RESUMO
BACKGROUND: We investigated the association between cigarette smoking and risk of amyotrophic lateral sclerosis (ALS) in a pooled analysis of population-based case-control studies and explored the independent effects of intensity, duration and time-since-quitting. METHODS: ALS cases and controls, matched by age, sex and region, were recruited in the Netherlands, Italy and Ireland (*Euro-MOTOR project). Demographics and detailed lifetime smoking histories were collected through questionnaires. Effects of smoking status, intensity (cigarettes/day), duration (years), pack-years and time-since-quitting (years) on ALS risk were estimated using logistic regression models, adjusting for age, sex, alcohol, education and centre. We further investigated effect modification of the linear effects of pack-years by intensity, duration and time-since-quitting using excess OR (eOR) models. RESULTS: Analyses were performed on 1410 cases and 2616 controls. Pack-years were positively associated with ALS risk; OR=1.26 (95% CI: 1.03 to 1.54) for the highest quartile compared with never smokers. This association appeared to be predominantly driven by smoking duration (ptrend=0.001) rather than intensity (ptrend=0.86), although the trend for duration disappeared after adjustment for time-since-quitting. Time-since-quitting was inversely related to ALS (ptrend<0.0001). The eOR decreased with time-since-quitting smoking, until about 10 years prior to disease onset. High intensity smoking with shorter duration appeared more deleterious than lower intensity for a longer duration. CONCLUSIONS: Our findings provide further support for the association between smoking and ALS. Pack-years alone may be insufficient to capture effects of different smoking patterns. Time-since-quitting appeared to be an important factor, suggesting that smoking may be an early disease trigger.
Assuntos
Esclerose Lateral Amiotrófica/epidemiologia , Abandono do Hábito de Fumar , Fumar/epidemiologia , Adulto , Idoso , Estudos de Casos e Controles , Fumar Cigarros , Feminino , Humanos , Irlanda/epidemiologia , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Medição de Risco , Fatores de Risco , Fumar/efeitos adversos , Fatores Socioeconômicos , Adulto JovemRESUMO
We explored the associations of occupational exposure to extremely low-frequency magnetic fields (ELF-MF) and electric shocks with the risk of amyotrophic lateral sclerosis (ALS) in a pooled case-control study (European Multidisciplinary ALS Network Identification to Cure Motor Neurone Degeneration (Euro-MOTOR)) of data from 3 European countries. ALS patients and population-based controls were recruited in Ireland, Italy, and the Netherlands between 2010 and 2015. Lifetime occupational and lifestyle histories were obtained using structured questionnaires. We applied previously developed job exposure matrices assigning exposure levels to ELF-MF and potential for electric shocks. Odds ratios and 95% confidence intervals were estimated by means of logistic regression for exposure to either ELF-MF or electric shocks, adjusted for age, sex, study center, education, smoking, and alcohol consumption and for the respective other exposure. Complete occupational histories and information on confounding variables were available for 1,323 clinically confirmed ALS cases and 2,704 controls. Both ever having had exposure to ELF-MF above the background level (odds ratio = 1.16, 95% confidence interval: 1.01, 1.33) and ever having had potential exposure above background for electric shocks (odds ratio = 1.23, 95% confidence interval: 1.05, 1.43) were associated with ALS. Adjustment for the respective other exposure resulted in similar risk estimates. Heterogeneity in risks across study centers was significant for both exposures. Our findings support possible independent associations of occupational exposure to ELF-MF and electric shocks with the risk of ALS.
Assuntos
Esclerose Lateral Amiotrófica/epidemiologia , Traumatismos por Eletricidade/epidemiologia , Campos Magnéticos/efeitos adversos , Doenças Profissionais/epidemiologia , Exposição Ocupacional/análise , Adulto , Esclerose Lateral Amiotrófica/etiologia , Estudos de Casos e Controles , Traumatismos por Eletricidade/etiologia , Feminino , Humanos , Irlanda/epidemiologia , Itália/epidemiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Doenças Profissionais/etiologia , Exposição Ocupacional/efeitos adversos , Razão de Chances , Fatores de RiscoRESUMO
OBJECTIVE: To investigate whether exposure to particulates and combustion products may explain the association between certain occupations and amyotrophic lateral sclerosis (ALS) risk in a large, multicentre, population-based, case-control study, based on full job histories, using job-exposure matrices, with detailed information on possible confounders. METHODS: Population-based patients with ALS and controls were recruited from five registries in the Netherlands, Ireland and Italy. Demographics and data regarding educational level, smoking, alcohol habits and lifetime occupational history were obtained using a validated questionnaire. Using job-exposure matrices, we assessed occupational exposure to silica, asbestos, organic dust, contact with animals or fresh animal products, endotoxins, polycyclic aromatic hydrocarbons and diesel motor exhaust. Multivariate logistic regression models adjusting for confounding factors were used to determine the association between these exposures and ALS risk. RESULTS: We included 1557 patients and 2922 controls. Associations were positive for all seven occupational exposures (ORs ranging from 1.13 to 1.73 for high vs never exposed), and significant on the continuous scale for silica, organic dust and diesel motor exhaust (p values for trend ≤0.03). Additional analyses, adding an exposure (one at a time) to the model in the single exposure analysis, revealed a stable OR for silica. We found similar results when patients with a C9orf72 mutation were excluded. CONCLUSION: In a large, multicentre study, using harmonised methodology to objectively quantify occupational exposure to particulates and combustion products, we found an association between ALS risk and exposure to silica, independent of the other occupational exposures studied.
Assuntos
Poluentes Ocupacionais do Ar/efeitos adversos , Esclerose Lateral Amiotrófica/etiologia , Exposição Ocupacional/efeitos adversos , Material Particulado/efeitos adversos , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Exposição Ocupacional/estatística & dados numéricos , Fatores de Risco , Dióxido de Silício/efeitos adversos , Fumar/efeitos adversos , Poluição Relacionada com o Tráfego/efeitos adversosRESUMO
OBJECTIVES: Several studies focused on the association between alcohol consumption and amyotrophic lateral sclerosis (ALS), although with inconsistent findings. Antioxidants may play a role since lyophilised red wine was found to prolong SOD1 mice lifespan. The aim of this international population-based case-control study performed in Ireland, The Netherlands and Italy was to assess the role of alcohol, and red wine in particular, in developing ALS. METHODS: Euro-MOTOR is a case-control study where patients with incident ALS and controls matched for gender, age and area of residency were recruited in a population-based design. Logistic regression models adjusted for sex, age, cohort, education, leisure time physical activity, smoking, heart problems, hypertension, stroke, cholesterol and diabetes were performed. RESULTS: 1557 patients with ALS and 2922 controls were enrolled in the study. Exposure to alcohol drinking was not significantly associated with ALS risk. A stratified analysis of exposure to alcohol by cohort revealed significant ORs in The Netherlands and in Apulia, with opposite directions (respectively 0.68 and 2.38). With regard to red wine consumption, only in Apulia the double-fold increased risk (OR 2.53) remained significant. A decreased risk was found for current alcohol drinkers (OR 0.83), while a significantly increased risk was detected among former drinkers (OR 1.63). Analysis of cumulative exposure to alcohol revealed no significant associations with ALS risk. CONCLUSION: With few exceptions, no significant association was found between alcohol consumption and ALS. The study of the association between alcohol and ALS requires a thorough exploration, especially considering the role of different type of alcoholic beverages.
Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Esclerose Lateral Amiotrófica/epidemiologia , Vinho/estatística & dados numéricos , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Irlanda/epidemiologia , Itália/epidemiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Razão de Chances , Fatores de RiscoRESUMO
OBJECTIVE: To investigate the association between physical activity (PA) and amyotrophic lateral sclerosis (ALS) in population-based case-control studies in three European countries using a validated and harmonised questionnaire. METHODS: Patients with incident ALS and controls were recruited from five population-based registers in The Netherlands, Ireland and Italy. Demographic and data regarding educational level, smoking, alcohol habits and lifetime PA levels in both leisure and work time were gathered by questionnaire, and quantified using metabolic equivalent of task scores. Logistic regression models adjusting for PA-related factors were used to determine the association between PA and ALS risk, and forest plots were used to visualise heterogeneity between regions. RESULTS: 1557 patients and 2922 controls were included. We found a linear association between ALS and PA in leisure time (OR 1.07, P=0.01) and occupational activities (OR 1.06, P<0.001), and all activities combined (OR 1.06, P<0.001), with some heterogeneity between regions: the most evident association was seen in the Irish and Italian cohorts. After adjustment for other occupational exposures or exclusion of patients with a C9orf72 mutation, the ORs remained similar. CONCLUSION: We provide new class I evidence for a positive association between PA and risk of ALS in a large multicentre study using harmonised methodology to objectively quantify PA levels, with some suggestions for population differences.
Assuntos
Esclerose Lateral Amiotrófica/etiologia , Exercício Físico , Atividades de Lazer , Idoso , Esclerose Lateral Amiotrófica/epidemiologia , Estudos de Casos e Controles , Comparação Transcultural , Feminino , Humanos , Incidência , Irlanda/epidemiologia , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Fatores de RiscoRESUMO
OBJECTIVE: To investigate the theory of premorbid fitness in amyotrophic lateral sclerosis (ALS), we studied whether a common genetic profile for physical or cardiovascular fitness was manifest in progenitors leading to less cardiovascular death and a longer lifespan in parents of patients with ALS compared with parents of controls. METHODS: Patient and disease characteristics, levels of physical activity, parental cause and age of death were obtained using a structured questionnaire from a population-based, case-control study of ALS in the Netherlands. Logistic regression was used for the analyses of parental cause of death and levels of physical activity. Cox proportional hazard models were applied to study the association between parental survival and ALS, or specific patient subgroups. All models were adjusted for age at inclusion, level of education, body mass index, diabetes, hypercholesterolaemia and hypertension. RESULTS: 487 patients and 1092 controls were included. Parents of patients died less frequently from a cardiovascular disease compared with parents of controls (OR=0.78, p=0.009). Their survival, however, was neither significantly longer nor shorter. Neither rates of cardiovascular causes of death, nor survival of parents was related to the extent to which patients were physically active in leisure time (all p>0.05). CONCLUSIONS: Exploring the fitness hypothesis in the pathogenesis of ALS, our findings provide evidence for a shared mechanism underlying a favourable cardiovascular fitness profile and ALS susceptibility.
Assuntos
Esclerose Lateral Amiotrófica/epidemiologia , Estudos de Casos e Controles , Causas de Morte , Exercício Físico/fisiologia , Atividades de Lazer , Pais , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/metabolismo , Doenças Cardiovasculares/epidemiologia , Humanos , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is considered to be caused by both genetic and environmental factors. The causal cascade is, however, not known. We aimed to assess lifestyle during the presymptomatic phase of ALS, stratified by C9orf72 mutation, and examine evidence supporting causality of lifestyle factors. METHODS: This study was a longitudinal, population-based, case-control study that used data from the Prospective ALS study the Netherlands. We included patients with a C9orf72 mutation (C9+ group), patients without a C9orf72 mutation (C9- group), and controls. Patients fulfilled the revised El Escorial criteria and were recruited through neurologists and rehabilitation physicians in the Netherlands as well as the Dutch Neuromuscular Patient Association and ALS Centrum website. 1322 population-based controls, matched for age and sex, were enrolled via the patients' general practitioners. Blood relatives or spouses of patients were not eligible as controls. We studied the relationship between ALS risk and smoking, alcohol, physical activity, body-mass index (BMI), and energy intake by the use of structured questionnaires. Smoking, physical activity, and BMI were longitudinally assessed up to 50 years before onset (defined as the period before onset of muscle weakness or bulbar symptoms for cases, or age at completing the questionnaire for controls). We calculated posterior probabilities (P(θ|x)) for causal effects of smoking, alcohol, and BMI, using Bayesian instrumental variable analyses. FINDINGS: Between Jan 1, 2006 and Jan 27, 2016, we included 143 patients in the C9+ group, 1322 patients in the C9- group, and 1322 controls. Compared with controls, cigarette pack-years (C9+ group mean difference from control 3·15, 95% CI 0·36 to 5·93, p=0·027; C9- group 3·20, 2·02 to 4·39, p<0·0001) and daily energy intake at symptom onset (C9+ group 712 kJ, 95% CI 212 to 1213, p=0·0053; C9- group 497, 295 to 700, p<0·0001) were higher in the C9+ and C9- groups, whereas current BMI (C9+ group -2·01 kg/m2, 95% CI -2·73 to -1·29, p<0·0001; C9- group -1·35, -1·64 to -1·06, p<0·0001) and lifetime alcohol consumption (C9+ group -5388 units, 95% CI -9113 to -1663, p=0·0046; C9- group -2185, -3748 to -622, p=0·0062) were lower in the C9+ and C9- groups. Median BMI during the presymptomatic phase for the C9+ group was lower (-0·69 kg/m2, 95% CI -1·24 to -0·13, p=0·015) and physical activity was similar (-348 metabolic equivalent of task [MET], 95% CI -966 to 270, p=0·27) to controls, whereas both the median BMI during the presymptomatic phase (0·27 kg/m2, 95% CI 0·04 to 0·50, p=0·022) and physical activity (585 MET, 291 to 878, p=0·0001) were higher in the C9- group than controls. Longitudinal analyses showed more cigarette pack-years in the C9- (starting 47 years pre-onset) and C9+ (starting 24 years pre-onset) groups, and higher physical activity over time in the C9- group (starting >30 years pre-onset). BMI of the C9+ group increased more slowly and was significantly lower (starting at 36 years pre-onset) than in controls, whereas the BMI of the C9- group was higher than controls (23-49 years pre-onset, becoming lower 10 years pre-onset). Instrumental variable analyses supported causal effects of alcohol consumption (P(θ|x)=0·9347) and smoking (P(θ|x)=0·9859) on ALS in the C9- group. We found evidence supporting a causal effect of increased BMI at younger age (mean 33·8 years, SD 11·7) in the C9- group (P[θ|x]=0·9272), but not at older ages. INTERPRETATION: Lifestyle during the presymptomatic phase differs between patients with ALS and controls decades before onset, depends on C9- status, and is probably part of the presymptomatic causal cascade. Identification of modifiable disease-causing lifestyle factors offers opportunities to lower risk of developing neurodegenerative disease. FUNDING: Netherlands ALS Foundation.
Assuntos
Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/psicologia , Proteína C9orf72/genética , Estilo de Vida , Mutação/genética , Fatores Etários , Idoso , Esclerose Lateral Amiotrófica/fisiopatologia , Índice de Massa Corporal , Estudos de Casos e Controles , Ingestão de Energia , Exercício Físico , Feminino , Genótipo , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Países Baixos , Fumar , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive, fatal motor neuron disease with a variable natural history. There are no accurate models that predict the disease course and outcomes, which complicates risk assessment and counselling for individual patients, stratification of patients for trials, and timing of interventions. We therefore aimed to develop and validate a model for predicting a composite survival endpoint for individual patients with ALS. METHODS: We obtained data for patients from 14 specialised ALS centres (each one designated as a cohort) in Belgium, France, the Netherlands, Germany, Ireland, Italy, Portugal, Switzerland, and the UK. All patients were diagnosed in the centres after excluding other diagnoses and classified according to revised El Escorial criteria. We assessed 16 patient characteristics as potential predictors of a composite survival outcome (time between onset of symptoms and non-invasive ventilation for more than 23 h per day, tracheostomy, or death) and applied backward elimination with bootstrapping in the largest population-based dataset for predictor selection. Data were gathered on the day of diagnosis or as soon as possible thereafter. Predictors that were selected in more than 70% of the bootstrap resamples were used to develop a multivariable Royston-Parmar model for predicting the composite survival outcome in individual patients. We assessed the generalisability of the model by estimating heterogeneity of predictive accuracy across external populations (ie, populations not used to develop the model) using internal-external cross-validation, and quantified the discrimination using the concordance (c) statistic (area under the receiver operator characteristic curve) and calibration using a calibration slope. FINDINGS: Data were collected between Jan 1, 1992, and Sept 22, 2016 (the largest data-set included data from 1936 patients). The median follow-up time was 97·5 months (IQR 52·9-168·5). Eight candidate predictors entered the prediction model: bulbar versus non-bulbar onset (univariable hazard ratio [HR] 1·71, 95% CI 1·63-1·79), age at onset (1·03, 1·03-1·03), definite versus probable or possible ALS (1·47, 1·39-1·55), diagnostic delay (0·52, 0·51-0·53), forced vital capacity (HR 0·99, 0·99-0·99), progression rate (6·33, 5·92-6·76), frontotemporal dementia (1·34, 1·20-1·50), and presence of a C9orf72 repeat expansion (1·45, 1·31-1·61), all p<0·0001. The c statistic for external predictive accuracy of the model was 0·78 (95% CI 0·77-0·80; 95% prediction interval [PI] 0·74-0·82) and the calibration slope was 1·01 (95% CI 0·95-1·07; 95% PI 0·83-1·18). The model was used to define five groups with distinct median predicted (SE) and observed (SE) times in months from symptom onset to the composite survival outcome: very short 17·7 (0·20), 16·5 (0·23); short 25·3 (0·06), 25·2 (0·35); intermediate 32·2 (0·09), 32·8 (0·46); long 43·7 (0·21), 44·6 (0·74); and very long 91·0 (1·84), 85·6 (1·96). INTERPRETATION: We have developed an externally validated model to predict survival without tracheostomy and non-invasive ventilation for more than 23 h per day in European patients with ALS. This model could be applied to individualised patient management, counselling, and future trial design, but to maximise the benefit and prevent harm it is intended to be used by medical doctors only. FUNDING: Netherlands ALS Foundation.
Assuntos
Esclerose Lateral Amiotrófica/diagnóstico , Progressão da Doença , Modelos Neurológicos , Índice de Gravidade de Doença , Análise de Sobrevida , Idoso , Esclerose Lateral Amiotrófica/classificação , Esclerose Lateral Amiotrófica/fisiopatologia , Europa (Continente) , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Medicina de Precisão , Prognóstico , Reprodutibilidade dos TestesRESUMO
OBJECTIVE: To investigate the role of hormonal risk factors for amyotrophic lateral sclerosis (ALS) among women from 3 European countries. METHODS: ALS cases and matched controls were recruited over 4 years in Ireland, Italy, and the Netherlands. Hormonal exposures, including reproductive history, breastfeeding, contraceptive use, hormonal replacement therapy, and gynecologic surgical history, were recorded with a validated questionnaire. Logistic regression models adjusted for age, education, study site, smoking, alcohol, and physical activity were used to determine the association between female hormones and ALS risk. RESULTS: We included 653 patients and 1,217 controls. Oral contraceptive use was higher among controls (odds ratio [OR] 0.65, 95% confidence interval [CI] 0.51-0.84), and a dose-response effect was apparent. Hormone replacement therapy (HRT) was associated with a reduced risk of ALS only in the Netherlands (OR = 0.57, 95% CI 0.37-0.85). These findings were robust to sensitivity analysis, but there was some heterogeneity across study sites. CONCLUSIONS: This large case-control study across 3 different countries has demonstrated an association between exogenous estrogens and progestogens and reduced odds of ALS in women. These results are at variance with previous findings, which may be partly explained by differential regulatory, social, and cultural attitudes toward pregnancy, birth control, and HRT across the countries included. Our results indicate that hormonal factors may be important etiologic factors in ALS; however, a full understanding requires further investigation.
Assuntos
Esclerose Lateral Amiotrófica , Anticoncepcionais Orais Hormonais/farmacologia , Terapia de Reposição de Estrogênios , Estrogênios/farmacologia , Progestinas/farmacologia , Idoso , Esclerose Lateral Amiotrófica/etiologia , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/prevenção & controle , Estudos de Casos e Controles , Relação Dose-Resposta a Droga , Feminino , Humanos , Irlanda , Itália , Pessoa de Meia-Idade , Países Baixos , Fatores de RiscoRESUMO
To examine evidence for a role of gluten sensitivity (GS) or celiac disease (CD) in ALS etiology, we included participants from a population-based case-control study in The Netherlands between January 2006 and December 2015. We compared levels and seroprevalence of IgA antibodies to tissue transglutaminase 6 (TG6) in 359 ALS patients and 359 controls, and to transglutaminase 2 (TG2) and endomysium (EMA) in 199 ALS patients and 199 controls. Questionnaire data on 1829 ALS patients and 3920 controls were examined for CD or gluten-free diets (GFD). Genetic correlation and HLA allele frequencies were analyzed using two genome-wide association studies: one on ALS (12,577 cases, 23,475 controls), and one on CD (4533 cases, 10,750 controls). We found one patient with TG6, TG2 and EMA antibodies who had typical ALS and no symptoms of GS. TG6 antibody concentrations and positivity, CD prevalence and adherence to a GFD were similar in patients and controls (p > 0.66) and in these patients disease progression was compatible with typical ALS. CD and ALS were not found to be genetically correlated (p > 0.37). CD-associated HLA allele frequencies were similar in patients and controls (p > 0.28). In conclusion, we found no serological evidence for involvement of gluten-related antibodies in ALS etiology nor did we observe an association between CD and ALS in medical history or genetic data, indicating that there is no evidence in our data for an association between the two diseases. Hence, a role for a GFD in the ALS treatment seems unlikely.
Assuntos
Esclerose Lateral Amiotrófica/sangue , Anticorpos/sangue , Glutens/genética , Glutens/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/epidemiologia , Esclerose Lateral Amiotrófica/genética , Estudos de Casos e Controles , Estudos de Coortes , Dieta Livre de Glúten/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Análise de Regressão , Inquéritos e Questionários , Transglutaminases/imunologia , Adulto JovemRESUMO
Backround: Political and sociocultural differences between countries can affect the outcome of clinical and epidemiological studies in ALS. Cross-national studies represent the ideal process by which risk factors can be assessed using the same methodology in different geographical areas. METHODS: A survey of three European countries (The Netherlands, Ireland and Italy) has been conducted in which incident ALS patients and matched controls were recruited in a population-based study based on age, gender and area of residency, under the Euro-MOTOR systems biology programme of research. FINDINGS: We have identified strengths and limitations during the trajectory of the Euro-MOTOR study, from the research design to data analysis. We have analysed the implications of factors including cross-national differences in healthcare systems, sample size, types of matching, the definition of exposures and statistical analysis. CONCLUSIONS: Addressing critical methodological aspects of the design of the Euro-MOTOR project minimises bias and will facilitate scientific assessment of the independent role of well-defined exposures.
Assuntos
Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/epidemiologia , Inquéritos e Questionários/normas , Idoso , Esclerose Lateral Amiotrófica/genética , Estudos de Casos e Controles , Estudos de Coortes , Exposição Ambiental , Europa (Continente)/epidemiologia , Feminino , Humanos , Irlanda/epidemiologia , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Sistema de RegistrosRESUMO
BACKGROUND: Recently, there has been increasing evidence that exposure to air pollution is linked to neurodegenerative diseases, but little is known about the association with amyotrophic lateral sclerosis (ALS). OBJECTIVES: We investigated the association between long-term exposure to air pollution and risk of developing ALS. METHODS: A population-based case-control study was conducted in Netherlands from 1 January 2006 to 1 January 2013. Data from 917 ALS patients and 2,662 controls were analyzed. Annual mean air pollution concentrations were assessed by land use regression (LUR) models developed as part of the European Study of Cohorts for Air Pollution Effects (ESCAPE). Exposure estimates included nitrogen oxides (NO2, NOx), particulate matter (PM) with diameters of <2.5 µm (PM2.5), <10 µm (PM10), between 10 µm and 2.5 µm (PMcoarse), and PM2.5 absorbance. We performed conditional logistic regression analysis using two different multivariate models (model 1 adjusted for age, gender, education, smoking status, alcohol use, body mass index, and socioeconomic status; model 2 additionally adjusted for urbanization degree). RESULTS: Risk of ALS was significantly increased for individuals in the upper exposure quartile of PM2.5 absorbance [OR=1.67; 95% confidence interval (CI): 1.27, 2.18], NO2 (OR=1.74; 95% CI: 1.32, 2.30), and NOx concentrations (OR=1.38; 95% CI: 1.07, 1.77). These results, except for NOx, remained significant after adjusting additionally for urbanization degree. CONCLUSIONS: Based on a large population-based case-control study, we report evidence for the association between long-term exposure to traffic-related air pollution and increased susceptibility to ALS. Our findings further support the necessity for regulatory public health interventions to combat air pollution levels and provide additional insight into the potential pathophysiology of ALS. https://doi.org/10.1289/EHP1115.
Assuntos
Poluição do Ar/efeitos adversos , Esclerose Lateral Amiotrófica/etiologia , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Óxidos de Nitrogênio/efeitos adversos , Material Particulado/efeitos adversosRESUMO
Sporadic amyotrophic lateral sclerosis (ALS) is believed to be a complex disease in which multiple exogenous and genetic factors interact to cause motor neuron degeneration. Elucidating the association between medical conditions prior to the first symptoms of ALS could lend support to the theory that specific subpopulations are at risk of developing ALS and provide new insight into shared pathogenic mechanisms. We performed a population-based case-control study in the Netherlands, including 722 sporadic ALS patients and 2,268 age and gender matched controls. Data on medical conditions and use of medication were obtained through a structured questionnaire. Multivariate analyses showed that hypercholesterolemia (OR 0.76, 95% CI 0.63-0.92, P = 0.006), the use of statins (OR 0.45, 95% CI 0.35-0.59, P = 1.86 × 10(-9)) or immunosuppressive drugs (OR 0.26, 95% CI 0.08-0.86, P = 0.03) were associated with a decreased risk of ALS. Head trauma was associated with an increased ALS susceptibility (OR 1.95, 95% CI 1.11-3.43, P = 0.02). No association was found with autoimmune diseases, cancer, psychiatric disorders or cardiovascular diseases, or survival. The lower frequency of hypercholesterolemia and less use of statins in ALS patients indicate a favorable lipid profile prior to symptom onset in at least a subpopulation of ALS. Prior head trauma is a risk factor for ALS and the significantly lower use of immunosuppressive drugs in ALS patients could suggest a protective effect. The identification of specific subpopulations at risk for ALS may provide clues towards possible pathogenic mechanisms.
Assuntos
Esclerose Lateral Amiotrófica/epidemiologia , Esclerose Lateral Amiotrófica/etiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hipercolesterolemia/complicações , Imunossupressores/efeitos adversos , Idade de Início , Idoso , Doenças Autoimunes/complicações , Doenças Cardiovasculares/complicações , Estudos de Casos e Controles , Planejamento em Saúde Comunitária , Traumatismos Craniocerebrais/complicações , Feminino , Humanos , Masculino , Transtornos Mentais/complicações , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Estudos Retrospectivos , Risco , Inquéritos e QuestionáriosRESUMO
Inclusion body myopathy (IBM) associated with Paget disease of the bone, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), sometimes called IBMPFD/ALS or multi system proteinopathy, is a rare, autosomal dominant disorder characterized by progressive degeneration of muscle, brain, motor neurons, and bone with prominent TDP-43 pathology. Recently, 2 novel genes for multi system proteinopathy were discovered; heterogenous nuclear ribonucleoprotein (hnRNP) A1 and A2B1. Subsequently, a mutation in hnRNPA1 was also identified in a pedigree with autosomal dominant familial ALS. The genetic evidence for ALS and other neurodegenerative diseases is still insufficient. We therefore sequenced the prion-like domain of these genes in 135 familial ALS, 1084 sporadic ALS, 68 familial FTD, 74 sporadic FTD, and 31 sporadic IBM patients in a Dutch population. We did not identify any mutations in these genes in our cohorts. Mutations in hnRNPA1 and hnRNPA2B1 prove to be a rare cause of ALS, FTD, and IBM in the Netherlands.
Assuntos
Esclerose Lateral Amiotrófica/genética , Demência Frontotemporal/genética , Estudos de Associação Genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/genética , Miosite de Corpos de Inclusão/genética , Osteíte Deformante/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Ribonucleoproteína Nuclear Heterogênea A1 , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Países BaixosRESUMO
BACKGROUND: Amyotrophic lateral sclerosis shares characteristics with some cancers, such as onset being more common in later life, progression usually being rapid, the disease affecting a particular cell type, and showing complex inheritance. We used a model originally applied to cancer epidemiology to investigate the hypothesis that amyotrophic lateral sclerosis is a multistep process. METHODS: We generated incidence data by age and sex from amyotrophic lateral sclerosis population registers in Ireland (registration dates 1995-2012), the Netherlands (2006-12), Italy (1995-2004), Scotland (1989-98), and England (2002-09), and calculated age and sex-adjusted incidences for each register. We regressed the log of age-specific incidence against the log of age with least squares regression. We did the analyses within each register, and also did a combined analysis, adjusting for register. FINDINGS: We identified 6274 cases of amyotrophic lateral sclerosis from a catchment population of about 34 million people. We noted a linear relationship between log incidence and log age in all five registers: England r(2)=0·95, Ireland r(2)=0·99, Italy r(2)=0·95, the Netherlands r(2)=0·99, and Scotland r(2)=0·97; overall r(2)=0·99. All five registers gave similar estimates of the linear slope ranging from 4·5 to 5·1, with overlapping confidence intervals. The combination of all five registers gave an overall slope of 4·8 (95% CI 4·5-5·0), with similar estimates for men (4·6, 4·3-4·9) and women (5·0, 4·5-5·5). INTERPRETATION: A linear relationship between the log incidence and log age of onset of amyotrophic lateral sclerosis is consistent with a multistage model of disease. The slope estimate suggests that amyotrophic lateral sclerosis is a six-step process. Identification of these steps could lead to preventive and therapeutic avenues. FUNDING: UK Medical Research Council; UK Economic and Social Research Council; Ireland Health Research Board; The Netherlands Organisation for Health Research and Development (ZonMw); the Ministry of Health and Ministry of Education, University, and Research in Italy; the Motor Neurone Disease Association of England, Wales, and Northern Ireland; and the European Commission (Seventh Framework Programme).