Oct. 13, 2009 Individuals with Parkinson's disease who have higher levels of a metabolite called urate in their blood and in cerebrospinal fluid (CSF) have a slower rate of disease progression, according to a study funded by the National Institutes of Health. A clinical trial is under way to examine the safety and potential benefits of supplemental urate elevation for recently diagnosed Parkinson's patients who have low urate levels.
Investigators demonstrated the link with urate by mining a repository of clinical data and tissue samples collected from Parkinson's patients more than 20 years ago as part of a pioneering study called DATATOP, funded by NIH's National Institute of Neurological Disorders and Stroke (NINDS). The new study appears in Archives of Neurology. It was funded primarily by NINDS, with additional support from the Department of Defense and private organizations.
"This study speaks to the value of saving data and biospecimens from large clinical studies, and making them available to the research community to pursue new, unanticipated ideas," said Michael Schwarzschild, M.D., Ph.D., an associate professor of neurology at Massachusetts General Hospital in Boston, who lead the study together with Alberto Ascherio, M.D., Dr.PH, a professor of epidemiology and nutrition at the Harvard School of Public Health.
Experts emphasize there is no proof that elevating urate levels will help against Parkinson's disease, and that it should not be attempted outside of a clinical trial, where physicians can closely monitor possible benefits and risks, such as gout and heart disease.
Parkinson's disease attacks cells in the brain that regulate movement by releasing a chemical called dopamine. The loss of those cells leads to progressively disabling symptoms, including involuntary shaking, slow movement, stiffened muscle tone, and impaired balance. Levodopa, a precursor of dopamine, provides some relief from those symptoms but does not alter the disease course.
"Effective treatments for Parkinson's disease have been elusive. By taking a fresh look at the repository of clinical data and stored samples from the two-decade old DATATOP trial, this study has identified urate as a biomarker for the progression of the disease and suggests a potential new pathway for targeted therapy development," said Margaret Sutherland, Ph.D., a program director at NINDS.
Urate (or uric acid) is a product of the body's metabolism. Diets high in liver, seafood, and dried beans and peas tend to cause higher levels of urate in the blood, and are also associated with gout – a painful buildup of urate crystals in the joints. Urate is a natural antioxidant, and many studies have found that antioxidants slow the course of Parkinson's disease in animal models. Also, prior research from Dr. Ascherio's epidemiology group has shown that people who have gout or who consume foods associated with high urate have a lower incidence of Parkinson's disease.
Drs. Ascherio and Schwarzschild and their collaborators in the Parkinson Study Group are the first to examine whether urate levels are related to the course of Parkinson's disease. Last year, after mining data from another large clinical trial, they reported that high levels of urate in blood were associated with a slower disease course. The new study is an expansion of that work and the first time that investigators have looked for a connection between the course of Parkinson's and levels of urate in CSF, the fluid that fills spaces in the brain and spinal cord.
The DATATOP trial began in the late 1980s, and was designed to test whether vitamin E, the drug deprenyl (selegiline), or a combination of both could slow the course of early-stage Parkinson's disease. The trial enrolled 800 patients and followed them for two years. Deprenyl, which inhibits the breakdown of dopamine, was found to provide short-term relief from symptoms. Vitamin E showed no significant benefit.
As part of the DATATOP trial, samples of blood and CSF were acquired from more than 90 percent of the participants at enrollment. In the new study, the researchers analyzed whether blood and CSF urate levels were related to the course of Parkinson's by relying on blood measurements done at the time of the DATATOP trial and by taking new measurements from the 20-year-old, frozen samples of CSF.
Looking across all of the treatment groups in the study, the researchers found that patients with the highest urate levels in their blood and CSF had a slower functional decline as measured by their need for levodopa treatment. The results suggest that urate elevation might slow the course of Parkinson's in patients with early-stage disease and low urate levels.
The Safety of URate Elevation in Parkinson Disease (SURE-PD) study, led by Dr. Schwarzschild, is a placebo-controlled trial designed to test that hypothesis. Patients in the treatment arm of the trial will take daily, oral doses of a urate precursor called inosine for up to two years. The trial is funded by the Michael J. Fox Foundation, and is recruiting recently diagnosed patients who do not yet require Parkinson's medication at 11 sites across the United States. For more information, visit http://www.clinicaltrials.gov and search by the identifier NCT00833690.
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The above story is reprinted from materials provided by NIH/National Institute of Neurological Disorders and Stroke, via EurekAlert!, a service of AAAS.
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- Alberto Ascherio; Peter A. LeWitt; Kui Xu; Shirley Eberly; Arthur Watts; Wayne R. Matson; Connie Marras; Karl Kieburtz; Alice Rudolph; Mikhail B. Bogdanov; Steven R. Schwid; Marsha Tennis; Caroline M. Tanner; M. Flint Beal; Anthony E. Lang; David Oakes; Stanley Fahn; Ira Shoulson; Michael A. Schwarzschild; for the Parkinson Study Group DATATOP Investigators. Urate as a Predictor of the Rate of Clinical Decline in Parkinson Disease. Archives of Neurology, 2009; 66 (12) DOI: 10.1001/archneurol.2009.247
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