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: 10092484
• 负责人: RAYMOND Charles KOEHLER
• 金额: $ 43.28万
• 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/10092484
• 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; Pathologic; Pathologic Processes; Peptides; Phase; 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 是一个关键的研究空白。 CT 和传统结构 MRI 已被证明在以下方面非常有效： 识别宏观病变。然而，这些标准成像技术在以下方面有明显的局限性： 评估重要的显微病变和神经病理学。通过影像学进行 TBI 的临床诊断， 特别是轻微的 TBI，仍然存在争议，因为大脑在传统 CT 上通常显得相当正常 和核磁共振成像。因此，常规临床实践中非常需要新的敏感 TBI 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 基于组织 pH 值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冲击 (CCI) 诱导的大鼠 TBI 模型。我们的 初步结果表明，APTw-MRI在不同时间点具有独特的信号特征。 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，APT 受伤后几小时，影像显示受影响区域周围存在基于酸中毒的缺血半暗带。 这些初步结果非常有希望。然而，进一步的发展和放射学-组织病理学 使用不同的 TBI 模型和在其他研究地点进行验证对于转化这一创新至关重要 技术以及这些对临床的重要成果。该应用程序的总体目标是展示 基于蛋白质的 APT-MRI 信号作为 TBI 功能标记的可行性、潜力和可重复性 轻度、中度或重度 TBI 的动物模型。我们假设使用 APT-MRI 的分子成像可以 敏感且非侵入性地可视化缺血性损伤、炎症反应和其他几个关键 从而提高 MRI 客观评估 TBI 的能力。我们三个 具体目标是： (i) 评估 TBI 的 APT-MRI 时空演化特征及其潜在机制 大鼠CCI模型的病理机制； (ii) 评估 APT-MRI 是否可以预测治疗结果 大鼠CCI模型； (iii) 验证 APT-MRI 在评估外部部位 TBI 时的敏感性和可靠性。 使用 APT-MRI 进行 TBI 分子成像开辟了 APT 成像的新研究领域，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得以实现，那么结果将提供坚实的依据 将这一重要的 MRI 技术转化为 TBI 患者的临床研究所需的基础。