Longitudinal assessment of white matter pathology in the injured mouse spinal cord through ultra-high field (16.4T) in vivo diffusion tensor imaging

This study examined the sensitivity of ultra-high field (16.4 T) diffusion tensor imaging (DTI; 70 mu m in-plane resolution, 1 mm slice thickness) to evaluate the spatiotemporal development of severe mid-thoracic contusive spinal cord injury (SCI) in mice. In vivo imaging was performed prior to SCI, then again at 2 h, 1 day, 3 days, 7 days, and 30 days post-SCI using a Bruker 16.4 T small animal nuclear magnetic resonance spectrometer. Cross-sectional spinal cord areas were measured in axial slices and various DTI parameters, i.e. fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (lambda(parallel to)) and radial diffusivity (lambda(perpendicular to)), were calculated for the total spared white matter (WM), ventral funiculi (VF), lateral funiculi (LF) and dorsal columns (DCs) and then correlated with histopathology. Cross-sectional area measurements revealed significant atrophy (32% reduction) of the injured spinal cord at the lesion epicentre in the chronic phase of injury. Analysis of diffusion tensor parameters further showed that tissue integrity was most severely affected in the DCs, i.e. the site of immediate impact, which demonstrated a rapid and permanent decrease in FA and lambda(parallel to). In contrast, DTI parameters for the ventrolateral white matter changed more gradually with time, suggesting that these regions are undergoing more delayed degeneration in a manner that may be amenable to therapeutic intervention. Of all the DTI parameters, lambda(perpendicular to) was most closely correlated to myelin content whereas changes in FA and lambda(parallel to) appeared more indicative of axonal integrity, Wallerian degeneration and associated presence of macrophages. We conclude that longitudinal DTI at 16.4 T provides a clinically relevant, objective measure for assessing white matter pathology following contusive SCI in mice that may aid the translation of putative neuroprotective strategies into the clinic. (C) 2013 Elsevier Inc. All rights reserved

Improved Techniques for Acquisition and Analysis of Dynamic Contrast-Enhanced Magnetic Resonance Imaging for Detecting Vascular Permeability in the Central Nervous System

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a noninvasive technique for quantitative assessment of the integrity of blood-brain barrier and blood-spinal cord barrier (BSCB) in the presence of central nervous system pathologies. However, the results of DCE-MRI show substantial variability. The high variability can be caused by a number of factors including inaccurate T1 estimation, insufficient temporal resolution and poor contrast-to-noise ratio. My thesis work is to develop improved methods to reduce the variability of DCE-MRI results. To obtain fast and accurate T1 map, the Look-Locker acquisition technique was implemented with a novel and truly centric k-space segmentation scheme. In addition, an original multi-step curve fitting procedure was developed to increase the accuracy of T1 estimation. A view sharing acquisition method was implemented to increase temporal resolution, and a novel normalization method was introduced to reduce image artifacts. Finally, a new clustering algorithm was developed to reduce apparent noise in the DCE-MRI data. The performance of these proposed methods was verified by simulations and phantom studies. As part of this work, the proposed techniques were applied to an in vivo DCE-MRI study of experimental spinal cord injury (SCI). These methods have shown robust results and allow quantitative assessment of regions with very low vascular permeability. In conclusion, applications of the improved DCE-MRI acquisition and analysis methods developed in this thesis work can improve the accuracy of the DCE-MRI results

In Vivo Cellular MRI In Experimental Traumatic Spinal Cord Injury

Spinal cord injury (SCI) remains one of the most devastating conditions in medicine; it is a complex medical condition with no cure currently available. Inflammation plays an important role in SCI as it can have both beneficial and detrimental effects. Cell therapy has emerged as a promising treatment for SCI due to the potential for stem cells, including multipotent mesenchymal stromal cells (MSC), for tissue regeneration and immunomodulation of the inflammatory cascade after the initial trauma. However, there are still important, unresolved questions regarding cell therapy that magnetic resonance imaging (MRI) can help to address by producing high-resolution images with exquisite soft tissue contrast in a non-invasive, non-destructive and three-dimensional (3D) manner, allowing a dynamic view of changing pathology and cellular events in vivo. In this thesis in vivo longitudinal imaging of SCI in mouse and rat models is presented using MRI. A resolution of 200μm in all three planes was achieved using a balanced steady state free precession (bSSFP) pulse sequence in a 3T whole-body clinical scanner. Using iron oxide particles as a contrast agent, cellular MRI was used to assess direct MSC transplantation in a mouse model and acute inflammation in a rat model. This was the first study to use cellular MRI for cell tracking in a mouse SCI model. We report on the use of cellular MRI to locate transplanted cells and monitor their overall distribution as well as to evaluate the delivery of transplanted cells to the target tissue in the early phase. Limitations of long-term cell tracking using iron oxide are also discussed. This is also the first study using cellular MRI to image in vivo cells associated with the inflammatory response within the lesion in a rat SCI model and the first demonstration of the use of bSSFP at 3T for rat body imaging. Having the tools for longitudinal in vivo cell monitoring in SCI will help gain a better understanding of both inflammation and response to cell therapy. As these tools are refined, they can be used to test different potential treatments for SCI and optimize them