F010 Shield-HD: a longitudinal natural history study with implications for interventional trials

<h3>Background</h3> Shield-HD is a longitudinal natural history study well-positioned to answer questions about how biomarkers, clinical assessments, and volumetric MRI data interrelate over the course of disease progression. Participants were recruited and assigned to three cohorts based on CAP score (&lt;290, 290–400, &gt;400). Ultimately, N = 68 subjects passed screening and were followed for up to 120 weeks. <h3>Aims</h3> Our goals are threefold: 1) To explore the role of the Huntington’s Disease Integrated Staging System (HD-ISS) in Shield and its adoption in future studies. 2) To estimate departures from baseline for common endpoints and to compare these results to those from previous studies. 3) To estimate correlations between outcomes, fully leveraging Shield’s high-resolution multimodal data. <h3>Methods</h3> Analyses are based on regression techniques for correlated error terms (such as mixed models). Subject-specific effects are extracted from these models in order to compute correlations between multiple longitudinal variables. Results are augmented with data from Enroll PDS6 and Track-HD/TrackOn-HD. <h3>Results</h3> We mention several results pertaining to the second goal above. Putamen and Caudate volumes declined at estimated rates of 1.9% and 6.5% per year respectively. Concentrations of plasma NfL increased slightly (1.0 ng/L per year) while no analogous changes were found in the CSF. Clinical composite scores showed either no significant changes (HD-CAB) or slight decline (cUHDRS; .3 points per year). These statistically detectable changes from baseline were generally smaller than expected. <h3>Conclusions</h3> Shield-HD is particularly valuable in guiding future interventional trials. We emphasize this perspective throughout, especially with respect to recruitment and the selection of endpoints.