Amyotrophic lateral sclerosis (ALS) is a largely adult-onset, progressive, fatal (death usually occurring in 3-5 years) neurodegenerative disease with a multifactorial etiology and a heterogenous clinical presentation. There are numerous genetic and non-genetic risk factors, with new ones discovered frequently. Among the non- genetic risk factors, age, male sex and several environmental factors, including military service, are the most salient. Accordingly, ALS is a fully compensable condition in the Department of Veterans Affairs (VA) Veterans Health Administration (VHA). As the Veteran population ages, the incidence and prevalence of ALS, with its staggering personal, financial and societal costs, will continue to increase. Establishing large national cohorts essential for ALS research is limited by the low prevalence (6-8 cases per 100,000) and short survival time (3-5 years) of persons with ALS (PALS). This is particularly true for efforts to develop biorepositories that collect central nervous system (CNS) tissue samples annotated with clinical information essential to biomedical ALS research. Although a number of mouse models have been developed to study ALS, these models are limited and the need for research quality human CNS tissue for genomic and proteomic research in ALS is critical. The VA funded the VA Biorepository Brain Bank (VABBB) to support ALS research and improve clinical care. The VABBB is presently the only national prospective cohort study and CNS tissue bank in the U.S. that is enrolling and conducting ongoing follow-up on Veterans with ALS. The VABBB is a multi-site collaboration among VA Boston Healthcare System (VABHS) and the Southern Arizona VA Healthcare System (SAVAHCS). The VABBB utilizes the strengths across the Boston and Tucson sites in enrollment, assessment, tissue banking operations, neuropathological diagnosis, medical informatics and data management. The VABBB cohort is notable for its size (over 300 PALS), the amount and quality of CNS tissue and clinical data available, and for the relatively long duration and slow disease progression in this unique cohort. Tissue and clinical data from the VABBB are available for distribution to qualified researchers. In this application, we seek to further our support of cutting-edge ALS research and enhance the value of VA’s investment in the VABBB. Over the next four years our specific aims are: 1) To continue, and further enhance, the VA Biorepository Brain Bank (VABBB) as the nation’s only national prospective cohort study and central nervous system (CNS) tissue/biofluid bank supporting international ALS research; 2) Conduct state-of-the-art diagnostic neuropathological evaluation; and 3) To continue our characterization of cognitive and behavioral dysfunction in our cohort to support emerging clinicopathological studies of ALS and frontotemporal lobar degeneration. Specific Aim 1 will involve 1) generation of a larger and more diverse (e.g., sex) national sample of ...