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

Human biomonitoring studies are of increasing importance in regulatory toxicology; however, there is a paucity of human biomonitoring data for the Irish population. In this study, we provide new data for urinary biomarker concentrations of aluminium, arsenic, cadmium, chromium, copper, mercury, manganese, lead and selenium. One hundred urine samples, collected between 2011 and 2014 from healthy participants of the EuroMOTOR project, were randomly selected. Metal concentrations were measured via ICPMS. Descriptive statistics for each of the metals stratified by gender were performed. There were 58 male and 42 female participants and metals were detectable for all samples. Geometric mean urinary concentrations for each metal in males were as follows: aluminium 8.5 μg/L, arsenic 8.1 μg/L, cadmium 0.3 μg/L, chromium 0.5 μg/L, copper 5.1 μg/L, mercury 0.4 μg/L, manganese 0.3 μg/L, lead 1.3 μg/L and selenium 10.8 μg/L; and in females: aluminium 8.5 μg/L, arsenic 10.2 μg/L, cadmium 0.4 μg/L, chromium 0.6 μg/L, copper 5.6 μg/L, mercury 0.3 μg/L, manganese 0.2 μg/L, lead 1.6 μg/L and selenium 13.7 μg/L. We observed higher geometric mean concentrations in women for arsenic, cadmium, chromium, copper, lead and selenium, with equal geometric mean concentrations for aluminium and manganese, leaving only mercury with lower geometric mean concentrations in women. Aluminium, cadmium, chromium, lead and urinary concentrations of metals were slightly elevated compared to European data, while for arsenic, copper, manganese and selenium, Irish levels were lower. Our findings highlight that there are differences in urinary metal concentrations between European populations.

First and second-degree relatives of people with Amyotrophic Lateral Sclerosis report higher rates of neuropsychiatric disorders, indicating that risk genes may be pleiotropic, causing multiple phenotypes within kindreds. Such phenotypes may constitute a disease endophenotype that associates with disease liability. We have directly investigated cognitive functioning and neuropsychiatric traits among relatives of people with Amyotrophic Lateral Sclerosis to identify potential endophenotypes of the disease. In a family-based, cross-sectional study design, first- and second-degree relatives of people with Amyotrophic Lateral Sclerosis (n = 149) were compared to controls (n = 60) using an in-depth neuropsychological and neuropsychiatric assessment. Subgroup analyses examined the effect of family history and C9orf72 repeat expansion status (n = 16 positive carriers). Relatives of people with Amyotrophic Lateral Sclerosis had lower scores on executive functioning, language, and memory tasks compared to controls, with large effect sizes observed on object naming (d = 0.91, P = 0.00001) and phonemic verbal fluency (d = 0.81, P = 0.0003). Relatives also had higher Autism Quotient attention to detail traits (d = -0.52, P = 0.005), lower conscientiousness (d = 0.57, P = 0.003) and lower openness to experience personality traits (d = 0.54, P = 0.01) than controls. These effects were typically larger in relatives of people with familial, rather than sporadic Amyotrophic Lateral Sclerosis, and were present in both gene carrier and non-carrier relatives of probands with a C9orf72 repeat expansion. Poorer phonemic fluency and object naming, along with Autism and personality traits are more frequent in relatives of people with Amyotrophic Lateral Sclerosis. Among kindreds carrying the C9orf72 repeat expansion, these traits were identified in relatives regardless of their carrier status, suggesting the presence of a disease associated endophenotype that is not exclusively mediated by the C9orf72 expansion.

Primary lateral sclerosis (PLS) is a slowly progressing disorder, which is characterized primarily by the degeneration of upper motor neurons (UMNs) in the primary motor area (M1). It is not yet clear how the function of sensorimotor networks beyond M1 are affected by PLS. The aim of this study was to use cortico-muscular coherence (CMC) to characterize the oscillatory drives between cortical regions and muscles during a motor task in PLS and to examine the relationship between CMC and the level of clinical impairment. We recorded EEG and EMG from hand muscles in 16 participants with PLS and 18 controls during a pincer-grip task. In PLS, higher CMC was observed over contralateral-M1 (α- and γ-band) and ipsilateral-M1 (β-band) compared with controls. Significant correlations between clinically assessed UMN scores and CMC measures showed that higher clinical impairment was associated with lower CMC over contralateral-M1/frontal areas, higher CMC over parietal area, and both higher and lower CMC (in different bands) over ipsilateral-M1. The results suggest an atypical engagement of both contralateral and ipsilateral M1 during motor activity in PLS, indicating the presence of pathogenic and/or adaptive/compensatory alterations in neural activity. The findings demonstrate the potential of CMC for identifying dysfunction within the sensorimotor networks in PLS.

With the advent of gene therapies for amyotrophic lateral sclerosis, there is a surge in gene testing for ALS. 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 with genetic variants with large and small effect sizes. Guidelines for 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 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 (OR 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. 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.

Background Bulbar dysfunction is a cardinal feature of ALS with important quality of life and management implications. The objective of this study is the longitudinal evaluation of a large panel imaging metrics pertaining to bulbar dysfunction, encompassing cortical measures, structural and functional cortico-medullary connectivity indices and brainstem metrics. Methods A standardised, multimodal imaging protocol was implemented with clinical and genetic profiling to systematically appraise the biomarker potential of specific metrics. A total of 198 patients with ALS and 108 healthy controls were included. Results Longitudinal analyses revealed progressive structural and functional disconnection between the motor cortex and the brainstem over time. Cortical thickness reduction was an early feature on cross-sectional analyses with limited further progression on longitudinal follow-up. Receiver operating characteristic analyses of the panel of MR metrics confirmed the discriminatory potential of bulbar imaging measures between patients and controls and area-under-the-curve values increased significantly on longitudinal follow-up. C9orf72 carriers exhibited lower brainstem volumes, lower cortico-medullary structural connectivity and faster cortical thinning. Sporadic patients without bulbar symptoms, already exhibit significant brainstem and cortico-medullary connectivity alterations. Discussion Our results indicate that ALS is associated with multi-level integrity change from cortex to brainstem. The demonstration of significant corticobulbar alterations in patients without bulbar symptoms confirms considerable presymptomatic disease burden in sporadic ALS. The systematic assessment of radiological measures in a single-centre academic study helps to appraise the diagnostic and monitoring utility of specific measures for future clinical and clinical trial applications.

Introduction The incidence of Frontotemporal Lobar Degeneration (FTLD)-related disorders and their characteristics are not well known. The "FRONTotemporal dementia Incidence European Research Study" (FRONTIERS) is designed to fill this gap. Methods FRONTIERS is a European prospective, observational population study based on multinational registries. FRONTIERS comprises 11 tertiary referral centers across Europe with long-lasting experience in FTLD-related disorders and comprehensive regional referral networks, enabling incidence estimation over well-defined geographical areas. Endpoints The primary endpoints are (1) the incidence of FTLD-related disorders across Europe; (2) geographic trends of FTLD-related disorders; (3) the distribution of FTLD phenotypes in different populations and ethnicities in Europe; (4) inheritance of FTLD-related disorders, including the frequencies of monogenic FTLD as compared to overall disease burden; and (5) implementation of data banking for clinical and biological material. Expected impacts FRONTIERS will improve the understanding of FTLD-related disorders and their epidemiology, promoting appropriate public health service policies and treatment strategies.

While primary lateral sclerosis (PLS) has traditionally been regarded as a pure upper motor neuron disorder, recent clinical, neuroimaging and postmortem studies have confirmed significant extra-motor involvement. Sporadic reports have indicated that in addition to the motor cortex and corticospinal tracts, the cerebellum may also be affected in PLS. Cerebellar manifestations are difficult to ascertain in PLS as the clinical picture is dominated by widespread upper motor neuron signs. The likely contribution of cerebellar dysfunction to gait disturbance, falls, pseudobulbar affect and dysarthria may be overlooked in the context of progressive spasticity. The objective of this study is the comprehensive characterization of cerebellar gray and white matter degeneration in PLS using multiparametric quantitative neuroimaging methods to systematically evaluate each cerebellar lobule and peduncle. Forty-two patients with PLS and 117 demographically-matched healthy controls were enrolled in a prospective MRI study. Complementary volumetric and voxelwise analyses revealed focal cerebellar alterations instead of global cerebellar atrophy. Bilateral gray matter volume reductions were observed in lobules III, IV and VIIb. Significant diffusivity alterations within the superior cerebellar peduncle indicate disruption of the main cerebellar outflow tracts. These findings suggest that the considerable intra-cerebellar disease-burden is coupled with concomitant cerebro-cerebellar connectivity disruptions. While cerebellar dysfunction is challenging to demonstrate clinically, cerebellar pathology is likely to be a significant contributor to disability in PLS.

© 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license., Amyotrophic lateral sclerosis is a heterogeneous, fatal neurodegenerative disease, characterized by motor neuron loss and in 50% of cases also by cognitive and/or behavioral changes. Mendelian forms of ALS comprise approximately 10-15% of cases. The majority is however considered sporadic, but also with a high contribution of genetic risk factors. To explore the contribution of somatic mutations and/or epigenetic changes to disease risk, we performed whole genome sequencing and methylation analyses using samples from multiple tissues on a cohort of 26 monozygotic twins discordant for ALS, followed by in-depth validation and replication experiments. The results of these analyses implicate several mechanisms in ALS pathophysiology, which include a role for de novo mutations, defects in DNA damage repair and accelerated aging., This study was funded by the Thierry Latran Foundation and the Dutch ALS foundation. Project MinE Belgium was supported by a grant from IWT (n° 140935), the ALS Liga België, the National Lottery of Belgium and the KU Leuven Opening the Future Fund. M.A.v.E. is additionally supported by the Rudolf Magnus Brain Center Talent Fellowship. P.V.D. holds a senior clinical investigatorship of FWO-Vlaanderen and is supported by the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders, the ALS Liga België and the KU Leuven funds “Een Hart voor ALS,” “Laeversfonds voor ALS Onderzoek” and the “Valéry Perrier Race against ALS Fund.” Several authors of this publication are member of the European Reference Network for Rare Neuromuscular Diseases (ERN-NMD). A.A.-C. receives salary support from the National Institute for Health Research (NIHR) Dementia Biomedical Research Unit and Biomedical Research Centre in Mental Health at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. O.H. is funded by the Health Research Board Clinician Scientist Programme and Science Foundation Ireland. R.L.M is also supported by the Thierry Latran Foundation (ALSIBD) and the ALS Association (2284). The Swedish Brain Foundation (grants nr. 2012-0262, 2012-0305, 2013-0279, 2016-0303), the Swedish Science Council (grants nr 2012-3167, 2017-03100), the Knut and Alice Wallenberg Foundation (grants nr. 2012.0091, 2014.0305), the Bertil Hållsten Foundation, the Ulla-Carin Lindquist Foundation, the Neuroförbundet Association, the Torsten and Ragnar Söderberg Foundation, Umeå University Insamlingsstiftelsen (223-2808-12, 223-1881-13, 2.1.12-1605-14), Västerbotten County Council, Swedish Brain Power, King Gustaf V:s and Queen Victoria's Freemason's Foundation.

Imaging studies of FTD typically present group-level statistics between large cohorts of genetically, molecularly or clinically stratified patients. Group-level statistics are indispensable to appraise unifying radiological traits and describe genotype-associated signatures in academic studies. However, in a clinical setting, the primary objective is the meaningful interpretation of imaging data from individual patients to assist diagnostic classification, inform prognosis, and enable the assessment of progressive changes compared to baseline scans. In an attempt to address the pragmatic demands of clinical imaging, a prospective computational neuroimaging study was undertaken in a cohort of patients across the spectrum of FTD phenotypes. Cortical changes were evaluated in a dual pipeline, using standard cortical thickness analyses and an individualised, z-score based approach to characterise subject-level disease burden. Phenotype-specific patterns of cortical atrophy were readily detected with both methodological approaches. Consistent with their clinical profiles, patients with bvFTD exhibited orbitofrontal, cingulate and dorsolateral prefrontal atrophy. Patients with ALS-FTD displayed precentral gyrus involvement, nfvPPA patients showed widespread cortical degeneration including insular and opercular regions and patients with svPPA exhibited relatively focal anterior temporal lobe atrophy. Cortical atrophy patterns were reliably detected in single individuals, and these maps were consistent with the clinical categorisation. Our preliminary data indicate that standard T1-weighted structural data from single patients may be utilised to generate maps of cortical atrophy. While the computational interpretation of single scans is challenging, it offers unrivalled insights compared to visual inspection. The quantitative evaluation of individual MRI data may aid diagnostic classification, clinical decision making, and assessing longitudinal changes.

Amyotrophic lateral sclerosis is a devastating disease characterized primarily by motor system degeneration, with clinical evidence of cognitive and behavioural change in up to 50% of cases. Amyotrophic lateral sclerosis is both clinically and biologically heterogeneous. Subgrouping is currently undertaken using clinical parameters, such as site of symptom onset (bulbar or spinal), burden of disease (based on the modified El Escorial Research Criteria) and genomics in those with familial disease. However, with the exception of genomics, these subcategories do not take into account underlying disease pathobiology, and are not fully predictive of disease course or prognosis. Recently, we have shown that resting-state EEG can reliably and quantitatively capture abnormal patterns of motor and cognitive network disruption in amyotrophic lateral sclerosis. These network disruptions have been identified across multiple frequency bands, and using measures of neural activity (spectral power) and connectivity (comodulation of activity by amplitude envelope correlation and synchrony by imaginary coherence) on source-localized brain oscillations from high-density EEG. Using data-driven methods (similarity network fusion and spectral clustering), we have now undertaken a clustering analysis to identify disease subphenotypes and to determine whether different patterns of disruption are predictive of disease outcome. We show that amyotrophic lateral sclerosis patients (n = 95) can be subgrouped into four phenotypes with distinct neurophysiological profiles. These clusters are characterized by varying degrees of disruption in the somatomotor (α-band synchrony), frontotemporal (β-band neural activity and γl-band synchrony) and frontoparietal (γl-band comodulation) networks, which reliably correlate with distinct clinical profiles and different disease trajectories. Using an in-depth stability analysis, we show that these clusters are statistically reproducible and robust, remain stable after reassessment using a follow-up EEG session, and continue to predict the clinical trajectory and disease outcome. Our data demonstrate that novel phenotyping using neuroelectric signal analysis can distinguish disease subtypes based exclusively on different patterns of network disturbances. These patterns may reflect underlying disease neurobiology. The identification of amyotrophic lateral sclerosis subtypes based on profiles of differential impairment in neuronal networks has clear potential in future stratification for clinical trials. Advanced network profiling in amyotrophic lateral sclerosis can also underpin new therapeutic strategies that are based on principles of neurobiology and designed to modulate network disruption.

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

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 iPSC-derived 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.

MotivationLiterature-Based Discovery (LBD) aims to help researchers to identify relations between concepts which are worthy of further investigation by text-mining the biomedical literature. While the LBD literature is rich and the field is considered mature, standard practice in the evaluation of LBD methods is methodologically poor and has not progressed on par with the domain. The lack of properly designed and decent-sized benchmark dataset hinders the progress of the field and its development into applications usable by biomedical experts.ResultsThis work presents a method for mining past discoveries from the biomedical literature. It leverages the impact made by a discovery, using descriptive statistics to detect surges in the prevalence of a relation across time. This method allows the collection of a large amount of time-stamped discoveries which can be used for LBD evaluation or other applications. The validity of the method is tested against a baseline representing the state of the art “time sliced” method.AvailabilityThe source data used in this article are publicly available. The implementation and the resulting data are published under open-source license:https://github.com/erwanm/medline-discoveries(code)https://zenodo.org/record/5888572(datasets). An online exploration tool is also provided athttps://brainmend.adaptcentre.ie/.Contacterwan.moreau@adaptcentre.ie

A roundtable convened in July 2020 examined issues concerning respiratory support in amyotrophic lateral sclerosis (ALS), with reference to the potential for an early-phase orally administered medication that might either postpone the introduction of noninvasive ventilation (NIV) and/or enhance the benefits to be gained from it. Attention was also given to the impact of the COVID-19 pandemic on usual practice in the assessment and management of ALS-related respiratory difficulties. Implementation of NIV marks a step-change in clinical status for patients and a major increase in burden for caregivers. All means to ease this transition should be explored: an oral therapy that supported respiratory function and patients' independence and sense of well-being would aid discussions to facilitate the eventual successful introduction of NIV. Assessment of a candidate oral therapy that might support respiratory function in ALS patients would be aided by the development of improved patient-reported outcome measures for robust quantification of treatment effect and quality of life. Such instruments could also be used to monitor patients' status during the COVID-19 pandemic, averting some of the risks of face-to-face assessment plus the patient burden and costs of traditional methods. Several oral candidate therapies have recently failed to meet their primary endpoints in clinical trials. However, understanding of the underlying physiology and appropriate trial design have grown and will inform future developments in this field.

Forced vital capacity (FVC) is an essential respiratory measurement for assessment and monitoring of patients with Amyotrophic Lateral Sclerosis (ALS). Our clinic rapidly implemented remote assessment of FVC after COVID-19 related restrictions on respiratory testing were imposed, using mini-spirometers and video consultation. We sought to evaluate the patient's experiences of performing remote respiratory assessments to guide future development and optimisation of the service. Twenty-five patients completed surveys. The mean age was 65.2 years and average time from diagnosis was 17.04 (2-99) months. Seventy-two percent (n = 18) required help from a caregiver to perform the tests. Ninety-two percent (n = 23) of patients reported that overall, they were satisfied and were happy to continue with remote respiratory assessment. Reducing the number of clinic visits for review and assessment was valued by 92% (n = 23) and reducing the risk associated with COVID-19 was valued by 96% (n = 24). The highest frequency reported as acceptable for performing the remote breathing assessments was monthly (60%, n = 15), followed by every second month (28%, n = 7). Remote respiratory testing is viewed positively by patients. These technologies used in combination with video-consultations and other novel forms of remote monitoring implemented in response to the COVID-19 crisis will continue to be valuable tools for clinical care in future. However, further evaluation of the validity of remote respiratory assessment is required.

Amyotrophic Lateral Sclerosis (ALS) is a rare neurodegenerative disease that causes a rapid decline in motor functions and has a fatal trajectory. ALS is currently incurable, so the aim of the treatment is mostly to alleviate symptoms and improve quality of life (QoL) for the patients. The goal of this study is to develop a Clinical Decision Support System (CDSS) to alert clinicians when a patient is at risk of experiencing low QoL. The source of data was the Irish ALS Registry and interviews with the 90 patients and their primary informal caregiver at three time-points. In this dataset, there were two different scores to measure a person's overall QoL, based on the McGill QoL (MQoL) Questionnaire and we worked towards the prediction of both. We used Extreme Gradient Boosting (XGBoost) for the development of the predictive models, which was compared to a logistic regression baseline model. Additionally, we used Synthetic Minority Over-sampling Technique (SMOTE) to examine if that would increase model performance and SHAP (SHapley Additive explanations) as a technique to provide local and global explanations to the outputs as well as to select the most important features. The total calculated MQoL score was predicted accurately using three features - age at disease onset, ALSFRS-R score for orthopnoea and the caregiver's status pre-caregiving - with a F1-score on the test set equal to 0.81, recall of 0.78, and precision of 0.84. The addition of two extra features (caregiver's age and the ALSFRS-R score for speech) produced similar outcomes (F1-score 0.79, recall 0.70 and precision 0.90). European Commission - European Regional Development Fund Health Research Board Science Foundation Ireland FutureNeuro industry partners

Introduction To capture the patient’s attitude toward remote monitoring of motor neuron disease (MND) in care and clinical trials, and their concerns and preferences regarding the use of digital technology. Methods We performed an international multi-centre survey study in three MND clinics in The Netherlands, the United Kingdom, and Australia. The survey was co-developed by investigators and patients with MND, and sent to patients by e-mail or postal-mail. The main topics included: patients’ attitude towards remote care, participating in decentralized clinical trials, and preferences for and concerns with digital technology use. Results In total, 332 patients with MND participated. A majority of patients indicated they would be happy to self-monitor their health from home (69%), be remotely monitored by a multidisciplinary care team (75%), and would be willing to participate in clinical trials from home (65%). Patients considered respiratory function and muscle strength most valuable for home-monitoring. The majority of patients considered the use of at least three devices/apps (75%) once a week (61%) to be acceptable for home-monitoring. Fifteen percent of patients indicated they would not wish to perform home-measurements; reporting concerns about the burden and distress of home-monitoring, privacy and data security. Conclusion Most patients with MND exhibited a positive attitude toward the use of digital technology in both care and clinical trial settings. A subgroup of patients reported concerns with home-monitoring, which should be addressed in order to improve widespread adoption of remote digital technology in clinical MND care.

The contribution of cerebellar pathology to cognitive and behavioural manifestations is increasingly recognised, but the cerebellar profiles of FTD phenotypes are relatively poorly characterised. A prospective, single-centre imaging study has been undertaken with a high-resolution structural and diffusion tensor protocol to systematically evaluate cerebellar grey and white matter alterations in behavioural-variant FTD(bvFTD), non-fluent variant primary progressive aphasia(nfvPPA), semantic-variant primary progressive aphasia(svPPA), C9orf72-positive ALS-FTD(C9 + ALSFTD) and C9orf72-negative ALS-FTD(C9-ALSFTD). Cerebellar cortical thickness and complementary morphometric analyses were carried out to appraise atrophy patterns controlling for demographic variables. White matter integrity was assessed in a study-specific white matter skeleton, evaluating three diffusivity metrics: fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD). Significant cortical thickness reductions were identified in: lobule VII and crus I in bvFTD; lobule VI VII, crus I and II in nfvPPA; and lobule VII, crus I and II in svPPA; lobule IV, VI, VII and Crus I and II in C9 + ALSFTD. Morphometry revealed volume reductions in lobule V in all groups; in addition to lobule VIII in C9 + ALSFTD; lobule VI, VIII and vermis in C9-ALSFTD; lobule V, VII and vermis in bvFTD; and lobule V, VI, VIII and vermis in nfvPPA. Widespread white matter alterations were demonstrated by significant fractional anisotropy, axial diffusivity and radial diffusivity changes in each FTD phenotype that were more focal in those with C9 + ALSFTD and svPPA. Our findings indicate that FTD subtypes are associated with phenotype-specific cerebellar signatures with the selective involvement of specific lobules instead of global cerebellar atrophy.

Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disease typically presenting with bulbar or limb weakness. There is increasing evidence that amyotrophic lateral sclerosis is a multisystem disease with early and frequent impacts on cognition, behaviour, sleep, pain and fatigue. Dysfunction of normal physiological and metabolic processes also appears common. Evidence from pre-symptomatic studies and large epidemiological cohorts examining risk factors for the future development of amyotrophic lateral sclerosis have reported a high prevalence of changes in behaviour and mental health before the emergence of motor weakness. This suggests that changes beyond the motor system are underway at an early stage with dysfunction across brain networks regulating a variety of cognitive, behavioural and other homeostatic processes. The full impact of non-motor dysfunction continues to be established but there is now sufficient evidence that the presence of non-motor symptoms impacts overall survival in amyotrophic lateral sclerosis, and with up to 80% reporting non-motor symptoms, there is an urgent need to develop more robust therapeutic approaches. This review provides a contemporary overview of the pathobiology of non-motor dysfunction, offering readers a practical approach with regard to assessment and management. We review the current evidence for pharmacological and non-pharmacological treatment of non-motor dysfunction in amyotrophic lateral sclerosis and highlight the need to further integrate non-motor dysfunction as an important outcome measure for future clinical trial design.

Primary lateral sclerosis (PLS) is classically considered a 'pure' upper motor neuron disorder. Motor cortex atrophy and pyramidal tract degeneration are thought to be pathognomonic of PLS, but extra-motor cerebral changes are poorly characterized. In a prospective neuroimaging study, forty PLS patients were systematically evaluated with a standardised imaging, genetic and clinical protocol. Patients were screened for ALS and HSP associated mutations, as well as C9orf72 hexanucleotide repeats. Clinical assessment included composite reflex scores, spasticity scales, functional rating scales, and screening for cognitive and behavioural deficits. The neuroimaging protocol evaluated cortical atrophy patterns, subcortical grey matter changes and white matter alterations in whole-brain and region-of-interest analyses. PLS patients tested negative for known ALS- and HSP-associated mutations and C9orf72 repeat expansions. Voxel-wise analyses revealed anterior cingulate, dorsolateral prefrontal, insular, opercular, orbitofrontal and bilateral mesial temporal grey matter changes and white matter alterations in the fornix, brainstem, temporal lobes, and cerebellum. Significant thalamus, caudate, hippocampus, putamen and accumbens nucleus volume reductions were also identified. Extra-motor clinical manifestations were dominated by verbal fluency deficits, language deficits, apathy and pseudobulbar affect. Our clinical and radiological evaluation confirms considerable extra-motor changes in a population-based cohort of PLS patients. Our data suggest that PLS should no longer be considered a neurodegenerative disorder selectively affecting the pyramidal system. PLS is associated with widespread extra-motor changes and manifestations which should be carefully considered in the multidisciplinary management of this low-incidence condition.

Amyotrophic Lateral Sclerosis (ALS) is a systemic and terminal disorder of the central nervous system which causes paralysis of limbs, respiratory and bulbar muscles, impacting on physical, communication, cognitive and behavioural functioning. Informal caregivers play a key role in the care of people with ALS. This study aimed to explore experiences of burden along with any beneficial aspects of caregiving in ALS. An understanding of both burden and benefit is important to support the informal caregiver and the person with ALS.This exploratory mixed methods study characterizes two groups of informal caregivers in Ireland (n = 76) and the Netherlands (n = 58). In a semi-structured interview, quantitative data were collected in the form of standardized measures assessing psychological distress, quality of life and burden. Qualitative data were collected from an open ended question, in which caregivers identified positive aspects in their caregiving experience. These data types were purposefully mixed in the analysis and interpretation stages, to provide a greater depth of evidence through diverse research lenses.The caregiver cohorts were predominantly female (69%) and spouse/partners (84%) of the person with ALS. Greater levels of self-assessed burden were found among the caregivers in the Netherlands (p 0.05), and higher levels of quality of life among the cohort from Ireland (p 0.05). Themes generated through qualitative analysis identified caregiver satisfaction, ability to meet the patient's needs and the (re) evaluation of meaning and existential aspects of life as positive aspects of caregiving. Existential factors were identified frequently by the caregivers in Ireland, and personal satisfaction and meeting their care recipient's needs by caregivers in the Netherlands. Three percent of all respondents reported there was nothing positive about caregiving.Based on our findings, we suggest that both burden and the presence of positive factors should be evaluated and monitored. The possibility of concurrent positive and challenging experiences should be considered in the design and delivery of supportive interventions for informal caregivers.

Presymptomatic studies in ALS have consistently captured considerable disease burden long before symptom manifestation and contributed important academic insights. With the emergence of genotype-specific therapies, however, there is a pressing need to address practical objectives such as the estimation of age of symptom onset, phenotypic prediction, informing the optimal timing of pharmacological intervention, and identifying a core panel of biomarkers which may detect response to therapy. Existing presymptomatic studies in ALS have adopted striking different study designs, relied on a variety of control groups, used divergent imaging and electrophysiology methods, and focused on different genotypes and demographic groups. We have performed a systematic review of existing presymptomatic studies in ALS to identify common themes, stereotyped shortcomings, and key learning points for future studies. Existing presymptomatic studies in ALS often suffer from sample size limitations, lack of disease controls and rarely follow their cohort until symptom manifestation. As the characterisation of presymptomatic processes in ALS serves a multitude of academic and clinical purposes, the careful review of existing studies offers important lessons for future initiatives.

To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow...