Swedish National Registers I have collaborated with Weimin Ye at the Karolinska Institute on studies based on the Swedish National Registers. ALS and Head Injury: Using 4,004 ALS cases from the Swedish Patient Register and 20,020 matched controls, we evaluated hospitalization for severe head injury before ALS diagnosis. Injury in the year preceding diagnosis was associated with ALS (OR 3.9, 95% CI 2.66.1). This relationship may be due to reverse causation, because individuals experience increased falls and injuries shortly before diagnosis of ALS. No association was observed for severe head injury 3 or more years before ALS diagnosis. These findings provide little support for an association of severe head injury in adulthood with ALS risk but do not exclude a relationship with less severe injury not requiring hospitalization or with injuries occurring in childhood. ALS and Sepsis: Severe infections may increase ALS risk by increasing inflammation. We studied 4,004 ALS cases from the Swedish Patient Register and 20,020 matched controls. Neither previous CNS infection nor sepsis was associated with ALS risk. Our results suggest that severe acute infections are unlikely to contribute to ALS risk. ALS and Cancer: We studied 5,481 ALS cases from the Swedish Patient Register and 27,405 population controls. Overall, a previous cancer diagnosis was not associated with ALS risk either for all cancers or for any specific cancer although increased risk of ALS was observed during the first year after cancer diagnosis (OR 1.5, 95% CI 1.2-1.9). In contrast, a lower risk of cancer was observed in ALS patients after diagnosis compared to ALS-free individuals (IRR 0.8;95% CI 0.7-1.0). Our results provide little evidence for comorbidity of cancer and ALS;surveillance bias seems the most likely explanation for the limited associations previously detected. Occupational Cohorts Certain occupations and occupational exposures may be related to ALS, but data are sparse and inconsistent. Our results from the New England ALS study identified several associations with ALS. To extend this work, we collaborated with Lynne Pinkerton at NIOSH to study two cohorts. Formaldehyde: We studied ALS mortality in a cohort of 11,022 US garment workers exposed to formaldehyde. We ascertained vital status through 2008 and conducted life table analyses to obtain standardized mortality ratios. We observed 8 deaths from ALS. Compared to the US general population, ALS mortality was not elevated in the overall cohort or among subgroups with greater exposure based on exposure duration or year of first exposure. These results suggest that ALS is not associated with formaldehyde exposure but need confirmation in a larger study. Flight Attendants: Concern exists about the potential chronic neurological effects among flight crew of exposure to contaminants from engine oil in aircraft cabin air. We evaluated mortality from neurodegenerative diseases among 11,311 former US flight attendants. We ascertained vital status through 2007 and conducted life table analyses to obtain standardized mortality ratios. ALS mortality was elevated two-fold compared to the US population, based on 9 deaths. There was no clear pattern in risk related to exposure duration. Mortality from other neurodegenerative diseases was not elevated. Our findings are limited due to small numbers of observed deaths, but suggest that flight attendants may have an increased risk of ALS, possibly related to exposure to tricresyl phosphates in engine oil. GENEVA (Genes and Environment in Veterans with ALS) Reports that ALS risk might be increased among veterans deployed to the 19901991 Persian Gulf War prompted the Department of Veterans Affairs (VA) to establish a National Registry of Veterans with ALS. The registry, established in 2004, enrolled 1,573 US veterans with neurologist-confirmed ALS. Information in the VA Registry includes ALS diagnosis and other clinical details based on medical record review and information gathered during an initial screen and six-month follow-up interviews. Mortality has been ascertained through December 31, 2010. GENEVA is a case-control study comparing 631 ALS cases from the VA registry and 975 matched veteran controls. A structured telephone interview conducted collected information on demographics, lifetime occupational history, hobbies, home pesticide use, use of tobacco, caffeine, and alcohol, residential history, physical trauma, and family history of ALS or other neurodegenerative diseases. Extensive genotyping of cases and controls was also conducted. We conducted an add-on study, Veterans with ALS and Lead Exposure (VALE), to evaluate the relationship of blood lead to ALS. We collected whole blood samples in metal-free tubes from 200 ALS cases and 229 matched controls. We measured metals with inductively coupled plasma mass spectrometry, a highly sensitive assay, and evaluated bone turnover using biomarkers of bone formation and resorption. We found that age-adjusted blood lead levels were higher among cases compared with controls. Bone resorption was also greater in cases than controls, although bone formation was the same. ALS was associated with blood lead levels;the OR for each unit increase in log-transformed blood lead was 2.6 (1.9-3.7). The association persisted after adjustment for or stratification by bone turnover biomarkers. These results corroborate our earlier finding that elevated blood lead is associated with increased ALS risk and suggest that increased bone turnover in ALS cases does not fully explain this association. We are presently using VALE data to evaluate the relationship of blood lead to survival. Initial results suggest at best a weak association, consistent with that observed in the New England study. Of great interest is the fact that increased CTX, a marker of bone resorption, was associated with shorter survival, even after controlling for physical activity and respiratory function. Elevated CTX may be a clinically useful marker of prognosis. We are also using VALE data to evaluate the relationship of ALS to other metals. We measured several metals other than lead, including cadmium, chromium, copper, manganese, and nickel. We will evaluate the relationships of these metals to ALS risk. An interesting possibility is that combinations of metals will be related to ALS risk, as previously suggested for Parkinsons disease. GENEVA was initially developed by Silke Schmidt at Duke University Medical Center. Dr Schmidt was unable to continue work with the study, and consequently I have taken the lead in analyses of questionnaire data. We are planning several studies. Military Exposures: Studies suggesting increased ALS risk among veterans of the first Persian Gulf War and potentially all military veterans provided the impetus for development of the VA ALS registry on which GENEVA is based. Detailed data on military service (eg, war, if any, years of service, military branch, etc) and military-specific exposures was collected in the GENEVA interviews. We plan to evaluate associations of these military exposures with ALS risk and survival. We will investigate (i) military service by branch and war;(ii) deployment-specific exposures, including several unique to the first Persian Gulf War;(iii) specific exposures including pesticides. Occupational Exposures: A complete occupational history was collected from GENEVA participants. Susan Woskie, an industrial hygienist, and a team of specialists are evaluating these histories in order to assign exposures to several agents of interest, all of which have been implicated in ALS by one or more studies but none conclusively. These exposures include lead, mercury, selenium, arsenic, PCBs, hydrocarbon solvents, chlorinated solvents, formaldehyde, EMF, and viral agents.

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Beard, John D; Engel, Lawrence S; Richardson, David B et al. (2016) Military service, deployments, and exposures in relation to amyotrophic lateral sclerosis etiology. Environ Int 91:104-15
Pinkerton, Lynne E; Hein, Misty J; Grajewski, Barbara et al. (2016) Mortality from neurodegenerative diseases in a cohort of US flight attendants. Am J Ind Med 59:532-7
Peters, Tracy L; Beard, John D; Umbach, David M et al. (2016) Blood levels of trace metals and amyotrophic lateral sclerosis. Neurotoxicology 54:119-26
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Eum, Ki-Do; Seals, Ryan M; Taylor, Kathryn M et al. (2015) Modification of the association between lead exposure and amyotrophic lateral sclerosis by iron and oxidative stress related gene polymorphisms. Amyotroph Lateral Scler Frontotemporal Degener 16:72-9
Beard, John D; Kamel, Freya (2015) Military service, deployments, and exposures in relation to amyotrophic lateral sclerosis etiology and survival. Epidemiol Rev 37:55-70
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
Pinkerton, Lynne E; Hein, Misty J; Meyers, Alysha et al. (2013) Assessment of ALS mortality in a cohort of formaldehyde-exposed garment workers. Amyotroph Lateral Scler Frontotemporal Degener 14:353-5

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