Diffusion Tensor Imaging of the Injured Spinal Cord

说明： 理论基础和初步数据：我们将对实验性胸部挫伤后颈髓的扩散张量成像变化和组织病理学进行验证和表征。与传统的神经学检查相比，使用T2加权成像检测水肿的常规MRI扫描并不能更好地预测脊髓损伤(SCI)患者的恢复程度。弥散张量成像(DTI)有望成为脊髓损伤预后的生物标志物。然而，损伤部位的DTI经常受到脊柱固定硬件的伪影的阻碍。我们在大鼠身上进行的临床前研究表明，高位颈髓(HcDTI)的DTI改变与损伤严重程度和功能恢复相关。因此，我们的初步数据表明，DTI测量的高位颈髓的弥散率是脊髓损伤后神经损伤的潜在生物标志物。虽然前景看好，但更全面的验证对于人类脊髓损伤的准确诊断是必要的。为此，我们将使用我们的胸部挫伤的临床前模型来促进对颈髓DTI变化作为损伤标志的理解。假设和具体目的：我们假设高位颈髓的高级MRI是组织损伤和损伤严重程度的准确生物标记物，可以预测预后。为了验证这一假设，我们将采用大鼠胸部挫伤脊髓损伤的模型，并进行活体磁共振成像、功能评估和组织病理学检查。我们将通过进行弥散峰度成像(DKI)和定量T2(QT2)来检验我们的假设，以改善急性情况下的预后能力(目标1)，建立这些指标作为损伤部位组织损伤的替代指标(目标2)，并使用金标准组织病理学(目标3)阐明远离损伤部位的MRI变化的病理生理学机制。为了实现这些目标，使用体内DKI和qT2、定量组织病理学分析和功能评估的多学科方法将提供对非侵入性成像标记物与其生物学基础和功能含义之间的关系的全面理解。我们假设，DKI和qT2磁共振技术将增强对急性环境中损伤的检测。此外，颈髓DTI的变化被认为能准确地反映损伤部位的损伤程度，以备用白质的数量来评估。最后，推测除了轴突变性和脱髓鞘外，星形胶质细胞的反应性是损伤的一个显著特征，发生在离损伤较远的地方，并与功能恢复的程度有关。总之，这些研究将建立和验证hcDTI作为脊髓损伤的敏感生物标志物，具有改善预后的潜力，并将指导向人类脊髓损伤的翻译。

DESCRIPTION: Rationale and Preliminary Data: We will conduct a validation and characterization of the diffusion tensor imaging changes and histopathology of the cervical spinal cord following experimental thoracic contusion injury. Conventional MRI scans to detect edema using T2-weighted imaging are no better at predicting the degree of recovery in patients with spinal cord injury (SCI) than a traditional neurological examination. Diffusion tensor imaging (DTI) is showing promise as a prognostic imaging biomarker in SCI. However, DTI at the injury site is often hampered by artifacts from spinal fixation hardware. Our preclinical studies in the rat have demonstrated robust DTI alterations in the high cervical spinal cord (hcDTI) that correlate with injury severity and functional recovery. Thus, our preliminary data indicates that diffusivity in te high cervical spinal cord, as measured by DTI, is a potential biomarker of neural injury in SCI. While promising, a more comprehensive validation is necessary for accurate diagnosis in human SCI. To that end, we will employ our preclinical model of thoracic contusion injury to advance the understanding of the DTI changes in the cervical cord as markers of injury. Hypothesis and Specific Aims: We hypothesize that advanced MRI of the high cervical spinal cord is an accurate biomarker of tissue damage and injury severity that is prognostic of outcome. To examine this hypothesis, we will employ a rat model of thoracic contusion spinal cord injury and perform in vivo MRI, functional assessments, and histopathology. We will test our hypothesis by performing diffusion kurtosis imaging (DKI) and quantitative T2 (qT2) to improve the prognostic ability in the acute setting (Aim 1), establish these measures as a surrogate maker of tissue damage at the site of injury (Aim 2), and elucidate the pathophysiological mechanisms of MRI changes remote from the site of injury using gold-standard histopathology (Aim 3). To accomplish these aims, a multidisciplinary approach using in vivo DKI and qT2, quantitative histopathological analysis, and functional assessments will provide a comprehensive understanding of the relationship between noninvasive imaging markers and their biological underpinnings and functional implications. We hypothesize that detection of injury in the acute setting will be enhanced by DKI and qT2 MRI techniques. Furthermore, it is believed that the cervical cord DTI changes accurately reflect the degree of injury at the site of injury assessed by the amount of spared white matter. Finally, it is postulatd that in addition to axonal degeneration and demyelination, astrocyte reactivity is a prominent feature of injury that occurs distant from the injury and relates to the degree of functional recovery. Collectively, these studies will establish and validate hcDTI as a sensitive biomarker of SCI with the potential to improve prognostication and will guide translation to human SCI.