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ObjectiveTo detect the clinical characteristics of patients with amyotrophic lateral sclerosis (ALS) carrying an intermediateATXN2polyQ number of repeats in a large population-based series of Italian patients with ALS.MethodsThe study population includes 1330 patients with ALS identified through the Piemonte and Valle d’Aosta Register for ALS, diagnosed between 2007 and 2019 and not carryingC9orf72, SOD1, TARDBPandFUSmutations. Controls were 1274 age, sex and geographically matched Italian subjects, identified through patients’ general practitioners.ResultsWe found 42 cases and 4 controls with≥31 polyQ repeats, corresponding to an estimated OR of 10.4 (95% CI 3.3 to 29.0). Patients with≥31 polyQ repeats (ATXN2+) compared with those without repeat expansion (ATXN2−) had more frequently a spinal onset (p=0.05), a shorter diagnostic delay (p=0.004), a faster rate of ALSFRS-R progression (p=0.004) and King’s progression (p=0.004), and comorbid frontotemporal dementia (7 (28.0%) vs 121 (13.4%), p=0.037). ATXN2+ patients had a 1-year shorter survival (ATXN2+ patients 1.82 years, 95% CI 1.08 to 2.51; ATXN2− 2.84 years, 95% CI 1.67 to 5.58, p=0.0001).ATXN2polyQ intermediate repeats was independently related to a worse outcome in Cox multivariable analysis (p=0.006).ConclusionsIn our population-based cohort, ATXN2+ patients with ALS have a distinctive phenotype, characterised by a more rapid disease course and a shorter survival. In addition, ATXN2+ patients have a more severe impairment of cognitive functions. These findings have relevant implications on clinical practice, including the possibility of refining the individual prognostic prediction and improving the design of ALS clinical trials, in particular as regards as those targeted explicitly toATXN2.

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive degenerative disease of upper and lower motor neurons. Approximately 15% of patients display clinical features consistent with frontotemporal dementia (FTD) and 35% display milder degrees of cognitive and behavioural impairment at some stage during their illness.1 Several genes have been reported to cause both ALS and FTD. Nevertheless, it remains unclear why some patients with ALS develop cognitive impairment, while other cases, often within the same family, remain unaffected. The GBA gene (OMIM *606463) encodes glucocerebrosidase (GCase), a lysosomal enzyme that converts glucocerebroside into glucose and ceramide. Heterozygous GBA mutations increase the risk of Parkinson’s disease (PD) and the risk of cognitive impairment in patients with PD.2 It is increasingly recognised that variants in genes causing Mendelian neurodegenerative diseases may exhibit pleiotropic effects and impact the phenotypic heterogeneity of those disorders. Moreover, lysosomal dysfunction has recently been associated with both Dementia with Lewy Bodies and FTD spectrum (online supplemental table 1). Based on this, we postulated that GBA variants may influence the cognitive status of patients with ALS. ### Supplementary data [jnnp-2021-327426supp001.pdf] We examined the GBA variants’ association with the risk of cognitive impairment in 751 patients with ALS from the population-based Piemonte and Valle d’Aosta Register for ALS that had undergone both a detailed neuropsychological evaluation and a whole-genome sequencing screening.3 Patients were classified as ALS with normal cognitive function (ALS-CN), ALS-FTD and ALS with intermediate cognitive deficits. The characteristics of the study population and a detailed description of neuropsychological testing and genetic screening are reported in online supplementarl materials in the Methods section. A mutational screening of GBA exonic variants was performed and their frequencies were compared with an internal control cohort (see online supplemental methods, Subjects). To assess whether pathogenic rare variants (minor allele frequency

ObjectiveTo identify the metabolic changes related to the various levels of cognitive deficits in amyotrophic lateral sclerosis (ALS) using 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG-PET) imaging.Methods274 ALS patients underwent neuropsychological assessment and brain 18F-FDG-PET at diagnosis. According to the criteria published in 2017, cognitive status was classified as ALS with normal cognition (ALS-Cn, n=132), ALS with behavioural impairment (ALS-Bi, n=66), ALS with cognitive impairment (ALS-Ci, n=30), ALS with cognitive and behavioural impairment (ALS-Cbi, n=26), ALS with frontotemporal dementia (ALS–FTD, n=20). We compared each group displaying some degree of cognitive and/or behavioural impairment to ALS-Cn patients, including age at PET, sex and ALS Functional Rating Scale-Revised as covariates.ResultsWe identified frontal lobe relative hypometabolism in cognitively impaired patients that resulted more extensive and significant across the continuum from ALS-Ci, through ALS-Cbi, to ALS–FTD. ALS–FTD patients also showed cerebellar relative hypermetabolism. ALS-Bi patients did not show any difference compared with ALS-Cn.ConclusionsThese data support the concept that patients with cognitive impairment have a more widespread neurodegenerative process compared with patients with a pure motor disease: the more severe the cognitive impairment, the more diffuse the metabolic changes. Otherwise, metabolic changes related to pure behavioural impairment need further characterisation.

Since its first description by Charcot, amyotrophic lateral sclerosis (ALS) has been classified as a single neurodegenerative disease involving motor neurons. More recently, however, it has become clear that ALS is pleiotropic and its phenotype could vary depending on several factors: age of onset, prevalent damage to the upper (UMN) or the lower motor neuron, body region mostly affected, progression rate and presence of non-motor symptoms, the most frequent being cognitive impairment.1 As a consequence, different phenotypes have been described.2 It remains unclear whether these presentations should be considered as distinct clinical entities or as variants of the same disease.3 More importantly, we do not know if different aetiologies justify this variability.3 Despite these uncertainties, we approach clinical trials by administering the same treatment to all patients with ALS.3 Spatial epidemiology could give some clues on aetiology by identifying clusters and subsequently seeking for causative genetic or environmental factors. Previously, we analysed the spatial distribution of a large ALS cohort in Northwestern Italy. Patients resulted to be homogeneously distributed, suggesting either that a single environmental factor was evenly distributed or that multiple factors acted on distinct subgroups, the latter being the more likely.4 Moving from the hypothesis that aetiology could vary according to phenotypes, here we performed a spatial analysis of ALS cases stratified according to their clinical presentation. Data from the Piemonte and Valle d’Aosta ALS Register were used.4 All patients with ALS diagnosed between 2007 and 2014 and who were resident in Piemonte at the time of diagnosis were included. The cluster analysis was conducted considering municipalities; …

There is still a lack of consensus among different guidelines about the right timing for starting non-invasive mechanical ventilation (NIMV) in amyotrophic lateral sclerosis (ALS).1–3 The importance of spirometry as a reliable prognostic factor in ALS has been widely recognised; conversely, very few studies investigated the role of arterial blood gas analysis (ABG). With respiratory failure being the main cause of death in ALS, we aimed at investigating the role of ABG as proxy for pulmonary function tests (PFTs) in a large cohort of patients with ALS, identifying the best cut-off values for forced vital capacity (FVC%), carbon dioxide (pCO2), carbonate (HCO3-) and standard base excess (SBE) to predict NIMV starting and survival. We included 488 patients with concomitant ABGs, PFTs and Amyotrophic Lateral Sclerosis Functional Rating Scale - revised (ALSFRS-r) score, followed up in the Turin ALS Center, resident in Piemonte and Valle d’Aosta, diagnosed between 2000 and 2015, excluding patients with severe pulmonary and kidney comorbidities. Descriptive statistic of the population is shown in the online supplementary material 1. Two-hundred and seventy-four patients (56.1%) underwent NIMV. Median time between ABG/PFT and NIMV initiation was 5.0 months (IQR 1.0–12.0). NIMV was started at a median FVC% value of 57.4% (IQR 44.2–73.6). Median overall survival after NIMV initiation was 225 days (IQR 104–491). Patients who did not undergo NIMV (n=214) were significantly older (68.6 years vs 64.9 years, p

IntroductionAmyotrophic lateral sclerosis (ALS) is a fatal progressive neurological disorder characterised by a selective degeneration of motor neurons (MNs). Stem cell transplantation is considered as a promising strategy in neurological disorders therapy and the possibility of inducing bone marrow cells (BMCs) to circulate in the peripheral blood is suggested to investigate stem cells migration in degenerated ALS nerve tissues where potentially repair MN damage. Granulocyte-colony stimulating factor (G-CSF) is a growth factor which stimulates haematopoietic progenitor cells, mobilises BMCs into injured brain and it is itself a neurotrophic factor for MN. G-CSF safety in humans has been demonstrated and many observations suggest that it may affect neural cells. Therefore, we decided to use G-CSF to mobilise BMCs into the peripheral circulation in patients with ALS, planning a clinical trial to evaluate the effect of G-CSF administration in ALS patients compared with placebo.Methods and analysisSTEMALS-II is a phase II multicentre, randomised double-blind, placebo-controlled, parallel group clinical trial on G-CSF (filgrastim) and mannitol in ALS patients. Specifically, we investigate safety, tolerability and efficacy of four repeated courses of intravenous G-CSF and mannitol administered in 76 ALS patients in comparison with placebo (indistinguishable glucose solution 5%). We determine increase of G-CSF levels in serum and cerebrospinal fluid as CD34+cells and leucocyte count after treatment; reduction in ALS Functional Rating Scale-Revised Score, forced vital capacity, Scale for Testing Muscle Strength Score and quality of life; the adverse events/reactions during the treatment; changes in neuroinflammation biomarkers before and after treatment.Ethics and disseminationThe study protocol was approved by the Ethics Committee of Azienda Ospedaliera Universitaria ‘Città della Salute e della Scienza’, Torino, Italy. Results will be presented during scientific symposia or published in scientific journals.Trial registration numberEudract 2014-002228-28.

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease causing progressive muscle weakness and wasting. Death usually occurs within 3–5 years from respiratory failure. Approximately 10% of cases are familial (fALS).The frequency of SOD1 gene mutations in patients with fALS varies among populations, from 0% in Ireland to 13.6% in Italy and 23.5% in Scandinavia.1 SOD1 encodes for the Cu/Zn Superoxide Dismutase 1. Mutations are usually autosomal dominant, but the p.D90A and the p.D96N may be autosomal recessive.2 Performing the genetic screening of an Italian fALS series, we found a novel c.442g>t heterozygous missense mutation of SOD1 gene leading to a substitution of cysteine for glycine (p.G147C). Such mutation was absent in healthy controls (n=130). The patient provided written informed consent. The index case displayed progressive weakness and wasting of both hands when he was 52 years old. One year after the onset he also exhibited tongue hypotrophy with fasciculations, spastic paraparesis, impairment of feet extension and brisk jaw jerk and lower limbs reflexes. Plantar response was absent bilaterally. He referred diffuse cramps and fasciculations. Dysphagia, dysarthria, dysphonia and dyspnoea were absent. The amyotrophic lateral sclerosis funcional rating scale revised (ALSFRS-R) was 44/48. Needle electromyography (EMG) showed chronic and active denervation in bulbar and spinal regions. Forced vital capacity was 106%. The neuropsychological evaluation showed an impaired performance in the Rey-Osterrieth Complex Figure (ROCF) Test, in copy and recall task, while other tests had normal scores. Brain MRI showed selective atrophy of the right supramarginal gyrus (figure 1 …