A mixtures approach to solvent exposures and amyotrophic lateral sclerosis: a population-based study in Denmark.

Studies of occupational solvent exposures and amyotrophic lateral sclerosis (ALS) have been conflicting. We conducted a population-based case-control study of mixed occupational solvent exposures and ALS. Using the Danish National Patient Registry, we identified ALS cases in Denmark from 1982 to 2013, and matched them to 100 controls based on sex and birth year. We estimated cumulative exposures to solvents (benzene, methylene chloride, toluene, trichloroethylene, perchloroethylene, and 1,1,1-trichloroethane) via job exposure matrices and applied them to occupational history from the Danish Pension Fund. Sex-stratified conditional logistic regression analyses revealed higher adjusted odds of ALS for men with exposure to benzene (aOR = 1.20; 95% CI 1.02, 1.41) and methylene chloride (aOR = 1.23; 95% CI 1.07, 1.42). We used weighted quantile sum regression to explore combined solvent exposures and risk of ALS in exposed subjects and found increased odds of 26 to 28% in all exposure lag periods for every one-unit increase in the mixture index in men. Weights of methylene chloride predominated the mixture index in all lag periods. Our study suggests an increased risk of ALS in men exposed to multiple solvents, with the greatest influence being from methylene chloride. These findings highlight the need to utilize mixtures analysis when considering co-occurring exposures.

Population-based study of amyotrophic lateral sclerosis and occupational lead exposure in Denmark.

OBJECTIVES: Previous research has indicated links between lead (Pb) exposure and increased risk of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). In this study, we evaluated the association between occupational Pb exposures and ALS. METHODS: ALS cases were ascertained through the Danish National Patient Registry from 1982 to 2013 and age and sex-matched to 100 controls. Using complete employment history since 1964 from the Danish Pension Fund, cumulative Pb exposure was estimated for each subject via a Danish job exposure matrix. Associations were evaluated using conditional logistic regression analyses and stratified by sex. RESULTS: For men with >50% probability of exposure, there was an increase in odds of ALS for exposures in the 60th percentile or higher during any time 5 years prior to diagnosis (aOR: 1.35; 95% CI 1.04 to 1.76) and 10 years prior to diagnosis (aOR: 1.33; 95% CI 1.03 to 1.72). No significant associations were observed in women, and there were no linear trends seen for Pb exposures for either sex. CONCLUSIONS: Our study indicates an association between consistently higher occupational Pb exposures and ALS. These findings support those of previously reported associations between ALS and specific occupations that commonly experience Pb exposure.

The effect of 8 weeks of treatment with transcranial pulsed electromagnetic fields on hand tremor and inter-hand coherence in persons with Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) tremor comprises asymmetric rest and postural tremor with unilateral onset. Tremor intensity can be amplified by stress and reduced by attention, and the medical treatment is complex. Mirror movements and unintentional synchronization of bimanual movements, possibly caused by insufficient inhibition of inter-hemispheric crosstalk, have been reported in PD, indicating a lag of lateralization. Potential neuroprotective effects of pulsed electromagnetic fields (PEMF) have been reported in-vitro and in rodents, as have influences of PEMF on human tremor. The aim was to investigate the effect of 8 weeks daily transcranial PEMF treatment (T-PEMF) of persons with PD on rest and postural hand tremor characteristics and on inter-hand coherence. METHODS: Hand accelerations of 50 PD participants with uni- or bilateral tremor participating in a clinical trial were analysed. A rest and postural tremor task performed during serial subtraction was assessed before and after 8 weeks of T-PEMF (30 min/day, 50 Hz, ±50 V, 3 ms squared pulses) or placebo treatment (sham stimulation 30 min/day). Forty matched healthy persons (no treatment) were included as reference. Intensity and inter-hand coherence related measures were extracted. RESULTS: The T-PEMF treatment decreased the inter-hand coherence in the PD group with unilateral postural tremor. The PD group with unilateral postural tremor was less clinically affected by the disease than the PD group with bilateral postural tremor. However, no differences between T-PEMF and placebo treatment on either intensity related or coherence related measures were found when all persons with PD were included in the analyses. The peak power decreased and the tremor intensity tended to decrease in both treatment groups. CONCLUSIONS: Eight weeks of T-PEMF treatment decreased inter-hand coherence in the PD group with unilateral postural tremor, while no effects of T-PEMF treatment were found for the entire PD group. The unilateral postural tremor group was less clinically affected than the bilateral postural tremor group, suggesting that early treatment initiation may be beneficial. In theory, a reduced inter-hand coherence could result from a neuronal treatment response increasing inter-hemispheric inhibition. However, this requires further studies to determine. Studies of even longer treatment periods would be of interest. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02125032. Registered 29 April 2014, https://clinicaltrials.gov/ct2/show/NCT02125032?term=NCT02125032&rank=1.

The influence of posture duration on hand tremor during tasks with attention-distraction in persons with Parkinson's disease.

BACKGROUND: Tremor is one of the hallmarks and most bothersome symptoms in Parkinson's disease (PD). The classical PD tremor is present at rest, but postural tremor also occurs. PD tremor can be continuous or intermittently present and can have a re-emergent nature. The tremor intensity is affected by attention and stress level. Observations of PD tremor have indicated increased tremor intensity with time during 30-s tremor assessments. This phenomenon has not previously been studied systematically. Thus, in order to contribute to our understanding of the mechanisms associated with PD tremor, our aim was to investigate the influence of time during a posture holding and a resting task on hand tremor characteristics in persons with PD compared to healthy peers. METHOD: Fifty persons with PD and at least one tremoring hand (tremor intensity exceeding mean + 2SD of a healthy reference group (REF), N = 40) were included from a clinical trial population. Hand accelerations in a rest and postural condition were measured in 30-s assessments while the participants performed a self-paced simple subtraction task with eyes closed to standardize attention without inducing stress. Tremor intensity, maximal power, frequency of maximal power and tremor onset time was calculated for three consecutive 10-s time intervals. RESULTS: Tremor intensity and maximal power increased significantly during the 30-s recording in the PD-group in both conditions (1st-3rd time-interval, tremor intensity: rest + 65% p < 0.0001, postural + 55% p < 0.0001; maximal power: rest + 93% p < 0.0001, postural + 82% p < 0.001). No effect of time was found on frequency of maximal power in the PD-group or on any effect measure in the REF-group. CONCLUSION: Tremor intensity and maximal power increased with time in the PD-group during 30-s tasks, while no change with time was found in the REF-group. In contrast, frequency of maximal power remained unchanged, which may suggest that the same neural circuits were responsible for the tremor generation throughout the tasks. The increase in tremor intensity and maximal power could not solely be explained by re-emergence of tremor. This suggests an increasing or gradually more synchronized cortico-spinal drive throughout the tasks. However, this requires further studies to determine.

Amyotrophic Lateral Sclerosis and Exposure to Diesel Exhaust in a Danish Cohort.

Previous studies have suggested an increased risk of amyotrophic lateral sclerosis (ALS) and other motor neuron diseases for persons in occupations commonly involving exposure to diesel exhaust (DE). In this study, we investigated the association between occupational exposure to DE and odds of ALS. ALS cases were identified from the Danish National Patient Registry (1982-2013) and individually matched to 100 controls per case on the basis of birth year and sex. Using information on occupational history from 1964 onward obtained from the Danish Pension Fund, we estimated cumulative DE exposures using a job exposure matrix. We evaluated associations using conditional logistic regression analyses and stratified the analyses by sex. Using a 10-year lag period, DE exposure was positively associated with ALS among men who had ever been exposed (adjusted odds ratio (aOR) = 1.20, 95% confidence interval (CI): 1.05, 1.38). For men with greater than 50% probability of DE exposure, we observed a positive association between ALS and highest-quartile exposure during the 5-year (aOR = 1.35, 95% CI: 1.07, 1.70) and 10-year (aOR = 1.41, 95% CI: 1.11, 1.79) lag periods. Our study suggests an association between consistently higher exposures to DE and ALS in men, but not in women. These findings support previous reports of associations between ALS and occupations commonly involving DE exposure.

Study of occupation and amyotrophic lateral sclerosis in a Danish cohort.

OBJECTIVES: Several manuscripts have proposed associations between amyotrophic lateral sclerosis (ALS) and occupational toxicant exposures-not to mention physical activity and trauma/injury. Some have also reported associations in investigations of specific occupations. Using data from a prospective Danish cohort study, we investigated the association between employment in certain industries and ALS diagnosis. METHODS: We identified 1826 ALS cases who were 25 years old or less in 1964 and diagnosed from 1982 to 2013 from the Danish National Patient Registry then matched 100 population controls to each case based on birth year and sex. Demographic data were linked to the Danish Pension Fund to determine occupation history. Conditional logistic regression models were adjusted for socioeconomic status, marital status and residential location at the index date. RESULTS: There was an increase in odds of ALS among men who worked in agriculture, hunting, forestry or fishing (adjusted OR (aOR)=1.21; 95% CI 1.02 to 1.45). There was also a positive association for men employed in construction (aOR=1.21; 95% CI 1.05 to 1.39). In women, a protective association was seen with employment in the cleaning industry (aOR=0.69; 95% CI 0.52 to 0.93). CONCLUSIONS: Our study shows various occupations with exposure to toxicants, such as diesel exhaust and lead, and strenuous physical activity associated with increased odds of ALS in men. Future studies should have a particular focus on gathering detailed information on physical exertion and toxicant exposures specific to certain job tasks.

The Hawthorne effect as a pre-placebo expectation in Parkinsons disease patients participating in a randomized placebo-controlled clinical study.

BACKGROUND: The Hawthorne effect on clinical studies in Parkinson's disease has not been thoroughly investigated. Evidently the Hawthorne effect may have impact on study outcomes acting as a 'pre-placebo' effect in the recruitment phase, hence before inclusion. AIM: The aim of this study was to discuss the Hawthorne effect in relation to clinical and self-reported outcome measures in a randomized clinical study in the recruitment phase and during the study. METHODS: Data from 97 participants with Parkinson's disease treated with Transcranial Pulsed Electromagnetic Fields were applied, randomized to an active (n = 49) or a placebo treated group (n = 48). The participants received one home treatment session, for eight consecutive weeks. Outcome measures were the Unified Parkinson's Disease Rating Scale, The 39-item Parkinson's Disease Questionnaire and the WHO-5. RESULTS: No difference in treatment effect between the two groups was found pertaining the Unified Parkinson's Disease Rating Scale. No difference in treatment effect between the two groups was found pertaining the 39-item Parkinson's Disease Questionnaire, apart from the dimension mobility. No difference in treatment effect between the two groups was found pertaining the WHO-5 scale. CONCLUSIONS: The Hawthorne effect may have caused a 'pre-placebo' effect on the outcome measures even before obtaining baseline outcomes measures. This study may have been particularly prone to a Hawthorne effect due to the intense contact with the participants before and during the study. Moreover, the Hawthorne effect should not be viewed upon as a single entity but rather as entities affecting outcome measures throughout the full study period.

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.

Physical Trauma and Amyotrophic Lateral Sclerosis: A Population-Based Study Using Danish National Registries.

Prior studies have suggested that physical trauma might be associated with the development of amyotrophic lateral sclerosis (ALS). We conducted a population-based, individually matched case-control study in Denmark to assess whether hospitalization for trauma is associated with a higher risk of developing ALS. There were 3,650 incident cases of ALS in the Danish National Patient Register from 1982 to 2009. We used risk-set sampling to match each case to 100 age- and sex-matched population controls alive on the date of the case's diagnosis. Odds ratios and 95% confidence intervals were calculated using a conditional logistic regression model. History of trauma diagnosis was also obtained from the Danish Patient Register. When traumas in the 5 years prior to the index date were excluded, there was a borderline association between any trauma and ALS (odds ratio (OR) = 1.09, 95% confidence interval (CI): 0.99, 1.19). A first trauma before age 55 years was associated with ALS (OR = 1.22, 95% CI: 1.08, 1.37), whereas first traumas at older ages were not (OR = 0.97, 95% CI: 0.85, 1.10). Our data suggest that physical trauma at earlier ages is associated with ALS risk. Age at first trauma could help explain discrepancies in results of past studies of trauma and ALS.

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.

Subarachnoid haemorrhage and intracranial aneurysms in Greenland in the period 2018-2021: incidence, outcome and familial disposition.

Subarachnoid haemorrhages (SAH) caused by rupture of intracranial aneurysms (IA) are a severe condition. Earlier studies found a higher incidence of SAH in Greenlandic patients compared to Danish patients, with familial aggregation also higher in Greenland. However, updated data is lacking. To investigate the contemporary incidence, outcome, and familial disposition of SAH/IA in Greenlandic patients in 2018-2021. Greenlandic patients diagnosed with ruptured or unruptured IA (UIA) during 2018-2021 were included. Data was obtained from patient files, x-ray department, and discharge registry. Incidence rates were estimated as cases/100,000/year. Direct age-standardised incidence rates were calculated using WHO 2000-2025 as standards. Of 30 SAH patients, 20 (66.7%) were females, 10 (33.3%) males. Of 36 UIA patients, 27 (75.0%) were females, 9 (25.0%) males. For SAH, crude incidence was 13.4/100,000/year, age-standardised incidence was 10.8/100,000/year. Familial history was observed in 30.0% of SAH patients. 5 patients (16.7%) died before treatment, 28-day case-fatality rate (CFR) for all patients was 23.3%. Overall and age-standardised incidence rates were similar to previous studies but higher among females and compared to neighbouring countries. A high occurrence of familial history was reported. SAH remains a serious condition in Greenland, as evidenced by five fatalities before treatment was administered.

Age-period-cohort analysis of trends in amyotrophic lateral sclerosis in Denmark, 1970-2009.

Amyotrophic lateral sclerosis (ALS) is a disease of the motor neuron with poorly understood etiology. Recent studies have suggested that the incidence rate of ALS and the rate of death from ALS are increasing, but it is unclear whether this is due to changing exposures or improvements in diagnosis. We used age-period-cohort models to investigate trends in ALS incidence (hospitalization) from 1982 to 2009 and ALS mortality from 1970 to 2009 in Denmark. Among those 45 years of age or older, 4,265 deaths (incidence rate = 5.35 per 100,000 person-years) and 3,228 incident diagnoses (incidence rate = 5.55 per 100,000 person-years) were recorded. Age-adjusted mortality rates increased by an average of 3.0% annually between 1970 and 2009 and by an average of 2.1% annually after 1982. Age-period-cohort analyses suggested that the full age-period-cohort model provided the best fit to the mortality data (P < 0.001), although restriction to the post-1982 period suggested that the age-cohort model provided the best fit. Age-adjusted incidence rates increased by 1.6% annually after 1982 (P < 0.001), which was best explained by the age-period model, with borderline significant cohort effects (P = 0.08). A consistent finding regardless of parameterization or data subset appeared to be an increase in ALS incidence and mortality rate with later birth cohorts, up to a birth year of at least 1910.

Ataxin-2 intermediate-length polyglutamine expansions in European ALS patients.

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease primarily affecting motor neurons. We recently identified intermediate-length polyglutamine (polyQ) expansions (27-33 Qs) in ataxin 2 as a genetic risk factor for sporadic ALS in North American ALS patients. To extend these findings, we assessed the ataxin 2 polyQ repeat length in 1294 European ALS patients and 679 matched healthy controls. We observed a significant association between polyQ expansions and ALS (>30 Qs; P= 6.2 × 10(-3)). Thus, intermediate-length ataxin 2 polyQ repeat expansions are associated with increased risk for ALS also in the European cohort. The specific polyQ length cutoff, however, appears to vary between different populations, with longer repeat lengths showing a clear association. Our findings support the hypothesis that ataxin 2 plays an important role in predisposing to ALS and that polyQ expansions in ataxin 2 are a significant risk factor for the disease.

Treatment of glioblastoma in Greenlandic patients.

Glioblastoma (GBM), WHO grade IV, is the most common primary malignant brain tumour among adults with a devastating overall survival of 14-22 months. Standard treatment of GBM includes maximum safe resection, radiotherapy plus concomitant and adjuvant temozolomide (TMZ), given over a period of approximately 9 months. Treatment and follow-up for Greenlandic patients with GBM are managed at Rigshospitalet (RH), Copenhagen. Greenlandic GBM patients, therefore, travel back and forth to RH, often unaccompanied, and challenged by cognitive failure or other symptoms from their disease and/or treatment. Few Greenlandic patients are diagnosed with GBM annually, but considering the poor prognosis and short remaining lifespan, it would be preferable to limit their travels. TMZ is administrated as capsules. Health personnel at Queen Ingrid's Hospital (DIH), Nuuk, are trained in treating other oncological diseases and handling side effects. Hence, it could be investigated whether administration of adjuvant TMZ at DIH could be feasible after personnel education as well as economic consideration and compensation, in close collaboration with neuro oncologists at RH. In this article, we describe the Greenlandic cancer treatment, and the typical workflow from diagnosis of GBM to treatment to progression.

Novel TARDBP mutations in Nordic ALS patients.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative syndrome primarily affecting the upper and lower motor neurons. A characteristic neuropathological finding in ALS patients is neuronal inclusions positive for TAR DNA-binding protein 43 (TDP-43). Subsequently, mutations in the gene encoding TDP-43, TARDBP, proved to be involved in the development of ALS. We thus sequenced TARDBP in 177 Nordic ALS patients and found two previously reported (p.A90V and p.S379P) and two novel (p.G357R and p.R361T) missense variations in three familial ALS patients. The p.A90V and p.G357R variations were detected in the same patient and p.R361T was present in a family with both ALS and frontotemporal dementia-ALS. None of the missense variations were present in 200 neurologically healthy controls. However, p.A90V has also been reported in healthy individuals by others. Thus, the data suggest that these variations are rare and p.G357R, p.R361T and p.S379P are likely pathogenic but further functional characterization is needed to prove their pathogenicity. The mutation frequency in TARDBP in Nordic ALS patients was 1.7%. The ALS cohort was highly selected for a positive family history suggesting that mutations in TARDBP generally are a rare cause of ALS in Nordic countries.

Diagnosing dementia in the Arctic: translating tools and developing and validating an algorithm for assessment of impaired cognitive function in Greenland Inuit.

Background: The ageing Arctic populations raise the need for work-up of cognitive function that reflects language and cultural understandings.Aim: To translate and evaluate tools for work-up of cognitive impairment in Greenland.Methods: Step A: An expert panel was established to select tools suitable for the work-up of cognitive impairment at three different settings in Greenland. Step B: Tools were translated in a multiple-step process of independent translations with back-translation and adaptations by two independent translators and two Greenlandic physicians. Step C: a testing and validation process of the tools at three locations: the national hospital in the capital city; regional hospital in a town; health care centre in a small town.Results: Tools selected were Mini-Cog and RUDAS. Participants for testing of tools were 43 of 61 invited, of which six had dementia. RUDAS and Mini-Cog scores were associated (p < 0.001). The smoothed AUC was 0.87 (95%-CI, 0.65-0.95) for Mini-Cog and 0.90 (95%-CI, 0.76-0.97) for RUDAS. The sensitivity of Mini-Cog with a cut-off at ≤3 was 83.3%, and specificity was 62.2%. For RUDAS with a cut-off at ≤23, these were 100% and 75.7%, respectively.Conclusion: Requested tools have been translated for assessing cognitive function in the native Arctic setting. Small town residents with a Mini-Cog score of 3 or lower should be referred to a regional hospital for RUDAS, and a score of 23 or less should cause referral to the national hospital for a full work-up of cognitive function.

Joint and interactive effects between health comorbidities and environmental exposures in predicting amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare yet devastating neurodegenerative condition. The mechanisms leading to ALS are most certainly complex and likely involve a joint contribution of several factors with possible synergistic or antagonistic interactions. To provide a better understanding of the association between non-genetic factors and ALS, we evaluated the joint exposure to multiple health and environmental factors linked with ALS in our previous studies, also screening for high-dimensional interactions. METHODS: We used data from a nested case-control study within the Danish population, with 1086 ALS cases from 1982 to 2009, jointly investigating 4 hospital-based diagnoses - diabetes, obesity, physical/stress trauma, cardiovascular disease (CVD) during 1977-2009; and 4 environmental exposures - lead, formaldehyde, diesel exhaust, and solvents, assessed from individual occupational history. All covariates were evaluated as ever/never exposed, and we used targeted machine learning techniques to screen for important joint predictors and interactions. These were then evaluated in a final logistic regression model adjusting for potential confounders (age, SES, geography). All analyses were stratified by sex. RESULTS: Among men, trauma and solvents were associated with higher odds of ALS (OR = 1.55, 95% CI: 1.08-2.23; OR = 1.49, 95% CI: 1.17-1.89, respectively), and presented a negative interaction (OR = 0.49, 95% CI: 0.30-0.80). A positive diesel/CVD interaction was observed (OR = 1.56, 95% CI: 0.94-2.60). Among women, solvents, trauma, lead, and CVD were associated with higher odds of ALS, and a negative lead/solvents interaction was documented (OR = 0.52, 95% CI: 0.42-0.63). CONCLUSIONS: This study is one of the first attempts to evaluate joint and interactive effects of multiple risk factors on ALS, identifying potential synergistic and antagonistic mechanisms.

Study of Occupational Chromium, Iron, and Nickel Exposure and Amyotrophic Lateral Sclerosis in Denmark.

Studies of occupational metal exposures and amyotrophic lateral sclerosis (ALS) have focused primarily on known neurotoxicants, including lead, mercury, selenium, and cadmium. However, these exposures are often co-occurring with other lesser studied metals. We conducted a population-based case-control study with the aim of assessing associations between occupational chromium, iron, and nickel exposures and risk of ALS. We identified ALS cases in Denmark from 1982 through 2013 from the Danish National Patient Registry and matched them to 100 controls based on birth year and sex. Cumulative metal exposures were estimated using job exposure matrices applied to occupational history from the Danish Pension Fund. Although mutually adjusted odds of ALS were higher in men with chromium exposures in the third quartile (aOR = 1.24; 95% CI 0.91, 1.69) and fourth quartile (aOR = 1.19; 95% CI: 0.80, 1.76) compared to those with no exposure, differences did not reach statistical significance. We also observed higher odds of ALS in women with nickel exposures in the third quartile (aOR = 2.21; 95% CI: 1.14, 4.28), but not for the fourth quartile (aOR = 0.61; 95% CI: 0.23, 1.64). Our findings do not suggest associations between occupational exposures to these metals and ALS. However, unavoidable non-differential misclassification from the use of JEMs may have masked truly increased risk.