Natural history of disease in the YAC128 mouse reveals a discrete signature of pathology in Huntington disease
Natural history of disease in the YAC128 mouse reveals a discrete signature of pathology in Huntington disease
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DOI：
10.1016/j.nbd.2011.03.018
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发表时间：
2011-07-01
影响因子：
6.1
通讯作者：
Hayden, Michael R.
中科院分区：
文献类型：
--
作者：
Carroll, Jeffrey B.;Lerch, Jason P.;Hayden, Michael R.
亨廷顿病（HD）模型概括了该疾病的一些神经病理特征。然而，尚未对表达全长亨廷顿蛋白的小鼠神经解剖学的全球自然历史进行研究。我们利用磁共振成像（MRI）技术研究了HD小鼠YAC128模型的神经病理变化。在YAC128小鼠中，受人类HD影响的结构在绝对数量和脑容量百分比上都减少了。抗HD变性的结构，包括小脑和海马体，在YAC128小鼠中得以保留。主要白质结构的分割证实了HD患者白质的特异性、进行性损失。在比体积损失的同时，YAC128小鼠也表现出心室总容积的进行性增加，与人类HD患者相似。YAC128小鼠的皮质萎缩是层特异性的，这是在人类HD患者中观察到的皮质丧失模式。最后，我们使用分类树分析，以客观的方式最大限度地分离所有62个结构体积的基因型。这一分析表明，皮层下灰质结构（纹状体、苍白球、丘脑）和大脑白质结构（胼胝体、前连骨、纤维）是最具歧视性的。当前研究的高分辨率能够对细微的早期病理变化进行可靠的测量。小鼠的使用进一步使我们能够解决难以在人类中解决的问题，包括HD从基线开始的顺序变化以及MRI和立体测量之间的关系。(C) 2011出版的爱思唯尔公司。
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. (C) 2011 Published by Elsevier Inc.