D020 Cerebrospinal fluid neurofilament light as a sensitive biomarker for early neurobiological changes in HD-ISS Stages 0 and 1: insights from the Huntington’s disease young adult study (HD-YAS)

<h3>Background</h3> Advances in HD therapeutics underscore the need for early intervention to delay or prevent the onset of clinical symptoms. To identify the optimal treatment window, it is crucial to detect neurobiological changes before functional impairment occurs. HD-YAS provides a unique opportunity to examine premanifest gene expansion carriers (GECs) at an earlier stage than previously studied. <h3>Aims</h3> To determine when disease-related fluid biomarkers first become detectable, how they change over time, and to thereby identify the best measures for future clinical trial surrogate endpoints in GECs at HD Integrated Staging System (HD-ISS) Stages 0 and 1. <h3>Methods</h3> 514 participants were recruited across two longitudinal visits spanning 4.5 years. Baseline data collection (2017-2019) included 131 participants (64 GECs, 67 controls). An additional 23 participants (9 GECs, 14 controls) were recruited for the second visit (2022-2024). 216 paired fasting cerebrospinal fluid (CSF) and plasma samples were collected to assess biofluid markers of neuronal health. <h3>Results</h3> Cross-sectional analysis revealed significantly elevated levels of CSF neurofilament light (NfL) (FDR=8.24E-15), plasma NfL (FDR=2.23E-04), and CSF YKL-40 (FDR=0.00156) in GECs, compared to controls. These biomarkers were higher in HD-ISS Stage 1, compared to HD-ISS Stage 0, and correlated with age, CAG length, and CAG-by-age interaction. Longitudinally, significant increases were observed in CSF NfL (FDR=4.14E-12) and YKL-40 (FDR=0.077) levels. <h3>Conclusions</h3> Our findings suggest that CSF NfL is a highly sensitive biomarker for detecting early neurobiological and longitudinal changes in GECs, thus rendering CSF NfL a promising likely surrogate endpoint for HD-ISS Stages 0 and 1 clinical trials.