Description: The overall goal of this project is to define gene defects that cause ALS-FTD, starting with a subset of families in whom this disease has been mapped to a locus on chromosome 9. The study will test the following hypotheses: 1 ) that a single gene defect, transmitted as a dominant trait, initiates cell death in two distinctive populations of neurons, and 2) this condition is accompanied by oxidative pathology. The aims of the study are to collect and clinically characterize ALS-FTD families; to use genetic-linkage analysis to determine if new families are genetically homogeneous (linked to the same locus); to develop a physical map of the ALS-FTD loci to identify candidate genes; to screen candidates for mutations; and, when an ALS-FTD gene is identified, screen for this gene in a large series of individuals with ALS or dementia alone. A parallel objective is to assess levels of oxidative cytopathology in the brains and fluids of these patients, testing the hypothesis that, as in many other neurodegenerative disorders, brain tissue of patients with ALS-FTD will show oxidative pathology. To date, no causative gene defects have been identified in ALS-FTD, nor have tissues from these patients been systematically analyzed for markers of excitatory and oxidative pathology. It is the long-term goal of this study that insights into novel mechanisms of cellular death which are prominent in two functionally distinct sets of neurons may illuminate the pathogenesis of other types of motor neuron disease and other forms of dementia and, ultimately, open new avenues for treating these diseases.