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，反映感兴趣组织的微观结构组织。之前，我们已经证明了平行于纤维的水扩散，轴向扩散率，比垂直于纤维的水扩散率，径向扩散率要大得多。我们进一步证明，在小鼠白质损伤模型中，脱髓鞘导致径向弥散性增加，轴突损伤导致轴向弥散性降低。在本研究中，我们假设轴突损伤的体内DTI生物标志物，即轴向弥散性降低，可以作为脊髓损伤（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突损伤是脊髓损伤患者长期神经功能障碍的主要原因。因此，本研究的主要目标是确定DTI在损伤后的什么时间点可以用来准确预测啮齿动物脊髓损伤模型的功能（行为和电生理）结果。DTI生物标志物轴突损伤对脊髓型颈椎病（CSM）患者的翻译应用也将继续进行，以测试该标志物在临床环境中的疗效。我们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脊髓损伤小鼠潜在的结构变化并预测了长期神经预后？(2)体内DTI生物标志物是否与体内电生理测量的轴突功能相关？(3)人脊髓型颈椎病（CSM）患者体内DTI生物标志物是否与神经功能障碍准确相关？这些问题将通过使用YFP和shiveryfp小鼠对体内DTI衍生的轴突损伤生物标志物及其作为脊髓损伤预后预测因子的机制评估（Aim 1），体内DTI轴突损伤生物标志物与电生理学的功能相关性（Aim 2）以及该生物标志物在CSM患者中的人类翻译（Aim 3）来解决。公共卫生相关性：脊髓损伤（SCI）可导致毁灭性的医疗、心理、社会和经济后果。关注超急性期白质保存的实验策略对创伤性脊髓损伤后的功能恢复具有最大的潜力。研究中所提出的白质体内弥散张量成像生物标志物的成功应用，将为脊髓损伤患者提供更准确的预后和改进的治疗分层。

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.