Abstract
Huntington’s disease (HD) is a genetically-determined neurodegenerative disease. Characterising neuropathology in mouse models of HD is commonly restricted to cross-sectional ex vivo analyses, beset by tissue fixation issues. In vivo longitudinal magnetic resonance imaging (MRI) allows for disease progression to be probed non-invasively. In the HdhQ150 mouse model of HD, in vivo MRI was employed at two time points, before and after the onset of motor signs, to assess brain macrostructure and white matter microstructure. Ex vivo MRI, immunohistochemistry, transmission electron microscopy and behavioural testing were also conducted. Global brain atrophy was found in HdhQ150 mice at both time points, with no neuropathological progression across time and a selective sparing of the cerebellum. In contrast, no white matter abnormalities were detected from the MRI images or electron microscopy images alike. The relationship between motor function and MR-based structural measurements was different for the HdhQ150 and wild-type mice, although there was no relationship between motor deficits and histopathology. Widespread neuropathology prior to symptom onset is consistent with patient studies, whereas the absence of white matter abnormalities conflicts with patient data. The myriad reasons for this inconsistency require further attention to improve the translatability from mouse models of disease.
Highlights
Huntington’s disease (HD) is a genetically-determined neurodegenerative disease
Animal models is that the whole disease course can be studied; in patients it is difficult to study structural brain changes in vivo in more advanced disease stages due to the incompatibility of chorea with magnetic resonance imaging (MRI)
Longitudinal MRI enables a region- and temporally-specific readout of neuropathology, which can inform on the design of future animal studies, allowing for the most appropriate mouse line to be selected
Summary
Huntington’s disease (HD) is a genetically-determined neurodegenerative disease. Characterising neuropathology in mouse models of HD is commonly restricted to cross-sectional ex vivo analyses, beset by tissue fixation issues. In the HdhQ150 mouse model of HD, in vivo MRI was employed at two time points, before and after the onset of motor signs, to assess brain macrostructure and white matter microstructure. Animal models is that the whole disease course can be studied; in patients it is difficult to study structural brain changes in vivo in more advanced disease stages due to the incompatibility of chorea with magnetic resonance imaging (MRI). The primary value of pre-clinical (animal) MRI lies in the capability for within-subject longitudinal designs with increased power and experimental control to study the disease time course and evaluate therapeutic outcomes at different disease stages. Longitudinal MRI enables a region- and temporally-specific readout of neuropathology, which can inform on the design of future animal studies, allowing for the most appropriate mouse line to be selected. Previous work in a mouse model with a different YFP expression pattern (YFP(H)-R6/2) found no axonal disruption[7], suggesting that axonal pathology is spatially and temporally selective and dependent on the specific genetic model of HD
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