LOCALIZATION AND CHARACTERIZATION OF IRON DEPOSITS IN MULTIPLE SCLEROSIS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In this proposal we combine the unique capabilities of synchrotron x-ray fluorescence (XRF) and magnetic resonance imaging (MRI) with classical immunopathology to elucidate the role of iron deposits in human multiple sclerosis (MS) and in animal models that recapitulate important features of human MS. First, thick human autopsy brain slices, both MS affected and unaffected, will be imaged using MRI sequences commonly used in the diagnosis of MS patients. Using the MRI image as a guide, each brain will be sliced 2 mm thick and the fresh face will be mapped for iron and other abundant elements (calcium, copper and zinc) using rapid-scanning XRF (100 micron beam). The ability to map multiple elements, by SRS-XRF, is crucial because preliminary data shows that MS lesions are low in zinc, regions of active disease are high in iron and copper is also abnormal. Regions of interest will be excised for microprobe analysis and immunopathology and to determine the chemical form of iron. Iron chemistry associated with active disease (microglia) will be compared with iron seen around vessels draining the brain that may result from chronic cerebral venous insufficiency (CCSVI). CCSVI is linked to many types of MS. Where tissue is available, iron K-edge spectra will be collected at 10K from ROI excised from frozen human brain tissue. In a second study combining MRI with rapid scanning (50 micron beam) and microprobe XRF, we will map iron in a mouse model of progressive MS. In this murine model, demyelination is produced by viral infection. In a third study we will examine the role of multiple metals in the healing process using a rat model of focal demyelination in the brain and sciatic nerve induced by lipopolysaccharide. This is a model of relapsing remitting MS in which the healing process and remyelination can be followed over time. Preliminary work shows that a 20 micron capillary optic will provide the sufficient flux and resolution for initial mapping in this study.