Brain Microstructural MRI in a Piglet Model of Hypoxia-Ischemia

仔猪缺氧缺血模型的脑微结构 MRI

基本信息

批准号：
9910472
负责人：
Jennifer Kim Lee
金额：
$ 35.82万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9910472
关键词：
Acute Address Adjuvant Therapy Adult Anatomy Asphyxia Neonatorum Atlases Birth Brain Brain Hypoxia Brain Hypoxia-Ischemia Brain Injuries Cause of Death Cell Death Cell Survival Cells Cellular Morphology Cerebrum Clinical Communities Cross-Sectional Studies Custom Data Dependence Development Diagnosis Diffuse Diffusion Diffusion Magnetic Resonance Imaging Dimensions Evaluation Exhibits Family suidae Frequencies Goals Growth Histologic Human Hypoxia Hypoxic-Ischemic Brain Injury Image Image Analysis Injury Investigation Investments Ischemic Stroke Lead Libraries Magnetic Resonance Imaging Magnetism Measurement Measures Methods Modeling Monitor Neonatal Neuroanatomy Neurologic Neurological outcome Neuronal Injury Neurons Newborn Infant Organelles Outcome Pathology Patients Phenotype Pre-Clinical Model Predictive Value Property Prosencephalon Recovery Research Resolution Resources Rodent Scanning Sensitivity and Specificity Signal Transduction Stratification Survivors Swelling System Techniques Term Birth Testing Therapeutic Intervention Therapeutic Uses Time Tissues Validation Water analysis pipeline analytical tool base cell injury cellular pathology clinical translation clinically relevant diagnostic accuracy disability functional outcomes gray matter hypoxia neonatorum image processing imaging Segmentation improved ischemic injury mouse model natural hypothermia neonate neurobehavior neurobehavioral test neuropathology novel novel marker oscillating gradient spin echo outcome forecast postnatal tool tractography translational study treatment strategy white matter white matter injury

项目摘要

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.

项目概要：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）新生仔猪模型中的脑损伤，并开发表征进化过程的新型 MRI 标记损伤进展期间的细胞病理学。虽然 MRI 已广泛应用于 HI，但图像解读传统 MRI 标记（如 T1 和 T2 加权 MRI 或扩散 MRI）的预测准确性（dMRI），还有很多不足之处。在这个项目中，我们将使用扩散时间 (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 将通过使用振荡设备测量不同 td 下的水扩散率来实现梯度自旋回波 (OGSE) dMRI 序列，以确定 td 依赖性，反映细胞形态学。在新生儿 HI 小鼠模型中，我们证明 td-dMRI 对小早期损伤期间细胞和亚细胞器的微观结构变化，以及此类微观结构细节传统的 dMRI 无法访问。在这里，我们将使用临床相关的全脑 HI 仔猪模型，它表现出与人类足月相对应的明确的灰质和白质损伤表型新生儿出生时缺氧。该模型中 MRI 标记的开发和研究新 MRI 标记物的神经病理学底物将产生很高的临床影响。 td-的临床翻译然而，dMRI 具有挑战性，因为临床扫描仪上的梯度系统限制了可达到的 td 和可检测的微观结构分辨率。我们将开发新颖的 OGSE 序列来解决梯度问题局限性并使用仔猪模型评估 td-dMRI 的临床潜力。该研究将在 3T 人体扫描仪，因此 MRI 技术将很容易转化为临床领域。我们假设 TD-dMRI 对 HI 后神经元和细胞器的急性肿胀敏感，并且早期 dMRI 测量可预测长期神经病理学和神经系统结果。在目标 1 中，我们将建立一个仔猪 MRI 平台，具有多测量 MRI 标记，包括体积测量、高阶 dMRI（DTI、DKI、纤维束成像）、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 在检测急性和急性期微结构损伤中的效用。亚急性 HI（6 小时 - 7 天），并探索早期 MRI 标记与细胞和细胞之间的相关性亚细胞器病理学。在目标 3 中，我们将进行多指标 MRI 来跟踪损伤进展情况仔猪HI后恢复30天以上，评估早期神经元损伤与白斑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。本研究开发的 MRI 标记物将有可能改善临床诊断和预后新生儿 HI，这可能会导致对这些新生儿的辅助治疗进行准确和无创的评估。