The main objective of this project is to gain insight into the progression of gray matter (GM) atrophy in multiple sclerosis (MS) patients through advanced magnetic resonance imaging (MRI) and newly developed image analysis methods. Gray matter tissue damage is a major component of overall MS pathology in the brain. However, relatively little is known about GM pathology in MS patients because the majority of focal GM lesions cannot be detected with MRI. GM atrophy, on the other hand, can be measured reliably with accurate image analysis methods and can be used to estimate the total extent of destructive GM pathology. GM atrophy is likely due to a combination of severe tissue damage in the GM itself and neurodegeneration secondary to damage in the white matter (WM). The relative contributions of each and how these change over the course of disease are unknown. In this project, a longitudinal MRI study of 70 MS patients and 17 healthy controls will be extended (from 9 to 14 years) and new image analysis methods, based explicitly on findings from post-mortem MRI/pathology correlation studies, will be developed and applied in order to (1) Determine the relationship between specific types of pathologically-validated, MRI-defined WM lesion subtypes and GM atrophy;(2) Assess the degree to which specific types of pathologically-validated, MRI-defined damage in normal-appearing brain tissue regions are related to GM atrophy;and (3) Determine the pathologic and clinical significance of GM atrophy in post-mortem and long-term follow-up studies. The first two aims seek to identify new in vivo MRI markers that are strongly correlated to GM tissue damage based on the pathologic correlates of MRI characterstics in MS brains post-mortem. Application of these new markers in the longitudinally-followed patient group will help to elucidate the mechanisms and time course of GM atrophy progression.
The third aim will help to validate GM atrophy measurements. In the first part of Aim 3, post-mortem MRI-guided pathology will be used to determine how cortical thinning relates to focal pathology in GM. The second part of Aim 3 will use data from the longitudinal study to determine how overall GM atrophy and regional changes in cortical thickness relate to the progression of disability and cognitive deficits in patients with MS. Through discovery and validation of new MRI markers of MS pathology in gray matter, this study will lead to a better understanding of MS and improved tools for patient monitoring and evaluation of potential neuroprotective therapies.

Public Health Relevance

Multiple sclerosis affects the gray matter as much as the white matter in the brain. MRI is commonly used to monitor MS patients, but it is insensitive to most gray matter tissue damage. This study will develop and validate new MRI markers of GM pathology in order to provide a more complete picture of the disease. MRI-based measurements of GM tissue damage will lead to a better understanding of MS and improved tools for monitoring MS patients and for evaluating potential neuroprotective therapies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center (P50)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cleveland Clinic Lerner
United States
Zip Code
Trapp, Bruce D; Vignos, Megan; Dudman, Jessica et al. (2018) Cortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: a retrospective study. Lancet Neurol 17:870-884
Lowe, Mark J; Sakaie, Ken E; Beall, Erik B et al. (2016) Modern Methods for Interrogating the Human Connectome. J Int Neuropsychol Soc 22:105-19
Paz Soldán, M Mateo; Novotna, Martina; Abou Zeid, Nuhad et al. (2015) Relapses and disability accumulation in progressive multiple sclerosis. Neurology 84:81-8
Takeshita, Yukio; Obermeier, Birgit; Cotleur, Anne et al. (2014) An in vitro blood-brain barrier model combining shear stress and endothelial cell/astrocyte co-culture. J Neurosci Methods 232:165-72
Criste, Gerson; Trapp, Bruce; Dutta, Ranjan (2014) Axonal loss in multiple sclerosis: causes and mechanisms. Handb Clin Neurol 122:101-13
Dutta, Ranjan; Trapp, Bruce D (2014) Relapsing and progressive forms of multiple sclerosis: insights from pathology. Curr Opin Neurol 27:271-8
Beall, Erik B; Lowe, Mark J (2014) SimPACE: generating simulated motion corrupted BOLD data with synthetic-navigated acquisition for the development and evaluation of SLOMOCO: a new, highly effective slicewise motion correction. Neuroimage 101:21-34
Tutuncu, Melih; Tang, Junger; Zeid, Nuhad Abou et al. (2013) Onset of progressive phase is an age-dependent clinical milestone in multiple sclerosis. Mult Scler 19:188-98
Rudick, Richard A; Fisher, Elizabeth (2013) Preventing brain atrophy should be the gold standard of effective therapy in MS (after the first year of treatment): Yes. Mult Scler 19:1003-4
Dutta, Ranjan; Chomyk, Anthony M; Chang, Ansi et al. (2013) Hippocampal demyelination and memory dysfunction are associated with increased levels of the neuronal microRNA miR-124 and reduced AMPA receptors. Ann Neurol 73:637-45

Showing the most recent 10 out of 34 publications