STUDIES OF A MOUSE MODEL OF ALS-PDC

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。通过饮食暴露于苏铁（Cycas micronesica K.D. Hill）毒素已被证明可诱导体内神经变性，模仿进行性神经系统疾病als -帕金森性痴呆复合体（ALS-PDC）。在以前的研究中，特异性皮层和皮层下细胞损失是用常规染色切片测量的。我们研究了磁共振（MR）显微镜在分离的完整脑和脊髓中用于三维检查神经退行性变的效用。给小鼠喂食水洗苏铁2个月，小鼠表现出类似于人ALS-PDC的进行性运动障碍。动物灌注并在17.6特斯拉下成像中枢神经系统组织。对脊髓和脑样本进行T2*扫描，各向同性分辨率为41 mm。苏铁喂养小鼠腰髓灰质、黑质、纹状体、基底核/内囊和嗅球体积显著减少。皮层测量显示，苏铁喂养的小鼠也表现出皮层厚度下降。这些结果表明，MR显微镜足够敏感，可以测量进行性神经疾病早期模型的退变，并且可能适用于同一模型的体内实验。类似的分析可能在未来被用作一种诊断辅助，用于跟踪临床前人类受试者神经系统疾病的早期进展。研究正在评估DTI在检查相同脑组织和检测畸形方面的效用。我们也开始对同一动物的脊髓样本进行类似的检查。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Exposure to cycad (Cycas micronesica K.D. Hill) toxins via diet has been shown to induce neurodegeneration in vivo that mimics the progressive neurological disease, ALS-parkinsonism dementia complex (ALS-PDC). In previous studies, specific cortical and subcortical cell loss was measured with conventional stained sections. We have examined the utility of magnetic resonance (MR) microscopy was used to examine neurodegeneration in 3D in the isolated intact brain and spinal cord. Mice were fed washed cycad for 2 months and showed progressive motor deficits resembling human ALS-PDC. Animals were perfused and CNS tissue was imaged at 17.6 Tesla. T2* scans were conducted on both spinal cord and brain samples with an isotropic resolution of 41 mm. Cycad-fed mice showed significantly decreased volumes in lumbar spinal cord gray matter, substantia nigra, striatum, basal nucleus/internal capsule, and olfactory bulb. Cortical measurements revealed that cycad-fed mice also showed decreased cortical thickness. These results show that MR microscopy is sensitive enough to measure degeneration in this early stage model of a progressive neurological disease, and may be applicable in vivo on the same model. Similar analysis may be used in the future as a diagnostic aid in tracking the early progression of neurological disorders in pre-clinical human subjects. Studies are underway to evaluate the utility of DTI to examine the same brain tissue and detect deformities. We have also begun similar examinations on spinal cord samples from the same animals.