Ryan M. Seals

Diabetes Mellitus, Obesity, and Diagnosis of Amyotrophic Lateral Sclerosis: A Population-Based Study

IMPORTANCE Although prior studies have suggested a role of cardiometabolic health on pathogenesis of amyotrophic lateral sclerosis (ALS), the association with diabetes mellitus has not been widely examined. Amyotrophic lateral sclerosis is the most common motor neuron disorder. Several vascular risk factors have been associated with decreased risk for ALS. Although diabetes is also a risk factor for vascular disease, the few studies of diabetes and ALS have been inconsistent. OBJECTIVE To examine the association between diabetes and obesity, each identified through International Statistical Classification of Diseases, Eighth or Tenth Revision codes in a hospital registry, and ALS using data from the Danish National Registers. DESIGN, SETTING, AND PARTICIPANTS Population-based nested case-control study of 3650 Danish residents diagnosed as having ALS between January 1, 1982, and December 31, 2009, and 365,000 controls (100 for each ALS case) matched on age and sex. The analysis was conducted in September and October 2014. MAIN OUTCOMES AND MEASURES Adjusted odds ratio for ALS associated with diabetes or obesity diagnoses at least 3 years prior to the ALS diagnosis date. RESULTS When considering diabetes and our obesity indicator together, the estimated odds ratio for ALS was 0.61 (95% CI, 0.46-0.80) for diabetes and 0.81 (95% CI, 0.57-1.16) for obesity. We observed no effect modification on the association with diabetes by sex. We did find a significant modification by age at ALS diagnosis and age at first mention of diabetes in the hospital registers. The protective association was stronger with increasing age at ALS diagnosis (P = .01), and the odds ratio for first mention of diabetes was 1.66 (95% CI, 0.85-3.21) before age 40 years but 0.52 (95% CI, 0.39-0.70) for older ages. These results are consistent with different associations for type 1 vs type 2 diabetes. CONCLUSIONS AND RELEVANCE In this Danish nationwide study to investigate the association between diabetes and ALS diagnosis, our findings are in agreement with previous reports of a protective association between vascular risk factors and ALS and suggest that type 2 diabetes, but not type 1, is protective for ALS.

Comparison of diagnoses of amyotrophic lateral sclerosis by use of death certificates and hospital discharge data in the Danish population.

Abstract Because ALS is rare, large-scale studies are difficult. Hospital and death certificate data are valuable tools, but understanding of how well they capture cases is needed. We identified 3650 incident cases in the Danish National Patient Register (NPR) between 1982 and 2009, using ICD-8 (before 1994) or ICD-10 codes. Death certificates were obtained from the Danish Register of Causes of Death. We obtained medical records for 173 of the cases identified in the NPR and classified these according to the El Escorial criteria. We compared ALS identification from death certificates to hospital discharges, and both to medical records. Results showed that the sensitivity for use of death certificates was 84.2% (95% CI 82.9–85.5%) and was significantly higher for females, subjects younger than 77 years, and when coded with ICD-8. Using only the underlying cause of death resulted in significantly lower sensitivity. The estimated overall positive predictive value (PPV) was 82.0% (95% CI 80.0–83.8%). Sensitivity and PPV were similar compared with medical records. In conclusion, we found that use of hospital discharges and death certificates is highly reliable and, therefore, a valuable tool for ALS epidemiologic studies. The possible effects on findings of slight differences by age, gender, and ICD coding should be considered.

Modification of the association between lead exposure and amyotrophic lateral sclerosis by iron and oxidative stress related gene polymorphisms

Abstract Our objective was to examine whether functional polymorphisms in hemochromatosis (HFE; H63D and C282Y), transferrin (TfC2), and glutathione-s-transferase Pi1 (GSTP1; Ile105Val) genes modify any lead-ALS association. We measured blood lead using atomic absorption spectroscopy and bone lead – a biomarker of cumulative lead exposure – using K-shell-X-ray fluorescence in 100 neurologist-confirmed ALS cases and 194 controls, the latter recruited as part of two separate studies; all subjects lived in New England. Participants were considered variant carriers or wild-type for each polymorphism. To assess effect modification, we included cross-product terms between lead biomarkers and each polymorphism in separate adjusted polytomous logistic regression models. Compared with wild-type, the odds ratio (OR) per 15.6 μg/g patella lead (interquartile range; IQR) was 8.24 (95% CI 0.94–72.19) times greater among C282Y variant carriers, and 0.34 (95% CI 0.15–0.78) times smaller among H63D variant carriers. Results were weaker for tibia lead. Compared with wild-type the OR per 2 μg/dl blood lead (IQR) was 0.36 (95% CI 0.19–0.68) times smaller among H63D variant carriers, and 1.96 (95% CI 0.98–3.92) times greater among GSTP1 variant carriers. In conclusion, we found that HFE and GSTP1 genotypes modified the association between lead biomarkers and ALS. Contrasting modification by the HFE polymorphisms H63D and C282Y may suggest that the modification is not simply the result of increased iron.

Amyotrophic Lateral Sclerosis and the Military: A Population-based Study in the Danish Registries.

Background: Prior studies have suggested that military service may be associated with the development of amyotrophic lateral sclerosis (ALS). We conducted a population-based case–control study in Denmark to assess whether occupation in the Danish military is associated with an increased risk of developing ALS. Methods: There were 3,650 incident cases of ALS recorded in the Danish National Patient Registry between 1982 and 2009. Each case was matched to 100 age- and sex-matched population controls alive and free of ALS on the date of the case diagnosis. Comprehensive occupational history was obtained from the Danish Pension Fund database, which began in 1964. Results: 2.4% (n = 8,922) of controls had a history of employment in the military before the index date. Military employees overall had an elevated rate of ALS (odds ratio [OR] = 1.3; 95% confidence interval [CI]: 1.1, 1.6). A 10-year increase in years employed by the military was associated with an OR of 1.2 (95% CI: 1.0, 1.4), and all quartiles of time employed were elevated. There was little suggestion of a pattern across calendar year of first employment, but there was some evidence that increasing age at first employment was associated with increased ALS rates. Rates were highest in the decade immediately following the end of employment (OR = 1.6; 95% CI: 1.2, 2.2). Conclusions: In this large population-based case–control study, employment by the military is associated with increased rates of ALS. These findings are consistent with earlier findings that military service or employment may entail exposure to risk factors for ALS.

Occupational formaldehyde and amyotrophic lateral sclerosis

Prior studies have yielded inconsistent evidence regarding the association between formaldehyde exposure and amyotrophic lateral sclerosis (ALS). We conducted a population case–control study in the Danish National Registries on the relationship between occupationally-derived formaldehyde exposure and ALS. Occupational history was obtained from a comprehensive and prospectively recorded pension database of all paid work in Denmark since 1964, and was linked to a job-exposure matrix to derive individual exposure estimates. Each case was matched to 4 age- and sex-matched population controls alive on the date of the case diagnosis via risk set sampling, and odds ratios and confidence intervals (CI) were calculated via conditional logistic regression, adjusting for potential confounders. There were 3650 incident cases of ALS in the Danish National Patient Register from 1982 to 2009. Among controls, 25% were ever employed in jobs with a positive prevalence of formaldehyde exposure. Exposure to formaldehyde was associated with a 1.3-fold increased rate of ALS (95% CI 1.2–1.4). This study suggests that formaldehyde exposure, or employment in formaldehyde-exposed occupations, is related to the risk of ALS.

Cardiovascular disease and diagnosis of amyotrophic lateral sclerosis: A population based study.

Abstract Amyotrophic lateral sclerosis (ALS) is a rapidly fatal neurodegenerative disease of unknown etiology. We investigated the association between ALS diagnosis and prior cardiovascular disease (CVD), and CVD-specific, hospital admissions in the Danish population. We conducted a population based nested case-control study, including 3182 Danish residents diagnosed with ALS at age ≥20 years (1982–2009) and 100 randomly selected controls for each case, matched on age, gender and vital status. We estimated odds ratios (OR) associated with CVD, and CVD-specific hospital admissions, adjusting for socioeconomic and marital status, region of residence and past diabetes and obesity diagnoses. The estimated adjusted OR for any CVD admission at least three years prior to the date of ALS diagnosis was 1.15 (95% CI 1.04–1.27). Our results varied across cause-specific admissions; for atherosclerosis the OR was 1.36 (95% CI 1.02–1.80) and for ischemic heart disease 1.14 (95% CI 0.99–1.31), while we observed no association with hypertensive and cerebrovascular diseases. Adjusting for or stratifying by COPD status, a cigarette-smoking correlate, did not change our results. In conclusion, in our population based study we found evidence for a moderately elevated association with CVD that was stronger for specific conditions, such as atherosclerosis. Our findings may have important implications for ALS pathogenesis.

Cognitive decline and depression in 29 U.S. Alzheimer's disease centers

exposures were baseline bodymass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR). We used the Western Australian Data Linkage System to establish the presence of new cases of dementia between 1996 and 2009 according to the International Classification of Diseases. Crude and adjusted hazard ratio (HR, 95% confidence interval, 95%CI) of dementia for each adiposity marker was calculated using Cox regression models. Other measured factors included age, marital status, education, alcohol use, smoking, fat consumption, physical activity, and prevalent diabetes, dyslipidaemia and cardiovascular disease. Results: Compared with men with BMI < 25, participants with BMI between 25-30 had lower adjusted HR of dementia (HR 1⁄4 0.83, 95% CI 1⁄4 0.72-0.97). The HR of dementia for men with BMI 1⁄4 30 was comparable to men with BMI < 25 (HR 1⁄4 0.85, 95%CI1⁄4 0.70-1.05). Waist circumference showed no obvious association with dementia hazard.MenwithWHR1⁄4 0.9 had lower adjusted HR of dementia than men with WHR< 0.9 (HR1⁄4 0.82, 95%CI1⁄4 0.68-0.98). We found a “J” shape association betweenmeasures of obesity and the hazard of dementia, with the nadir of risk being in the overweight range of BMI and about 1 for WHR. Conclusions: Higher adiposity is not associated with incident dementia in older men. Overweight men and those with WHR 1⁄4 0.9 have lower hazard of dementia than men with normal weight and withWHR < 0.9.