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STUDY OBJECTIVES: To analyze (1) the impact of a protocol of early respiratory evaluation of the indications for home mechanical ventilation (HMV) in patients with amyotrophic lateral sclerosis (ALS), and (2) the effects of the protocol and of bulbar involvement on the survival of patients receiving noninvasive ventilation (NIV). DESIGN AND SETTING: Retrospective study in a tertiary care referral center. PATIENTS: HMV was indicated in 86 patients with ALS, with 22 patients (25%) presenting with intolerance to treatment associated with bulbar involvement. Treatment with HMV had been initiated in 15 of 64 patients prior to initiating the protocol (group A) and in the remaining 49 patients after protocol initiation (group B). RESULTS: In group A, the majority of patients began treatment with HMV during an acute episode requiring ICU admission (p = 0.001) and tracheal ventilation (p = 0.025), with a lower percentage of patients beginning HMV treatment without respiratory insufficiency (p = 0.013). No significant differences in survival rates were found between groups A and B among patients treated with NIV. Greater survival was observed in group B (p = 0.03) when patients with bulbar involvement were excluded (96%). Patients without bulbar involvement at the start of therapy with NIV presented a significantly better survival rate (p = 0.03). Multivariate analysis showed bulbar involvement to be an independent prognostic factor for survival (relative risk, 1.6; 95% confidence interval, 1.01 to 2.54; p = 0.04). No significant differences in survival were observed between patients with bulbar involvement following treatment with NIV and those with intolerance, except for the subgroup of patients who began NIV treatment with hypercapnia (p = 0.0002). CONCLUSIONS: Early systematic respiratory evaluation in patients with ALS is necessary to improve the results of HMV. Further studies are required to confirm the benefits of NIV treatment in patients with bulbar involvement, especially in the early stages. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is caused by biallelic mutations of SMN1 gene, with wide spectrum of phenotypes. One of the best-known disease modifiers is a paralogous SMN2 gene and its copy numbers. Other well-known genetic modifiers are the c.859G>C andc.835-44A>G variants in SMN2. SMA was classified in 4 clinical types (1-4) depending on the acquisition of motor milestones, but there is a significant overlap in their clinical characteristics and genetic background, especially in late-onset patients. Moreover, with the approval of disease-modifying therapies (DMT), new phenotypes are arising, which do not fit with the traditional classification. In this context, describing the natural history according to the number of SMN2 copies and other well-known genetic modifiers has become more and more important. In this study, patients with 3 or 4 SMN2 copies included in the national Spanish registry for SMA (CUIDAME) who signed informed consent were assessed. The age of acquisition and loss of four main motor milestones (head control, sitting without support, walking with and without support) and other important milestones (scoliosis surgery, first long bone fracture and ventilation initiation) was collected with well-known SMN2 genetic modifiers and sex. Data on natural history were collected retrospectively from questionnaires and medical records and prospectively on subsequent clinical visits until treatment initiation. Multivariable models will be used to assess the influence of genetic modifiers and sex in the acquisition and loss of motor milestones. As for April 2024 253 patients with 3 SMN2 copies and 71 patients with 4 SMN2 copies were identified in the CUIDAME registry. Data on their natural history and the influence of sex and genetic modifiers will be presented. The description of SMA natural history according to genetic modifiers and sex will be key to predict the prognosis of asymptomatic untreated carriers and to assess the long-term efficacy of DMT. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is a genetic, neurodegenerative disease characterized by progressive muscle weakness and atrophy leading to disability and paralysis. Nusinersen is an SMN2 -directed antisense oligonucleotides (ASO) working by blocking splicing once they are bound to pre-mRNA, which allows exon 7 to be preferentially included and therefore produce more full-length SMN protein. Nusinersen is available since 2016 in USA and 2018 in Spain. The CUIDAME project is an observational Spanish SMA population database where clinical data are collected through a digital platform. Here we present a descriptive analysis of the cohort treated with Nusinersen included in the platform until April 2024. 146 and 106 pediatric and adult patients respectively had been treated with Nusinersen at the time of recruitment, representing the 66.6% and 43.3% of the pediatric and adult population. Regarding SMA type and treatment outcomes: 60 SMA1 pediatric patients had been treated with CHOP-ATEND score change from 19.3 at the beginning of the treatment to 47.9 in last measure; 58 SMA2 pediatric patients had been treated with CHOP-ATEND score change from 44.1 to 51.2 and HFMSE score change from 20 to 26.9; 26 SMA3 pediatric patients had been treated with CHOP-ATEND score change from 61 to 61.8 and HFMSE score change from 45.1 to 51.7. 29 SMA2 adult patients had been treated with HFMSE score change from 5 to 4.6 and EK2 score change from 20.3 to 18.8; 75 SMA3 adult patients had been treated with HFMSE score change from 36.4 to 34.9, EK2 score change from 10 to 6.3 and 6MWT score change from 282.5 to 388.2 meters. Just two pre-symptomatic patients had been treated with Nusinersen. Considering nutritional status, 54% of treated pediatric SMA1 require nutritional support, 18% of treated pediatric SMA2 and no pediatric SMA3. No adult SMA patient treated with Nusinersen requires nutritional support. Focusing on respiratory situation, 83.9% of treated pediatric SMA1 require any type of ventilation being just 11.1% invasive, 34.5% of treated pediatric SMA2 require ventilation being just 7% invasive and no treated pediatric SMA3 requires ventilation. 56% of treated adult SMA2 and 6% of treated adult SMA3 require ventilation, all of them non-invasive. In conclusion, both the pediatric and adult population included in the CUIDAME registry treated with Nusinersen show an improvement either in motor or functional scales. Regarding nutritional or respiratory implications, a high percentage of SMA2 require support of some kind, being lower in SMA3 and in the adult population. [ABSTRACT FROM AUTHOR]

Introduction: The therapeutic options for spinal muscular atrophy (SMA) are encouraging. However, there is currently no cure for amyotrophic lateral sclerosis (ALS). The clinical and economic uncertainty surrounding innovative treatments for rare neurodegenerative diseases makes it necessary to understand managed entry agreements (MEAs). The aim of this study was to review whether models of MEAs in SMA could be extrapolated to ALS., Methods: We performed a scoping review with information on MEAs on SMA in Web of Science (WOS), PubMed, Lyfegen Library, the National Institute for Health and Care Excellence (NICE), and the Canadian Agency for Drugs and Technologies in Health (CADTH)., Results: We found 45 results in WOS and PubMed. After an initial survey, 10 were reviewed to assess eligibility, and three were selected. We obtained 44 results from Lyfegen Library, and three results each from NICE and CADTH., Conclusion: The main objective of MEAs is to reduce uncertainty in the financing of drugs with a high budgetary impact and clinical concerns, as is the case with drugs for SMA and ALS. While the information available on MEAs in SMA is scarce, some conceptual models are publicly available. MEAs for long-term treatments for SMA could be used for the design of MEAs in ALS because of their similarities in economic and clinical uncertainty.

This is the first study aimed to detect morphological abnormalities in vivo in the skin capillaries of amyotrophic lateral sclerosis patients (ALS). Videocapillaroscopy assessed subungueal capillaries in 28 ALS patients (cases) and 35 controls (p = 0.42). The mean age was 61.46 and 61.23 years, respectively (p > 0.99). No statistically significant differences were observed between the groups regarding dominant hand, arterial hypertension, dyslipidemia, diabetes mellitus, active smoker, and former smoker variables. 78.57% of cases had spinal onset and 21.43% bulbar. The median disease duration (time between the onset of symptoms and the date of videocapillarscopy) was 29.71 months. Dilated capillaries were detected in 17.8% of cases and 11.43% of controls (p = 0.49). The median of capillary diameter in cases was 10.15 µm and 8.72 µm in controls (p = 0.011). 35.71% of cases and 2.86% of controls had severe capillary tortuosities (p < 0.001). Ramified capillaries were observed in 46.43% of cases and 11.43% of controls (p < 0.002). Micro-hemorrhages were only observed in 10.71% of cases. No significant correlations were observed between disease duration and dilated capillaries, tortuosity, ramified capillaries, and micro-hemorrhages. The present in vivo study shows abnormalities in the skin capillaries of ALS patients that do not depend on disease duration., (© 2024. The Author(s).)

This study aimed to assess differences in the enteral microbiome of relatively recent-onset amyotrophic lateral sclerosis (ALS) patients (< 6-15 months since symptom onset) compared to healthy individuals, focusing on short-chain fatty acids (SCFAs) as potential mediators of host metabolism. We included 28 volunteers (16 ALS, 12 controls) with informed consent. No significant effect of ALS on alpha diversity (measuring the variety and abundance of species within a single sample, and indicating the health and complexity of the microbiome) was observed, but ALS patients had higher abundances of Fusobacteria and Acidobacteria. ALS subtypes influenced specific species, with increased Fusobacteria and Tenericutes in spinal ALS compared to bulbar ALS. ALS patients showed increased Enterobacter, Clostridium, Veillonella, Dialister, Turicibacter, and Acidaminococcus species and decreased Prevotella, Lactobacillus, and Butyricimonas. Correlations between species varied between ALS patients and healthy individuals and among ALS subtypes. No significant differences in SCFA concentrations were found, but spinal ALS samples showed a trend towards decreased propionate content. Relationships between SCFAs and phyla colonization differed by disease status. This study suggests distinct enteral microbiome characteristics in ALS patients, though the implications are unclear. Further research is needed to determine if these differences are causative or consequential and to explore their potential as diagnostic or therapeutic targets. The study also underscores the heterogeneity of microbiome constraints in ALS and the need for more research into ALS and SCFA metabolism., (© 2024. The Author(s).)

Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease with a mean survival time of three years. The 97% of the cases have TDP-43 nuclear depletion and cytoplasmic aggregation in motor neurons. TDP-43 prevents non-conserved cryptic exon splicing in certain genes, maintaining transcript stability, including ATG4B, which is crucial for autophagosome maturation and Microtubule-associated proteins 1A/1B light chain 3B (LC3B) homeostasis. In ALS mice (G93A), Atg4b depletion worsens survival rates and autophagy function. For the first time, we observed an elevation of LC3ylation in the CNS of both ALS patients and atg4b -/- mouse spinal cords. Furthermore, LC3ylation modulates the distribution of ATG3 across membrane compartments. Antisense oligonucleotides (ASOs) targeting cryptic exon restore ATG4B mRNA in TARDBP knockdown cells. We further developed multi-target ASOs targeting TDP-43 binding sequences for a broader effect. Importantly, our ASO based in peptide-PMO conjugates show brain distribution post-IV administration, offering a non-invasive ASO-based treatment avenue for neurodegenerative diseases., (© 2024. The Author(s).)

Amyotrophic lateral sclerosis is a debilitating and lethal neurodegenerative disorder marked by the gradual deterioration of motor neurons. Diagnosing amyotrophic lateral sclerosis is challenging due to the lack of reliable diagnostic tools, with clinical assessment being the primary criterion. Recently, increased levels of neurofilament light chain in CSF have been considered a useful biomarker in disease, correlating with disease progression but not specific for diagnosis. This study utilized enzyme-linked immunosorbent assay to measure CSF C-X-C motif chemokine ligand 12 levels in healthy controls, amyotrophic lateral sclerosis patients and patients with amyotrophic lateral sclerosis-mimic disorders, assessing its potential as a diagnostic biomarker and comparing it with neurofilament light chain levels. Our results confirmed previous findings, showing increased C-X-C motif chemokine ligand 12 levels in amyotrophic lateral sclerosis patients compared to healthy control (797.07 ± 31.84 pg/mL versus 316.15 ± 16.6 pg/mL; P = 0.000) and increased CSF neurofilament light chain levels in amyotrophic lateral sclerosis (4565.63 ± 263.77 pg/mL) compared to healthy control (847.86 ± 214.37 pg/mL; P = 0.000). Increased C-X-C motif chemokine ligand levels were specific to amyotrophic lateral sclerosis, not seen in amyotrophic lateral sclerosis-mimic conditions like myelopathies (252.20 ± 23.16 pg/mL; P = 0.000), inflammatory polyneuropathies (270.24 ± 32.23 pg/mL; P = 0.000) and other mimic diseases (228.91 ± 29.20 pg/mL; P = 0.000). In contrast, CSF neurofilament light chain levels in amyotrophic lateral sclerosis overlapped with those in myelopathies (2900.11 ± 872.20 pg/mL; P = 0.821) and other mimic diseases (3169.75 ± 1096.65 pg/mL; P = 0.63), but not with inflammatory polyneuropathies (1156.4 ± 356.6 pg/mL; P = 0.000). Receiver operating characteristic curve analysis indicated significant differences between the area under the curve values of C-X-C motif chemokine ligand and neurofilament light chain in their diagnostic capacities. C-X-C motif chemokine ligand could differentiate between amyotrophic lateral sclerosis and myelopathies (area under the curve 0.99 ± 0.005), inflammatory polyneuropathies (area under the curve 0.962 ± 0.027) and other mimic diseases (area under the curve 1.00 ± 0.00), whereas neurofilament light chain was only effective in inflammatory polyneuropathies cases (area under the curve 0.92 ± 0.048), not in myelopathies (area under the curve 0.71 ± 0.09) or other mimic diseases (area under the curve 0.69 ± 0.14). We also evaluated C-X-C motif chemokine ligand levels in plasma [amyotrophic lateral sclerosis (2022 ± 81.8 pg/mL) versus healthy control (1739.43 ± 77.3 pg/mL; P = 0.015)] but found CSF determination (area under the curve 0.97 ± 0.012) to be more accurate than plasma determination (area under the curve 0.65 ± 0.063). In plasma, single molecule array (SIMOA) neurofilament light chain determination [amyotrophic lateral sclerosis (86.00 ± 12.23 pg/mL) versus healthy control (12.69 ± 1.15 pg/mL); P = 0.000] was more accurate than plasma C-X-C motif chemokine ligand 12 (area under the curve 0.98 ± 0.01405). These findings suggest that CSF C-X-C motif chemokine ligand 12 levels can enhance diagnostic specificity in distinguishing amyotrophic lateral sclerosis from amyotrophic lateral sclerosis-mimic disorders, compared to neurofilament light chain. Larger studies are needed to validate these results, but C-X-C motif chemokine ligand 12 determination shows promising diagnostic potential., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease (MND) that shares a common clinical, genetic and pathologic spectrum with frontotemporal dementia (FTD). It is highly heterogeneous in its presentation and features. Up to 50% of patients with MND develop cognitive-behavioural symptoms during the course of the disease, meeting criteria for FTD in 10%-15% of cases. In the absence of a precise biomarker, neuropathology is still a valuable tool to understand disease nosology, reach a definite diagnostic confirmation and help define specific subgroups of patients with common phenotypic, genetic and biomarker profiles. However, few neuropathological series have been published, and the frequency of frontotemporal lobar degeneration (FTLD) in MND is difficult to estimate. In this work we describe a large clinicopathological series of MND patients, analysing the frequency of concurrent FTLD changes and trying to define specific subgroups of patients based on their clinical, genetic and pathological characteristics. We performed an observational, retrospective, multicentre case study. We included all cases meeting neuropathological criteria for MND from the Neurological Tissue Bank of the FRCB-IDIBAPS-Hospital Clínic Barcelona Biobank between 1994 and 2022, regardless of their last clinical diagnosis. While brain donation is encouraged in all patients, it is performed in very few, and representativeness of the cohort might not be precise for all patients with MND. We retrospectively reviewed clinical and neuropathological data and describe the main clinical, genetic and pathogenic features, comparing neuropathologic groups between MND with and without FTLD changes and aiming to define specific subgroups. We included brain samples from 124 patients, 44 of whom (35.5%) had FTLD neuropathologic features (i.e. FTLD-MND). Pathologic TDP-43 aggregates were present in 93.6% of the cohort and were more extensive (higher Brettschneider stage) in those with concurrent FTLD (P < 0.001). Motor symptom onset was more frequent in the bulbar region in FTLD-MND cases than in those with isolated MND (P = 0.023), with no differences in survival. We observed a better clinicopathological correlation in the MND group than in the FTLD-MND group (93.8% versus 61.4%; P < 0.001). Pathogenic genetic variants were more common in the FTLD-MND group, especially C9orf72. We describe a frequency of FTLD of 35.5% in our series of neuropathologically confirmed cases of MND. The FTLD-MND spectrum is highly heterogeneous in all aspects, especially in patients with FTLD, in whom it is particularly difficult to define specific subgroups. In the absence of definite biomarkers, neuropathology remains a valuable tool for a definite diagnosis, increasing our knowledge in disease nosology., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction : Clinical trials location is determined by many factors, including the availability of patient populations, regulatory environment, scientific expertise, and cost considerations. In clinical drug development of amyotrophic lateral sclerosis (ALS), where genetic differences have been described and may be related to geographic setting, this could have implications for the clinical interpretation of results in underrepresented geographic settings. Objective : The aim of this study was to review country participation in ALS clinical research based on available data from clinical trial registries and databases. Methods : We performed a scoping review with available information about clinical trials on ALS in ClinicalTrials.gov (CT), EU clinical trials register (EudraCT), WHO International Clinical Trials Registry Platform (ICTRP) and Web of Science (WOS). Inclusion criteria were clinical trials in phase 2 and 3 to treat ALS, recruiting or active not recruiting, from 23/06/2018 to 23/06/2023. Results : The total number of clinical trials identified were 188; 54 studies in CT, 38 in EudraCT, 47 in ICTRP and 49 in WOS. We identified 77 clinical trials after deleting duplicates and applying exclusion criteria. The countries with most studies conducted were the US with 35 studies (10.9%), followed by the United Kingdom, Belgium, France and Germany with 21 studies each one of them (6.5%). Conclusion : The data obtained in our review showed a non-homogeneous distribution in clinical trials at the international level, which may influence the interpretation of the results obtained.

The objective of this study is to evaluate biomarkers for neurodegenerative disorders in adult SMA patients and their potential for monitoring the response to nusinersen. Biomarkers for neurodegenerative disorders were assessed in plasma and CSF samples obtained from a total of 30 healthy older adult controls and 31 patients with adult SMA type 2 and 3. The samples were collected before and during nusinersen treatment at various time points, approximately at 2, 6, 10, and 22 months. Using ELISA technology, the levels of total tau, pNF-H, NF-L, sAPPβ, Aβ40, Aβ42, and YKL-40 were evaluated in CSF samples. Additionally, plasma samples were used to measure NF-L and total tau levels using SIMOA technology. SMA patients showed improvements in clinical outcomes after nusinersen treatment, which were statistically significant only in walkers, in RULM ( p = 0.04) and HFMSE ( p = 0.05) at 24 months. A reduction in sAPPβ levels was found after nusinersen treatment, but these levels did not correlate with clinical outcomes. Other neurodegeneration biomarkers (NF-L, pNF-H, total tau, YKL-40, Aβ40, and Aβ42) were not found consistently changed with nusinersen treatment. The slow progression rate and mild treatment response of adult SMA types 2 and 3 may not lead to detectable changes in common markers of axonal degradation, inflammation, or neurodegeneration, since it does not involve large pools of damaged neurons as observed in pediatric forms. However, changes in biomarkers associated with the APP processing pathway might be linked to treatment administration. Further studies are warranted to better understand these findings.

Objective: The Latin American Epidemiologic study of ALS (LAENALS) aims to gather data on ALS epidemiology, phenotype, and risk factors in Cuba, Chile, and Uruguay, to understand the impact of genetic and environmental factors on ALS., Methods: A harmonized data collection protocol was generated, and a Latin-American Spanish language Register was constructed. Patient data were collected in Uruguay in 2018, in Chile from 2017 to 2019, and in Cuba between 2017 and 2018. Statistical analysis was performed using SPSS 25.0.0 software. Crude cumulative incidence, standardized incidence, and prevalence were calculated in the population aged 15 years and older., Results: During 2017-2019, 90 people with ALS from Uruguay (55.6% men), 219 from Chile (54.6% men), and 49 from Cuba (55.1% men) were included. The cumulative crude incidence in 2018 was 1.73/100,000 persons in Uruguay, 1.08 in Chile and 0.195 in Cuba. Crude prevalence in 2018 was 2.19 per 100,000 persons in Uruguay, 1.39 in Chile and 0.55 in Cuba. Mean age at onset was 61.8 ± 11.96 SD years in Uruguay, 61.9 ± 10.4 SD years in Chile, and 60.21 ± 12.45 SD years in Cuba ( p  = 0.75). Median survival from onset was 32.43 months (21.93 - 42.36) in Uruguay, 24 months (13.5 - 33.5) in Chile, and 29 months (15 - 42.5) in Cuba ( p  = 0.006)., Conclusions: These preliminary data from LAENALS confirm the lower incidence and prevalence of ALS in counties with admixed populations. The LAENALS database is now open to other Latin American countries for harmonized prospective data collection.

Introduction: The objective of this study is to develop a clinical tool for the evaluation and follow-up of adolescent and adult patients with 5q spinal muscular atrophy (SMA) and to design its validation., Methods: This prospective, non-interventional study will be carried out at five centres in Spain and will include patients aged 16 years or older with a confirmed diagnosis of 5q SMA (biallelic mutation of the survival motor neuron 1 [SMN1] gene). A panel of experts made up of neurologists, physiatrists and Spanish patients' association (FundAME), participated in the design of the clinical tool. Physicians will administer the tool at three time points (baseline, 12 months and 24 months). Additionally, data from other questionnaires and scales will be collected. Once recruitment is achieved, an interim statistical analysis will be performed to assess its psychometric properties by applying Rasch analysis and classical statistical tests., Results: The tool will consist of up to 53 items to assess functional status from a clinical perspective in seven key dimensions (bulbar, respiratory, axial, lower, upper, fatigability and other symptoms), which will be collected together with objective clinical measures (body mass index, forced vital capacity, pinch strength and 6-minute walk test)., Conclusions: The validation of this tool will facilitate the clinical evaluation of adult and adolescent patients with SMA and the quantification of their response to new treatments in both clinical practice and research., (© 2024. The Author(s).)

With the advent of gene therapies for amyotrophic lateral sclerosis (ALS), there is a surge in gene testing for this disease. Although there is ample experience with gene testing for C9orf72, SOD1, FUS and TARDBP in familial ALS, large studies exploring genetic variation in all ALS-associated genes in sporadic ALS (sALS) are still scarce. Gene testing in a diagnostic setting is challenging, given the complex genetic architecture of sALS, for which there are genetic variants with large and small effect sizes. Guidelines for the interpretation of genetic variants in gene panels and for counselling of patients are lacking. We aimed to provide a thorough characterization of genetic variability in ALS genes by applying the American College of Medical Genetics and Genomics (ACMG) criteria on whole genome sequencing data from a large cohort of 6013 sporadic ALS patients and 2411 matched controls from Project MinE. We studied genetic variation in 90 ALS-associated genes and applied customized ACMG-criteria to identify pathogenic and likely pathogenic variants. Variants of unknown significance were collected as well. In addition, we determined the length of repeat expansions in C9orf72, ATXN1, ATXN2 and NIPA1 using the ExpansionHunter tool. We found C9orf72 repeat expansions in 5.21% of sALS patients. In 50 ALS-associated genes, we did not identify any pathogenic or likely pathogenic variants. In 5.89%, a pathogenic or likely pathogenic variant was found, most commonly in SOD1, TARDBP, FUS, NEK1, OPTN or TBK1. Significantly more cases carried at least one pathogenic or likely pathogenic variant compared to controls (odds ratio 1.75; P-value 1.64 × 10-5). Isolated risk factors in ATXN1, ATXN2, NIPA1 and/or UNC13A were detected in 17.33% of cases. In 71.83%, we did not find any genetic clues. A combination of variants was found in 2.88%. This study provides an inventory of pathogenic and likely pathogenic genetic variation in a large cohort of sALS patients. Overall, we identified pathogenic and likely pathogenic variants in 11.13% of ALS patients in 38 known ALS genes. In line with the oligogenic hypothesis, we found significantly more combinations of variants in cases compared to controls. Many variants of unknown significance may contribute to ALS risk, but diagnostic algorithms to reliably identify and weigh them are lacking. This work can serve as a resource for counselling and for the assembly of gene panels for ALS. Further characterization of the genetic architecture of sALS is necessary given the growing interest in gene testing in ALS., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: To describe the clinical and demographic characteristics of patients with MND treated with riluzole by comparing two dosage forms (oral suspension and tablets), as well as the impact on survival in patients with and without dysphagia according to the form of dosage. Methods: Retrospective and prospective cohort of patients diagnosed with MND at the multidisciplinary functional unit of Motor Neuron Disease in our center in the period between 1 of January 2011 and 31 of December 2020 ( n  = 742). A descriptive analysis (univariate and bivariate) was carried out and survival curves were estimated. Results: During the follow-up period, 402 males (54.18%) and 340 females (45.82%) were diagnosed with MND. Of these patients, 632 (97.23%) were being treated with 100mg riluzole: 282 (54.55%) patients took this in tablet form and 235 (45.45%) oral suspension. Riluzole in tablet form is taken more frequently by men than women, in younger age ranges, and mostly without dysphagia (78.31%). Also, it is the predominant dosage form for classic spinal ALS and respiratory phenotypes. Dosages via oral suspension are taken by patients in the older age ranges (over 64.8 years), mostly with dysphagia (53.67%) and more frequently with bulbar phenotypes such as classic bulbar ALS and PBP. Because of this, patients using oral suspension (most of them with dysphagia) had a poorer survival rate (at 90% CI) than patients using tablets (most of them without dysphagia). Conclusions: The most appropriate dosage form should be given according to the patient's needs at each stage of the disease and, furthermore, oral suspension could improve adherence to treatment because it avoids having to change from one form (tablet) to the other (suspension) when swallowing disorders appear.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that results in progressive weakness of skeletal muscles including respiratory muscles. Epidemiological and clinical aspects of ALS are derived from a few world regions with very little representation of low- and middle-income countries. We therefore set out to determine the epidemiological and clinical phenotype of individuals with ALS in Ethiopia. Methods: Multicenter retrospective analysis was conducted using clinical records from ALS patients seen in Ethiopia at Tikur Anbessa Specialized Hospital and Yehuleshet specialty clinic between January 2016 and August 2021. The data collected included clinical characteristics, disease-related symptoms, a revised ALS functional rating scale, and medications. Results: Patients in Ethiopia had a younger age of onset with a mean age of disease onset of 51.9 years. 2.9% of patients had juvenile ALS, and the male-to-female ratio was almost 2:1. 4.9% had a positive family history of the disease. 68% of patients had spinal region involvement at onset, while 32% had bulbar region involvement at onset. Riluzole was used by 31% of ALS patients. 20.6% of patients had some respiratory symptoms, but none received a standard respiratory function assessment. 33.3% of patients were wheelchair-bound. Conclusion: In this retrospective study spanning 5 years, we examined the clinical phenotype of ALS in Ethiopian patients. Our findings suggest that most patients had clinically definite ALS with spinal region involvement. Further research, including genetic and epigenetic information, is necessary to understand the early onset of the disease in Ethiopia.

Aims: (Phospho)proteomics of old-aged subjects without cognitive or behavioral symptoms, and without AD-neuropathological changes and lacking any other neurodegenerative alteration will increase understanding about the physiological state of human brain aging without associate neurological deficits and neuropathological lesions., Methods: (Phospho)proteomics using conventional label-free- and SWATH-MS (Sequential window acquisition of all theoretical fragment ion spectra mass spectrometry) has been assessed in the frontal cortex (FC) of individuals without NFTs, senile plaques (SPs) and age-related co-morbidities classified by age (years) in four groups; group 1 (young, 30-44); group 2 (middle-aged: MA, 45-52); group 3 (early-elderly, 64-70); and group 4 (late-elderly, 75-85)., Results: Protein levels and deregulated protein phosphorylation linked to similar biological terms/functions, but involving different individual proteins, are found in FC with age. The modified expression occurs in cytoskeleton proteins, membranes, synapses, vesicles, myelin, membrane transport and ion channels, DNA and RNA metabolism, ubiquitin-proteasome-system (UPS), kinases and phosphatases, fatty acid metabolism, and mitochondria. Dysregulated phosphoproteins are associated with the cytoskeleton, including microfilaments, actin-binding proteins, intermediate filaments of neurons and glial cells, and microtubules; membrane proteins, synapses, and dense core vesicles; kinases and phosphatases; proteins linked to DNA and RNA; members of the UPS; GTPase regulation; inflammation; and lipid metabolism. Noteworthy, protein levels of large clusters of hierarchically-related protein expression levels are stable until 70. However, protein levels of components of cell membranes, vesicles and synapses, RNA modulation, and cellular structures (including tau and tubulin filaments) are markedly altered from the age of 75. Similarly, marked modifications occur in the larger phosphoprotein clusters involving cytoskeleton and neuronal structures, membrane stabilization, and kinase regulation in the late elderly., Conclusions: Present findings may increase understanding of human brain proteostasis modifications in the elderly in the subpopulation of individuals not having AD neuropathological change and any other neurodegenerative change in any telencephalon region.

A new polyvalent wide-scope analytical method, valid for both raw and processed (juices) fruits, combining target and non-target strategies, has been developed and validated to determine low concentrations of 260 pesticides, as well as many potential non-target substances and metabolites. The target approach has been validated according to SANTE Guide requirements. Trueness, precision, linearity, and robustness values were validated in raw fruit (apple) and juice (apple juice) as representative solid and liquid food commodities. Recoveries were between 70-120% and two ranges of linearity were observed: 0.5-20 μg kg -1 (0.5-20 μg L -1 apple juice) and 20-100 μg kg -1 (20-100 μg L -1 apple juice). The limits of quantification (LOQs) reached were lower than 0.2 μg kg -1 in apple (0.2 μg L -1 apple juice) in most cases. The developed method, based on QuEChERS extraction followed by gas chromatography-high resolution mass spectrometry (GC-HRMS), achieves part-per-trillions lower limits, which allowed the detection of 18 pesticides in commercial samples. The non-target approach is based on a retrospective analysis of suspect compounds, which has been optimized to detect up to 25 additional compounds, increasing the scope of the method. This made it possible to confirm the presence of two pesticide metabolites which were not considered in the target screening, phtamlimide and tetrahydrophthalimide.

Background and Objective: Bulbar dysfunction is a term used in amyotrophic lateral sclerosis (ALS). It refers to motor neuron disability in the corticobulbar area of the brainstem which leads to a dysfunction of speech and swallowing. One of the earliest symptoms of bulbar dysfunction is voice deterioration characterized by grossly defective articulation, extremely slow laborious speech, marked hypernasality and severe harshness. Recently, research efforts have focused on voice analysis to capture this dysfunction. The main aim of this paper is to provide a new methodology to diagnose this dysfunction automatically at early stages of the disease, earlier than clinicians can do., Methods: The study focused on the creation of a voiceprint consisting of a pattern generated from the quasi-periodic components of a steady portion of the five Spanish vowels and the computation of the five principal and independent components of this pattern. Then, a set of statistically significant features was obtained using multivariate analysis of variance and the outcomes of the most common supervised classification models were obtained., Results: The best model (random forest) obtained an accuracy, sensitivity and specificity of 88.3%, 85.0% and 95.0% respectively when classifying bulbar vs. control participants but the results worsened when classifying bulbar vs. no-bulbar patients (accuracy, sensitivity and specificity of 78.7%, 80.0% and 77.5% respectively for support vector machines). Due to the great uncertainty found in the annotated corpus of the ALS patients without bulbar involvement, we used a safe semi-supervised support vector machine to relabel the ALS participants diagnosed without bulbar involvement as bulbar and no-bulbar. The performance of the results obtained increased, especially when classifying bulbar and no-bulbar patients obtaining an accuracy, sensitivity and specificity of 91.0%, 83.3% and 100.0% respectively for support vector machines. This demonstrates that our model can improve the diagnosis of bulbar dysfunction compared not only with clinicians, but also the methods published to date., Conclusions: The results obtained demonstrate the efficiency and applicability of the methodology presented in this paper. It may lead to the development of a cheap and easy-to-use tool to identify this dysfunction in early stages of the disease and monitor progress., Competing Interests: Declaration of Competing Interest Authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier B.V.)

Introduction: Outcome measures traditionally used in spinal muscular atrophy (SMA) clinical trials are inadequate to assess the full range of disease severity. The aim of this study was to assess the psychometric properties of a set of existing questionnaires and new items, gathering information on the impact of SMA from the patient and caregiver perspectives., Methods: This was a multicenter, prospective, noninterventional study including patients with a confirmed diagnosis of 5q-autosomal-recessive SMA aged 8 years and above, or their parents (if aged between 2 and 8 years). The set of outcome measurements included the SMA Independence Scale (SMAIS) patient and caregiver versions, the Neuro-QoL Fatigue Computer Adaptive Test (CAT), the Neuro-QoL Pain Short Form-Pediatric Pain, the PROMIS adult Pain Interference CAT, and new items developed by Fundación Atrofia Muscular España: perceived fatigability, breathing and voice, sleep and rest, and vulnerability. Reliability, construct validity, discriminant validity, and sensitivity to change (4 months from baseline) were measured., Results: A total of 113 patients were included (59.3% 2-17 years old, 59.3% male, and 50.4% with SMA type II). Patients required moderate assistance [mean patient and caregiver SMAIS (SD) scores were 31.1 (12.8) and 7.6 (11.1), respectively]. Perceived fatigability was the most impacted domain, followed by vulnerability. Cronbach's alpha coefficient for perceived fatigability, breathing and voice, and vulnerability total scores were 0.92, 0.88, and 0.85, respectively. The exploratory factor analysis identified the main factors considered in the design, except in the sleep and rest domain. All questionnaires were able to discriminate between the Clinical Global Impression-Severity scores and SMA types. Sensitivity to change was only found for the SMAIS caregiver version and vulnerability items., Conclusions: This set of outcome measures showed adequate reliability, construct validity, and discriminant validity and may constitute a valuable option to measure symptom severity in patients with SMA., (© 2022. The Author(s).)

Our research project computed the direct health costs of patients with amyotrophic lateral sclerosis (ALS) in a Spanish multidisciplinary unit and explored the main factors associated. Besides analyzing a context with universal health care provision, we used an administrative health care dataset from the most crucial center unit treating ALS in Catalonia (80% of total patients). Our results show that the direct health cost of caring for an ALS patient in our unit was 5,158€per patient/year. This cost was not influenced by the onset of the disease, sex or age, but it increased if the patient lived near our center since this facilitates the frequency of follow-up visits. Finally, the higher the educational level, the lower the direct health costs.

Background and Objective: Forced vital capacity (FVC) less than 50% of predicted is one of the main parameters used for Non-Invasive Ventilation (NIV) initiation in Amyotrophic Lateral Sclerosis (ALS). Recent studies suggest that higher values of FVC could be considered as a threshold. The aim of this study is to evaluate whether early use of NIV improves the prognosis of ALS patients compared with standard initiation., Methods: This is a randomized, parallel, multicenter, open-label, controlled clinical trial, with recruitment at the ALS outpatient multidisciplinary units of six Spanish hospitals. Patients were included when their FVC reached the 75% threshold and were randomized by computer, stratifying by center in an allocation ratio of 1:1 to Early NIV (FVC below 75%) or Standard NIV (FVC below 50%) initiation. The primary outcome was time to death or tracheostomy.Trial registration number ClinicalTrials.gov: NCT01641965., Results: Between May 2012 and June 2014, 42 patients were randomized to two groups, 20 to Early NIV and 22 to Standard NIV initiation. We found differences in survival in favor of the intervention group: an incidence of mortality (2.68 [1.87-5.50] vs. 3.33 [1.34-4.80] person-months) and a median survival (25.2 vs. 19.4 months), although without reaching statistical significance (p = 0.267)., Conclusions: This trial did not reach the primary endpoint of survival; nevertheless, it is the first Randomized Controlled Trial (RCT) to demonstrate the benefits of early NIV in slowing the decline of respiratory muscle strength and reducing adverse events. Although not all the results reached statistical significance, all the analyzed data favor early NIV. In addition, this study demonstrates good tolerance and compliance with early NIV without quality of sleep impairment. These data reinforce the early respiratory evaluation of ALS patients and NIV initiation with an FVC of around 75%.

Introduction: The aim of this study is to describe the frequency and distribution of SOD1 mutations in Spain, and to explore those factors contributing to their phenotype and prognosis., Methods: Seventeen centres shared data on amyotrophic lateral sclerosis (ALS) patients carrying pathogenic or likely pathogenic SOD1 variants. Multivariable models were used to explore prognostic modifiers., Results: In 144 patients (from 88 families), 29 mutations (26 missense, 2 deletion/insertion and 1 frameshift) were found in all 5 exons of SOD1, including 7 novel mutations. 2.6% of ALS patients (including 17.7% familial and 1.3% sporadic) were estimated to carry SOD1 mutations. Its frequency varied considerably between regions, due to founder events. The most frequent mutation was p.Gly38Arg (n = 58), followed by p.Glu22Gly (n = 11), p.Asn140His (n = 10), and the novel p.Leu120Val (n = 10). Most mutations were characterized by a protracted course, and some of them by atypical phenotypes. Older age of onset was independently associated with faster disease progression (exp(Estimate) = 1.03 [0.01, 0.05], p = 0.001) and poorer survival (HR = 1.05 [1.01, 1.08], p = 0.007), regardless of the underlying mutation. Female sex was independently associated to faster disease progression (exp(Estimate) = 2.1 [1.23, 3.65], p = 0.012) in patients carrying the p.Gly38Arg mutation, resulting in shorter survival compared with male carriers (236 vs 301 months)., Conclusions: These data may help to evaluate the efficacy of SOD1 targeted treatments, and to expand the number of patients that might benefit from these treatments., (This article is protected by copyright. All rights reserved.)

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., (© 2022. The Author(s).)

Background and Purpose: Mos scales currently used to evaluate spinal muscular atrophy (SMA) patients have only been validated in children. The aim of this study was to assess the construct validity and responsiveness of several outcome measures in adult SMA patients., Methods: Patients older than 15 years and followed up in five referral centres for at least 6 months, between October 2015 and August 2020, with a motor function scale score (Hammersmith Functional Motor Scale Expanded [HFMSE], Revised Upper Limb module [RULM]) were included. Bedside functional scales (Egen Klassification [EK2], Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) were also collected when available. Spearman's rho correlations (rs) and Bangdiwala's concordance test (B) were used to evaluate the scales' construct validity. Monthly slopes of change were used to calculate their responsiveness of the scales., Results: The study included 79 SMA patients, followed up for a mean of 16 months. All scales showed strong correlations with each other (rs &gt; 0.70). A floor effect in motor function scales was found in the weakest patients (HFMSE &lt; 5 and RULM &lt; 10), and a ceiling effect was found in stronger patients (HFMSE &gt; 60 and RULM &gt; 35). The ALSFRS-R (B = 0.72) showed a strong ability to discriminate between walkers, sitters and non-sitters, and the HFMSE (B = 0.86) between walkers and sitters. The responsiveness was low overall, although in treated patients a moderate responsiveness was found for the ALSFRS-R and HFMSE in walkers (0.69 and 0.61, respectively) and for EK2 in sitters (0.65) and non-sitters (0.60)., Conclusions: This study shows the validity and limitations of the scales most frequently used to assess adult SMA patients. Overall, bedside functional scales showed some advantages over motor scales, although all showed limited responsiveness., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Introduction: Spinal muscular atrophy (SMA) is a rare disease whose diagnosis and treatment are complex. In Spain, there are two orphan medicines that are currently financed by the state, nusinersen and onasemnogene abeparvovec and, a third in process, risdiplam. The objective was to detect possible causes of inequity in the diagnosis and treatment of SMA in Spain., Materials and Method: Descriptive study realized in two phases: a first phase of bibliographic revision and a second phase of semi-structured interviews with clinical experts in SMA in Andalusia, Castilla-La Mancha, Catalonia and Murcia., Results: The number of centers, services or units of reference, the availability of regional autonomous plans for rare diseases and pilot programs of neonatal screenings can regulate access to treatments. The number of new patients diagnosed per year is estimated between one and six in the four autonomous communities (ACs) of Spain studied. Differences were not found in logistical resources. Two of the four ACs studied have regional autonomous plans for rare diseases, however, their utility has only had relevance in one of two of the ACs., Conclusions: Important differences in access to nusinersen were not identified in the studied ACs The diagnosis of SMA requires clinical specialized experts and specialized centers for early intervention of disease-modifying therapies.

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 (<18 years) with ALS in Europe. Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS. Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS. Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information.

Background and Purpose: The aim was to assess the safety and efficacy of nusinersen in adult 5q spinal muscular atrophy (SMA) patients., Methods: Patients older than 15 years and followed for at least 6 months with one motor scale (Hammersmith Functional Motor Scale Expanded, HFMSE; Revised Upper Limb Module, RULM) in five referral centers were included. The clinical and patients' global impression of change (CGI-C and PGI-C) were recorded in treated patients at the last visit. Functional scales (Egen Klassification, EK2; Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, ALSFRS-R) and the percentage predicted forced vital capacity were collected when available., Results: Seventy-nine SMA patients (39 treated with nusinersen) were included. Compared with untreated patients, treated patients showed a significant improvement of 2 points (±0.46) in RULM (p &lt; 0.001) after 6 months. After a mean follow-up of 16 months, nusinersen treatment was associated with a significant improvement in HFMSE (odds ratio [OR] 1.15, p = 0.006), the 6-min walk test (OR = 1.07, p &lt; 0.001) and the EK2 (OR = 0.81, p = 0.001). Compared with untreated patients, more treated patients experienced clinically meaningful improvements in all scales, but these differences were statistically significant only for RULM (p = 0.033), ALSFRS-R (p = 0.005) and EK2 (p &lt; 0.001). According to the CGI-C and PGI-C, 64.1% and 61.5% of treated patients improved with treatment. Being a non-sitter was associated with less response to treatment, whilst a longer time of treatment was associated with better response. Most treated patients (77%) presented at least one adverse event, mostly mild., Conclusions: Nusinersen treatment is associated with some improvements in adult SMA patients. Most severely affected patients with complex spines are probably those with the most unfavorable risk-benefit ratio., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease, both in its onset phenotype and in its rate of progression. The aim of this study was to establish whether the dysfunction of the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) measured through cerebrospinal fluid (CSF) proteins and the albumin-quotient (QAlb) are related to the speed of disease progression. An amount of 246 patients diagnosed with ALS were included. CSF and serum samples were determined biochemically for different parameters. Survival analysis based on phenotype shows higher probability of death for bulbar phenotype compared to spinal phenotype ( p -value: 0.0006). For the effect of CSF proteins, data shows an increased risk of death for spinal ALS patients as the value of CSF proteins increases. The same model replicated for CSF albumin yielded similar results. Statistical models determined that the lowest cut-off value for CSF proteins able to differentiate patients with a good prognosis and worse prognosis corresponds to CSF proteins ≥ 0.5 g/L ( p -value: 0.0189). For the CSF albumin, the QAlb ≥0.65 is associated with elevated probability of death ( p -value: 0.0073). High levels of QAlb are a bad prognostic indicator for the spinal phenotype, in addition to high CSF proteins levels that also act as a marker of poor prognosis.

To evaluate senescence mechanisms, including senescence-associated secretory phenotype (SASP), in the motor neuron disease model hSOD1-G93A, we quantified the expression of p16 and p21 and senescence-associated β-galactosidase (SA-β-gal) in nervous tissue. As SASP markers, we measured the mRNA levels of Il1a, Il6, Ifna and Ifnb. Furthermore, we explored whether an alteration of alternative splicing is associated with senescence by measuring the Adipor2 cryptic exon inclusion levels, a specific splicing variant repressed by TAR DNA-binding protein (TDP-43; encoded by Tardbp). Transgenic mice showed an atypical senescence profile with high p16 and p21 mRNA and protein in glia, without the canonical increase in SA-β-gal activity. Consistent with SASP, there was an increase in Il1a and Il6 expression, associated with increased TNF-R and M-CSF protein levels, with females being partially protected. TDP-43 splicing activity was compromised in this model, and the senolytic drug Navitoclax did not alter the disease progression. This lack of effect was reproduced in vitro, in contrast to dasatinib and quercetin, which diminished p16 and p21. Our findings show a non-canonical profile of senescence biomarkers in the model hSOD1-G93A., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Background: Plasma exchange (PE) is used to treat a range of neurological disorders. Based on results demonstrated in Alzheimer's disease, we theorized that PE with albumin replacement (PE-A) might alter the metabolic profile of plasma and cerebrospinal fluid in patients with amyotrophic lateral sclerosis (ALS) by removing disease-inducing molecules. The aim of this study was to evaluate the effect of PE-A on disease progression in ALS., Methods: In this open-label, non-controlled, single-arm, prospective pilot study, 13 adults with ALS had 6 months' treatment with PE-A 5% and 6 months' follow-up. Primary endpoints were changes from baseline in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score and forced vital capacity (FVC) through 48 weeks. A post hoc analysis compared individual patient data with the expected ALSFRS-R progression slope., Results: The median ALSFRS-R score declined throughout the study, although the rate of decline was slower than expected in seven patients at treatment end and in five patients at study end. Six patients remained in the same baseline slope progression category, and four patients improved their slope category at treatment end. Median FVC decreased significantly during the study. Treatment was well tolerated. Of 330 PE-A procedures, 0.9% were associated with potentially related adverse events., Conclusion: Although functional impairment progressed, about two-thirds of patients showed a slower than expected rate of decline at treatment end. Most patients had unaltered (54.5%) or reduced (36.4%) ALSFRS-R slope progression at treatment end. Further evaluation of PE-A in controlled studies involving more patients is warranted., Eudract Number: 2013-004842-40., Trial Registration: ClinicalTrials.gov identifier: NCT02479802., (© 2021. The Author(s).)