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Amyotrophic Lateral Sclerosis (ALS) is an incurable neurodegenerative condition. Despite significant advances in pre-clinical models that enhance understanding of disease pathobiology, translation of candidate drugs to effective human therapies has been disappointing. There is increasing recognition of the need for a precision medicine approach toward drug development, as many failures in translation can be attributed in part to disease heterogeneity in humans. PRECISION-ALS is an academic industry collaboration between clinicians, Computer Scientists, Information engineers, technologists, data scientists and industry partners that will address the key clinical, computational, data science and technology associated research questions to generate a sustainable precision medicine based approach toward new drug development. Using extant and prospectively collected population based clinical data across nine European sites, PRECISION-ALS provides a General Data Protection Regulation (GDPR) compliant framework that seamlessly collects, processes and analyses research-quality multimodal and multi-sourced clinical, patient and caregiver journey, digitally acquired data through remote monitoring, imaging, neuro-electric-signaling, genomic and biomarker datasets using machine learning and artificial intelligence. PRECISION-ALS represents a first-in-kind modular transferable pan-European ICT framework for ALS that can be easily adapted to other regions that face similar precision medicine related challenges in multimodal data collection and analysis. ispartof: AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION vol:24 issue:5-6 ispartof: location:England status: Published online

The prediction of the disease course is one of the main targets of ALS research, particularly considering its wide phenotypic heterogeneity. Despite many attempts to classify patients in prognostic categories according to the different spreading patterns at diagnosis, a precise regional progression rate and the time of involvement of each region has yet to be clarified.In a population-based dataset of ALS patients, we analyse the functional decline in different body regions according to time and order of regional involvement. We calculated the regional progression intervals (RPIs) from the initial involvement (Inv) to the severe functional impairment (SevI), using the ALS Functional Rating Scale revised (ALSFRS-r) subscores of bulbar, upper limbs, lower limbs and respiratory/thoracic regions. Time-to-event analyses, adjusted for age, sex, ALSFRS-r pre-slope (ΔALSFRS-R), cognitive and mutational status were performed.RPI duration differed significantly among ALS phenotypes, being the RPI of first region involved significantly longer than RPIs of regions involved later. Cox proportional hazard models showed that the time between disease onset and initial regional involvement is invariably related to a reduced RPI duration in each different body region (bulbar region, HR 1.11, 95% CI 1.06-1.16, p0.001; upper limbs region, HR 1.16, 95% CI 1.06-1.28, p=0.002; lower limbs region, HR 1.11, 95% CI 1.03-1.19, p=0.009; respiratory/thoracic region, HR 1.10, 95% CI 1.06-1.14, p=0.005).We found that the progression of functional decline accelerates in regions involved later during disease course. Our findings can be useful in patients' management and prognosis prediction.

Phosphorylated TDP-43 (pTDP-43) aggregates in the cytoplasm of motor neurons and neuroglia in the brain are one of the pathological hallmarks of amyotrophic lateral sclerosis. Although the axons exceed the total volume of motor neuron soma by several orders of magnitude, systematic studies investigating the presence and distribution of pTDP-43 aggregates within motor nerves are still lacking. The aim of this study is to define the TDP-43/pTDP-43 pathology in diagnostic motor nerve biopsies performed on a large cohort of patients presenting with a lower motor neuron syndrome and to assess whether this might be a discriminating tissue biomarker for amyotrophic lateral sclerosis and non-amyotrophic lateral sclerosis cases. We retrospectively evaluated 102 lower motor neuron syndrome patients referred to our centre for a diagnostic motor nerve biopsy. Histopathological criteria of motor neuron disease and motor neuropathy were applied by two independent evaluators, who were blind to clinical data. TDP-43 and pTDP-43 were evaluated by immunohistochemistry, and results compared to final clinical diagnosis. We detected significant differences between amyotrophic lateral sclerosis and non-amyotrophic lateral sclerosis cases in pTDP-43 expression in myelinated fibres: axonal accumulation was detected in 98.2% of patients with amyotrophic lateral sclerosis versus 30.4% of non-amyotrophic lateral sclerosis samples (P < 0.0001), while concomitant positive staining in Schwan cell cytoplasm was found in 70.2% of patients with amyotrophic lateral sclerosis versus 17.4% of patients who did not have amyotrophic lateral sclerosis (P < 0.001). Importantly, we were also able to detect pTDP-43 aggregates in amyotrophic lateral sclerosis cases displaying normal features at standard histopathological analysis. Our findings demonstrated that a specific pTDP-43 signature is present in the peripheral nervous system of patients with amyotrophic lateral sclerosis, and could be exploited as a specific, accessible tissue biomarker. The detection of pTDP-43 aggregates within motor nerves of living patients with amyotrophic lateral sclerosis, occurring before axonal degeneration, suggests that this is an early event that may contribute to amyotrophic lateral sclerosis pathogenesis.

(1) Background: Motor neuron diseases (MNDs) are fatal neurodegenerative diseases. Biomarkers could help in defining patients’ prognosis and stratification. Beyond neurofilaments, chitinases are a promising family of possible biomarker, which correlate with neuroinflammatory status. We evaluated plasmatic levels of CHI3L1 in MNDs, MND mimics and healthy controls (HCs); (2) Methods: We used Sandwich ELISA to quantify CHI3L1 in plasma samples from 44 MNDs, 7 HSP, 9 MND mimics and 19 HCs. We collect also ALSFRSr scale, MRC scale, spirometry, mutational status, progression rate (PR), blood sampling, neuropsychological evaluation; (3) Results: Plasma levels of CHI3L1 resulted to be different among groups (p= 0.005). Particularly, MND mimics showed higher CHI3L1 levels compared to MNDs and HCs. CHI3LI levels did not differ among PMA, PLS and ALS and we do not find correlation among CHI3L1 levels and clinical scores, spirometry parameters, PR, and neuropsychological features. Of note, red blood cells count and haemoglobin correlated with CHI3L1 levels (respectively, p

We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer’s dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia.

Summary Background There is an urgent unmet need for new therapies in amyotrophic lateral sclerosis. In a clinical study with healthy volunteers, levosimendan, a calcium sensitiser, was shown to improve neuromechanical efficiency and contractile function of the human diaphragm. We aimed to evaluate the safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis, with a focus on respiratory function. Methods The REFALS study is a randomised, double-blind, placebo-controlled phase 3 trial at 99 amyotrophic lateral sclerosis specialist centres in 14 countries worldwide. People with amyotrophic lateral sclerosis were eligible for participation if they were at least 18 years of age and had a sitting slow vital capacity (SVC) of 60–90% predicted. Participants were randomly assigned (2:1) by interactive web-response system to receive either levosimendan or placebo. The capsules for oral administration were identical in appearance to maintain blinding of participants and investigators. The primary endpoint was the change from baseline in supine SVC at 12 weeks, assessed as the percentage of predicted normal sitting SVC. The key secondary endpoint was the combined assessment of function and survival (CAFS) up to 48 weeks. Analyses were done in the intention-to-treat population, comprising all participants who were randomly assigned. This trial is registered at ClinicalTrials.gov (NCT03505021) and has been completed. An extension study (REFALS-ES; NCT03948178 ) has also been completed, but will be reported separately. Findings Between June 21, 2018, and June 28, 2019, 871 people were screened for the study, of whom 496 were randomly assigned either levosimendan (n=329) or placebo (n=167). Participants were followed up between June 27, 2018 and June 26, 2020, for a median duration of 50·1 (IQR 37·5–51·1) weeks. The median duration of treatment was 47·9 (IQR 26·4–48·1) weeks. Change from baseline in supine SVC at 12 weeks was –6·73% with levosimendan and –6·99% with placebo, with no significant difference between the treatments (estimated treatment difference 0·26%, 95% CI –2·03 to 2·55, p=0·83). Similarly, at week 48, CAFS did not differ between treatment groups (least squares mean change from baseline 10·69, 95% CI –15·74 to 37·12; nominal p value=0·43). The most frequent adverse events were increased heart rate (106 [33%] of 326 receiving levosimendan vs 12 [7%] of 166 receiving placebo), fall (85 [26%] vs 48 [29%]), headache (93 [29%] vs 36 [22%]), and dyspnoea (59 [18%] vs 32 [19%]). 33 (10%) participants allocated levosimendan and 20 (12%) assigned placebo died during the trial, mainly due to respiratory failure or progression of amyotrophic lateral sclerosis. Interpretation Levosimendan was not superior to placebo in maintaining respiratory function in a broad population with amyotrophic lateral sclerosis. Although levosimendan was generally well tolerated, increased heart rate and headache occurred more frequently with levosimendan than with placebo. The possibility of a clinically relevant subgroup of responsive individuals requires further evaluation. Funding Orion Corporation.

Being exposed to electromagnetic fields has been suggested to increase the risk of developing Amyotrophic Lateral Sclerosis (ALS). Here, we investigated the effect of exposure to electromagnetic fields on ALS onset age and progression rate (ΔALSFRS-r). A large cohort of ALS patients (n = 1098) was geolocalized at the time of their diagnosis. Concomitantly, data on the distribution of power lines and repeater antennas (extremely low frequency electromagnetic fields) during the same period were retrieved. Exposure to each repeater antenna was calculated as the sum of 1/(distance from each antenna)^2. Exposure to power lines was calculated assuming each patient's address as the center of several circles of variable radius (100, 250, 500, 1000, and 2000 m). For each radius, the exposure was calculated as the length of the power lines included in the circle. Finally, patients were divided into low- and high-exposed based on the median of the exposure and compared using the Mann-Whitney test. A regression model (one for each radius) was also performed. Neither the onset age nor the ΔALSFRS-r differed among patients' low- and high-exposed to electromagnetic fields. Similarly, we could not find any significant relationship using the regression models. Our findings suggest that electromagnetic fields do not modify the ALS phenotype or progression.

ObjectiveTo determine if the co-presence of genetic polymorphisms related to ALS has additive effects on the course of the disease in a population-based cohort of Italian patients.MethodsThe study population includes 1245 ALS patients identified through the Piemonte Register for ALS, diagnosed between 2007 and 2016 and not carrying SOD1, TARDBP and FUS mutations. Controls were 766 age, sex, and geographically matched Italian subjects. We considered UNC13A (rs12608932), CAMTA1 (rs2412208), SLC112A (rs407135) and ZNF512B (ZNF512B) polymorphisms, as well as ATXN2 polyQ intermediate repeats and C9ORF72 GGGGCC intronic expansion.ResultsThe variants in C9orf72 (p=0.016), ATXN2 (pUNC13A (pCAMTA1 emerged to be independently related to survival. When assessing the interaction by pairs of genes, we found that the presence of both detrimental alleles/expansion was correlated with significantly shorter survival compared to subjects non-carrying both detrimental alleles/expansions. Each association of pairs of detrimental alleles was characterized by specific clinical phenotypes.Conclusionswe demonstrated that gene polymorphisms acting as genetic modifiers of ALS survival can act on their own or in unison. Overall, 54% of patients carried at least one detrimental common polymorphism or repeat expansion, highlighting the clinical impact of our findings. In addition, the identification of the synergic effects of modifier genes represents an essential clue for explaining ALS clinical heterogeneity and should be considered in designing and interpreting clinical trials.Key messagesWhat is already known on this topicBesides the disease-causing genes, several other genes have been reported to act as modifiers of ALS phenotype, especially patients’ survival. However, the interactions of these genes at clinical level have never been explored.What this study addsWe demonstrated that gene polymorphisms and expansions acting as genetic modifiers of ALS survival can act on their own or in unison. Overall, 54% of patients carried at least one detrimental allele at common polymorphism or repeat expansion, highlighting the clinical impact of our findings.How this study might affect research, practice, or policThe identification of the synergic effects of modifier genes represents an essential clue for explaining ALS clinical heterogeneity, will have deep effects on clinical trial design and interpretation and support the inclusion of these polymorphisms in ALS genetic panels.

BackgroundAmyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative rare disease that affects motor neurons in the brain, brainstem, and spinal cord, resulting in progressive weakness and atrophy of voluntary skeletal muscles. Although much has been achieved in understanding the disease pathogenesis, treatment options are limited, and in Europe, riluzole is the only approved drug. Recently, some other drugs showed minor effects.MethodsThe TUDCA-ALS trial is a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial. The study aims to enroll 320 patients in 25 centers across seven countries in Europe. Enrolled patients are randomized to one of two treatment arms: TUDCA or identical placebo by oral route. The study measures disease progression during the treatment period and compares it to natural progression during a no-treatment run-in phase. Clinical data and specific biomarkers are measured during the trial. The study is coordinated by a consortium composed of leading European ALS centers.ConclusionThis trial is aimed to determine whether TUDCA has a disease-modifying activity in ALS. Demonstration of TUDCA efficacy, combined with the validation of new biomarkers, could advance ALS patient care.Clinical trial registrationClinicalTrials.gov, identifier: NCT03800524.

The intrathecally administered antisense oligonucleotide tofersen reduces synthesis of the superoxide dismutase 1 (SOD1) protein and is being studied in patients with amyotrophic lateral sclerosis (ALS) associated with mutations inIn this phase 3 trial, we randomly assigned adults withA total of 72 participants received tofersen (39 predicted to have faster progression), and 36 received placebo (21 predicted to have faster progression). Tofersen led to greater reductions in concentrations of SOD1 in CSF and of neurofilament light chains in plasma than placebo. In the faster-progression subgroup (primary analysis), the change to week 28 in the ALSFRS-R score was -6.98 with tofersen and -8.14 with placebo (difference, 1.2 points; 95% confidence interval [CI], -3.2 to 5.5; P = 0.97). Results for secondary clinical end points did not differ significantly between the two groups. A total of 95 participants (88%) entered the open-label extension. At 52 weeks, the change in the ALSFRS-R score was -6.0 in the early-start cohort and -9.5 in the delayed-start cohort (difference, 3.5 points; 95% CI, 0.4 to 6.7); non-multiplicity-adjusted differences favoring early-start tofersen were seen for other end points. Lumbar puncture-related adverse events were common. Neurologic serious adverse events occurred in 7% of tofersen recipients.In persons with

BackgroundSystemic inflammation has been proposed as a relevant mechanism in Amyotrophic Lateral Sclerosis (ALS). Recent evidence shows that an increased inflammatory status correlates with survival in ALS. Still, comprehensive data on ALS patients’ innate and adaptive immune responses and their effect on the clinical phenotype are lacking. Here, we investigate the role and characteristics of systemic immunity in a population-based ALS cohort using readily available hematological indexes that reflect changes in innate and adaptive immunity.MethodsWe collected the complete blood count (CBC) at diagnosis in ALS patients from the Piemonte and Valle d’Aosta Register for ALS (PARALS) from 2007 to 2019. Demographic and clinical data were collected using registry data. Leukocytes populations, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII) and lymphocyte-to-monocyte ratio (LMR) were derived from CBC. All variables were analyzed for association with clinical features in the entire cohort and then in sex- and age-based subgroups. Logistic, linear and Cox regression models were used as appropriate.ResultsAfter adjustment for relevant covariates, neutrophils (p=0.001) and markers of increased innate immunity (NLR, p=0.008 and SII, p=0.006) were associated with a faster disease progression. Similarly, elevated innate immunity markers correlated with worse pulmonary function and shorter survival. Sex-based differences emerged, as the prognosis in women also correlated with a low lymphocyte (p=0.045) and a decreased LMR (p=0.013). ALS patients with cognitive impairment exhibited lower levels of monocytes (p=0.0415) and, although only in later-onset ALS (age at onset > 70 years), lower lymphocytes (p=0.006) and increased NLR (p=0.021) and SII (p=0.030).Conclusions and RelevanceOur results confirm that a dysregulated systemic immune system participates in ALS progression. More specifically, an elevated innate immune response is associated with faster progression and reduced survival. The immune response varied according to sex and age, thus prompting the speculation that involved immune pathways are patient-specific. Finally, we observed that ALS patients with greater cognitive impairment showed a reduction in monocytes count. Those data revealed that systemic inflammation plays a multifaceted role in ALS: further studies will help translate those findings into clinical practice or targeted treatments.

Objective To employ Artificial Intelligence to model, predict and simulate the amyotrophic lateral sclerosis (ALS) progression over time in terms of variable interactions, functional impairments, and survival. Methods We employed demographic and clinical variables, including functional scores and the utilisation of support interventions, of 3940 ALS patients from four Italian and two Israeli registers to develop a new approach based on Dynamic Bayesian Networks (DBNs) that models the ALS evolution over time, in two distinct scenarios of variable availability. The method allows to simulate patients’ disease trajectories and predict the probability of functional impairment and survival at different time points. Results DBNs explicitly represent the relationships between the variables and the pathways along which they influence the disease progression. Several notable inter-dependencies were identified and validated by comparison with literature. Moreover, the implemented tool allows the assessment of the effect of different markers on the disease course, reproducing the probabilistically expected clinical progressions. The tool shows high concordance in terms of predicted and real prognosis, assessed as time to functional impairments and survival (integral of the AU-ROC in the first 36 months between 0.80–0.93 and 0.84–0.89 for the two scenarios, respectively). Conclusions Provided only with measurements commonly collected during the first visit, our models can predict time to the loss of independence in walking, breathing, swallowing, communicating, and survival and it can be used to generate in silico patient cohorts with specific characteristics. Our tool provides a comprehensive framework to support physicians in treatment planning and clinical decision-making.

Objective: To investigate the role of arterial blood gas (ABG) analysis parameters (blood carbon dioxide, pCO2; oxygen, pO2; carbonate, HCO3−; standard base excess, SBE) in monitoring respiratory f...

Objectives: To investigate the extent of synaptic loss, and the contribution of gray matter (GM) inflammation and demyelination to synaptic loss, in multiple sclerosis (MS) brain tissue. Methods: This study was performed on two different post-mortem series of MS and control brains, including deep GM and cortical GM. MS brain samples had been specifically selected for the presence of active demyelinating GM lesions. Over 1,000,000 individual synapses were identified and counted using confocal microscopy, and further characterized as glutamatergic/GABAergic. Synaptic counts were also correlated with neuronal/axonal loss. Results: Important synaptic loss was observed in active demyelinating GM lesions (−58.9%), while in chronic inactive GM lesions, synaptic density was only mildly reduced compared to adjacent non-lesional gray matter (NLGM) (−12.6%). Synaptic loss equally affected glutamatergic and GABAergic synapses. Diffuse synaptic loss was observed in MS NLGM compared to control GM (−21.2% overall). Conclusion: This study provides evidence, in MS brain tissue, of acute synaptic damage/loss during active GM inflammatory demyelination and of synaptic reorganization in chronically demyelinated GM, affecting equally glutamatergic and GABAergic synapses. Furthermore, this study provides a strong indication of widespread synaptic loss in MS NLGM also independently from focal GM demyelination.

Background 5–10% of amyotrophic lateral sclerosis (ALS) patients presented a positive family history (fALS). More than 30 genes have been identified in association with ALS/frontotemporal dementia (FTD) spectrum, with four major genes accounting for 60–70% of fALS. In this paper, we aimed to assess the contribution to the pathogenesis of major and rare ALS/FTD genes in ALS patients. Methods We analyzed ALS and ALS/FTD associated genes by direct sequencing or next-generation sequencing multigene panels in ALS patients. Results Genetic abnormalities in ALS major genes included repeated expansions of hexanucleotide in C9orf72 gene (7.3%), mutations in SOD1 (4.9%), FUS (2.1%), and TARDBP (2.4%), whereas variants in rare ALS/FTD genes affected 15.5% of subjects overall, most frequently involving SQSTM1 (3.4%), and CHMP2B (1.9%). We found clustering of variants in ALS major genes in patients with a family history for “pure” ALS, while ALS/FTD related genes mainly occurred in patients with a family history for other neurodegenerative diseases (dementia and/or parkinsonism). Conclusions Our data support the presence of two different genetic components underlying ALS pathogenesis, related to the presence of a family history for ALS or other neurodegenerative diseases. Thus, family history may help in optimizing the genetic screening protocol to be applied.

MRI studies reported that ALS patients with bulbar and spinal onset showed focal cortical changes in corresponding regions of the motor homunculus. We evaluated the capability of brain 2-[We classified as pure bulbar (PB) patients with bulbar onset and a normal score in the spinal items of the ALSFRS-R, and as pure spinal (PS) patients with spinal onset and a normal score in the bulbar items at the time of PET. Forty healthy controls (HC) were enrolled. We compared PB and PS, and each patient group with HC. Metabolic clusters showing a statistically significant difference between PB and PS were tested to evaluate their accuracy in discriminating the two groups. We performed a leave-one-out cross-validation (LOOCV) over the entire dataset. Four classifiers were considered: support vector machines (SVM), K-nearest neighbours, linear classifier, and decision tree. Then, we used a separate test set, including 10% of patients, with the remaining 90% composing the training set.We included 63 PB, 271 PS, and 40 HC. PB showed a relative hypometabolism compared to PS in bilateral precentral gyrus in the regions of the motor cortex involved in the control of bulbar function. SVM showed the best performance, resulting in the lowest error rate in both LOOCV (4.19%) and test set (9.09 ± 2.02%).Our data support the concept of the focality of ALS onset and the use of 2-[

The identification of prognostic tools in amyotrophic lateral sclerosis (ALS) would improve the design of clinical trials, the management of patients, and life planning. We aimed to evaluate the accuracy of brain 2-[A prospective cohort study enrolled 418 ALS patients, who underwent brain 2-[Data were discretized in three survival profiles: 0-2 years, 2-5 years, and5 years. SVM resulted in an error rate20% for two out of three classes separately. As for class one, the discriminant clusters included left caudate body and anterior cingulate cortex. The most discriminant regions were bilateral cerebellar pyramid in class two, and right cerebellar dentate nucleus, and left cerebellar nodule in class three.Brain 2-[

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

BACKGROUND AND PURPOSE The purpose was to assess the prognostic role of neck muscle weakness at diagnosis in amyotrophic lateral sclerosis (ALS) patients with respect to survival and respiratory impairment. METHODS A retrospective cohort study was conducted. All ALS patients seen in the Turin ALS Centre from 2007 to 2014 were included. Muscle strength at diagnosis was evaluated using the Medical Research Council (MRC) scale. Survival was considered as the time from diagnosis to death or tracheostomy; time to respiratory impairment was considered as the interval from diagnosis to the first event amongst an ALS Functional Rating Scale revised item 10

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.

ObjectiveTo assess the burden of rare genetic variants and to estimate the contribution of known amyotrophic lateral sclerosis (ALS) genes in an Italian population-based cohort, we performed whole genome sequencing in 959 patients with ALS and 677 matched healthy controls.MethodsWe performed genome sequencing in a population-based cohort (Piemonte and Valle d'Aosta Registry for ALS [PARALS]). A panel of 40 ALS genes was analyzed to identify potential disease-causing genetic variants and to evaluate the gene-wide burden of rare variants among our population.ResultsA total of 959 patients with ALS were compared with 677 healthy controls from the same geographical area. Gene-wide association tests demonstrated a strong association with SOD1, whose rare variants are the second most common cause of disease after C9orf72 expansion. A lower signal was observed for TARDBP, proving that its effect on our cohort is driven by a few known causal variants. We detected rare variants in other known ALS genes that did not surpass statistical significance in gene-wise tests, thus highlighting that their contribution to disease risk in our cohort is limited.ConclusionsWe identified potential disease-causing variants in 11.9% of our patients. We identified the genes most frequently involved in our cohort and confirmed the contribution of rare variants in disease risk. Our results provide further insight into the pathologic mechanism of the disease and demonstrate the importance of genome-wide sequencing as a diagnostic tool.

ObjectiveTo determine whether the neuropsychological profiles of patients with amyotrophic lateral sclerosis (ALS) with (ALSC9+) and without (ALSC9−) C9orf72 expansion are different, we administered a battery of neuropsychological tests to 741 patients with ALS (68 ALSC9+ and 673 ALSC9−) and 129 controls.MethodsThe study population includes 741 patients with ALS who were consecutively diagnosed at the Turin ALS expert center in the 2010–2018 period and who underwent both cognitive/behavioral and genetic testing. Patients' neuropsychological patterns were compared (1) at the same degree of cognitive and behavioral deficit according to the revised ALS–Frontotemporal Dementia Consensus Criteria and (2) at the same level of motor impairment according to the King staging system.ResultsDespite being about 7 years younger, ALSC9+ patients had significantly lower scores in tests exploring executive function and verbal memory both when classified as cognitively normal and when diagnosed in the intermediate cognitive categories. Considering the clinical perspective, ALSC9+ patients showed significantly lower scores compared to ALSC9− patients at King stage 1 and 3 in almost all the examined neuropsychological domains; at King stage 2, ALSC9+ patients were more severely affected only in the verbal memory domain. Behavioral function was comparably impaired in the 2 cohorts.ConclusionsALSC9+ patients show a different neuropsychological profile compared to ALSC9− patients, being more impaired in executive functions and verbal memory domains at all King stages. Verbal memory emerged as a particularly vulnerable function in ALSC9+, with worse performances even when patients were still classified as cognitively normal.

We describe the telemedicine experience of an Italian ALS tertiary Center during COVID-19 pandemic. A total of 144 visits were scheduled between 6th March and 6th April 2020. These mostly consisted of neurological or psychological visits (139, 96.5%). One hundred thirty-nine (96.5%) visits were performed as telemedicine and mostly via phone call (112, 80.6%). Three (2.1%) visits were considered as urgent and maintained as outpatient care. Additionally, patients were still able to telephone, being put through directly to their neurologists. Many requests of contact were addressed at getting information about the scheduled visits or examinations (45, 43.3%). Globally, patients and caregivers were satisfied with the telemedicine service. However, the majority (85, 65.9%) would prefer a face-to-face visit. In conclusion, telemedicine could be considered a good complement to face-to-face care, even after social restrictions have been eased.

Background Clinical registers constitute an invaluable resource in the medical data-driven decision making context. Accurate machine learning and data mining approaches on these data can lead to faster diagnosis, definition of tailored interventions, and improved outcome prediction. A typical issue when implementing such approaches is the almost unavoidable presence of missing values in the collected data. In this work, we propose an imputation algorithm based on a mutual information-weighted k-nearest neighbours approach, able to handle the simultaneous presence of missing information in different types of variables. We developed and validated the method on a clinical register, constituted by the information collected over subsequent screening visits of a cohort of patients affected by amyotrophic lateral sclerosis. Methods For each subject with missing data to be imputed, we create a feature vector constituted by the information collected over his/her first three months of visits. This vector is used as sample in a k-nearest neighbours procedure, in order to select, among the other patients, the ones with the most similar temporal evolution of the disease over time. An ad hoc similarity metric was implemented for the sample comparison, capable of handling the different nature of the data, the presence of multiple missing values and include the cross-information among features captured by the mutual information statistic. Results We validated the proposed imputation method on an independent test set, comparing its performance with those of three state-of-the-art competitors, resulting in better performance. We further assessed the validity of our algorithm by comparing the performance of a survival classifier built on the data imputed with our method versus the one built on the data imputed with the best-performing competitor. Conclusions Imputation of missing data is a crucial –and often mandatory– step when working with real-world datasets. The algorithm proposed in this work could effectively impute an amyotrophic lateral sclerosis clinical dataset, by handling the temporal and the mixed-type nature of the data and by exploiting the cross-information among features. We also showed how the imputation quality can affect a machine learning task.

A change in our current approach toward drug development is required to improve the likelihood of finding effective treatment for patients with amyotrophic lateral sclerosis (ALS). The aim of the Treatment Research Initiative to Cure ALS (TRICALS) is to extend the collective effort with industry and consolidate drug development paths. TRICALS has begun a series of meetings on how to best move the field forward collaboratively, thereby addressing five major topics in ALS clinical trials: (1) preclinical research, (2) biomarker development, (3) eligibility criteria, (4) efficacy endpoints and (5) innovative trial design. There is an appetite for ongoing discussions of these major topics in clinical trials between representatives from academia, patient advocacy groups, industry partners and funding bodies. Industry is open to fundamentally change drug development for ALS and shorten the time to effective therapy for patients by implementing promising innovations in biomarker development, trial design, and patient selection. There is however, a pressing need from all stakeholders for regulatory discussions and amendments of current guidelines to successfully adopt innovation in future clinical development lines. ispartof: AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION vol:21 issue:7-8 pages:496-501 ispartof: location:England status: published

Background and purpose The aim was to assess the frequency of plateaus in amyotrophic lateral sclerosis (ALS) progression using a large population-based cohort. Methods Data from the Piemonte and Valle d'Aosta ALS register were used. Patients who were diagnosed between 2007 and 2014 were considered. The follow-up period was extended until 31 December 2018. Visits after tracheostomy were excluded. A plateau was defined as a stable Amyotrophic Lateral Sclerosis Functional Rating Scale revised (ALSFRSr) score lasting at least 6, 12 or 18 months. Results Out of 1214 patients, 200 (16.5%), 93 (7.7%) and 52 (4.3%) showed at least one plateau lasting a minimum of 6, 12 and 18 months, respectively. Plateaus occurred mostly at high ALSFRSr scores and were more frequent during the initial phases of the disease course. Spinal onset [odds ratio (OR) 1.83, 95% confidence interval (CI) 1.16-2.95, P value 0.01) and predominant upper motor neuron phenotype (OR 2.18, 95% CI 1.36-3.48, P value 0.001) conferred a higher risk for the subsequent appearance of plateaus; conversely, older age at diagnosis (OR 0.25, 95% CI 0.11-0.54, P value 0.002 for >75 year age class) reduced this risk. Conclusions Plateaus in ALS progression lasting at least 6 months appear in about one out of six patients and could last even 12, 18 months or more in a smaller subgroup of patients. Plateau occurrence should not lead the neurologist to automatically reconsider ALS diagnosis and should be considered for future clinical trial design.

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Amyotrophic lateral sclerosis (ALS) is a highly complex and heterogeneous neurodegenerative disease that affects motor neurons. Since life expectancy is relatively low, it is essential to promptly understand the course of the disease to better target the patient’s treatment. Predictive models for disease progression are thus of great interest. One of the most extensive and well-studied open-access data resources for ALS is the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) repository. In 2015, the DREAM-Phil Bowen ALS Prediction Prize4Life Challenge was held on PRO-ACT data, where competitors were asked to develop machine learning algorithms to predict disease progression measured through the slope of the ALSFRS score between 3 and 12 months. However, although it has already been successfully applied in several studies on ALS patients, to the best of our knowledge deep learning approaches still remain unexplored on the ALSFRS slope prediction in PRO-ACT cohort. Here, we investigate how deep learning models perform in predicting ALS progression using the PRO-ACT data. We developed three models based on different architectures that showed comparable or better performance with respect to the state-of-the-art models, thus representing a valid alternative to predict ALS disease progression.

Objectives: The diagnostic capabilities of specific cognitive screeners are clinically crucial for an early detection of frontotemporal features in amyotrophic lateral sclerosis (ALS) patients. This study aimed at providing diagnostic properties of the cognitive section of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) in Italian ALS patients. Methods: Eighty-nine consecutive Italian ALS patients were classified according to Strong et al. (2017) criteria with a comprehensive neuropsychological assessment. The Italian version of ECAS was also administered, and its accuracy, sensitivity (SE), specificity (SP), negative and positive predictive values (PPV; NPV) and likelihood ratios (LR+; LR-) were computed against clinical diagnoses. Results: The ECAS and its subscales yielded moderate-to-high accuracy (AUC =.7–.87). High SP was overall found (81.8%–100%). The most sensitive measures were ALS-specific and Executive (73.9–78.3%) subscales, while the least were the ALS-non-specific subscales (8.7–17.4%). ECAS measures showed good PPVs (60%–100%) and NPVs (75.9%–91.5%). Acceptable LRs were found (LR+: 6.97–4.3; LR–:.29–.91), with total and ALS-specific measures yielding the best estimates. Conclusions: This is the first study demonstrating the diagnostic value of the ECAS against a thorough neuropsychological assessment in Italy. ECAS-total and -ALS-specific scores are diagnostically sound as to both intrinsic and post-test features, whereas ALS-non-specific measures perform slightly worse.

Humans are thought to be more susceptible to neurodegeneration than equivalently-aged primates. It is not known whether this vulnerability is specific to anatomically-modern humans or shared with other hominids. The contribution of introgressed Neanderthal DNA to neurodegenerative disorders remains uncertain. It is also unclear how common variants associated with neurodegenerative disease risk are maintained by natural selection in the population despite their deleterious effects. In this study, we aimed to quantify the genome-wide contribution of Neanderthal introgression and positive selection to the heritability of complex neurodegenerative disorders to address these questions.We used stratified-linkage disequilibrium score regression to investigate the relationship between five SNP-based signatures of natural selection, reflecting different timepoints of evolution, and genome-wide associated variants of the three most prevalent neurodegenerative disorders: Alzheimer’s disease, amyotrophic lateral sclerosis and Parkinson’s disease.We found no evidence for enrichment of positively-selected SNPs in the heritability of Alzheimer’s disease, amyotrophic lateral sclerosis and Parkinson’s disease,, suggesting that common deleterious disease variants are unlikely to be maintained by positive selection. There was no enrichment of Neanderthal introgression in the SNP-heritability of these disorders, suggesting that Neanderthal admixture is unlikely to have contributed to disease risk.These findings provide insight into the origins of neurodegenerative disorders within the evolution ofHomo sapiensand addresses a long-standing debate, showing that Neanderthal admixture is unlikely to have contributed to common genetic risk of neurodegeneration in anatomically-modern humans.

(1) Background: Motor neuron diseases (MNDs) are fatal neurodegenerative diseases. Biomarkers could help with defining patients’ prognoses and stratifications. Besides neurofilaments, chitinases are a promising family of possible biomarkers which correlate with neuroinflammatory status. We evaluated the plasmatic levels of CHI3L1 in MNDs, MND mimics, and healthy controls (HCs). (2) Methods: We used a sandwich ELISA to quantify the CHI3L1 in plasma samples from 44 MND patients, 7 hereditary spastic paraplegia (HSP) patients, 9 MND mimics, and 19 HCs. We also collected a ALSFRSr scale, MRC scale, spirometry, mutational status, progression rate (PR), blood sampling, and neuropsychological evaluation. (3) Results: The plasma levels of the CHI3L1 were different among groups (p = 0.005). Particularly, the MND mimics showed higher CHI3L1 levels compared with the MND patients and HCs. The CHI3L1 levels did not differ among PMA, PLS, and ALS, and we did not find a correlation among the CHI3L1 levels and clinical scores, spirometry parameters, PR, and neuropsychological features. Of note, the red blood cell count and haemoglobin was correlated with the CHI3L1 levels (respectively, p < 0.001, r = 0.63; p = 0.022, and r = 0.52). (4) Conclusions: The CHI3L1 plasma levels were increased in the MND mimics cohort compared with MNDs group. The increase of CHI3L1 in neuroinflammatory processes could explain our findings. We confirmed that the CHI3L1 plasma levels did not allow for differentiation between ALS and HCs, nor were they correlated with neuropsychological impairment.

Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA).Objective: To assess the feasibility of clinical studies on the effect of therapy in children (

Camillo Negro is considered one of the most outstanding Italian neurologists ever. Between the 19th and the 20th century, he founded the Neurological School in Turin. He was one of the precursors of the separation of neurology and psychiatry, a forerunner of the modern communication of scientific discoveries through the establishment of several scientific journals, as well as his famous movie Neuropatologia. Negro was also a keen scientist and authored more than one hundred papers. He described the three Negro’s signs: (1) the cogwheel rigidity in Parkinson’s disease, (2) the bulbo-palpebral event in peripheral palsy of the facial nerve, and (3) the meso-rotuleus sign associated with the pyramidal deficit. He also supported the doctrine proposed by Santiago Ramón y Cajal in the section titled, “The Theory of Neurons,” of the manual Patologia e Clinica del Sistema Nervoso. Finally, he mentored many students, including Carlo Angela, Mario Gozzano, and Luisa Levi.

BackgroundA genetic diagnosis in Amyotrophic Lateral Sclerosis (ALS) can inform genetic counselling, prognosis and, in the light of incoming gene-targeted therapy, management. However, conventional genetic testing strategies are often costly and time-consuming.ObjectiveTo evaluate the diagnostic yield and advantages of whole-genome sequencing (WGS) as a standard diagnostic genetic test for ALS.MethodsIn this population-based cohort study, 1043 ALS patients from the Piemonte and Valle d’Aosta Register for ALS and 755 healthy individuals were screened by WGS for variants in 42 ALS-related genes and for repeated-expansions in C9orf72 and ATXN2.ResultsA total of 279 ALS cases (26.9%) received a genetic diagnosis, namely 75.2% of patients with a family history of ALS and 21.5% of sporadic cases. The mutation rate among early-onset ALS patients was 43.9%, compared with 19.7% of late-onset patients. An additional 14.6% of the cohort carried a genetic factor that worsen prognosis.ConclusionsOur results suggest that, because of its high diagnostic yield and increasingly competitive costs, along with the possibility of retrospectively reassessing newly described genes, WGS should be considered as standard genetic testing for all ALS patients. Additionally, our results provide a detailed picture of the genetic basis of ALS in the general population.

The aetiology of Amyotrophic Lateral Sclerosis (ALS) is still poorly understood. The discovery of genetic forms of ALS pointed out the mechanisms underlying this pathology, but also showed how complex these mechanisms are. Excitotoxicity is strongly suspected to play a role in ALS pathogenesis. Excitotoxicity is defined as neuron damage due to excessive intake of calcium ions (Ca2+) by the cell. This study aims to find a relationship between the proteins coded by the most relevant genes associated with ALS and intracellular Ca2+ accumulation. In detail, the profile of eight proteins (TDP-43, C9orf72, p62/sequestosome-1, matrin-3, VCP, FUS, SOD1 and profilin-1), was analysed in three different cell types induced to raise their cytoplasmic amount of Ca2+. Intracellular Ca2+ accumulation causes a decrease in the levels of TDP-43, C9orf72, matrin3, VCP, FUS, SOD1 and profilin-1 and an increase in those of p62/sequestosome-1. These events are associated with the proteolytic action of two proteases, calpains and caspases, as well as with the activation of autophagy. Interestingly, Ca2+ appears to both favour and hinder autophagy. Understanding how and why calpain-mediated proteolysis and autophagy, which are physiological processes, become pathological may elucidate the mechanisms responsible for ALS and help discover new therapeutic targets.

Mutations in FUS gene have been described classically in young ALS patients with aggressive disease course. Here we report a large family carrying a missense mutation c.1520 GA in FUS gene with a tight association with an atypical FUS-ALS phenotype. A 60-year-old man with unilateral leg involvement at onset showed very slow disease progression with selective posterior legs atrophy, tracing his aunt's disease history. His father and uncle died for ALS after a long disease course. Another patient with a 14 years history of ALS with the same phenotype, was found to belong to the same family. In all cases, genetic analysis of FUS gene revealed a missense mutation c.1520 GA (p.G507D) inherited with a heterozygous pattern. Co-segregation of p.G507D mutation and a specific disease phenotype within the family, characterised by predominant involvement at the lower limbs, slow progression, late bulbar and respiratory failure, demonstrates pathogenicity of this mutation, establishes a well-defined genotype-phenotype correlation and expands the clinical spectrum of heterogeneity in FUS-ALS.

ObjectiveMutations in the TARDBP gene are a rare cause of genetic motor neuron disease (MND). Morphologic MRI characteristics of MND patients carrying this mutation have been poorly described. Our objective was to investigate distinctive clinical and MRI features of a relatively large sample of MND patients carrying TARDBP mutations.MethodsEleven MND patients carrying a TARDBP mutation were enrolled. Eleven patients with sporadic MND (sMND) and no genetic mutations were also selected and individually matched by age, sex, clinical presentation and disease severity, along with 22 healthy controls. Patients underwent clinical and cognitive evaluations, as well as 3D T1-weighted and diffusion tensor (DT) MRI on a 3 Tesla scanner. Gray matter (GM) atrophy was first investigated at a whole-brain level using voxel-based morphometry (VBM). GM volumes and DT MRI metrics of the main white matter (WM) tracts were also obtained. Clinical, cognitive and MRI features were compared between groups.ResultsMND with TARDBP mutations was associated with all possible clinical phenotypes, including isolated upper/lower motor neuron involvement, with no predilection for bulbar or limb involvement at presentation. Greater impairment at naming tasks was found in TARDBP mutation carriers compared with sMND. VBM analysis showed significant atrophy of the right lateral parietal cortex in TARDBP patients, compared with controls. A distinctive reduction of GM volumes was found in the left precuneus and right angular gyrus of TARDBP patients compared to controls. WM microstructural damage of the corticospinal tract (CST) and inferior longitudinal fasciculi (ILF) was found in both sMND and TARDBP patients, compared with controls, although decreased fractional anisotropy of the right CST and increased axial diffusivity of the left ILF (p = 0.017) was detected only in TARDBP mutation carriers.ConclusionsTARDBP patients showed a distinctive parietal pattern of cortical atrophy and greater damage of motor and extra-motor WM tracts compared with controls, which sMND patients matched for disease severity and clinical presentation were lacking. Our findings suggest that TDP-43 pathology due to TARDBP mutations may cause deeper morphologic alterations in both GM and WM.

Background Given the large genetic heterogeneity in amyotrophic lateral sclerosis (ALS), it seems likely that genetic subgroups may benefit differently from treatment. An exploratory meta-analysis identified that patients homozygous for the C-allele at SNP rs12608932, a single nucleotide polymorphism in the gene UNC13A, had a statistically significant survival benefit when treated with lithium carbonate. We aim to confirm the efficacy of lithium carbonate on the time to death or respiratory insufficiency in patients with ALS homozygous for the C-allele at SNP rs12608932 in UNC13A. Methods A randomized, group-sequential, event-driven, double-blind, placebo-controlled trial will be conducted in 15 sites across Europe and Australia. Patients will be genotyped for UNC13A; those homozygous for the C-allele at SNP rs12608932 will be eligible. Patients must have a diagnosis of ALS according to the revised El Escorial criteria, and a TRICALS risk-profile score between −6.0 and −2.0. An expected number of 1200 patients will be screened in order to enroll a target sample size of 171 patients. Patients will be randomly allocated in a 2:1 ratio to lithium carbonate or matching placebo, and treated for a maximum duration of 24 months. The primary endpoint is the time to death or respiratory insufficiency, whichever occurs first. Key secondary endpoints include functional decline, respiratory function, quality of life, tolerability, and safety. An interim analysis for futility and efficacy will be conducted after the occurrence of 41 events. Discussion Lithium carbonate has been proven to be safe and well-tolerated in patients with ALS. Given the favorable safety profile, the potential benefits are considered to outweigh the burden and risks associated with study participation. This study may provide conclusive evidence about the life-prolonging potential of lithium carbonate in a genetic ALS subgroup. Trial registration EudraCT number 2020-000579-19. Registered on 29 March 2021.

Background MRI studies reported that ALS patients with bulbar and spinal onset showed focal cortical changes in corresponding regions of the motor homunculus. We evaluated the capability of brain 2-[18F]FDG-PET to disclose the metabolic features characterizing patients with pure bulbar or spinal motor impairment. Methods We classified as pure bulbar (PB) patients with bulbar onset and a normal score in the spinal items of the ALSFRS-R, and as pure spinal (PS) patients with spinal onset and a normal score in the bulbar items at the time of PET. Forty healthy controls (HC) were enrolled. We compared PB and PS, and each patient group with HC. Metabolic clusters showing a statistically significant difference between PB and PS were tested to evaluate their accuracy in discriminating the two groups. We performed a leave-one-out cross-validation (LOOCV) over the entire dataset. Four classifiers were considered: support vector machines (SVM), K-nearest neighbours, linear classifier, and decision tree. Then, we used a separate test set, including 10% of patients, with the remaining 90% composing the training set. Results We included 63 PB, 271 PS, and 40 HC. PB showed a relative hypometabolism compared to PS in bilateral precentral gyrus in the regions of the motor cortex involved in the control of bulbar function. SVM showed the best performance, resulting in the lowest error rate in both LOOCV (4.19%) and test set (9.09 ± 2.02%). Conclusions Our data support the concept of the focality of ALS onset and the use of 2-[18F]FDG-PET as a biomarker for precision medicine-oriented clinical trials.

Purpose Neuropathological data suggest that ALS with SOD1 mutations (SOD1-ALS) is a distinct form of ALS. We evaluated brain metabolic changes characterizing SOD1-ALS as compared to sporadic ALS (sALS), employing 18fluorodeoxyglucose-positron-emission tomography (18F-FDG-PET). Methods We included 18 SOD1-ALS patients, 40 healthy controls (HC), and 46 sALS patients without mutations in SOD1, TARDBP, FUS, and C9ORF72, randomly selected from 665 subjects who underwent brain 18F-FDG-PET at diagnosis between 2008 and 2019 at the ALS Centre of Turin. We excluded patients with frontotemporal dementia. We used the full factorial design in SPM12 to evaluate whether differences among groups exist overall. In case the hypothesis was confirmed, group comparisons were performed through the two-sample t-test model of SPM12. In all the analyses, the height threshold was P < 0.001 (P < 0.05 FWE-corrected at cluster level). Results The full factorial design resulted in a significant main effect of groups. We identified a relative hypometabolism in sALS patients compared to SOD1-ALS cases in the right precentral and medial frontal gyrus, right paracentral lobule, and bilateral postcentral gyrus. SOD1 patients showed a relative hypermetabolism as compared to HC in the right precentral gyrus and paracentral lobule. As compared to HC, sALS patients showed relative hypometabolism in frontal, temporal, and occipital cortices. Conclusion SOD1-ALS was characterized by a relative hypermetabolism in the motor cortex as compared to sALS and HC. Since promising, targeted, therapeutic strategies are upcoming for SOD1-ALS, our data support the use of PET to study disease pathogenesis and to track its course in clinical trials, in both asymptomatic and symptomatic mutation carriers.

Amyotrophic lateral sclerosis (ALS) is known to represent a collection of overlapping syndromes. Various classification systems based on empirical observations have been proposed, but it is unclear to what extent they reflect ALS population substructures. We aimed to use machine-learning techniques to identify the number and nature of ALS subtypes to obtain a better understanding of this heterogeneity, enhance our understanding of the disease, and improve clinical care.In this retrospective study, we applied unsupervised Uniform Manifold Approximation and Projection [UMAP]) modelling, semi-supervised (neural network UMAP) modelling, and supervised (ensemble learning based on LightGBM) modelling to a population-based discovery cohort of patients who were diagnosed with ALS while living in the Piedmont and Valle d'Aosta regions of Italy, for whom detailed clinical data, such as age at symptom onset, were available. We excluded patients with missing Revised ALS Functional Rating Scale (ALSFRS-R) feature values from the unsupervised and semi-supervised steps. We replicated our findings in an independent population-based cohort of patients who were diagnosed with ALS while living in the Emilia Romagna region of Italy.Between Jan 1, 1995, and Dec 31, 2015, 2858 patients were entered in the discovery cohort. After excluding 497 (17%) patients with missing ALSFRS-R feature values, data for 42 clinical features across 2361 (83%) patients were available for the unsupervised and semi-supervised analysis. We found that semi-supervised machine learning produced the optimum clustering of the patients with ALS. These clusters roughly corresponded to the six clinical subtypes defined by the Chiò classification system (ie, bulbar, respiratory, flail arm, classical, pyramidal, and flail leg ALS). Between Jan 1, 2009, and March 1, 2018, 1097 patients were entered in the replication cohort. After excluding 108 (10%) patients with missing ALSFRS-R feature values, data for 42 clinical features across 989 patients were available for the unsupervised and semi-supervised analysis. All 1097 patients were included in the supervised analysis. The same clusters were identified in the replication cohort. By contrast, other ALS classification schemes, such as the El Escorial categories, Milano-Torino clinical staging, and King's clinical stages, did not adequately label the clusters. Supervised learning identified 11 clinical parameters that predicted ALS clinical subtypes with high accuracy (area under the curve 0·982 [95% CI 0·980-0·983]).Our data-driven study provides insight into the ALS population substructure and confirms that the Chiò classification system successfully identifies ALS subtypes. Additional validation is required to determine the accuracy and clinical use of these algorithms in assigning clinical subtypes. Nevertheless, our algorithms offer a broad insight into the clinical heterogeneity of ALS and help to determine the actual subtypes of disease that exist within this fatal neurodegenerative syndrome. The systematic identification of ALS subtypes will improve clinical care and clinical trial design.US National Institute on Aging, US National Institutes of Health, Italian Ministry of Health, European Commission, University of Torino Rita Levi Montalcini Department of Neurosciences, Emilia Romagna Regional Health Authority, and Italian Ministry of Education, University, and Research.For the Italian and German translations of the abstract see Supplementary Materials section.