D022 Baseline clinical and imaging associations of fluid biomarkers in early manifest Huntington’s disease (HD) for the tominersen phase 3 trial generation-HD1 (Gen-HD1)

<h3>Background</h3> The relationship between clinical status and fluid and imaging biomarkers is poorly understood in HD. <h3>Aims</h3> Describing the cross-sectional associations at baseline between wet biomarkers, imaging and clinical endpoints for one of the largest clinical trial data sets in HD to date (Gen-HD1). <h3>Methods/Techniques</h3> Associations were explored between levels of Neurofilament Light Chain protein (NfL), Chitinase-3-like protein 1 (YKL40), total Tau protein and Glial fibrillary acidic protein (GFAP) and the Unified Huntington’s Disease Rating Scale (UHDRS), the HD digital motor score (HDDMS) as well as volumetric imaging. <h3>Results/Outcome</h3> NfL and GFAP levels in cerebrospinal fluid (CSF) were most robustly associated across different clinical endpoints of the UHDRS as well as the HDDMS. Total Tau and YKL40 were mostly associated with the total motor score (TMS). Notably, plasma NfL was the only robust cross-sectional marker of functional status assessed via the Total Functional Capacity Score (TFC). CSF NfL as well as GFAP were strongly associated with the volume of the caudate nucleus, in line with HD neurodegeneration. We observed a more complex pattern for the size of the lateral ventricles with a positive association (higher concentration, larger volume) for NfL and GFAP and negative association (higher concentration, smaller volume) for YKL40 and total Tau. <h3>Conclusions</h3> These observations confirm the relevance of wet biomarkers in HD and suggest that NfL measured in CSF and plasma may be particularly well positioned to corroborate the biological and symptomatic disease status and response to treatment in HD clinical trials.