Incident Amyotrophic Lateral Sclerosis Cases Research Articles

Fighting Amyotrophic Lateral Sclerosis by Protecting the Liver? A Prospective Cohort Study.

Previous studies have observed liver abnormalities in amyotrophic lateral sclerosis (ALS) patients. This study aimed to investigate whether early signs of liver disease, measured by magnetic resonance imaging-derived iron-corrected T1-mapping (cT1), are risk factors for developing ALS. cT1 and proton density fat fraction were measured and automatically analyzed using LiverMultiScan® software. The Fibrosis-4 index was calculated using an established formula based on age and blood markers. Cox proportional hazard models were used to examine the relationship between liver disease, liver biomarkers, and incident ALS. In a cohort of 533,707 individuals from UK Biobank, 24 ALS cases were identified among 28,328 participants with liver disease during the follow-up period. Among a total of 33,959 individuals with complete liver imaging data, 15 incident ALS cases were observed during a median follow-up period of 5.6 years. Individuals with liver disease had a higher risk of developing ALS, with an adjusted hazard ratio of 7.35 (95% CI 4.47-12.09; p < 0.001). An increase in cT1 was also associated with a higher risk of ALS. After adjusting for age, sex, Townsend deprivation index, smoking status, alcohol intake frequency, body mass index, proton density fat fraction, Fibrosis-4, and metabolic syndrome, an increase in cT1 remained significantly associated with a higher risk of ALS, with an adjusted hazard ratio of 3.15 (95% CI 1.79-5.55) per 1-SD increase. Sensitivity analyses confirmed these robust results. Liver disease activity, indicated by cT1, increases the risk of developing ALS, independent of metabolic syndrome, liver fat, or fibrosis. ANN NEUROL 2024.

Pharmacological and non‐pharmacological treatments in amyotrophic lateral sclerosis: an Italian real‐world data study

AbstractBackground and purposeThe purpose was to describe the use patterns of pharmacological and non‐pharmacological therapies and investigate potential determinants of riluzole use in patients newly diagnosed with amyotrophic lateral sclerosis (ALS) in three Italian regions.MethodsAmyotrophic lateral sclerosis patients were selected from administrative healthcare databases of Latium, Tuscany and Umbria from 1 January 2014 to 31 December 2019 based on hospital‐ and disease‐specific co‐payment exemption data. The first trace of ALS was considered the index date. Incident ALS cases were those without a trace of ALS during the 3‐year look back. Patients were described in terms of demographics, clinical characteristics and drug use at baseline, and were classified into four categories based on riluzole use in the 2 years before and 1 year after the index date: prevalent, incident, former users and non‐users. Use of symptomatic pharmacological and non‐pharmacological therapies was described across these categories during 12 months after the index date. Determinants of riluzole use were also investigated.Results and conclusionsA total of 1636 ALS incident subjects were detected in the three regions, mainly aged 65–74 years. Patients were generally fragile with a high prevalence of comorbidities at baseline. Riluzole was used by 27.4% of the overall study cohort at baseline and steeply increased in the first year after the index date differently between regions (Latium 61.2%, Tuscany 85.0%, Umbria 76.5%), with about half of the subjects being incident users. In the 12 months after the index date, also symptomatic therapies increased, in riluzole users and non‐users. Determinants analysis showed that higher patient severity and complexity were associated with a lower likelihood of being treated with riluzole.

Type 2 diabetes, obesity, and risk of amyotrophic lateral sclerosis: A population-based cohort study.

Type 2 diabetes and obesity may be inversely associated with amyotrophic lateral sclerosis (ALS), but the evidence is controversial. Using Danish, nationwide registries (1980-2016), we identified patients with a diagnosis of type 2 diabetes (N=295,653) and patients with a diagnosis of obesity (N=312,108). Patients were matched (1:3) to persons from the general population on birth year and sex. We computed incidence rates and Cox regression derived hazard ratios (HRs) of a diagnosis of ALS. In multivariable analyses, HRs were controlled for sex, birth year, calendar year, and comorbidities. We observed 168 incident cases of ALS (0.7 [95% confidence interval (CI): 0.6-0.8] per 10,000 person-years) among patients with type 2 diabetes and 859 incident cases of ALS (0.9 [95% CI: 0.9-1.0] per 10,000 person-years) among matched comparators. The adjusted HR was 0.87 (95% CI: 0.72-1.04). The association was present among men (adjusted HR: 0.78 [95% CI: 0.62-0.99]) but not women (adjusted HR: 1.03 [95% CI: 0.78-1.37]), and among those aged ≥60 years (adjusted HR: 0.75 [95% CI: 0.59-0.96]) but not younger. We observed 111 ALS events (0.4 [95% CI: 0.4-0.5] per 10,000 person-years) among obesity patients and 431 ALS events (0.5 [95% CI: 0.5-0.6] per 10,000 person-years) among comparators. The adjusted HR was 0.88 (95% CI: 0.70-1.11). Diagnoses of type 2 diabetes and obesity were associated with a reduced rate of ALS compared with general population comparators, particularly among men and patients aged 60 years or above. However, absolute rate differences were small.

Cardiovascular Diseases, Medications, and ALS: A Population-Based Case-Control Study

Introduction: We investigated the associations between antecedent all-cause CVD diagnoses, cause-specific CVD diagnosis, and CVD medication prescriptions with the risk of developing amyotrophic lateral sclerosis (ALS). Materials and Methods: We conducted a population-based case-control study of U.S. Medicare enrollees from 2006 to 2013. The final sample included 3,714 incident ALS cases and 18,570 controls (matched on age, sex, enrollment length, and county). Information was collected from Medicare Parts A, B, and D administrative claims data on hypertension, ischemic heart disease, heart failure, acute myocardial infarction, atrial fibrillation, prescriptions of angiotensin-converting enzyme inhibitors, angiotensin II receptors blockers, calcium channel blockers, beta blockers, and antiarrhythmics. Associations were evaluated using conditional logistic regression adjusting for age, sex, race/ethnicity, geographical location, alcohol and tobacco use, and socioeconomic status. Results: The odds ratio (OR) for having one or more ICD-9 codes for any cardiovascular disease diagnosis at least 24 months prior to the date of ALS diagnosis was 0.85 (95% confidence interval [CI]: 0.78–0.92). Cardiovascular conditions that were inversely associated with ALS included heart failure (OR = 0.79; 95% CI 0.70–0.89), atrial fibrillation (OR = 0.81; 95% CI 0.77–0.92), and hypertension (OR = 0.91; 95% CI 0.84–0.98). Exposures to several classes of cardiovascular medications were inversely associated with ALS risk even after adjusting for confounding by indication, including ACE inhibitors (OR = 0.84, 95% CI 0.77–0.91), calcium channel blockers (OR = 0.64, 95% CI 0.59–0.70), and beta blockers (OR = 0.76, 95% CI 0.71–0.83). Discussion/Conclusion: These findings merit additional research, including animal studies and pilot clinical trials, to further evaluate and evidence the effects of ACEIs, CCBs, and BBs on the risk of developing and clinical expression of ALS.

Spatio-temporal clustering of amyotrophic lateral sclerosis in France: A population-based study.

To assess spatial aggregates of amyotrophic lateral sclerosis (ALS) incident cases, using a solid geo-epidemiological statistical method, in France. This population-based study (2003-2011) investigated 47.1 million person-years of follow-up (PYFU). Case ascertainment of incident ALS cases was based on multiple sources (ALS referral centers, hospital centres and health insurance data). Neurologists confirmed all ALS diagnoses. Exhaustiveness was estimated through capture-recapture. Aggregates were investigated in four steps: (a) geographical modelling (standardized incidence ratio (SIR) calculation), (b) analysis of the spatial distribution of incidence (Phothoff-Winttinghill's test, Global Moran's Index, Kulldorf's spatial scan statistic, Local Moran's Index), (c) classification of the level of certainty of spatial aggregates (i.e. definite cluster; probable over-incidence area; possible over-incidence area) and (d) evaluation of the robustness of the results. The standardized incidence of ALS was 2.46/100,000 PYFU (95% CI 2.31-2.63, European population as reference) based on 1199 incident cases. We identified 13 areas of spatial aggregates: one cluster (stable in robustness analysis), five probable over-incidence areas (2 stable in robustness analysis) and seven possible over-incidence areas (including 4 stable areas in robustness analysis). A cluster was identified in the Rhône-Alpes region: 100 observed vs 54.07 expected cases for 2,411,514 PYFU, SIR: 1.85 (95% CI 1.50-2.25). We report here one of the largest investigations of incidence and spatial aggregation of ALS ever performed in a western country. Using a solid methodology framework for case ascertainment and cluster analysis, we identified 13 areas that warrant further investigation.

Incidence of amyotrophic lateral sclerosis in older adults.

We investigated the age- and sex-specific incidence and survival of Medicare beneficiaries with amyotrophic lateral sclerosis (ALS) in patients 66 to 90 years of age. We identified all incident ALS cases within a population-based sample of Medicare beneficiaries in 2009 (total: 22 000 177 person-years at risk for ALS). We calculated age- and sex-specific incidence in 2009 according to multiple, progressively more stringent case definitions. Our most inclusive definition required one ALS code, whereas the most restrictive definition required at least one additional ALS code more than 6months after the first code, including one from a neurologist. We identified associated imaging studies and electrodiagnostic testing and followed all cases through the end of 2014 to determine survival. The overall incidence for our most inclusive definition was 22.84 per 100 000 person-years for men and 16.05 per 100 000 person-years for women. The overall incidence was 5.72 per 100 000 person-years for men and 3.99 per 100 000 person-years for women for our most restrictive definition. For our most inclusive definition, fewer than 39.7% of cases ever had an ALS diagnosis from a neurologist, more than 50% had an electrodiagnostic test or imaging study, and 40.1% survived less than 1 year after diagnosis, with 25.5% of these cases surviving no more than 6months. Cases not meeting the most restrictive definition were more likely than those who did meet the restrictive definition to be older, black, or Asian. The oldest and marginalized Medicare beneficiaries diagnosed with ALS are less likely to be included in epidemiological studies with restrictive definitions, but future studies will need to assess the accuracy of diagnosis.

Role of plasma phosphorylated neurofilament heavy chain (pNfH) in amyotrophic lateral sclerosis.

The phosphorylated neurofilament heavy chain (pNfH) is a promising biomarker in amyotrophic lateral sclerosis (ALS). We examined plasma pNfH concentrations in order to corroborate its role as a diagnostic and prognostic biomarker in ALS. Incident ALS cases enrolled in a population‐based registry were retrospectively selected and matched by sex and age with a cohort of healthy volunteers. Plasma pNfH levels were measured by an ELISA kit and correlated with clinical parameters. Discrimination ability of pNfH was tested using receiving operating characteristic (ROC) curves. Kaplan–Meier (KM) analysis and Cox proportional hazard models were used for survival analysis. Plasma pNfH was significantly higher in patients compared to controls. An optimal cut‐off of 39.74 pg/ml discriminated cases from controls with an elevated sensitivity and specificity. Bulbar‐onset cases had higher plasma pNfH compared to spinal onset (p = 0.0033). Furthermore, plasma pNfH positively correlated with disease progression rate (r = 0.19, p = 0.031). Baseline plasma pNfH did not influence survival in our cohort. Our findings confirmed the potential utility of plasma pNfH as a diagnostic biomarker in ALS. However, further studies with longitudinal data are needed to corroborate its prognostic value.

Incidence of amyotrophic lateral sclerosis in the United States, 2014–2016

Objective: To estimate the incidence of amyotrophic lateral sclerosis (ALS) in the United States for calendar years 2014–2016 using data from the National ALS Registry (Registry). The Registry collects data on ALS patients in the United States to better describe the epidemiology of ALS, examine risk factors such as environmental and occupational exposures, and characterize the demographics of those living with the disease. Methods: To identify adult incident cases of ALS, the Registry compiles data from three national administrative databases (maintained by the Centers for Medicare and Medicaid Services, the Veterans Health Administration, and the Veterans Benefits Administration). For cases that are not included in these databases, the Registry includes data collected from patients who voluntarily enroll via a secure web portal. Results: The Registry identified 5695 ALS cases in 2014; 6045 cases in 2015; and 4861 cases in 2016 for age-adjusted incidence rates of 1.8 (2014), 1.6 (2015), and 1.6 (2016) per 100,000 U.S. population, respectively. ALS was more common among whites, males, and persons aged 60–79 years. Conclusions: This is the first time administrative and self-reported databases have been used to describe the incidence of ALS for the United States resulting in a better estimate of disease demographics.

Comparison of the ability of the King’s and MiToS staging systems to predict disease progression and survival in amyotrophic lateral sclerosis

Background: Assessing clinical progression in amyotrophic lateral sclerosis (ALS) remains a challenge. We evaluated the validity and predictive capabilities of the King’s and Milano-Torino Staging (MiToS) systems in a cohort of patients with ALS to demonstrate their benefit in clinical practice. Methodology: A cohort study was performed by including ALS incident cases in a referral center from 2007 to 2016. The staging systems were determined at time of diagnosis and follow-up. The standardized median times to reach each stage were computed. A multi-state model in the framework of the Cox model evaluated the predictive value of measurements. The survival C-statistic was reported as a measure of prediction ability. Results: Overall, 298 incident cases were included. The King’s and MiToS systems described a progressive increase in the risk of dying with each elapsed stage. However, a lower resolution for late disease description for the King’s system was observed, and late stages overlapped for the MiToS system. Slight variations in the staging systems appeared to improve performance based on validity and prediction abilities: (i) in the King’s (C-statistic = 0.783), by adding a new stage involving the need for both gastrostomy and NIV: (ii) in the MiToS (C-statistic = 0.792), by merging stage 3 and stage 4 into a single stage 3. Conclusion: Both King’s and MiToS are valid systems but have certain limitations. Variations in the staging systems may provide a more suitable framework for describing progression and survival. Further research is needed to evaluate the variations in the staging systems.

Patterns of Language Impairment in Early Amyotrophic Lateral Sclerosis.

To investigate the incidence and nature of language change and its relationship to executive dysfunction in a population-based incident amyotrophic lateral sclerosis (ALS) sample, with the hypothesis that patterns of frontotemporal involvement in early ALS extend beyond areas of executive control to regions associated with language processing. One hundred seventeen population-based incident ALS cases without dementia and 100 controls matched by age, sex, and education were included in the study. A detailed assessment of language processing including lexical processing, word spelling, word reading, word naming, semantic processing, and syntactic/grammatical processing was undertaken. Executive domains of phonemic verbal fluency, working memory, problem-solving, cognitive flexibility, and social cognition were also evaluated. Language processing was impaired in this incident cohort of individuals with ALS, with deficits in the domains of word naming, orthographic processing, and syntactic/grammatical processing. Conversely, phonological lexical processing and semantic processing were spared. Although executive dysfunction accounted in part for impairments in grammatical and orthographic lexical processing, word spelling, reading, and naming, primary language deficits were also present. Language impairment is characteristic of ALS at early stages of the disease and can develop independently of executive dysfunction, reflecting selective patterns of frontotemporal involvement at disease onset. Language change is therefore an important component of the frontotemporal syndrome associated with ALS.

Increased risk and early onset of ALS in professional players from Italian Soccer Teams

Objective: Since the observation of several deaths from amyotrophic lateral sclerosis (ALS) among Italian professional soccer players, an association between ALS and soccer has been postulated. The objective of the study is to investigate the association between professional soccer and the risk of ALS in a large cohort of former professional soccer players with prolonged follow-up. Methods: All professional soccer players practicing in the period 1959–2000 were identified through the archives of an Italian soccer cards publisher. For each player, date and place of birth, playing role, and team history were recorded. Each player was followed since 15 years of age. Incident ALS cases were all soccer players first diagnosed during the period 1959–2018. The expected incidence rate was the number of ALS cases/100,000 person-years expected in the cohort. SIR was the ratio between observed and expected incidence rate. Results: 34 ALS cases were detected. The number of expected cases was 17.8. The SIR was 1.91 (95% CI 1.32–2.67) in the entire sample and 4.66 (95% CI 2.66–7.57) in subjects aged less than 45 years. The mean age at diagnosis was 45.0 years. Compared to the mean age of onset of ALS in the general population (65.2 years), the disease in former soccer players occurred 20.2 years earlier. Conclusions: Professional soccer players are at higher risk of developing ALS than the general population. Soccer players with ALS develop the disease at a younger than expected age.

Amyotrophic lateral sclerosis incidence following exposure to inorganic selenium in drinking water: A long-term follow-up

Some studies have reported an association between overexposure to selenium and risk of amyotrophic lateral sclerosis (ALS), a rare degenerative disease of motor neurons. From 1986 through 2015, we followed a cohort in Northern Italy that had been inadvertently consuming tap water with unusually high concentrations of inorganic hexavalent selenium from 1974 to 1985. We had previously documented an excess incidence of ALS in this cohort during 1986–1994. Here, we report extended follow-up of the cohort for an additional 21 years, encompassing 50,100 person-years of the exposed cohort and 2,233,963 person-years of the unexposed municipal cohort. We identified 7 and 112 incident ALS cases in the exposed and unexposed cohorts, respectively, yielding crude incidence rates of 14 and 5 cases per 100,000 person-years. A Poisson regression analysis, adjusting for age, sex and calendar year, produced an overall incidence rate ratio (IRR) for ALS of 2.8 (95% confidence interval (CI) 1.3, 6), with a substantially stronger IRR in 1986–1994 (8.2, 95% CI 2.7, 24.7) than in 1995–2015 (1.5, 95% CI 0.5, 4.7), and among women (5.1, 95% CI 1.8, 14.3) than men (1.7, 95% CI 0.5, 5.4). Overall, these results indicate an association between high exposure to inorganic selenium, a recognized neurotoxicant, and ALS incidence, with declining rates after cessation of exposure and stronger effects among women.

Residential exposure to ultra high frequency electromagnetic fields emitted by Global System for Mobile (GSM) antennas and amyotrophic lateral sclerosis incidence: A geo-epidemiological population-based study

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of unknown etiology. Mobile communication antennas have increased over the last few decades. Consequently, there has been a steady increase in environmental exposure to ultra high frequency electromagnetic fields (UHF-EMFs) emitted by Global System for Mobile (GSM) communication antennas, which raises concerns about possible health risks in the general population. We aimed to evaluate the relationship between residential exposure to UHF-EMFs generated by GSM antennas and the risk of ALS in general population. A geo-epidemiological population-based study was performed in Limousin (France). ALS incident cases were identified through a register (FRALim, 2000–2012 period). A model to estimate UHF-EMF exposure was developed based on the distance and the power of GSM antennas. Exposure to multiple emissions from multiple directions was considered. A non-cumulative and a cumulative model were established. A geographic information system integrated the raster model of exposure, and the residential distribution of observed and expected cases. A generalized linear model was performed to test the association. Overall, 312 ALS cases were included. We estimated exposures below 1.72 V/m in urban areas and below 1.23 V/m in rural areas for 90% of the population. A gradient effect between UHF-EMF exposure and ALS incidence was apparent with a statistically significant trend. A significant increased risk of ALS was observed between the non-exposure category and the highest exposure category, with a relative risk of 1.78 (95% CI: 1.28–2.48) in the non-cumulative model and 1.83 (95% CI: 1.32–2.54) in the cumulative model. Our results suggest a possible association between residential UHF-EMF exposure and ALS. Ecological studies are a means of generating hypotheses. Further studies are needed to clarify the potential role of EMFs on neurodegeneration.

Epidemiology of amyotrophic lateral sclerosis in Friuli-Venezia Giulia, North-Eastern Italy, 2002–2014: a retrospective population-based study

Objectives: To describe the epidemiology of Amyotrophic Lateral Sclerosis (ALS) in Friuli-Venezia Giulia (FVG) region, Italy, over a 13-year period (2002–2014), estimating ALS (a) incidence, prevalence, and clinical features; (b) mortality, also comparing Udine municipality to the rest of FVG.Methods: We conducted a retrospective population-based study. ALS incident cases were ascertained using multiple sources and validated through expert review. We calculated crude and standardized incidence rate (IR), point prevalence and mortality rate (MR), each with 95% confidence interval. Standardized incidence (SIR) and mortality (SMR) ratio were calculated to compare Udine to FVG.Results: Among 444 incident cases (50.0% men, median age 68.5 years), onset was bulbar in 30.2%, spinal in 59.9%, mixed in 9.9%; 3.6% had familial ALS. Crude and 2000 European population standardized IR was respectively 2.81 (2.56–3.09) and 2.09 (1.89–2.29) per 100,000 person-years. Standardized male-to-female incidence ratio was 1.05. IR peaked at age 65–74 years (men: 9.93, 8.04–12.32; women: 7.74, 6.18–9.67) and decreased thereafter. Prevalence was 8.36 (6.74–9.97) cases per 100,000 inhabitants on 30 June 2009 and 7.98 (6.40–9.56) on 30 June 2014. SIR was 1.20 and SMR 1.11.Conclusions: When assessed over a long period, incidence of ALS was in the range of Italian and European population-based registries and showed a consistent pattern by age and sex. IR and MR were only slightly higher in Udine vs. FVG.

The impact of percutaneous endoscopic gastrostomy on the survival of patients with amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing degenerative motor neuron disease that leads to significant muscle weakness. Patients can present with severe dysphagia and require nutritional support. While percutaneous endoscopic gastrostomy (PEG) is a standard procedure for these patients, its effect on survival is not yet clear. Therefore, we aimed to evaluate the impact of PEG placement on ALS patients survival. We retrospectively reviewed health records of ALS patients followed at a Neurological Department in the northeast region of Portugal for the 2005–2016 period. Potentially relevant clinical information was collected for survival analysis using Kaplan–Meier estimator and Mantel–Cox regression. In the studied period, 75 incident ALS cases were identified. Information regarding symptom onset was available for 62 (83%) patients, and PEG was placed after informed consent in 27 (36%) patients. The overall median survival from symptom onset was 1142 (95% CI: 866–1418) days and did not differ between PEG and non-PEG groups (Fig. 1). In the PEG group ( n = 27), 19 (70%) died by the end of the follow-up period. Overall median survival post-PEG placement was 320 (95% CI: 135–505) days. Bulbar ALS cases ( n = 18) had a median survival of 249 days while the remaining 9 Spinal cases had a median survival of 709 days (Fig. 2). Both LogRank test and Mantel–Cox regression using ALS subtype as covariate did not yield significant results regarding post-PEG survival ( P = 0.312; HR = 0.566 [95% CI: 0.185–1.730], P = 0.566; respectively). In conclusion, PEG did not impact ALS survival in our study. Post-PEG survival was also similar in both bulbar- and spinal-onset groups. However, our analysis is limited by the small sample size. Studies with more participants are required to more effectively estimate the impact of PEG in overall and subgroups ALS survival.

Pseudobulbar affect as a negative prognostic indicator in amyotrophic lateral sclerosis.

To evaluate whether the presence of pseudobulbar affect (PBA) in an early stage of the disease influences survival in a population-based incident cohort of amyotrophic lateral sclerosis (ALS). Incident ALS cases, diagnosed according to El Escorial criteria, were enrolled from a prospective population-based registry in Puglia, Southern Italy. The Center for Neurologic Study-Lability Scale (CNS-LS), a self-administered questionnaire, was used to evaluate PBA. Total scores range from 7 to 35. A score ≥13 was used to identify PBA. Cox proportional hazard models were used for survival analysis. The modified C-statistic for censored survival data was used for models' discrimination. RECursive Partitioning and AMalgamation (RECPAM) analysis was used to identify subgroups of patients with different patterns of risk, depending on baseline characteristics. We enrolled 94 sporadic ALS, median age of 64years (range: 26-80). At the censoring date, 65 of 94 (69.2%), 39 of 60 (65.0%), and 26 of 34 (76.5%) patients reached the outcome (tracheotomy/death), in the whole, non-PBA and in the PBA groups, respectively. Kaplan-Meier survival curves for the two subgroups were not significantly different (log-rank test: 1.3, P=.25). The discrimination ability of a multivariable model with demographic and clinical variables of interest was not improved by adding PBA. In the RECPAM analysis, ALSFRSr and the total score of CNS-LS scale (</≥10) were the most important variables for differentiating all risk categories. These preliminary results underlie that the presence of PBA at entry negatively influences survival in a specific subgroup of patients with ALS characterized by less functional impairment.

Risk factors in Swedish young men for amyotrophic lateral sclerosis in adulthood

Recent research suggests that the incidence of amyotrophic lateral sclerosis (ALS) may be on the rise. Since ALS becomes predominant in later life, most studies on causal factors are conducted in middle-aged or older populations where potentially important influences from early life can usually not be adequately captured. We aimed to investigate predictors in young Swedish men for ALS in adulthood. Therefore, we performed a prospective cohort study of young men (aged 16–25, n = 1,819,817) who enlisted 1968–2005 and took part in comprehensive conscription examinations. Incident cases of ALS (n = 526) during up to 46 years of follow-up were identified in the National Hospital Register and Swedish Cause of Death Register. Those who developed ALS had lower BMI (body mass index) at conscription than their peers (p = 0.03). The risk of ALS during follow-up was calculated with Cox proportional hazards models. No associations were found with physical fitness, erythrocyte sedimentation rate, or non-psychotic mental disorders. Low overall muscle strength compared to high overall muscle strength [hazard ratio (HR) 1.36; 95% confidence interval (CI) 1.01–1.83] and low BMI (a one-unit increase HR 0.96; 95% CI 0.93–0.99) and lower erythrocyte volume fraction (a one-unit increase HR 0.96; 95% CI 0.92–0.998) were the statistically significant predictors for ALS in adjusted models. These findings provide novel epidemiologic evidence of a prospective association between low overall muscle strength and erythrocyte volume fraction in young men and ALS risk.

Characteristics and Prognosis of Oldest Old Subjects with Amyotrophic Lateral Sclerosis

Background: Amyotrophic Lateral Sclerosis (ALS) is an age-related neurodegenerative disease with unclear characteristics and prognosis in the oldest old (80 years and over). The aim of this study was to compare the oldest old and younger ALS patients in terms of clinical and socio-demographic characteristics, and prognosis. Methods: ALS incident cases from the register of ALS in Limousin (FRALim), diagnosed between January 2000 and July 2013, were included. Descriptive and comparative analyses by age group were carried out. For time to event univariate analysis, Kaplan-Meier estimator and log rank test were used. Univariate and multivariate survival analyses were carried out with Cox's proportional hazard model. Results: Out of 322 patients, 50 (15.5%) were aged 80 or over (“oldest old” ALS) at the time of diagnosis. Among them, the male:female gender-ratio was 1.27, and 32.6% had a bulbar onset (not different from subjects aged less than 80 years). With increasing age, there was a worsening of the clinical state of the patients at time of diagnosis in terms of weight loss, forced vital capacity, ALSFRS-R and manual muscular testing. Access to ALS referral centres decreased with age, and the use of riluzole tended to be lower in the oldest old group. The median survival of oldest old patients appeared to be 10 months shorter than that of subjects aged less than 80 years (7.4 vs. 17.4 months). Conclusion: The survival of oldest old ALS patients is particularly short. It relates to prognostic features at baseline and to an independent effect of advanced age.

Exploring the diagnosis delay and ALS functional impairment at diagnosis as relevant criteria for clinical trial enrolment*

Objectives were: i) to describe the phenotypic heterogeneity of incident amyotrophic lateral sclerosis (ALS) patients diagnosed in 2012 in French ALS centres; ii) to look at the associations between ALSFRS-R score and ALSFRS-R slope (ΔFS) at time of diagnosis with diagnosis delay, ALS phenotypes and Airlie House diagnosis criteria (AHDC); iii) to describe the rate of progression on ΔFS, according to diagnosis delay. Methods: Incident ALS cases diagnosed in French ALS centres were included. The rate of progression was evaluated as follows: ΔFS = (48 – ALSFRS-R at time of diagnosis)/duration from onset to diagnosis (months). Fast and slow progressors were defined by ΔFS >1 and <0.5, respectively. Results: At time of diagnosis, 476 patients were classified into eight phenotypes: bulbar (33.0%), spinal lumbar (28.2%), spinal cervical (23.1%), flail leg (4.4%), ALS/FTD (4.2%), possible flail arm (4.0%), respiratory (2.1%), dropped-head (1.0%). Median ΔFS (n = 358/476) was 1.0 [0.5–2.0]. ΔFS was associated with AHDC (p = 0.009), but not with clinical phenotype (p = 0.902). Stratification on diagnosis delay (<12 months or ≥18 months) allowed to differentiate fast progressors from slow progressors. Conclusion: At time of inclusion in therapeutic trial closed to diagnosis, ΔFS or diagnosis delay may discriminate the rate of progression.

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.