EVALUATION OF SPINAL CORD WHITE MATTER INJURY USING DTI

描述（由申请人提供）：扩散张量成像（DTI）测量水分子的扩散，其反映了感兴趣组织的微观结构组织。以前，我们已经证明，水的扩散平行于纤维，轴向扩散，是远远大于垂直于纤维，径向扩散。我们进一步证明了脱髓鞘导致径向扩散率增加，轴突损伤导致白色损伤小鼠模型轴向扩散率降低。在这个提议中，我们假设轴突损伤的体内DTI生物标志物，即，降低轴向扩散率，可作为脊髓损伤（SCI）预后预测的早期和准确的替代终点。脊髓损伤后急性期发生的轴索损伤是导致脊髓损伤后长期神经功能障碍的主要原因。因此，拟议研究的主要目标是确定在什么损伤后的时间点可以使用DTI准确预测功能（行为和电生理）的SCI啮齿动物模型的结果。还将对脊髓型颈椎病（CSM）患者轴索损伤的DTI生物标志物的使用进行翻译，以测试该标志物在临床环境中的疗效。提出了三个关键问题：（1）体内DTI轴突损伤生物标志物是否反映了SCI小鼠的潜在结构变化并预测了长期神经学结果？(2)体内DTI生物标志物与轴突功能相关吗？(3)在脊髓型颈椎病（CSM）患者中，体内DTI生物标记物与神经功能障碍准确相关吗？这些问题将通过使用YFP和shiverer-YFP小鼠（目标1）进行轴突损伤的体内DTI衍生生物标志物的机制评估及其作为SCI结果预测因子的应用，轴突损伤的体内DTI生物标志物与电生理学的功能相关性（目标2）以及该生物标志物对CSM患者的人类翻译（目标3）来解决。脊髓损伤（SCI）可能导致毁灭性的医疗，心理，社会和经济后果。在超急性期注重保留白色物质的实验策略对创伤性SCI后的功能恢复具有最大的潜力。在拟议的研究中成功应用拟议的白色物质的体内扩散张量成像生物标志物将为SCI患者提供更准确的分类和改善的治疗分层。

DESCRIPTION (provided by applicant): Diffusion tensor imaging (DTI) measures the diffusion of water molecules, which reflects the microstructural organization of the tissues of interest. Previously, we have demonstrated that water diffusion parallel to the fibers, axial diffusivity, is much greater than that perpendicular to the fibers, radial diffusivity. We further demonstrated that demyelination leads to an increase in radial diffusivity and axonal damage leads to a decrease in axial diffusivity in mouse models of white matter injuries. In this proposal, we hypothesized that the in vivo DTI biomarker of axonal injury, i.e., decreased axial diffusivity, may serve as an early and accurate surrogate endpoint for outcome prediction in spinal cord injury (SCI). Axonal damage occurring in the acute period following SCI is the primary cause of long-term neurological disabilities in SCI. Thus, the primary goal of the proposed study is to determine at what post-injury time points can DTI be used to accurately predict functional (behavioral and electrophysiological) outcomes in rodent models of SCI. A translation of the use of DTI biomarker of axonal injury to cervical spondylotic myelopathy (CSM) patients will also be pursued to test the efficacy of this marker in the clinical setting. Three key questions are asked: (1) Does the in vivo DTI axonal injury biomarker reflect the underlying structural changes and predict long-term neurological outcome in SCI mice? (2) Do the in vivo DTI biomarkers correlate with axon function as measured with in vivo electrophysiology? (3) Do the in vivo DTI biomarkers accurately correlate with neurological disabilities in human cervical spondylotic myelopathy (CSM) patients? These questions will be addressed by performing the mechanistic assessment of the in vivo DTI derived biomarker of axonal injury and its application as the outcome predictor of SCI using YFP and shiverer-YFP mice (Aim 1), functional correlation of in vivo DTI biomarker of axonal injury with electrophysiology (Aim 2), and the human translation of this biomarker to CSM patients (Aim 3). PUBLIC HEALTH RELEVANCE: Spinal cord injury (SCI) can lead to devastating medical, psychological, social, and financial consequences. Experimental strategies that focus on white matter preservation during the hyperacute phase hold the greatest potential for functional recovery following traumatic SCI. The successful application of the proposed in vivo diffusion tensor imaging biomarker of white matter in the proposed studies will offer a more accurate prognostication and improved treatment stratification for SCI patients.