Multiple Sclerosis (MS) is an inflammatory demyelinating and neurodegenerative disease of the human central nervous system. MS affects over 2.0 million individuals worldwide and is the major cause of non-traumatic neurological disability in young adults in the United States. The classical view of MS as a myelin and white matter disease has been extended to include axonal transection, cortical demyelination and neuronal degeneration. While the clinical impact of gray matter pathology in MS brains is unknown, greater than 50% of MS patients are cognitively impaired. There is minimal or no correlation between physical disability and cognitive dysfunction in MS patients. Although focal hippocampal pathology causes cognitive dysfunction in several CNS diseases, the hippocampus has received little attention in MS research. The overall goal of the proposal is to determine if hippocampal changes contribute to episodic memory loss and cognitive decline in MS patients. Our studies are based upon the hypothesis that hippocampal demyelination reduces synaptic plasticity and causes episodic memory dysfunction. Preliminary studies identify significant hippocampal demyelination and alterations in hippocampal gene transcripts that facilitate memory and learning. Our studies are translational, MS patient based and divided into three specific aims.
The first aim will determine if memory impaired MS patients have characteristic hippocampal pathology as determined by MRI. Preliminary studies suggest that diffusion tensor imaging (DTI) measures of the fornix will provide reliable and non-invasive surrogate markers for the episodic memory impairment in MS patients.
The second aim will characterize hippocampal demyelination and neuronal pathology in MS hippocampi and establish pathological correlates of MRI alterations with hippocampus and fornix obtained by rapid autopsy of MS patients.
The third aim will define molecular mechanisms of hippocampal dysfunction in MS patients. Preliminary studies support the hypothesis that hippocampal demyelination decreases delivery of synaptic vesicles to presynaptic terminals. This will reduce the glutamate and Ca entry into post synaptic terminals and decrease second messenger signally that facilitates hippocampal memory function in MS patients. Collectively, this proposal presents an integrated multi-disciplinary approach designed to elucidate causes of memory dysfunction in MS patients.

Public Health Relevance

Multiple sclerosis (MS) afflicts over 2 million individuals worldwide and is a major cause of neurological disability in the USA. Most MS research investigates the cause of physical disability in MS patients. Despite the fact that over half of MS patients have reduced memory function, very little research has been performed on the cause of memory loss in MS patients. This is surprising as memory loss is a major contributor to unemployment of MS patients. Research in this proposal will determine the causes of reduced memory function in MS patients. We will study MS patients with reduced memory, develop brain imaging techniques to identify MS patients at risk for memory problems and identify ways to treat MS patients with memory loss.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS035058-13
Application #
8112479
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
1996-04-01
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
13
Fiscal Year
2011
Total Cost
$384,650
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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Criste, Gerson; Trapp, Bruce; Dutta, Ranjan (2014) Axonal loss in multiple sclerosis: causes and mechanisms. Handb Clin Neurol 122:101-13
Prins, Marloes; Dutta, Ranjan; Baselmans, Bart et al. (2014) Discrepancy in CCL2 and CCR2 expression in white versus grey matter hippocampal lesions of Multiple Sclerosis patients. Acta Neuropathol Commun 2:98
Koenig, Katherine A; Sakaie, Ken E; Lowe, Mark J et al. (2014) Hippocampal volume is related to cognitive decline and fornicial diffusion measures in multiple sclerosis. Magn Reson Imaging 32:354-8
Dutta, Ranjan (2013) Gene expression changes underlying cortical pathology: clues to understanding neurological disability in multiple sclerosis. Mult Scler 19:1249-54
Koenig, Katherine A; Sakaie, Ken E; Lowe, Mark J et al. (2013) High spatial and angular resolution diffusion-weighted imaging reveals forniceal damage related to memory impairment. Magn Reson Imaging 31:695-9
Koenig, K A; Lowe, M J; Lin, J et al. (2013) Sex differences in resting-state functional connectivity in multiple sclerosis. AJNR Am J Neuroradiol 34:2304-11
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
Schmidt, Fanny; van den Eijnden, Monique; Pescini Gobert, Rosanna et al. (2012) Identification of VHY/Dusp15 as a regulator of oligodendrocyte differentiation through a systematic genomics approach. PLoS One 7:e40457
Dutta, Ranjan; Trapp, Bruce D (2012) Gene expression profiling in multiple sclerosis brain. Neurobiol Dis 45:108-14

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