Rationale and Preliminary Data: We will conduct a validation and characterization of the diffusion tensor imaging changes and histopathology of the cervical spinal cord following experimental thoracic contusion injury. Conventional MRI scans to detect edema using T2-weighted imaging are no better at predicting the degree of recovery in patients with spinal cord injury (SCI) than a traditional neurological examination. Diffusion tensor imaging (DTI) is showing promise as a prognostic imaging biomarker in SCI. However, DTI at the injury site is often hampered by artifacts from spinal fixation hardware. Our preclinical studies in the rat have demonstrated robust DTI alterations in the high cervical spinal cord (hcDTI) that correlate with injury severity and functional recovery. Thus, our preliminary data indicates that diffusivity in te high cervical spinal cord, as measured by DTI, is a potential biomarker of neural injury in SCI. While promising, a more comprehensive validation is necessary for accurate diagnosis in human SCI. To that end, we will employ our preclinical model of thoracic contusion injury to advance the understanding of the DTI changes in the cervical cord as markers of injury. Hypothesis and Specific Aims: We hypothesize that advanced MRI of the high cervical spinal cord is an accurate biomarker of tissue damage and injury severity that is prognostic of outcome. To examine this hypothesis, we will employ a rat model of thoracic contusion spinal cord injury and perform in vivo MRI, functional assessments, and histopathology. We will test our hypothesis by performing diffusion kurtosis imaging (DKI) and quantitative T2 (qT2) to improve the prognostic ability in the acute setting (Aim 1), establish these measures as a surrogate maker of tissue damage at the site of injury (Aim 2), and elucidate the pathophysiological mechanisms of MRI changes remote from the site of injury using gold-standard histopathology (Aim 3). To accomplish these aims, a multidisciplinary approach using in vivo DKI and qT2, quantitative histopathological analysis, and functional assessments will provide a comprehensive understanding of the relationship between noninvasive imaging markers and their biological underpinnings and functional implications. We hypothesize that detection of injury in the acute setting will be enhanced by DKI and qT2 MRI techniques. Furthermore, it is believed that the cervical cord DTI changes accurately reflect the degree of injury at the site of injury assessed by the amount of spared white matter. Finally, it is postulatd that in addition to axonal degeneration and demyelination, astrocyte reactivity is a prominent feature of injury that occurs distant from the injury and relates to the degree of functional recovery. Collectively, these studies will establish and validate hcDTI as a sensitive biomarker of SCI with the potential to improve prognostication and will guide translation to human SCI.
Presently, more than 40,000 Veterans with spinal cord injury (SCI) are eligible for care under the Department of Veteran Affairs. Attempts at restoring neurological function for these Veterans remains a challenge, largely due to our limited understanding of the disease. The current proposal aims to validate a novel spinal cord imaging technique to improve diagnosis and prognostication in SCI. We anticipate that this study will help us delineate changes in spinal cord architecture after SCI, thereby establishing the biological basis for altered imaging indices measured using diffusion tensor imaging. The results of this study will help establish diffusion imaging as a non-invasive biomarker for SCI prognostication and offer newer approaches for monitoring therapeutic interventions in injured Veterans.
|Skinner, Nathan P; Kurpad, Shekar N; Schmit, Brian D et al. (2017) Rapid in vivo detection of rat spinal cord injury with double-diffusion-encoded magnetic resonance spectroscopy. Magn Reson Med 77:1639-1649|
|Budde, Matthew D; Skinner, Nathan P; Muftuler, L Tugan et al. (2017) Optimizing Filter-Probe Diffusion Weighting in the Rat Spinal Cord for Human Translation. Front Neurosci 11:706|
|Skinner, Nathan P; Kurpad, Shekar N; Schmit, Brian D et al. (2015) Detection of acute nervous system injury with advanced diffusion-weighted MRI: a simulation and sensitivity analysis. NMR Biomed 28:1489-506|
|Zakszewski, Elizabeth; Schmit, Brian; Kurpad, Shekar et al. (2015) Diffusion imaging in the rat cervical spinal cord. J Vis Exp :|
|Vedantam, Aditya; Jirjis, Michael B; Schmit, Brian D et al. (2014) Diffusion tensor imaging of the spinal cord: insights from animal and human studies. Neurosurgery 74:1-8; discussion 8; quiz 8|