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Inflammation and neuronal pathology in multiple sclerosis

Peterson, John Wesley
http://rave.ohiolink.edu/etdc/view?acc_num=osu1054659240

Abstract Details

2003, Doctor of Philosophy, Ohio State University, Neuroscience.
Our concept of multiple sclerosis (MS) has expanded from an inflammatory demyelinating disease of the central nervous system (CNS) to one incorporating the concept of MS having an inflammatory mediated neurodegenerative component causing extensive neuronal damage resulting in permanent neurological disability. The majority (80-90%) of typical MS patients have a relapsing-remitting (RR) disease course. Early in the disease, RR-MS patients often benefit from anti-inflammatory therapeutics and recover neurological function with resolution of inflammation and edema. Eventually, many patients enter the secondary progressive phase of the disease characterized by increasing neurological disability, minimal recovery and poor efficacy of anti-inflammatory therapeutics. Why is the progression of RR-MS biphasic? Demyelination and inflammation certainly cause reversible neurological disability and may cause permanent neurological disability in MS. However, neurological decline doesn’t always associate with inflammatory lesions in MS and recent evidence indicates chronically demyelinated axons are capable of conducting signals suggesting irreversible neurological disability is due to additional mechanisms. We identified significant amounts of axonal transection in WM lesions from MS patients with short disease duration, indicating axonal transection occurs from disease onset. Additionally, we identified numerous cortical lesions in MS brains containing extensive neuronal pathology characterized by transected axons, transected dendrites, and apoptotic neurons. Widespread cortical pathology in MS brains identifies another component in the physiopathogenesis of MS and further implicates neuronal pathology in the development of irreversible neurological disabilities. We along with others suggest recovery early in the disease from neurological disability is due to resolution of inflammation and edema, remyelination, and the capacity of the CNS to compensate for neuronal injury. Eventually, accumulation of neuronal damage surpasses the capability of the CNS to compensate resulting in permanent neurological disability. Both inflammation and demyelination were associated with the neuronal pathology identified in the MS lesions. Identification of VCAM-1 on a subset of microglia at lesion edges contacting oligodendrocytes further supports the hypothesis that microglia target oligodendrocytes in MS brains and cause oligodendrocyte death and demyelination. Further characterization of MS lesions using microarray analysis was done to identify pathways activated or inhibited during lesion formation in an effort to better understand MS pathogenesis. Our concept of multiple sclerosis (MS) has expanded from an inflammatory demyelinating disease of the central nervous system (CNS) to one incorporating the concept of MS having an inflammatory mediated neurodegenerative component causing extensive neuronal damage resulting in permanent neurological disability. The majority (80-90%) of typical MS patients have a relapsing-remitting (RR) disease course. Early in the disease, RR-MS patients often benefit from anti-inflammatory therapeutics and recover neurological function with resolution of inflammation and edema. Eventually, many patients enter the secondary progressive phase of the disease characterized by increasing neurological disability, minimal recovery and poor efficacy of anti-inflammatory therapeutics. Why is the progression of RR-MS biphasic? Demyelination and inflammation certainly cause reversible neurological disability and may cause permanent neurological disability in MS. However, neurological decline doesn’t always associate with inflammatory lesions in MS and recent evidence indicates chronically demyelinated axons are capable of conducting signals suggesting irreversible neurological disability is due to additional mechanisms. We identified significant amounts of axonal transection in WM lesions from MS patients with short disease duration, indicating axonal transection occurs from disease onset. Additionally, we identified numerous cortical lesions in MS brains containing extensive neuronal pathology characterized by transected axons, transected dendrites, and apoptotic neurons. Widespread cortical pathology in MS brains identifies another component in the physiopathogenesis of MS and further implicates neuronal pathology in the development of irreversible neurological disabilities. We along with others suggest recovery early in the disease from neurological disability is due to resolution of inflammation and edema, remyelination, and the capacity of the CNS to compensate for neuronal injury. Eventually, accumulation of neuronal damage surpasses the capability of the CNS to compensate resulting in permanent neurological disability. Both inflammation and demyelination were associated with the neuronal pathology identified in the MS lesions. Identification of VCAM-1 on a subset of microglia at lesion edges contacting oligodendrocytes further supports the hypothesis that microglia target oligodendrocytes in MS brains and cause oligodendrocyte death and demyelination. Further characterization of MS lesions using microarray analysis was done to identify pathways activated or inhibited during lesion formation in an effort to better understand MS pathogenesis.
Michael Beattie (Advisor)
220 p.
Multiple sclerosis; inflammation; demyelination; axonal transection; dendritic transection; neuronal apoptosis; neuronal pathology; microarray; gene chips; gene expression analysis

Recommended Citations

Citations

  • Peterson, J. W. (2003). Inflammation and neuronal pathology in multiple sclerosis [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1054659240

    APA Style (7th edition)

  • Peterson, John. Inflammation and neuronal pathology in multiple sclerosis. 2003. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1054659240.

    MLA Style (8th edition)

  • Peterson, John. "Inflammation and neuronal pathology in multiple sclerosis." Doctoral dissertation, Ohio State University, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=osu1054659240

    Chicago Manual of Style (17th edition)

osu1054659240
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© 2003, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.