Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, Canada V5Z 4H4.
Neurobiol Dis. 2011 Jul;43(1):257-65. doi: 10.1016/j.nbd.2011.03.018. Epub 2011 Mar 31.
Models of Huntington disease (HD) recapitulate some neuropathological features of the disease. However, a global natural history of neuroanatomy in a mouse expressing full-length huntingtin has not been conducted. We investigated neuropathological changes in the YAC128 murine model of HD using magnetic resonance imaging (MRI). Structures affected in human HD are reduced in the YAC128 mice both in absolute terms and in terms of percentage of brain volume. Structures resistant to degeneration in HD, including the cerebellum and hippocampus, are spared in the YAC128 mice. Segmentation of major white matter structures confirms specific, progressive, loss of white matter in HD. In parallel with their specific volume loss, the YAC128 mice also show progressive increases in total ventricular volume, similarly to human HD patients. Cortical atrophy in the YAC128 mice is layer specific, which is the observed pattern of cortical loss in human HD patients. Finally, we have used a classification tree analysis to maximize separation of genotypes using all 62 structure volumes in an objective manner. This analysis demonstrates that sub-cortical gray matter structures (striatum, globus pallidus, thalamus) and cerebral white matter structures (corpus callosum, anterior commisure, fimbria) are the most discriminatory. The high resolution of the current study enables robust measurement of subtle early pathological changes. The use of mice furthermore enables us to address questions difficult to address in humans, including the sequential changes of HD from baseline and the relation between MRI and stereological measures.
亨廷顿病 (HD) 的模型再现了该疾病的一些神经病理学特征。然而，尚未对表达全长亨廷顿蛋白的小鼠进行全脑神经解剖学的全球自然史研究。我们使用磁共振成像 (MRI) 研究了 YAC128 小鼠 HD 模型的神经病理学变化。在 YAC128 小鼠中，人类 HD 中受影响的结构无论是绝对值还是脑体积百分比都减少了。在 YAC128 小鼠中，对退化有抵抗力的结构，包括小脑和海马体，免受影响。主要白质结构的分割证实了 HD 中白质的特异性、进行性丧失。与它们特定的体积损失平行，YAC128 小鼠的总脑室体积也呈进行性增加，类似于人类 HD 患者。YAC128 小鼠的皮质萎缩是分层特异性的，这是人类 HD 患者皮质丧失的观察模式。最后，我们使用分类树分析以客观的方式使用所有 62 个结构体积最大化分离基因型。该分析表明，皮质下灰质结构（纹状体、苍白球、丘脑）和大脑白质结构（胼胝体、前连合、穹窿）是最具区分性的。目前研究的高分辨率能够稳健地测量细微的早期病理变化。使用小鼠还使我们能够解决在人类中难以解决的问题，包括从基线开始的 HD 的连续变化以及 MRI 和立体学测量之间的关系。
