8OHdG as a marker for Huntington disease progression

Abstract

Leukocyte 8-hydroxydeoxyguanosine (8OHdG) is an indicator of oxidative stress, impaired metabolism, and mitochondrial dysfunction, features that have been implicated in Huntington disease (HD). Increased levels of 8OHdG have been reported in the caudate, parietal cortex, and peripherally in the serum and leukocytes, in patients diagnosed with HD. However, little is known about levels in prodromal patients and changes that might occur as the disease progresses. To address these issues, 8OHdG was tracked over time for a subset of participants enrolled in the PREDICT-HD study. Participants were stratified into four groups based on proximity to HD diagnosis at study entry: Controls (gene-negative individuals), Low (low probability of near-future diagnosis), Medium, and High. Blood samples were analyzed using Liquid Chromatography Electrochemical Array, and for comparison purposes, a separate cross-sectional sample was analyzed using liquid chromatography coupled with multiple-reaction-monitoring mass spectrometry. Longitudinal data analysis showed that initial status (at study entry) and annual rate of change varied as a function of proximity group, adjusting for sex, education, age at study entry, and site effects. Overall levels were lowest for the Control group and highest for the High group, and the rate of increase varied in a similar manner. The finding that 8OHdG concentrations increased as a function of proximity to projected disease diagnosis and duration indicates support for the continued assessment of 8OHdG as a robust clinical HD biomarker.

Fig. 1

8OHdG levels over time (duration) for individuals (dashed lines) and groups (solid lines). The individual curves are observed 8OHdG levels and the group curves are 8OHdG levels based on linear fits.

Fig. 2

Cross-sectional sample observed 8OHdG values (filled circles) and linear fitted curves (solid lines) by CAP group.

Fig. 3

Observed 8OHdG for two methods of processing by duration and CAP group. Open circles and gray lines indicate LCECA processing; filled circles and solid lines indicate LC– MS/MS processing.