OBJECTIVE: Huntington's disease (HD) is a monogenic, fully penetrant neurodegenerative disorder, providing an ideal model for understanding brain changes occurring in the years prior to disease onset. Diffusion tensor imaging (DTI) studies show widespread white matter disorganization in the early pre-manifest stages (pre-HD). However, while DTI has proved informative, it provides only limited information about underlying changes in tissue properties. Neurite Orientation Dispersion and Density Imaging (NODDI) is a novel MRI technique for characterizing axonal pathology more specifically, providing metrics that separately quantify axonal density and axonal organization. Here, we provide the first in vivo characterization of white matter pathology in pre-HD using NODDI. METHODS: Diffusion-weighted MRI data that support DTI and NODDI were acquired from 38 pre-HD and 45 control participants. Using whole-brain and region-of-interest analyses, NODDI metrics were compared between groups and correlated with clinical scores of disease progression. Whole-brain changes in DTI metrics were also examined. RESULTS: The pre-HD group displayed widespread reductions in axonal density compared with control participants; this correlated with measures of clinical disease progression in the body and genu of the corpus callosum. There was also evidence in the pre-HD group of increased coherence of axonal packing in the white matter surrounding the basal ganglia. INTERPRETATION: Our findings suggest that reduced axonal density is one of the major factors underlying white matter pathology in pre-HD, coupled with increased local organization in areas surrounding the basal ganglia. NODDI metrics show promise in providing more specific information about the biological processes underlying HD and neurodegeneration per se
