Although MRI is the major diagnostic and prognostic tool used in the care of patients with multiple sclerosis (MS), many aspects of MS pathology are still not well visualized. Recent histopathologic studies in MS have shed light on a previously unrecognized phenomenon without a proven MRI correlate- meningeal inflammation. Pathologic data suggests that meningeal inflammation in MS is not a bystander phenomenon, with strong links found between meningeal inflammation and pathologic findings of cortical pathology and neurodegeneration and a clinical phenotype characterized by rapid disability accumulation, progressive subtypes, and an earlier time to death. To date, explorations of the role of meningeal inflammation in MS have been primarily limited to autopsy studies. In this application, we propose to use gadolinium-enhanced 7 Tesla (7T) MPFLAIR MRI as a non- invasive biomarker of meningeal inflammation in MS. Our preliminary data utilizing this approach demonstrates leptomeningeal contrast enhancement, which we propose as a marker of meningeal inflammation, in 76% of participants with MS. We will use this tool to investigate a hypothesis that meningeal inflammation in MS may be more ubiquitous than previously thought, is not effectively targeted by current treatments, and is related to some of the more damaging and poorly addressed aspects of MS (cortical injury, cognitive deficits, fatigue, and progressive disability accumulation). Participants with MS will undergo annual study visits including a 7T MRI of the brain, physical and cognitive disability assessments, and optical coherence tomography (OCT), in addition to a one-time lumbar puncture. The choice of leptomeningeal enhancement on 7T MPFLAIR MRI as an in vivo biomarker of meningeal inflammation will be justified through comparisons to other MRI sequences and other field strengths in addition to demonstration of a link between leptomeningeal enhancement and spinal fluid markers of meningeal inflammation through cytokine profiling and flow cytometry. We will also use this imaging tool to demonstrate an association between meningeal inflammation and a more disabling MS phenotype through clinical data, in addition to cognitive and physical disability scales. Finally, we will use this imaging tool to demonstrate an association between meningeal inflammation and cortical pathology (cortical lesions and cortical relaxometry alterations on 7T MRI) and neurodegeneration (retinal nerve fiber layer thinning on OCT). Validation of neuroimaging methods for in vivo quantification of meningeal pathology and confirmation of its clinical relevance has the potential to change the treatment landscape in MS. The tools developed in this study would find future use as non-invasive surrogate outcome measures in clinical trials of drugs designed to reduce meningeal inflammation and its impact, in addition to acting as a means to select patients in whom such treatments would be justified and to monitor treatment response.

Public Health Relevance

Recent histopathologic studies in multiple sclerosis (MS) have shown inflammation of the meninges may be responsible for damage to the gray matter of the brain and spinal cord, neurodegeneration, and a more disabling form of MS. In this study, we will validate a brain imaging tool for visualization of meningeal inflammation and explore this hypothesis in living patients. If this tool is validated and the hypothesis is supported, this study spur development of treatments geared towards meningeal inflammation and provide a tool to screen those who may benefit and monitor treatment response.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Utz, Ursula
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University of Maryland Baltimore
Schools of Medicine
United States
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Jonas, S N; Izbudak, I; Frazier, A A et al. (2018) Longitudinal Persistence of Meningeal Enhancement on Postcontrast 7T 3D-FLAIR MRI in Multiple Sclerosis. AJNR Am J Neuroradiol 39:1799-1805