Magnetic resonance imaging (MRI) is the most important diagnostic and prognostic tool used in the care of patients with multiple sclerosis (MS). Despite many advances in technology, however, current MRI techniques are not able to fully visualize all elements of pathology contributing to disability in MS patients. It has long ben known from autopsy studies that the brains of MS patients have lesions in the grey matter and degradation of axons in the white matter, neither of which can be effectively imaged by standard MRI. In this proposal, the candidate aims to demonstrate that novel imaging techniques using 7-Tesla (7T) MRI are capable of imaging grey matter lesions and degenerative white matter pathology, and that quantification of pathologic disease burden in this manner helps to explain cognitive and physical disability in MS. The increased magnet strength of 7T MRI allows for remarkable improvements in resolution over conventional MRI. The increased resolution not only improves the ability to visualize small structures, but also allows for improvement in quantitative measurements of pathology due to the reduction in imaging noise. Such noise can contribute to unclear boundaries between structures and between brain and spinal fluid, thus leading to false measurements. Study subjects will undergo 7T MRIs and physical and cognitive disability testing at baseline and yearly for two years. Grey matter lesion burden will b quantified and lesion subtypes will be identified. The integrity of axons in the white matter will e quantified by a new technology; diffusion tensor spectroscopy (DTS). These imaging findings will then be evaluated for their links with cognitive and physical disability and clinical disease course. It is hypothesized that cortical lesion burden will be strongly correlated with cognitive and physical disability, and will be greatest in patients with progressive MS. Also, subpial cortical lesions (a cortical lesion subtype), which are highly difficult to visualize at lower fiel strengths, are hypothesized to be readily visualized and will be greatest in progressive MS. Lastly, it is hypothesized that quantification of diffusion properties of neuronal n-acetyl aspartae by DTS will correlate with disability and a progressive clinical course. The candidate anticipates that the study will establish the clinical relevance of DTS and high field cortical lesion analysis Such techniques might potentially be used to screen current and future pharmaceutical agents for their ability to prevent grey matter lesions and degeneration of axons, and thus prevent the cognitive and physical disability that plagues many patients with MS. The candidate's career goal is to continue to perform studies of this nature, improving the ability of neuroimaging to visualize cortical and neurodegenerative pathology and drive forward developments in therapeutics. With the supervision of the study mentors and collaboration with the study team, the candidate will obtain the skills necessary to not only complete this project, but also to begin a career as an independent investigator.

Public Health Relevance

This study aims to demonstrate that the grey matter pathology and white matter degeneration that may cause cognitive and physical disability can be visualized by 7-Tesla MRI. If this is proven to be true, this study will for the first time provde an effective tool to monitor the effects of medical treatments on these aspects of the disease. This is of great importance to the multiple sclerosis community as a whole, as the development of new pharmaceutical treatments that address these problems will help to prevent disability and improve the quality of life of patients with this disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Mentored Patient-Oriented Research Career Development Award (K23)
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NST-1 Subcommittee (NST-1)
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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
Harrison, Daniel M; Wang, Kevin Y; Fiol, Julie et al. (2017) Leptomeningeal Enhancement at 7T in Multiple Sclerosis: Frequency, Morphology, and Relationship to Cortical Volume. J Neuroimaging 27:461-468
Harrison, D M; Li, X; Liu, H et al. (2016) Lesion Heterogeneity on High-Field Susceptibility MRI Is Associated with Multiple Sclerosis Severity. AJNR Am J Neuroradiol 37:1447-53
Li, Xu; Harrison, Daniel M; Liu, Hongjun et al. (2016) Magnetic susceptibility contrast variations in multiple sclerosis lesions. J Magn Reson Imaging 43:463-73
Harrison, Daniel M; Oh, Jiwon; Roy, Snehashis et al. (2015) Thalamic lesions in multiple sclerosis by 7T MRI: Clinical implications and relationship to cortical pathology. Mult Scler 21:1139-50
Harrison, Daniel M; Roy, Snehashis; Oh, Jiwon et al. (2015) Association of Cortical Lesion Burden on 7-T Magnetic Resonance Imaging With Cognition and Disability in Multiple Sclerosis. JAMA Neurol 72:1004-12