Here we present the Mutant huntingtin (mHTT) and neurofilament light (NfL) findings from the two-year prospective longitudinal HD-CSF study, in which an 80-participant cohort of Huntington’s disease (HD) mutation carriers and controls underwent clinical assessments, sampling of CSF and plasma, and MR imaging, under strictly standardised conditions.

mHTT and NfL have emerged as leading biofluid biomarker candidates for HD. However, we lack robust data from repeated sampling of individual HD mutation carriers to define the longitudinal dynamics of these markers.

We quantified mHTT in CSF and NfL in CSF and blood at baseline and 24-months in the prospective HD-CSF study (20 controls, 20 premanifest HD, 40 manifest HD). We characterised longitudinal trajectories of each analyte using mixed effects models and their relationships with disease progression with partial correlations and linear regression. We computed clinical trial simulations to inform clinical trial design.

mHTT in CSF and NfL in CSF and plasma all increased over time (Figure A-C), had distinct patterns in HD mutation carriers compared with controls (Figure D-F) and increased in a manner dependent on HTT CAG count (Figure G-I). We defined the age where each measure departed from normality for a given CAG count. The baseline value of each analyte predicted subsequent clinical progression and brain atrophy, better than rate of change in the analytes. Unlike baseline concentrations, rate of change in all analytes did not predict disease status. NfL would require fewer participants per arm than mHTT to run clinical trials as an outcome measure.

NfL is a stronger progression biomarker for HD than mHTT and could be used to inform clinical trial design. CSF mHTT nonetheless possesses prognostic value, and will remain an intrinsically valuable pharmacodynamic marker for huntingtin-lowering trials.