Among subjects with early PD participating in a large randomized trial we found that both serum urate and CSF urate, measured at baseline, were inversely related to clinical progression. The internal consistency of the results across the primary and secondary endpoints supports their validity. These findings, like data from a similar early PD trial (the PRECEPT study),10
demonstrate a robust link between blood urate concentrations and the rate of clinical progression in PD. In addition, the association of CSF urate with disease progression strengthens the possibility that brain urate (or its determinants) might protect against the neurodegeneration of PD. Taken together, these data establish urate as the first molecular predictor of clinical progression in PD and provide a rationale for investigating the possibility that a therapeutic increase of urate in patients with PD might act favorably to slow the disease course. Interestingly, the inverse relation between urate and clinical progression was not observed among patients randomized to α-tocopherol 2000 IU daily, suggesting that there may be an interaction between these antioxidants.
There is strong evidence that oxidative and nitrative stress are major pathogenetic mechanisms in PD.10,19,20
Urate is an effective antioxidant,1
and ascorbate stabilizer.24
In models of induced neurodegeneration, urate can reduce oxidative stress, mitochondrial dysfunction, and cell death of cultured neurons and human dopaminergic cells exposed to the pesticide rotenone, MPP+
, glutamate, and iron ions.25,26
Although urate appears to have the potential for neuroprotection, it is possible that the predictive association between urate and PD progression reflects instead the effect of a urate precursor, such as adenosine or inosine, or another determinant of systemic urate concentrations.
As compared to serum urate, the weaker association of CSF urate with respect to clinical progression of PD may seem at odds with the hypothesis that urate (or its metabolic precursors) exert a beneficial effect through CNS presence. CSF urate concentrations, however, display a strong caudo-rostral gradient from the lumbar space, with lumbar region values approximately 50% higher than those arising at the cisterna magna (brainstem) level.27,28
Although we consistently used CSF aliquots obtained from the 18 to 20th
mL of CSF flow, variations in CSF circulation patterns between patients29
- along with freezer storage for 20 years - may have contributed to reduce the accuracy of this measure compared to assays of freshly collected serum samples. In addition to technical variability, substantial biological differences between the urate in CSF sampled from the subarachnoid space and that in the degenerating neurons themselves may lessen the strength of a CSF urate-clinical correlation in PD. CSF may also have limited value as a measure of brain urate actions and interactions.
The finding that the inverse relation between urate and clinical progression of PD was modified by α-tocopherol treatment was unforeseen because, as originally reported, no favorable effect of α-tocopherol on PD progression was found among study participants in DATATOP.13
The mechanisms for a possible interaction between urate and α-tocopherol remain uncertain. Although hydrophilic (e.g., urate) and hydrophobic (e.g., α-tocopherol) antioxidants target different subcellular compartments, their functional interactions are well known.30,31
Further, α-tocopherol at doses commonly used in vitamin E supplements may reduce concentrations of other endogenous antioxidants,32,33
and at high doses, may have pro-oxidant rather than antioxidant effects.34,35
Alternatively, a simple competitive interaction or ‘ceiling effect’ may have contributed to the observed lack of α-tocopheral benefits among PD patients with higher urate concentrations, as well as to the loss of the inverse association between urate and PD progression among those receiving supplemental α-tocopherol. Regardless of the mechanism for a possible interaction between α-tocopherol and urate, our results raise the possibility that such an interaction may have obscured a protective effect of α-tocopherol among those subjects with low baseline concentrations of urate in the DATATOP trial. Further investigations are therefore needed to consider the possibility that α-tocopherol supplementation may be beneficial in individuals with low urate.
Serum urate may also affect the progression of cognitive impairment, in that higher concentrations seem to be associated with slower rates of cognitive decline and lower risk of dementia.36-38
As in the present study, among participants in a randomized trial, this association was observed in patients treated with placebo, but not in those treated with α-tocopherol.37
Higher serum urate concentration has also been linked to a lower rate of worsening in Huntington disease.39
Although each of these neurodegenerative disorders differs greatly from PD, the relationships between urate and these disorders may be indicative of a more general influence of urate (or its precursors) on neuronal cell death.
The main results of the present study are strikingly consistent with those recently reported from the PRECEPT study.10
Although the overall inverse relation between serum urate and the clinical progression of PD was greater in PRECEPT than in DATATOP, results among subjects in DATATOP not assigned to α-tocopherol were virtually identical to those observed in PRECEPT (which did not include an α-tocopherol treatment arm). In both trials, hazard ratios for risk of disability progression showed a decline in patients whose values were above the median concentration but still within the normal range of serum urate. Moreover, in both trials, the concentration-dependent inverse relationship was robust in men, but weak and non-significant among women. This consistent difference between men and women could result in part from a biological effect of sex on urate mechanisms in PD,40
or else could reflect the small number of women with urate concentration high enough to impart slowing of disease progression.
A potentially therapeutic effect of elevating serum urate warrants consideration. Urate levels can be elevated by dietary means, including increased intake of fructose41,42,43
or by pharmacological means. The latter may include administration of the purine metabolite and urate precursor inosine, which is being investigated as a therapy for multiple sclerosis in a phase II randomized clinical trial.45,46
The potential benefit of elevating urate in individuals with PD, however, has to be weighed against possible adverse effects, which may include an increased risk of hypertension, coronary heart disease and stroke,6,47-49
in addition to the known risks of gout and urolithiasis. Available data are therefore insufficient to support a therapeutic recommendation.
The discovery of a urate link to PD progression was achieved through additional analyses of two rigorously conducted clinical trials whose databases were made available to test an unforeseen hypothesis months50
after conclusion of the primary investigations. These latent insights highlight a broader opportunity to achieve further advances through explorations of the growing repository of high quality data collected from neuroprotection trials of PD and other neurodegenerative disorders.