In patients with early Parkinson's disease, levels of urate in both serum and cerebrospinal fluid show a robust inverse correlation with clinical progression, according to a new analysis of data from the multicenter Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) study.
The research builds on recent epidemiological data that have demonstrated a reduced risk of developing the disease among healthy individuals with higher urate levels.
Laboratory studies have shown that urate is a major antioxidant as well as the end product of purine metabolism in humans, and that it can prevent dopaminergic cell degeneration in culture models of Parkinson's disease.
This finding “strengthens the possibility that brain urate [or its determinants] might protect against the neurodegeneration of Parkinson's disease,” Dr. Alberto Ascherio, of the Harvard School of Public Health, Boston, and his associates wrote online in the Archives of Neurology (2009 [doi:10.1001/archneruol.2009.247]).
Taken together with the results of the recent Parkinson Research Examination of CEP-1347 Trial (PRECEPT), “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,” Dr. Ascherio and his colleagues noted in the article.
To test the hypothesis that higher urate levels in blood and CSF samples would predict slower clinical progression, the investigators used data from the randomized DATATOP trial, the primary outcome of which has already been published (N. Engl. J. Med. 1993;328:176-83).
In that study, subjects with typical early Parkinson's disease were enrolled in 1987-1988 at 28 sites throughout the United States and Canada.
Baseline urate concentrations were determined from serum specimens (774 subjects) and CSF specimens (713 subjects), and were found to closely correlate with each other.
During 2 years of follow-up, 369 (48%) subjects reached the primary end point of progressing to the extent that they required levodopa therapy. The hazard ratio of reaching this end point was 36% lower among subjects in the top quintile of urate levels than in subjects in the bottom quintile of urate levels, the investigators found.
In addition, the rate of decline in scores on the Unified Parkinson's Disease Rating Scale, which measures disability in motor performance, cognitive function, and activities of daily living, also correlated with urate levels among men. Men in the lowest quintile of urate level showed a decline of 14.8 points per year, while men in the highest quintile of urate level declined only 8.9 points per year.
Higher serum urate previously has also been linked to favorable outcomes in other diseases of neuronal degeneration and injury. Preliminary reports have suggested a slower rate of progression of cognitive decline and dementia, as well as a lower rate of worsening of Huntington's disease.
Determining whether raising serum urate levels might be therapeutic in Parkinson's disease or other neurologic disorders “warrants consideration.” Urate levels can be raised pharmacologically or by increasing the intake of fructose or purines in the diet, they added.
Such treatment would need to be weighed against possible adverse effects, “which may include an increased risk of hypertension and [cardiovascualr disease], in addition to the known risks of gout and urolithiasis.”
Dr. Michael Schwarzschild of the MassGeneral Institute for Neurodegenerative Disease at the Massachusetts General Hospital in Boston said that enrollment has begun in a multicenter, randomized, placebo-controlled, phase II trial of inosine in early untreated Parkinson's disease. Inosine is a urate precursor and a purine metabolite.
The trial is being conducted under an Investigational New Drug application to the Food and Drug Administration and is intended to set the stage for a larger “disease modification” trial of inosine in Parkinson's disease, he said.
The Safety of URate Elevation in Parkinson's Disease (SURE-PD) trial is designed to assess the safety and ability of different doses of oral inosine to raise serum and cerebrospinal fluid concentrations of urate, he said. “However, we caution that at present it is unsafe to take or recommend taking inosine to elevate urate outside of a well-designed clinical trial that carefully balances the potential risks and benefits.”
Dr. Schwarzschild said that the doses of inosine being tested are titrated to produce mild or moderate elevations of serum urate. “Because only subjects with lower serum urate levels [less than 6 mg/dL] will be eligible to enroll, the increased levels being targeted still fall in what's generally considered a normal range [up to 8 mg/dL].”
In addition, inosine is being investigated as a treatment for multiple sclerosis. And urate itself is being administered intravenously as a candidate protectant in a clinical trial for acute ischemic stroke.
“The relationships between urate concentration and [neurological] disorders may be indicative of a more general influence of urate [or its precursors] on neuronal cell death,” Dr. Ascherio and his associates suggested.
Dr. Ascherio and Dr. Schwarzschild reported no financial conflicts of interest in their work.
Renée Matthews contributed to this report.
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