Tracking labeled stem cells in TBI model by cellular MRI

通过细胞 MRI 追踪 TBI 模型中的标记干细胞

• 批准号: 10255217
• 负责人: Joseph Frank
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10255217
• 关键词: Accidents; Acute; Affect; Animal Experimentation; Animals; Anisotropy; Anti-Inflammatory Agents; Autopsy; Autoradiography; Axon; Brain; Brain Injuries; Cell model; Cellularity; Cerebrum; Chemicals; Chronic; Closed head injuries; Demyelinations; Diffuse; Diffuse Axonal Injury; Diffusion Magnetic Resonance Imaging; Exhibits; Experimental Models; Female; Finite Element Analysis; Gliosis; Glucose; Goals; Growth Factor; Head; Hemorrhage; Histologic; Histology; Image; Imaging Techniques; Immunohistochemistry; Inflammation; Inflammatory; Inflammatory Response; Injury; Label; Longitudinal Studies; Magnetic Resonance Imaging; Mechanics; Metabolic; Metabolic Diseases; Modeling; Monitor; Morphology; Myelin; Natural History; Nervous System Physiology; Neurologic Deficit; Noise; Pathologic; Pathology; Patients; Pattern; Physiologic pulse; Radial; Radiology Specialty; Rattus; Reaction; Replacement Therapy; Reporting; Reproducibility; Sensitivity and Specificity; Structure; Time; Trauma; Traumatic Brain Injury; Variant; astrogliosis; axon injury; base; blood-brain barrier disruption; brain abnormalities; contrast imaging; cytokine; glucose metabolism; glucose uptake; gray matter; improved; in vivo; insight; mild traumatic brain injury; neuron loss; paracrine; response; stem cell therapy; stem cells; white matter

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.

实验模型中创伤性脑损伤的病理包括急性炎症反应，血液脑屏障破坏，出血，脱髓鞘，轴突横断，以及轴突神经元丧失和胶状病。干细胞（SC）治疗是一种潜在的疗法作为替代疗法或通过旁分泌作用，生长因子的释放和抗炎细胞因子用于TBI损伤。我们报告了基于MRI的轻度TBI大鼠模型的纵向研究，并在2个月内与组织学相关。我们报告说，扩散张量成像（DTI）轴向扩散率和分数各向异性（FA）对轴突完整性敏感，而径向扩散率与髓磷脂的紧凑性显着相关。我们还观察到，FA与灰质中的星形胶质症相关，而平均扩散率与细胞的增加和磁化转移率（MTR）相关，表现出与轴突和髓磷脂完整性均有很强的相关性。我们还能够证明，在轻度心室肿瘤（MVM）的大鼠中，FA表现出微不足道的变化，这表明与轻度TBI相比，与正常大鼠相比，轴突损伤较少。 轻度TBI与正常大鼠相比，MVM动物的MTR显着增加。在组织学检查中，与正常动物相比，MVM大脑中的小胶质细胞增多症和星形胶质细胞增多的显着增加，轴突损伤有限。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筛选在TBI研究中使用的实验动物中脑异常的重要性，并且在TBI研究中观察到的差异可能是由于结构形态的响应诱导创伤的差异造成的。 扩散张量成像（DTI）与磁化转移成像（MTI）的变化与潜在的病理之间的关系仍然相对未知。我们使用TBI的闭合头大鼠模型研究了这些成像技术与免疫组织化学之间的放射学表征相关性。 TBI在雌性大鼠上进行纵向进行磁共振成像（MRI），直到30天后进行，其中一部分动物选择进行组织病理学分析。生成了基于MRI的有限元分析，以表征机械侮辱的模式，并估计脑损伤的程度，以指导与成像发现的病理相关性。我们观察到DTI轴向扩散率和分数各向异性（FA）对轴突完整性敏感，而径向扩散率与髓磷脂紧凑性显着相关。 FA与灰质中的星形胶质细胞增多相关，而平均扩散率与细胞增加相关。次级炎症反应还部分影响了这些DTI指标的变化。在3.5ppm处的磁化转移比（MTR）表现出与轴突和髓磷脂完整性的强相关性。 20ppm时MTR的降低与灰质和白质中星形胶质细胞增多的程度有关。传统的T2加权MRI在TBI，DTI和MTI后未检测到异常，对反映了随着时间的推移反映了变化的损伤状态的潜在病理提供了互补的见解，因此可以代替组织学揭示VIVO中的扩散轴突损伤。 与长期神经缺陷有关的TBI患者通常观察到代谢异常。我们使用化学交换饱和转移（CEST）MRI研究了可行性和可重复性，以检测实验性TBI中的脑代谢性疾病。在优化CEST加权成像参数之后，我们研究了评估葡萄糖浓度时的图像对比度灵敏度和特异性。结果表明，脉冲功率1.52T的12秒饱和持续时间可改善灰质和白质之间的对比度比，与2dg自显影仪相当。然后，在Rats31中的弥漫性TBI的闭合头模型中进行葡萄糖加权成像，并将结果与​​后验尸2-脱氧-D-14C-葡萄糖（2DG）放射率进行比较，以确定TBI之前和之后的葡萄糖摄取和代谢的变化。在这项研究中，我们能够证明TBI后内源性葡萄糖对比降低，并且与在2DG自显影术上的发现相关。这些结果表明，葡萄糖加权成像可能有助于检测TBI后的代谢异常。