Mapping brain volume changes in the zQ175DN mouse model of Huntington’s disease: a longitudinal MRI study

BACKGROUND: Huntington's disease (HD) is a progressive neurodegenerative disease affecting motor and cognitive abilities, as well as exhibiting psychiatric manifestations. Studies in people with HD (PwHD) consistently report atrophy of the caudate and putamen as an early pathological event and is therefore considered an early biomarker. Investigating whether similar phenotypic features are apparent in rodent HD models is important since it could have translational potential in evaluating the efficacy of novel therapeutic strategies. METHODS: We used high-resolution anatomical images to longitudinally investigate brain morphology in the zQ175DN heterozygous mouse model (HET) and wildtype littermates (WT) at 3, 6, and 10 months of age (M), which reflect different stages of phenotypic progression. We investigated volumetric alterations using semi-automatic segmentations of HD on relevant regions-of-interest (striatum, cerebellum, corpus callosum, cerebral cortex, ventricles, and total brain volume) and whole brain voxel-wise Tensor Based Morphometry (TBM) analysis. RESULTS: The striatum showed the earliest progressive lower absolute volume in HET mice compared to WT, starting from 3 M, followed by lower absolute volume of cortex and corpus callosum concomitantly at 6 and 10 M. TBM highlighted lower relative local volume in the rostral-medial striatum at all ages, and in cerebral cortex in HET mice at 6 and 10 M. A bigger relative local volume in the cerebellum was observed at all ages in HET mice, and in the globus pallidus, substantia nigra, at 6 and 10 M. CONCLUSIONS: Overall, this study revealed key structural abnormalities that resemble the natural history of PwHD. Hence, analysis of brain structure through MRI in the zQ175DN heterozygous mouse model holds potential for testing disease-modifying treatments expected to slow down or prevent structural degeneration.