Tracking motor impairments in the progression of Huntington's disease

Abstract

The Unified Huntington's Disease Rating Scale is used to characterize motor impairments and establish motor diagnosis. Little is known about the timing of diagnostic confidence level categories and the trajectory of motor impairments during the prodromal phase. Goals of this study were to estimate the timing of categories, model the prodromal trajectory of motor impairments, estimate the rate of motor impairment change by category, and provide required sample size estimates for a test of efficacy in clinical trials. In total, 1010 gene-expanded participants from the Neurobiological Predictors of Huntington's Disease (PREDICT-HD) trial were analyzed. Accelerated failure time models were used to predict the timing of categories. Linear mixed effects regression was used to model the longitudinal motor trajectories. Age and length of gene expansion were incorporated into all models. The timing of categories varied significantly by gene expansion, with faster progression associated with greater expansion. For the median expansion, the third diagnostic confidence level category was estimated to have a first occurrence 1.5 years before diagnosis, and the second and first categories were estimated to occur 6.75 years and 19.75 years before diagnosis, respectively. Motor impairments displayed a nonlinear prodromal course. The motor impairment rate of change increased as the diagnostic confidence level increased, with added acceleration for higher progression scores. Motor items can detect changes in motor impairments before diagnosis. Given a sufficiently high progression score, there is evidence that the diagnostic confidence level can be used for prodromal staging. Implications for Huntington's disease research and the planning of clinical trials of efficacy are discussed.

Keywords: Huntington's disease; cohort studies; movement disorders; neurodegenerative disease; predictive testing.

FIG. 1

The predicted year of diagnostic confidence level (DCL) category occurrence is illustrated with 95% confidence interval as a function of cytosine-adenine-guanine (CAG) repeat length. A vertical line denotes the time of motor diagnosis (DCL=4).

FIG. 2

Trajectories of motor impairments for converters are illustrated as a function of age-CAG product (CAP). Light gray lines are the empirical trajectories of the participants, and colored lines are the fitted spline model curves. A vertical line denotes the time of motor diagnosis (diagnostic confidence level=4).