The long-term goal of this proposal is to elucidate the pathogenic mechanisms that are responsible for irreversible neurological disability in Multiple Sclerosis (MS) patients. Our studies are based on the hypothesis that neuronal loss and neuronal pathology are the major determinants of permanent disability in MS. Inflammatory demyelination causes axon transection early in the course of MS, but remains clinically silent because the brain has a remarkable ability to compensate for loss of neuronal function. Continuous neurological decline during secondary progressive MS occurs because the brain can no longer compensate for additional axonal or neuronal loss. Characterizing the full extent of neuronal pathology in MS brains is essential for understanding its pathogenesis and for developing neuroprotection therapies. In this regard, we have identified significant neuronal death and neuronal pathology in demyelinated regions of the cerebral cortex from MS brains. Studies in Specific Aim 1 will correlate cortical demyelination and neuronal pathologies in a prospective analysis of brains from clinically characterized MS patients obtained by rapid autopsy. Neuronal pathology and loss in cortical lesions may contribute substantially to the total disease burden in MS and play a significant role in the progression of secondary progressive (SP- MS). The second Specific Aim will test the hypothesis that progressive neurological disability in SP-MS occurs by a progressive neuronal loss and deafferentiation that is pre- programmed by axonal transection and neuronal degeneration in relapsing-remitting MS but independent of inflammatory lesions during SP-MS. Extreme variation (1-31 yrs) in the rate of neurological decline in relapsing-remitting stage of MS (RR-MS) and a relatively constant decline in SP-MS support this hypothesis.
Specific Aim 3 will investigate an animal model of site-specific inflammatory cortical lesions to determine if activated microglia strip synapses from cortical neurons and whether the chemokine MCP-1 is responsible for microglial-neuron associations. Collectively, our studies should identify new targets for therapeutic intervention that will reduce and delay neurodegeneration and the progression of permanent neurological disability in MS patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS035058-09
Application #
6881097
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Utz, Ursula
Project Start
1996-03-01
Project End
2008-02-28
Budget Start
2005-03-01
Budget End
2008-02-28
Support Year
9
Fiscal Year
2005
Total Cost
$327,038
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
Koenig, Katherine A; Rao, Stephen M; Lowe, Mark J et al. (2018) The role of the thalamus and hippocampus in episodic memory performance in patients with multiple sclerosis. Mult Scler :1352458518760716
Koenig, Katherine A; Sakaie, Ken E; Lowe, Mark J et al. (2015) The relationship between cognitive function and high-resolution diffusion tensor MRI of the cingulum bundle in multiple sclerosis. Mult Scler 21:1794-801
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
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
Dutta, Ranjan (2013) Gene expression changes underlying cortical pathology: clues to understanding neurological disability in multiple sclerosis. Mult Scler 19:1249-54
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

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