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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options and an incompletely understood pathophysiology. Although genomewide association studies (GWAS) have advanced our understanding of the disease, the precise manner in which risk polymorphisms contribute to disease pathogenesis remains unclear. Of relevance, GWAS have shown that a polymorphism (rs12608932) in theUNC13Agene is associated with risk for both ALS and frontotemporal dementia (FTD). Homozygosity for the C-allele at rs12608932 modifies the ALS phenotype, as these patients are more likely to have bulbar-onset disease, cognitive impairment and FTD at baseline as well as shorter survival. UNC13A is expressed in neuronal tissue and is involved in maintaining synaptic active zones, by enabling the priming and docking of synaptic vesicles. In the absence of functional TDP-43, risk variants inUNC13Alead to the inclusion of a cryptic exon inUNC13Amessenger RNA, subsequently leading to nonsense mediated decay, with loss of functional protein. Depletion ofUNC13Aleads to impaired neurotransmission. Recent discoveries have identifiedUNC13Aas a potential target for therapy development in ALS, with a confirmatory trial with lithium carbonate inUNC13Acases now underway and future approaches with antisense oligonucleotides currently under consideration. ConsideringUNC13Ais a potent phenotypic modifier, it may also impact clinical trial outcomes. This present review describes the path from the initial discovery ofUNC13Aas a risk gene in ALS to the current therapeutic options being explored and how knowledge of its distinct phenotype needs to be taken into account in future trials.

Objectives/AimsAmyotrophic Lateral Sclerosis (ALS), also known as Motor Neuron Disease (MND), is a progressive and life-limiting neurodegenerative disease which can involve behavioural change. There are five commonly reported disease-specific screening tools of behavioural change but it is not clear how they differ in applicability. This study therefore set out to investigate the extent to which these measures similarly identify impairment by examining i) intercorrelations between scores on the measures completed about the same people with ALS, and ii) the percentage of people with ALS characterised as impaired on each measure.MethodsThe behavioural component of the ALS-Cognitive Behavioural Screen (ALS-CBS-b), behavioural component of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS-b), ALS-Frontotemporal Dementia Questionnaire (ALS-FTD-Q), Beaumont Behavioural Inventory (BBI), and MND Behavioural Instrument (MiND-B) were all completed by 35 carers of people with ALS. Total scores for each measure underwent Spearman correlation analysis. Classifications of impairment (for behavioural impairment or ALS-FTD) were determined using published cut-offs and agreement between measures was determined by calculating Cohens kappa coefficients.ResultsThe behavioural measures were significantly intercorrelated (pConclusionsExisting measures of behavioural change in people with ALS may yield very differing conclusions and cannot be assumed to be interchangeable. Variability in the detection of impairment between measures may result from differing item content, behaviours sampled or cut-off scores for impairment. This inconsistency between measures may lead to inappropriate healthcare provision and discrepancies in research conclusions.FundingMND Association

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder without effective neuroprotective therapy. Known genetic variants impair pathways including RNA processing, axonal transport and protein homeostasis. Here we report mutations in a new ALS gene encoding the glycosyltransferase GLT8D1; this class of proteins has not previously been associated with neurodegeneration. Exome sequencing in an autosomal dominant ALS pedigree identified p.R92C mutations in GLT8D1 which co-segregate with disease. Sequencing of local and international cohorts demonstrated significant ALS-association in the same exon, including additional rare deleterious mutations in conserved amino acids. Mutations are associated with the substrate binding site and both R92C and G78W changes impair GLT8D1 enzyme activity. Mutated GLT8D1 exhibits in vitro cytotoxicity and induces motor deficits in zebrafish consistent with ALS. Relative toxicity of mutations in model systems mirrors clinical severity. In conclusion, we have discovered a previously uncharacterised pathophysiological pathway for ALS caused by inherited mutations within a glycosyltransferase enzyme.

Systematic explorations of language abilities in patients with amyotrophic lateral sclerosis (ALS) are lacking in the context of wider cognitive change.Neuropsychological assessment data were obtained from 51 patients with ALS and 35 healthy controls matched for age, gender and IQ. Composite scores were derived for the domains of language and executive functioning. Domain impairment was defined as a composite score ≤5th centile relative to the control mean. Cognitive impairment was also classified using recently published consensus criteria.The patients with ALS were impaired on language and executive composite scores. Language domain impairment was found in 43% of patients with ALS, and executive domain impairment in 31%. Standardised language and executive composite scores correlated in the ALS group (r=0.68, p0.001). Multiple regression analyses indicated that scores on the executive composite accounted for 44% of the variance in language composite scores.Language impairments are at least as prevalent as executive dysfunction in ALS. While the two domains are strongly associated, executive dysfunction does not fully account for the profile of language impairments observed, further highlighting the heterogeneity of cognitive impairment in non-demented patients with ALS.

Background Amyotrophic Lateral Sclerosis (ALS) is typified by degeneration of upper and/or lower motor neurons (U/LMNs). Progression varies significantly with median survival approximately 3 years from symptom onset, but ~10% survive over 5 years. It is unknown how the relative involvement of cranial and limb UMN and LMN burden is associated with disease prognosis. Methods An adapted scoring system of U/LMN signs was used to retrospectively grade U/LMN burden in the limbs and bulbar region near to diagnosis for 90 individuals diagnosed with ALS between 2011–2016. Other prognostic information was also collected. Survival analysis was conducted using log-rank testing and Cox regression. Results Statistical analysis indicated the following variables measured near exam were significantly associated (p≤0.05) with reduced survival: short diagnostic delay, unintended weight loss, limb LMN signs and bulbar UMN signs. Discussion The results both support previous research into the importance of LMN limb signs for prognostic value, as well as reporting for the first time that UMN bulbar signs may be associated with reduced survival. These may be due to the nature of the neurological exam or ALS pathophysiology. Future work is needed to better characterise these results for potential use in clinical settings and research.

Sensory involvement is thought not to be a feature of amyotrophic lateral sclerosis (ALS). However, in the setting of a specialist motor neuron disease clinic, we have identified five patients with sporadic ALS and a sensory neuropathy for which an alternative cause could not be identified. In three individuals, sensory nerve biopsy was performed, demonstrating axonal loss without features of an alternative aetiology. These findings support the hypothesis that ALS is a multisystem neurodegenerative disorder that may occasionally include sensory neuropathy among its non‐motor features.

Electrical injury may act as a potential precipitating or risk factor for amyotrophic lateral sclerosis (ALS). A systematic review of the literature was undertaken to assess the relationship between electrical injury and the development of ALS. Information for the review was obtained using five medical databases, and from manual searching of individual papers. Patients presenting with a neurological syndrome after electrical injury, including lightning, were included and classified into four categories: ALS; progressive upper motor neurone (UMN) syndrome; progressive lower motor neurone (LMN) syndrome; and non-progressive syndrome. Linear regression and chi2 testing were used for analysis of the data. 96 individuals, comprising 44 with ALS, 1 with a progressive UMN syndrome, 7 with a progressive LMN syndrome and 44 with a non-progressive syndrome, were identified from 31 papers with publication dates between 1906 and 2002. The median interval between electrical injury and disease onset was 2.25 years for all progressive syndromes and just over 1 week for the non-progressive syndrome. The more severe the shock (excluding lightning), the more likely individuals were to have a non-progressive motor syndrome. A non-progressive spinal cord syndrome is associated with more severe electrical injury. Overall, the evidence reviewed does not support a causal relationship between ALS and electric shock.

The management of motor neurone disease (MND) has evolved rapidly over the last two decades. Although still incurable, MND is not untreatable. From an attitude of nihilism, treatments and interventions that prolong survival have been developed. These treatments do not, however, arrest progression or reverse weakness. They raise difficult practical and ethical questions about quality of life, choice, and end of life decisions. Coordinated multidisciplinary care is the cornerstone of management and evidence supporting this approach, and for symptomatic treatment, is growing.1–3 Hospital based, community rehabilitation teams and palliative care teams can work effectively together, shifting emphasis and changing roles as the needs of the individuals affected by MND evolve. In the UK, MND care centres and regional networks of multidisciplinary teams are being established. Similar networks of MND centres exist in many other European countries and in North America. Here, we review current practice in relation to diagnosis, genetic counselling, the relief of common symptoms, multidisciplinary care, the place of gastrostomy and assisted ventilation, the use of riluzole, and end of life issues. View this table: Table 1 Clinical syndromes of MND (ALS—amyotrophic lateral sclerosis) and related disorders (modified from Kato et al , 2003*, with permission) The average delay from onset of symptoms to diagnosis is about 14 months, about one third of expected survival. Occasionally, survival following diagnosis may be less than six months. The patient may already suspect the diagnosis …

Objectives Using a historical amyotrophic lateral sclerosis (ALS) dataset comprising detailed cognitive and clinical assessments, we used a novel event-based model to analyse the likely ordering of these biomarkers in the progression of ALS. Methods The dataset was derived from a cross-sectional sample of 28 ALS patients who were not classified as having ALS-FTD and 26 matched controls (see1 regarding cognitive and clinical assessments). The event-based model was adapted for ALS from previous work in Alzheimer9s disease.23 Unlike traditional models of disease progression, event-based models do not rely on a priori staging of patients but extract the event ordering directly from the data, thus minimising subjective bias. Results The most likely order of progression showed that changes in executive function occur at an early stage of disease evolution. Language impairment tended to occur after executive dysfunction. Changes in functional ability assessed by rate of change of ALSFRS-R occurred after the changes in executive function. Conclusions These findings suggest that executive dysfunction occurs early in the evolution of ALS.

Background 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. Methods 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. Results and discussion 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.

Motor neuron disease is a clinically heterogeneous disease with significant differences in survival. The authors have characterised a subset of long term survivors seen in a tertiary clinic over a 12 year period in terms of clinical variables and demographics, comparing them with short term survivors and the remaining population. Thirty of 769 patients survived more than 10 years, corresponding to 4% of the total population. Significantly younger onset of disease symptoms and a predominance of pure upper motor neuron signs at presentation characterised the long term survivors, but factors traditionally regarded as being associated with poor prognosis were also well represented. For a few people with motor neuron disease there remains the hope, whatever the initial presentation, that their subsequent survival will be longer than expected.

BackgroundAmyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. We examined the phylogenetics of ALS-susceptibility genes from our previously-published genome-wide association study (GWAS).MethodsWe examined the association between ALS-susceptibility genes and hybridisation from the Neanderthal genome using a modified gene set enrichment analysis (GSEA). These gene sets comprise thirteen candidate regions for Neanderthal to non-African human gene flow [UCSC Genome Browser]. We ranked the ascending p-values of 442,057 GWAS SNPs and simulated the distribution 100,000 times. The resulting empirical p-value, comparing observed with expected mean rank, identified which gene sets are over-represented at the top of the rank list. Bonferroni corrections for multiple testing were applied.Results6,402 imputed GWAS SNPs fell into the thirteen gene sets. We found that the regions on chromosomes 6 and 9 accrued the lowest observed mean ranks (8,594 and 7,096 respectively) and were not different from expected mean ranks after simulation for those regions – empirical p-values before Bonferroni correction were 0.086 for chromosome 6 and 0.071 for chromosome 9.DiscussionUsing GSEA to evaluate European ALS GWAS data in the context of pre-defined gene sets refutes the theory that ALS-susceptibility loci may have arisen from Neanderthal to non-African modern human gene flow.

BackgroundProgressive supranuclear palsy (PSP) is a debilitating Parkinsonian movement disorder characterised by tau protein burden. We aimed to identify common genetic variants influencing PSP susceptibility through a genome-wide association analysis (GWAS) of a multi-centre European study, Neuroprotection and Natural History in Parkinson's Plus Syndromes (NNIPPS), recruiting clinically well-characterised patients. We combined this with a meta-analysis of previously-identified gene variants.MethodsWe genotyped 275,684 single nucleotide polymorphisms using Illumina microarrays in 212 PSP cases from the UK, Germany and France, and compared these with 4,707 matched controls. GWAS was performed using PLINK. Meta-analysis was performed with METAL. Genome-wide significance was defined as pResultsWe observed multiple associations on chromosome 17 within or close to the MAPT gene, a well-established risk locus for PSP, confirming the sample and method validity. Of nine other previously reported associations, meta-analysis only confirmed that the MOBP variation (rs1768208) modified PSP risk (p=3.29×10^–13).ConclusionIn the GWAS and meta-analysis, we found the chromosome 17 inversion region to be associated with PSP susceptibility. Furthermore, we have shown that MOBP can modify the risk of PSP, possibly through influencing oligodendrocyte tau inclusions. These identified gene variants provide novel insights into the underlying genetics of sporadic PSP.

BACKGROUND The aetiology of apparently sporadic amyotrophic lateral sclerosis (ALS) is unknown, but prenatal factors are known to influence disease development. In both men and women, motor neurons require testosterone for survival and axonal regeneration after injury, and androgen insensitivity leads to a form of motor neuron degeneration in men. Reduction in the ratio of index to ring finger length (2D:4D ratio) is considered a surrogate marker for high prenatal testosterone levels in both men and women. The authors therefore tested the hypothesis that prenatal testosterone irrespective of gender is an independent risk factor for the development of ALS later in life, and that this would be reflected in a lower 2D:4D ratio in both men and women with ALS. METHODS Patients and unrelated control individuals attending a specialist tertiary referral centre for ALS were studied. A digital camera was used to photograph hands. Finger lengths were measured by four independent scorers blind to case-control status, and the mean 2D:4D ratio derived. Analysis was by linear regression and receiver-operator-curve analysis. RESULTS Controlling for differences in sex ratio between groups, the 2D:4D ratio was lower for people with ALS (n=47) than for controls (n=63) (r=-0.25, two-tailed p=0.009). CONCLUSIONS Patients with ALS have a lower 2D:4D ratio, consistent with higher prenatal circulating levels of testosterone, and possibly a prenatal influence of testosterone on motor-neuron vulnerability in later life.

Background An intronic GGGGCC hexanucleotide repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Thirty repeats is the suggested pathogenic cut-off. However, the 9p21 risk haplotype has been associated with C9orf72 expansions >7 repeats, leading to the description of 7–24 repeats as intermediate. The pathogenicity of intermediate repeat lengths is unknown. Studies have suggested phenotypic similarities between patients with intermediate length expansions and those with larger repeat lengths, although given the broad phenotypic spectrum of ALS this is not conclusive. Previously, there has been no pathological characterisation of an intermediate expansion patient. Materials and Methods Pathological material was obtained from the Sheffield Brain Tissue Bank. Genomic DNA was extracted from cerebellar material and reverse primed PCR and Southern hybridisation was conducted to size the expansion. Immunohistochemistry and RNA fluorescence in-situ hybridisation (FISH) was used to screen for pathology typical of C9orf72-ALS. Results Repeat-primed PCR and Southern hybridisation revealed a repeat expansion size of 16 repeats in a sporadic ALS (SALS) patient. Neuropathological analysis demonstrated loss of motor neurons and immunohistochemistry revealed coarse neuronal skein-like inclusions identified by ubiquitin and P62 immunostaining. Pathology characteristic of C9orf72-disease, including extramotor neuronal inclusions, RNA foci and neuronal inclusions containing poly-(Gly-Ala)- dipeptide repeat protein, were absent in this patient. Conclusion A patient with an intermediate C9orf72 expansion of 16 repeats did not show the characteristic C9orf72 pathology suggesting that, in this case, the disease process was distinct from C9orf72-ALS, and the intermediate expansion is an incidental finding. This is consistent with current toxic gain-of-function theories of C9orf72-ALS. The 9p21 risk haplotype may predispose to expansion of the GGGGCC repeat locus, but we suggest that this must occur to some length larger than 16 repeats to cause the pathology characteristic of the C9orf72 subtype of ALS.

Introduction A published report of 44 patients with amyotrophic lateral sclerosis (ALS) of whom 16 were randomly selected to take lithium and riluzole and the remainder riluzole alone, suggested a dramatic effect of lithium carbonate on survival. In the group treated with lithium there was 100% survival by the end of the study, 15 months after recruitment, while in the riluzole-only group only 71% survived. Because the trial was small, not double blind or placebo-controlled, we sought to perform a definitive study to test the hypothesis that lithium carbonate improves survival in ALS. Methods Detailed methods are provided in the published protocol. We used a multi-centre, double blind, randomized, parallel group controlled trial of lithium carbonate (LiCO3) at doses to achieve stable ‘therapeutic’ plasma levels (0.4–0.8 mmol/l) versus matched placebo in patients with ALS. All patients were on standard ALS treatment of riluzole 100 mg per day. The primary outcome measure was death from any cause at 18 months from the date of randomization. Results 214 patients were enrolled from 10 centres in England, 107 in each arm. 117 patients (54.7%) were still alive at the study end, 54 on lithium arm and 63 on placebo. The primary outcome showed no difference in survival between groups, either unadjusted (Mantel-Cox log rank χ 2 statistic 1.64, p=0.2) or adjusted for differences between sites (Mantel-Cox Log rank χ 2 statistic 2.11, p=0.147). Conclusion Lithium carbonate does not improve survival in ALS.

Objectives To generate a prognostic classification method for Amyotrophic Lateral Sclerosis (ALS) from a prognostic model built using clinical variables from a population register. Materials and Methods We carried out a retrospective multivariate analysis of 713 patients with ALS over a 20 year period from the South-East England Amyotrophic Lateral Sclerosis (SEALS) population register. Patients were randomly allocated to ‘discovery’ or ‘test’ cohorts. A prognostic score was calculated using the discovery cohort and then used to predict survival in the test cohort. This score was used as a predictor variable in subsequent survival analyses, either as a raw value for a Cox regression or split into four prognostic categories (good, moderate, average, poor). Results A prognostic score generated from one cohort of patients predicted survival for a second cohort of patients (r2=0.72). Six variables were included in the survival model: age at onset, diagnostic delay, El Escorial category, use of riluzole, gender and site of onset. Cox regression demonstrated a strong relationship between these variables and survival (χ2 80.8, df 1, p Conclusion It is possible to correctly classify patients into prognostic categories using clinical data easily available at time of diagnosis.

Objective This study set out to investigate the relationship between mood and physical and psychological factors in amyotrophic lateral sclerosis (ALS). Method As part of a longitudinal study investigating decision-making in ALS, 69 ALS patients, recruited from the South East ALS register, were assessed at baseline on measures of mood (Beck Depression Inventory Fast Screen), purpose in life (Purpose in Life Scale) and illness perceptions (Brief Illness Perceptions Questionnaire). Demographic and illness characteristics were also recorded. Hierarchical multiple regression was used to determine the extent to which psychological variables (purpose in life; and illness perceptions—consisting of perceived consequences of illness, personal control, identity, concern and emotions) predicted mood, after accounting for the effects of demographic (age, years of education) and illness characteristics (symptom severity, measured by ALSFRS-R). Results 42.0% of patients exceeded the recommended clinical cut-off score on the BDI-Fast Screen, suggestive of depression, although most of these (34.8% of the total sample) fell in the mild range. Multiple regression showed that psychological variables (purpose in life and illness perceptions) explained an additional 42% (adjusted R 2 =0.406) of the variance in mood, over and above that explained by demographic and illness characteristics, which only explained a total of 7% of the variance. In the final model, purpose in life was the only statistically significant predictor of mood among ALS patients. Conclusion Purpose in life, based on the work of Frankl (1959), refers to the degree to which a person experiences a sense of meaning in life and includes, for example, having goals to strive for and relationships to maintain (Hedberg et al , 2011; White, 2004). Frankl (1958) suggested that a lack of purpose in life can weaken the will to confront life situations, producing an “existential vacuum” and resulting in depression and anxiety (Hedberg et al , 2011). Current results suggest that purpose in life may play a more significant role in influencing mood among ALS patients than the beliefs about their illness or the severity of their physical symptoms. Findings, therefore, emphasise the importance of understanding psychological factors leading to risk of mental health problems in this population, and ultimately their relation to prognosis and treatment choices. Funding This study is funded by the MNDA, UK.

The ALS Online Genetics Database (ALSOD) is a central repository of genetic information on amyotrophic lateral sclerosis (ALS). In 1999, when the database was started, the only genetic cause of ALS known was mutation in the SOD1 gene. There have since been rapid advances in our knowledge. We therefore aim to provide a single, continuously updated resource summarising the current state of ALS genetics including automated meta-analysis of published linkage and association studies, deposition of rare genetic variants and documentation of associated core clinical features to generate phenotypic correlations. The requirements of the ALS genetics research community have been collected from the ALSOD feedback page. The web-based application has public pages accessible to all, and secure pages accessible to registered users who are able to access more detailed clinical and statistical information, as well as deposit new data. Integration with existing databases and analysis software means that ALSOD is a powerful resource for exploring existing genetic and phenotypic information in ALS. New tools are in development, and will be made live after initial beta-testing is passed. ALSOD is widely used by the ALS genetics research community. We aim to make it an indispensable tool for ALS research.

We have successfully developed the chick embryo model of ALS. We carried out overexpression of HA and Myc tagged TDP-43WT, TDP-43Q331K and TDP-43M337V constructs (Sreedharan et al, 2008). We also carried out over-expression of pEGFPC1 as a control. TUNEL staining demonstrated that GFP transfection resulted in low levels of apoptotic TUNEL +ve cells. However, embryos electroporated with the WT and MT forms of TDP-43 showed a marked increase. A two-tailed t test of GFP vs HA-TDP-43WT-Myc, GFP vs HA-TDP-43Q331K-Myc and GFP vs HA-TDP-43M337V-Myc gave p-values of 0.1252, 0.0179 and 0.0079 respectively. We also carried out electroporation of N-terminal GFP tagged constructs expressing the same wild-type and mutant genes ( GFP-TDP-43WT , GFP-TDP-43Q331K and GFP-TDP-43M337V ). TUNEL staining showed a statistically significant increase in the number of apoptotic nuclei in embryos electroporated with TDP-43WT, TDP-43Q331K and TDP-43M337V as compared to those expressing pEGFPC1. A two-tailed t test of GFP vs GFP-TDP-43WT gave a p-value of 0.0337; GFP vs GFP-TDP-43Q331K gave a p-value of 0.0026 and GFP vs GFP-TDP-43M337V gave a p-value of 0.0045. The mutant forms of TDP-43 showed predominantly cytoplasmic localisation as compared to TDP-43WT. Moreover, we observed nuclear aggregates in the sections of embryos electroporated with mutant TDP-43. A two-tailed t-test of GFP-TDP-43WT vs GFP-TDP-43Q331K gave a p-value of 0.012 and that of GFP-TDP-43WT vs GFP-TDP-43M337V gave a p-value of 0.009.

ObjectiveAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system. The split hand sign in ALS refers to observed preferential weakness of the lateral hand muscles, which is unexplained. One possibility is larger cortical representation of the lateral hand compared with the medial. Biceps strength is usually preserved relative to triceps in neurological conditions, but biceps has a larger cortical representation and might be expected to show preferential weakness in ALS.MethodsUsing the South-East England Register for Amyotrophic Lateral Sclerosis, we performed a retrospective longitudinal cohort study and extracted the modified Medical Research Council (MRC) muscle strength score for biceps and triceps in patients with a diagnosis of upper limb-onset ALS in the 19-year period 1996–2015. A Wilcoxon signed-rank test was used to assess the relative strength of the muscles within the total sum of the upper limbs involved in the study.ResultsThere were 659 people with upper limb onset of weakness. In 215 there were insufficient data to perform the analysis, and a further 33 were excluded for other reasons, leaving 411 for analysis. Biceps was stronger than triceps in 87 limbs, and triceps was stronger than biceps in 258 limbs, with no difference seen in the remaining 477. Triceps strength scores (mean rank=186.1) were higher than ipsilateral biceps strength scores (mean rank=134.2), Z=−10.1, pConclusionTriceps strength is relatively preserved compared with biceps in ALS. This is consistent with a broadly corticofugal hypothesis of selective vulnerability, in which susceptibility might be associated with larger cortical representation.