Tissue injury and inflammation in MS (P50)

Summary

Principal Investigator: Bruce D Trapp
Abstract: DESCRIPTION (provided by applicant): Multiple sclerosis (MS) remains the leading cause of neurological nontraumatic disability for young adults in North America and outcomes of current therapy are often unsatisfactory. This P50 competing renewal application directly extends and amplifies our research during the previous two cycles of support. We focus here on gray matter pathology, extending our previous work addressing interlinked hypotheses regarding the destructive inflammatory and neurodegenerative processes in MS patients. The P50 encompasses several unique resources including a rapid-autopsy program which has yielded insights into MRI-pathology correlations;a longitudinal MRI cohort which has illuminated the mechanisms underlying brain atrophy in MS;and newly-recruited, a series of MS biopsy cases which can be studied to understand cortical pathology early in MS. Core A: Tissue acquisition, imaging, biostatistics. administration (R Ransohoff) will establish, maintain and distribute a unique resource of MS autopsy tissue with dedicated postmortem imaging, as well as coordinate database management and provide administrative and biostatistical support for all projects. Project 1: Cortical demyelination and leukocyte trafficking early in MS (R Ransohoff;C Lucchinetti) will address the hypothesis that meningeal inflammation and cortical demyelination early in the MS process are implicated in facilitating white matter demyelination. This project will also address mechanisms of selective leukocyte trafficking to meninges and cortex. Project 2: Cellular and molecular mechanisms of cortical remyelination in MS patients (B Trapp) will examine cortical demyelination and remyelination in MS brains, and characterize both the cells mediating repair and the factors that inhibit repair. Project 3: Gray matter atrophy in multiple sclerosis (E Fisher) will use novel quantification techniques, developed as part of the P50 research, address in a longitudinal MRI cohort, the relationship between gray matter atrophy and white matter lesions as well as normal-appearing white matter changes. This project will also define relationships between gray matter atrophy and neuropsychological changes. Project 4: Gray matter atrophy in multiple sclerosis: Clinical implications (R Rudick) will extend the use of our new MRI analytic software to define the time course of gray matter atrophy, and evaluate the effects of immunomodulatory therapy, using files from completed clinical trials of a diversity of agents Extending our established research approaches to address gray matter pathology in MS will provide new insights into disease mechanisms and identify novel therapeutic targets.
Funding Period: 1999-12-01 - 2014-12-31
more information: NIH RePORT

Top Publications

  1. ncbi Modulating CCR2 and CCL2 at the blood-brain barrier: relevance for multiple sclerosis pathogenesis
    Don Mahad
    Department of Neurosciences, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
    Brain 129:212-23. 2006
  2. pmc A case of multiple sclerosis presenting with inflammatory cortical demyelination
    B F Gh Popescu
    Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
    Neurology 76:1705-10. 2011
  3. pmc Excessive biologic response to IFNβ is associated with poor treatment response in patients with multiple sclerosis
    Richard A Rudick
    Mellen Center for Multiple Sclerosis, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
    PLoS ONE 6:e19262. 2011
  4. pmc Inflammatory cortical demyelination in early multiple sclerosis
    Claudia F Lucchinetti
    Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    N Engl J Med 365:2188-97. 2011
  5. pmc Multiple sclerosis normal-appearing white matter: pathology-imaging correlations
    Natalia M Moll
    Neuroinflammation Research Center and Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Ann Neurol 70:764-73. 2011
  6. pmc Inflammatory cell trafficking across the blood-brain barrier: chemokine regulation and in vitro models
    Yukio Takeshita
    Neuroinflammation Research Center, Department of Neuroscience, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Immunol Rev 248:228-39. 2012
  7. pmc Onset of progressive phase is an age-dependent clinical milestone in multiple sclerosis
    Melih Tutuncu
    Mayo Clinic Center for Multiple Sclerosis and CNS Demyelinating Diseases, Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    Mult Scler 19:188-98. 2013
  8. 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
  9. ncbi Capture, crawl, cross: the T cell code to breach the blood-brain barriers
    Britta Engelhardt
    Theodor Kocher Institute, University of Bern, Freiestrasse 1, CH 3012 Bern, Switzerland
    Trends Immunol 33:579-89. 2012
  10. pmc A technical approach to dissecting and assessing cadaveric veins pertinent to chronic cerebrospinal venous insufficiency in multiple sclerosis
    Claudiu I Diaconu
    Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Avenue, NA24, Cleveland, OH 44195, USA
    Neurol Res 34:810-8. 2012

Research Grants

  1. HEALTHY AGING AND SENILE DEMENTIA
    John Morris; Fiscal Year: 2013

Detail Information

Publications38

  1. ncbi Modulating CCR2 and CCL2 at the blood-brain barrier: relevance for multiple sclerosis pathogenesis
    Don Mahad
    Department of Neurosciences, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
    Brain 129:212-23. 2006
    ....
  2. pmc A case of multiple sclerosis presenting with inflammatory cortical demyelination
    B F Gh Popescu
    Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
    Neurology 76:1705-10. 2011
    ....
  3. pmc Excessive biologic response to IFNβ is associated with poor treatment response in patients with multiple sclerosis
    Richard A Rudick
    Mellen Center for Multiple Sclerosis, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
    PLoS ONE 6:e19262. 2011
    ....
  4. pmc Inflammatory cortical demyelination in early multiple sclerosis
    Claudia F Lucchinetti
    Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    N Engl J Med 365:2188-97. 2011
    ..Magnetic resonance imaging studies indicate that cortical damage occurs early in the disease...
  5. pmc Multiple sclerosis normal-appearing white matter: pathology-imaging correlations
    Natalia M Moll
    Neuroinflammation Research Center and Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Ann Neurol 70:764-73. 2011
    ....
  6. pmc Inflammatory cell trafficking across the blood-brain barrier: chemokine regulation and in vitro models
    Yukio Takeshita
    Neuroinflammation Research Center, Department of Neuroscience, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Immunol Rev 248:228-39. 2012
    ....
  7. pmc Onset of progressive phase is an age-dependent clinical milestone in multiple sclerosis
    Melih Tutuncu
    Mayo Clinic Center for Multiple Sclerosis and CNS Demyelinating Diseases, Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    Mult Scler 19:188-98. 2013
    ..Ascertainment of patients with PPMS from clinic-based populations can facilitate a powerful comparison of age at progression onset between secondary progressive MS (SPMS) and PPMS but may introduce unclear biases...
  8. 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...
  9. ncbi Capture, crawl, cross: the T cell code to breach the blood-brain barriers
    Britta Engelhardt
    Theodor Kocher Institute, University of Bern, Freiestrasse 1, CH 3012 Bern, Switzerland
    Trends Immunol 33:579-89. 2012
    ..With a focus on multiple sclerosis (MS) and its animal models, this review summarizes the distinct molecular mechanisms required for immune cell migration across the different CNS barriers...
  10. pmc A technical approach to dissecting and assessing cadaveric veins pertinent to chronic cerebrospinal venous insufficiency in multiple sclerosis
    Claudiu I Diaconu
    Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Avenue, NA24, Cleveland, OH 44195, USA
    Neurol Res 34:810-8. 2012
    ....
  11. pmc Cortical remyelination: a new target for repair therapies in multiple sclerosis
    Ansi Chang
    Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Ann Neurol 72:918-26. 2012
    ....
  12. ncbi Measurement and clinical effect of grey matter pathology in multiple sclerosis
    Jeroen J G Geurts
    Department of Anatomy and Neurosciences, Section of Clinical Neuroscience, VU University Medical Center, Amsterdam, Netherlands
    Lancet Neurol 11:1082-92. 2012
    ..By focusing on the latest insights into the in-vivo measurement of grey matter lesions and atrophy, we can assess their clinical effects...
  13. pmc Clinically feasible MTR is sensitive to cortical demyelination in MS
    Jacqueline Tien Hsiang Chen
    Department of Neurosciences, Lerner Research Institute, USA
    Neurology 80:246-52. 2013
    ..The objective of this study is to determine if clinically feasible magnetization transfer ratio (MTR) imaging is sensitive to cortical demyelination in MS...
  14. 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...
  15. pmc Reliability of classifying multiple sclerosis disease activity using magnetic resonance imaging in a multiple sclerosis clinic
    Edru Erbayat Altay
    Cleveland Clinic Mellen Center for Multiple Sclerosis Treatment and Research, 9500 Euclid Ave, Cleveland, OH 44195 5244, USA
    JAMA Neurol 70:338-44. 2013
    ..To assess the reliability of new magnetic resonance imaging (MRI) lesion counts by clinicians in a multiple sclerosis specialty clinic...
  16. 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. ..
  17. pmc Relapsing and progressive forms of multiple sclerosis: insights from pathology
    Ranjan Dutta
    Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
    Curr Opin Neurol 27:271-8. 2014
    ..This review provides insight into the pathological differences during relapsing and progressive phases of multiple sclerosis...
  18. ncbi Challenges to clinical trials in multiple sclerosis: outcome measures in the era of disease-modifying drugs
    Megan Hyland
    Department of Neurology, Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
    Curr Opin Neurol 24:255-61. 2011
    ..This review summarizes standard and evolving outcome measures in multiple sclerosis (MS) clinical trials...
  19. 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...
  20. pmc Evolution of a neuroprotective function of central nervous system myelin
    Xinghua Yin
    Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
    J Cell Biol 172:469-78. 2006
    ..These data support the hypothesis that the P0-PLP shift during vertebrate evolution provided a vital neuroprotective function to myelin-forming CNS glia...
  21. 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
  22. ncbi Evidence for synaptic stripping by cortical microglia
    Bruce D Trapp
    Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic, Cleveland, OH 44195, USA
    Glia 55:360-8. 2007
    ..Since neuronal pathology was not a feature of either the acute or immune-mediated lesion, synaptic stripping by activated microglia may have neuroprotective consequences...
  23. 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...
  24. 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...
  25. ncbi Interferons at age 50: past, current and future impact on biomedicine
    Ernest C Borden
    Taussig Cancer Center, Case Comprehensive Cancer Center, Mellen Center for Multiple Sclerosis, and Lerner Research Institute, The Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA
    Nat Rev Drug Discov 6:975-90. 2007
    ..Our goal is to offer a molecular and clinical perspective that will enable IFNs or their TLR agonist inducers to reach their full clinical potential...
  26. pmc Multiple roles of chemokine CXCL12 in the central nervous system: a migration from immunology to neurobiology
    Meizhang Li
    Neuroinflammation Research Center, Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Mail Code NC30, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Prog Neurobiol 84:116-31. 2008
    ....
  27. ncbi Axon-glial signaling and the glial support of axon function
    Klaus Armin Nave
    Department of Neurogenetics, Max Planck Institute of Experimental Medicine, D 37075 Gottingen, Germany
    Annu Rev Neurosci 31:535-61. 2008
    ..Loss of glial support causes progressive axon degeneration and possibly local inflammation, both of which are likely to contribute to a variety of neuronal diseases in the central and peripheral nervous systems...
  28. ncbi Multiple sclerosis: chemokine receptor expression on circulating lymphocytes in correlation with radiographic measures of tissue injury
    R J Fox
    Department of Neurology, Mellen Center, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
    Mult Scler 14:1036-43. 2008
    ..This observation suggests a CKR "set-point" within individuals, which might relate to inflammatory injury in MS. We evaluated the correlation between CKR levels and magnetic resonance imaging (MRI) measures of disease activity...
  29. pmc Imaging correlates of leukocyte accumulation and CXCR4/CXCL12 in multiple sclerosis
    Natalia M Moll
    Neuroinflammation Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Arch Neurol 66:44-53. 2009
    ..We studied the following ROIs: normal-appearing white matter (NAWM); regions abnormal only on T2-weighted images (T2 only); and regions abnormal on T2- and T1-weighted images with an abnormal magnetization transfer ratio (T2/T1/MTR)...
  30. pmc Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function
    B O Khatri
    Regional Multiple Sclerosis Center and Center for Neurological Disorders, Aurora St Luke s Medical Center, Milwaukee, WI, USA
    Neurology 72:402-9. 2009
    ..Restoration of leukocyte transmigratory capacity was evaluated using an in vitro blood-brain barrier (ivBBB)...
  31. pmc alpha4 Integrin/FN-CS1 mediated leukocyte adhesion to brain microvascular endothelial cells under flow conditions
    Shumei Man
    Neuroinflammation Research Center, Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, OH 44195, USA
    J Neuroimmunol 210:92-9. 2009
    ..These results established a novel in vitro dynamic BBB model. We also demonstrated the dependence of leukocyte-endothelial interactions in this model on alpha4 integrins and FN-CS1...
  32. pmc Chemokines and chemokine receptors: standing at the crossroads of immunobiology and neurobiology
    Richard M Ransohoff
    Neuroinflammation Research Center Lerner Research Institute and Mellen Center for MS Treatment and Research Neurological Institute, Cleveland Clinic, Mail Code NC30, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Immunity 31:711-21. 2009
    ..The challenge is to integrate knowledge of the roles of key receptors (as well as their ligands) into a coherent account of events during pathologic processes, in order to guide therapeutic development...
  33. pmc Heterogeneous, longitudinally stable molecular signatures in response to interferon-beta
    M R Sandhya Rani
    Neuroinflammation Research Center, Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
    Ann N Y Acad Sci 1182:58-68. 2009
    ..Our data suggest that clinical response to IFN-beta therapy for MS differs among patients because of qualitative rather than quantitative variability in the primary molecular response to the drug...
  34. pmc CLADA: cortical longitudinal atrophy detection algorithm
    Kunio Nakamura
    Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
    Neuroimage 54:278-89. 2011
    ..These results show that CLADA can be used for reliable measurement of cortical atrophy in longitudinal studies, even in lower resolution images...
  35. 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...
  36. 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...
  37. pmc An in vitro blood-brain barrier model combining shear stress and endothelial cell/astrocyte co-culture
    Yukio Takeshita
    Neuroinflammation Research Center, Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
    J Neurosci Methods 232:165-72. 2014
    ..Desirable features of such a model include shear stress, non-transformed cells and co-cultures of brain microvascular endothelial cells with astrocytes. Recovery of transmigrated leukocytes for further analysis is also appealing...

Research Grants30

  1. HEALTHY AGING AND SENILE DEMENTIA
    John Morris; Fiscal Year: 2013
    ..Together, these projects and their supporting cores will focus on preclinical DAT in comparison with healthy brain aging and address the issue of detecting preclinical disease. ..