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.
To our knowledge, this is the first prospective, in-depth multicenter, interdisciplinary, molecular epidemiological investigation of oxidative stress (OS) in ALS. We will investigate whether environmental, lifestyle, psychological, and dietary factors are linked to abnormal OS biomarkers and whether a variety of factors and abnormal OS biomarkers are associated with disease progression. Our study 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 OS in ALS.
| Woolley, Susan; Goetz, Ray; Factor-Litvak, Pam et al. (2018) Longitudinal Screening Detects Cognitive Stability and Behavioral Deterioration in ALS Patients. Behav Neurol 2018:5969137 |
| Murphy, Jennifer; Factor-Litvak, Pam; Goetz, Raymond et al. (2016) Cognitive-behavioral screening reveals prevalent impairment in a large multicenter ALS cohort. Neurology 86:813-20 |
| Nieves, Jeri W; Gennings, Chris; Factor-Litvak, Pam et al. (2016) Association Between Dietary Intake and Function in Amyotrophic Lateral Sclerosis. JAMA Neurol 73:1425-1432 |
| Rabkin, Judith G; Goetz, Raymond; Factor-Litvak, Pam et al. (2015) Depression and wish to die in a multicenter cohort of ALS patients. Amyotroph Lateral Scler Frontotemporal Degener 16:265-73 |
| Mitsumoto, Hiroshi; Factor-Litvak, Pam; Andrews, Howard et al. (2014) ALS Multicenter Cohort Study of Oxidative Stress (ALS COSMOS): study methodology, recruitment, and baseline demographic and disease characteristics. Amyotroph Lateral Scler Frontotemporal Degener 15:192-203 |
| Goldman, Jill S; Quinzii, Catarina; Dunning-Broadbent, Jane et al. (2014) Multiple system atrophy and amyotrophic lateral sclerosis in a family with hexanucleotide repeat expansions in C9orf72. JAMA Neurol 71:771-4 |
| Kirk, Kathryne; Gennings, Chris; Hupf, Jonathan C et al. (2014) Bioenergetic markers in skin fibroblasts of sporadic amyotrophic lateral sclerosis and progressive lateral sclerosis patients. Ann Neurol 76:620-4 |
| Kariya, Shingo; Sampson, Jacinda B; Northrop, Lesley E et al. (2014) Nuclear localization of SMN and FUS is not altered in fibroblasts from patients with sporadic ALS. Amyotroph Lateral Scler Frontotemporal Degener 15:581-7 |
| D'Amico, Emanuele; Pasmantier, Meredith; Lee, Yei-Won et al. (2013) Clinical evolution of pure upper motor neuron disease/dysfunction (PUMMD). Muscle Nerve 47:28-32 |
| Factor-Litvak, Pam; Al-Chalabi, Ammar; Ascherio, Alberto et al. (2013) Current pathways for epidemiological research in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 14 Suppl 1:33-43 |
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