Development of Novel Functional Markers for TBI Using Molecular MRI

使用分子 MRI 开发 TBI 的新型功能标记物

• 批准号: 10256740
• 负责人: RAYMOND Charles KOEHLER
• 金额: $ 42.07万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10256740
• 关键词: Acidosis; Acute; Address; Amides; Animal Model; Animals; Anti-Inflammatory Agents; Area; Brain; Brain Injuries; Cavia; Cell Density; Cerebral Ischemia; Characteristics; Clinic; Clinical; Clinical Research; Clinical assessments; Collaborations; Contrast Media; Contusions; Development; Diagnosis; Diagnostic radiologic examination; Disease; Edema; Evolution; Foundations; Goals; Hemorrhage; Heterogeneity; Hour; Image; Imaging Techniques; Imaging technology; Inflammation; Inflammatory Response; Injections; Injury; Ischemia; Ischemic Penumbra; Lesion; Magnetic Resonance Imaging; Malignant neoplasm of brain; Medical Imaging; Microscopic; Modeling; Molecular; Neurologic; Pathologic; Pathologic Processes; Peptides; Prevention; Proteins; Protons; Public Health; Rattus; Recovery of Function; Reproducibility; Research; Research Personnel; Signal Transduction; Site; Solid; Spinal cord injury; Structure; Surrogate Markers; TBI Patients; Techniques; Technology; Testing; Time; Tissues; Translating; Trauma; Traumatic Brain Injury; Validation; Work; axon injury; base; clinical Diagnosis; clinical practice; controlled cortical impact; excitotoxicity; improved; innovative technologies; mild traumatic brain injury; molecular imaging; neuroinflammation; neurological pathology; novel; physical assault; preclinical study; severe injury; spatiotemporal; therapy outcome

ABSTRACT Traumatic brain injury (TBI) is an important public health problem. Currently, the ability to objectively assess TBI is a critical research gap. CT and conventional structural MRI have proven to be highly effective in identifying macroscopic lesions. However, these standard imaging techniques have clear limitations in assessing important microscopic lesions and neurologic pathology. The clinical diagnosis of TBI via imaging, particularly mild TBI, remains controversial, because the brain often appears quite normal on conventional CT and MRI. Therefore, new sensitive surrogate biomarkers for TBI are greatly needed in routine clinical practice. Amide proton transfer (APT) imaging is an important molecular MRI technique that can generate contrast based on tissue pH or concentrations of endogenous mobile proteins and peptides. In our preliminary study, we have applied the APTw-MRI approach to a rat TBI model, induced by controlled cortical impact (CCI). Our preliminary results have demonstrated unique APTw-MRI signal characteristics at different time points after injury that are associated with ischemia (at a few hours) and neuroinflammation (at 2-3 days). Notably, APT imaging revealed an acidosis-based ischemic penumbra around the impacted area at a few hours post-injury. These initial results are very promising. However, further development and radiographic-histopathologic validation with different TBI models and at other research sites is crucial for translating this innovative technology and these important results to the clinic. The overall goal of this application is to demonstrate the feasibility, potential, and reproducibility of protein-based APT-MRI signals as functional markers for TBI using animal models of mild, moderate, or severe TBI. We hypothesize that molecular imaging using APT-MRI can sensitively and non-invasively visualize ischemic damage, inflammatory responses, and several other key pathological processes in TBI, thus improving the capability of MRI to objectively assess TBI. Our three specific aims are: (i) to assess APT-MRI spatio-temporal evolution characteristics of TBI and the underlying pathological mechanisms in rat CCI models; (ii) to assess whether APT-MRI predicts therapeutic outcomes in rat CCI models; and (iii) to validate the sensitivity and reliability of APT-MRI in assessing TBI at external sites. Molecular imaging of TBI using APT-MRI opens up a new research area of APT imaging that could address many unmet clinical needs. If our aims in this preclinical study are achieved, the results will provide the solid foundation required to translate this important MRI technology to clinical studies in patients with TBI.

抽象的 创伤性脑损伤（TBI）是一个重要的公共卫生问题。目前，能够客观地 评估TBI是一个关键的研究差距。 CT和常规结构MRI已被证明是非常有效的 识别宏观病变。但是，这些标准成像技术在 评估重要的显微镜病变和神经病理学。通过成像对TBI的临床诊断， 特别是轻度TBI，仍然存在争议，因为在常规CT上大脑通常看起来很正常 和MRI。因此，在常规临床实践中，非常需要新的TBI敏感替代生物标志物。 酰胺质子转移（APT）成像是一种重要的分子MRI技术，可以产生对比度 基于组织pH或内源性移动蛋白和肽的浓度。在我们的初步研究中 我们已将APTW-MRI方法应用于由受控皮质影响（CCI）引起的大鼠TBI模型。我们的 初步结果表明在不同时间点的不同时间点显示了独特的APTW-MRI信号特征 与缺血（几个小时）和神经炎症（2-3天）相关的损伤。值得注意的是，很容易 成像显示在伤害后几个小时，受影响区域周围的基于酸中毒的缺血性半阴茎。 这些最初的结果非常有前途。但是，进一步的发展和射线照相术 使用不同的TBI模型验证和其他研究站点对于翻译这种创新性至关重要 技术和这些重要结果是诊所的。该应用程序的总体目标是证明 使用基于蛋白质的APT-MRI信号作为TBI的功能标记的可行性，潜力和可重复性 轻度，中度或严重TBI的动物模型。我们假设使用APT-MRI的分子成像可以 敏感和非侵入性可视化缺血性损害，炎症反应和其他几个钥匙 TBI中的病理过程，从而提高了MRI客观评估TBI的能力。我们的三个 具体目的是：（i）评估TBI和基础的APT-MRI时空演化特征 大鼠CCI模型中的病理机制； （ii）评估APT-MRI是否预测 大鼠CCI模型； （iii）验证APT-MRI在评估外部部位的TBI方面的敏感性和可靠性。 使用APT-MRI对TBI进行分子成像打开了一个新的APT成像研究领域，该领域可以解决 许多未满足的临床需求。如果我们在这项临床前研究中的目标，结果将提供固体 将这种重要的MRI技术转化为TBI患者的临床研究所需的基础。