From the Departments of Physiology (K.H., R.Y., Y.K., H.O.) and Diagnostic Radiology (S.M.), Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Central Institute for Experimental Animals, Kawasaki, Japan (K.H., K.A., R.Y., K.K., Y.K., T. Inoue, T. Itoh); Faculty of Radiological Technology, Fujita Health University School of Health Sciences, Toyoake, Japan (M.Y.); Division of Regenerative Medicine, Jikei University School of Medicine, Tokyo, Japan (H.J.O.); and Laboratory for Marmoset Neural Architecture, RIKEN Brain Science Institute, Wako, Japan (H.O.).
Radiology. 2015 May;275(2):430-7. doi: 10.1148/radiol.14140601. Epub 2015 Jan 15.
To investigate the use of diffusion-tensor imaging (DTI) to detect denervation of the nigrostriatal pathway in a nonhuman primate model of Parkinson disease (PD) after treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
This study was approved by the institutional committee for animal experiments. DTI was performed in marmosets (n = 6) by using a 7-T magnetic resonance (MR) imager before and 10 weeks after administration of MPTP. Fixed brains of a normal marmoset and a marmoset model of PD (n = 1) were analyzed by using microscopic tractography. Tyrosine-hydroxylase staining of dopaminergic neurons and three-dimensional histologic analysis also were performed in normal marmosets (n = 2) and a PD marmoset model (n = 2) to validate the course of the nigrostriatal pathway revealed at tractography. Statistical analysis of voxel-based and post hoc region-of-interest analyses of DTI maps was performed by using a paired t test.
At voxel-based analysis of DTI before and after treatment, MPTP-treated marmoset brains showed significantly increased axial and radial diffusivity in the bilateral nigrostriatal pathway (P < .05, false discovery rate corrected). The largest area of significantly increased diffusivity was an area of axial diffusivity in the right hemispere (177 mm(3)) that corresponded to the location of dopaminergic neurodegeneration at histologic evaluation. Region-of-interest analysis revealed a 27% increase in axial diffusivity in the right hemisphere (1.198 mm(2)/sec ± 0.111 to 1.522 mm(2)/sec ± 0.118; P = .002). Three-dimensional histologic analysis with tyrosine-hydroxylase staining showed the course of the nigrostriatal pathway and degeneration in the PD marmoset model as the absence of a tyrosine-hydroxylase stained region. Microscopic tractography showed that the connection of the substantia nigra to the striatum followed the same course as the nigrostriatal pathway and fewer fiber tracts in the PD marmoset model.
DTI and microscopic tractography showed the loss of fiber structures of the nigrostriatal pathway in the marmoset model of PD. The results of this study provide a potential basis for the use of DTI in the clinical diagnosis of PD.
利用弥散张量成像（DTI）检测 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）治疗后非人类灵长类帕金森病（PD）模型黑质纹状体通路的去神经支配。
本研究经机构动物实验委员会批准。在 MPTP 给药前和给药后 10 周，使用 7-T 磁共振（MR）成像仪对 6 只狨猴进行 DTI 检查。通过微观轨迹法分析正常狨猴和 PD 狨猴模型（n=1）的固定脑。还对 2 只正常狨猴和 2 只 PD 狨猴模型进行酪氨酸羟化酶染色和三维组织学分析，以验证轨迹法显示的黑质纹状体通路的过程。通过配对 t 检验对 DTI 图的基于体素和事后感兴趣区分析进行统计分析。
在治疗前后的基于体素的 DTI 分析中，MPTP 治疗的狨猴大脑双侧黑质纹状体通路的轴向和径向弥散度显著增加（P<0.05，假发现率校正）。弥散度显著增加的最大区域是右侧半球的轴向弥散度区域（177mm3），与组织学评估时多巴胺能神经退行性变的位置相对应。感兴趣区分析显示右侧半球轴向弥散度增加 27%（1.198mm2/sec±0.111 至 1.522mm2/sec±0.118；P=0.002）。用酪氨酸羟化酶染色的三维组织学分析显示，PD 狨猴模型中的黑质纹状体通路和变性的过程是酪氨酸羟化酶染色区域的缺失。微观轨迹法显示，黑质与纹状体的连接与黑质纹状体通路的相同，PD 狨猴模型中的纤维束较少。
DTI 和微观轨迹法显示 PD 狨猴模型中黑质纹状体通路的纤维结构丢失。本研究结果为 DTI 在 PD 的临床诊断中的应用提供了潜在的基础。
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