Differences in white matter detected by ex vivo 9.4 T MRI are associated with axonal changes in the R6/1 model of Huntington's disease

White matter volume loss has been reported as one of the first indicators in Huntington's disease (HD) patients, but the cellular basis of this deficit remains to be elucidated. To address this, we assessed white matter microstructure in the transgenic R6/1 mouse model of HD with ex vivo MRI. Specifically, a tractometry approach was employed to inspect region-specific differences across the corpus callosum (CC), while voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) were used to identify brain-wise white matter macro- and microstructure abnormalities. Alterations in the macromolecular proton fraction (MPF) from quantitative magnetization transfer (qMT) and in the intra-axonal signal fraction (FR) from the composite hindered and restricted model of diffusion (CHARMED) suggested regional decreases in myelin content and widespread increases in axonal density in this mouse model of HD. A cohort of sex/age-matched mice was assessed on cognitive and simple motor tasks to demonstrate that functional impairments were coincident with imaging deficits. Finally, the neurobiological basis of the MRI phenotype was assessed with histological and electron microscopy analyses in a cohort of sex/age-matched mice, revealing disruptions in axonal morphology (i.e. less complex, thinner axons) and organization (i.e. more densely packed axons) in this mouse model of HD. Furthermore, our results indicate that, at least early in disease progression, R6/1 mice present a reduction in the expression or content of myelin-associated proteins without significant alterations in the structure of myelin sheaths. Crucially, our findings highlight the potential of FR, an in vivo estimate of axon density, as a novel MRI biomarker of HD-associated changes in white matter microstructure.