Development of Novel Functional Markers for TBI Using Molecular MRI

摘要 创伤性脑损伤（TBI）是一个重要的公共卫生问题。目前，客观地 评估TBI是一个关键的研究空白。CT和常规结构MRI已被证明是非常有效的， 识别肉眼可见的损伤。然而，这些标准成像技术在以下方面具有明显的局限性： 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， 特别是轻度TBI，仍然存在争议，因为大脑在常规CT上通常表现得很正常 和MRI。因此，在常规临床实践中，非常需要新的敏感的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， 基于组织pH或内源性移动的蛋白质和肽的浓度。在我们的初步研究中， 我们已经将APTw-MRI方法应用于由受控皮质撞击（CCI）诱导的大鼠TBI模型。我们 初步结果表明，在不同时间点的独特APTw-MRI信号特征， 与局部缺血（几小时）和神经炎症（2-3天）相关的损伤。特别是，APT 成像显示在损伤后数小时，在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 在不同的TBI模型和其他研究地点进行验证对于将这一创新成果转化为 技术和这些重要的临床结果。此应用程序的总体目标是演示 基于蛋白质的APT-MRI信号作为TBI功能标志物的可行性、潜力和再现性 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 敏感和非侵入性地可视化缺血性损伤，炎症反应，和其他几个关键 TBI的病理过程，从而提高MRI客观评估TBI的能力。我们的三 具体目标是：（i）评估TBI的APT-MRI时空演变特征和潜在的 （ii）评估APT-MRI是否可预测CCI大鼠模型的治疗结果; 大鼠CCI模型;和（iii）验证APT-MRI在评估外部部位TBI中的灵敏度和可靠性。 使用APT-MRI的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，结果将提供坚实的基础。 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。

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.