Postmortem Brain Levels of Urate and Precursors in Parkinson's Disease and Related Disorders

McFarland, Nikolaus R.; Burdett, Thomas C.; Desjardins, Cody A.; Frosch, Matthew P.; Schwarzschild, Michael A.

doi:10.1159/000346370

Cited by 57 publications

(50 citation statements)

References 40 publications

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“…Church and Ward in 1994 (150) examined postmortem caudate and substantia nigra samples from PD patients and controls (n=4 for each group) and found that urate levels were lower in the SN (p<0.05) and caudate (p<0.1) of PD patients compared with controls, consistent with others and our subsequent findings in a larger post-mortem series (151, 152). They also observed a higher dopamine oxidation rate constant in PD compared to the control striatum homogenates, supporting a “pro-oxidative stress” state in PD.…”

Section: Urate Levels In Pd Brainsupporting

confidence: 77%

Targeting urate to reduce oxidative stress in Parkinson disease

Crotty

Ascherio

Schwarzschild

2017

Experimental Neurology

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112

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Oxidative stress has been implicated as a core contributor to the initiation and progression of multiple neurological diseases. Genetic and environmental factors can produce oxidative stress through mitochondrial dysfunction leading to the degeneration of dopaminergic and other neurons underlying Parkinson disease (PD). Although clinical trials of antioxidants have thus far failed to demonstrate slowed progression of PD, oxidative stress remains a compelling target. Rather than prompting abandonment of antioxidant strategies, these failures have raised the bar for justifying drug and dosing selections and for improving study designs to test for disease modification by antioxidants. Urate, the main antioxidant found in plasma as well as the end product of purine metabolism in humans, has emerged as a promising potential neuroprotectant with advantages that distinguish it from previously tested antioxidant agents. Uniquely, higher urate levels in plasma or cerebrospinal fluid (CSF) have been linked to both a lower risk of developing PD and to a slower rate of its subsequent progression in numerous large prospective epidemiological and clinical cohorts. Laboratory evidence that urate confers neuroprotection in cellular and animal models of PD, possibly via the Nrf2 antioxidant response pathway, further strengthened its candidacy for rapid clinical translation. An early phase trial of the urate precursor inosine demonstrated its capacity to safely produce well tolerated, long-term elevation of plasma and CSF urate in early PD, supporting a phase 3 trial now underway to determine whether oral inosine dosed to elevate urate to concentrations predictive of favorable prognosis in PD slows clinical decline in people recently diagnosed, dopamine transporter-deficient PD.

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Section: Urate Levels In Pd Brainsupporting

confidence: 77%

Targeting urate to reduce oxidative stress in Parkinson disease

Crotty

Ascherio

Schwarzschild

2017

Experimental Neurology

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112

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“…Thereby, an abnormal content of urea and related amino acids has been previously found in serum [19,20,33] and brain [8,9] of AD, accompanied by altered levels of expression in different enzymes and the corresponding genes [40]. Other studies reported an increased concentration of inosine in response to an accelerated degradation of nucleotides in brain from human patients [41] and APP/PS1 mice [9], which is finally reflected in peripheral blood as revealed our metabolomic fingerprinting platform. However, Jiang et al surprisingly described the lack of inosine in serum from the SAMP8 mice [12], demonstrating the disparity between different existing models of AD and the need to select the correct one to mimic metabolic features detected in human AD.…”

Section: Biological Hypothesissupporting

confidence: 53%

Application of metabolomics based on direct mass spectrometry analysis for the elucidation of altered metabolic pathways in serum from the APP/PS1 transgenic model of Alzheimer's disease

González‐Domínguez

García-Barrera

Vitórica

et al. 2015

Journal of Pharmaceutical and Biomedical Analysis

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Metabolomic analysis of brain tissue from transgenic mouse models of Alzheimer's disease has demonstrated a great potential for the study of pathological mechanisms and the development of new therapies and biomarkers for diagnosis. However, in order to translate these investigations to the clinical practice it is necessary to corroborate these findings in peripheral samples. To this end, this work considers the application of a novel metabolomic platform based on the combination of a two-steps extraction procedure with complementary analysis by direct infusion electrospray mass spectrometry and flow infusion atmospheric pressure photoionization mass spectrometry for a holistic investigation of metabolic abnormalities in serum samples from APP/PS1 mice. A number of metabolites were found to be perturbed in this mouse model, including increased levels of di- and tri-acylglycerols, eicosanoids, inosine, choline and glycerophosphoethanolamine; reduced content of cholesteryl esters, free fatty acids, lysophosphocholines, amino acids, energy-related metabolites, phosphoethanolamine and urea, as well as abnormal distribution of phosphocholines depending on the fatty acid linked to the molecular moiety. This allowed the elucidation of possible pathways disturbed underlying to disease (abnormal homeostasis of phospholipids leading to membrane breakdown, energy-related failures, hyperammonemia and hyperlipidemia, among others), thus demonstrating the utility of peripheral samples to investigate pathology in the APP/PS1 model.

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“…36 In a recent postmortem study, urate levels in cortical and striatal tissue was lower in PD compared to controls in men only. 37 The biological mechanisms underlying such sex specificity remain unclear. Interestingly, several cardiovascular risk factors, such as hypercholesterolemia 38 and hypertension, 39 have been reported to be associated with increased risk of PD in women but not in men.…”

Section: Resultsmentioning

confidence: 99%

Prospective study of plasma urate and risk of Parkinson disease in men and women

et al. 2016

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Objective: To examine whether higher plasma urate concentrations are associated with a lower risk of developing Parkinson disease (PD) and whether there is a sex difference in the potential urate-PD relationship. Methods:We conducted a nested case-control study based on 90,214 participants of 3 ongoing US cohorts. We identified 388 new PD cases (202 men and 186 women) since blood collection, which were then matched to 1,267 controls. PD cases were confirmed by medical record review. Conditional logistic regression estimated relative risks (RRs) and 95% confidence intervals (95% CIs), after adjustment for age, smoking, caffeine intake, plasma concentrations of cholesterol and ferritin, and other covariates. We also conducted a meta-analysis to combine our study with 3 previously published prospective studies on urate and PD risk. Results:In the present nested case-control study, the multivariate-adjusted RRs of PD comparing extreme quartiles of urate were 0.63 (95% CI 0.35, 1.10; p trend 5 0.049) in men and 1.04 (95% CI 0.61, 1.78; p trend 5 0.44) in women (p heterogeneity 5 0.001). In the meta-analysis, the pooled RRs comparing 2 extreme quartiles of urate were 0.63 (95% CI 0.42, 0.95) in men and 0.89 (95% CI 0.57, 1.40) in women. Conclusion:We observed that men, but not women, with higher urate concentrations had a lower future risk of developing PD, suggesting that urate could be protective against PD risk or could slow disease progression during the preclinical stage of disease. Urate is a potent antioxidant and contributes to approximately 60% of the free radical scavenging activity in human serum.1,2 Serum urate concentrations in humans and apes are many-fold higher than those in other mammals as a consequence of evolutionary urate oxidase gene mutations.1 Results from in vitro and in vivo experimental studies suggest that urate could be a potential neuroprotective agent via its capacity to modify the cerebral damage induced by reactive nitrogen and oxidative species.2,3 In most, 4-8 but not all, 9 prospective observational studies in humans, higher concentrations of plasma urate were associated with a lower risk of developing Parkinson disease (PD). Further, patients with PD with higher urate levels have been found to have a slower disease progression relative to those with lower urate concentrations. 10,11 However, significant associations of higher urate levels with lower PD risk and slower progression were observed only in men. [4][5][6][7][8][9] Studies relating blood urate levels to PD risk were limited by their small sample sizes (PD case number , 160 in all studies) and underrepresentation of women. Therefore, it remains unclear whether this sex difference reflects a true difference in underlying biology or is due to lack of statistical power because women generally have lower urate concentration and lower PD incidence compared with men. Further, only one previous study 7 controlled for plasma ferritin and cholesterol levels, which have been found to be

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Postmortem Brain Levels of Urate and Precursors in Parkinson's Disease and Related Disorders

Cited by 57 publications

References 40 publications

Targeting urate to reduce oxidative stress in Parkinson disease

Targeting urate to reduce oxidative stress in Parkinson disease

Application of metabolomics based on direct mass spectrometry analysis for the elucidation of altered metabolic pathways in serum from the APP/PS1 transgenic model of Alzheimer's disease

Prospective study of plasma urate and risk of Parkinson disease in men and women

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