Innovative Non-Invasive Imaging of Traumatic Brain Injury

项目摘要 创伤性脑损伤（TBI）的发生是由于机械力对脑的瞬时施加， 会对细胞膜轴突和脑血管造成损伤TBI影响美国数百万人 每年都有数十万人住院，数千人死亡， 幸存者。除了急性损伤，TBI导致进行性病理生理学，包括局灶性出血和 血脑屏障（BBB）的短暂开放。准确、快速地诊断TBI的严重程度是必要的， 更好地制定治疗方案，减少相关的死亡、发病率和残疾。然而，TBI的诊断 通常依赖于患者病史、主观主诉和神经生理状态，并对严重程度进行分类 仍然具有挑战性。计算机断层扫描和磁共振成像是快速和准确的伤害 需要紧急手术，但仅限于脑出血过多和肿胀等慢性问题。 磁共振成像（MRI）可以评价队列中TBI的白色微病理学，但不能 评估个体TBI。因此，需要创新的非侵入性成像技术， 改善创伤性脑损伤的诊断，加速临床和临床前阶段的研究。 该提案将采用一种称为磁粒子成像（MPI）的创新成像方式来监测 TBI的血管病理生理学。MPI能够实现非侵入性、明确和定量成像， 生物相容性超顺磁性氧化铁（SPION）示踪剂的生物分布。MPI在监控中的应用 TBI包括SPION的全身给药，SPION在局部BBB破坏部位积聚，导致 与SPION MPI性能、累积速率和累积时间成比例的信号。的PI 开发了一种新的合成方法，使SPION具有增强的MPI性能和初步结果 证明这些SPION比市售纳米颗粒更上级， 循环半衰期PI假设使用SPION的MPI优化了灵敏度和血液循环 时间将是一个强大的非侵入性的补充成像工具，研究TBI的临床前啮齿动物模型。这 我们将通过两个具体目标来检验这一假设。目标1中的研究将确定SPION在 TBI的受控皮质撞击（CCI）损伤小鼠模型作为给药剂量和时间的函数， 将建立与SPION蓄积的MPI测量相关的组织学因素。目标2中的研究将比较 CCI损伤小鼠模型中SPION蓄积的MPI测量与SPION的MRI测量 与TBI相关的累积和其他变化。总之，拟议中的研究将测试 MPI用于临床前模型中TBI的无创、灵敏和定量评估，与地面相比 真实性和已建立的非侵入性成像模式。拟议的工作得到了一个多元化的团队的支持， 具有互补专业知识的研究人员，并可使用最先进的MPI和MRI仪器。

Project Summary Traumatic brain injury (TBI) occurs due to the transient application of mechanical force to the brain, which causes damage to cellular membranes, axons, and brain vasculature. TBI affects millions of people in the US each year, resulting in hundreds of thousands of hospitalizations, thousands of deaths, and significant disability in survivors. In addition to acute injury, TBI leads to progressive pathophysiology, including focal bleeding and transient opening of the blood brain barrier (BBB). Accurate and fast diagnosis of severity of TBI is necessary to better prescribe treatments and reduce associated death, morbidity, and disability. However, diagnosis of TBI often relies on patient history, subjective complaints, and neurophysiological status, and classifying severity remains challenging. Computed tomography and magnetic resonance imaging are fast and accurate for injuries requiring emergency surgery but are limited to chronic issues such as excessive brain bleeding and swelling. Magnetic resonance imaging (MRI) can evaluate white matter micropathology of TBI in cohorts but fail to evaluate TBI in individuals. Therefore, innovative non-invasive imaging technologies are necessary to improve TBI diagnosis and accelerate research at the clinical and pre-clinical stage. This proposal will apply an innovative imaging modality called magnetic particle imaging (MPI) to monitor vascular pathophysiology of TBI. MPI enables non-invasive, unambiguous, and quantitative imaging of the biodistribution of biocompatible superparamagnetic iron oxide (SPION) tracers. Application of MPI to monitor TBI consists of systemic administration of SPIONs that accumulate at sites of local BBB disruption, resulting in a signal that is proportional to SPION MPI performance, rate of accumulation, and accumulation time. The PI developed a new synthesis method resulting in SPIONs with enhanced MPI performance and preliminary results demonstrate these SPIONs are superior to commercially available nanoparticles and possess long blood circulation half-life. The PI hypothesizes that MPI using SPIONs optimized for sensitivity and blood circulation time will be a powerful non-invasive complementary imaging tool to study TBI in pre-clinical rodent models. This hypothesis will be tested through two specific aims. Studies in Aim 1 will determine SPION accumulation in a controlled cortical impact (CCI) injury mouse model of TBI as a function of dose and time of administration and will establish histological factors linked to MPI measures of SPION accumulation. Studies in Aim 2 will compare MPI measures of SPION accumulation in the CCI injury mouse model against MRI measures of SPION accumulation and other changes associated with TBI. Together, the proposed studies will test the potential of MPI for non-invasive, sensitive, and quantitative evaluation of TBI in pre-clinical models by comparison to ground truth and established non-invasive imaging modalities. The proposed work is supported by a diverse team of investigators with complementary expertise and access to state-of-the-art MPI and MRI instrumentation.