The pathogenesis of human presenile and senile demetias will be investigated in rodent models developed in this laboratory. In these models human Creutzfeldt-Jakob disease (CJD) and related dementias associated with aging are transmitted to small laboratory animals. In he experimental disease, as in many human dementias, there is a chronic and nonremitting course, and pathological lesions are entirely restricted to the CNS, without any inflammatory reactions. Our long term goal is to use these models to unravel common pathways in the production of human dementias and aging. Events that are obscured or inaccessible in end stages of the human disease can be clarified by study of early stages in experimental models. We intend to isolate more primary agents from human senile and presenile dementias, and to define overlapping and/or characteristics of lesions in these. Lesions in models will be compared with lesions occurring in aging, using temporal studies and a variety of morphological techniques. Isolation of variant strains of the CJ agent will be attempted in inbred strains of hamsters, evaluating variations in clinical signs and lesion profiles. The efficacy of HPA-23, found to be effective in scrapie will be tested in experimental CJD, and evaluated for lesion production and mode of action. Age related maturation of resistance of lymphoreticular cells will be tested and infectivity of subpopulations of these cells investigated. Brain subfractions will be systematically evaluated with special emphasis on RNA species and in vitro analysis. The studies have wide ramifications for reevaluation and approach as to the group of human dementias.
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