title: Pathological mechanisms in progressive multiple sclerosis.
abstract: A better understanding of the pathological mechanisms that drive neurodegeneration in individuals with multiple sclerosis is needed to develop therapies that will effectively treat patients in the primary and secondary progressive stages of the disease. We propose that the inflammatory demyelinating disease process in early multiple sclerosis triggers a cascade of events that lead to neurodegeneration and are amplified by pathogenic mechanisms related to brain ageing and accumulated disease burden. Key elements driving neurodegeneration include microglia activation, chronic oxidative injury, accumulation of mitochondrial damage in axons, and age-related iron accumulation in the human brain. Altered mitochondrial function in axons might be of particular importance. This process leads to chronic cell stress and imbalance of ionic homoeostasis, resulting in axonal and neuronal death. The evidence suggests that treatment of progressive multiple sclerosis should be based on a combination of anti-inflammatory, regenerative, and neuroprotective strategies.
authors.affiliation: Centre for Neuroregeneration, University of Edinburgh, Edinburgh, UK.
authors.forename: Don H
authors.initials: DH
authors.lastname: Mahad
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Trapp
authors.affiliation: Center for Brain Research, Medical University of Vienna, Austria. Electronic address: hans.lassmann@meduniwien.ac.at.
authors.forename: Hans
authors.initials: H
authors.lastname: Lassmann
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D020528:Multiple Sclerosis, Chronic Progressive / Q000175:diagnosis* / Q000378:metabolism*; D009410:Nerve Degeneration / Q000175:diagnosis / Q000378:metabolism; D016897:Respiratory Burst / Q000502:physiology
chemical_list: D018836:Inflammation Mediators