Project Summary We propose to optimize and validate two novel diffusion MRI models/methods that have direct clinical relevance for cervical spinal cord evaluation in health and multiple sclerosis (MS): Neurite Orientation Dispersion and Density Imaging (NODDI) and Spherical Means Technique (SMT). While diffusion tensor imaging (DTI) has existed for 20 years, advanced biophysical models for evaluating neurological disease in the CSC are lacking. Advanced diffusion MRI can extract indices related to neural architecture and axonal loss, yet evaluating the pathological substrates of MS (specifically axonal loss) in the CSC is undertested and questions remain if the models as-developed are relevant for pathology. Lastly, it is not clear if advanced diffusion MRI offers greater clinical value over DTI. We address the current knowledge gap in human CSC diffusion MRI by optimizing and evaluating two clinically-approachable diffusion techniques: NODDI and SMT in healthy volunteers and patients with relapsing-remitting MS (RRMS) to 1) study lesion and normal appearing white matter (NAWM) in comparison with conventional DTI (assessing value), lesion burden, and atrophy (reflecting axonal loss) and 2) to assess the sensitivity of diffusion MRI to tissue change over time. In MS, spinal cord health is integral to neurological function, yet current studies rely on identifying lesions and/or tissue atrophy; the biological substrates of CSC tissue damage are poorly characterized, and their relationship to neurological function is weak. Advanced diffusion MRI provides estimates of axonal volume, cellular inflammation, and neurite dispersion and may provide greater specificity than DTI for microstructural changes in the CSC throughout MS evolution. However, advanced diffusion MRI has only recently been explored due to lack of CSC-optimized acquisitions and models that account for pathology, which we show are surmountable. We will test the hypotheses that NODDI and SMT diffusion MRI, can 1) detect sub-radiological axonal pathology in MS (CSC areas devoid of lesions), 2) offer improved value and specificity over conventional DTI, and 3) characterize axonal-sensitive indices longitudinally concomitant with neurological deterioration. We optimize, and acquire NODDI and SMT data in addition to DTI, T2-, T2*-, T1 MRI in the CSC of patients with RRMS. We published NODDI and SMT in the CSC in a small cohort of RRMS patients, but now evaluate the value that advanced diffusion modeling in the CSC can add to the clinical assessment of MS patients. As in the brain, NODDI and SMT can be acquired in a reasonable exam time, but are untested for spinal cord pathology in MS. If successful, we will offer clinically-relevant, optimized acquisition and analysis tools for the application of advanced diffusion MRI in CSC pathology in comparison with clinical radiological standards. Alternatively, we will solidify the importance (and provide optimized CSC sequences) for rapid, conventional CSC DTI for clinical deployment. A byproduct is the evaluation of alternative models in pathology, which has not been tested before and have direct benefit to understanding other spinal cord diseases.

Project Narrative Multiple sclerosis (MS) is one of the most prevalent (~1 million MS patients in the US) and debilitating neurological diseases that affects patients in early adulthood and is the second leading cause of non-traumatic paralysis. Importantly, the spinal cord is damaged in MS, potentially leading to neurological deterioration, however, magnetic resonance imaging (MRI) and in particular, diffusion MRI are poorly suited to offer information about the biological substrates of MS in the spinal cord primarily because of its size and constant motion. Recently advancements in diffusion MRI (and associated modeling of diffusion contrasts) have been made and hold the promise of providing insight into the biophysical substrates of tissue damage in MS, but the application in the cervical spinal cord, the relationship between diffusion MRI and conventional MRI, and a more complete description of neurological damage in the spinal cord with advanced diffusion MRI has not been adequately evaluated or vetted, which is the thrust of this proposal.