Age-period-cohort analysis of trends in amyotrophic lateral sclerosis incidence

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease with an unknown cause. Studies have reported that the incidence rate of ALS might be changing. As ALS is an age related disease, crude incidence could increase as population structure changes and overall life expectancy improves. Age-period-cohort (APC) models are frequently used to investigate trends in demographic rates such as incidence. Age-specific incidence rate for ALS from 1996 to 2014 were taken from a population-based ALS register in Ireland. To circumvent the well-known identifiability issue in APC models, we apply the method of Partial Least Squares Regression to separate the effects of Age, Period and Cohort on ALS incidence over time. This APC analysis shows no cohort effect and the initial signs of a period effect; increasing incidence of ALS in the most recently diagnosed group. As further years of data accrue to the Irish register it will become clear if this effect emerges as a strong trend in the incidence of ALS in Ireland and replication of these analyses in other populations will show if our findings on temporal patterns in ALS incidence are shared elsewhere

FATTORI AMBIENTALI DI RISCHIO DELLA SCLEROSI LATERALE AMIOTROFICA: UNO STUDIO CASO-CONTROLLO DI POPOLAZIONE BASATO SU QUESTIONARI ANAMNESTICI

Introduzione: La sclerosi laterale amiotrofica (SLA) \ue8 una malattia neurodegenerativa progressiva la cui eziologia \ue8 ancora sostanzialmente ignota, ad eccezione di alcune rare forme di origine genetica. Numerosi suoi possibili fattori di rischio ambientali sono attualmente oggetto di indagine. Metodi: Abbiamo realizzato uno studio caso-controllo di popolazione nelle province di Modena, Reggio Emilia e Catania, al fine di valutare il ruolo eziologico di alcuni possibili fattori ambientali di rischio. Abbiamo somministrato per via postale un questionario finalizzato alla raccolta di informazioni anamnestiche ai casi di SLA diagnosticati nel periodo 2008-2011 e ad un gruppo di controlli di popolazione appaiati per alcune variabili confondenti. Risultati: Il 35% (n=162, 61 casi e 101 controlli) dei questionari inviati \ue8 stato compilato e restituito. In un modello di regressione logistica, i pregressi traumatismi soggetti a valutazione medica sono risultati associati ad un odds ratio (OR) di SLA pari a 1.20 (intervalli di confidenza al 95% (IC 95%) 0.62-2.30), con un valore pi\uf9 elevato (3.04, 1.22-7.55) per traumi alla testa. Gli shock elettrici hanno evidenziato un OR di 2.25 (0.66-7.63). Con riferimento alla storia occupazionale, l\u2019OR associata all\u2019attivit\ue0 lavorativa in ambito agricolo o come saldatore \ue8 risultata rispettivamente pari a 2.44 (1.02-5.79) e 1.25 (0.27-5.80). Aver vissuto in zona agricola \ue8 stato associato ad un lieve aumento del rischio (OR=1.67, 0.87-3.20), a differenza della pratica sportiva e specificatamente del calcio (OR 0.84 (0.46-1.51) e 1.04 (0.44-2.47). Conclusioni: I risultati ottenuti appaiono di potenziale interesse eziologico e meritevoli di ulteriori approfondimenti, pur tenendo conto del rischio di distorsioni di selezione del campione o di informazione, specie nei pazienti

Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials

OBJECTIVE: To assess whether genetic subgroups in recent amyotrophic lateral sclerosis (ALS) trials responded to treatment with lithium carbonate, but that the treatment effect was lost in a large cohort of nonresponders. METHODS: Individual participant data were obtained from 3 randomized trials investigating the efficacy of lithium carbonate. We matched clinical data with data regarding the UNC13A and C9orf72 genotype. Our primary outcome was survival at 12 months. On an exploratory basis, we assessed whether the effect of lithium depended on the genotype. RESULTS: Clinical data were available for 518 of the 606 participants. Overall, treatment with lithium carbonate did not improve 12-month survival (hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.7-1.4; p = 0.96). Both the UNC13A and C9orf72 genotype were independent predictors of survival (HR 2.4, 95% CI 1.3-4.3; p = 0.006 and HR 2.5, 95% CI 1.1-5.2; p = 0.032, respectively). The effect of lithium was different for UNC13A carriers (p = 0.027), but not for C9orf72 carriers (p = 0.22). The 12-month survival probability for UNC13A carriers treated with lithium carbonate improved from 40.1% (95% CI 23.2-69.1) to 69.7% (95% CI 50.4-96.3). CONCLUSIONS: This study incorporated genetic data into past ALS trials to determine treatment effects in a genetic post hoc analysis. Our results suggest that we should reorient our strategies toward finding treatments for ALS, start focusing on genotype-targeted treatments, and standardize genotyping in order to optimize randomization and analysis for future clinical trials

Erythropoietin in amyotrophic lateral sclerosis: a multicentre, randomised, double blind, placebo controlled, phase III study

OBJECTIVE: To assess the efficacy of recombinant human erythropoietin (rhEPO) in amyotrophic lateral sclerosis (ALS). METHODS: Patients with probable laboratory-supported, probable or definite ALS were enrolled by 25 Italian centres and randomly assigned (1:1) to receive intravenous rhEPO 40,000 IU or placebo fortnightly as add-on treatment to riluzole 100 mg daily for 12 months. The primary composite outcome was survival, tracheotomy or >23 h non-invasive ventilation (NIV). Secondary outcomes were ALSFRS-R, slow vital capacity (sVC) and quality of life (ALSAQ-40) decline. Tolerability was evaluated analysing adverse events (AEs) causing withdrawal. The randomisation sequence was computer-generated by blocks, stratified by centre, disease severity (ALSFRS-R cut-off score of 33) and onset (spinal or bulbar). The main outcome analysis was performed in all randomised patients and by intention-to-treat for the entire population and patients stratified by severity and onset. The study is registered, EudraCT 2009-016066-91. RESULTS: We randomly assigned 208 patients, of whom 5 (1 rhEPO and 4 placebo) withdrew consent and 3 (placebo) became ineligible (retinal thrombosis, respiratory insufficiency, SOD1 mutation) before receiving treatment; 103 receiving rhEPO and 97 placebo were eligible for analysis. At 12 months, the annualised rate of death (rhEPO 0.11, 95% CI 0.06 to 0.20; placebo: 0.08, CI 0.04 to 0.17), tracheotomy or >23 h NIV (rhEPO 0.16, CI 0.10 to 0.27; placebo 0.18, CI 0.11 to 0.30) did not differ between groups, also after stratification by onset and ALSFRS-R at baseline. Withdrawal due to AE was 16.5% in rhEPO and 8.3% in placebo. No differences were found for secondary outcomes. CONCLUSIONS: RhEPO 40,000 IU fortnightly did not change the course of ALS