Tracking labeled stem cells in TBI model by cellular MRI

创伤性脑损伤的病理变化包括急性炎症反应、血脑屏障破坏、出血、脱髓鞘、轴突横断和慢性轴突神经元丢失和胶质增生。干细胞治疗是一种潜在的治疗方法，无论是作为替代治疗还是通过旁分泌效应释放生长因子和抗炎细胞因子来治疗TBI损伤。我们报告了一项基于MRI的轻度TBI大鼠模型的纵向研究，并与2个月以上的组织学相关。我们报道，扩散张量成像（DTI）轴向扩散率和各向异性分数（FA）是敏感的轴突的完整性，而径向扩散率表现出显着的相关性髓鞘致密性。我们还观察到，FA与灰质中的星形胶质细胞增生相关，而平均扩散率与细胞结构增加相关，磁化传递率（MTR）与轴突和髓鞘完整性具有很强的相关性。我们还能够证明，在轻度脑室扩大（MVM）的大鼠中，FA的变化不明显，这表明与轻度TBI后的正常大鼠相比，轴突损伤较少。 与正常大鼠相比，轻度TBI后MVM动物的MTR显著增加。组织学检查显示，与正常动物相比，MVM脑内轴突损伤有限，小胶质细胞和星形胶质细胞增生明显增加。与正常大鼠大脑相比，MVM大鼠在TBI后表现出更大的炎症。 这些结果表明，使用MRI筛查TBI研究中使用的实验动物的脑异常的重要性，并且在TBI研究中观察到的变化可能是由于结构形态对诱导创伤的反应的可变性 扩散张量成像（DTI）和磁化传递成像（MTI）的变化与基础病理之间的关系仍然是相对未知的。我们研究了这些成像技术和免疫组化之间的放射病理学相关性使用封闭的头部大鼠模型TBI。对雌性大鼠进行TBI，随后纵向进行磁共振成像（MRI），直至损伤后30天，选择一组动物进行组织病理学分析。生成基于MRI的有限元分析以表征机械损伤的模式并估计脑损伤的程度以指导与成像结果的病理相关性。我们观察到，DTI轴向扩散率和各向异性分数（FA）是敏感的轴突的完整性，而径向扩散率表现出显着的相关性髓鞘致密性。FA与灰质中的星形胶质细胞增生相关，而平均扩散率与细胞密度增加相关。继发性炎症反应也部分影响这些DTI指标的变化。磁化传递率（MTR）在3.5ppm表现出与轴突和髓鞘完整性的强相关性。20 ppm时MTR的降低与灰质和白色物质中星形胶质细胞增生的程度相关。传统的T2加权MRI没有检测到TBI后的异常，DTI和MTI提供了对反映随时间变化的损伤状态的潜在病理学的补充见解，因此可以替代组织学来揭示体内弥漫性轴突损伤病理学。 代谢异常通常在与长期神经功能缺损相关的TBI患者中观察到。我们研究了化学交换饱和转移（CEST）MRI检测实验性TBI脑代谢紊乱的可行性和可重复性。在优化CEST加权成像参数后，我们研究了评估葡萄糖浓度的图像对比敏感性和特异性。结果表明，在1.52 T脉冲功率下12秒的饱和持续时间导致灰色和白色物质之间的对比噪声比改善，这与2DG放射自显影相当。然后在大鼠弥漫性TBI的闭合头部模型中进行GlucoCEST加权成像31，并将结果与死后2-脱氧-D-14 C-葡萄糖（2DG）放射自显影进行比较，以确定TBI前后葡萄糖摄取和代谢的变化。在这项研究中，我们能够表明，内源性glucoCEST对比度降低TBI后，并与2DG放射自显影的发现，这些结果表明，glucoCEST加权成像可能是有用的检测代谢异常TBI后。

The pathology of traumatic brain injury in experimental models includes acute inflammatory reaction, blood brain barrier disruption, hemorrhage, demyelination, axonal transection and chronically with axonal neuronal loss and gliosis. Stem cell (SC) therapy is a potential treatment either as replacement therapy or via paracrine effect with release of growth factors and anti-inflammatory cytokines for TBI injury. We reported on a longitudinal study in a mild TBI rat model based on MRI and correlated to histology over 2 months. We reported that diffusion tensor imaging (DTI) axial diffusivity and fractional anisotropy (FA) were sensitive to axonal integrity, whereas radial diffusivity showed significant correlation to the myelin compactness. We also observed that FA was correlated with astrogliosis in the gray matter, whereas mean diffusivity was correlated with increased cellularity and magnetization transfer ratio (MTR) demonstrated a strong correlation with both axon and myelin integrity. We also were able to demonstrate that in rats with mild ventriculomegaly (MVM) demonstrated insignificant changes in FA, suggesting less axonal injury compared to normal rats following mild TBI. The MVM animals had significant increase in MTR compared to normal rats following mild TBI. On histological examination, limited axonal injury with significant increase of microgliosis and astrogliosis in MVM brains compared with normal animals. MVM rats exhibited greater inflammation following TBI compared to normal rat brains. These results indicated the importance of using MRI to screen for brain abnormalities in experimental animals used in TBI studies and that the variation observed in TBI studies may be due to the variability in response to induced trauma as a result of structural morphology The relationship between changes in diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI) and the underlying pathologies is still relatively unknown. We investigated the radiological-pathological correlation between these imaging techniques and immunohistochemistry using a closed head rat model of TBI. TBI was performed on female rats followed longitudinally by magnetic resonance imaging (MRI) out to 30 days postinjury, with a subset of animals selected for histopathological analyses. An MRI-based finite element analysis was generated to characterize the pattern of the mechanical insult and estimate the extent of brain injury to direct the pathological correlation with imaging findings. We observed that DTI axial diffusivity and fractional anisotropy (FA) were sensitive to axonal integrity, whereas radial diffusivity showed significant correlation to the myelin compactness. FA was correlated with astrogliosis in the gray matter, whereas mean diffusivity was correlated with increased cellularity. Secondary inflammatory responses also partly affected the changes of these DTI metrics. The magnetization transfer ratio (MTR) at 3.5ppm demonstrated a strong correlation with both axon and myelin integrity. Decrease in MTR at 20ppm correlated with the extent of astrogliosis in both gray and white matter. Conventional T2-weighted MRI did not detect abnormalities following TBI, DTI and MTI afforded complementary insight into the underlying pathologies reflecting varying injury states over time, and thus may substitute for histology to reveal diffusive axonal injury pathologies in vivo. Metabolic abnormalities are commonly observed in TBI patients associated with long-term neurological deficits. We investigated the feasibility and reproducibility using the chemical exchange saturation transfer (CEST) MRI to detect cerebral metabolic disorders in experimental TBI. Following the optimization of the CEST weighted imaging parameters we investigated the image contrast sensitivity and specificity in assessing glucose concentrations. The results demonstrated that saturation duration of 12 seconds at pulses powers 1.52T resulted in improved contrast-to-noise ratio between the gray and white matter that was comparable to 2DG autoradiographs. GlucoCEST weighted imaging was then performed in a closed head model of diffuse TBI in rats31 and the results were compared to postmortem 2-deoxy-D-14C-glucose (2DG) autoradiography to determine changes of glucose uptake and metabolism before and after TBI. In this study, we were able to show that the endogenous glucoCEST contrast was decreased following TBI, and correlated to finding on 2DG autoradiography.These results demonstrate that glucoCEST weighted imaging may be useful to detect metabolic abnormalities following TBI.