Brain Microstructural MRI in a Piglet Model of Hypoxia-Ischemia

项目概要： 我们建议建立一个完整的磁共振成像和分析平台，以检查缺氧缺血（HI） 新生仔猪模型中的脑损伤，并开发新的MRI标记物， 损伤进展过程中的细胞病理学虽然MRI已广泛用于HI，但图像解释 以及常规MRI标记物（如T1和T2加权MRI或扩散MRI）的预测准确性 （dMRI），留下许多需要改进的地方。在这个项目中，我们将开发微结构MRI标记使用 扩散时间（td）依赖性dMRI，这可能会提高识别的灵敏度和特异性 HI中的细胞损伤。td-dMRI将通过测量不同td的水扩散率来实现，使用振荡 梯度自旋回波（OGSE）dMRI序列，以确定td依赖性，这反映了细胞 形态学在新生儿HI的小鼠模型中，我们已经证明了td-dMRI对小的 损伤早期细胞和亚细胞器的显微结构变化，以及这些显微结构细节 是常规dMRI无法触及的。在这里，我们将使用全脑HI的临床相关仔猪模型， 其表现出明确定义的灰和白色物质损伤表型，对应于人类足月妊娠， 新生儿缺氧症在该模型中开发MRI标记物并研究 新的MRI标记物的神经病理学底物将具有很高的临床影响。临床翻译td- 然而，由于临床扫描仪上的梯度系统限制了可达到的td， 可检测的显微结构分辨率。我们将开发新的OGSE序列，以解决梯度 限制，并使用仔猪模型评估td-dMRI的临床潜力。本研究将于 3 T人体扫描仪，因此，MRI技术将很容易转化为临床领域。 我们推测，td-dMRI对HI后神经元和细胞器的急性肿胀敏感，并且在HI后早期， dMRI测量可预测长期神经病理学和神经学结局。在目标1中，我们将建立一个 具有多度量MRI标记的仔猪MRI平台，包括体积测量、高阶dMRI（DTI，DKI， 纤维束成像）、磁转移成像、沿着td-dMRI测量。我们还将建立 开发猪脑和基于图谱的图像分析，以实现多指标的自动量化 MRI数据。在目标2中，我们将研究td-dMRI在检测急性和急性脑梗死过程中微结构损伤的实用性。 亚急性HI（6小时-7天），并探讨早期MRI标记物与细胞和 亚细胞器病理学在目标3中，我们将进行多测量MRI，以跟踪 HI后恢复30天以上的仔猪，并评估早期神经元损伤与白色之间的关系 连接束的物质损伤，以及神经行为测试的长期功能结果。 本研究中开发的MRI标记物可能会改善临床诊断和预后 新生儿HI，这可能会导致准确和非侵入性评估这些新生儿的辅助治疗。

Project summary: We propose to establish an integrated MR imaging and analysis platform to examine hypoxic-ischemic (HI) brain injury in a neonatal piglet model, and to develop novel MRI markers that characterizes the evolving cellular pathology during injury progression. While MRI has been used extensively in HI, image interpretation and predictive accuracy of the conventional MRI markers, such as T1 and T2-weighted MRI or diffusion MRI (dMRI), leave much to be desired. In this project, we will develop microstructural MRI markers using the diffusion-time (td) dependent dMRI, which potentially improves the sensitivity and specificity of identifying cellular injury in HI. td-dMRI will be achieved by measuring water diffusivity at varying td's, using an oscillating gradient spin-echo (OGSE) dMRI sequence, to determine the td-dependency, which reflects the cell morphology. In a mouse model of neonatal HI, we have demonstrated that td-dMRI is sensitive to small microstructural changes in cells and subcellular organelles during early injury, and such microstructural details are not accessible by conventional dMRI. Here we will use a clinically-relevant piglet model of whole-brain HI, which exhibits well-defined phenotypes of gray and white matter injury that corresponds to human full-term newborns with birth hypoxia. Development of MRI markers in this model and investigation of the neuropathological substrates of the new MRI markers will have a high clinical impact. Clinical translation of td- dMRI, however, is challenging due to the gradient system on clinical scanners that limits the attainable td and detectable microstructural resolution. We will develop novel OGSE sequences to address the gradient limitation and evaluate the clinical potentials of td-dMRI using the piglet model. The study will be performed on 3T human scanners, and therefore, the MRI techniques will be readily translatable to clinical realm. We hypothesize that td-dMRI is sensitive to acute swelling of neurons and organelles after HI, and that early dMRI measures are predictive of long-term neuropathologic and neurologic outcomes. In Aim 1, we will build a piglet MRI platform with multi-metric MRI markers, including volumetric measures, high-order dMRI (DTI, DKI, tractography), magnetic transfer imaging, along with td-dMRI measures. We will also establish atlases of the developing piglet brains and atlas-based image analysis to achieve automated quantification of the multi-metric MRI data. In Aim 2, we will investigate the utility of td-dMRI in detecting microstructural injury during acute and subacute HI (6hrs - 7days), and explore the correlations between the early MRI markers with cellular and subcellular organelle pathology. In Aim 3, we will perform multimetric MRI to follow the injury progression in piglets over 30 days of recovery after HI, and evaluate the relations between early neuronal injury and white matter injury in the connecting tracts, as well as the long-term functional outcome with neurobehavioral tests. The MRI markers developed in this study will potentially improve the diagnosis and prognosis in clinical neonatal HI, which may lead to accurate and noninvasive evaluations of adjuvant therapies in these neonates.