Increased Risk Of Amyotrophic Lateral Sclerosis Research Articles

Genome-Wide and Transcriptome-Wide Association Studies on Northern New England and Ohio Amyotrophic Lateral Sclerosis Cohorts.

Amyotrophic lateral sclerosis (ALS) is an age-associated, fatal neurodegenerative disorder causing progressive paralysis and respiratory failure. The genetic architecture of ALS is still largely unknown. We performed a genome-wide association study (GWAS) and transcriptome-wide association study (TWAS) to understand genetic risk factors for ALS using a population-based case-control study of 435 ALS cases and 279 controls from Northern New England and Ohio. Single nucleotide polymorphism (SNP) genotyping was conducted using the Illumina NeuroChip array. Odds ratios were estimated using covariate-adjusted logistic regression. We also performed a genome-wide SNP-smoking interaction screening. TWAS analyses used PrediXcan to estimate associations between predicted gene expression levels across 15 tissues (13 brain tissues, skeletal muscle, and whole blood) and ALS risk. GWAS analyses identified the p.A382T missense variant (rs367543041, p = 3.95E-6) in the TARDBP gene, which has previously been reported in association with increased ALS risk and was found to share a close affinity with the Sardinian haplotype. Both GWAS and TWAS analyses suggested that ZNF235 is associated with decreased ALS risk. Our results support the need for future evaluation to clarify the role of these potential genetic risk factors for ALS and to understand genetic susceptibility to environmental risk factors.

Multiple metal exposures associate with higher amyotrophic lateral sclerosis risk and mortality independent of genetic risk and correlate to self-reported exposures: a case-control study

BackgroundThe pathogenesis of amyotrophic lateral sclerosis (ALS) involves both genetic and environmental factors. This study investigates associations between metal measures in plasma and urine, ALS risk and survival and exposure...

Mendelian randomization study supports relative carbohydrate intake as an independent risk factor for amyotrophic lateral sclerosis

ABSTRACT Objectives Observational studies suggested a potential correlation between dietary intake and amyotrophic lateral sclerosis (ALS), but conflicting findings exist and causality remains unclear. Here, we performed a Mendelian randomization (MR) analysis to evaluate the causal impact of relative intake of (i) carbohydrate, (ii) fat, and (iii) protein on ALS risk. Methods The genome-wide association summary statistics of three dietary macronutrient intake traits and ALS were obtained. Initially, forward and reverse univariable MR (UVMR) analysis were conducted using the inverse variance weighted (IVW) method as the primary approach, supplemented by MR-Egger, weighted median, and maximum likelihood. Subsequently, multivariable MR (MVMR) analysis was performed to assess the independent causal effects of each dietary. Additionally, diverse sensitivity tests were conducted to evaluate the reliability of the MR analyses. Results The forward UVMR analysis conducted by IVW indicated that relative carbohydrate intake significantly increased ALS risk. Furthermore, results from three other MR methods paralleled those from IVW. However, the other two dietary intake traits did not have a causative impact on ALS risk. The reverse UVMR analysis indicated that ALS did not causatively influence the three dietary intake traits. The MVMR analysis showed that after adjusting for the effects of the other two dietary intake traits, relative carbohydrate intake independently and significantly increased ALS risk. Sensitivity tests indicated no significant heterogeneity or horizontal pleiotropy. Discussion MR analysis supported relative carbohydrate independently increasing ALS risk. Nevertheless, further validation of this finding in future large cohorts is required. Abbreviations: ALS: amyotrophic lateral sclerosis; CI: confidence interval; GWAS: genome-wide association study; IV: instrumental variable; IVW: iverse variance weighted; MR: Mendelian randomization; MVMR: multivariable Mendelian randomization; OR: odds ratio; RCT: randomized controlled trial; SNPs: single-nucleotide polymorphisms; UVMR: univariable Mendelian randomization

Residential exposure associations with ALS risk, survival, and phenotype: a Michigan-based case-control study

Background Environmental exposures impact amyotrophic lateral sclerosis (ALS) risk and progression, a fatal and progressive neurodegenerative disease. Better characterization of these exposures is needed to decrease disease burden. Objective To identify exposures in the residential setting that associate with ALS risk, survival, and onset segment. Methods ALS and control participants recruited from University of Michigan completed a survey that ascertained exposure risks in the residential setting. ALS risk was assessed using logistic regression models followed by latent profile analysis to consider exposure profiles. A case-only analysis considered the contribution of the residential exposure variables via a Cox proportional hazards model for survival outcomes and multinomial logistic regression for onset segment, a polytomous outcome. Results This study included 367 ALS and 255 control participants. Twelve residential variables were associated with ALS risk after correcting for multiple comparison testing, with storage in an attached garage of chemical products including gasoline or kerosene (odds ratio (OR) = 1.14, p adjusted < 0.001), gasoline-powered equipment (OR = 1.16, p adjusted < 0.001), and lawn care products (OR = 1.15, p adjusted < 0.001) representing the top three risk factors sorted by p adjusted. Latent profile analysis indicated that storage of these chemical products in both attached and detached garages increased ALS risk. Although residential variables were not associated with poorer ALS survival following multiple testing corrections, storing pesticides, lawn care products, and woodworking supplies in the home were associated with shorter ALS survival using nominal p values. No exposures were associated with ALS onset segment. Conclusion Residential exposures may be important modifiable components of the ALS susceptibility and prognosis exposome.

Medication use and risk of amyotrophic lateral sclerosis: using machine learning for an exposome-wide screen of a large clinical database

Background Accumulating evidence suggests that non-genetic factors have important etiologic roles in amyotrophic lateral sclerosis (ALS), yet identification of specific culprit factors has been challenging. Many medications target biological pathways implicated in ALS pathogenesis, and screening large pharmacologic datasets for signals could greatly accelerate the identification of risk-modulating pharmacologic factors for ALS. Method We conducted a high-dimensional screening of patients’ history of medication use and ALS risk using an advanced machine learning approach based on gradient-boosted decision trees coupled with Bayesian model optimization and repeated data sampling. Clinical and medication dispensing data were obtained from a large Israeli health fund for 501 ALS cases and 4,998 matched controls using a lag period of 3 or 5 years prior to ALS diagnosis for ascertaining medication exposure. Results Of over 1,000 different medication classes, we identified 8 classes that were consistently associated with increased ALS risk across independently trained models, where most are indicated for control of symptoms implicated in ALS. Some suggestive protective effects were also observed, notably for vitamin E. Discussion Our results indicate that use of certain medications well before the typically recognized prodromal period was associated with ALS risk. This could result because these medications increase ALS risk or could indicate that ALS symptoms can manifest well before suggested prodromal periods. The results also provide further evidence that vitamin E may be a protective factor for ALS. Targeted studies should be performed to elucidate the possible pathophysiological mechanisms while providing insights for therapeutics design.

Premorbid lipid levels and long-term risk of ALS—a population-based cohort study

Objective To assess the temporal relationship between premorbid lipid levels and long-term amyotrophic lateral sclerosis (ALS) risk. Methods From Norwegian cardiovascular health surveys (1974–2003), we collected information on total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), glucose, and other cardiovascular risk factors. ALS incidence and mortality were identified through validated Norwegian health registries. The relation between premorbid lipid levels and ALS risk was assessed by Cox regression models. Results Out of 640,066 study participants (51.5% females), 974 individuals (43.5% females) developed ALS. Mean follow-up time was 23.7 (SD 7.1) years among ALS cases. One mmol/l increase in LDL-C was associated with 6% increase in risk for ALS (hazard ratio 1.06 [95% CI: 1.01–1.09]). Higher levels of TC and TG were also associated with increased ALS risk, but only within the last 6–7 years prior to ALS diagnosis or death. No association between HDL-C and ALS risk was found. Adjusting for body mass index, birth cohort, smoking, and physical activity did not alter the results. Conclusions Higher levels of LDL-C are associated with increased ALS risk over 40 years later, compatible with a causal relationship. The temporal relationship between TG, TC, and ALS risk suggests that increased levels of these lipid biomarkers represent consequences of ALS.

Exposure to ambient air toxicants and the risk of amyotrophic lateral sclerosis (ALS): A matched case control study

BackgroundAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with few risk factors identified and no known cure. Gene-environment interaction is hypothesized especially for sporadic ALS cases (90–95%) which are of unknown etiology. We aimed to investigate risk factors for ALS including exposure to ambient air toxics. MethodsThis population-based case-control study included 267 ALS cases (from the United States [U.S.] Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry National ALS Registry and Biorepository) and 267 age, sex, and county-matched controls identified via a commercial database. Exposure assessment for 34 ambient air toxicants was performed by assigning census tract-level U.S. Environmental Protection Agency (EPA) 2011 National Air Toxics Assessment (NATA) data to participants’ residential ZIP codes. Conditional logistic regression was used to compute adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for individual compounds, chemical classes, and overall exposure. Sensitivity analyses using both conditional logistic regression and Bayesian grouped weighted quartile sum (GWQS) models were performed to assess the integrity of findings. ResultsUsing the 2011 NATA, the highest exposure quartile (Q4) compared to the lowest (Q1) of vinyl chloride (aOR = 6.00, 95% CI: 1.87–19.25), 2,4-dinitrotoluene (aOR = 5.45, 95% CI: 1.53–19.36), cyanide (aOR = 4.34, 95% CI: 1.52–12.43), cadmium (aOR = 3.30, 95% CI: 1.11–9.77), and carbon disulfide (aOR = 2.98, 95% CI: 1.00–8.91) was associated with increased odds of ALS. Residential air selenium showed an inverse association with ALS (second quartile [Q2] vs. Q1: aOR = 0.38, 95% CI: 0.18–0.79). Additionally, residential exposure to organic/chlorinated solvents (Q4 vs Q1: aOR = 2.62, 95% CI: 1.003–6.85) was associated with ALS. ConclusionsOur findings using the 2011 NATA linked by census tract to residential area provide evidence of increased ALS risk in cases compared to controls for 2,4-dinitrotoluene, vinyl chloride, cyanide, and the organic/chlorinated solvents class. This underscores the importance of ongoing surveillance of potential exposures for at-risk populations.

Cystatin C based estimation of chronic kidney disease and amyotrophic lateral sclerosis in the ALS registry Swabia: associated risk and prognostic value

Kidney function as part of metabolic changes could be associated with amyotrophic lateral-sclerosis (ALS). We investigated the associations between estimated chronic kidney disease (CKD), based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) cystatin C equation, and the risk at onset and prognostic value of CKD for ALS. Between October 2010 and June 2014, 362 ALS cases (59.4% men, mean age 65.7 years) and 681 controls (59.5% men, means age 66.3 years) were included in a population-based case–control study based on the ALS registry Swabia in Southern Germany. All ALS cases were followed-up (median 89.7 months), 317 died. Serum samples were measured for cystatin C to estimate the glomerular filtration rate (eGFR) according to the CKD-EPI equation. Information on covariates were assessed by an interview-based standardized questionnaire. Conditional logistic regression models were applied to calculate odds ratios (OR) for risk of ALS associated with eGFR/CKD stages. Time-to-death associated with renal parameters at baseline was assessed in ALS cases only. ALS cases were characterized by lower body mass index, slightly lower smoking prevalence, more intense occupational work and lower education than controls. Median serum cystatin-C based eGFR concentrations were lower in ALS cases than in controls (54.0 vs. 59.5 mL/min pro 1.73 m2). The prevalence of CKD stage ≥ 3 was slightly higher in ALS cases than in controls (14.1 vs. 11.0%). In the adjusted models, CKD stage 2 (OR 1.82, 95% CI 1.32, 2.52) and stage 3 (OR 2.34, 95% CI 1.38, 3.96) were associated with increased ALS risk. In this cohort of ALS cases, eGFR and CKD stage ≥ 3 (HR 0.94; 95% CI 0.64, 1.38) were not associated with prognosis. In this case–control study, higher CKD stages were associated with increased ALS risk, while in the prospective cohort of ALS cases, no indication of an association of CysC-based CKD on mortality was seen. In addition, our work strengthens the importance to evaluate renal function using a marker independent of muscle mass in ALS patients.

Association between genetically proxied lipid-lowering drug targets, lipid traits, and amyotrophic lateral sclerosis: a mendelian randomization study.

The use of circulating lipid traits as biomarkers to predict the risk of amyotrophic lateral sclerosis (ALS) is currently controversial, and the evidence-based medical evidence for the use of lipid-lowering agents, especially statins, on ALS risk remains insufficient. Our aim was to apply a Mendelian randomization (MR) approach to assess the causal impact of lipid-lowering agents and circulating lipid traits on ALS risk. Our study included primary and secondary analyses, in which the risk associations of lipid-lowering gene inhibitors, lipid traits, and ALS were assessed by the inverse variance weighting method as the primary approach. The robustness of the results was assessed using LDSC assessment, conventional MR sensitivity analysis, and used Mediating MR to explore potential mechanisms of occurrence. In the secondary analysis, the association of lipid-lowering genes with ALS was validated using the Summary data-based Mendelian Randomization (SMR) method. Our results showed strong evidence between genetic proxies for Apolipoprotein B (ApoB) inhibitor (OR = 0.76, 95% CI = 0.68 - 0.86; P = 5.58 × 10-6) and reduced risk of ALS. Additionally, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitor (OR = 1.06, 95% CI = 0. 85-1.33) was not found to increase ALS risk. SMR results suggested that ApoB expression was associated with increased ALS risk, and colocalization analysis did not support a significant common genetic variation between ApoB and ALS. Mediator MR analysis suggested a possible mediating role for interleukin-6 and low-density lipoprotein cholesterol (LDL-C). While elevated LDL-C was significantly associated with increased risk of ALS among lipid traits, total cholesterol (TC) and ApoB were weakly associated with ALS. LDSC results suggested a potential genetic correlation between these lipid traits and ALS. Using ApoB inhibitor can lower the risk of ALS, statins do not trigger ALS, and LDL-C, TC, and ApoB levels can predict the risk of ALS.

Loss of amyotrophic lateral sclerosis risk factor SCFD1 causes motor dysfunction in Drosophila

Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease mostly resulting from a complex interplay between genetic, environmental and lifestyle factors. Common genetic variants in the Sec1 Family Domain Containing 1 (SCFD1) gene have been associated with increased ALS risk in the most extensive genome-wide association study (GWAS). SCFD1 was also identified as a top-most significant expression Quantitative Trait Locus (eQTL) for ALS. Whether loss of SCFD1 function directly contributes to motor system dysfunction remains unresolved. Here we show that moderate gene silencing of Slh, the Drosophila orthologue of SCFD1, is sufficient to cause climbing and flight defects in adult flies. A more severe knockdown induced a significant reduction in larval mobility and profound neuromuscular junction (NMJ) deficits prior to death before metamorphosis. RNA-seq revealed downregulation of genes encoding chaperones that mediate protein folding downstream of Slh ablation. Our findings support the notion that loss of SCFD1 function is a meaningful contributor to ALS and disease predisposition may result from erosion of the mechanisms protecting against misfolding and protein aggregation.

Associations of self-reported occupational exposures and settings to ALS: a case–control study

BackgroundEnvironmental exposures contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal and progressive neurological disease. Identification of these exposures is important for targeted screening and risk factor modification.ObjectiveTo identify occupational exposures that are associated with a higher risk of ALS using both survey and standard occupational classification (SOC) coding procedures, and to highlight how exposure surveys can complement SOC coding.MethodsALS participants and neurologically healthy controls recruited in Michigan completed a detailed exposure assessment on their four most recent and longest held occupations. Exposure scores were generated from the exposure survey, and occupations were assigned to SOC codes by experienced exposure scientists.ResultsThis study included 381 ALS and 272 control participants. ALS participants reported higher duration-adjusted occupational exposure to particulate matter (OR = 1.45, 95% CI 1.19–1.78, p < 0.001), volatile organic compounds (OR = 1.22, 95% CI 1.02–1.45, p = 0.029), metals (OR = 1.48, 95% CI 1.21–1.82, p < 0.001), and combustion and diesel exhaust pollutants (OR = 1.20, 95% CI 1.01–1.43, p = 0.041) prior to ALS diagnosis, when adjusted for sex, age, and military service compared to controls. In multivariable models, only occupational exposure to metals remained significant risk (OR = 1.56, 95% CI 1.11–2.20, p = 0.011), although in an adaptive elastic net model, particulate matter (OR = 1.203), pesticides (OR = 1.015), and metals (1.334) were all selected as risk factors. Work in SOC code “Production Occupations” was associated with a higher ALS risk. SOC codes “Building and Grounds Cleaning and Maintenance Occupations”, “Construction and Extraction Occupations”, “Installation, Maintenance, and Repair Occupations”, and “Production Occupations” were all associated with a higher exposure to metals as determined using survey data.DiscussionOccupational exposure to particulate matter, volatile organic compounds, metals, pesticides, and combustion and diesel exhaust and employment in “Production Occupations” was associated with an increased ALS risk in this cohort.

Airborne lead and polychlorinated biphenyls (PCBs) are associated with amyotrophic lateral sclerosis (ALS) risk in the U.S

Amyotrophic lateral sclerosis (ALS) risk is linked to environmental exposures. The National Emissions Inventory (NEI) database compiles mandatory reports of levels of airborne contaminants from a variety of stationary and mobile pollution sources across the U.S. The objective of this study was to identify airborne contaminants that may be associated with ALS etiology for future study. We geospatially estimated exposure to airborne contaminants as risk factors for ALS in a nationwide large de-identified medical claims database, the SYMPHONY Integrated Dataverse®. We extracted zip3 of residence at diagnosis of ~26,000 nationally distributed ALS patients and n = 3 non-ALS controls matched per case for age and sex. We individually aggregated the median levels of each of 268 airborne contaminants recorded in the NEI database for 2008 to estimate local residential exposure. We randomly broke the dataset into two independent groups to form independent discovery and validation cohorts. Contaminants associated with increased ALS risk in both the discovery and validation studies included airborne lead (false discovery rate (FDR) = 0.00077), and polychlorinated biphenyls (PCBs), such as heptachlorobiphenyl (FDR = 3.60E−05). Small aircraft were the largest source of airborne lead, while the PCB emissions came from certain power plants burning biomass, and from industrial boilers. Associations with residential history of lead exposure were confirmed in two additional cohorts (10 year top quartile in New Hampshire/Vermont OR 2.46 95% CI 1.46–2.80, and in Ohio OR 1.60 95% CI 1.28–1.98). The results of our geospatial analysis support neurotoxic airborne metals and PCBs as risk factors for ALS.

Life Course of Physical Activity and Risk and Prognosis of Amyotrophic Lateral Sclerosis in a German ALS Registry.

Whether physical activity (PA) is a risk factor for amyotrophic lateral sclerosis (ALS) is controversial because data on lifelong PA are rare. The main objective of this study is to provide insight into PA as a potential risk factor for ALS, reporting data on cumulative PA, leisure-time PA, and occupational PA. This study also aims to gather evidence on the role of PA as a prognostic factor in disease course. Lifetime PA values collected by questionnaires addressing work and leisure time were quantified into metabolic equivalents (METs). A population-based case-control study embedded in the ALS Registry Swabia served to calculate the odds ratio (OR) of ALS by PA in different time intervals and prognosis. In ALS cases (393 cases, 791 age- and sex-matched controls), we observed reduced total PA at interview and up to 5 years before interview compared to controls. Total PA was not associated with ALS risk 5 to 55 years before interview. Heavy occupational work intensity was associated with increased ALS risk (OR 1.97, 95% confidence interval 1.34, 2.89). Total PA levels were associated with survival in a nonlinear manner: inactive patients and highest activity levels (25 MET-h/wk) revealed the worst survival time of 15.4 and 19.3 months, respectively. Best median survival with 29.8 months was seen at 10.5 MET-h/wk after adjustment for other prognostic factors. Lifetime combined PA decreased sharply several years before disease onset compared to controls. The risk of developing ALS was not associated with former total PA levels 5 to 55 years before interview in contrast to occupational PA, probably reflecting work-associated exposures. We found a strong nonlinear association of current and prediagnostic PA level and survival in ALS cases with the best survival with moderate PA. PA intensity may be a disease-modifying factor with an unfavorable outcome in sedentary and hyperactive behavior. This study provides Class III evidence that PA was not associated with the development of ALS.

Sleep/wake cycle alterations as a cause of neurodegenerative diseases: A Mendelian randomization study

Sleep and/or wake cycle alterations are common in neurodegenerative diseases (ND). Our aim was to determine whether there is a causal relationship between sleep and/or wake cycle patterns and ND (Parkinson's disease (PD) age at onset (AAO), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS)) using two-sample Mendelian Randomization (MR). We selected 12 sleep traits with available Genome-Wide Association Study (GWAS) to evaluate their causal relationship with the ND risk through Inverse-Variance Weighted regression as main analysis. We used as outcome the latest ND GWAS with available summary-statistics: PD-AAO (N=17,996), AD (N=21,235) and ALS (N=40,136). MR results pointed to a causal effect of subjective and objective-measured morning chronotype on later PD-AAO (95%CI:0.33-1.81, p=8.47×10-09 and 95%CI:-7.28 to -4.44, p=5.87×10-16, respectively). Sleep efficiency was causally associated with a decreased AD risk (95%CI:-20.408 to -0.66, p=0.04) and daytime sleepiness with an increased ALS risk (95%CI:0.15 to 1.61, p=0.01). Our study suggests that sleep and/or wake patterns have causal relationship with ND. Given that sleep and/or wake patterns are modifiable risk factors, sleep interventions should be investigated as a potential treatment in PD-AAO, AD and ALS.

Occupation and amyotrophic lateral sclerosis risk: a case-control study in the isolated island population of Malta

Objective: Amyotrophic lateral sclerosis (ALS) is a mostly sporadic neurodegenerative disease. The role of environmental factors has been extensively investigated but associations remain controversial. Considering that a substantial proportion of adult life is spent at work, identifying occupations and work-related exposures is considered an effective way to detect factors that increase ALS risk. This process may be further facilitated in population isolates due to environmental and genetic homogeneity. Our study investigated occupations and occupational exposures potentially associated with ALS risk in the isolated island population of Malta, using a case-control study design. Methods: Patients with ALS and randomly identified matched controls (1:1) were recruited throughout a four-year window, from 2017 through 2020. Data on educational level, residence, main occupation, smoking, and alcohol history were collected. Results: We found that compared to controls (44.4%), a higher percentage (73.7%) of ALS patients reported a blue-collar job as their main occupation (OR 2.04, 95% CI 1.2–3.72; p = 0.0072). Through regression analysis, craft and related trades occupations such as carpentry and construction (ISCO-08 major group 7), were found to be positively associated with ALS, with patients in this occupational category found to be more prone to develop bulbar-onset ALS (p = 0.0297). Overall, patients with ALS reported a significantly higher exposure to work-related strenuous physical activity (OR 2.35, 95% CI 1.53–3.59; p = 0.0002). Conclusion: Our findings suggest that manual workers particularly those working in the carpentry and construction industries have an increased ALS risk, possibly due to a history of intense or sustained physical activity.

Is Chronic Exposure to Raw Water a Possible Risk Factor for Amyotrophic Lateral Sclerosis? A Pilot Case-Control Study.

Background: The etiopathogenesis of amyotrophic lateral sclerosis (ALS) is still largely unknown. Methods: We performed a case-control study (33 cases and 35 controls) in Umbria, Italy. We investigated associations between common lifestyle, clinical factors, as well as environmental exposures potentially implicated with ALS onset. Face-to-face interviews were carried out. All cases were recruited and diagnosed according to El Escorial criteria. Case-control comparisons were made for educational and residential status, occupational exposures, and clinical and lifestyle factors prior to cases’ dates of diagnosis. Results: Our results showed an increased risk of ALS for subjects chronically exposed to raw water use (odds ratio (OR) = 6.55, 95% confidence interval (CI): 2.24–19.12). Garden activities showed a tight association with ALS as well, very likely as a consequence of chronic raw water exposure. Indeed, we could exclude an impact for pesticides, as no significant differences were observed in pesticide exposure in the two groups interviewed. However, cases were more often exposed to fertilizers. After adjustment for age, sex, and heavy physical activities, exposure to raw water was still associated with increased ALS risk (OR = 4.74, 95% CI: 1.33–16.85). Discussion: These findings suggest an association between ALS and exposure to raw water, which should be further investigated for the presence of chemicals interfering with nervous system functionality.

Risk of Amyotrophic Lateral Sclerosis and Exposure to Particulate Matter from Vehicular Traffic: A Case-Control Study.

(1) Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with still unknown etiology. Some occupational and environmental risk factors have been suggested, including long-term air pollutant exposure. We carried out a pilot case-control study in order to evaluate ALS risk due to particulate matter with a diameter of ≤10 µm (PM10) as a proxy of vehicular traffic exposure. (2) Methods: We recruited ALS patients and controls referred to the Modena Neurology ALS Care Center between 1994 and 2015. Using a geographical information system, we modeled PM10 concentrations due to traffic emissions at the geocoded residence address at the date of case diagnosis. We computed the odds ratio (OR) and 95% confidence interval (CI) of ALS according to increasing PM10 exposure, using an unconditional logistic regression model adjusted for age and sex. (3) Results: For the 132 study participants (52 cases and 80 controls), the average of annual median and maximum PM10 concentrations were 5.2 and 38.6 µg/m3, respectively. Using fixed cutpoints at 5, 10, and 20 of the annual median PM10 levels, and compared with exposure <5 µg/m3, we found no excess ALS risk at 5–10 µg/m3 (OR 0.87, 95% CI 0.39–1.96), 10–20 µg/m3 (0.94, 95% CI 0.24–3.70), and ≥20 µg/m3 (0.87, 95% CI 0.05–15.01). Based on maximum PM10 concentrations, we found a statistically unstable excess ALS risk for subjects exposed at 10–20 µg/m3 (OR 4.27, 95% CI 0.69–26.51) compared with those exposed <10 µg/m3. However, risk decreased at 20–50 µg/m3 (OR 1.49, 95% CI 0.39–5.75) and ≥50 µg/m3 (1.16, 95% CI 0.28–4.82). ALS risk in increasing tertiles of exposure showed a similar null association, while comparison between the highest and the three lowest quartiles lumped together showed little evidence for an excess risk at PM10 concentrations (OR 1.13, 95% CI 0.50–2.55). After restricting the analysis to subjects with stable residence, we found substantially similar results. (4) Conclusions: In this pilot study, we found limited evidence of an increased ALS risk due to long-term exposure at high PM10 concentration, though the high statistical imprecision of the risk estimates, due to the small sample size, particularly in some exposure categories, limited our capacity to detect small increases in risk, and further larger studies are needed to assess this relation.

Blood Metal Levels and Amyotrophic Lateral Sclerosis Risk: A Prospective Cohort.

ObjectiveMetals have been suggested as a risk factor for amyotrophic lateral sclerosis (ALS), but only retrospective studies are available to date. We compared metal levels in prospectively collected blood samples from ALS patients and controls, to explore whether metals are associated with ALS mortality.MethodsA nested ALS case–control study was conducted within the prospective EPIC (European Prospective Investigation into Cancer and Nutrition) cohort. Cases were identified through death certificates. We analyzed metal levels in erythrocyte samples obtained at recruitment, as a biomarker for metal exposure from any source. Arsenic, cadmium, copper, lead, manganese, mercury, selenium, and zinc concentrations were measured by inductively coupled plasma–mass spectrometry. To estimate ALS risk, we applied conditional logistic regression models.ResultsThe study population comprised 107 cases (65% female) and 319 controls matched for age, sex, and study center. Median time between blood collection and ALS death was 8 years (range = 1–15). Comparing the highest with the lowest tertile, cadmium (odds ratio [OR] = 2.04, 95% confidence interval [CI] = 1.08–3.87) and lead (OR = 1.89, 95% CI = 0.97–3.67) concentrations suggest associations with increased ALS risk. Zinc was associated with a decreased risk (OR = 0.50, 95% CI = 0.27–0.94). Associations for cadmium and lead remained when limiting analyses to noncurrent smokers.InterpretationThis is the first study to compare metal levels before disease onset, minimizing reverse causation. The observed associations suggest that cadmium, lead, and zinc may play a role in ALS etiology. Cadmium and lead possibly act as intermediates on the pathway from smoking to ALS. ANN NEUROL 20209999:n/a–n/a

Risk factors for amyotrophic lateral sclerosis: A regional United States case-control study.

Most amyotrophic lateral sclerosis (ALS) cases are considered sporadic, without a known genetic basis, and environmental exposures are thought to play a causal role. To learn more about sporadic ALS etiology, we recruited n = 188 ALS patients from northern New England and Ohio and matched controls 2:1 from the general population of the same regions. Questionnaires evaluated the association between a variety of lifestyle, behavioral (ie, hobbies and activities), and occupational factors and the risk of ALS, including the duration of time between exposure and ALS onset, and exposure frequency. Head trauma was associated with increased ALS risk (adjusted odds ratio [OR] 1.60 95% confidence interval [CI] 1.04‐2.45), with significantly greater effects for injuries occurring 10 or more years prior to symptom onset (P = .037). ALS risk was increased for those reporting severe electrical burns (adjusted OR 2.86, 95% CI 1.37‐6.03), with odds ratios highest for burns after age 30 (OR 3.14), and for burns 10 or more years prior to symptom onset (OR 3.09). Hobbies involving lead were the most strongly associated with ALS risk (adjusted OR 2.92, 95% CI 1.45‐5.91). Exposures to lead 20 or more years prior to diagnosis had larger effect sizes compared to those occurring more recently. Holding a job in mechanics, painting, or construction was associated with ALS. The identification of these specific environmental factors associated with ALS highlight the need for future prospective and laboratory studies to assess causality, biological mechanisms, and find prevention or treatment opportunities.

Pre-symptomatic blood metal levels and the risk of ALS

OPS 40: Metals: neurological effects, Room 412, Floor 4, August 28, 2019, 10:30 AM - 12:00 PM Background: Metals have been suggested as risk factor for amyotrophic lateral sclerosis (ALS), but only retrospective studies on this possible association are available to date. We aimed to compare metal levels in prospectively collected blood samples from ALS patients and matched controls, to explore whether metals are associated with ALS risk. Methods: A nested case-control study for ALS was conducted within a large prospective European cohort. ALS cases were defined as those subjects for whom “motor neuron disease” was reported as an immediate, antecedent or underlying cause of death. We analysed erythrocytes metal levels in stored blood samples that were obtained at recruitment, as a biomarker for metal exposure from any source. Lead, mercury, manganese, selenium, copper, zinc, cadmium and arsenic concentrations were measured by sensitive and high-throughput methods, based on inductively coupled plasma-mass spectrometry. To estimate the risk of ALS in relation to pre-symptomatic blood metal levels, we applied conditional logistic regression models, adjusted for educational level, physical activity and smoking. Results: The study population comprised 107 cases (65% male) and 319 matched controls. The median age at recruitment was 60 and the median time between blood collection at recruitment and ALS death was 8 years (ranging from 1 to 15 years). Cadmium and lead levels were associated with increased ALS risk, but ORs attenuate after adjustment. Zinc levels were significantly associated with decreased ALS risk, but non-significant when adjusted. Conclusion: The metal concentrations in pre-symptomatic blood from ALS patients and controls indicated that cadmium and lead may be associated with an increased risk of ALS. This is the first study to compare metal levels before the disease onset, and hence avoiding any reverse causation, and our findings support previous suggestions that these metals play a role in the aetiology of ALS.