TY - JOUR
T1 - Spatiotemporal mapping of brain atrophy in mouse models of Huntington's disease using longitudinal in vivo magnetic resonance imaging
AU - Aggarwal, Manisha
AU - Duan, Wenzhen
AU - Hou, Zhipeng
AU - Rakesh, Neal
AU - Peng, Qi
AU - Ross, Christopher A.
AU - Miller, Michael I.
AU - Mori, Susumu
AU - Zhang, Jiangyang
N1 - Funding Information:
This research was supported by grants from the CHDI Inc. Foundation (to W. Duan), NINDS NS16375 (to CAR), NIH EB003543 , RR15241 , and ES012665 (to S. Mori), and NIH NS065306 (to J. Zhang).
PY - 2012/5/1
Y1 - 2012/5/1
N2 - Mouse models of Huntington's disease (HD) that recapitulate some of the phenotypic features of human HD, play a crucial role in investigating disease mechanisms and testing potential therapeutic approaches. Longitudinal studies of these models can yield valuable insights into the temporal course of disease progression and the effect of drug treatments on the progressive phenotypes. Atrophy of the brain, particularly the striatum, is a characteristic phenotype of human HD, is known to begin long before the onset of motor symptoms, and correlates strongly with clinical features. Elucidating the spatial and temporal patterns of atrophy in HD mouse models is important to characterize the phenotypes of these models, as well as evaluate the effects of neuroprotective treatments at specific time frames during disease progression. In this study, three dimensional in vivo magnetic resonance imaging (MRI) and automated longitudinal deformation-based morphological analysis was used to elucidate the spatial and temporal patterns of brain atrophy in the R6/2 and N171-82Q mouse models of HD. Using an established MRI-based brain atlas and mixed-effects modeling of deformation-based metrics, we report the rates of progression and region-specificity of brain atrophy in the two models. Further, the longitudinal analysis approach was used to evaluate the effects of sertraline and coenzyme Q 10 (CoQ 10) treatments on progressive atrophy in the N171-82Q model. Sertraline treatment resulted in significant slowing of atrophy, especially in the striatum and frontal cortex regions, while no significant effects of CoQ 10 treatment were observed. Progressive cortical and striatal atrophy in the N171-82Q mice showed significant positive correlations with measured functional deficits. The findings of this report can be used for future testing and comparison of potential therapeutics in mouse models of HD.
AB - Mouse models of Huntington's disease (HD) that recapitulate some of the phenotypic features of human HD, play a crucial role in investigating disease mechanisms and testing potential therapeutic approaches. Longitudinal studies of these models can yield valuable insights into the temporal course of disease progression and the effect of drug treatments on the progressive phenotypes. Atrophy of the brain, particularly the striatum, is a characteristic phenotype of human HD, is known to begin long before the onset of motor symptoms, and correlates strongly with clinical features. Elucidating the spatial and temporal patterns of atrophy in HD mouse models is important to characterize the phenotypes of these models, as well as evaluate the effects of neuroprotective treatments at specific time frames during disease progression. In this study, three dimensional in vivo magnetic resonance imaging (MRI) and automated longitudinal deformation-based morphological analysis was used to elucidate the spatial and temporal patterns of brain atrophy in the R6/2 and N171-82Q mouse models of HD. Using an established MRI-based brain atlas and mixed-effects modeling of deformation-based metrics, we report the rates of progression and region-specificity of brain atrophy in the two models. Further, the longitudinal analysis approach was used to evaluate the effects of sertraline and coenzyme Q 10 (CoQ 10) treatments on progressive atrophy in the N171-82Q model. Sertraline treatment resulted in significant slowing of atrophy, especially in the striatum and frontal cortex regions, while no significant effects of CoQ 10 treatment were observed. Progressive cortical and striatal atrophy in the N171-82Q mice showed significant positive correlations with measured functional deficits. The findings of this report can be used for future testing and comparison of potential therapeutics in mouse models of HD.
KW - Brain atrophy
KW - Huntington's disease
KW - Longitudinal
KW - Magnetic resonance imaging
KW - Mouse
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U2 - 10.1016/j.neuroimage.2012.01.141
DO - 10.1016/j.neuroimage.2012.01.141
M3 - Article
C2 - 22342677
AN - SCOPUS:84862806580
SN - 1053-8119
VL - 60
SP - 2086
EP - 2095
JO - NeuroImage
JF - NeuroImage
IS - 4
ER -