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：
10393563
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 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10393563
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 Prognosis 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 brain magnetic resonance imaging cell injury cellular pathology clinical translation clinically relevant diagnostic accuracy disability functional outcomes gray matter hypoxia neonatorum hypoxic ischemic injury image processing imaging Segmentation improved mouse model natural hypothermia neonate neurobehavior neurobehavioral test neuropathology novel novel marker oscillating gradient spin echo porcine model 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.

项目摘要：我们建议建立一个集成的MR成像和分析平台，以检查缺氧缺血（HI）新生儿小猪模型中的脑损伤，并开发出表征不断发展的新型MRI标记损伤进展过程中的细胞病理。虽然MRI已在HI中广泛使用，但图像解释常规MRI标记物的预测准确性，例如T1和T2加权MRI或扩散MRI （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敏感性和特异性 HI中的细胞损伤。通过振荡梯度自旋回波（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，我们证明了TD-DMRI对小敏感早期受伤期间细胞和亚细胞细胞器的微观结构变化以及此类微观结构细节常规DMRI无法访问。在这里，我们将使用与临床相关的全脑hi模型表现出明确定义的灰色和白质损伤表型，与人类的完整期相对应出生缺氧的新生儿。在此模型中开发MRI标记和研究新MRI标记的神经病理底物将对临床影响很高。 TD-的临床翻译然而，由于临床扫描仪的梯度系统，DMRI限制了可达到的TD和可检测的微结构分辨率。我们将开发新颖的OGSE序列来解决梯度使用小猪模型限制和评估TD-DMRI的临床潜力。该研究将在 3T人类扫描仪，因此，MRI技术将很容易被翻译成临床领域。我们假设TD-DMRI对HI之后的神经元和细胞器的急性肿胀敏感 DMRI测量可以预测长期神经病理和神经系统结局。在AIM 1中，我们将建立一个具有多量表MRI标记的Piglet MRI平台，包括体积测量，高阶DMRI（DTI，DKI，DKI，拖拉术），磁传递成像，以及TD-DMRI措施。我们还将建立开发仔猪的大脑和基于ATLAS的图像分析，以实现多金属的自动量化 MRI数据。在AIM 2中，我们将研究TD-DMRI在急性期间检测微结构损伤的效用亚急性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细胞器病理学。在AIM 3中，我们将执行多项MRI以跟随损伤进展 HI后30天恢复的小猪，并评估早期神经元损伤与白色之间的关系连接区的物质损伤以及神经行为测试的长期功能结果。这项研究中开发的MRI标记物将有可能改善临床的诊断和预后新生儿HI，这可能导致对这些新生儿辅助疗法的准确和无创评估。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dynamic glucose enhanced MRI of the placenta in a mouse model of intrauterine inflammation.

DOI：
10.1016/j.placenta.2018.07.012
发表时间：
2018-09
期刊：
Placenta
影响因子：
3.8
作者：
Wu D;Xu J;Lei J;Mclane M;van Zijl PC;Burd I
通讯作者：
Burd I

Later cooling within 6 h and temperatures outside 33-34 °C are not associated with dysfunctional autoregulation during hypothermia for neonatal encephalopathy.

DOI：
10.1038/s41390-020-0876-8
发表时间：
2021-01
期刊：
Pediatric research
影响因子：
3.6
作者：
Gilmore MM;Tekes A;Perin J;Parkinson C;Spahic H;Chavez-Valdez R;Northington FJ;Lee JK
通讯作者：
Lee JK

Neonatal cerebrovascular autoregulation.