Urate levels predict survival in amyotrophic lateral sclerosis: Analysis of the expanded Pooled Resource Open‐Access ALS clinical trials database

Paganoni, Sabrina; Nicholson, Katharine; Chan, James; Shui, Amy; Schoenfeld, David; Sherman, Alexander; Berry, James; Cudkowicz, Merit; Atassi, Nazem

doi:10.1002/mus.25950

Cited by 38 publications

(33 citation statements)

References 46 publications

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“…This result is in line with prior studies demonstrating that higher levels of urate are associated with a lower risk 25 and slower progression in ALS. 26,27 None of the metabolites in the 16 pathways most commonly reported to be altered in previous studies, which included the metabolism of several amino acids, caffeine metabolism, aminoacyl RNA biosynthesis, and pantothenate and CoA biosynthesis, 2 were associated with ALS risk after we accounted for multiple comparisons. The inconsistent results are likely because of the different study designs, where our study evaluated the association between the prediagnostic metabolomic profile and ALS risk, while all of the previous studies compared the metabolome in patients with ALS with controls.…”

Section: Discussionmentioning

confidence: 99%

Prediagnostic plasma metabolomics and the risk of amyotrophic lateral sclerosis

et al. 2019

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Objective To identify prediagnostic plasma metabolomic biomarkers associated with amyotrophic lateral sclerosis (ALS). Methods We conducted a global metabolomic study using a nested case-control study design within 5 prospective cohorts and identified 275 individuals who developed ALS during follow-up. We profiled plasma metabolites using liquid chromatography-mass spectrometry and identified 404 known metabolites. We used conditional logistic regression to evaluate the associations between metabolites and ALS risk. Further, we used machine learning analyses to determine whether the prediagnostic metabolomic profile could discriminate ALS cases from controls. Results A total of 31 out of 404 identified metabolites were associated with ALS risk (p < 0.05). We observed inverse associations (n = 27) with plasma levels of diacylglycerides and triacylglycerides, urate, purine nucleosides, and some organic acids and derivatives, while we found positive associations for a cholesteryl ester, 2 phosphatidylcholines, and a sphingomyelin. The number of significant associations increased to 67 (63 inverse) in analyses restricted to cases with blood samples collected within 5 years of onset. None of these associations remained significant after multiple comparison adjustment. Further, we were not able to reliably distinguish individuals who became cases from controls based on their metabolomic profile using partial least squares discriminant analysis, elastic net regression, random forest, support vector machine, or weighted correlation network analyses. Conclusions Although the metabolomic profile in blood samples collected years before ALS diagnosis did not reliably separate presymptomatic ALS cases from controls, our results suggest that ALS is preceded by a broad, but poorly defined, metabolic dysregulation years before the disease onset.

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Section: Discussionmentioning

confidence: 99%

Prediagnostic plasma metabolomics and the risk of amyotrophic lateral sclerosis

et al. 2019

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“…Participants were ALS patients at greater risk of clinical progression based on having serum urate levels below the population median of 5.5 mg/dL. [17][18][19][20][21][22] In this population, treatment with inosine was safe and well tolerated at doses that elevated serum urate concentrations from a mean of 4.1 mg/dL to target levels of 7 to 8 mg/dL.…”

Section: Discussionmentioning

confidence: 99%

“…In ALS observational studies, high urate levels are predictive of improved survival. [17][18][19][20][21][22][23] Whether these associations reflect a causal protective role of urate is unknown though growing evidence supports urate as a neuroprotectant in several models of neurodegeneration, including a cellular model of ALS. 12,[27][28][29][30][31][32]45 In this pilot trial, the addition of biomarkers to track oxidative (and closely related nitrosative) 13,46 stress and damage supported the biologically relevant effects of inosine.…”

Section: Discussionmentioning

confidence: 99%

“…Urate, the end‐product of human purine metabolism, is an endogenous antioxidant10, 11 and proposed neuroprotectant12, 13, 14, 15 and its levels may be increased by edaravone treatment 6, 16. High urate levels correlate with improved survival in ALS epidemiologic studies17, 18, 19, 20, 21, 22, 23 and with favorable outcomes in other neurodegenerative diseases, most notably Parkinson's disease (PD) 24, 25, 26. Further, urate is neuroprotective in several models of neurodegeneration 12, 27, 28, 29, 30, 31, 32…”

Section: Introductionmentioning

confidence: 99%

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Pilot trial of inosine to elevate urate levels in amyotrophic lateral sclerosis

Nicholson

Chan²,

Macklin³

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo test the safety, tolerability, and urate‐elevating capability of the urate precursor inosine taken orally or by feeding tube in people with amyotrophic lateral sclerosis (ALS).MethodsThis was a pilot, open‐label trial in 25 participants with ALS. Treatment duration was 12 weeks. The dose of inosine was titrated at pre‐specified time points to elevate serum urate levels to 7–8 mg/dL. Primary outcomes were safety (as assessed by the occurrence of adverse events [AEs]) and tolerability (defined as the ability to complete the 12‐week study on study drug). Secondary outcomes included biomarkers of oxidative stress and damage. As an exploratory analysis, observed outcomes were compared with a virtual control arm built using prediction algorithms to estimate ALSFRS‐R scores.ResultsTwenty‐four out of 25 participants (96%) completed 12 weeks of study drug treatment. One participant was unable to comply with study visits and was lost to follow‐up. Serum urate rose to target levels in 6 weeks. No serious AEs attributed to study drug and no AEs of special concern, such as urolithiasis and gout, occurred. Selected biomarkers of oxidative stress and damage had significant changes during the study period. Observed changes in ALSFRS‐R did not differ from baseline predictions.InterpretationInosine appeared safe, well tolerated, and effective in raising serum urate levels in people with ALS. These findings, together with epidemiological observations and preclinical data supporting a neuroprotective role of urate in ALS models, provide the rationale for larger clinical trials testing inosine as a potential disease‐modifying therapy for ALS.

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“…It has been reported that serum UA is reduced in patients with neurodegenerative disorders such as PD (Havelund et al, 2017; Sakuta et al, 2017; Wen et al, 2017), ALS (Abraham and Drory, 2014; Paganoni et al, 2018; Zhang et al, 2018), and AD (Euser et al, 2009; Lu et al, 2016), and as mentioned above, many researchers consider that these observations represent a direct protective role of UA suppressing ROS in the brain (Kori et al, 2016). However, since XOR is not expressed in the brain, and UA levels in the brain are naturally very low, it is more likely that low UA in neurodegenerative disorder patients reflects physiologic and biochemical changes that result in decreased energy production and low ATP consumption.…”

Section: Cellular Energy-charge and Atp Turnovermentioning

confidence: 94%

Shortage of Cellular ATP as a Cause of Diseases and Strategies to Enhance ATP

2019

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Germline mutations in cellular-energy associated genes have been shown to lead to various monogenic disorders. Notably, mitochondrial disorders often impact skeletal muscle, brain, liver, heart, and kidneys, which are the body’s top energy-consuming organs. However, energy-related dysfunctions have not been widely seen as causes of common diseases, although evidence points to such a link for certain disorders. During acute energy consumption, like extreme exercise, cells increase the favorability of the adenylate kinase reaction 2-ADP -> ATP+AMP by AMP deaminase degrading AMP to IMP, which further degrades to inosine and then to purines hypoxanthine -> xanthine -> urate. Thus, increased blood urate levels may act as a barometer of extreme energy consumption. AMP deaminase deficient subjects experience some negative effects like decreased muscle power output, but also positive effects such as decreased diabetes and improved prognosis for chronic heart failure patients. That may reflect decreased energy consumption from maintaining the pool of IMP for salvage to AMP and then ATP, since de novo IMP synthesis requires burning seven ATPs. Similarly, beneficial effects have been seen in heart, skeletal muscle, or brain after treatment with allopurinol or febuxostat to inhibit xanthine oxidoreductase, which catalyzes hypoxanthine -> xanthine and xanthine -> urate reactions. Some disorders of those organs may reflect dysfunction in energy-consumption/production, and the observed beneficial effects related to reinforcement of ATP re-synthesis due to increased hypoxanthine levels in the blood and tissues. Recent clinical studies indicated that treatment with xanthine oxidoreductase inhibitors plus inosine had the strongest impact for increasing the pool of salvageable purines and leading to increased ATP levels in humans, thereby suggesting that this combination is more beneficial than a xanthine oxidoreductase inhibitor alone to treat disorders with ATP deficiency.

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Urate levels predict survival in amyotrophic lateral sclerosis: Analysis of the expanded Pooled Resource Open‐Access ALS clinical trials database

Abstract: Our pooled analysis provides further support for urate as a prognostic factor for survival in ALS and confirms the utility of the PRO-ACT database as a powerful resource for ALS epidemiological research. Muscle Nerve 57: 430-434, 2018.

Cited by 38 publications

References 46 publications

Prediagnostic plasma metabolomics and the risk of amyotrophic lateral sclerosis

Prediagnostic plasma metabolomics and the risk of amyotrophic lateral sclerosis

Pilot trial of inosine to elevate urate levels in amyotrophic lateral sclerosis

Shortage of Cellular ATP as a Cause of Diseases and Strategies to Enhance ATP

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