The applicants have recently described a hereditary presenile dementia in a seven generation pedigree. Affected family members presented with symptoms at an average age of 48.8 years (range 39-59). The initial clinical features included disequilibrium, memory loss and dysphagia processing to further cognitive decline, dystaxia, and extrapyramidal signs consisting of marked superior gaze palsy. Neuropathologic studies have shown neuronal loss in the central nervous system along with argentophilic, tau-immunopositive inclusions in neurons, and oligodendroglia cells. Twisted filaments isolated from brains of affected family members were composed of tau and differed in diameter and periodicity from the paired helical filaments of Alzheimer's disease.These lesions were not accompanied by s-amyloid deposits. Because of the clinical and molecular pathological characteristics of this family, the disease has been termed familial multiple system tauopathy with presenile dementia (MSTD). A limited genomic screen using DNA from family members localized the disease to a 3 cM region (THRA1-D17S791) of chromosome 17q. The purpose of this proposal is to (1) identify the pathologic phenotype of the first MSTD family and of the new family recently identified, as well as of any new kindred if they will become available; (2) characterize the pathological phenotype of two MSTD families and any other that may arise, (3) elucidate the mechanisms responsible for the development of the neurofibrillary lesions that characterize the disease; and (4) isolate the gene responsible. In view of the fact that MSTD shares dome molecular pathological characteristics with Alzheimer disease, corticobasal degeneration, and progressive supranuclear palsy, determining the genetic basis of MSTD would be the first step in understanding the molecular pathogenesis of these neurodegenerative diseases. Our studies represent a multidisciplinary team approach directed to the study of hereditary degenerative dementias, an approach that has been successful preciously in the study of familial Alzheimer disease and prion diseases. The members of the team are highly experienced investigators in their field of endeavor.
