Selective Cingulum Degeneration in Huntington's Disease: A Clinically Relevant Event

BACKGROUND: Huntington's disease (HD) is a neurodegenerative disorder with striatal atrophy and widespread white matter abnormalities. The cingulum bundle, central to executive and emotional functions, may be particularly vulnerable in HD. OBJECTIVE: The objective of this study was to characterize cross-sectional and longitudinal diffusion magnetic resonance imaging (MRI) changes in the cingulum bundle in HD and to determine whether these changes are clinically meaningful. METHODS: This longitudinal diffusion MRI study included 66 participants (26 with HD, 20 with premanifest HD [PHD], 20 healthy control subjects) assessed at two or three time points over a mean follow-up of 4.8 years. Multishell acquisitions were analyzed using free water elimination imaging and neurite orientation dispersion and density imaging. Values were extracted from the cingulate (CCG) and angular (CAB) subdivisions of the cingulum bundle. Group differences were assessed cross-sectionally and longitudinally, and associations with Unified Huntington's Disease Rating Scale (UHDRS) Total Functional Capacity (TFC) were examined. RESULTS: At baseline, HD showed widespread diffusion alterations in the CCG, whereas changes in the CAB were more limited. Longitudinally, only the CCG showed progressive change, with reduced fractional anisotropy (FAt) and neurite density index (NDI), as well as increased diffusivity and orientation dispersion. Steeper reduction of UHDRS TFC was associated with a steeper decline in NDI and FAt within the CCG. CONCLUSIONS: These findings indicate more extensive and progressive changes in the CCG than in the CAB in HD, whereas PHD showed no measurable differences. The diffusion profile suggests combined axonal loss and demyelination in fronto-cingulate pathways and supports cingulate NDI and FAt as candidate markers of disease progression in symptomatic HD. © 2026 International Parkinson and Movement Disorder Society.