Causative gene mutations have been identified in about 2% of those with amyotrophic lateral sclerosis (ALS), often, but not always, when there is a strong family history. There is an assumption that ...there is a genetic component to all ALS, but genome-wide association studies have yet to produce a robustly replicated result. A definitive estimate of ALS heritability is therefore required to determine whether ongoing efforts to find susceptibility genes are worth while.
The authors performed two twin studies, one population- and one clinic-based. The authors used structural equation modelling to perform a meta-analysis of data from these studies and an existing twin study to estimate ALS heritability, and identified 171 twin pairs in which at least one twin had ALS.
Five monozygotic twin pairs were concordant-affected, and 44 discordant-affected. No dizygotic twin pairs were concordant-affected, and 122 discordant-affected. The heritability of sporadic ALS was estimated as 0.61 (0.38 to 0.78) with the unshared environmental component 0.39 (0.22 to 0.62). ALS has a high heritability, and efforts to find causative genes should continue.
Reactivation of Human Endogenous Retrovirus K (HERV-K), subtype HML-2, has been associated with pathophysiology of amyotrophic lateral sclerosis (ALS). We aimed to assess the efficacy of ...antiretroviral therapy in inhibiting HML-2 in patients with ALS and a possible association between the change in HML-2 levels and clinical outcomes. We studied the effect of 24-weeks antiretroviral combination therapy with abacavir, lamivudine, and dolutegravir on HML-2 levels in 29 ALS patients. HML-2 levels decreased progressively over 24 weeks (P = 0.001) and rebounded within a week of stopping medications (P = 0.02). The majority of participants (82%), defined as “responders”, experienced a decrease in HML-2 at week 24 of treatment compared to the pre-treatment levels. Differences in the evolution of some of the clinical outcomes could be seen between responders and non-responders: FVC decreased 23.69% (SE = 11.34) in non-responders and 12.71% (SE = 8.28) in responders. NPI score decreased 91.95% (SE = 6.32) in non-responders and 53.05% (SE = 10.06) in responders (P = 0.01). Thus, participants with a virological response to treatment showed a trend for slower progression of the illness. These findings further support the possible involvement of HML-2 in the clinical course of the disease.
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•Antiretroviral therapy for 24 weeks decreased HERV-K (HML-2) levels in most patients with ALS.•A rebound in HML-2 levels occurred after discontinuation of the antiretroviral drugs.•Patients that had an antiviral effect against HML-2 showed a trend for slower progression in several clinical parameters.
Focality of onset of amyotrophic lateral sclerosis (ALS) is not understood. Attempts to implicate physical exercise in the aetiology of ALS have provided inconsistent results. If physical use of a ...limb were important in defining the site of onset, then handedness might be expected to influence the side of upper limb-onset disease and footedness likewise in lower limb-onset ALS.
ALS patients registered with an internet-based support site were invited to complete an online questionnaire concerning site of onset of symptoms and their dominant hand and foot. A binomial test of proportions was used to investigate the null hypothesis that handedness and footedness do not influence side of onset in upper and lower limb-onset ALS, respectively.
343 ALS patients with limb-onset disease were studied. For upper limb-onset patients, there was concordance for side of onset and handedness (64%; p<0.0006). For lower limb-onset patients, concordance for side of onset and footedness was absent. The frequency of left handedness was commensurate with that found in the general population.
These results are potentially consistent with the hypothesis that exercise influences pathogenesis in ALS since routine physical demands on the upper limb are heavily influenced by limb dominance, whereas in the lower limbs the commonest function is standing or locomotion, which uses both legs equally. However, there may also be an inherent cortical vulnerability underlying upper limb-onset laterality, possibly influenced by changes in neuronal connectivity and cortical excitability in relation to handedness and reflected by the "split hand" phenomenon consistently observed in ALS.
We sought to define the significance of brachial amyotrophic diplegia (flail arm syndrome FA) and the pseudopolyneuritic variant (flail leg syndrome FL) of amyotrophic lateral sclerosis (ALS; motor ...neuron disease).
We analyzed survival in clinic cohorts in London, UK (1,188 cases), and Melbourne, Australia (432 cases). Survival from disease onset was analyzed using the Kaplan- Meier method and Cox proportional hazards model.
In the London cohort, the FA syndrome represented 11% and the FL syndrome 6% of the sample. Median survival was 35 months for limb onset and 27 months for bulbar onset ALS, whereas this was 61 months for FA syndrome (p < 0.001) and 69 months for FL syndrome (p < 0.001). Five-year survival in this cohort was 8.8% for bulbar onset, 20% for limb onset, 52% for FA syndrome, and 64% for FL syndrome. The ratio of men to women was 4:1 in the FA group compared to 2:1 in other limb onset cases. Excluding lower motor neuron FA and FL cases, progressive muscular atrophy comprised 4% of the sample and had a prognosis similar to typical limb onset ALS. In the Melbourne cohort, median survival for limb onset ALS was 31 months, bulbar onset 27 months, FA syndrome 66 months (p < 0.001), and FL syndrome 71 months (p = 0.001).
The flail arm (FA) and flail leg (FL) syndromes had significantly better survival than typical amyotrophic lateral sclerosis (ALS) or progressive muscular atrophy cases that were not classified as FA or FL. Our findings underline the clinical and prognostic importance of the FA and FL variants of ALS.
The objective was to identify factors associated with decisions made by patients with amyotrophic lateral sclerosis (ALS) to accept or decline non-invasive ventilation (NIV) and/or gastrostomy in a ...prospective population-based study. Twenty-one people with ALS, recruited from the South-East ALS Register who made an intervention decision during the study timeframe underwent a face-to-face in-depth interview, with or without their informal caregiver present. Sixteen had accepted an intervention (11 accepted gastrostomy, four accepted NIV and one accepted both interventions). Five patients had declined gastrostomy. Thematic analysis revealed three main themes: (1) patient-centric factors (including perceptions of control, acceptance and need, and aspects of fear); (2) external factors (including roles played by healthcare professionals, family, and information provision); and (3) the concept of time (including living in the moment and the notion of ‘right thing, right time’). Many aspects of these factors were inter-related. Decision-making processes for the patients were found to be complex and multifaceted and reinforce arguments for individualised (rather than ‘algorithm-based’) approaches to facilitating decision-making by people with ALS who require palliative interventions.
Next Generation Sequencing (NGS) is a commonly used technology for studying the genetic basis of biological processes and it underpins the aspirations of precision medicine. However, there are ...significant challenges when dealing with NGS data. Firstly, a huge number of bioinformatics tools for a wide range of uses exist, therefore it is challenging to design an analysis pipeline. Secondly, NGS analysis is computationally intensive, requiring expensive infrastructure, and many medical and research centres do not have adequate high performance computing facilities and cloud computing is not always an option due to privacy and ownership issues. Finally, the interpretation of the results is not trivial and most available pipelines lack the utilities to favour this crucial step.
We have therefore developed a fast and efficient bioinformatics pipeline that allows for the analysis of DNA sequencing data, while requiring little computational effort and memory usage. DNAscan can analyse a whole exome sequencing sample in 1 h and a 40x whole genome sequencing sample in 13 h, on a midrange computer. The pipeline can look for single nucleotide variants, small indels, structural variants, repeat expansions and viral genetic material (or any other organism). Its results are annotated using a customisable variety of databases and are available for an on-the-fly visualisation with a local deployment of the gene.iobio platform. DNAscan is implemented in Python. Its code and documentation are available on GitHub: https://github.com/KHP-Informatics/DNAscan . Instructions for an easy and fast deployment with Docker and Singularity are also provided on GitHub.
DNAscan is an extremely fast and computationally efficient pipeline for analysis, visualization and interpretation of NGS data. It is designed to provide a powerful and easy-to-use tool for applications in biomedical research and diagnostic medicine, at minimal computational cost. Its comprehensive approach will maximise the potential audience of users, bringing such analyses within the reach of non-specialist laboratories, and those from centres with limited funding available.
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.
Objectives
Spasticity is a common and disabling feature of amyotrophic lateral sclerosis (ALS). There are currently no validated ALS‐specific measures of spasticity. The aim of this study was to ...develop and use a self‐report outcome measure for spasticity in ALS.
Methods
Following semi‐structured interviews with 11 ALS patients, a draft scale was administered across ALS clinics in the UK. Internal validity of the scale was examined using the Rasch model. The numerical rating scale (NRS) for spasticity and Leeds Spasticity scale (LSS) were co‐administered. The final scale was used in a path model of spasticity and quality of life.
Results
A total of 465 patients (mean age 64.7 years (SD 10), 59% male) with ALS participated. Spasticity was reported by 80% of subjects. A pool of 71 items representing main themes of physical symptoms, negative impact and modifying factors was subject to an iterative process of item reduction by Rasch analysis resulting in a 20‐item scale—the Spasticity Index for ALS (SI‐ALS)—which was unidimensional and free from differential item functioning. Moderate correlations were found with LSS and NRS‐spasticity. Incorporating the latent estimate of spasticity into a path model, greater spasticity reduced quality of life and motor function; higher motor function was associated with better quality of life.
Conclusions
The SI‐ALS is a disease‐specific self‐report scale, which provides a robust interval‐level measure of spasticity in ALS. Spasticity has a substantial impact on quality of life in ALS.
Introduction
The diagnosis of neurodegenerative and psychiatric disorders (NPDs) in primary care can suffer from inefficiencies resulting in misdiagnoses and delayed diagnosis, limiting effective ...treatment options. The development of speech and language-based profiling biomarkers could aid in achieving earlier motor diagnosis for PD for instance, or more accurate diagnosis of clinically similar or late presenting NPDs.
Objectives
RHAPSODY aims to investigate the feasibility of the remote administration of a battery of speech tasks in eliciting continuous narrative speech across a range of NPDs. The project also aims to determine the feasibility of using acoustic and linguistic biomarkers from speech data to support the clinical assessment and disambiguation of common NPDs
Methods
All participants (n=250) will take part in a single virtual telemedicine video conference with a researcher in which they are screened and complete a battery of speech tasks, in addition to cohort-specific screening measures. Over the following month, participants will be asked to complete a series of short, self-administered speech assessments via a smartphone application.
Results
The speech tasks will be audio-recorded and analysed on Novoic’s technology platform. Objectives will be analysed using measures including average length of speech elicitation for speech tasks, intra- and inter-subject variance, differences in linguistic patterns, and response rates to speech assessments.
Conclusions
The analyses could help to identify and validate speech-derived clinical biomarkers to support clinicians in detecting and disambiguating between NPDs with heterogeneous presentations. This should further support earlier intervention, improved treatment options and improved quality of life.
Disclosure
In terms of significant financial interest and relationships, it is emphasised that the private organisation Novoic, who aim to develop speech algorithms for diagnostic use, is the study’s sponsor and employees or former employees of this company comprise
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