PATHOGENESIS OF DEMYELINATION IN MS BRAINS

Summary

Principal Investigator: Bruce Trapp
Affiliation: Cleveland Clinic Foundation
Country: USA
Abstract: 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.
Funding Period: 1996-03-01 - 2008-02-28
more information: NIH RePORT

Top Publications

  1. pmc Hippocampal volume is related to cognitive decline and fornicial diffusion measures in multiple sclerosis
    Katherine A Koenig
    Imaging Institute, Cleveland Clinic, Cleveland, OH, USA Electronic address
    Magn Reson Imaging 32:354-8. 2014
  2. ncbi Axonal loss in multiple sclerosis: causes and mechanisms
    Gerson Criste
    Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
    Handb Clin Neurol 122:101-13. 2014
  3. pmc Gene expression changes underlying cortical pathology: clues to understanding neurological disability in multiple sclerosis
    Ranjan Dutta
    Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Mult Scler 19:1249-54. 2013
  4. ncbi Sex differences in resting-state functional connectivity in multiple sclerosis
    K A Koenig
    Imaging Institute
    AJNR Am J Neuroradiol 34:2304-11. 2013
  5. pmc Hippocampal demyelination and memory dysfunction are associated with increased levels of the neuronal microRNA miR-124 and reduced AMPA receptors
    Ranjan Dutta
    Department of Neurosciences, Cleveland Clinic, Cleveland, OH 44195, USA
    Ann Neurol 73:637-45. 2013
  6. pmc High spatial and angular resolution diffusion-weighted imaging reveals forniceal damage related to memory impairment
    Katherine A Koenig
    Imaging Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Magn Reson Imaging 31:695-9. 2013
  7. pmc Identification of VHY/Dusp15 as a regulator of oligodendrocyte differentiation through a systematic genomics approach
    Fanny Schmidt
    Merck Serono S A, Geneva, Switzerland
    PLoS ONE 7:e40457. 2012
  8. pmc Demyelination causes synaptic alterations in hippocampi from multiple sclerosis patients
    Ranjan Dutta
    Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, OH 44195, USA
    Ann Neurol 69:445-54. 2011
  9. pmc Gene expression profiling in multiple sclerosis brain
    Ranjan Dutta
    Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Neurobiol Dis 45:108-14. 2012
  10. pmc Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis
    Ranjan Dutta
    Department of Neurosciences NC30, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Prog Neurobiol 93:1-12. 2011

Scientific Experts

  • Bruce Trapp
  • J A Black
  • Ranjan Dutta
  • Ansi Chang
  • Katherine A Koenig
  • Susan M Staugaitis
  • Robert J Fox
  • Elizabeth A Young
  • Grahame J Kidd
  • Richard Rudick
  • Gerson Criste
  • Erik B Beall
  • Stephen M Rao
  • Micheal D Phillips
  • Lael Stone
  • Robert A Bermel
  • Mark J Lowe
  • Jian Lin
  • Ken E Sakaie
  • K A Koenig
  • Mary K Doud
  • Michael V Ribaudo
  • Fanny Schmidt
  • Wendy B Macklin
  • Xinghua Yin
  • Karoly Mirnics
  • Jennifer McDonough
  • Gerson A Criste
  • John W Peterson
  • M D Phillips
  • S M Rao
  • R A Bermel
  • J Lin
  • Dale D Edberg
  • Michael Li
  • E B Beall
  • L Stone
  • Brian Bai
  • K E Sakaie
  • Sadie A Deckard
  • M J Lowe
  • Anthony M Chomyk
  • Sergio E Baranzini
  • Rosanna Pescini Gobert
  • Sandrine Pouly
  • Susanna Carboni
  • Chantal Alliod
  • Monique Van Den Eijnden
  • Gabriela P Saborio
  • Rob Hooft van Huijsduijnen
  • Maria C Smith
  • Elizabeth Fisher
  • Christie D Fowler
  • Alan Siu
  • Lakshman Swamy
  • John Peterson
  • Thalia Torres
  • Tatyana Gudz
  • David A Lewis

Detail Information

Publications19

  1. pmc Hippocampal volume is related to cognitive decline and fornicial diffusion measures in multiple sclerosis
    Katherine A Koenig
    Imaging Institute, Cleveland Clinic, Cleveland, OH, USA Electronic address
    Magn Reson Imaging 32:354-8. 2014
    ....
  2. ncbi Axonal loss in multiple sclerosis: causes and mechanisms
    Gerson Criste
    Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
    Handb Clin Neurol 122:101-13. 2014
    ..The current chapter reviews existing data on mechanisms of axonal pathology in MS. ..
  3. pmc Gene expression changes underlying cortical pathology: clues to understanding neurological disability in multiple sclerosis
    Ranjan Dutta
    Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Mult Scler 19:1249-54. 2013
    ..In this review, we summarize existing data from gene expression changes in cortical tissues from MS brains and how they may provide clues to the pathogenesis. ..
  4. ncbi Sex differences in resting-state functional connectivity in multiple sclerosis
    K A Koenig
    Imaging Institute
    AJNR Am J Neuroradiol 34:2304-11. 2013
    ..This study used functional connectivity MRI to investigate sex differences in the strength of functional connectivity of the default mode network in patients with MS and healthy control subjects...
  5. pmc Hippocampal demyelination and memory dysfunction are associated with increased levels of the neuronal microRNA miR-124 and reduced AMPA receptors
    Ranjan Dutta
    Department of Neurosciences, Cleveland Clinic, Cleveland, OH 44195, USA
    Ann Neurol 73:637-45. 2013
    ..How demyelination alters neuronal gene expression is unknown...
  6. pmc High spatial and angular resolution diffusion-weighted imaging reveals forniceal damage related to memory impairment
    Katherine A Koenig
    Imaging Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Magn Reson Imaging 31:695-9. 2013
    ..This study sought to investigate correlations between DTI measures in the fornix and common cognitive deficits in MS patients, including episodic memory, working memory and attention...
  7. pmc Identification of VHY/Dusp15 as a regulator of oligodendrocyte differentiation through a systematic genomics approach
    Fanny Schmidt
    Merck Serono S A, Geneva, Switzerland
    PLoS ONE 7:e40457. 2012
    ..Finally, we identified PDGFR-beta and SNX6 as novel and specific Dusp15 substrates, providing an indication as to how this PTP might exert control over OL differentiation...
  8. pmc Demyelination causes synaptic alterations in hippocampi from multiple sclerosis patients
    Ranjan Dutta
    Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, OH 44195, USA
    Ann Neurol 69:445-54. 2011
    ..Although the clinical impact of gray matter pathology in MS brains is unknown, 30 to 40% of MS patients demonstrate memory impairment. The molecular basis of this memory dysfunction has not yet been investigated in MS patients...
  9. pmc Gene expression profiling in multiple sclerosis brain
    Ranjan Dutta
    Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Neurobiol Dis 45:108-14. 2012
    ..In this review, we summarize existing data from different gene expression profiling studies and how they relate to understand the pathogenesis of MS...
  10. pmc Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis
    Ranjan Dutta
    Department of Neurosciences NC30, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Prog Neurobiol 93:1-12. 2011
    ..This review discusses the etiology, mechanisms and progress made in determining the cause of axonal and neuronal loss in MS...
  11. pmc Neurogenesis in the chronic lesions of multiple sclerosis
    Ansi Chang
    Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Brain 131:2366-75. 2008
    ..These results support neurogenesis in a subpopulation of demyelinated subcortical white matter lesions in multiple sclerosis brains...
  12. ncbi Multiple sclerosis: an immune or neurodegenerative disorder?
    Bruce D Trapp
    Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
    Annu Rev Neurosci 31:247-69. 2008
    ....
  13. ncbi Imaging correlates of decreased axonal Na+/K+ ATPase in chronic multiple sclerosis lesions
    Elizabeth A Young
    Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA
    Ann Neurol 63:428-35. 2008
    ..To date, however, the distribution of Na+/K+ ATPase has not been studied in MS lesions...
  14. ncbi Activation of the ciliary neurotrophic factor (CNTF) signalling pathway in cortical neurons of multiple sclerosis patients
    Ranjan Dutta
    Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Brain 130:2566-76. 2007
    ..Induction of CNTF signalling and the anti-apoptotic molecule, Bcl2, thus represents a compensatory response to disease pathogenesis and a potential therapeutic target in MS patients...
  15. ncbi Sodium channel expression within chronic multiple sclerosis plaques
    Joel A Black
    Department of Neurology and Paralyzed Veterans of America United Spinal Association Neuroscience Research Center, Yale University School of Medicine, New Haven, CT, USA
    J Neuropathol Exp Neurol 66:828-37. 2007
    ..6 and NCX in acute lesions but independent of coexpression of these 2 molecules in chronic lesions...
  16. ncbi Pathogenesis of axonal and neuronal damage in multiple sclerosis
    Ranjan Dutta
    Department of Neuroscience, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Neurology 68:S22-31; discussion S43-54. 2007
    ..Therapeutic interventions directed toward each of these mechanisms need to be tested for their efficacy in enhancing axon survival and, ultimately, their ability to delay progression of neurologic disability in patients with MS...
  17. ncbi N-acetyl-L-aspartate in multiple sclerosis
    Gerson A Criste
    Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
    Adv Exp Med Biol 576:199-214; discussion 361-3. 2006
  18. ncbi Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients
    Ranjan Dutta
    Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, OH 44195, USA
    Ann Neurol 59:478-89. 2006
    ..Development of neuroprotective therapies will require elucidation of the molecular mechanisms by which neurons and axons degenerate...
  19. ncbi Neuropathobiology of multiple sclerosis
    John W Peterson
    Department of Neurosciences, The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Neurol Clin 23:107-29, vi-vii. 2005