J028 Preparing for secondary prevention treatment trials in HD-ISS Stages 0 and 1: Insights from the Huntington’s disease young adult study (HD-YAS)

<h3>Background</h3> With numerous disease-modification trials underway in Huntington’s disease (HD), there is considerable interest in secondary prevention treatments, yet sensitive biomarkers for early stages are lacking. HD-YAS are a unique cohort of HD Integrated Staging System (HD-ISS) Stage 0 and 1 gene expansion carriers (GECs) with deep phenotyping at baseline and ~4.5 year follow-up, providing an opportunity to validate potential biomarkers decades from predicted disease onset. <h3>Aims</h3> To identify robust biomarkers in HD-ISS Stages 0 and 1 and determine their sensitivity to change over time. <h3>Methods</h3> 154 participants were recruited over two visits spanning ~4.5 years: 131 participants (64 GECs, 67 controls) at visit 1 with an additional 23 (9 GECs, 14 controls) at visit 2. Retention was 89% for GECs and 69% for controls, providing 103 longitudinal datasets. Clinical, cognitive, neuropsychiatric and multi-modal imaging assessments together with blood and cerebrospinal fluid (CSF) samples were acquired. <h3>Results</h3> GECs showed significant increases in CSF neurofilament light (NfL) (FDR=4E-12) and YKL-40 (FDR=0.08) over time compared with controls as well as significantly increased rates of atrophy in the putamen and caudate (FDR=1E-09), and all global brain measures (FDR&lt;0.02). There was no significant decline in cognitive or neuropsychiatric function over time (FDR&gt;0.8). Sample size calculations for biofluid and brain measures suggest feasible numbers for secondary prevention clinical trials in HD-ISS Stages 0 and 1. <h3>Conclusions</h3> CSF NfL and striatal and global brain measures are robust and sensitive to disease progression, making them promising biomarkers with feasible sample sizes for HD-ISS Stage 0 and 1 clinical trials.