Antioxidant Linked to Parkinson's Disease Progression

By Crystal Phend
BOSTON, 14 april 2008-- For patients with Parkinson's disease, progression may be directly linked to blood levels of the antioxidant urate, researchers found. Patients with the highest urate levels were half as likely to wind up needing dopaminergic therapy as those with the lowest levels (P<0.001 for trend), reported Alberto Ascherio, M.D., Dr.Ph., of the Harvard School of Public Health, and colleagues online in the Archives of Neurology. This would make urate the first biomarker for Parkinson's progression, Dr. Ascherio said. Other factors linked to worsening of the condition have centered on complex behavioral characteristics, the researchers said.
Targeting urate or its precursors, they suggested, could be a way to therapeutically modify the course of the disease, although urate itself may not inform treatment decisions or risk prediction. Measurement of urate on its own in patients with newly diagnosed Parkinson's disease as an indicator of an individual patient's future rate of progression is likely to be of modest clinical utility," they wrote.
As a potent antioxidant, urate may delay the oxidative destruction of dopaminergic neurons that occurs as Parkinson's disease worsens, the researchers speculated.
Animal models of Parkinson's have supported a protective role of urate, a derivative of uric acid. But the best evidence in humans has been the lower Parkinson's risk among healthy adults with higher uric acid levels consistently found in prospective epidemiological studies.
So, the researchers looked for a link between serum urate concentrations and subsequent Parkinson's progression in the randomized Parkinson Research Examination of CEP-1347 Trial (PRECEPT), which was originally designed to test the investigational agent CEP-1347 as a neuroprotectant.
The trial randomized 806 men and women with early Parkinson's disease that did not yet require dopaminergic therapy to active or control treatment.
Dr. Ascherio's group focused on serum urate concentration data from patients' baseline visit collected as part of routine safety monitoring.
During an average 21.4 months of follow-up, 61% reached the primary endpoint of disability sufficient to require dopaminergic therapy.
Higher urate levels were associated with lower likelihood of progression to dopaminergic therapy (P<0.001 for trend).
This advantage was significant for patients in the two highest urate quintiles. Compared with patients in lowest quintile averaging 3.8 mg/dL urate, risk of progression was 35% lower for those with urate levels averaging 6.3 mg/dL (P=0.006) and 49% lower for those with levels averaging 7.5 mg/dL (P<0.001).
The association between urate and disease progression was substantially stronger among men than women. Men had a modestly but significantly slower rate of disease progression measured by scores on the Unified Parkinson's Disease Rating Scale for those in the highest versus lowest urate groups (P=0.02 for trend) whereas the same was not true for women (P=0.52).
The authors had no explanation for the differences observed between the sexes.
Despite these indications that lower urate levels were predictive of neurodegeneration, "that information alone is not sufficient to change the course of treatment or to provide specific advice to patients," Dr. Ascherio said.
Further study is needed to determine whether higher serum urate itself is neuroprotective or simply serves as an indirect marker of protection, he and colleagues wrote.
Meanwhile, urate testing could be useful in designing neuroprotective trials in Parkinson's disease because potential neuroprotectants targeting
oxidative stress pathways might be most effective in patients whose urate and other antioxidant levels are lowest at baseline, they said.
The real hope, though, is that urate may offer a new pathway for Parkinson's disease-modifying therapy, Dr. Ascherio said. But he cautioned there may be a tradeoff in risk.
"Increasing urate could have adverse effects on the cardiovascular system and increase the risk of kidney stones and gout," he said. "So this is not a risk-free intervention."
The analysis was supported by National Institutes of Health grants and the Beeson Scholars Program of the American Federation for Aging Research. The PRECEPT study was supported by Cephalon and H. Lundbeck A/S.
The researchers reported no conflicts of interest.
Primary source: Archives of NeurologySource reference:Schwarzschild MA, et al "Serum urate as a predictor of clinical and radiographic progression in Parkinson disease" Arch Neurol 2008; DOI: 10.1001/archneur.2008.65.6.nct70003.