A large Indiana kindred is affected by an autosomal dominant neurologic disorder. The disease of the Indiana kindred is characterized clinically by cerebral ataxia, parkinsonism and dementia, and pathologically by amyloid plaques, neuritic plaques, neurofibrillary tangles (as in Alzheimer disease), nerve-cell loss and presence of iron deposits in the striatum and substantia nigra. Abnormal eye movements are present early in the disease and may precede onset of neurologic signs. Amyloid of plaques is not recognized by polyclonal antibodies against the Alzheimer disease beta- protein, but does contain epitopes recognized by antibodies against a prion protein (PrP). However, unlike PrP-positive cases of Gerstmann-Straussler- Scheinker syndrome, in which there are mutations in the open reading frame (ORF) of the PrP gene, no putative disease-causing mutation has been found in the PrP ORF of the Indiana kindred. We postulate that the disease of the Indiana kindred is a distinct entity that shares clinical and pathologic similarities with Gerstmann-Straussler-Scheinker syndrome on the one hand and with Alzheimer disease on the other. Our overall goal is to expand and correlate information on several aspects of the Indiana kindred, each relevant to a Program Project to be developed within the next three years. We propose to: (I) Conduct prospective clinical and brain magnetic resonance imaging to clarify the natural history of the disease; (II) Define the ocular motor functions in at-risk and affected subjects; (III) Continue defining the pathology of the Indiana kindred; (IV) Biochemically characterize the amyloid of the Indiana kindred and (V) Determine the chromosomal map position of the disease-causing gene. The study of this neurodegenerative process will contribute to the understanding of the basic mechanisms operating in central nervous system amyloidogenesis and neurofibrillary tangle formation.
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