Based on a remarkable convergence of evolutionary, laboratory, epidemiological and clinical findings, urate has emerged as a promising biomarker for the risk, diagnosis and prognosis of PD. The biochemical plausibility of endogenous urate also having a pivotal protective influence has added therapeutic significance as well. Indeed, these biomarker and mechanistic data have facilitated rapid translation to an initial clinical trial of urate elevation as a candidate disease-modifying strategy for PD [101
The putative antioxidant mechanism suggests that any true neuroprotective effect of urate could be expected to extend beyond dopaminergic neuron degeneration in PD. Indeed, the evidence that urate may serve as diagnostic biomarker for cognitive function in PD, as described previously, is consistent with increasingly appreciated cortical involvement in the disease. Furthermore, a few studies suggest that urate as a biomarker for favorable CNS outcomes in neurodegeneration is not specific for PD. For example, preliminary findings have identified blood urate as a potential biomarker of favorable prognosis in Huntington’s disease [81
] and, possibly, the conversion from mild cognitive impairment to Alzheimer’s disease [71
]. Whether urate is, in fact, as strongly linked to outcomes of neurodegenerative diseases other than PD, will be addressed in the coming years.
Despite the association between serum or CSF urate and multiple favorable PD outcomes, several caveats should be noted. Although it is tempting to make clinical use of the emerging biomarker properties of urate for PD – particularly for its prognosis – it remains an experimental link. It is unlikely to be sufficiently predictive, alone, to warrant its routine measurement in clinical practice; at least not without integrating it into a composite index of risk, diagnosis or prognosis – indices that have not yet been developed and validated. Over the next 10 years, it is likely that the field of PD biomarkers will advance in this direction, in a manner analogous to that of the cardiovascular field, in which composite indices of cardiac risk are routinely employed in both research and clinical practice. Therefore, it can be envisioned that a ‘Parkinson’s Risk Index’ will soon be quantifiable and useful, and might be based on genetic test results, family and exposure histories, olfaction testing, and simple blood tests for urate, specific α-synuclein species and other factors. A similar ‘Parkinson’s Progression Index’ may comprise information from functional neuroimaging of dopaminergic deficits, blood and CSF determinations of urate, gene tests and other molecular factors that are yet to be validated, as well as clinical phenotype (e.g., tremor predominance).
Although urate elevation has compelling neuroprotective potential therapeutically, and can be achieved in humans through the administration of widely available nutritional supplements, this candidate treatment strategy is unproven and carries substantial health risks (e.g., gout, urolithiasis and possible cardiovascular disease), and should not be attempted outside of a carefully conducted clinical study in which the potential risks and benefits can be balanced. Over the next 10 years, the prospects for targeting urate, or related purines and antioxidants, as disease-modifying therapy are likely to be clarified.
Similarly, although urate testing as a PD biomarker cannot be recommended in routine clinical practice yet, its link to PD outcomes is sufficiently robust to warrant immediate application in research studies of PD. For example, measurement of baseline serum urate in a randomized clinical trial of a candidate neuroprotectant should now be standard in any new ‘disease modification’ trial for PD. Its inclusion in the analysis as a covariate linked to progression will increase the power and/or reduce the sample size/cost of the trial. Testing for an interaction between endogenous urate levels and the study drug in a neuroprotection trial is also important, as urate may have a predictive biomarker role, as was suggested in our post-hoc
analysis of its interaction with α-tocopherol in the DATATOP trial, described previously [60
]. Therefore, under some circumstances, serum urate measurement might be conducted as a screening test prior to enrollment, in order to select PD subjects with relatively low urate as potential ‘responders’ based on low endogenous antioxidant capacity.
Finally, in addition to further developing the risk, diagnostic, prognostic and possibly other applications of urate as a biomarker of PD, it is critical to enhance our insufficient understanding of why urate is linked to the disease. Carefully designed laboratory and clinical studies are required to elucidate the exact role of urate and related purines in the development and progression of the disease.