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Increased awareness of cognitive and behavioural change in amyotrophic lateral sclerosis has been driven by various clinic-based and population-based studies. A frontotemporal syndrome occurs in a substantial proportion of patients, a subgroup of whom present with frontotemporal dementia. Deficits are characterised by executive and working-memory impairments, extending to changes in language and social cognition. Behaviour and social cognition abnormalities are closely similar to those reported in behavioural variant frontotemporal dementia, implying a clinical spectrum linking amyotrophic lateral sclerosis and frontotemporal dementia. Cognitive impairment should be considered in clinical management, but few specialist assessment resources are available, and thus the cognitive status of most patients is unknown. Standard assessment procedures are not appropriate to detect dysfunction due to progressive physical disability; techniques that better measure the problems encountered by this group of patients are needed to further establish disease effects. Screening instruments are needed that are validated specifically for amyotrophic lateral sclerosis, encompass the heterogeneity of impairment, and accommodate physical disability.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a rapid course, characterized by motor neuron dysfunction, leading to progressive disability and death. This Review, which is aimed at neurologists, psychologists and other health professionals who follow evidence-based practice relating to ALS and frontotemporal dementia (FTD), examines the neuropsychological evidence that has driven the reconceptualization of ALS as a spectrum disorder ranging from a pure motor phenotype to ALS–FTD. It focuses on changes in cognition and behaviour, which vary in severity across the spectrum: around 50% individuals with ALS are within the normal range, 15% meet the criteria for ALS–FTD, and the remaining 35% are in the mid-spectrum range with milder and more focal impairments. The cognitive impairments include deficits in verbal fluency, executive functions, social cognition and language, and apathy is the most prevalent behavioural change. The pattern and severity of cognitive and behavioural change predicts underlying regional cerebral dysfunction from brain imaging and post-mortem pathology. Our increased recognition of cognition and behaviour as part of the ALS phenotype has led to the development and standardization of assessment tools, which have been incorporated into research and clinical care. Measuring change over the course of the disease is vital for clinical trials, and neuropsychology is proving to be a biomarker for the earliest preclinical changes.The term amyotrophic lateral sclerosis (ALS)–frontotemporal spectrum disorder encompasses a spectrum ranging from pure motor ALS to ALS with frontotemporal dementia. This Review focuses on the cognitive and behavioural impairments that are found in the mid-range of this spectrum.

Current measures of social cognition have shown inconsistent findings regarding the effects of healthy aging. Moreover, no tests are currently available that allow clinicians and researchers to examine cognitive and affective theory of mind (ToM) and understanding of social norms within the same test. To address these limitations, we present the Edinburgh Social Cognition Test (ESCoT) which assesses cognitive and affective ToM and inter- and intrapersonal understanding of social norms. We examined the effects of age, measures of intelligence and the Broader Autism Phenotype (BAP) on the ESCoT and established tests of social cognition. Additionally, we investigated the convergent validity of the ESCoT based on traditional social cognition measures. The ESCoT was administered alongside Reading the Mind in Films (RMF), Reading the Mind in Eyes (RME), Judgement of Preference and Social Norm Questionnaire to 91 participants (30 aged 18-35 years, 30 aged 45-60 years and 31 aged 65-85 years). Poorer performance on the cognitive and affective ToM ESCoT subtests were predicted by increasing age. The affective ToM ESCoT subtest and RMF were predicted by gender, where being female predicted better performance. Unlike the ESCoT, better performance on the RMF was predicted by higher verbal comprehension and perceptual reasoning abilities, while better performance on the RME was predicted by higher verbal comprehension scores. Lower scores on inter-and intrapersonal understanding of social norms were both predicted by the presence of more autism-like traits while poorer interpersonal understanding of social norms performance was predicted by increasing age. These findings show that the ESCoT is a useful measure of social cognition and, unlike established tests of social cognition, performance is not predicted by measures of verbal comprehension and perceptual reasoning. This is particularly valuable to obtain an accurate assessment of the influence of age on our social cognitive abilities.

BackgroundUp to 50% of people with amyotrophic lateral sclerosis (ALS) experience cognitive dysfunction, whilst depression and anxiety are reported in up to 44% and 33%, respectively. These symptoms impact on quality of life, and are associated with a poorer prognosis. Historically, outcomes in clinical trials have focused on the effect of candidate drugs on physical functioning.MethodsWe reviewed the past 25 years of clinical trials of investigative medicinal products in people with ALS, since the licensing of riluzole, and extracted data on frequency and type of assessment for neuropsychiatric symptoms and cognitive impairment. Trial registry databases, including WHO International Trials Registry, European Clinical Trials Register, clinicaltrials.gov, and PubMed, were systematically searched for Phase II, III or IV trials registered, completed or published between 01/01/1994 and 31/10/2019. No language restrictions were applied. Outcome measures, exclusion criteria and assessment tool used were extracted.Results216 trials, investigating 26,326 people with ALS, were reviewed. 35% assessed neuropsychiatric symptoms, and 22% assessed cognition, as Exclusion Criteria or Outcome Measures. 3% (n = 6) of trials assessed neuropsychiatric symptoms as a Secondary Outcome Measure, and 4% (n = 8) assessed cognition as Outcome Measures; only one trial included assessments for both cognition and neuropsychiatric symptoms as Outcome Measures. Three ALS-specific assessments were used in six trials.ConclusionsTrials for people with ALS have neglected the importance of neuropsychiatric symptoms and cognitive impairment. Evaluation of these extra-motor features is essential to understanding the impact of candidate drugs on all symptoms of ALS.PROPSERO registrationCRD42020175612.

BackgroundAmyotrophic lateral sclerosis (ALS) is increasingly recognised as a multi-system disorder, presenting with common and impactful non-motor symptoms, such as neuropsychiatric symtpoms, cognitive and behavioural changes, pain, disordered sleep, fatigue and problematic saliva.Aim/hypothesisWe aimed to systematically review 25 years of ALS clinical trials data to identify if non-motor features were evaluated, in addition to the traditional measures of motor functioning and survival, and where evaluated to describe the instruments used to assess. We hypothesised that assessment of non-motor symptoms has been largely neglected in trial design and not evaluated with ALS-suitable instruments.MethodsWe reviewed clinical trials of investigative medicinal products in ALS, since the licensing of riluzole in 1994. Trial registry databases including WHO International Trials Registry, European Clinical Trials Register, clinicaltrials.gov, and PubMed were systematically searched for Phase II, III or IV trials registered, completed or published between 01/01/1994 and 16/09/2020. No language restrictions were applied.Results237 clinical trials, including over 29,222 participants, were investigated for their use of non-motor outcome measures. These trials evaluated neuropsychiatric symptoms (75, 32%), cognitive impairment (16, 6.8%), behavioural change (34, 14%), pain (55, 23%), sleep disturbances (12, 5%) and fatigue (18, 8%). Problematic saliva was assessed as part of composite ALS-FRS(R) scores in 184 trials (78%) but with no focus on this as an isolated symptom. 31 (13%) trials including 3585 participants did not include any assessment of non-motor symptoms.ConclusionsNon-motor symptoms such as neuropsychiatric, cognitive and behavioural changes, pain, disordered sleep, fatigue, and problematic saliva have not been consistently evaluated in trials for people with ALS. Where evaluated, non-symptoms were primarily assessed using instruments and impairment thresholds that are not adapted for people with ALS. Future trials should include non-motor symptom assessments to evaluate the additional potential therapeutic benefit of candidate drugs.PROPSERO registrationCRD42020223648.

The present study aims at clarifying the nature of the Theory of Mind (ToM) deficits associated with Amyotrophic Lateral Sclerosis (ALS). ToM is the ability to attribute mental states such as intentions and beliefs to others in order to understand and predict their behaviour and to behave accordingly. Several neuroimaging studies reported the prefrontal cortices as the brain region underlying a key ToM ability, i.e. the comprehension of social intentions. Dysfunction of the prefrontal cortices in patients with ALS has been indicated by a range of neuroimaging studies. The frontal syndrome that appears to characterize up to 50% of ALS has been noted to be similar to the profile that characterizes patients with frontotemporal dementia (FTD), a neurodegenerative condition characterised by ToM deficits. In the present paper, we hypothesize that the performance of patients with ALS is significantly worse than healthy controls' performance on tasks requiring the comprehension of social contexts, whereas patients' performance is comparable to healthy controls' performance on tasks not requiring the comprehension of social contexts. To this end, we tested 15 patients with ALS with an experimental protocol that distinguishes between private (non-social) intentions and social intentions. The pattern of results followed the experimental hypothesis: the performance of patients with ALS and healthy controls significantly differed on the comprehension of social context only, with an impairment in patients with ALS. Single case analysis confirmed the findings at an individual level. The present study is the first which has examined and compared the understanding of social and non-social contexts in patients with ALS and shown a specific and selective deficit in the former only. The current findings further support the notion of a continuum of cognitive dysfunction ranging from ALS to FTD, with parallel cognitive profiles in both disorders.

IntroductionMotor neuron disease (MND) is a rapidly progressive and fatal neurodegenerative disorder with limited treatment options. The Motor Neuron Disease Systematic Multi-Arm Randomised Adaptive Trial (MND-SMART) is a multisite UK trial seeking to address the paucity in effective disease-modifying drugs for people with MND (pwMND). Historically, neurological trials have been plagued by suboptimal recruitment and high rates of attrition. Failure to recruit and/or retain participants can cause insufficiently representative samples, terminated trials or invalid conclusions. This study investigates patient-specific factors affecting recruitment and retention of pwMND to MND-SMART. Improved understanding of these factors may improve trial protocol design, optimise recruitment and retention.Methods and analysisPwMND on the Scottish MND Register, Clinical Audit Research and Evaluation of MND (CARE-MND), will be invited to participate in a prospective observational cohort study that investigates factors affecting trial participation and attrition. We hypothesise that patient-specific factors will significantly affect trial recruitment and retention. Participants will complete the Hospital Anxiety and Depression Scale, 9-Item Patient Health Questionnaire and State-Trait Anxiety Inventory-Form Y to evaluate neuropsychiatric symptoms, the ALS-Specific Quality of Life Questionnaire-Brief Form and Centre for Disease Control and Prevention-Health-Related Quality of Life for quality of life and a novel study-specific questionnaire on Attitudes towards Clinical Trial Participation (ACT-Q). Clinical data on phenotype, cognition (Edinburgh Cognitive and Behavioural ALS Screen) and physical functioning (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised) will also be collated. Caregivers will complete the Brief Dimensional Apathy Scale. After 12 months, a data request to MND-SMART will evaluate recruitment and retention. Descriptive statistics will summarise and compare assessments and participants reaching impairment thresholds. Variable groupings: attitudes, quality of life, cognition, behaviour, physical functioning, neuropsychiatric and phenotype. Univariate and multivariable logistic regression will explore association with participation/withdrawal in MND-SMART; presented as ORs and 95% CIs.Ethics and disseminationEthical approval was provided by the West of Scotland Research Ethics Committee 3 (20/WS/0067) on 12 May 2020. The results of this study will be published in a peer-reviewed journal, presented at academic conferences and disseminated to participants and the public.

Objective. Several studies have reported that people with Parkinson’s disease (PD) perform poorly on tests of ‘Theory of Mind’ (ToM), suggesting impairment in the ability to understand and infer other people’s thoughts and feelings. However, few studies have sought to separate the processes involved in social reasoning from those involved in managing the inhibitory demands on these tests. In this study, we investigated the contribution of inhibition to ToM performance in PD. Methods. 18 PD patients and 22 age-matched healthy controls performed a ToM test that separates the ability to infer someone else’s perspective from the ability to inhibit one’s own. Participants also completed a battery of standard measures of social and executive functioning, including measures of inhibition. Results. The PD patients performed worse on the ToM test only when the inhibitory demands were high. When the level of inhibition required was reduced, there were no significant group differences. Furthermore, executive impairments in PD patients were limited to measures of inhibition, with disadvantages associated with poorer ToM performance in this group. Conclusions. This study provides convincing evidence that the apparent impairment observed on ToM tests in PD is explained by deficits in inhibition.

Objective To characterize disease evolution in amyotrophic lateral sclerosis using an event‐based model designed to extract temporal information from cross‐sectional data. Conventional methods for understanding mechanisms of rapidly progressive neurodegenerative disorders are limited by the subjectivity inherent in the selection of a limited range of measurements, and the need to acquire longitudinal data. Methods The event‐based model characterizes a disease as a series of events, each comprising a significant change in subject state. The model was applied to data from 154 patients and 128 healthy controls selected from five independent diffusion MRI datasets acquired in four different imaging laboratories between 1999 and 2016. The biomarkers modeled were mean fractional anisotropy values of white matter tracts implicated in amyotrophic lateral sclerosis. The cerebral portion of the corticospinal tract was divided into three segments. Results Application of the model to the pooled datasets revealed that the corticospinal tracts were involved before other white matter tracts. Distal corticospinal tract segments were involved earlier than more proximal (i.e., cephalad) segments. In addition, the model revealed early ordering of fractional anisotropy change in the corpus callosum and subsequently in long association fibers. Interpretation These findings represent data‐driven evidence for early involvement of the corticospinal tracts and body of the corpus callosum in keeping with conventional approaches to image analysis, while providing new evidence to inform directional degeneration of the corticospinal tracts. This data‐driven model provides new insight into the dynamics of neuronal damage in amyotrophic lateral sclerosis.

In the Taylor et al 6 report a comprehensive language assessment was undertaken and although the profile of impairment was not analysed in detail the study provides the simple yet striking demonstration that these language deficits may indeed be at least as common if not more common than the typically reported executive dysfunction. [...]the data demonstrates that such language deficits may be found in patients who do not have executive dysfunction; regression analysis demonstrated that executive dysfunction accounted for only 44% of the variance in language scores indicating some independence of these cognitive deficits and more specifically that executive dysfunction in ALS is not the whole story.