Hutchinson Elizabeth B, Romero-Lozano Anakaren, Johnson Hannah R, Knutsen Andrew K, Bosomtwi Asamoah, Korotcov Alexandru, Shunmugavel Anandakumar, King Sarah G, Schwerin Susan C, Juliano Sharon L, Dardzinski Bernard J, Pierpaoli Carlo
Department of Biomedical Engineering, University of Arizona, Tucson, AZ, United States.
Center for Neuroscience and Regenerative Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, United States.
Front Neurosci. 2022 Feb 23;15:779533. doi: 10.3389/fnins.2021.779533. eCollection 2021.
Pre-clinical models of traumatic brain injury (TBI) have been the primary experimental tool for understanding the potential mechanisms and cellular alterations that follow brain injury, but the human relevance and translational value of these models are often called into question. Efforts to better recapitulate injury biomechanics and the use of non-rodent species with neuroanatomical similarities to humans may address these concerns and promise to advance experimental studies toward clinical impact. In addition to improving translational aspects of animal models, it is also advantageous to establish pre-clinical outcomes that can be directly compared with the same outcomes in humans. Non-invasive imaging and particularly MRI is promising for this purpose given that MRI is a primary tool for clinical diagnosis and at the same time increasingly available at the pre-clinical level. The objective of this study was to identify which commonly used radiologic markers of TBI outcomes can be found also in a translationally relevant pre-clinical model of TBI. The ferret was selected as a human relevant species for this study with folded cortical geometry and relatively high white matter content and the closed head injury model of engineered rotation and acceleration (CHIMERA) TBI model was selected for biomechanical similarities to human injury. A comprehensive battery of MRI protocols based on common data elements (CDEs) for human TBI was collected longitudinally for the identification of MRI markers and voxelwise analysis of T2, contrast enhancement and diffusion tensor MRI values. The most prominent MRI findings were consistent with focal hemorrhage and edema in the brain stem region following high severity injury as well as vascular and meningeal injury evident by contrast enhancement. While conventional MRI outcomes were not highly conspicuous in less severe cases, quantitative voxelwise analysis indicated diffusivity and anisotropy alterations in the acute and chronic periods after TBI. The main conclusions of this study support the translational relevance of closed head TBI models in intermediate species and identify brain stem and meningeal vulnerability. Additionally, the MRI findings highlight a subset of CDEs with promise to bridge pre-clinical studies with human TBI outcomes.
创伤性脑损伤（TBI）的临床前模型一直是理解脑损伤后潜在机制和细胞改变的主要实验工具，但这些模型与人类的相关性和转化价值常常受到质疑。更好地重现损伤生物力学以及使用与人类具有神经解剖学相似性的非啮齿类动物的努力，可能会解决这些问题，并有望推动实验研究产生临床影响。除了改善动物模型的转化方面，建立可以直接与人类相同结果进行比较的临床前结果也具有优势。鉴于MRI是临床诊断的主要工具，同时在临床前水平也越来越容易获得，非侵入性成像尤其是MRI在这方面很有前景。本研究的目的是确定在与人类TBI具有转化相关性的临床前模型中也能找到哪些常用的TBI结果影像学标志物。雪貂因其折叠的皮质几何结构和相对较高的白质含量被选为与人类相关的物种，而工程旋转和加速闭合性颅脑损伤模型（CHIMERA）TBI模型则因其与人类损伤的生物力学相似性而被选中。基于人类TBI的通用数据元素（CDE），纵向收集了一系列全面的MRI方案，用于识别MRI标志物以及对T2、对比增强和扩散张量MRI值进行体素分析。最显著的MRI结果与重度损伤后脑干区域的局灶性出血和水肿一致，以及对比增强显示的血管和脑膜损伤。虽然在较轻的病例中传统MRI结果不太明显，但定量体素分析表明TBI后急性期和慢性期的扩散率和各向异性发生了改变。本研究的主要结论支持闭合性颅脑损伤模型在中间物种中的转化相关性，并确定了脑干和脑膜的易损性。此外，MRI结果突出了一部分有希望将临床前研究与人类TBI结果联系起来的CDE。
