STUDIES OF A MOUSE MODEL OF ALS-PDC

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。研究表明，通过饮食摄入苏铁(苏铁K.D.Hill)毒素可在体内诱导神经退行性变，类似于进行性神经系统疾病--ALS-帕金森氏痴呆综合征(ALS-PDC)。在以前的研究中，特定的皮质和皮质下细胞丢失是用常规染色切片测量的。我们已经检验了磁共振(MR)显微镜用于检查分离的完整大脑和脊髓中的3D神经变性的实用性。小鼠喂食洗净的苏铁2个月后，表现出类似人类ALS-PDC的进行性运动障碍。动物被灌流，中枢神经系统组织以17.6特斯拉的速度成像。T2*扫描在脊髓和脑标本上进行，各向同性分辨率为41 mm。给予苏铁的小鼠腰髓灰质、黑质、纹状体、基底核/内囊和嗅球的体积显著减少。皮质测量显示，喂食苏铁的小鼠也显示出皮质厚度减少。这些结果表明，在这种进行性神经系统疾病的早期模型中，MR显微镜具有足够的灵敏度来测量退化，并且可能适用于同一模型的活体实验。类似的分析在未来可能被用作跟踪临床前人类受试者神经疾病的早期进展的诊断辅助。目前正在进行研究，以评估DTI在检查相同脑组织和检测畸形方面的效用。我们也开始对相同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.