A new study has investigated the safety and tolerability of administering inosine, a urate precursor, in patients with early untreated Parkinson’s disease with baseline levels of urate below normal median of 6 mg/dL. In the SURE-PD (Safety of Urate Elevation in PD) trial, 75 subjects (mean age 62 years) received inosine or placebo for up to 24 months (Parkinson Study Group SURE-PD Investigators et al. JAMA Neurol 2014;71:141-150).  Inosine dosing was titrated to produce mildly (6.1-7.0 mg/dL) or moderately (7.1-8.0 mg/dL) elevated serum urate levels; the maximum dose of inosine was 500-1000 mg TID.

Serum urate levels rose significantly in the two treatment groups (by 2.3 and 3.0 mg/dL, respectively) versus placebo, and were elevated in CSF at 3 months. Treatment was generally well tolerated; no subjects withdrew due to adverse effects. Three patients developed symptomatic urolithiasis. There were no cases of gout. The frequency of serious adverse events was similar in the treated groups compared to placebo. An exploratory secondary outcome was percentage of individuals requiring dopaminergic therapy, which was reached in 63%, but was not significant between groups. A futility analysis suggested some potential for elevated urate to slow change in total UPDRS.

Uric acid (UA) has important antioxidant effects, and the rationale for raising serum urate levels is that it may provide some degree of neuroprotection in PD. Two decades ago, a postmortem study reported that uric acid levels were significantly lower in the substantia nigra of PD patients compared to controls, suggesting that uric acid levels were a marker of oxidative stress (Church & Ward. Brain Res Bull 1994;33:419-425). Several epidemiologic studies then investigated this possible connection. In the 30-year prospective Honolulu Heart Program study, subjects with higher baseline UA levels had a 40% lower rate of PD (Davis et al. Am J Epidemiol 1996;144:480-484; free full text at http://aje.oxfordjournals.org/content/144/5/480.long). This association between higher serum urate and lower PD risk was also seen in the Health Professionals Follow-up Study (Weisskopf et al. Am J Epidemiol 2007;166:561-567; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC2391073/pdf/nihms44448.pdf; Gao et al. Am J Epidemiol 2008;167:831-838; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC2367211/pdf/nihms-44283.pdf). These findings were supported by the observation of a lower PD risk in patients with gout (De Vera et al. Arthritis Rheum 2008;59:1549-1554, free full text at http://onlinelibrary.wiley.com/doi/10.1002/art.24193/pdf). A recent meta-analysis of six studies (n=33,185) concluded that there was a 40% reduced incidence of PD in men with high serum urate levels (Shen et al. Can J Neurol Sci 2013;40:73-79).

However, the relationship between serum UA and either risk of developing disease or rate of decline in PD is not clear-cut. The Cardiovascular Health Study found that low urate concentrations were indeed associated with a higher PD risk, but high urate concentrations were not associated with a decreased PD risk (Jain et al. Neuroepidemiology 2011;36:223-229; free full text at

www.ncbi.nlm.nih.gov/pmc/articles/PMC3124452/pdf/ned0036-0223.pdf). Moreover, the association between UA and PD risk was not seen in women in this analysis, nor was it evident in the Nurses’ Health Study, the General Practice Research Database or in a recent meta-analysis (O’Reilly et al. Am J Epidemiol 2010;172:666-670; Alonso et al. Neurology 2007;69:1696-1700; Shen 2013).

In people with PD, the PRECEPT study reported that serum urate levels were predictive of the rate of clinical progression (Schwarzschild et al. Arch Neurol 2008;65:716-723; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC2574855/pdf/nihms51201.pdf). Similarly, there was a slower rate of decline in PD patients with higher urate levels in serum or CSF in the DATATOP study (Ascherio et al. Arch Neurol 2009;66:1460-1468; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC2795011/pdf/nihms-160945.pdf).

A recent study has also reported that in newly-diagnosed PD patients, lower UA levels were associated with non-motor symptoms such as attention/memory, cardiovascular and sleep, as evaluated by the NMS Questionnaire (Moccia et al. Parkinsonism Relat Disord 2014;20:772-775). The authors concluded that UA may be a biomarker of early clinical features in PD.

Comment
Dr. Susan Fox: Slowing disease progression in PD is a major focus of research. To date, no intervention has proven clinically efficacious. This trial shows that elevating UA using inosine is safe in early PD, and does not induce symptoms such as gout. The next stage will need to be a randomized controlled trial using appropriate numbers of patients to assess the benefit of inosine on disease progression. The challenge will be the same as in all other studies in this area, i.e. how to accurately measure disease progression, although inosine does not have an effect on PD motor symptoms and so it may be easier to separate symptomatic changes from neuroprotection. Inosine is easy to use and safe, thus making it a promising agent for early PD.