18 April 2008. Blood levels of the antioxidant molecule urate are associated with the risk of progression in patients with Parkinson disease, according to a new study. The work correlated high urate levels in people with early PD with a lower chance of progressing to the need for dopamine therapy over two years. In conjunction with the publication of the results in the April 14 issue of the Annals of Neurology, the Michael J. Fox Foundation announced a grant to support a Phase 2 trial to look at the possibility of using the urate precursor inosine to increase urate levels as a treatment for PD.
The new study comes from Michael Schwarzschild of the Massachusetts General Hospital in Boston, Alberto Ascherio of the Harvard School of Public Health and Harvard Medical School, and colleagues on the Parkinson Study Group. Schwarzschild and Ascherio, along with Karl Kieburtz of the University of Rochester School of Medicine in New York, will receive $5.6 million from the Fox Foundation to investigate the clinical application of the work.
Urate is a product of purine metabolism and an antioxidant that occurs at high levels in the blood. Oxidative stress is linked to death of dopaminergic neurons in PD, and previous epidemiological work by Ascherio and colleagues showed that people with higher blood levels of urate have a lower risk of Parkinson disease. As was frequently the case in AD research, as well, an epidemiological link does not make for a predictive marker, though. For example, it was not known if urate levels affected the prognosis among people with early PD.
To address this question, Schwarzschild and colleagues performed a prospective study of urate levels and risk of progression in 814 people with early PD, drawn from an earlier trial of the kinase inhibitor CEP-1487. The trial failed to show any effect of the drug (Parkinson Study Group PRECEPT Investigators, 2007), but the collected data offered an opportunity to look at the relationship between serum urate and progression.
The primary endpoint of the PRECEPT trial was progression to a level of disability that called for dopamine therapy, and the researchers compared the likelihood of reaching that endpoint for patients with different baseline serum urate concentrations. Overall, 61 percent of subjects reached the endpoint during the two-year trial, but this percentage declined from a high of 67.8 percent in the lowest quintile of blood urate concentration to 53.3 percent in the highest. The hazard ratio indicated that the risk of progression for the subjects with the highest urate level was half of that for those with the lowest. The association was seen for both sexes, but was stronger for men. This may be because men tend to have higher urate levels than do women, so that they made up the majority of subjects in the higher quintiles.
The study also measured the health of striatal dopamine neurons in a subset of patients by uptake of [123I]β-CIT, a substrate for the dopamine transporter. This SPECT analysis revealed that patients in the top quintile showed less loss of CIT labeling than those with lower urate levels. “These findings identify serum urate as the first molecular factor directly linked to the progression of typical PD and suggest that targeting urate or its determinants could be an effective disease-modifying therapy for PD,” the authors conclude.
Coincident with the publication of these findings, the Michael J. Fox Foundation announced its support for a clinical trial to gauge the potential for elevating urate levels pharmacologically in patients with early PD. That trial will test inosine, a natural product that is converted to urate in the body. The study will determine the safety and effectiveness of inosine to raise cerebrospinal fluid urate concentration. Ninety patients will receive test doses of inosine for three months. If inosine is well tolerated at doses that raise urate levels, the subjects will continue on treatment for up to two years to assess long-term safety.
In a press release, Fox Foundation CEO Katie Hood said, “Because inosine is a publicly available compound, no corporate entity has the financial incentive to fund clinical research to definitively assess its potential.” That is where foundations like MJFF can step in, she wrote, to ensure that innovative but commercially unappealing approaches do not stall for lack of resources.
Inosine is indeed available as a dietary supplement, but that does not mean people with PD should start taking it on their own. Elevated urate levels carry risks, including kidney stones, gout, and possibly heart disease. “A long-term neuroprotective effect of urate or its precursors would have to be weighed against potential adverse cardiovascular effects,” the authors write. The planned clinical trial will help to define these risks. On the plus side, inosine has been shown to raise serum urate concentrations over the long term in patients with multiple sclerosis, without apparent adverse side effects (Spitsin et al., 2001).—Pat McCaffrey.
Schwarzschild MA, Schwid SR, Marek K, Watts A, Lang AE, Oakes D, Shoulson I, Ascherio A; and the Parkinson Study Group PRECEPT Investigators. Serum Urate as a Predictor of Clinical and Radiographic Progression in Parkinson Disease. Arch Neurol. 2008 Apr 14; [Epub ahead of print] Abstract