Objective Motor neuron disease is a rapidly progressing neurological condition. People with life-limiting conditions generally prefer to die at home and avoid hospital admissions, with Specialist Palliative Care Team involvement often pivotal. Our aim was to investigate the role of advance care planning, Specialist Palliative Care Team input and other relevant variables on place of death and unscheduled hospital admissions in a Scottish population of people with motor neuron disease. Methods: National CARE-MND audit data, primary and secondary care data, and local Palliative Care records were interrogated. Chi-square, point-biserial correlation and binary logistic regression analysed associations (p < 0.05 statistically significant). Participants (188) were deceased, having a verified motor neuron disease diagnosis between 2015-2017, diagnosis occurring >= 28 days before death. Results: Advance care planning and Specialist Palliative Care Team input of >= 28 days were associated with increased odds of dying outside hospital (BLR:OR 3.937, CI 1.558-9.948, p = 0.004 and OR 2.657, CI 1.135-6.222, p = 0.024 respectively). Non-invasive ventilation decreased the odds of dying outside hospital (BLR:OR 0.311, CI 0.124-0.781, p = 0.013). Having a gastrostomy increased odds of >= 1 admissions in the last year of life (BLR:OR 5.142, CI 1.715-15.417, p = 0.003). Statistical significance was retained with removal of gastrostomy-related complications. Conclusion: Early Specialist Palliative Care input and advance care planning may increase the likelihood of death outside of hospital for persons with motor neuron disease. Further research is warranted into barriers of facilitating death outside of hospital with home non-invasive ventilation use and the association between gastrostomy status and unscheduled admissions.

Using the Clinical Audit Research and Evaluation of Motor Neuron Disease (CARE-MND) database and the Scottish Regenerative Neurology Tissue Bank, we aimed to outline the genetic epidemiology and phenotypes of an incident cohort of people with MND (pwMND) to gain a realistic impression of the genetic landscape and genotype–phenotype associations. Phenotypic markers were identified from the CARE-MND platform. Sequence analysis of 48 genes was undertaken. Variants were classified using a structured evidence-based approach. Samples were also tested for C9orf72 hexanucleotide expansions using repeat-prime PCR methodology. 339 pwMND donated a DNA sample: 44 (13.0

Many genes have been linked to amyotrophic lateral sclerosis (ALS), including never in mitosis A (NIMA)-related kinase 1 (NEK1), a serine/threonine kinase that plays a key role in several cellular functions, such as DNA damage response and cell cycle regulation. Whole-exome sequencing studies have shown that NEK1 mutations are associated with an increased risk for ALS, where a significant enrichment of NEK1 loss-of-function (LOF) variants were found in individuals with ALS compared to controls. In particular, the p.Arg261His missense variant was associated with significantly increased disease susceptibility. This case series aims to understand the neuropathological phenotypes resulting from NEK1 mutations in ALS. We examined a cohort of three Scottish patients with a mutation in the NEK1 gene and evaluated the distribution and cellular expression of NEK1, as well as the abundance of phosphorylated TDP-43 (pTDP-43) aggregates, in the motor cortex compared to age- and sex-matched control tissue. We show pathological, cytoplasmic TDP-43 aggregates in all three NEK1-ALS cases. NEK1 protein staining revealed no immunoreactivity in two of the NEK1-ALS cases, indicating a LOF and corresponding to a reduction in NEK1 mRNA as detected by in situ hybridisation. However, the p.Arg261His missense mutation resulted in an increase in NEK1 mRNA molecules and abundant NEK1-positive cytoplasmic aggregates, with the same morphologic appearance, and within the same cells as co-occurring TDP-43 aggregates. Here we show the first neuropathological assessment of a series of ALS cases carrying mutations in the NEK1 gene. Specifically, we show that TDP-43 pathology is present in these cases and that potential NEK1 LOF can either be mediated through loss of NEK1 translation or through aggregation of NEK1 protein as in the case with p.Arg261His mutation, a potential novel pathological feature of NEK1-ALS.

Objectives Motor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here, we detail a systematic and structured evidence-based approach to inform consensus decision making to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART: NCT04302870), an adaptive platform trial. We aim to identify and prioritise candidate drugs which have the best available evidence for efficacy, acceptable safety profiles and are feasible for evaluation within the trial protocol.Methods We conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and multiple sclerosis, identifying drugs described in at least one MND publication or publications in two or more other diseases. We scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, we reviewed efficacy of drugs in MND animal models, multicellular eukaryotic models and human induced pluripotent stem cell (iPSC) studies. An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in MND-SMART.Results From the clinical review, we identified 595 interventions. 66 drugs met our drug/disease logic. Of these, 22 drugs with supportive clinical and preclinical evidence were shortlisted at round 1. Seven drugs proceeded to round 2. The panel reached a consensus to evaluate memantine and trazodone as the first two arms of MND-SMART.Discussion For future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs.

ABSTRACTBackgroundMotor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial.ObjectivesHere we detail a systematic, structured, and unbiased evidence-based approach to guide selection of drugs for clinical evaluation in the Motor Neuron Disease – Systematic Multi-arm Adaptive Randomised Trial (MND-SMART, clinicaltrials.gov registration number: NCT04302870), an adaptive platform trial.MethodsWe conducted a two-stage systematic review and meta-analysis to identify potential neuroprotective interventions. In stage one, we identified drugs from the clinical literature tested in at least one study in MND or in two or more cognate diseases with potential shared pivotal pathways (Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, or multiple sclerosis). We scored and ranked 66 drugs thus identified using a predefined framework evaluating safety, efficacy, study size and quality of studies. In stage two, we conducted a systematic review of the MND preclinical literature describing efficacy of these drugs in animal models, multicellular eukaryotic models and human induced pluripotent stem cell studies; 17 of these drugs were reported to improve survival in at least one preclinical study. An expert panel then shortlisted and ranked 22 drugs considering stage one and stage two findings, mechanistic plausibility, safety and tolerability, findings from previous clinical trials in MND, and feasibility for use in clinical trials.ResultsBased on this process, the panel selected memantine and trazodone for testing in MND-SMART.DiscussionFor future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human induced pluripotent stem cells.STRENGTHS AND LIMITATIONS OF THIS STUDYWe described a systematic, evidence-based approach towards drug repurposing in motor neuron disease (MND), specifically for Motor Neuron Disease – Systematic Multi-arm Adaptive Randomised Trial (MND-SMART), a phase III multi-arm multi-stage clinical trial in MND.Systematic reviews of clinical studies in neurodegenerative diseases and MND preclinical studies provided a robust evidence base to inform expert panel decisions on drug selection for clinical trials.Providing a contemporary evidence base using traditional systematic reviews is challenging given their time-consuming and labour-intensive nature.Incorporation of machine learning and automation tools for systematic reviews, and data from experimental drug screening can be helpful for future drug selection.

Background and Objectives Understanding risk factors and spatial variation of risk may provide insights into the pathological mechanism of motor neuron disease (MND). Socioeconomic status (SES) has been hypothesised as a risk factor, but results from previous studies are inconsistent. No spatial epidemiology studies examining geographic clustering of MND have been performed in Scotland to date. We investigated the effect of SES and geography on MND risk in Scotland using the highly curated and nationally representative Scottish MND Register (CARE-MND) that has over 95% case ascertainment.Methods Patients on the Scottish Clinical Audit Research Evaluation for Motor Neurone Disease platform, with date of diagnosis between 01 Jan 2015 and 28 Feb 2021 were included and geocoded with data zones using their residence at diagnosis. Indirectly standardised incidence ratio (SIR) accounting for age and sex was calculated for each health board. Poisson regression was used to examine the effect of SES on MND risk, adjusted for age and sex of population at risk. Geographic clustering was assessed using global Moran’s Index, Bayesian conditional autoregressive models and SaTScan software.Results Among 1149 patients included, 1126 (98%) were successfully geocoded. Significantly lower SIR was shown in Highland (0.60, 95% CI 0.44 – 0.80, p <0.001). After adjusting for age and sex in Poisson regression, there was no significant effect of SES on MND risk. Moran’s Index indicated a weak but significant spatial autocorrelation (I=0.017, p =0.008). However, risk maps using Bayesian modelling showed a relatively homogeneous distribution without distinct patterns across Scotland. Similarly, SaTScan did not detect any significant cluster of high or low risks.Discussion Our findings support the notion that MND risk is mostly random-distributed and independent of SES in Scotland. Our results are generalizable to other MND populations.### Competing Interest StatementThe authors have declared no competing interest.### Funding StatementY.T. Chang and P.K.A. Kearns have received funding from Rowling Scholar Fellowship Fund of the Anne Rowling Regenerative Neurology Clinic. P.K.A. Kearns is funded by an ECAT/Wellcome PhD Studentship. S. Chandran received grant from Dementia Research Institute.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethical approvals for the CARE-MND were granted by the Scotland A Research Ethics Committee 15/SS/0126.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData from the CARE-MND platform in this study are not publicly available due to patient identifiable information. Qualified investigators may request access to anonymized data for a reasonable purpose.

Background We investigated the phenotypes and genotypes of a cohort of ‘long-surviving’ individuals with motor neuron disease (MND) to identify potential targets for prognostication. Methods Patients were recruited via the Clinical Audit Research and Evaluation for MND (CARE-MND) platform, which hosts the Scottish MND Register. Long survival was defined as > 8 years from diagnosis. 11 phenotypic variables were analysed. Whole genome sequencing (WGS) was performed and variants within 49 MND-associated genes examined. Each individual was screened for C9orf72 repeat expansions. Data from ancestry-matched Scottish populations (the Lothian Birth Cohorts) were used as controls. Results 58 long survivors were identified. Median survival from diagnosis was 15.5 years. Long survivors were significantly younger at onset and diagnosis than incident patients and had a significantly longer diagnostic delay. 42% had the MND subtype of primary lateral sclerosis (PLS). WGS was performed in 46 individuals: 14 (30.4%) had a potentially pathogenic variant. 4 carried the known SOD1 p.(Ile114Thr) variant. Significant variants in FIG4 , hnRNPA2B1, SETX, SQSTM1, TAF15, and VAPB were detected. 2 individuals had a variant in the SPAST gene suggesting phenotypic overlap with hereditary spastic paraplegia (HSP). No long survivors had pathogenic C9orf72 repeat expansions. Conclusions Long survivors are characterised by younger age at onset, increased prevalence of PLS and longer diagnostic delay. Genetic analysis in this cohort has improved our understanding of the phenotypes associated with the SOD1 variant p.(Ile114Thr). Our findings confirm that pathogenic expansion of C9orf72 is likely a poor prognostic marker. Genetic screening using targeted MND and/or HSP panels should be considered in those with long survival, or early-onset slowly progressive disease, to improve diagnostic accuracy and aid prognostication.

Abstract Amyotrophic lateral sclerosis is a progressive and devastating neurodegenerative disease. Despite decades of clinical trials, effective disease-modifying drugs remain scarce. To understand the challenges of trial design and delivery, we performed a systematic review of Phase II, Phase II/III and Phase III amyotrophic lateral sclerosis clinical drug trials on trial registries and PubMed between 2008 and 2019. We identified 125 trials, investigating 76 drugs and recruiting more than 15 000 people with amyotrophic lateral sclerosis. About 90% of trials used traditional fixed designs. The limitations in understanding of disease biology, outcome measures, resources and barriers to trial participation in a rapidly progressive, disabling and heterogenous disease hindered timely and definitive evaluation of drugs in two-arm trials. Innovative trial designs, especially adaptive platform trials may offer significant efficiency gains to this end. We propose a flexible and scalable multi-arm, multi-stage trial platform where opportunities to participate in a clinical trial can become the default for people with amyotrophic lateral sclerosis.

Melanie Reid’s chronicle of her life-changing spinal injury in The World I Fell Out Of was discussed at the second meeting of the Glasgow Neurology Book Club. Reid has previously documented her ‘adapt or die’ approach to post-injury life within her column in The Times magazine. From the immediate recognition that her life was forever changed when her chestnut mare refused a jump, to the practicalities of daily life nine years following her accident, this account is ferociously honest. We are introduced to the terrifying world of tetraplegia and what it means for a 52-year-old woman suddenly to be disconnected from her body, losing her physical, personal and sexual identity in an instant. In her account, Reid vividly and entertainingly describes the staff and patients of the Queen Elizabeth National Spinal Injuries Unit, …

Objective In this population-based study, we aimed to determine whether neuropsychiatric history, medication or family history of neuropsychiatric disorders predicted cognitive and/or behavioural impairment in motor neuron disease (MND). Methods People with MND (pwMND) on the Scottish Clinical, Audit, Research and Evaluation of MND (CARE-MND) register, diagnosed from January 2015 to January 2018, with cognitive and/or behavioural data measured using the Edinburgh Cognitive and Behavioural ALS Screen were included. Data were extracted on patient neuropsychiatric, medication and family history of neuropsychiatric disorders. We identified patients with cognitive impairment (motor neuron disease with cognitive impairment (MNDci)), behavioural impairment (motor neuron disease with behavioural impairment (MNDbi), both (motor neuron disease with cognitive and behavioural impairment (MNDcbi)) or motor neuron disease–frontotemporal dementia (MND-FTD). Results Data were available for 305 pwMND (mean age at diagnosis=62.26 years, SD=11.40), of which 60 (19.7%) had a neuropsychiatric disorder. A family history of neuropsychiatric disorders was present in 36/231 (15.58%) of patients. Patient premorbid mood disorders were associated with increased apathy (OR=2.78, 95% CI 1.083 to 7.169). A family history of any neuropsychiatric disorder was associated with poorer visuospatial scores, MNDbi (OR=3.14, 95% CI 1.09 to 8.99) and MND-FTD (OR=5.08, 95% CI 1.26 to 20.40). A family history of mood disorders was associated with poorer overall cognition (exp(b)=0.725, p=0.026), language, verbal fluency and visuospatial scores, and MND-FTD (OR=7.57, 95% CI 1.55 to 46.87). A family history of neurotic disorders was associated with poorer language (exp(b)=0.362, p<0.001), visuospatial scores (exp(b)=0.625, p<0.009) and MND-FTD (OR=13.75, 95% CI 1.71 to 110.86). Conclusion Neuropsychiatric disorders in patients and their families are associated with cognitive and behavioural changes post-MND diagnosis, with many occurring independently of MND-FTD and C9orf72 status. These findings support an overlap between MND, frontotemporal dementia and neuropsychiatric disorders, particularly mood disorders.

Objectives: To undertake a preliminary hypothesis-generating analysis exploring putative risk factors for coronavirus diseae 2019 (COVID-19) population-adjusted deaths, compared with non-COVID-19 related deaths, at a local authority district (LAD) level in hospital, care homes and at home. Design: Ecological retrospective cohort study Setting Local authority districts (LADs) in England, Scotland and Wales (Great Britain (GB)). Participants All LAD deaths registered by week 16 of 2020. Main Outcome Measures Death registration where COVID-19 is mentioned as a contributing factor per 100,000 people in all settings, and in i) cares homes, ii) hospitals or iii) home only, in comparison to non-COVID-19 related deaths. Results Across GB by week 16 of 2020, 20,684 deaths had been registered mentioning COVID-19, equivalent to 25.6 per 100,000 people. Significant risk factors for LAD COVID-19 death in comparison to non-COVID-19 related death were air pollution and proportion of the population who were female. Significant protective factors were higher air temperature and proportion of the population who were ex-smokers. Conversely, for all COVID-19 unrelated deaths in comparison to COVID-19 deaths, higher rates of communal living, higher population rates of chronic kidney disease, chronic obstructive pulmonary disease, cerebrovascular disease deaths under 75 and dementia were predictive of death, whereas, higher rates of flight passengers was protective. Looking at individual setttings, the most notable findings in care homes was Scotland being a significant risk factor for COVID-19 related deaths compared to England. For hospital setting, the proportion of the population who were from black and Asian minority ethnic (BAME) groups significantly predicted COVID-19 related death. Conclusions This is the first study within GB to assess COVID-19 related deaths in comparison to COVID-19 unrelated deaths across hospital, care homes and home combined. As an ecological study, the results cannot be directly extrapolated to individuals. However, the analysis may be informative for public health policy and protective measures. From our hypothesis-generating analysis, we propose that air pollution is a significant risk factor and high temperature a significant protective factor for COVID-19 related deaths. These factors cannot readily be modelled at an individual level. Scottish local authorities and local authorities with a higher proportion of individuals of BAME origin are potential risk factors for COVID-19 related deaths in care homes and in hospitals, respectively. Altogether, this analysis shows the benefits of access to high quality open data for public information, public health policy and further research.

ObjectivesScotland benefits from an integrated national healthcare team for motor neurone disease (MND) and a tradition of rich clinical data capture using the Scottish MND Register (launched in 1989; one of the first national registers). The Scottish register was re-launched in 2015 as Clinical Audit Research and Evaluation of MND (CARE-MND), an electronic platform for prospective, population-based research. We aimed to determine if incidence of MND is changing over time.MethodsCapture-recapture methods determined the incidence of MND in 2015-2016. Incidence rates for 2015-2016 and 1989-1998 were direct age and sex standardised to allow time-period comparison. Phenotypic characteristics and socioeconomic status of the cohort are described.ResultsCoverage of the CARE-MND platform was 99%. Crude incidence in the 2015-2017 period was 3.83/100,000 person-years (95% CI 3.53-4.14). Direct age-standardised incidence in 2015 was 3.42/100,000 (95% CI 2.99-3.91); in 2016, it was 2.89/100,000 (95% CI 2.50-3.34). The 1989-1998 direct standardised annual incidence estimate was 2.32/100,000 (95% CI 2.26-2.37). 2015-2016 standardised incidence was 66.9% higher than Northern European estimates. Socioeconomic status was not associated with MND.ConclusionsOur data show a changing landscape of MND in Scotland, with a rise in incidence by 36.0% over a 25-year period. This is likely attributable to ascertainment in the context of improved neurological services in Scotland. Our data suggest that CARE-MND is a reliable national resource and findings can be extrapolated to the other Northern European populations.

Objectives: Launched in 1989, the Scottish Motor Neuron Disease Register (SMNDR) has provided a resource for prospective clinical data collection. However, in 2015 we aimed to evolve a system to allow: i) A patient-centered approach to care based on recognized standards, ii) Harmonized data sharing between Scottish health professionals in real-time, iii) Regular audit of care to facilitate timely improvements in service delivery, and iv) Patient participation in a diverse range of observational and interventional research studies including clinical trials. Methods: We developed a standardized national electronic data platform-Clinical Audit Research and Evaluation of MND (CARE-MND) which integrates clinical audit and research data fields. Data completion pre- and post-CARE-MND were compared, guided by recently published National Institute for Clinical Excellence (NICE) recommendations. Statistical difference in data capture between time periods was assessed using Z-test of proportions. Results: Data field completion for the historical 2011-2014 period ranged from 4 to 95%; median 50%. CARE-MND capture ranged from 32 to 98%; median 87%. 15/17 fields were significantly more complete post-CARE-MND (p<0.001). All MND nurse/allied health specialists in Scotland use the CARE-MND platform. Management of MND in Scotland is now coordinated through a standardized template. Conclusions: Through CARE-MND, national audits of MND care and interventions have been possible, leading to protocols for harmonized service provision. Stratification of the MND population is facilitating participation in observational and interventional studies. CARE-MND can act as a template for other neurological disorders.

Abstract Objectives: Defining historical changes and outcomes in the use of gastrostomy in the management of Scottish MND patients. Methods: The 1989–1998 and 2015–2016 Scottish national MND cohorts were used to examine the frequency, timing, and survival related to gastrostomy. The cohorts were censored for survival analysis. Results: There were 261 cases, 119 (46%) from the new register (2015–2016) and 142 (54%) from the old register (1989–1999). Percutaneous endoscopic gastrostomy (PEG) tubes were used exclusively in the old register vs. the new register where PEG (45%), Radiologically inserted gastrostomy (RIG) (44%) and a small number of peroral image-guided gastrostomy (PIGG) tubes (11%), p < 0.01 were used. Odds of 30-d mortality in the old register were 2.8 times that in the new register, p < 0.01. Median survival time from gastrostomy was significantly higher in the new register, 2.7 months, p < 0.05. Median survival time from onset was also higher in the new register but non-significant, 3.2 months, p = 0.30. Multivariate analysis identified age at onset (hazard ratio [HR] 1.02 p = 0.01), time from onset to diagnosis (HR 0.74 p < 0.01), subtype of onset (HR 1.52 p = 0.01), with gastrostomy and Riluzole interacting as variables that predict risk of death. Conclusions: Gastrostomy use has increased with techniques changing over time. It is safer and survival time has increased post gastrostomy. Being older and diagnosed more quickly increases risk of death whilst taking Riluzole combined with gastrostomy reduced risk of death. Survival from onset has not significantly changed in Scottish MND patients having gastrostomy.

To assess the utility of the American College of Medical Genetics (ACMG) guidelines for ALS (amyotrophic lateral sclerosis)-associated genes and propose recommendations to minimize the number of variants of unknown significance (VOUS).

In addition to motor neurone degeneration, up to 50% of amyotrophic lateral sclerosis (ALS) patients present with cognitive decline. Understanding the neurobiological changes underlying these cognitive deficits is critical, as cognitively impaired patients exhibit a shorter survival time from symptom onset. Given the pathogenic role of synapse loss in other neurodegenerative diseases in which cognitive decline is apparent, such as Alzheimer’s disease, we aimed to assess synaptic integrity in the ALS brain. Here, we have applied a unique combination of high-resolution imaging of post-mortem tissue with neuropathology, genetic screening and cognitive profiling of ALS cases. Analyses of more than 1 million synapses using two complimentary high-resolution techniques (electron microscopy and array tomography) revealed a loss of synapses from the prefrontal cortex of ALS patients. Importantly, synapse loss was significantly greater in cognitively impaired cases and was not due to cortical atrophy, nor associated with dementia-associated neuropathology. Interestingly, we found a trend between pTDP-43 pathology and synapse loss in the frontal cortex and discovered pTDP-43 puncta at a subset of synapses in the ALS brains. From these data, we postulate that synapse loss in the prefrontal cortex represents an underlying neurobiological substrate of cognitive decline in ALS.

Genetic understanding of motor neuron disease (MND) has evolved greatly in the past 10 years, including the recent identification of association between MND and variants in TBK1 and NEK1. Our aim was to determine the frequency of pathogenic variants in known MND genes and to assess whether variants in TBK1 and NEK1 contribute to the burden of MND in the Scottish population. SOD1, TARDBP, OPTN, TBK1, and NEK1 were sequenced in 441 cases and 400 controls. In addition to 44 cases known to carry a C9orf72 hexanucleotide repeat expansion, we identified 31 cases and 2 controls that carried a loss-of-function or pathogenic variant. Loss-of-function variants were found in TBK1 in 3 cases and no controls and, separately, in NEK1 in 3 cases and no controls. This study provides an accurate description of the genetic epidemiology of MND in Scotland and provides support for the contribution of both TBK1 and NEK1 to MND susceptibility in the Scottish population.

Objective Motor neurone disease (MND) is a rapidly progressive neurodegenerative disease, typically affecting limb, bulbar and respiratory muscles. Cognitive and behavioural change are also key features of the disease in up to 50% of patients (1). Neuropsychiatric symptoms may precede motor symptoms. A recent study highlighted that depression may be an independent risk factor for MND (2). We aimed to review the frequency of i) premorbid neuropsychiatric disease ii) premorbid psychotropic medication use iii) neuropsychiatric presentation of MND and iv) neuropsychiatric evolution of MND in an incident Scottish cohort. Method Patients were recruited via the Scottish MND Register (SMNDR). Patient characteristics (past medical and drug history, symptom onset and progression) were collected via the Scottish Clinical Audit Research and Evaluation for MND (CARE-MND) national care proforma. Results Incident cases of MND diagnosed in 2015/16 from a population-based national cohort will be presented. At interim analysis, 267 patients were eligible for review. 38 (14%) of patients had a documented past history of neuropsychiatric disease; 29 (11%) of mood disorder. 66 (25%) of patients had a history of psychotropic medication use. Frequency of premorbid neuropsychiatric disease will be compared with recent UK survey results (3). In 11 (4%) of patients, emotional lability, memory change or behavioural change was the presenting symptom. 32 (12%) of patients developed these features later in disease course. Conclusion From our preliminary analysis, rates of premorbid neuropsychiatric disease in patients with MND are comparable with population estimates. However, symptoms of low mood have been shown to have a negative impact on quality of life and are associated with faster disease progression (4). Clinical teams need to be mindful of these symptoms in all aspects of patient care, and ensure that appropriate therapies are offered and monitored.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with no cure and limited treatment options. There is therefore an urgent need for effective therapeutic interventions in this disease. This protocol outlines the strategy for a systematic review and meta‐analysis to identify, from in vivo animal and human induced pluripotent stem cell (hiPSC) studies, potential therapeutic interventions for ALS. Our aim is to perform a comprehensive review of the ALS literature to compile a list of (1) candidate interventions and (2) target pathways that may be of therapeutic benefit in patients with ALS.