Innovative Non-Invasive Imaging of Traumatic Brain Injury

创伤性脑损伤的创新非侵入性成像

• 批准号: 10527640
• 负责人: Carlos M Rinaldi-Ramos
• 金额: $ 40.07万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527640
• 关键词: Acute; Affect; Aging; Anatomy; Animal Model; Attenuated; Axon; Biodistribution; Biological Markers; Biomechanics; Blood - brain barrier anatomy; Blood Circulation; Blood Circulation Time; Blood Vessels; Brain; Brain Edema; Brain Injuries; Cellular Membrane; Cerebrovascular Circulation; Cerebrovascular system; Cessation of life; Chronic; Clinical; Computers and Advanced Instrumentation; Contusions; Detection; Diagnosis; Diffuse; Diffusion Magnetic Resonance Imaging; Dose; Emergency Situation; Ferritin; Florida; Functional disorder; Half-Life; Hemoglobin; Hemorrhage; Histologic; Hospitalization; Human; Image; Imaging Device; Imaging technology; Individual; Injury; Ionizing radiation; Iron; Ischemia; Life; Link; Liquid substance; Magnetic Resonance Imaging; Magnetism; Measures; Methods; Microscopic; Monitor; Morbidity - disease rate; Noise; Operative Surgical Procedures; Oxygen; Pathology; Patients; Penetration; Performance; Persons; Physiological; Pre-Clinical Model; Principal Investigator; Prognosis; Property; Quantitative Evaluations; Recording of previous events; Recovery; Reporting; Research; Research Personnel; Resolution; Rodent Model; Secondary to; Severities; Signal Transduction; Site; Skull Fractures; Survivors; Swelling; T2 weighted imaging; Testing; Time; Tissues; Tracer; Traumatic Brain Injury; Universities; Work; X-Ray Computed Tomography; biomaterial compatibility; blood-brain barrier disruption; clinical imaging; cohort; controlled cortical impact; density; disability; imager; imaging capabilities; imaging detection; imaging modality; improved; in vivo; innovation; instrumentation; iron oxide; magnetic field; mechanical force; mild traumatic brain injury; molecular imaging; mouse model; nanoparticle; neurophysiology; non-invasive imaging; optical imaging; particle; pre-clinical; quantitative imaging; routine imaging; spectroscopic imaging; superparamagnetism; tool; white matter; white matter damage

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.

项目概要 创伤性脑损伤 (TBI) 是由于短暂地向大脑施加机械力而发生的， 对细胞膜、轴突和脑血管系统造成损害。 TBI 影响着数百万人的美国 每年导致数十万人住院、数千人死亡和严重残疾 在幸存者中。除了急性损伤外，TBI 还会导致进行性病理生理学变化，包括局灶性出血和 血脑屏障（BBB）短暂开放。准确、快速地诊断 TBI 的严重程度对于 更好地制定治疗方案并减少相关的死亡、发病和残疾。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可快速准确地诊断损伤 需要紧急手术，但仅限于脑过度出血和肿胀等慢性问题。 磁共振成像 (MRI) 可以评估队列中 TBI 的白质微病理学，但无法 评估个人 TBI。因此，需要创新的非侵入性成像技术 改善 TBI 诊断并加速临床和临床前阶段的研究。 该提案将应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 能够对物体进行非侵入性、明确的定量成像 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 包括全身性施用 SPION，这些 SPION 会在局部 BBB 破坏部位积聚，从而导致 与 SPION MPI 性能、累积速率和累积时间成比例的信号。 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 优于市售纳米颗粒并具有长血 循环半衰期。 PI 假设 MPI 使用针对灵敏度和血液循环进行优化的 SPION time 将成为一种强大的非侵入性补充成像工具，用于研究临床前啮齿动物模型中的 TBI。这 假设将通过两个具体目标进行检验。目标 1 的研究将确定 SPION 的积累 TBI 受控皮质冲击 (CCI) 损伤小鼠模型作为给药剂量和时间的函数 将建立与 SPION 积累的 MPI 测量相关的组织学因素。目标 2 中的研究将进行比较 CCI 损伤小鼠模型中 SPION 积累的 MPI 测量与 SPION MRI 测量 积累和其他与 TBI 相关的变化。总之，拟议的研究将测试潜力 MPI 通过与地面比较，对临床前模型中的 TBI 进行非侵入性、灵敏且定量的评估 真相和已建立的非侵入性成像方式。拟议的工作得到了多元化团队的支持 研究人员具有互补的专业知识并可以使用最先进的 MPI 和 MRI 仪器。