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Higher serum urate concentration is associated with decreased risk of Parkinson’s disease (PD) as well as slower disease progression, but its relationship with severity of PD remains unclear. This study investigated whether changes in serum urate concentration over 5 years were associated with disease progression assessed by MDS-UPDRS Part III score, Hoehn and Yahr stage, or DaTscan imaging. Average serum urate concentration was stable over time and change in serum urate concentration did not correlate with worsening of measures of PD progression. These results suggest that serum urate concentration is not a monitoring biomarker of PD progression in early stages.

ObjectiveTo identify markers of resistance to developing Parkinson disease (PD) among LRRK2 mutation carriers (LRRK2+), we carried out metabolomic profiling in individuals with PD and unaffected controls (UC), with and without the LRRK2 mutation.MethodsPlasma from 368 patients with PD and UC in the LRRK2 Cohort Consortium (LCC), comprising 118 LRRK2+/PD+, 115 LRRK2+/UC, 70 LRRK2−/PD+, and 65 LRRK2−/UC, and CSF available from 68 of them, were analyzed by liquid chromatography with mass spectrometry. For 282 analytes quantified in plasma and CSF, we assessed differences among the 4 groups and interactions between LRRK2 and PD status, using analysis of covariance models adjusted by age, study site cohort, and sex, with p value corrections for multiple comparisons.ResultsPlasma caffeine concentration was lower in patients with PD vs UC (p < 0.001), more so among LRRK2+ carriers (by 76%) than among LRRK2− participants (by 31%), with significant interaction between LRRK2 and PD status (p = 0.005). Similar results were found for caffeine metabolites (paraxanthine, theophylline, 1-methylxanthine) and a nonxanthine marker of coffee consumption (trigonelline) in plasma, and in the subset of corresponding CSF samples. Dietary caffeine was also lower in LRRK2+/PD+ compared to LRRK2+/UC with significant interaction effect with the LRRK2+ mutation (p < 0.001).ConclusionsMetabolomic analyses of the LCC samples identified caffeine, its demethylation metabolites, and trigonelline as prominent markers of resistance to PD linked to pathogenic LRRK2 mutations, more so than to idiopathic PD. Because these analytes are known both as correlates of coffee consumption and as neuroprotectants in animal PD models, the findings may reflect their avoidance by those predisposed to develop PD or their protective effects among LRRK2 mutation carriers.

Two purines, caffeine and urate, have been associated with a reduced risk of idiopathic Parkinson's disease (PD) in multiple cohorts and populations. The Harvard Biomarkers Study (HBS) is a longitudinal study designed to accelerate the discovery and validation of molecular diagnostic and progression markers of early-stage PD. To investigate whether these 'reduced risk' factors are associated with PD within this cohort, we conducted a cross-sectional, case-control study in 566 subjects consisting of idiopathic PD patients and healthy controls. Caffeine intake as assessed by a validated questionnaire was significantly lower in idiopathic PD patients compared to healthy controls in males (mean difference -125 mg/day, p < 0.001) but not in females (mean difference -30 mg/day, p = 0.29). A strong inverse association was also observed with plasma urate levels both in males (mean difference -0.46 mg/dL, p = 0.017) and females (mean difference -0.45 mg/dL, p = 0.001). Both analyses stratified for sex and adjusted for age, body mass index, and either urate level or caffeine consumption, respectively. These results highlight the robustness of caffeine intake and urate as factors inversely associated with idiopathic PD.

ObjectiveTo investigate whether women and men with Parkinson disease (PD) differ in their biochemical and clinical responses to long-term treatment with inosine.MethodsThe Safety of Urate Elevation in Parkinson’s Disease (SURE-PD) trial enrolled 75 people with early PD and baseline serum urate below 6 mg/dL and randomized them to 3 double-blinded treatment arms: oral placebo or inosine titrated to produce mild (6.1–7.0 mg/dL) or moderate (7.1–8.0 mg/dL) serum urate elevation for up to 2 years. Parkinsonism, serum urate, and plasma antioxidant capacity were measured at baseline and repeatedly on treatment; CSF urate was assessed once, at 3 months. Here in secondary analyses results are stratified by sex.ResultsInosine produced an absolute increase in average serum urate from baseline that was 50% greater in women (3.0 mg/dL) than in men (2.0 mg/dL), consistent with expected lower baseline levels in women. Similarly, only among women was CSF urate significantly greater on mild or moderate inosine (+87% [p < 0.001] and +98% [p < 0.001], respectively) than on placebo (in contrast to men: +10% [p = 0.6] and +14% [p = 0.4], respectively). Women in the higher inosine dosing group showed a 7.0 Unified Parkinson’s Disease Rating Scale (UPDRS) points/year lower rate of decline vs placebo (p = 0.01). In women, slower rates of UPDRS change were associated with greater increases in serum urate (r = −0.52; p = 0.001), and with greater increases in plasma antioxidant capacity (r = −0.44; p = 0.006). No significant associations were observed in men.ConclusionsInosine produced greater increases in serum and CSF urate in women compared to men in the SURE-PD trial, consistent with the study's design and with preliminary evidence for slower clinical decline in early PD among women treated with urate-elevating doses of inosine.Clinicaltrials.gov identifierNCT00833690.Classification of evidenceThis study provides Class II evidence that inosine produced greater urate elevation in women than men and may slow PD progression in women.

OBJECTIVE LRRK2 mutations, the most common genetic cause of Parkinson disease (PD), display incomplete penetrance, indicating the importance of other genetic and environmental influences on disease pathogenesis in LRRK2 mutation carriers. The present study investigates whether urate, an antioxidant, Nrf2 activator, and inverse risk factor for idiopathic PD, is one such candidate biomarker of PD risk modulation in pathogenic LRRK2 mutation carriers. METHODS Banked plasma samples or urate levels were obtained for 3 cohorts of age- and sex-matched subjects with and without a known LRRK2 mutation in PD and unaffected controls to conduct a pilot study of 192 subjects from the LRRK2 Cohort Consortium (LCC) and 2 validation studies of 380 additional subjects from the LCC and 922 subjects from the Parkinson's Progression Markers Initiative. Urate levels were compared by multiple regression between subjects with and without a PD diagnosis conditional on LRRK2 status, controlling for age and sex. RESULTS Nonmanifesting LRRK2 mutation carriers had significantly higher levels of urate than those who developed PD in each of the 3 independent cohorts. A meta-analysis demonstrated an adjusted mean difference of 0.62 mg/dL (p

Objective To 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). Methods This 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. Results Twenty‐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. Interpretation Inosine 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.

Introduction Higher serum urate predicts slower progression in PD. The aim of this work was to assess whether oral inosine alters antioxidant capacity of plasma or CSF or urinary markers of oxidative injury in early PD. Methods We assayed plasma and CSF antioxidant capacity by ferric-reducing antioxidant power and measured DNA oxidation adduct 8-hydroxydeoxyguanosine from urine in Safety of URate Elevation in PD, a randomized, placebo-controlled trial of oral inosine assessing safety of elevating serum urate from

Peroxisome proliferator-activated receptor γcoactivator 1α(PGC-1α) is a central regulator of cellular and mitochondrial metabolism. Cellular bioenergetics are critically important in “energy-guzzling” neurons, but the components and wiring of the transcriptional circuit through whichPGC-1αregulates the neuronal electron transport chain have not been established. This information may be vital for restoring neuronal bioenergetics gene expression that is compromised during incipient Parkinson’s neuropathology and in aging-dependent brain diseases. Here we delineate a neuronal transcriptional circuit controlled by endogenousPGC-1α. We show that a feed-forward circuit of endogenous neuronalPGC-1αand the orphan nuclear estrogen-related receptorα(ERRα) activates the nuclear-encoded mitochondrial electron transport chain.PGC-1αnot onlytrans-activated expression ofERRα, but also coactivatedERRαtarget genes in complexes I, II, IV, and V of the neuronal electron transport chain via association with evolutionary conservedERRαpromoter binding motifs. Chemical activation of this transcriptional program induced transcription of the neuronal electron transport chain. These data highlight a neuronal transcriptional circuit regulated byPGC-1αthat can be therapeutically targeted for Parkinson’s and other neurodegenerative diseases.