Amyotrophic lateral sclerosis (ALS) is a devastating, rapidly fatal neurodegenerative disease of largely unknown cause. It is clinically characterized by progressive skeletal muscle paralysis and eventual respiratory failure, with a mean survival of about 40 months after symptom onset. No prospective investigations have attempted to determine what factors accelerate or slow disease progression. Recent clinical and epidemiological studies suggest that diverse environmental and lifestyle factors are associated with ALS and that these generate oxidative stress (OS). We hypothesize that these extrinsic factors act throughout the disease course, generating varying levels of OS, and thus influence disease progression. We propose to test this hypothesis in 420 newly diagnosed ALS patients from 11 ALS centers across the US. We specifically aim: 1. To determine whether markers of increased exposure to OS, measured via questionnaire or biomarkers, are associated with the progression of ALS. ALS progression will be determined with a widely used and well-validated ALS functional scale (the ALSFRS-R) every 3 to 6 months for 24 months. At baseline and follow-up, we will obtain measures of OS biomarkers (urinary 15-F2t-isoprostane and 8- oxodeoxyguanosine, plasma paraoxonase I [PON1] levels, and PON1 functional status) and, through structured interviews, measures of current environmental, psychological, dietary, and lifestyle factors associated with OS. 2. To examine the associations between OS biomarkers, an OS index, and survival of patients with ALS. An OS index will be developed based on a sum of the external factors (Goodman et al. 2007). Survival will be followed at the ALS Centers during the grant period and thereafter by using National Death Index data. We will test whether increased and continuing OS as measured by the index and biomarkers affect survival;3. To determine whether a variety of environmental, lifestyle, and psychological factors are associated with increased levels of OS biomarkers at baseline;4. To evaluate associations between lipid profile and ALS progression, as measured by ALSFRS-R and survival. Lipids will be analyzed at several time points to determine whether high cholesterol and LDL are associated with longer survival, as recently reported (Dupuis et al 2008);and 5. In exploratory analyses, to determine whether OS markers and exposures are associated with distinct subtypes of ALS, such as bulbar- or spinal-onset ALS, and ALS with or without fronto-temporal dementia (FTD). To our knowledge, this is the first prospective, interdisciplinary, in-depth multicenter epidemiological investigation of OS in ALS. Our project will increase the understanding of the disease mechanisms involved in disease prognosis and may be the first step toward new treatment and prevention approaches, such as multiple anti- oxidant therapy, to target oxidative stress sites in ALS.