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Automatic disease progression prediction models require large amounts of training data, which are seldom available, especially when it comes to rare diseases. A possible solution is to integrate data from different medical centres. Nevertheless, various centres often follow diverse data collection procedures and assign different semantics to collected data. Ontologies, used as schemas for interoperable knowledge bases, represent a state-of-the-art solution to homologate the semantics and foster data integration from various sources. This work presents the BrainTeaser Ontology (BTO), an ontology that models the clinical data associated with two brain-related rare diseases (ALS and MS) in a comprehensive and modular manner. BTO assists in organizing and standardizing the data collected during patient follow-up. It was created by harmonizing schemas currently used by multiple medical centers into a common ontology, following a bottom-up approach. As a result, BTO effectively addresses the practical data collection needs of various real-world situations and promotes data portability and interoperability. BTO captures various clinical occurrences, such as disease onset, symptoms, diagnostic and therapeutic procedures, and relapses, using an event-based approach. Developed in collaboration with medical partners and domain experts, BTO offers a holistic view of ALS and MS for supporting the representation of retrospective and prospective data. Furthermore, BTO adheres to Open Science and FAIR (Findable, Accessible, Interoperable, and Reusable) principles, making it a reliable framework for developing predictive tools to aid in medical decision-making and patient care. Although BTO is designed for ALS and MS, its modular structure makes it easily extendable to other brain-related diseases, showcasing its potential for broader applicability. Database URL https://zenodo.org/records/7886998. [ABSTRACT FROM AUTHOR]

Identifying groups of patients with similar disease progression patterns is key to understand disease heterogeneity, guide clinical decisions and improve patient care. In this paper, we propose a data-driven temporal stratification approach, ClusTric, combining triclustering and hierarchical clustering. The proposed approach enables the discovery of complex disease progression patterns not found by univariate temporal analyses. As a case study, we use Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease with a non-linear and heterogeneous disease progression. In this context, we applied ClusTric to stratify a hospital-based population (Lisbon ALS Clinic dataset) and validate it in a clinical trial population. The results unravelled four clinically relevant disease progression groups: slow progressors, moderate bulbar and spinal progressors, and fast progressors. We compared ClusTric with a state-of-the-art method, showing its effectiveness in capturing the heterogeneity of ALS disease progression in a lower number of clinically relevant progression groups. The authors proposed ClusTric, a temporal stratification approach to find disease progression groups. Applied to Amyotrophic Lateral Sclerosis, the method identifies four progression groups with distinguished characteristics. [ABSTRACT FROM AUTHOR]

Objective: Neurofilament heavy‐chain gene (NEFH) variants are associated with multiple neurodegenerative diseases, however, their relationship with ALS has not been robustly explored. Still, NEFH is commonly included in genetic screening panels worldwide. We therefore aimed to determine if NEFH variants modify ALS risk. Methods: Genetic data of 11,130 people with ALS and 7,416 controls from the literature and Project MinE were analysed. We performed meta‐analyses of published case–control studies reporting NEFH variants, and variant analysis of NEFH in Project MinE whole‐genome sequencing data. Results: Fixed‐effects meta‐analysis found that rare (MAF <1%) missense variants in the tail domain of NEFH increase ALS risk (OR 4.55, 95% CI 2.13–9.71, p < 0.0001). In Project MinE, ultrarare NEFH variants increased ALS risk (OR 1.37 95% CI 1.14–1.63, p = 0.0007), with rod domain variants (mostly intronic) appearing to drive the association (OR 1.45 95% CI 1.18–1.77, pMadsen–Browning = 0.0007, pSKAT‐O = 0.003). While in the tail domain, ultrarare (MAF <0.1%) pathogenic missense variants were also associated with higher risk of ALS (OR 1.94, 95% CI 0.86–4.37, pMadsen–Browning = 0.039), supporting the meta‐analysis results. Finally, several tail in‐frame deletions were also found to affect disease risk, however, both protective and pathogenic deletions were found in this domain, highlighting an intricate architecture that requires further investigation. Interpretation: We showed that NEFH tail missense and in‐frame deletion variants, and intronic rod variants are risk factors for ALS. However, they are not variants of large effect, and their functional impact needs to be clarified in further studies. Therefore, their inclusion in routine genetic screening panels should be reconsidered. [ABSTRACT FROM AUTHOR]

Respiratory dysfunction is an important hallmark of amyotrophic lateral sclerosis (ALS). Elevation of creatine kinase (CK) has been reported in 23–75% of ALS patients, but the underlying mechanisms remain unknown. This work aims to enlighten the role of CK as a prognostic factor of respiratory dysfunction in ALS. A retrospective analysis of demographic and clinical variables, CK, functional decline per month (ΔFS), forced vital capacity (%FVC), and mean amplitude of the phrenic nerve compound motor action potential (pCMAP) in 319 ALS patients was conducted. These measurements were evaluated at study entry, and patients were followed from the moment of first observation until death or last follow-up visit. High CK values were defined as above the 90th percentile (CK ≥ P90) adjusted to sex. We analyzed survival and time to non-invasive ventilation (NIV) as proxies for respiratory impairment. Linear regression analysis revealed that high CK was associated with male sex (p < 0.001), spinal onset (p = 0.018), and FVC ≥ 80% (p = 0.038). CK was 23.4% higher in spinal-onset ALS patients (p < 0.001). High CK levels were not linked with an increased risk of death (p = 0.334) in Cox multivariate regression analysis. CK ≥ P90 (HR = 1.001, p = 0.038), shorter disease duration (HR = 0.937, p < 0.001), lower pCMAP (HR = 0.082, p < 0.001), and higher ΔFS (HR = 1.968, p < 0.001) were risk factors for respiratory failure. The association between high CK levels and poorer respiratory outcomes could derive from cellular metabolic stress or a specific phenotype associated with faster respiratory decline. Our study suggests that CK measurement at diagnosis should be more extensively investigated as a possible marker of poor respiratory outcome in future studies, including a larger population of patients. [ABSTRACT FROM AUTHOR]

Introduction/Aims: The frequency and distribution of upper motor neuron (UMN) signs in primary lateral sclerosis (PLS) are unknown. We aimed to study the spectrum of UMN signs in PLS and compare it with hereditary spastic paraplegia (HSP). Methods: We retrospectively analyzed the frequency of different UMN signs, including hyperreflexia (limbs and jaw), limb and tongue spasticity, Babinski, and Hoffman signs, in PLS patients at first observation and compared this respect to onset region and symptom duration. We also compared PLS versus HSP patients. Results: We included 34 PLS and 20 HSP patients, with a median symptom duration at first visit of 3.0 (interquartile range, IQR = 4.0) and 19.0 (IQR = 22.0) years, respectively. In PLS patients, hyperreflexia of upper (UL) (88.2%) and lower (LL) (91.2%) limbs, and LL spasticity (79.4%) were the most common findings. Spasticity of LL was significantly (p =.012) more frequent in LL‐spinal onset subgroup, tongue spasticity in bulbar‐onset subgroup (p =.021), and Hoffman sign in UL‐spinal onset subgroup (p =.024). The PLS subgroup with shorter disease duration had a higher frequency of abnormal jaw jerk reflex (p =.037). Compared with HSP, PLS patients had a higher frequency of UL hyperreflexia (88.2% vs. 42.1%, p <.001) and UL spasticity (44.1% vs. 0.0%, p <.001). Asymmetric distribution of UMN signs was present in PLS and not in HSP. Discussion: In PLS, UL UMN signs are nearly always present and UMN sign distribution appears to be associated with onset region. At first observation, bulbar involvement, asymmetrical distribution of UMN signs and UL spasticity may indicate PLS versus HSP. [ABSTRACT FROM AUTHOR]

Background: This update of the guideline on the management of amyotrophic lateral sclerosis (ALS) was commissioned by the European Academy of Neurology (EAN) and prepared in collaboration with the European Reference Network for Neuromuscular Diseases (ERN EURO‐NMD) and the support of the European Network for the Cure ALS (ENCALS) and the European Organization for Professionals and Patients with ALS (EUpALS). Methods: Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the effectiveness of interventions for ALS. Two systematic reviewers from Cochrane Response supported the guideline panel. The working group identified a total of 26 research questions, performed systematic reviews, assessed the quality of the available evidence, and made specific recommendations. Expert consensus statements were provided where insufficient evidence was available. Results: A guideline mapping effort revealed only one other ALS guideline that used GRADE methodology (a National Institute for Health and Care Excellence [NICE] guideline). The available evidence was scarce for many research questions. Of the 26 research questions evaluated, the NICE recommendations could be adapted for 8 questions. Other recommendations required updates of existing systematic reviews or de novo reviews. Recommendations were made on currently available disease‐modifying treatments, multidisciplinary care, nutritional and respiratory support, communication aids, psychological support, treatments for common ALS symptoms (e.g., muscle cramps, spasticity, pseudobulbar affect, thick mucus, sialorrhea, pain), and end‐of‐life management. Conclusions: This update of the guideline using GRADE methodology provides a framework for the management of ALS. The treatment landscape is changing rapidly, and further updates will be prepared when additional evidence becomes available. [ABSTRACT FROM AUTHOR]

Introduction: Nusinersen was approved for 5q spinal muscular atrophy (SMA), irrespective of age, SMA type or functional status. Nonetheless, long-term data on adults with milder phenotypes are scarce. We aimed to characterize evolution on motor and respiratory function in our cohort of adults with type 3 SMA. Methods: We conducted a longitudinal retrospective single-center study, including adults (≥18 years) with type 3 SMA under nusinersen for > 22 months. We reported on motor scores and spirometry parameters. Results: Ten patients were included, with a median follow-up of 34 months (range = 22–46). Four patients (40%) were walkers. None used non-invasive ventilation. In Revised Upper Limb Module (RULM) and Expanded Hammersmith Functional Motor Scale (HFMSE), difference of medians increased at 6, 22 and 46 months comparing to baseline (−0.5 vs. + 1.5 vs. + 2.5 in RULM; + 4.0 vs. + 7.5 vs. + 6.0 in HFMSE). Two (50%) walkers presented a clinically meaningful improvement in 6-min walk distance. We did not report any clinically meaningful decrement in motor scores. Spirometry parameters showed an increasing difference of medians in maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) (−3 vs. + 13.4 vs. + 28.7 percentage points of predicted value for MIP; + 11.8 vs. + 13.1 vs. 13.3 percentage points of predicted value for MEP). Discussion: Our cohort supports a sustained benefit of nusinersen in adults with type 3 SMA, in motor and respiratory function. Multicentric studies are still warranted. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive motor neuron disorder with a fatal outcome 3–5 years after disease onset due to respiratory complications. Superoxide dismutase 1 (SOD1) mutations are found in about 2% of all patients. Tofersen is a novel oligonucleotide antisense drug specifically developed to treat SOD1-ALS patients. Our review covers and discusses tofersen pharmacological properties and its phase I/II and III clinical trials results. Other available drugs and their limitations are also addressed. VALOR study failed to meet the primary endpoint (change in the revised Amyotrophic Lateral Sclerosis Functional Rating Scale score from baseline to week 28, tofersen arm vs. placebo), but a significant reduction in plasma neurofilament light chain (NfL) levels was observed in tofersen arm (60% vs. 20%). PrefALS study has proposed plasma NfL has a potential biomarker for presymptomatic treatment, since it increases 6–12 months before phenoconversion. There is probably a delay between plasma NfL reduction and the clinical benefit. ATLAS study will allow more insights regarding tofersen clinical efficacy in disease progression rate, survival, and even disease onset delay in presymptomatic SOD1 carriers. [ABSTRACT FROM AUTHOR]

Erythrocytes play a fundamental role in oxygen delivery to tissues and binding to inflammatory mediators. Evidences suggest that dysregulated erythrocyte function could contribute to the pathophysiology of several neurodegenerative diseases. We aimed to evaluate changes in morphological, biomechanical, and biophysical properties of erythrocytes from amyotrophic lateral sclerosis (ALS) patients, as new areas of study in this disease. Blood samples were collected from ALS patients, comparing with healthy volunteers. Erythrocytes were assessed using atomic force microscopy (AFM) and zeta potential analysis. The patients' motor and respiratory functions were evaluated using the revised ALS Functional Rating Scale (ALSFRS‐R) and percentage of forced vital capacity (%FVC). Patient survival was also assessed. Erythrocyte surface roughness was significantly smoother in ALS patients, and this parameter was a predictor of faster decline in ALSFRS‐R scores. ALS patients exhibited higher erythrocyte stiffness, as indicated by reduced AFM tip penetration depth, which predicted a faster ALSFRS‐R score and respiratory subscore decay. A lower negative charge on the erythrocyte membrane was predictor of a faster ALSFRS‐R and FVC decline. Additionally, a larger erythrocyte surface area was an independent predictor of lower survival. These changes in morphological and biophysical membrane properties of ALS patients' erythrocytes, lead to increased cell stiffness and morphological variations. We speculate that these changes might precipitate motoneurons dysfunction and accelerate disease progression. Further studies should explore the molecular alterations related to these observations. Our findings may contribute to dissect the complex interplay between respiratory function, tissue hypoxia, progression rate, and survival in ALS. [ABSTRACT FROM AUTHOR]

Introduction/Aims: In amyotrophic lateral sclerosis (ALS), the role of spinal interneurons in ALS is underrecognized. We aimed to investigate pre‐ and post‐synaptic modulation of spinal motor neuron excitability by studying the H reflex, to understand spinal interneuron function in ALS. Methods: We evaluated the soleus H reflex, and three different modulation paradigms, to study segmental spinal inhibitory mechanisms. Homonymous recurrent inhibition (H'RI) was assessed using the paired H reflex technique. Presynaptic inhibition of Ia afferents (H'Pre) was evaluated using D1 inhibition after stimulation of the common peroneal nerve. We also studied inhibition of the H reflex after cutaneous stimulation of the sural nerve (H'Pos). Results: Fifteen ALS patients (median age 57.0 years), with minimal signs of lower motor neuron involvement and good functional status, and a control group of 10 healthy people (median age 57.0 years) were studied. ALS patients showed reduced inhibition, compared to controls, in all paradigms (H'RI 0.35 vs. 0.11, p =.036; H'Pre 1.0 vs. 5.0, p =.001; H'Pos 0.0 vs. 2.5, p =.031). The clinical UMN score was a significant predictor of the amount of recurrent and presynaptic inhibition. Discussion: Spinal inhibitory mechanisms are impaired in ALS. We argue that hyperreflexia could be associated with dysfunction of spinal inhibitory interneurons. In this case, an interneuronopathy could be deemed a major feature of ALS. [ABSTRACT FROM AUTHOR]

Background and purpose: Respiratory insufficiency and its complications are the main cause of death in amyotrophic lateral sclerosis (ALS). The impact of diabetes mellitus (DM) on respiratory function of ALS patients is uncertain. Methods: A retrospective cohort study was carried out. From the 1710 patients with motor neuron disease followed in our unit, ALS and progressive muscular atrophy patients were included. We recorded demographic characteristics, functional ALS rating scale (Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised [ALSFRS‐R]) and its subscores at first visit, respiratory function tests, arterial blood gases, phrenic nerve amplitude (PhrenAmpl), and mean nocturnal oxygen saturation (SpO2mean). We excluded patients with other relevant diseases. Two subgroups were analysed: DIAB (patients with DM) and noDIAB (patients without DM). Independent t‐test, χ2, or Fisher exact test was applied. Binomial logistic regression analyses assessed DM effects. Kaplan–Meier analysis assessed survival. p < 0.05 was considered significant. Results: We included 1639 patients (922 men, mean onset age = 62.5 ± 12.6 years, mean disease duration = 18.1 ± 22.0 months). Mean survival was 43.3 ± 40.7 months. More men had DM (p = 0.021). Disease duration was similar between groups (p = 0.063). Time to noninvasive ventilation (NIV) was shorter in DIAB (p = 0.004); total survival was similar. No differences were seen for ALSFRS‐R or its decay rate. At entry, DIAB patients were older (p < 0.001), with lower forced vital capacity (p = 0.001), arterial oxygen pressure (p = 0.01), PhrenAmpl (p < 0.001), and SpO2mean (p = 0.014). Conclusions: ALS patients with DM had increased risk of respiratory impairment and should be closely monitored. Early NIV allowed for similar survival rate between groups. [ABSTRACT FROM AUTHOR]

Primary lateral sclerosis (PLS) is a rare, adult-onset and slowly progressive motor neuron disorder whose clinical core is characterized by upper motor neuron (UMN) dysfunction. Its formal diagnosis is clinically based and disease duration-dependent. Differentiating PLS from other disorders involving UMN can be challenging, particularly in the early stages. Our review covers and discusses different aspects of the PLS field, including the diagnostic criteria and its limitations, its differential diagnosis and their major pitfalls, and the actual role of neurophysiology, neuroimaging, genetics, and molecular biomarkers. Symptomatic treatment of the different manifestations is also addressed. The authors searched MEDLINE and Scopus. They also searched the reference lists of articles identified by our search strategy and reviewed and selected those deemed relevant. They selected papers and studies based on the quality of the report, significance of the findings, and on the author's critical appraise and expertise. It is important to investigate novel molecular biomarkers and plan multicenter clinical trials for PLS. However, this will require a large international project to recruit enough patients, particularly given the diagnostic uncertainty of the current clinical criteria. A better understanding of PLS pathophysiology is crucial for designing disease-targeted therapies. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that affects nerve cells in the brain and spinal cord, causing loss of muscle control, muscle atrophy and in later stages, death. Diagnosis has an average delay of 1 year after symptoms onset, which impairs early management. The identification of a specific disease biomarker could help decrease the diagnostic delay. MicroRNA (miRNA) expression levels have been proposed as ALS biomarkers, and altered function has been reported in ALS pathogenesis. The aim of this study was to assess the differential expression of plasma miRNAs in ALS patients and two control populations (healthy controls and ALS-mimic disorders). For that, 16 samples from each group were pooled, and then 1008 miRNAs were assessed through reverse transcription-quantitative polymerase chain reaction (RT-qPCR). From these, ten candidate miRNAs were selected and validated in 35 ALS patients, 16 ALS-mimic disorders controls and 15 healthy controls. We also assessed the same miRNAs in two different time points of disease progression. Although we were unable to determine a miRNA signature to use as disease or condition marker, we found that miR-7-2-3p, miR-26a-1-3p, miR-224-5p and miR-206 are good study candidates to understand the pathophysiology of ALS. [ABSTRACT FROM AUTHOR]

Motor Neuron Diseases (MND) have a large clinical spectrum, being the most common amyotrophic lateral sclerosis (ALS) but there is significant clinical heterogeneity. Our goal was to investigate this heterogeneity and any potential changes during a long period. We performed a retrospective cohort study among a large Portuguese cohort of MND patients (n = 1550) and investigated changing patterns in clinical and demographic characteristics over the 27-year period of our database. With that aim, patients were divided into three 9-year groups according to the date of their first visit to our unit: P1, 1994–2002; P2, 2003–2011; P3, 2012–2020. The overall cohort's clinical and demographic characteristics are consistent with clinical experience, but our findings point to gradual changes over time. Time pattern analysis revealed statistically significant differences in the distribution of clinical phenotypes, the average age of onset, diagnostic delay, the proportin of patients using respiratory support with noninvasive ventilation (NIV), time to NIV, and survival. Across time, in the overall cohort, we found an increasing age at onset (p = 0.029), a decrease of two months in diagnostic delay (p < 0.001) and a higher relative frequency of progressive muscular atrophy patients. For ALS patients with spinal onset, from P1 to P2, there was a more widespread (54.8% vs 69.4%, p = 0.005) and earlier (36.9 vs 27.2 months, p = 0.05) use of NIV and a noteworthy 13-month increase in median survival (p = 0.041). Our results probably reflect better comprehensive care, and they are relevant for future studies exploring the impact of new treatments on ALS patients. [ABSTRACT FROM AUTHOR]

Numerous potential amyotrophic lateral sclerosis (ALS)‐relevant pathways have been hypothesized and studied preclinically, with subsequent translation to clinical trial. However, few successes have been observed with only modest effects. Along with an improved but incomplete understanding of ALS as a neurodegenerative disease is the evolution of more sophisticated and diverse in vitro and in vivo preclinical modeling platforms, as well as clinical trial designs. We highlight proposed pathological pathways that have been major therapeutic targets for investigational compounds. It is likely that the failures of so many of these therapeutic compounds may not have occurred because of lack of efficacy but rather because of a lack of preclinical modeling that would help define an appropriate disease pathway, as well as a failure to establish target engagement. These challenges are compounded by shortcomings in clinical trial design, including lack of biomarkers that could predict clinical success and studies that are underpowered. Although research investments have provided abundant insights into new ALS‐relevant pathways, most have not yet been developed more fully to result in clinical study. In this review, we detail some of the important, well‐established pathways, the therapeutics targeting them, and the subsequent clinical design. With an understanding of some of the shortcomings in translational efforts over the last three decades of ALS investigation, we propose that scientists and clinicians may choose to revisit some of these therapeutic pathways reviewed here with an eye toward improving preclinical modeling, biomarker development, and the investment in more sophisticated clinical trial designs. [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease, and the time from symptom onset to diagnosis remains long. With the advent of disease‐modifying treatments, the need to identify and diagnose ALS in a timely fashion has never been greater. Methods: We reviewed the literature to define the severity of ALS diagnostic delay, the various factors that contribute to this delay (including patient and physician factors), and the role that site of symptom onset plays in a patient's diagnostic journey. Results: Diagnostic delay is influenced by general practitioners' lack of recognition of ALS due to disease rarity and heterogenous presentations. As a result, patients are referred to non‐neurologists, have unnecessary diagnostic testing, and may ultimately be misdiagnosed. Patient factors include their illness behavior—which impacts diagnostic delay—and their site of symptom onset. Limb‐onset patients have the greatest diagnostic delay because they are frequently misdiagnosed with degenerative spine disease or peripheral neuropathy. Conclusion: Prompt ALS diagnosis results in more effective clinical management, with earlier access to disease‐modifying therapies, multidisciplinary care, and, if desired, clinical trial involvement. Due to lack of commercially available ALS biomarkers, alternative strategies to identify and triage patients who likely have ALS must be employed. Several diagnostic tools have been developed to encourage general practitioners to consider ALS and make an urgent referral to ALS specialists, bypassing unnecessary referrals to non‐neurologists and unnecessary diagnostic workup. [ABSTRACT FROM AUTHOR]

Objectives: High-intensity physical activity and sports prone to repetitive injuries of the cervical spine and head (when associated with vigorous practice) have been suggested as possible risk factors for amyotrophic lateral sclerosis (ALS). Our objective was to evaluate the relationship between the practice of contact sports (boxing, hockey, football, rugby) and ALS. Methods: The study included 2247 individuals, 1326 patients and 921 controls from several European countries. Analysis of the effect of contact sports on ALS was conducted in male participants only, as very few women practiced contact sports. Logistic regression models were used with the response variable as the presence or absence of ALS, with α = 0.05 significance level. Results: A relationship between the practice of contact sports and ALS was found, with those practicing contact sports having 76% higher odds of an ALS diagnosis (OR = 1.76, p = 0.001). In addition, univariate analyses for age (higher risk for older people, p < 0.001), smoking status (higher risk for ex-smokers, p = 0.022) and tobacco exposure (higher risk for more exposure, p = 0.038) also indicated that these variables are risk factors for ALS. In multivariate models, in addition to age, the interaction term between practice of contact sports and tobacco exposure was still significant (p = 0.03). Conclusions: This is one of the largest studies on the role of contact sport in ALS development. Our results support the existence of a relationship between the practice of sports with repetitive trauma at the level of the cervical spine and head, and ALS. This risk appears to be enhanced by tobacco exposure. [ABSTRACT FROM AUTHOR]

Objective: To determine the target population and optimize the study design of the phase 3 clinical trial evaluating reldesemtiv in participants with amyotrophic lateral sclerosis (ALS). Methods: We evaluated the phase 2 study of reldesemtiv, FORTITUDE-ALS, to inform eligibility criteria and design features that would increase trial efficiency and reduce participant burden of the phase 3 trial. Results: In FORTITUDE-ALS, the effect of reldesemtiv was particularly evident among participants in the intermediate- and fast-progressing tertiles for pre-study disease progression. These participants most often had symptom onset ≤24 months and an ALS Functional Rating Scale-Revised (ALSFRS-R) total score ≤44 at baseline. Compared with the overall FORTITUDE-ALS population, the subgroup meeting these criteria declined by fewer ALSFRS-R points at 12 weeks (difference of least-squares mean [SE] versus placebo 1.84 [0.49] and 0.87 [0.35] for the overall population). These inclusion criteria will be used for the phase 3 clinical trial, COURAGE-ALS, in which the primary outcome is the change in ALSFRS-R total score at week 24. We also measure durable medical equipment use and evaluate strength in muscles expected to change rapidly. To reduce participant burden, study visits are often remote, and strength evaluation is simplified to reduce time and effort. Conclusions: In COURAGE-ALS, the phase 3 clinical trial to evaluate reldesemtiv, the sensitivity of detecting a potential treatment effect may be increased by defining eligibility criteria that limit the proportion of participants who have slower disease progression. Implementing remote visits and simplifying strength measurements will reduce both site and participant burden. ClinicalTrials.gov identifiers: NCT03160898 (FORTITUDE-ALS) and NCT04944784 (COURAGE-ALS) [ABSTRACT FROM AUTHOR]

Objectives: Transcranial magnetic stimulation (TMS) is a technique to assess motor system function which has been used extensively in amyotrophic lateral sclerosis (ALS). Information on the changes during disease progression is scarce. We aimed to collect this information in a single source. Methods: Literature search tools and personal searching were used to find relevant data. Results: In ALS, 1. Motor threshold tends to increase in hand muscles over disease progression. 2. Central motor conduction time is not a sensitive measurement. 3. Motor evoked potential amplitude decreases, in particular in lower limbs. 4. Primary peak from the peristimulus time histogram (PSTH) reduces in amplitude and synchronicity, but longer duration. 5. Inhibitory responses using PSTH are more pronounced over the disease course. 6. In hand muscles central silent period (CSP) is shorter early in the disease but increases with time. 7. Short inhibitory cortical interval (SICI) is abnormal in the very early disease stage and shows greater abnormality over time. 8. Area and volume in cortical maps of hand muscle decrease markedly with disease progression. Discussion: TMS studies evaluating changes over time in ALS suggest that measuring interneuronal inhibitory dysfunction is a promising method to track progression but motor amplitude and cortical maps should be investigated further. Conclusions: Available TMS studies quantifying central motor dysfunction are insufficient to propose a single physiological measurement for evaluating progression in ALS. [ABSTRACT FROM AUTHOR]

Background and purpose: Respiratory insufficiency and its complications are the main cause of death in amyotrophic lateral sclerosis (ALS). Respiratory symptoms are scored in questions Q10 (dyspnoea) and Q11 (orthopnoea) of the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS‐R). The association of respiratory test alterations with respiratory symptoms is unclear. Methods: Patients with ALS and progressive muscular atrophy were included. We retrospectively recorded demographic data, ALSFRS‐R, forced vital capacity (FVC), maximal inspiratory (MIP) and expiratory (MEP) pressures, mouth occlusion pressure at 100 ms, nocturnal oximetry (SpO2mean), arterial blood gases, and phrenic nerve amplitude (PhrenAmpl). Three groups were categorized: G1, normal Q10 and Q11; G2, abnormal Q10; and G3, abnormal Q10 and Q11 or only abnormal Q11. A binary logistic regression model explored independent predictors. Results: We included 276 patients (153 men, onset age = 62.6 ± 11.0 years, disease duration = 13.0 ± 9.6 months, spinal onset in 182) with mean survival of 40.1 ± 26.0 months. Gender, onset region, and disease duration were similar in G1 (n = 149), G2 (n = 78), and G3 (n = 49). Time to noninvasive ventilation (NIV) was shorter in G3 (p < 0.001), but survival was similar. ALSFRS‐R subscores were significantly different (G1 > G2 > G3, p < 0.001), except for lower limb subscore (p = 0.077). G2 and G3 patients were older than G1 (p < 0.001), and had lower FVC, MIP, MEP, PhrenAmpl, and SpO2mean. Independent predictors for G2 were MIP and SpO2mean; for G3, the only independent predictor was PhrenAmpl. Conclusions: These three distinct ALS phenotypic respiratory categories represent progressive stages of ventilatory dysfunction, supporting ALSFRS‐R clinical relevance. Orthopnoea is a severe symptom that should prompt NIV, phrenic nerve response being an independent predictor. Early NIV promotes similar survival for G2 and G3. [ABSTRACT FROM AUTHOR]

This work proposes a new class of explainable prognostic models for longitudinal data classification using triclusters. A new temporally constrained triclustering algorithm, termed TCtriCluster, is proposed to comprehensively find informative temporal patterns common to a subset of patients in a subset of features (triclusters), and use them as discriminative features within a state-of-the-art classifier with guarantees of interpretability. The proposed approach further enhances prediction with the potentialities of model explainability by revealing clinically relevant disease progression patterns underlying prognostics, describing features used for classification. The proposed methodology is used in the Amyotrophic Lateral Sclerosis (ALS) Portuguese cohort (N = 1321), providing the first comprehensive assessment of the prognostic limits of five notable clinical endpoints: need for non-invasive ventilation (NIV); need for an auxiliary communication device; need for percutaneous endoscopic gastrostomy (PEG); need for a caregiver; and need for a wheelchair. Triclustering-based predictors outperform state-of-the-art alternatives, being able to predict the need for auxiliary communication device (within 180 days) and the need for PEG (within 90 days) with an AUC above 90%. The approach was validated in clinical practice, supporting healthcare professionals in understanding the link between the highly heterogeneous patterns of ALS disease progression and the prognosis. [ABSTRACT FROM AUTHOR]

Introduction: Caveolin-1 and Caveolin-2 (CAV1 and CAV2) are proteins associated with intercellular neurotrophic signalling. There is converging evidence that CAV1 and CAV2 (CAV1/2) genes have a role in amyotrophic lateral sclerosis (ALS). Disease-associated variants have been identified within CAV1/2 enhancers, which reduce gene expression and lead to disruption of membrane lipid rafts. Methods: Using large ALS whole-genome sequencing and post-mortem RNA sequencing datasets (5,987 and 365 tissue samples, respectively), and iPSCderived motor neurons from 55 individuals, we investigated the role of CAV1/2 expression and enhancer variants in the ALS phenotype. Results: We report a differential expression analysis between ALS cases and controls for CAV1 and CAV2 genes across various post-mortem brain tissues and three independent datasets. CAV1 and CAV2 expression was consistently higher in ALS patients compared to controls, with significant results across the primary motor cortex, lateral motor cortex, and cerebellum. We also identify increased survival among carriers of CAV1/2 enhancer mutations compared to non-carriers within Project MinE and slower progression as measured by the ALSFRS. Carriers showed a median increase in survival of 345 days. Discussion: These results add to an increasing body of evidence linking CAV1 and CAV2 genes to ALS. We propose that carriers of CAV1/2 enhancer mutations may be conceptualised as an ALS subtype who present a less severe ALS phenotype with a longer survival duration and slower progression. Upregulation of CAV1/2 genes in ALS cases may indicate a causal pathway or a compensatory mechanism. Given prior research supporting the beneficial role of CAV1/2 expression in ALS patients, we consider a compensatory mechanism to better fit the available evidence, although further investigation into the biological pathways associated with CAV1/2 is needed to support this conclusion. [ABSTRACT FROM AUTHOR]

Objective To describe the clinical features and progression of patients with respiratory onset amyotrophic lateral sclerosis (ALS). Methods: We analyzed the clinical features, including respiratory tests, functional score, noninvasive ventilation (NIV) time and survival of ALS patients with respiratory-onset in our database consisting of 1688 patients. In a subset of 625 ALS patients we analyzed the spreading pattern to other bodily regions. Results: We included 1579 patients with ALS. Sixty-three patients (4%) presented respiratory-onset (79.4% men, mean onset-age 67.7 ± 8.9yrs). All had predominant LMN involvement, and significant weight loss (>10%) was identified in 38.9%. The respiratory tests were abnormal in these respiratory-onset patients (p < 0.001). ALSFRS-R respiratory subscore was lower in this population (p < 0.001). NIV was adapted in 84.1%, sooner than in the larger group of ALS patients (p < 0.001), and survival from disease onset was shorter (p < 0.001). Respiratory-onset was a predictor of time to NIV (X2=42.0, p < 0.001) and of survival (X2=7.1, p = 0.008). The spreading pattern was studied in 18 patients with isolated respiratory-onset. The progression interval to the 2nd region was 4.7 ± 5.7mo and to a 3rd region 6.1 ± 8.7mo. Different patterns of spread had no impact on survival. Conclusions: This phenotype is typically seen in emaciated older men with predominant lower motor neuron involvement, and is associated with diaphragm paresis and central respiratory involvement. NIV adaptation is rapid but total survival is shorter than in the other patients. Spreading pattern did not affect time to NIV adaptation or total survival, as NIV support is a modifying treatment in the course of ALS. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) and myopathy have been already described as part of a common genetic syndrome called multisystem proteinopathy. They may occur together or not, and can be associated with other clinical features such as frontotemporal dementia and Paget's bone disease. In addition, primary skeletal muscle involvement has been also reported in inherited forms of lower motor neuron disease, in spinal–bulbar muscular atrophy and in spinal muscular atrophy. We aim to characterize three sporadic, spinal-onset ALS patients, one with a concurrent non-specific myopathy, and two with a previous diagnosis of myopathy before upper and lower motor neuron signs emerged. Perhaps our sporadic ALS cases associated with myopathy share a common, but still unknown, pathogenic background. These cases raise the paradigm of a possible interplay between skeletal muscle degeneration and motor neuron damage. [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with a median survival of 2--5 years. An early diagnosis is essential for providing ALS patients the finest management possible. Studies from different countries report a similar median diagnostic delay of around 12 months, which is still far from desirable. We analyzed the diagnostic pathway in different countries in order to identify the major challenges. Methods: We studied a cohort of 1,405 ALS patients fromfive different centers, in four different countries (Turkey, Germany, Poland, and Portugal), which collaborated in a common database. Demographic, disease and sociocultural factors were collected. Time from first symptom onset to first medical evaluation and to diagnosis, the specialist assessment and investigations requested were analyzed. Factors contributing to diagnostic delay were evaluated by multivariate linear regression. Results: Themedian diagnostic delay fromfirst symptomonset was 11months and was similar between centers. Major differences were seen in the time from symptom onset to first medical evaluation. An earlier first medical evaluation was associated with a longer time to diagnosis, highlighting that ALS diagnosis is not straightforward in the early stages of the disease. The odds for ALS diagnosis were superior when evaluated by a neurologist and increased over time. Electromyography was decisive in establishing the diagnosis. Conclusions: We suggest that a specific diagnostic test for ALS-- a specific biomarker--will be needed to achieve early diagnosis. Early referral to a neurologist and to electromyography is important for early ALS diagnosis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Amyotrophic Lateral Sclerosis is a devastating neurodegenerative disease causing rapid degeneration of motor neurons and usually leading to death by respiratory failure. Since there is no cure, treatment’s goal is to improve symptoms and prolong survival. Non-invasive Ventilation (NIV) is an effective treatment, leading to extended life expectancy and improved quality of life. In this scenario, it is paramount to predict its need in order to allow preventive or timely administration. In this work, we propose to use itemset mining together with sequential pattern mining to unravel disease presentation patterns together with disease progression patterns by analysing, respectively, static data collected at diagnosis and longitudinal data from patient follow-up. The goal is to use these static and temporal patterns as features in prognostic models, enabling to take disease progression into account in predictions and promoting model interpretability. As case study, we predict the need for NIV within 90, 180 and 365 days (short, mid and long-term predictions). The learnt prognostic models are promising. Pattern evaluation through growth rate suggests bulbar function and phrenic nerve response amplitude, additionally to respiratory function, are significant features towards determining patient evolution. This confirms clinical knowledge regarding relevant biomarkers of disease progression towards respiratory insufficiency. [ABSTRACT FROM AUTHOR]

Background and purpose: Progression rate is quite variable in amyotrophic lateral sclerosis (ALS); thus, tools for profiling disease progression are essential for timely interventions. The objective was to apply dynamic Bayesian networks (DBNs) to establish the influence of clinical and demographic variables on disease progression rate. Methods: In all, 664 ALS patients from our database were included stratified into slow (SP), average (AP) and fast (FP) progressors, according to the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS‐R) rate of decay. The sdtDBN framework was used, a machine learning model which learnt optimal DBNs with both static (gender, age at onset, onset region, body mass index, disease duration at entry, familial history, revised El Escorial criteria and C9orf72) and dynamic (ALSFRS‐R scores and sub‐scores, forced vital capacity, maximum inspiratory pressure, maximum expiratory pressure and phrenic amplitude) variables. Results: Disease duration and body mass index at diagnosis are the foremost influences amongst static variables. Disease duration is the variable that better discriminates the three groups. Maximum expiratory pressure is the respiratory test with prevalent influence on all groups. ALSFRS score has a higher influence on FP, but lower on AP and SP. The bulbar sub‐score has considerable influence on FP but limited on SP. Limb function has a more decisive influence on AP and SP. The respiratory sub‐score has little influence in all groups. ALSFRS‐R questions 1 (speech) and 9 (climbing stairs) are the most influential in FP and SP, respectively. Conclusions: The sdtDBN analysis identified five variables, easily obtained during clinical evaluation, which are the most influential for each progression group. This insightful information may help to improve prognosis and care. [ABSTRACT FROM AUTHOR]

Objective: Amyotrophic lateral sclerosis (ALS) pathogenesis is still unclear, its course is considerably variable, and prognosis is hard to determine. Despite much research, there is still a lack of easily accessible markers predicting prognosis. We investigated routine blood parameters in ALS patients regarding correlations with disease severity, progression rate, and survival. Additionally, we analyzed disease and patients' characteristics relating to baseline blood parameter levels. Methods: We analyzed creatine kinase (CK), albumin (ALB), creatinine (CREA), total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and triglycerides (TG) levels around time of diagnosis in 1,084 ALS patients. We carried out linear regression analyses including disease and patients' characteristics with each blood parameter to detect correlations with them. Linear regression models were performed for ALSFRS-R at study entry, its retrospectively defined rate of decay and prospectively collected progression rate. Different survival analysis methods were used to examine associations between blood parameters and survival. Results: We found higher CK (p-value 0.001), ALB (p-value <0.001), CREA (p-value <0.001), and HDL levels (p-value 0.044) at time of diagnosis being associated with better functional status according to ALSFRS-R scores at study entry. Additionally, higher CREA levels were associated with lower risk of death (p-value 0.003). Conclusions: Our results indicate potential of CK, ALB, CREA, and HDL as disease severity or progression markers, and may also provide clues to ALS pathogenesis. However, these values are highly dependent on other variables, and further careful, longitudinal analyses will be necessary to prove the relevance of our findings. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) causes dysphagia and consequent poor nutrition. Sometimes enteral feeding is offered. Percutaneous endoscopic gastrostomy (PEG) is currently the technique of choice for enteral nutrition of these patients. This systematic review addresses the role of PEG and other enteral feeding techniques in maintaining ALS patients' survival and quality of life and in identifying prognostic factors for survival, in order to optimize their usefulness. We also evaluated the mortality of enteral feeding in the first 30 days after each procedure and its complications. Studies were retrieved from Pubmed, Google Scholar, and Cochrane databases, using the relevant keywords, and by hand search. The inclusion criteria were prospective and retrospective designs of studies of people with clinically diagnosed ALS in whom gastrostomy or nasogastric enteral feeding were used in management, published in English. Studies with sample sizes <40, or which focused on a specific gastrostomy technique utilizing less than 30 subjects were excluded in order to avoid small sample bias. We conclude that PEG is safe and probably prolongs survival in non-malnourished ALS patients. However, older age at onset, marked loss of weight or reduced body mass index from symptomatic onset, and marked respiratory dysfunction negatively influence the outcome after PEG insertion. The currently available evidence does not meaningfully address the impact of PEG on quality of life in ALS. The literature about other enteral feeding techniques is insufficient for reliable conclusions. The optimum time for PEG insertion and preferences for specific gastrostomy techniques also require more investigation. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Age can affect hand muscles non‐uniformly. We investigated the influence of age on the compound muscle action potential (CMAP) amplitude of the hand muscles and the derived split‐hand index (SHI). Methods: We studied 244 subjects investigated for suspected myasthenia gravis but without neuromuscular disorders. Abductor pollicis brevis (APB), first dorsal interosseous (FDI), and abductor digiti minimi (ADM) CMAPs were obtained by supramaximal stimulation at the wrist, recording with surface electrodes while checking the best recording site. We applied Tukey's HSD and Kruskal–Wallis one‐way analysis of variance for comparing age groups defined by median and interquantile ranges (IQRs). Spearman's rank correlation coefficient and linear regression were used for testing age‐dependence of measurements. Results: Median age was 61.5 y (first IQR, 44.5; third IQR, 72.0; range 18–89). Age and neurophysiological measurements were similar between genders. APBCMAP, FDICMAP, ADMCMAP, and SHI were correlated with age (P <.001). Median and cutoff values were significantly different between age groups. APBCMAP, FDICMAP, and ADMCMAP decreased by 0.8/0.7/0.3 mV/y, respectively, and SHI decreased 0.15/y. Discussion: The CMAP amplitudes of hand muscles and derived SHI were strongly age‐dependent, although this effect was less in ADM. This represents a physiological phenomenon. Future studies using the SHI should consider age effects. [ABSTRACT FROM AUTHOR]

Introduction/Aims: The motor unit size index (MUSIX) may provide insight into reinnervation patterns in diseases such as amyotrophic lateral sclerosis (ALS). However, it is not known whether MUSIX detects clinically relevant changes in reinnervation, or if all muscles manifest changes in MUSIX in response to reinnervation after motor unit loss. Methods: Fifty‐seven patients with ALS were assessed at 3‐month intervals for 12 months in four centers. Muscles examined were abductor pollicis brevis, abductor digiti minimi, biceps brachii, and tibialis anterior. Results were split into two groups: muscles with increases in MUSIX and those without increases. Longitudinal changes in MUSIX, motor unit number index (MUNIX), compound muscle action potential amplitude, and Medical Research Council strength score were investigated. Results: One hundred thirty‐three muscles were examined. Fifty‐nine percent of the muscles exhibited an increase in MUSIX during the study. Muscles with MUSIX increases lost more motor units (58% decline in MUNIX at 12 months, P <.001) than muscles that did not increase MUSIX (34.6% decline in MUNIX at 12 months, P <.001). However, longitudinal changes in muscle strength were similar. When motor unit loss was similar, the absence of a MUSIX increase was associated with a significantly greater loss of muscle strength (P =.002). Discussion MUSIX increases are associated with greater motor unit loss but relative preservation of muscle strength. Thus, MUSIX appears to be measuring a clinically relevant response that can provide a quantitative outcome measure of reinnervation in clinical trials. Furthermore, MUSIX suggests that reinnervation may play a major role in determining the progression of weakness. [ABSTRACT FROM AUTHOR]

We describe three unrelated patients with sporadic motor neuron disease (MND) and hereditary amyloid transthyretin (ATTRv) amyloidosis family history, who were asymptomatic carriers of the pVal50Met mutation of transthyretin (TTR) gene. Patients 1 and 2 were a 43-year-old man with a spinal-onset of ALS and a 37-year-old woman with a bulbar-onset of ALS, who died due to respiratory complications five and two years after disease onset, respectively. Patient 3 is a 52-year-old woman, with a two-year history of a probable primary lateral sclerosis, and a frontotemporal dysfunction. Imaging, cerebrospinal fluid (CSF) and nerve conduction and small fiber tests were normal in all. Genetic testing for ALS was negative in the two patients tested. Previous studies in MND patients have identified reduced TTR levels in CSF and neuronal gene overexpression, suggesting a neuroprotective role of TTR. The association of MND in patients with TTR gene mutations has not yet been described. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Fasciculations can be symptomatic, yet not progress to amyotrophic lateral sclerosis (ALS), a condition categorized as benign fasciculation syndrome (BFS). We aimed to assess electrodiagnostic changes and clinical course over time in patients with BFS. Methods: This was a retrospective review of medical records of patients who were referred because of a suspicion of ALS or who had directly asked for a consultation because of a personal concern regarding ALS. All clinical and electromyography (EMG) investigations were performed by the same neurologist, following an established protocol. In addition, laboratory testing and imaging studies were performed as determined to be clinically necessary. Results: We included 37 subjects (mean age 46 ± 14.7 y, 29 male, 7 healthcare professionals). Most patients had experienced fasciculations in both upper and lower limb muscles (62.2%); the remaining patients had fasciculations only in their lower limbs. EMG in seven subjects showed chronic neurogenic potentials in addition to fasciculation potentials; all of these were older men. Follow‐up data were available in 24 patients (median 4.7 y), 21 with repeat EMGs, including all those with neurogenic EMG changes at baseline (median 6.5 y). Two‐thirds of patients reported symptomatic improvement: 57.1% of those with abnormal EMG and 61.1% with normal EMG. The EMG changes were stable. Discussion: Prognosis of BFS is favorable, regardless of minor EMG abnormalities. The latter do not necessarily imply progression to ALS. [ABSTRACT FROM AUTHOR]

Objective: To study disease characteristics, progression and outcome in a group of motor neuron disease (MND) patients beginning with frontotemporal dementia (FTD) by comparing them with patients with the typical motor-onset. Methods: 849 patients recruited from tertiary centers were studied according to FTD-onset and motor-onset. We studied clinical data, functional decline and survival. Results: Twenty six patients (3.1%) had FTD-onset of whom seven (26.9%) had coincident motor dysfunction. In those with isolated FTD-onset, motor symptoms developed after a median of 12 months (IQR: 4–18). FTD-onset patients were older at presentation; the bulbar-region was more frequently first affected than in the motor-onset group; there was a predominant upper motor neuron (UMN) phenotype; fasciculations were less common than in motor onset disease but facial and upper limb apraxia was more frequent; as well as ALS and FTD familial history. No differences were observed for gender, frequency of C9orf72 hexanucleotide repeat expansion, family history of Alzheimer's and Parkinson's diseases, median delay from motor symptoms to diagnosis, median ALSFRS-R rate of change, handedness, emotional lability, depression, weight loss, resting tremor, bradykinesia, sensory changes or neuropathy. Clinical and demographic features were similar between FTD-onset patients developing bulbar MND and bulbar-onset ALS patients. Once bulbar symptoms manifested functional progression and survival were similar to those of bulbar-onset ALS patients. Conclusions: MND patients with FTD-onset have a distinctive phenotype characterized by predominant UMN presentation and rapid progression to bulbar involvement. The main factor impacting functional decline and survival is the onset of bulbar dysfunction. [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with unsatisfactory treatment options. Best management and recruitment into clinical trials requires early diagnosis. However, diagnosis is often delayed. Analysis of the diagnostic pathway and identification of the causes of diagnostic delay are imperative. Methods: We studied a cohort of 580 ALS patients followed up in our ALS clinic in Lisbon. Demographic, disease, and sociocultural factors were collected. Time from first symptom onset to diagnosis, the specialist's assessment, and investigations requested were analyzed. Predictors of diagnostic delay were evaluated by multivariate linear regression, adjusting for potential confounders. Results: The median diagnostic delay from first symptom onset was 10 months. Spinal-onset, slower disease progression, cognitive symptoms at onset, and lower income were associated with increased diagnostic delay. Most patients were first assessed by general practitioners. Patients who were first evaluated by a neurologist were more likely to be correctly diagnosed, decreasing time to diagnosis. Electromyography was decisive in establishing the diagnosis. Conclusions: Late referral from non-neurologists to a neurologist is a potentially modifiable factor contributing to significant diagnostic delay. Educational interventions targeted to non-neurologists physicians, in order to increase awareness of ALS and, consequently, promote early referral to a neurologist at a tertiary center, will be important in reducing diagnostic delay. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting the upper and lower motor neurons. A key clinical feature of ALS is the absence of accurate, early-stage diagnostic indicators. 'Split-hand syndrome' was first described in ALS at the end of the last century and a considerable body of literature suggests that the split-hand phenomenon may be an important clinical feature of ALS. Considering the published investigations, it is conceivable that the 'split-hand syndrome' results from the associated upper and lower motor neuron degeneration, whose interaction remains to be fully clarified. Additionally, other split syndromes have been described in ALS involving upper or lower limbs, with a nuanced description of clinical and neurophysiological manifestations that may further aid ALS diagnosis. In this review, we endeavour to systematically present the spectrum of the 'split syndromes' in ALS from a clinical and neurophysiology perspective and discuss their diagnostic and pathogenic utility. [ABSTRACT FROM AUTHOR]

Introduction: Thyroid hormones influence neuromuscular function, and it has been thought that this might contribute to degeneration of motor neurons. Methods: We used case-control methods to investigate the prevalence of thyroid dysfunction (hyperthyroidism and hypothyroidism) in ALS patients followed in our centre, between 2015 and 2020. Data from patients with neuromuscular disorders not derived from thyroid dysfunction, followed within the same time frame, were used as controls. Thyroid dysfunction was defined by previous thyroid replacement medication managed by an endocrinologist. We used odds ratios (OR) with a 95% confidence interval (CI) to compare 579 ALS patients and 415 age-gender-matched disease controls. Additionally, we provide a summarized review of the literature. Results: Hypothyroidism (prevalence of 5.0 versus 8.6%; OR = 0.56, 95% CI 0.34–0.92, p = 0.023), hyperthyroidism (prevalence of 0.3 versus 1.2%; OR = 0.28, 95% CI 0.06–1.47, p = 0.134) and overall thyroid dysfunction (prevalence of 5.4 versus 9.9%; OR = 0.52, 95% CI 0.32–0.84, p = 0.015) were less prevalent in ALS patients than in controls, but similar to the national epidemiological data for thyroid disease. Our data are in line with the findings of most previous studies. Conclusions: We conclude that thyroid dysfunction is not associated with ALS. [ABSTRACT FROM AUTHOR]

Background and purpose: Short‐interval intracortical inhibition by threshold tracking (T‐SICI) has been proposed as a diagnostic tool for amyotrophic lateral sclerosis (ALS) but has not been compared directly with conventional amplitude measurements (A‐SICI). This study compared A‐SICI and T‐SICI for sensitivity and clinical usefulness as biomarkers for ALS. Methods: In all, 104 consecutive patients referred with suspicion of ALS were prospectively included and were subsequently divided into 62 patients with motor neuron disease (MND) and 42 patient controls (ALS mimics) by clinical follow‐up. T‐SICI and A‐SICI recorded in the first dorsal interosseus muscle (index test) were compared with recordings from 53 age‐matched healthy controls. The reference standard was the Awaji criteria. Clinical scorings, conventional nerve conduction studies and electromyography were also performed on the patients. Results: Motor neuron disease patients had significantly reduced T‐SICI and A‐SICI compared with the healthy and patient control groups, which were similar. Sensitivity and specificity for discriminating MND patients from patient controls were high (areas under the receiver operating characteristic curves 0.762 and 0.810 for T‐SICI and A‐SICI respectively at 1–3.5 ms). Paradoxically, T‐SICI was most reduced in MND patients with the fewest upper motor neuron (UMN) signs (Spearman ρ = 0.565, p = 4.3 × 10−6). Conclusions: Amplitude‐based measure of cortical inhibition and T‐SICI are both sensitive measures for the detection of cortical involvement in MND patients and may help early diagnosis of ALS, with T‐SICI most abnormal before UMN signs have developed. The gradation in T‐SICI from pathological facilitation in patients with minimal UMN signs to inhibition in those with the most UMN signs may be due to progressive degeneration of the subset of UMNs experiencing facilitation. [ABSTRACT FROM AUTHOR]

A number of conditions can mimic amyotrophic lateral sclerosis (ALS), which are in general excluded by neurophysiological and neuroimaging investigation. We present a novel mimicking disorder. A 58-year-old male, without relevant past medical history, presented with a 7-year history of progressive paraparesis. On examination, he had bilateral thigh atrophy, fasciculations, and asymmetric paraparesis (severe on the left side). Upper motor neuron signs were present in the lower limbs, with normal sensory examination. Needle EMG disclosed mild chronic neurogenic changes in the lower limbs. Brain and spinal cord neuroimaging was normal, namely, in the dorso-lumbar segment. Lumbar puncture showed mild hyperproteinorachia. Diagnosis of slowly progressive (possible) ALS was established. One year later, he required a bilateral support to walk, and neurological examination revealed weak tendon reflexes, abnormal pinprick, and proprioceptive sensation in the legs. Repeated lumbar MRI showed an extensive spinal cord oedema from T7 to the conus with multiple perimedullary vessel flow voids suggestive of a vascular malformation. Conventional angiography revealed a spinal dural arteriovenous fistula in L2–L3 with the left L4 lumbar branch as the afferent artery. Dural arteriovenous fistula is the most common vascular malformation of the spinal cord, despite being rare. It leads to arterialization of spinal veins, causing venous hypertension, spinal cord oedema, and ischaemia. The clinical picture includes a stepwise, sometimes fluctuant, myeloradiculopathy. In this case, EMG changes did not meet Awaji criteria. This case reinforces the need to critically follow atypical cases to ascertain clinical progression in patients with suspected ALS. [ABSTRACT FROM AUTHOR]

Introduction: Respiratory tests are fundamental for monitoring respiratory function in ALS, and essential in clinical trials. Slow vital capacity (SVC) was canceled in some countries to prevent COVID-19 transmission. We aimed to test phrenic nerve motor responses as an option to SVC in clinical trials. Methodology: Patients followed-up in our unit were selected respecting inclusion criteria used elsewhere: possible/probable/definite disease; onset-age 18–80years; disease duration from disease duration ≤24months; body mass index (BMI)>20kg/m2; respiratory subscore of the revised ALS functional rating scale (ALSFRS-R)≥11; upright SVC ≥ 70%. We added normal phrenic responses (meanPhrenAmpl, ≥0.4mV). All patients were on riluzole. SVC and meanPhrenAmpl were recorded at study entry (T0) and 24 weeks later (T1). Decays were determined. Sample size was calculated for a treatment effect of 30% on the decay rate. Results: We included 317 ALS patients (191 males, 225 spinal-onset), mean onset-age 59.9 ± 10.7 (31–80)years, mean onset BMI 25.48 ± 3.2 (20.1–35)kg/m2, mean disease duration 10.5 ± 5.6 (1–24)months, mean ALSFRS-R 41.54 ± 4.3 (22–47) and respiratory subscore 11.83 ± 0.38 (11–12). MeanPhrenAmpl and SVC were weakly but significantly correlated at T0 and T1. At T1, MeanPhrenAmpl decayed 16.94 ± 16.45% and SVC 13.5 ± 16.86%. For the proposed drug effect, 174 and 272 patients would be needed to recruit using respectively meanPhrenAmpl and SVC decline as the primary outcome measurement (accepting no dropouts). Discussion: Contrary to SVC, meanPhrenAmpl is non-volitional and not associated with aerosolization risk. Lower recruitment number (98 patients less) would be needed, translating shorter inclusion period, trial length and costs, and probable lower missed data rate. MeanPhrenAmp is an alternative test in ALS clinical trials. [ABSTRACT FROM AUTHOR]

Airway pressure in the first 100ms of an occluded inspiration (P0.1) evaluates the respiratory center activity, increasing in the presence of respiratory muscle weakness. It is uncertain if its activity can compensate for respiratory muscles weakness in amyotrophic lateral sclerosis (ALS). Methods: Consecutive ALS patients with P0.1 evaluated at first visit were included. Depending on P0.1 percentile, patients were divided in three groups: G1 (<25th percentile); G2 (25th–74th percentiles); G3 (≥75th percentile); two subgroups were further considered: SG0 (<10th percentile); SG1 (>90th percentile). Body mass index (BMI), functional ALS rating scale and its subscores, respiratory function tests, including forced vital capacity, maximal inspiratory (MIP) and expiratory pressures, percentage of P0.1 (%P0.1), blood gas analyses, phrenic nerve motor amplitude (MeanPhrenAmpl) were compared. P0.1/MIP and %P0.1 predictors were explored by linear and multinomial logistic regression analyses. p < 0.05 was considered as significant. Results: From the 497 patients included, 124 were in G1 and G3 each, 249 in G2, 49 in SG0 and SG1 each. G1 included more men, with higher BMI (p < 0.001). G3 had older women, with predominant bulbar phenotype (p < 0.001). Lower respiratory function (p < 0.05) was present in both groups. SG0 (%P0.1 < 51.73%, P0.1/MIP = 1.48 ± 1.02) had more spinal-onset men (p < 0.001) with lower MeanPhrenAmpl (p < 0.004). SG1 (P0.1 > 147.12, P0.1/MIP = 7.92 ± 4.62) predominantly included older patients (p = 0.033), women (p = 0.012), with lower MeanPhrenAmpl (p = 0.039). Discussion: ALS patients with respiratory failure can show high or low P01 values, related to phenotype. Possible central drive reactivity and exhaustion, and the role of respiratory-metabolic-renal buffering system should be further addressed. [ABSTRACT FROM AUTHOR]

Amyotrophic Lateral Sclerosis is one major disease in the group of neurodegenerative conditions. As with most other neurodegenerative diseases, clinical signs of the disease usually show among the elderly population, and most commonly around 60–65 years of age. Therefore the disease is not expected to impact the fertility of ALS patients. When examined from an evolutionary medicine and evolutionary biology perspective, there should be no selection pressure on the patient population due to the late onset of ALS. Methods: In this study, we tested the hypothesis that ALS does not affect fertility on a group of patients with ALS that we collected in a multi-center study. We recruited 511 patients diagnosed with ALS according to the revised El Escorial criteria, and 236 control cases without a neurodegenerative disease. We compared the ALS group's number of offspring with the control group in three consecutive generations. Results: No statistically significant difference was found between the number of siblings of ALS and control groups (p = 0.44). A statistically significant difference was found between the number of children of ALS and control groups (p < 0.001), indicating ALS patients had more children than controls. When the number of children is assessed by gender, for women, there was no statistically significant difference between the number of children of ALS and control groups (p = 0.067). Conclusions: This finding supports the view that ALS does not have a negative selection pressure on the patient population's fertility. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with clinical and etiological heterogeneity and a complex genetic contribution. Clinical, neuropathological, and genetic evidence revealed that ALS and frontotemporal dementia (FTD) are in part of a single disease continuum. Genetic causes have been identified in sporadic (SALS) and familial patients (FALS) and the recurrent genetic factor underlying ALS and FTD is the C9orf72 hexanucleotide repeat expansion (HRE). However, in our population, the concomitance of ALS and FTD cannot be explained by C9orf72 HRE in many FALS and SALS cases. Our aim is to further understand the genetic basis of ALS in Portuguese patients. 34 patients with FALS or SALS-FTD, negative for C9orf72 HRE, were screened for rare variants in a panel of 29 relevant genes by next-generation sequencing. We detected 15 variants in 11 genes, one classified as pathogenic in TARDBP, two as likely pathogenic in TARDBP and PRPH, and the others as variants of unknown significance (VUS). Gene variants, including VUS, were found in 41.2% FALS patients and 40% SALS-FTD. In most patients, no potential pathogenic variants were found. Our results emphasize the need to enhance the efforts to unravel the genetic architecture of ALS-FTD. [ABSTRACT FROM AUTHOR]

Primary lateral sclerosis (PLS) is a motor neuron disease characterized by spinobulbar spasticity, absence of progressive lower motor neuron (LMN) dysfunction and marked by a slow functional decline. Electromyography is essential to exclude significant LMN involvement, particularly in the context of distinguishing PLS from amyotrophic lateral sclerosis (ALS), given that the prognosis is substantially better, and respiratory complications are unusual, in PLS. Nevertheless, minor neurogenic changes and occasional fasciculation potentials can be observed in PLS. The most useful technique for the objective assessment of upper motor neuron (UMN) dysfunction is transcranial magnetic stimulation (TMS), which in PLS is characterized by a high cortical threshold and delayed central conduction times. TMS is sensitive to identify cortical dysfunction in PLS and might have potential for monitoring UMN function in longitudinal studies and in clinical trials. The findings of TMS need to be interpreted in the context of the clinical presentation and phenotype, particularly in the differentiation between PLS and ALS. While other neurophysiological techniques have been investigated, studies to date have tended to involve small patient cohorts and as such, their value in distinguishing PLS from ALS remains unclear. [ABSTRACT FROM AUTHOR]

Studies concerning young-adult amyotrophic lateral sclerosis (yALS) are uncommon, due to the rarity of this condition. We aimed to investigate this subject. Methods: A retrospective-prospective study was conducted in our ALS center, including 1278 ALS patients followed longitudinally. Patients were divided in two groups - yALS (onset ≤40 years) and adult-onset ALS (aALS, onset >40 years). We analyzed phenotype, survival and genetics. Results: Sixty-three out of 1278 (4.9%) patients were included in yALS group, while the majority were categorized as aALS (1215, 95.1%). Juvenile ALS (onset < 25 years) represented 14.3% (9 patients) of yALS. In yALS group mean onset age was 32.5 ± 6.6 years (14–40) and 68.3% were men. Spinal-onset was significantly more frequent in yALS (p < 0.001), while bulbar-onset was more common in aALS (p = 0.002). Diagnostic delay was longer in yALS group (p = 0.02). yALS patients survived longer than aALS (88.2 ± 81.9 versus 41.1 ± 34, p < 0.001), and functional decay was the only independent predictor found in the younger group (p = 0.007). No other significant differences were found, including familial history of ALS. Three yALS patients (4.8%) had C9orf72, SOD1 and FUS mutations identified by single-gene testing. A panel of 50 ALS-related genes investigated with next-generation sequencing in 9 yALS patients revealed no pathogenic mutation. Conclusions: yALS is a rare and specific ALS group. Disease progression is slower and survival longer in yALS, moreover and bulbar-onset phenotype is less common than in aALS. These observations are relevant to inform patients and for clinical trials design. [ABSTRACT FROM AUTHOR]