging may provide an attractive complementary opportunity to investigate potential effects of serum urate on PD risk. Approximately 10% of the participants in these trials have a scan without evidence of dopaminergic deficit (SWEDD),1013 and may not have PD, as suggested by the lack of disease progression and often by a revision of the clinical diagnosis at the end of the trial.10, 14 These subjects therefore constitute a useful control group for case-control studies of risk factors for PD in which the cases are those subjects with evidence of dopaminergic deficit recruited in the same trial -- if individuals with higher urate levels have a decreased risk of PD, the probability of a SWEDD would be expected to be higher in patients with higher urate.
We therefore examined cross-sectionally the relation between baseline serum urate concentrations and baseline imaging results among participants enrolled in the Parkinson Research Examination of CEP-1347 Trial (PRECEPT), a large randomized clinical trial that was originally designed to investigate a candidate neuroprotectant in PD using clinical and imaging assessments of disease progression due to continued neurodegeneration.13
Study population
The PRECEPT study 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. The present study was conducted on the data for all PRECEPT subjects with serum urate values and functional neuroimaging results at baseline. As previously described, subjects to be enrolled in the study had to have a diagnosis of early PD (modified Hoehn and Yahr stage of ≤2.5 with two of the cardinal signs: resting tremor, bradykinesia or rigidity) and no current or imminent (in the next 3 months) disability requiring dopaminergic therapy.13 Exclusion criteria included atypical parkinsonism, a diagnosis of PD ≥ 5 years duration, a tremor score ≥3, a Mini-Mental Status Exam score ≤ 26, a Beck Depression Inventory score ≥15 or the use of symptomatic therapy within six months prior to randomization. Subjects were randomly assigned to receive placebo or CEP-1347 10 mg, 25 mg, or 50 mg twice daily.
Serum urate and covariates
Serum urate 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 was high (r=0.88; p<0.0001), 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 in blood samples drawn under non-fasting conditions were determined using an enzymatic assay performed at a central commercial clinical laboratory (Covance, Indianapolis, IN). Information on past medical history and regular use of medications was collected at the screening visit.
Neuroimaging
Single-photon emission computed-tomography (SPECT) of iodine-123-labeled 2-β-carboxymethoxy-3-β-(4-iodophenyl)tropane ([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.15 Based on a previously acquired database of 100 healthy subjects, baseline scans were categorized as DAT deficient (≤ 80% age-expected lowest putamen [123I]β-CIT), or not DAT deficient (> 80% age-expected lowest putamen [123I]β-CIT).16
Statistical analysis
The relation between serum urate at baseline and SWEDDs was assessed by logistic regression, adjusting for age and gender. 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 odds ratios 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 gender, with mostly men in the top quintiles and mostly women in the bottom quintiles of serum urate, and thus in a loss of power of analyses within gender. These analyses were therefore complemented by estimating odds ratios for gender-specific quintiles. Tests for trend were conducted by including serum urate as a continuous variable in the logistic regression models (Wald test). Potential confounding was assessed by adjusting the regression analyses for body mass index (continuous), smoking (current smoking vs past or never), history of hypertension, history of high cholesterol, use of non-steroidal anti-inflammatory drugs, and use of thiazides. Possible interaction between serum urate and gender was explored by including in the logistic regression model the cross-product of serum urate as a continuous variable with gender.
All the p values presented are for 2-tailed tests with levels < 0.05 defined as significant.
Serum urate values and SPECT β-CIT imaging at baseline were available for 797 patients, including 90 classified as having SWEDDs (Table 1). Selected characteristics of these subjects according to imaging results are shown in Table 1.
Table 1
Table 1
Baseline characteristics by gender and SWEDD status
In analyses using quintiles of serum urate in men and women combined, the odds of a patient having a SWEDD increased with increasing urate levels (age- and gender-adjusted OR comparing the highest to the lowest urate quintile = 3.2; 95% CI: 1.5 to 7.2; p for trend = 0.0003) (Table 2). The trend of increasing odds of a SWEDD with increasing urate remained strong and significant after simultaneous adjustment for body mass index, smoking, history of hypertension, history of high cholesterol, use of non-steroidal anti-inflammatory drugs, and use of thiazides (p for trend = 0.01). The association was stronger in men than in women, although a test of interaction between serum urate (as a continuous variable) and gender was not significant (p=0.3). Because of the marked difference in serum urate levels between men and women, we also conducted analyses based on gender-specific quintiles of serum urate. Results were similar to those using common quintiles – among men, high serum urate was strongly associated with the odds of being a SWEDD, whereas a weaker and non-significant association was found in women (Table 3).
Table 2
Table 2
Odds ratios (OR) of SWEDD status at baseline according to common quintiles of serum urate, adjusted for age group and gender.
Table 3
Table 3
Odds ratios (OR) of SWEDD status at baseline according to gender specific quintiles of serum urate, adjusted for age group.
Urate, a major antioxidant as well as the end product of purine metabolism in humans, has emerged as a biomarker of PD at multiple stages of the disease process.17 Specifically, prior to diagnosis lower serum urate indicates an increased risk of the disease becoming clinically manifest years later.47 Shortly after symptoms have developed, urate can serve as a prognostic biomarker with lower serum or CSF levels foretelling a greater likelihood of faster disability progression,18, 19 or of faster loss of dopamine transporter binding sites in striatum15. The current findings demonstrate the potential diagnostic relevance of serum urate early in clinically manifest disease. They do so by identifying amongst those with mild parkinsonism a significant correlation between lower serum urate and reduced striatal uptake of a dopamine transporter ligand in a pattern indicative of idiopathic PD because of its characteristic deficit of nigrostriatal dopaminergic innervation. Conversely, higher -- but still normal – levels of urate were linked to SWEDDs and thus to a lesser likelihood of having true PD.
The correlation between urate and SWEDD status was robust in men but unclear in women. This apparent gender difference parallels similarly strong links between urate and PD risk or its progression18, 19 in men more than women. The gender difference in urate correlations may represent a true biological difference between men and women. Alternatively, the lack of significance for women might simply reflect the much smaller (here 6-fold compared to men) contribution of women to the highest two urate quintiles because of naturally lower levels of urate in women as well as the smaller number of women enrolling in PRECEPT.
Although higher serum urate amongst subjects recently diagnosed with ‘PD’ may be indicative of an alternative diagnosis, urate as biomarker of PD is not sufficiently specific on its own to distinguish PD and non-PD diagnoses. Nevertheless it may be combined with other diagnostic biomarkers to form a more useful composite indicator of non-PD diagnoses in early parkinsonism. In addition to SWEDD status, preserved olfaction has recently been substantiated as a potentially practical indicator of a non-PD diagnosis amongst newly diagnosed parkinsonian patients. It has been proposed that olfactory test performance, which has also been associated with SWEDDs in early parkinsonisim,20 in combination with distinctive PD motor features (e.g., asymmetric rest tremor21) may serve as a more accessible and less expensive diagnostic biomarker compared to this functional neuroimaging technique. Thus it will be conceptually informative and possibly clinically useful to combine multiple readily available, simple tests – e.g., of serum urate and olfactory function – to determine how the diagnostic value (i.e., of higher urate and preserved olfaction) compares to that with either test result alone. Similarly, a crude composite index of suspicion for a non-PD diagnosis may aid in triaging subjects for more incisive diagnostic assessment with DAT neuroimaging.22
Amongst subjects diagnosed with early PD in the PRECEPT18 and DATATOP19 trials, those with higher levels of serum urate were found to decline clinically and radiographically at a slower rate than those with lower urate levels. The current findings suggest that at least some of urate’s capacity as a prognostic biomarker amongst those newly diagnosed with PD can be explained by the higher proportion of SWEDDs amongst ‘early PD’ subjects with higher urate levels. Because SWEDD subjects show little evidence of clinical and radiographic progression for at least 2–4 years from baseline,10, 11, 20, 23, 24 their greater representation amongst those with higher urate likely contributed to the relatively favorable prognosis observed amongst those with a PD diagnosis and higher urate levels.18, 19 However, the urate-SWEDD link could only partially account for the predictive association between higher urate at baseline and slower clinical progression because the association remains strong even after excluding all 90 subjects with a baseline SWEDD from a secondary analysis of the PRECEPT cohort18 (unpublished observations, AA, KM, A. Watts, SE, IS, MAS). Specifically, the HR for reaching the endpoint still declined with increasing serum urate in analyses including men and women combined (p= 0.002 for trend) with the an HR of 0.61 for those in the highest versus the lowest serum urate quintile (95% CI: 0.43 to 0.86; p=0.005). As before,18 the HR reduction was even greater and more significant in men and was absent in women. Similarly, the reported18 predictive association between higher baseline urate and slower decline in striatal β -CIT uptake persisted after excluding those with a baseline SWEDD from analysis, and though diminished it remained statistically significant amongst men.
Accuracy in the diagnosis of PD early in the course of parkinsonian conditions is of considerable importance for clinical research as well as for prognostic counseling.25 Although experience and specialization in movement disorders neurology appears to improve the positive predictive value of an idiopathic PD diagnosis to nearly 99% based on definitive pathological assessment,26 this high level of probability was achieved only after following patients who presented with parkinsonism for five years on average before diagnostic revision. Diagnostic accuracy is naturally lower early in the course of parkinsonian conditions when symptoms are fewer and subtler and when responsiveness to dopaminergic drug therapy – an important diagnostic indicator in PD – has not yet been assessed. However, this early so-called de novo clinical phase of the disease has traditionally been the focus of therapeutic trials investigating potentially neuroprotective agents. Thus, it is not surprising that such clinical trials enroll a significant percentage of parkinsonian subjects who ultimately receive a diagnosis other than PD, for example, with 7% of the 800 subjects in the DATATOP trial who were initially thought to have PD upon enrollment being later deemed no longer likely to have the disease.14 In several more recent trials also investigating potentially disease-modifying agents in de novo PD a similar proportion (~10%) of subjects have been identified as possibly not having PD, though in these studies the evidence was available at baseline when functional brain scans unexpectedly showed normal labeling of dopaminergic innervation in the striatum, i.e., SWEDDs. The demonstration that higher urate is a predictor of SWEDD status suggests that urate may be useful as a component of a composite diagnostic indicator early in the course of parkinsonian conditions. The findings broaden the diagnostic biomarker potential of urate in PD, and lend further support to the possibility of a role for urate in the pathophysiology of the disease and its future treatment.
Acknowledgments
Acknowledgment/Disclosure: The present study is a secondary analysis of the database of a clinical trial PRECEPT, which was sponsored by Cephalon, Inc. (Frazer, PA), and H. Lundbeck A/S (Copenhagen, Denmark). Authors of the present report who are members of the Parkinson Study Group (PSG) and were Investigators in the PRECEPT study received grant support from the sponsors through their academic institutions, but neither had equity interests in nor received any personal remuneration from the sponsoring companies since initiation of the study. The PSG maintained the database and carried out independent analysis of the data. We thank Ms. Leslie Unger for assistance with manuscript preparation.
The present study was supported by the NIH (R01NS061858, K24NS060991), DoD (W81XWH-06-1-0679), and RJG Foundation. None of these funding organizations had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. Dr. Ira Shoulson 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.
Full Financial Disclosures of all Authors for the Past Year
Michael A. Schwarzschild
Stock Ownership in medically-related fields: noneIntellectual Property Rights: none
Consultancies: Parkinson’s disease case record review for Harvard University (in support of NIH grants; Alberto Ascherio, PI)Expert Testimony: none
Advisory Boards: Emory Univ advisory board for NIH PD-CERC grant (Gary Miller, PI)Employment: Massachusetts General Hospital (Boston, MA)
Partnerships: noneContracts: none
Honoraria: for serving on NINDS Board of Scientific Counselors ; for lecture via MGH Telemedicine; Saudi Aramco Medical Services Organization ; for speaking/teaching at Capital Medical Univ of Beijing, China ; for speaking/teaching at Soochow Univ of Souzhou, ChinaRoyalties: none
Grants: K24 NS060991 (PI: Schwarzschild) 7/1/08–6/30/13 NIH/NINDS "Pursuing Puringergic Pathways to Clinical Trials for Parkinson's Disease" ; R21 NS0558324 (PI: Schwarzschild) 6/15/09–5/31/1 NIH/NINDS “Uric Acid:novel therapeutic target for Parkinson's Disease” ; R01 NS054978 (PI: Schwarzschild) 4/1/06–3/31/11 NIH/NINDS “Translational Foundation of Adenosine Antagonist Use for Dyskinesias in Parkinson’s Disease” ; Michael J. Fox Foundation LEAPS Program (PI: Schwarzschild) 2/14/08–9/30/12 “Inosine for Parkinson's disease: Safety and trial design optimization” ; NETRP W81XWH-0410881 (PI: Schwarzschild) 10/1/04 – 9/30/10 Dept of Defense / USAMRAA (Parkinson’s research program) “Caffeine, Adenosine Receptors and Estrogen in Toxin Models of Parkinson's Disease” ; PRECEPT trial / PostCEPT study (PI: I. Shoulson) 3/1/02 – 12/31/10 Univ of Rochester / Cephalon, Inc. ‘Randomized, Double-Blind, Placebo-Controlled Study of CEP-1347 in PD with Long-term Follow-up’ Role: Co-investigator (site PI) ; RJG Foundation Parkinson’s research program (PI: Schwarzschild) 10/1/08 - 9/30/11 “Leveraging the SURE-PD Study: Metabolic Autonomic and Cognitive Effects on Inosine in PD”; NIH/NINDS RO1 NS061858 (PI: A. Ascherio) 4/15/2009 -- 3/31/2014 “Urate predictor Parkinson's Disease Risk and Progression” Role: Collaborator ; American Parkinson’s Disease Association (PI: Schwarzschild) 10/1/08 - 2/28/10 “Neuroprotection by Urate in Cellular Models of Parkinson’s Disease”Other: none
Kenneth Marek
Stock Ownership in medically-related fields: Molecular NeuroImaging, LLCIntellectual Property Rights: none
Consultancies: Bayer Healthcare; GE Healthcare; EMD Serono; AlseresExpert Testimony: none
Advisory Boards: Bayer Healthcare; GE Healthcare; EMD Serono; Biogen; Lilly; SanofiEmployment: none
Partnerships: noneContracts: none
Honoraria: noneRoyalties: none
Grants: Bayer HealthcareOther: none
Shirley Eberly
Stock Ownership in medically-related fields: Bristol-Myers Squibb and Abbott LaboratoriesIntellectual Property Rights: none
Consultancies: noneExpert Testimony: none
Advisory Boards: noneEmployment: none
Partnerships: noneContracts: none
Honoraria: noneRoyalties: none
Grants: noneOther: none
David Oakes
Stock Ownership in medically-related fields: noneIntellectual Property Rights: none
Consultancies: noneExpert Testimony: none
Advisory Boards: Member FDA EMDAC advisory committeeEmployment: Professor, University of Rochester
Partnerships: noneContracts: none
Honoraria: Service on NIH Study Sections, SURE-PD Steering CommitteeRoyalties: Book Royalties (less than $500)
Grants: PI of NIH grant Statistics and Coordination, QE3 studyOther: none
Ira Shoulson
Stock Ownership in medically-related fields: noneIntellectual Property Rights: none
Consultancies: noneExpert Testimony: none
Advisory Boards: noneEmployment: none
Partnerships: noneContracts: none
Honoraria: Adolor Corporation; Albert Einstein College of Medicine; Archives of Neurology; CSL LTD; Goodwin Proctor LLP; Link Medicine; Lundbeck Inc.; Medtronic/Alnylam; Merck Serono; Michael J. Fox Foundation; NIH Treasury; New York University; Partners HealthCare System (MGH); Prana Biotechnology; RJG Foundation; Salamandra LLC; Washington University in St. Louis.Royalties: none
Grants: University of Rochester from CHDI Foundation Inc; Department of Defense; the National Institutes of Health (NHGRI, NINDS); Neurogen Corporation; the Parkinson Disease Foundation.Other: none
Danna Jennings
Stock Ownership in medically-related fields: noneIntellectual Property Rights: none
Consultancies: noneExpert Testimony: none
Advisory Boards: noneEmployment: none
Partnerships: noneContracts: none
Honoraria: speaking honoraria for LundbeckRoyalties: none
Grants: noneOther: none
John Seibyl
Stock Ownership in medically-related fields: Equity interest- Molecular NeuroImaging, LLCIntellectual Property Rights: none
Consultancies: Bayer Healthcare; GE Healthcare; NeurologicaExpert Testimony: none
Advisory Boards: Bayer Healthcare; GE HealthcareEmployment: none
Partnerships: noneContracts: none
Honoraria: noneRoyalties: none
  Grants: Alzheimer’s Association Seibyl (PI)
   8/1/08- 7/31/11.
  Investigator-Initiated Research Grant
  Imaging Noradrenergic Function in Alzheimer's Imaging
  This study will evaluate a norepinephrine transporter imaging agent for elucidating pathophysiologic changes in Alzheimer’s disease.
  Role: Principal Investigator
  
  Michael J. Fox Foundation
  Parkinsons Progression Marker Initiative (PPMI) Core Imaging Lab Role: Principal Investigator
  
  W81XWH-09-1-0134 Seibyl (PI)
  DOD/USMRMC
  SPECT Imaging to Evaluate Post Traumatic Stress Disorder
  This project will evaluate neuroinflammatory imaging biomarkers in subjects with post traumatic stress disorder.
  Role: Principal Investigator
  
  W81XWH-05-1-0603 Marek (PI)
  Biomarkers of non-dopaminergic manifestations of Parkinsonism
  The major goals of this project are to establish and further validate physiologic, biochemical, and neuroimaging biomarkers for non-motor/non-dopaminergic manifestations of Parkinsonism
  Role: Investigator
  
  W81XWH-06-1-0679 Marek (PI)
  DOD/USMRMC
  Assessing the Determinants of PD Progression – Long Term
  Dopamine Transporter Imaging in the PRECEPT Cohort
  This study will investigate the utility of dopamine transporter imaging in monitoring and predicting the progression of PD
  Role: Investigator
  
  W81XWH-06-1-0678 Marek (PI)
  DOD/USMRMC
  Establishing an At-Risk Cohort for Parkinson’s Disease Neuroprevention Using Olfactory Testing and DAT Imaging
  This study will develop a strategy to detect pre-symptomatic parkinsonism in a large population of individuals at increased risk for PD. Role: Investigator
  
Other: none
Alberto Ascherio
Stock Ownership in medically-related fields: noneIntellectual Property Rights: none
Consultancies: noneExpert Testimony: none
Advisory Boards: noneEmployment: none
Partnerships: noneContracts: none
Honoraria: Merck Serono for scientific presentationRoyalties: none
Grants: National Institutes of Health; National Multiple Sclerosis Society; Michael J. Fox Foundation; Autism Speaks; Department of DefenseOther: none
Footnotes
Financial Disclosure: The present study is a secondary analysis of the database of a clinical trial PRECEPT, which was sponsored by Cephalon, Inc. (Frazer, PA), and H. Lundbeck A/S (Copenhagen, Denmark). The present study was supported by the NIH (R01NS061858, K24NS060991), DoD (W81XWH-06-1-0679), and RJG Foundation. None of these funding organizations had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. Dr. Ira Shoulson 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.
Dr. Marek is a consultant/AD board member for GE Healthcare, Alseres, EMD Serono, Lilly, Bayer Healthcare, Sanofi, and Biogen. He has ownership interest in Molecular NeuroImaging, LLC. Dr. Seibyl is a consultant/AD board member for Bayer Healthcare, GE Healthcare, and Neurologica. He has equity interest in Molecular NeuroImaging, LLC.
All remaining authors report no conflict of interest.
Author Roles:
  • Research project:
    • Conception Ascherio, Schwarzschild
    • Organization, Schwarzschild, Marek, Oakes, Shoulson, Ascherio
    • Execution; Schwarzschild, Marek, Eberly, Oakes, Shoulson, Jennings, Seibyl, Ascherio
  • Statistical Analysis:
    • Design, Ascherio, Oakes, Schwarzschild
    • Execution, Eberly
    • Review and Critique; Schwarzschild, Marek, Eberly, Oakes, Shoulson, Jennings, Seibyl, Ascherio
  • Manuscript:
    • Writing of the first draft, Ascherio, Schwarzschild
    • Review and Critique; Marek, Eberly, Oakes, Shoulson, Jennings, Seibyl
1. Ames BN, Cathcart R, Schwiers E, Hochstein 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]
2. Burkhardt CR, Weber HK. Parkinson's disease: a chronic, low-grade antioxidant deficiency? Med Hypotheses. 1994;43:111–114. [PubMed]
3. Beal MF. Mitochondria take center stage in aging and neurodegeneration. Ann Neurol. 2005;58(4):495–505. [PubMed]
4. Davis JW, Grandinetti A, Waslien CI, Ross GW, White LR, Morens DM. Observations on serum uric acid and the risk of idiopathic Parkinson's disease. Am J Epidemiol. 1996;144:480–484. [PubMed]
5. de Lau LM, Koudstaal PJ, Hofman A, Breteler MM. Serum uric acid levels and the risk of Parkinson disease. Ann Neurol. 2005;58(5):797–800. [PubMed]
6. Weisskopf MG, O'Reilly E, Chen H, Schwarzschild MA, Ascherio A. Plasma urate and risk of Parkinson's disease. Am J Epidemiol. 2007;166(5):561–567. [PMC free article] [PubMed]
7. Chen H, Mosley TH, Alonso A, Huang X. Plasma Urate and Parkinson's Disease in the Atherosclerosis Risk in Communities (ARIC) Study. Am J Epidemiol. 2009;169(9):1064–1069. [PMC free article] [PubMed]
8. Gao X, Chen H, Choi HK, Curhan G, Schwarzschild MA, Ascherio A. Diet, urate, and Parkinson's disease risk in men. Am J Epidemiol. 2008;167(7):831–838. [PMC free article] [PubMed]
9. Facheris MF, Hicks AA, Minelli C, et al. Variation in the Uric Acid Transporter Gene SLC2A9 and Its Association with AAO of Parkinson's Disease. J Mol Neurosci. 2010 [PubMed]
10. Marek K, Seibyl J. Beta-CIT scans without evidence of dopaminergic deficit (SWEDD) in the ELLDOPA-CIT and CALM-cit study: long-term imaging assessment. Neurology. 2003;60 Suppl 1:A298.
11. Whone AL, Watts RL, Stoessl AJ, et al. Slower progression of Parkinson's disease with ropinirole versus levodopa: The REAL-PET study. Ann Neurol. 2003;54(1):93–101. [PubMed]
12. Marek K, Jennings D, Seibyl J. The Parkinson Study Group. Long-term follow-up of patients with scans without evidence of dopaminergic deficit (SWEDD) in the ELLDOPA study. Neurology. 2005;64 Suppl 1:A274. [abstract]
13. The 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]
14. Marras C, McDermott MP, Rochon PA, et al. Survival in Parkinson disease: thirteen-year follow-up of the DATATOP cohort. Neurology. 2005;64(1):87–93. [PubMed]
15. Marek K, Innis R, van 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]
16. Jennings DL, Seibyl JP, Oakes D, Eberly S, Murphy J, Marek K. (123I) beta-CIT and single-photon emission computed tomographic imaging vs clinical evaluation in Parkinsonian syndrome: unmasking an early diagnosis. Arch Neurol. 2004;61(8):1224–1229. [PubMed]
17. Cipriani S, Chen X, Schwarzschild MA. Urate: a novel biomarker of Parkinson's disease risk, diagnosis and prognosis. Biomark Med. 2010;4(5):701–712. [PMC free article] [PubMed]
18. Schwarzschild MA, Schwid SR, Marek K, et al. Serum urate as a predictor of clinical and radiographic progression in Parkinson's disease. Arch Neurol. 2008;65(6):716–723. [PMC free article] [PubMed]
19. Ascherio A, Lewitt PA, Xu K, et al. Urate as a predictor of the rate of clinical decline in Parkinson disease. Arch Neurol. 2009;66(12):1460–1468. [PMC free article] [PubMed]
20. Silveira-Moriyama L, Schwingenschuh P, O'Donnell A, et al. Olfaction in patients with suspected Parkinsonism and scans without evidence of dopaminergic deficit (SWEDDs) J Neurol Neurosurg Psychiatry. 2009;80(7):744–748. [PubMed]
21. Schwingenschuh P, Ruge D, Edwards MJ, et al. Distinguishing SWEDDs patients with asymmetric resting tremor from Parkinson's disease: A clinical and electrophysiological study. Mov Disord. 2010 [PMC free article] [PubMed]
22. Ponsen MM, Stoffers D, Wolters EC, Booij J, Berendse HW. Olfactory testing combined with dopamine transporter imaging as a method to detect prodromal Parkinson's disease. J Neurol Neurosurg Psychiatry. 2010;81(4):396–399. [PubMed]
23. Fahn S, Oakes D, Shoulson I, et al. Levodopa and the progression of Parkinson's disease. N Engl J Med. 2004;351(24):2498–2508. [PubMed]
24. Marshall VL, Patterson J, Hadley DM, Grosset KA, Grosset DG. Two-year follow-up in 150 consecutive cases with normal dopamine transporter imaging. Nucl Med Commun. 2006;27(12):933–937. [PubMed]
25. Antonini A. Imaging for early differential diagnosis of parkinsonism. Lancet Neurol. 2010;9(2):130–131. [PubMed]
26. Hughes AJ, Daniel SE, Ben-Shlomo Y, Lees AJ. The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain. 2002;125:861–870. [PubMed]