Abstract
ObjectiveHuntington'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 premanifest stages (pre‐HD). However, although 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 magnetic resonance imaging (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.MethodsDiffusion‐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.ResultsThe 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.InterpretationOur findings suggest that reduced axonal density is one of the major factors underlying white matter pathology in pre‐HD, coupled with altered 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. Ann Neurol 2018;84:497–504
Highlights
Using Neurite orientation dispersion and density imaging (NODDI), a novel technique for analyzing multishell diffusion-weighted imaging (DWI) data, we have shown a widespread reduction in axonal density in tracts including the corpus callosum and those surrounding the basal ganglia in pre-Huntington’s disease (HD)
Axonal density reductions in callosal regions predicted clinical markers of disease progression. These findings support the view that axonal pathology is a major factor underlying white matter degeneration in premanifest HD (pre-HD)
We have shown that the coherence of axonal organization increased in those tracts surrounding the basal ganglia and in the internal and external capsules compared to controls
Summary
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. Neurite orientation dispersion and density imaging (NODDI), for example, applies a 3-compartment tissue model to multishell diffusion-weighted imaging (DWI) data, which allows the interrogation of both intra- and extracellular properties of white matter tissue and in turn enables differentiation of 2 key aspects of axonal pathology: the packing density of axons in white matter (neurite density index [NDI]) and the spatial organization of the axons (orientation dispersion index [ODI]).[14] The amount of free water present (free water fraction) is independently quantified Using this approach, changes in axonal density can be distinguished from those in axonal spatial organization, while removing the potentially confounding effect of free water, which increases in areas of tissue degeneration.[15]. We predicted that axonal density reduction would be the main feature of white matter pathology and would correlate with clinical markers of disease progression in pre-HD
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