Brain Microstructural MRI in a Piglet Model of Hypoxia-Ischemia

项目总结： 我们建议建立一个集成的磁共振成像和分析平台来检查缺氧缺血(HI)。 新生仔猪模型的脑损伤，并开发新的MRI标记物来表征进化中的 损伤进展过程中的细胞病理学。虽然磁共振成像在HI中得到了广泛的应用，但图像解释 以及常规MRI标志物的预测准确性，例如T1和T2加权MRI或弥散加权MRI (DMRI)，还有很多不尽如人意的地方。在这个项目中，我们将使用 依赖扩散时间(TD)的dMRI，潜在地提高了诊断的敏感性和特异性 缺氧缺血性脑病细胞损伤。TD-dMRI将通过测量不同TD下的水的扩散率来实现，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。在新生儿缺氧缺血性脑病的小鼠模型中，我们已经证明TD-dMRI对小的 损伤早期细胞和亚细胞细胞器的微结构变化以及这些微结构细节 是常规dMRI无法访问的。在这里，我们将使用一个临床相关的全脑HI仔猪模型， 它显示了明确的灰质和白质损伤的表型，与人类足月 出生时缺氧的新生儿。该模型中MRI标记物的研究进展及临床意义 新的MRI标记物的神经病理基础将对临床产生很高的影响。TD的临床翻译-- 然而，dMRI是具有挑战性的，因为临床扫描仪上的梯度系统限制了可获得的TD和 可检测的微结构分辨率。我们将开发新的OGSE序列来解决梯度问题 利用仔猪模型评价TD-dMRI的局限性和临床应用潜力。这项研究将在 3T人体扫描仪，因此，MRI技术将很容易移植到临床领域。 我们推测，TD-dMRI对HI后神经元和细胞器的急性肿胀很敏感，早期 DMRI测量可以预测长期的神经病理和神经学结果。在目标1中，我们将构建一个 具有多度量MRI标记的小猪MRI平台，包括体积测量、高阶dMRI(DTI、DKI、 成像)、磁转移成像以及TD-dMRI测量。我们还将建立地图集 开发仔猪大脑和基于图谱的图像分析，以实现多指标的自动量化 核磁共振数据。在目标2中，我们将研究TD-dMRI在急性和慢性脑损伤中的应用。 亚急性缺氧(6小时-7天)，并探讨早期MRI标志物与细胞和 亚细胞细胞器病理学。在目标3中，我们将进行多参数磁共振成像来跟踪损伤的进展 缺氧缺血后恢复30天以上的仔猪，并评估早期神经元损伤与白蛋白的关系 通过神经行为测试了解连接道的物质损伤情况以及远期功能结果。 本研究开发的核磁共振标记物将有可能改善临床诊断和预后。 新生儿HI，这可能导致对这些新生儿辅助治疗的准确和非侵入性评估。

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.