ObjectiveTo assess the determinants of amyotrophic lateral sclerosis (ALS) phenotypes in a population-based cohort.MethodsThe study population included 2,839 patients with ALS diagnosed in Piemonte, Italy (1995–2015). Patients were classified according to motor (classic, bulbar, flail arm, flail leg, predominantly upper motor neuron [PUMN], respiratory) and cognitive phenotypes (normal, ALS with cognitive impairment [ALSci], ALS with behavioral impairment [ALSbi], ALSci and ALSbi combined [ALScbi], ALS–frontotemporal dementia [FTD]). Binary logistic regression analysis was adjusted for sex, age, and genetics.ResultsBulbar phenotype correlated with older age (p < 0.0001), women were more affected than men at increasing age (p < 0.0001), classic with younger age (p = 0.029), men were more affected than women at increasing age (p < 0.0001), PUMN with younger age (p < 0.0001), flail arm with male sex (p < 0.0001) and younger age (p = 0.04), flail leg with male sex with increasing age (p = 0.008), and respiratory with male sex (p < 0.0001). C9orf72 expansions correlated with bulbar phenotype (p < 0.0001), and were less frequent in PUMN (p = 0.041); SOD1 mutations correlated with flail leg phenotype (p < 0.0001), and were less frequent in bulbar (p < 0.0001). ALS-FTD correlated with C9orf72 (p < 0.0001) and bulbar phenotype (p = 0.008), ALScbi with PUMN (p = 0.014), and ALSci with older age (p = 0.008).ConclusionsOur data suggest that the spatial–temporal combination of motor and cognitive events leading to the onset and progression of ALS is characterized by a differential susceptibility to the pathologic process of motor and prefrontal cortices and lower motor neurons, and is influenced by age, sex, and gene variants. The identification of those factors that regulate ALS phenotype will allow us to reclassify patients into pathologically homogenous subgroups, responsive to targeted personalized therapies.

ObjectivesTo assess the role of body mass index (BMI) and of the rate of weight loss as prognostic factors in amyotrophic lateral sclerosis (ALS) and to explore the clinical correlates of weight loss in the early phases of the disease.MethodsThe study cohort included all ALS patients in Piemonte/Valle d’Aosta in the 2007–2011 period. Overall survival and the probability of death/tracheostomy at 18 months (logistic regression model) were calculated.ResultsOf the 712 patients, 620 (87.1%) were included in the study. Patients ’ survival was related to the mean monthly percentage of weight loss at diagnosis (p<0.0001), but not to pre-morbid BMI or BMI at diagnosis. Spinal onset patients with dysphagia at diagnosis had a median survival similar to bulbar onset patients. About 20% of spinal onset patients without dysphagia at diagnosis had severe weight loss and initial respiratory impairment, and had a median survival time similar to bulbar onset patients.ConclusionsThe rate of weight loss from onset to diagnosis was found to be a strong and independent prognostic factor in ALS. Weight loss was mainly due to the reduction of nutritional intake related to dysphagia, but a subgroup of spinal onset patients without dysphagia at diagnosis had a severe weight loss and an outcome similar to bulbar patients. According to our findings, we recommend that in clinical trials patients should be stratified according to the presence of dysphagia at the time of enrolment and not by site of onset of symptoms.

Background and purpose: The literature on the association between diabetes and amyotrophic lateral sclerosis (ALS) consists of a limited number of studies. This cohort study was developed in order to assess the role of diabetes on the risk of developing ALS. Methods: The study population was represented by all residents in Turin (Italy) at the beginning of 1996 who participated in the 1991 census, over 14 years of age (n = 727 977) and followed up for ALS occurrence from 1998 to 2014. Presence of diabetes at baseline or during follow-up was ascertained through two Piedmont regional sources: the Diabetes Registry and the Anatomical Therapeutic Chemical Drug Prescription Archive. The risk of ALS was estimated using the Piedmont and Valle d'Aosta ALS Registry (PARALS). The association of diabetes, treated as a time-dependent variable, with ALS onset was estimated through Cox proportional hazard regression models adjusted for age, gender, education and marital status. Results: During follow-up, 397 subjects developed ALS, 24 of whom were already diabetic before ALS onset. Diabetes was associated with a significantly decreased risk of ALS [hazard ratio, 0.30 (95% confidence interval, 0.19-0.45)] without differences in risk by gender, age class or ALS phenotype. Conclusion:The results support the protective role of diabetes toward ALS.

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This large case-control study across 3 different countries has demonstrated an association between exogenous estrogens and progestogens and reduced odds of ALS in women. These results are at variance with previous findings, which may be partly explained by differential regulatory, social, and cultural attitudes toward pregnancy, birth control, and HRT across the countries included. Our results indicate that hormonal factors may be important etiologic factors in ALS; however, a full understanding requires further investigation.

We provide new class I evidence for a positive association between PA and risk of ALS in a large multicentre study using harmonised methodology to objectively quantify PA levels, with some suggestions for population differences.

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