Multi-parametric Magnetic Resonance and Positron Emission Tomography Imaging of Rat Spinal Cord Injury

Abstract

Spinal cord injuries (SCI) initiate a cascade of complex physiological and molecular mechanisms at and around the injury region. Beyond the initial damage, secondary and chronic neuropathological effects triggered by neuroinflammation and molecular changes at the injury site can severely impact spinal cord regeneration through inhibition of axonal regrowth and progressive cell death. Multi-parametric MRI (mpMRI) provides an array of imaging contrasts sensitive to changes that occur in SCIs. Quantitative magnetization transfer (qMT) imaging characterizes myelin concentration changes through measurements of immobile macromolecular content. Diffusion tensor imaging (DTI) provides complementary structural information by evaluating spinal cord axonal tract integrity post-injury. Resting-state functional MRI (rsfMRI) reports the integrity of gray matter resting state functional networks that are disrupted post-injury. Chemical exchange saturation transfer (CEST) and Nuclear Overhauser Enhancement (NOE) imaging generates Z-spectra that reflect changes in the concentrations and/or exchange rates of specific metabolites and macromolecules, providing high resolution molecular information from the SCI region. In addition, PET imaging can provide complementary high-resolution images of molecular activity and distribution. By using a radiotracer probe that targets the translocator protein TSPO, three-dimensional spatial maps of neuroinflammatory activity in the injured spine can be acquired and used to validate the interpretation of mpMRI measures. The work in this dissertation focused on utilizing mpMRI and TSPO PET imaging to detect and quantify relevant structural, functional, and molecular changes in the spinal cord, longitudinally over time, in a pre-clinical rat spinal cord injury model. CEST and TSPO imaging protocols were optimized and tested for evaluating molecular changes related to neuroinflammation after SCI. The combined mpMRI and PET imaging modalities were next applied to a pre-clinical pharmacological treatment study using the neuroprotective treatment riluzole, and correlated with behavioral metrics of functional recovery to evaluate the efficacy of a novel pharmacological intervention for SCIs. The results demonstrated that mpMRI and PET imaging modalities can be used to assess novel SCI treatments in pre-clinical studies, and to provide comprehensive information on structural, functional, and molecular changes in spinal cord injuries throughout the injury progression over time.