The average survival of patients with amyotrophic lateral sclerosis (ALS) ranges from 2 to 5 years from symptom onset. However, it remains unclear whether this estimate has improved over time. The objective of this study was to analyze the survival trend of a large population-based cohort of patients with ALS over a 24-year period. Patients from the Piemonte and Valle d'Aosta registry for ALS (PARALS) were categorized into the first (1995–2002), second (2003–2010), or third (2011–2018) epoch based on their diagnosis date. Survival was defined as the time from diagnosis to death, tracheostomy, or censoring date. A Cox proportional hazard model was developed with diagnosis epoch as the primary variable of interest, adjusted for sex, site of onset, age at onset, diagnostic delay, forced vital capacity at diagnosis, Δbody mass index from onset to diagnosis, noninvasive mechanical ventilation use, gastrostomy use, and site of follow-up. A subset analysis comparing the 2007–2012 and 2013–2018 cohorts was conducted, incorporating riluzole prescription, genetics, and preslope category as additional covariates. A total of 3,134 patients were included, evenly distributed across the 3 epochs (990, 1,023, and 1,121, respectively). The median survival remained stable during the first and second epoch (18.6 months vs 18.3 months) but improved during the third epoch (20.1 months; p = 0.0041), with a hazard ratio (HR) of 0.76 (95% CI 0.67–0.87, p = 0.00003). In the subset analysis, the most recent epoch (2013–2018) showed a continued survival advantage (HR 0.77, 95% CI 0.65–0.90). Of interest, the survival benefit was only evident among intermediate progressors (HR 0.60, 95% CI 0.45–0.80). In the PARALS, ALS survival increased over time. In a subset analysis, the beneficial effect of the epoch was only evident among intermediate progressors. The improvement in multidisciplinary care provided by tertiary centers may be one possible explanation for this finding, although further dedicated studies are needed to confirm this hypothesis.

Background and purpose: Social cognition (SC) deficits are included in amyotrophic lateral sclerosis (ALS)–frontotemporal spectrum disorder revised diagnostic criteria. However, SC performance among ALS patients is heterogeneous due to the phenotypic variability of the disease and the wide range of neuropsychological tools employed. The aim of the present study was to assess facial emotion recognition and theory of mind in ALS patients compared to controls and to evaluate correlations with the other cognitive domains and degree of motor impairment.Methods: Eighty‐three patients and 42 controls underwent a cognitive evaluation and SC assessment through the Ekman 60 Faces Test (EK‐60F), the Reading the Mind in the Eyes Test–36 Faces (RMET‐36), and the Story‐Based Empathy Task (SET).Results: ALS patients showed significantly worse performance compared to controls in EK‐60F global score (p < 0.001), recognition of disgust (p = 0.032), anger (p = 0.038), fear (p < 0.001), and sadness (p < 0.001); RMET‐36 (p < 0.001), and SET global score (p < 0.001). Also, cognitively normal patients (ALS‐CN) showed significantly worse performance compared to controls in EK‐60F global score (p < 0.001), recognition of fear (p = 0.002), sadness (p < 0.001), and SET (p < 0.001). RMET‐36 showed a significant correlation with the Category Fluency Test (p = 0.041). SC tests showed no correlation with motor impairment expressed by Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised.Conclusions: ALS patients, also when categorized as ALS‐CN, may show impairment in SC performance. The frequent identification of early SC impairment in ALS patients supports the need to routinely assess SC for its impact on end‐of‐life decisions and its potential influence on patients' quality of life.

Objective. Despite recent advances, it is not clear whether the various genes/genetic variants related to ALS interact in modifying patients phenotype. The aim of this study was to determine if the co-presence of genetic variants related to ALS has interactive effects on the course of the disease. Methods. The study population includes 1,245 ALS patients identified through the Piemonte Register for ALS between 2007 and 2016 and not carrying SOD1, TARDBP and FUS pathogenic variants. Controls were 766 Italian subjects age-, sex-, and geographically-matched to cases. We considered UNC13A (rs12608932), CAMTA1 (rs2412208), SLC11A2 (rs407135) and ZNF512B (rs2275294) variants, as well as ATXN2 polyQ intermediate repeats (≥31) and C9orf72 GGGGCC intronic expansions( ≥30). Results. The median survival time of the whole cohort was 2.67 years (IQR 1.67-5.25). In univariate analysis only C9orf72 (2.51 years, IQR 1.74-3.82; p=0.016), ATXN2 (1.82 years, IQR 1.08-2.33; p<0.001) and UNC13A^C/C (2.3 years, IQR 1.3-3.9; p<0.001) significantly reduced survival. In Cox multivariable analysis, also CAMTA1 emerged to be independently related to survival (HR 1.13, 95% c.i. 1.001-1.30, p=0.048). The co-presence of two detrimental alleles/expansions was correlated with shorter survival. In particular, the median survival of patients with CAMTA1^G/G+G/T and UNC13A^C/C alleles was 1.67 years (1.16-3.08) years compared to 2.75 years (1.67-5.26) of the patients not carrying these variants (p<0.001); the survival of patients with CAMTA1^G/G+G/T alleles and ATXN2^≥31 intermediate polyQ repeats was 1.75 years (0.84-2.18) (p<0.001); the survival of patients with ATXN2^≥31 polyQ repeats and UNC13A^C/C allele was 1.33 years (0.84-1.75) (p<0.001); the survival of patients with C9ORF72^≥30 and UNC13A^C/C allele was 1.66 years (1.41-2.16). Each pair of detrimental alleles/expansions was associated to specific clinical phenotypes. Conclusions. We showed that gene variants acting as modifiers of ALS survival or phenotype can act on their own or in unison. Overall, 54% of patients carried at least one detrimental common variant or repeat expansion, emphasizing the clinical impact of our findings. In addition, the identification of the interactive effects of modifier genes represents a crucial clue for explaining ALS clinical heterogeneity and should be considered when designing and interpreting clinical trials results.

Objective: Noninvasive mechanical ventilation (NIMV) improves amyotrophic lateral sclerosis (ALS) quality of life and survival. However, data about its effect on disease progression are still lacking. Here, we test whether NIMV use changed the rate of functional decline among ALS patients.Methods: In this retrospective observational study, we included 448 ALS patients followed up at the ALS Center in Turin, Italy, who underwent NIMV during the disease course. The primary outcome was the change in functional decline after NIMV initiation adjusting for covariates. Functional decline was based on the nonrespiratory items of the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS‐R).Results: NIMV initiation resulted in a slower functional decline (mean improvement = 0.16 points per month, 95% confidence interval = 0.12–0.19, p < 0.001), with consistent effects observed across various demographic factors, including sex, age at diagnosis, and disease duration before NIMV initiation. This finding was replicated using the PRO‐ACT (Pooled Resource Open‐Access ALS Clinical Trials) dataset. The favorable impact of NIMV on ALSFRS‐R progression was evident independently of disease stages. Notably, NIMV benefits were not dose‐dependent but were particularly prominent for nighttime respiratory support.Interpretation: NIMV significantly influences the rate of motor progression in ALS, and this effect is not determined by the nonlinearity of ALSFRS‐R trajectory. The functional decline slowed following NIMV initiation, independently of the site of disease onset or disease severity at the time of NIMV initiation. Our findings underscore the importance of timely NIMV initiation for all ALS patients and highlight the need to consider NIMV‐induced slowing of disease progression when evaluating clinical trial outcomes. ANN NEUROL 2024;95:817–822

Background and Objectives To characterize the clinical and cognitive behavioral phenotype and brain ¹⁸F-2-fluoro-2-deoxy-d-glucose-PET (¹⁸F-FDG-PET) metabolism of patients with amyotrophic lateral sclerosis (ALS) carrying the rs12608932 variant of the UNC13A gene. Methods The study population included 1,409 patients with ALS without C9orf72, SOD1, TARDBP, and FUS mutations identified through a prospective epidemiologic ALS register. Control participants included 1,012 geographically matched, age-matched, and sex-matched participants. Clinical and cognitive differences between patients carrying the C/C rs12608932 genotype and those carrying the A/A + A/C genotype were assessed. A subset of patients underwent ¹⁸F-FDG-PET. Results The C/C genotype was associated with an increased risk of ALS (odds ratio: 1.54, 95% confidence interval 1.18–2.01, p = 0.001). Patients with the C/C genotype were older, had more frequent bulbar onset, and manifested a higher rate of weight loss. In addition, they showed significantly reduced performance in the letter fluency test, fluency domain of Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and story-based empathy task (reflecting social cognition). Patients with the C/C genotype had a shorter survival (median survival time, C/C 2.25 years, interquartile range [IQR] 1.33–3.92; A/A + C/C: 2.90 years, IQR 1.74–5.41; p = 0.0001). In Cox multivariable analysis, C/C genotype resulted to be an independent prognostic factor. Finally, patients with a C/C genotype had a specific pattern of hypometabolism on brain ¹⁸F-FDG-PET extending to frontal and precentral areas of the right hemisphere. Discussion C/C rs12608932 genotype of UNC13A is associated with a specific motor and cognitive/behavioral phenotype, which reflects on ¹⁸F-FDG-PET findings. Our observations highlight the importance of adding the rs12608932 variant in UNC13A to the ALS genetic panel to refine the individual prognostic prediction and reduce heterogeneity in clinical trials.

Background Social cognition (SC) deficits are included in the amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTDS) revised diagnostic criteria. However, the impact of SC assessment on cognitive classification and the cognitive–behavioural correlates of SC remain unclear. This cross-sectional study aimed to assess the impact of SC assessment on ALS-FTDS categorisation and explore the relationship of SC with executive functions (EF) and behaviour changes in a cohort of ALS patients. Methods 121 patients and 56 healthy controls from the Turin ALS Centre underwent cognitive/behavioural testing, including the SC subdomains of facial emotion recognition, and cognitive and affective theory of mind (ToM). Results Patients performed significantly worse than controls in all SC explored domains, and 45% of patients exhibited a deficit in at least one SC test, dissociated from the presence of EF deficits. In 13% of cases, the SC deficit was isolated and subclinical. SC assessment contributed to the attribution of cognitive impairment in 10% of patients. Through a statistical clustering approach, we found that ToM only partially overlaps with EF while behaviour changes are associated with emotional disorders (anxiety and depression). Conclusions SC is overall independent of EF in ALS, with ToM only partially associated with specific EF measures, and behaviour changes associated with emotional disorders. The influence of SC on cognitive categorisation and the frequent identification of a subclinical SC impairment have implications in a clinical setting, considering the substantial impact of cognitive impairment on disease burden and therapeutic choices.