Urate as a Marker of Risk and Progression of Neurodegenerative Disease

Abstract

Urate is a naturally occurring antioxidant whose levels are associated with reduced risk of developing Parkinson's disease (PD) and Alzheimer's disease. Urate levels are also associated with favorable progression in PD, amyotrophic lateral sclerosis, Huntington's disease, and multisystem atrophy. These epidemiological data are consistent with laboratory studies showing that urate exhibits neuroprotective effects by virtue of its antioxidant properties in several preclinical models. This body of evidence supports the hypothesis that urate may represent a shared pathophysiologic mechanism across neurodegenerative diseases. Most importantly, beyond its role as a molecular predictor of disease risk and progression, urate may constitute a novel therapeutic target. Indeed, clinical trials of urate elevation in PD and amyotrophic lateral sclerosis are testing the impact of raising peripheral urate levels on disease outcomes. These studies will contribute to unraveling the neuroprotective potential of urate in human pathology. In parallel, preclinical experiments are deepening our understanding of the molecular pathways that underpin urate's activities. Altogether, these efforts will bring about new insights into the translational potential of urate, its determinants, and its targets and their relevance to neurodegeneration.

Inosine – a Multifunctional Treatment for Complications of Neurologic Injury

“…From a mechanistic standpoint, uric acid is a peroxynitrite scavenger that is thought to mitigate the oxidative damage that contributes to the pathogenesis of MS [86] or PD [87]. In human subjects, serum levels of uric acid are inversely correlated with risk of PD [57][58][59], providing the rationale for clinical trials aimed at increasing urate levels. The Phase II study in Parkinson's disease revealed that oral inosine was safe and tolerated well by patients, even at doses of up to 3 grams per day [61].…”

An Appraisal of Novel Biomarkers for Evaluating and Monitoring Neurologic Diseases: Editorial Introduction

“…Cell damage markers such as neurofilament in blood and cerebrospinal fluid may closely match other measures of disease progression, with reliability that may allow for a reduction in trial size in phase II trials. Blood urate, which increases in a large number of neurodegenerative diseases, may also be a marker for improved outcome; as urate has antioxidant properties, it is possible that urate levels may be a modifiable target for intervention as well [16]. In contrast, AD markers are being developed that reflect alterations of relevant pathways, and blood markers in MS hold the promise of being able to distinguish between inflammatory and neurodegenerative aspects of the disease.…”

Uric Acid as a Potential Peripheral Biomarker for Disease Features in Huntington’s Patients

“…Since these early observations, accumulating epidemiological studies, laboratory data, preclinical models, and early clinical trial results have provided substantial support for a neuroprotective role for UA and its potential as a disease biomarker for PD (Constantinescu and Zetterberg, 2011;Chen et al, 2012;Crotty et al, 2017). In particular, UA has been suggested as a promising biomarker of reduced risk and milder progression in PD (Schlesinger and Schlesinger, 2008;Paganoni and Schwarzschild, 2017;Wen et al, 2017).…”