Background Neurofilament light (NfL) protein in blood plasma has been proposed as a prognostic biomarker of neurodegeneration in a number of conditions, including Huntington’s disease (HD). Previous work has demonstrated elevated levels of NfL in HD gene expansion carriers when compared with controls, with NfL levels reflecting baseline motor and cognitive deficits as well as reduced global and regional brain volume. However, global measures provide limited insight into the regional distribution of NfL-associated pathology due to the HD gene mutation.

Aims This study aims to establish the regional distribution of NfL-associated pathology in HD using voxel-based morphometry (VBM).

Methods We examine associations between NfL measured in plasma and regionally-specific atrophy in cross-sectional (n=198) and longitudinal data (n=177) in HD gene expansion carriers from the international multisite TRACK-HD study. Using VBM we measured associations between baseline NfL levels and both baseline grey matter and white matter volume; and longitudinal change in grey matter and white matter over the subsequent three years in HD gene expansion carriers.

Results After controlling for demographics, associations between increased NfL levels and reduced brain volume were seen in cortical and subcortical grey matter and within the white matter. After also controlling for known predictors of disease progression (age and CAG repeat length), associations were limited to the caudate and putamen. Longitudinally, NfL predicted subsequent occipital grey matter atrophy and widespread white matter reduction, both before and after correction for other predictors of disease progression.

Conclusions These findings highlight the value of NfL as a dynamic marker of brain atrophy and, more generally, provide further evidence of the strong association between plasma NfL level, a candidate blood biomarker, and pathological neuronal change.