PROJECT SUMMARY (ABSTRACT) As genetic and disease-modifying interventions emerge, there is an urgent need for early and accurate assessment of disease-specific motor impairments in people with Huntington’s disease (HD). Traditional measures are subjective and episodic and have a limited ability to capture early, subtle motor features. Digital measures have the potential to remotely quantify disease-specific impairments in individuals with HD. A key next step is to evaluate the most promising digital measures in the early stages of HD. Gait impairments and involuntary choreic movements are clinical hallmarks of HD and two of the earliest motor signs. Chorea, which is characterized by involuntary writhing movements, can affect gait characteristics and make conventional approaches to quantifying gait using wearable sensors inaccurate in HD. Our pilot work has shown that wearable sensors can evaluate the quantity and quality of daily living gait in people with HD, even in the presence of chorea, with the aid of tailored machine learning. Exciting initial findings also suggest that chorea severity can be captured using digital health technologies (DHTs) like wearable sensors. Daily physical activity, heart rate variability, and sleep also differ in individuals with HD and healthy controls. All of these measures have the potential to be meaningful endpoints in HD clinical trials, but critical gaps first need to be addressed. We aim to demonstrate the reliability, validity, and meaningfulness of two key digital measures, daily living mobility (gait) and chorea, captured remotely and continuously using wearable sensors. We will also explore daily physical activity, heart rate variability, and sleep. In this remote, cross-sectional study, 40 individuals with early HD (HD Integrated Staging System, HD-ISS Stage 2, and early Stage 3) and 20 control participants will wear two sensors (trunk and wrist) for 1 and 2 weeks, respectively, and will complete telehealth assessments and interviews. Our long-term objective is to fully establish these digital measures as drug development tools and treatment response endpoints in early HD. Our two specific aims are: 1) demonstrate the construct validity and test-retest reliability of a) real-world gait and chorea and b) daily living physical activity, heart rate variability, and sleep quality using wrist-worn wearable sensors in people with early-stage HD; and 2) a) to map personally bothersome and important symptoms/impacts of HD and assess relevance of selected digital measures and b) to evaluate the relationship between the digital measures and patient-reported outcomes. The proposed work will be the first time that our innovative symptom mapping approach is applied to HD, the first time that DHTs are connected to patient-reported meaningfulness in HD, and the first time that real- world study of gait and chorea in HD is assessed as a function of the recently developed HD-ISS staging. This will also be the first s...