Naturally elevated levels of the antioxidant urate may slow the progression of Parkinson's disease in men. Researchers from the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND) and Harvard School of Public Health (HSPH) examined data from an earlier study and found that, among recently diagnosed Parkinson's patients, those with the highest urate levels had a significantly slower rate of disease progression during the two-year study period. The report appears in the April 2008 Archives of Neurology and may lead to urate-based therapies for the disorder.
Parkinson's disease - characterized by tremors, rigidity, difficulty walking and other symptoms - is caused by the destruction of brain cells that produce the neurotransmitter dopamine. Several epidemiologic studies, including the HSPH-based Health Professionals Follow-up Study, have found that healthy people with elevated levels of urate, a normal component of the blood, may have a reduced risk of developing Parkinson's disease.
"Because the neurodegenerative process that leads to Parkinson's disease starts years before the onset of symptoms and progresses throughout the disease course, we reasoned that blood urate could be slowing the rate of neurodegeneration and hypothesized that urate's beneficial effect might extend beyond the time of diagnosis," says Alberto Ascherio, MD, DrPH, of HSPH, the study's senior author.
To investigate this hypothesis, the MGH/HSPH team analyzed information from the PRECEPT trial conducted by the Parkinson Study Group, based at the University of Rochester. That study followed a group of recently diagnosed Parkinson's patients to see if an experimental medication could delay disease progression, measured by the need to begin standard drug therapy and by imaging of the brain structures that produce dopamine. Blood samples from about 800 PRECEPT trial participants were analyzed for urate levels, which were compared to information about symptom progression of the trial participants and the imaging study results.
The results showed that participants with the highest urate levels at the beginning of the study had about half the risk of needing to start Parkinson's treatment drugs as did those with the lowest levels. The brain scans indicated that participants with higher urate levels also lost the fewest dopamine-producing neurons. The association of urate levels with risk of progression was seen both in those receiving the drug studied in the PRECEPT trial - which did not have significant results - and in the placebo group. Men are known to have higher urate levels, and since there were only a few women among those with elevated urate, results of the current analysis were not significant for women. The potential of urate to treat female Parkinson's patients needs to be investigated in future studies, the researchers note.
"These findings, combined with prior knowledge of urate's protective properties in laboratory studies, raise the possibility that urate-elevating strategies could be used to slow the neurodegeneration of Parkinson's disease," says Michael Schwarzschild, MD, PhD, of MGH-MIND, the study's lead author. "Potential benefits of urate have to be tempered against the known risks of elevated urate levels, which include gout and kidney stones. From what we know now, urate elevation should only be attempted in the context of a closely monitored clinical trial, in which potential benefits and risks are carefully balanced."
Schwarzschild and Ascherio, with an award from The Michael J. Fox Foundation for Parkinson's Research, are teaming up with Parkinson Study Group doctors from across the country to conduct a multicenter Phase 2 trial, being announced by the Foundation today. Ninety people newly diagnosed with Parkinson's but not yet needing treatment will be treated with the urate precursor inosine or a placebo. Information about trial enrollment will be available later this year at www.pdtrials.org.
Schwarzschild is an associate professor of Neurology at Harvard Medical School and Ascherio is an associate professor of Nutrition and Epidemiology at Harvard School of Public Health. Additional co-authors of the report are Steven Schwid, MD, Arthur Watts, PhD, David Oakes, PhD, and Ira Shoulson, MD, University of Rochester; Kenneth Marek, MD, Institute for Neurodegenerative Disorders, New Haven, Conn.; and Anthony Lang, MD, Toronto Western Hospital. The Archives of Neurology study was supported by grants from the National Institutes of Health and the Beeson Scholars Program of the American Federation for Aging Research.
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