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

Jody Corey-Bloom,Sameer Aboufadel,Ameera Haque,Steven W Granger,Douglas A Granger,Elizabeth A Thomas,Chase Snell,Ryan S Fischer

doi:10.3389/fnins.2020.00073

Abstract

Oxidative stress has long been implicated in the pathophysiology and progression of Huntington’s disease (HD). Uric acid (UA) is a naturally occurring antioxidant that is present in the brain and periphery. Growing evidence has implicated UA as a molecular biomarker for several neurodegenerative diseases, most notably Parkinson’s disease (PD). In this study, we investigated UA levels in clinical samples from HD patients and normal controls (NCs) and assessed potential relationships between UA levels and disease and clinical data. UA levels were measured in plasma (n = 107) and saliva (n = 178) samples from premanifest (pre-HD) and manifest HD patients and control subjects. Gender effects of UA levels were observed in both biofluids, with male patients showing higher UA levels compared to female patients. Comparisons of UA levels across diagnostic groups, separated by gender, revealed that both plasma and salivary UA levels were significantly lower in female pre-HD and manifest HD patients compared to NCs. Salivary levels of UA were also significantly lower in male manifest HD patients versus controls, but not in plasma. Correlations of peripheral UA levels to clinical data also showed differences according to gender. In male HD patients, both plasma and salivary UA levels were significantly negatively correlated with total functional capacity (TFC), while positive correlations were observed with total motor score (TMS). Female HD patients showed a significant positive correlation between plasma UA levels and TMS, while salivary UA levels from female patients were significantly correlated to disease burden. Finally, in a separate cohort, we show that UA levels are decreased in postmortem prefrontal cortical samples (n = 20) from HD subjects compared to matched controls. These findings suggest that decreased levels of UA in the brains of HD patients can be reflected in peripheral fluids, with salivary measures of UA particularly offering significant promise as a potentially relevant, non-invasive biomarker of disease symptoms and burden. Our findings further highlight the impact of sexual dimorphism in HD pathophysiology.

Highlights

Huntington’s disease (HD) is an inherited, progressive neurodegenerative disorder caused by a CAG repeat expansion in the 5 coding region of the Huntington (HTT) gene (Huntington Disease Collaborative Research Group, 1993)
There was no significant difference in plasma Uric acid (UA) levels between genders in control subjects, levels were significantly higher in male compared to female patients in pre-HD and HD subjects (Figure 1A) consistent with previous studies (Andreadou et al, 2009; Kivity et al, 2013; Riis et al, 2018; Yang et al, 2019)
Using ANOVA, we found that female subjects showed significantly lower levels of UA in both pre-HD and manifest HD patients versus normal controls (NCs) (ANOVA p < 0.014; p < 0.05 for NC vs. pre-HD and NC vs. HD; Figure 2A)

Summary

Introduction

Huntington’s disease (HD) is an inherited, progressive neurodegenerative disorder caused by a CAG repeat expansion in the 5 coding region of the Huntington (HTT) gene (Huntington Disease Collaborative Research Group, 1993). Despite enormous progress in our understanding of this disease, the mechanisms connecting mutant huntingtin (Htt) protein with cell death and pathological symptoms remain unclear. The age of onset for HD varies inversely with the length of the disease-causing CAG repeat mutation, with the threshold being between 36 and 39 triplet repeats (Andresen et al, 2007). The age of onset and its progression vary considerable among patients, even among patients with identical CAG repeat lengths (Andrew et al, 1993; Wexler et al, 2004; Andresen et al, 2007), warranting the need for biomarkers that might help predict onset. There are several gender-related differences that have been reported in other neurodegenerative diseases as well, which have enhanced our current understanding of the impact of sexual dimorphism in neurological diseases and the implications for preventive and therapeutic outcomes (Zagni et al, 2016; Ullah et al, 2019)

Methods

Results

Conclusion