Multimodal, quantitative MRI in the lumbosacral spinal cord in progressive multiple sclerosis

PROJECT SUMMARY Clinical disability in multiple sclerosis (MS) is largely determined by the accumulation of demyelinating lesions in the spinal cord (SC), but conventional magnetic resonance imaging (MRI) methods lack the sensitivity to assess the full extent of SC pathology including sub-radiological tissue damage that occurs beyond MRI-visible lesions. Recent studies have revealed that cervical SC pathology correlates with disability in MS and is independent from MRI measures of disease in the brain. However, a lack of evidence on disease in the lumbosacral spinal cord (LSC) has limited our ability to fully understand primary progressive MS (PPMS) pathology and how LSC lesions and diffuse damage impact clinical disability and autonomic function, which hinders the selection and evaluation of therapies for patients. Advancing multimodal MRI and developing imaging biomarkers of PPMS targeting the LSC will deliver more accurate assessments of disease progression, enabling and informing decisions regarding treatment with disease-modifying therapies or symptom management strategies. Our long-term goal is to develop MRI biomarkers of MS pathology for the complete SC. We predict that MRI measures of the entire spinal axis will better inform clinicians on the extent of disease, which will likely dictate therapy. Our project objective is to identify and validate quantitative MRI biomarkers in the lower SC that are associated with clinical disability in PPMS. Our previous work demonstrated that advanced MRI methods (diffusion tensor imaging, quantitative magnetization transfer MRI, and resting-state functional MRI) provide measures related to pathology in the cervical and lumbar SC in relapsing-remitting MS, and we will now study the extent of imaging abnormalities in the LSC by applying these advanced MRI methods in PPMS. We also extend advanced MRI to the conus and cauda equina to explore associations between imaging indices and autonomic dysfunction seen in PPMS patients. Our specific aims are: (1) Establish reproducibility and validate quantitative MRI indices in the LSC, (2) Characterize quantitative MRI biomarkers of disease pathology in the LSC for PPMS in relation to clinical disability, and (3) Optimize the resolution of quantitative MRI methods to extend their application to the conus medullaris and cauda equina. This research is technically innovative because it refines advanced MRI methods for application in the LSC; to our knowledge, this will be the first application of these methods to the conus and cauda equina. The resulting novel, quantitative MRI biomarkers of PPMS pathology in these structures will complement existing brain and cervical SC MRI in monitoring disease progression and treatment response. The results will improve our understanding of the pathological substrates of disability in PPMS, which is expected to have a significant impact on future studies of potential therapies. The MRI methods will also benefit studies of other neurological disorders, and this research aligns with NINDS’s mission to reduce the burden of neurological disease by developing imaging biomarkers that enable more precise assessment of disease biology.