Éilis J. O'Reilly

Our objective was to determine if amyotrophic lateral sclerosis (ALS) risk varies according to body mass index (BMI) captured up to three decades earlier. At baseline 537,968 females and 562,942 males in five ongoing cohorts reported height, current weight and weight at age 18/21 years. During 14–28 years of follow-up, 1153 participants developed ALS. Cohort-specific Cox proportional hazards models were used to estimate rates that were then pooled with random-effects models. Results showed that lower BMI at baseline was associated with ALS; for each 5-unit increase in BMI, ALS rates were 21% lower (95% CI 14% 27%). Compared to individuals with healthy BMI, ALS rates were significantly lower among the overweight (RR = 0.76 (95% CI 0.62–0.93)) and obese (RR = 0.73 (95% CI 0.55–0.96)). Among never smokers the association persisted: RR = 0.75 (95% CI 0.65–0.85) for each 5-unit increase. Excluding the first seven years of follow-up, the associations were materially unchanged suggesting that weight loss from undiagnosed disease does not fully explain the findings. Overall, 75% of males and females had a healthy BMI at age 18/21 years, 15% of males and 8% of females were overweight or obese; there was no association with ALS although numbers with an unhealthy weight were small. In conclusion, these findings support an association between lower premorbid BMI and ALS.

The authors investigated whether vitamin E intake was associated with amyotrophic lateral sclerosis (ALS) in the Nurses’ Health Study (1976–2004), the Health Professionals Follow-up Study (1986–2004), the Cancer Prevention Study II Nutrition Cohort (1992–2004), the Multiethnic Cohort Study (1993–2005), and the National Institutes of Health-AARP Diet and Health Study (1995–2005). ALS deaths were identified through the National Death Index. In the Nurses' Health Study and the Health Professionals Follow-up Study, confirmed nonfatal ALS cases were also included. Cohort-specific results were estimated using Cox proportional hazards models and pooled using random-effects models. Among 1,055,546 participants, 805 developed ALS. Overall, using vitamin E supplements was not associated with ALS. However, within cohorts with information on duration of vitamin E supplement use (231 cases), ALS rates declined with increasing years of use (P-trend = 0.01). Compared with nonusers, the multivariable-adjusted relative risk was 1.05 (95% confidence interval (CI): 0.60, 1.84) among users for ≤1 year (12 cases), 0.77 (95% CI: 0.33, 1.77) among users for 2–4 years (7 cases), and 0.64 (95% CI: 0.39, 1.04) among users for ≥5 years (18 cases). For dietary vitamin E intake, the multivariable-adjusted relative risk comparing the highest quartile with the lowest was 0.79 (95% CI: 0.61, 1.03); an inverse dose-response was evident in women (P-trend = 0.002) but not in men (P-trend = 0.71). In this large, pooled prospective study, long-term vitamin E supplement use was associated with lower ALS rates. A possible protective effect of vitamin E deserves further consideration.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of motor neurons affecting more than 5500 newly diagnosed patients every year in the United States.¹ The consequence of ALS is a dramatic rapid deterioration of motor function.² There is no cure for ALS, and the few available treatments have limited efficacy.¹ About 90% of ALS cases are sporadic and of unknown, possibly environmental, origin.³ Cigarette smoking might contribute to the risk of ALS by a direct neurotoxic effect on motor neurons or by an increase in oxidative stress. Although the author of a 2009 review suggests that smoking can be considered an established risk factor for ALS, there have been few investigations, and results have been conflicting.⁴ A positive association between smoking and ALS has been reported in some case-control studies^5-7 but not all of them.^8-13 These discrepancies may in part be explained by small sample sizes and possible survival, selection, and recall bias.^8-13 However, results of previous longitudinal studies^14,15 have also been conflicting. In the Cancer Prevention Study II (CPS-II), an analysis that included 621 ALS deaths found that cigarette smoking was associated with increased ALS mortality in women but not in men.¹⁴ The lack of association between smoking and ALS in men was confirmed among a cohort of male construction workers in Sweden, 160 of whom died of ALS.¹⁵ However, in a 2009 multicenter prospective study¹⁶ in Europe that included 118 participants with ALS, current smokers had 2-fold increased rates of ALS compared with never smokers, with no significant differences by sex.

Plasma urate has been consistently associated with a lower risk of Parkinson's disease in men, but it is less clear if this relation exists in women. Between 1990 and 2004, the authors conducted a nested case-control study among participants of the female-only Nurses' Health Study. In controls (n = 504), plasma urate was positively associated with age, body mass index, alcohol consumption, hypertension, and use of diuretics and was inversely associated with physical activity and postmenopausal hormone use, as expected. Mean urate levels were 5.04 mg/dL for cases (n = 101) and 4.86 mg/dL for controls (P = 0.17). The age-, smoking-, and caffeine-adjusted rate ratio comparing women in the highest (≥5.8 mg/dL) with those in the lowest (<4.0 mg/dL) quartile was 1.33 (95% confidence interval: 0.69, 2.57; P(trend) = 0.4). Further adjustment for body mass index, physical activity, history of hypertension, and postmenopausal hormone use did not change the results. Unlike in men, these findings do not support the hypothesis that urate is strongly associated with lower rates of Parkinson's disease among women.

Diethylstilbestrol (DES) is an estrogenic endocrine disruptor with long-term health effects, possibly including depression, following exposure in utero. Understanding the relation between in utero DES exposure and depression will provide insight to the potential adverse effects of bisphenol A, a functionally similar and ubiquitous endocrine disruptor. The association between in utero DES exposure and depression was assessed among participants in the Nurses’ Health Study II who first reported their history of antidepressant use in 1993 and lifetime history of depressive symptoms in 2001. DES exposure was reported by 1,612 (2.2%) women. A history of depression at baseline was higher among women exposed to DES in utero compared with those not exposed (age-adjusted odds ratio (OR) = 1.47, 95% confidence interval (CI): 1.26, 1.72) (P < 0.001). Incident depression (first use of antidepressants among women who also reported depressive symptoms) during follow-up (1995–2005) was reported by 19.7% of women exposed to DES and 15.9% unexposed (age-adjusted OR = 1.41, 95% CI: 1.22, 1.63) (P < 0.001). Adjustment for risk factors of depression and correlates of DES exposure moderately attenuated the association (multivariable-adjusted OR = 1.30, 95% CI: 1.13, 1.51) (P = 0.0004). These results suggest that the neurophysiologic effects of in utero exposure to DES could lead to an increased risk of depression in adult life. Further research should assess whether in utero exposure to bisphenol A has similar adverse effects.

In epidemiologic studies and in studies of discordant twins, cigarette smoking has been consistently associated with a lower risk of Parkinson's disease, but whether this association is causal remains controversial. Alternatively, an infectious or toxic exposure in childhood or early adulthood could affect both the reward mechanisms that determine smoking behavior and the future risk of Parkinson's disease. If so, parental smoking, commonly established before the birth of the first child, would be unlikely to be related to Parkinson's disease risk. The authors assessed the association between Parkinson's disease and parental smoking during childhood in the Nurses’ Health Study and the Health Professionals Follow-up Study conducted in the United States. During 26 years and 18 years of follow-up, respectively, 455 newly diagnosed Parkinson's disease cases were documented among those who provided information on parental smoking. The age-adjusted, pooled relative rate of Parkinson's disease was 0.73 (95% confidence interval: 0.53, 1.00; P-trend = 0.04) comparing participants who reported that both parents smoked with those who reported that neither did. Adjustment for caffeine and alcohol intake did not materially change the results. If the inverse association between smoking and Parkinson's disease were due to confounding by an environmental factor or were the result of reverse causation, it is unlikely that parental smoking would predict Parkinson's disease.