Innovative Non-Invasive Imaging of Traumatic Brain Injury

点击翻译按钮获取中文摘要

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.