Differentiating Hyperkinetic and Hypokinetic Motor Features in the Progression of Huntington's Disease

Huntington's disease (HD) is a monogenic neurodegenerative disorder typically characterized by chorea, a hyperkinetic motor feature. Historical data suggest that hypokinetic features, like rigidity and bradykinesia, become more prominent in later stages of HD. No evidence-based analysis has confirmed this observation. Additionally, several motor features of the disease are not clearly defined as hypokinetic or hyperkinetic.

This study aimed to 1) elucidate the trajectory of hyperkinetic and hypokinetic features across the disease course and 2) to classify vague motor features as following a hyperkinetic or hypokinetic trajectory.

Data from 13,475 motor-manifest HD patients from the Enroll-HD platform were analyzed. Linear mixed-effects models were constructed for each of the 31 Unified Huntington's Disease Rating Scale (UHDRS) motor subscales, with disease burden as the primary predictor. The models were used to generate the trajectories of features known to represent hyperkinesis and hypokinesis, with the same being done for vague subscales. Dynamic time warping (DTW) was then used to classify said subscales as having a hyperkinetic or hypokinetic trajectory.

Hyperkinetic features rise initially and diminish in middle disease, while hypokinetic features continually increase across the disease course. All non-choreiform features demonstrated a hypokinetic-like trajectory.

HD is generally considered a hyperkinetic movement disorder, but the middle and late stages of the disease are predominated by hypokinesis. These findings suggest that hypokinetic features may be a larger contributor to the overall motor burden of HD. This has significant implications for clinical trial design, motor phenotype clustering, and pharmacotherapy.