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Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative diseasecaused in a minority of individuals by mutations in more than one classical ALS-associated Mendelian gene, consistent with ‘oligogenic’ inheritance.1 This observation complicates the dissection of precise genotype–phenotype relationships. In the absence of comprehensive genomic analysis (such as whole-exome sequencing) and molecular neuropathology, inferences of genotype–phenotype associations may be misleading, with potentially negative consequences for patient counselling, concepts of pathogenesis, disease modelling and patient selection for genomic therapeutics. Mutations in the autophagic adapter OPTN have been reported as causative of ALS2 and are associated with diverse neuropathology, while also coexisting with other Mendelian ALS gene variants.3 4 To help clarify the role of OPTN variants in the pathogenesis of ALS, and refine genotype–phenotype associations, we provide a comprehensive genomic, neuropathological and biochemical analysis of an individual with a novel, isolated, homozygous R217X (c.649A>T) OPTN mutation and clinically upper motor neuron-dominant form of ALS-TDP with severe oligodendrogliopathy. The proband presented to the Oxford Motor Neuron Disease Clinic and enrolled in the brain donation programme of the Oxford Brain Bank, enabling integration of clinical observations with molecular neuropathological data, including whole exome-sequencing, repeat-primed PCR, OPTN mRNA and protein analyses, and comparison with both healthy brain tissue and that from sporadic (s) ALS-TDP patients. Please refer to online supplemental data for comprehensive methods. ### Supplementary data [jnnp-2020-325803supp001.pdf] ### Clinical vignette A middle-aged man presented with slowly progressive spastic dysarthria associated with an exaggerated jaw jerk and no other abnormal neurological findings. Dysarthria progressed to anarthria over 2 years and neuropsychometry reported mild abnormalities in executive function, but no evidence of language or behavioural abnormalities. Over the following 4 years, weakness with marked increase in tone but without wasting or fasciculations extended to all four limbs. Mild executive dysfunction continued but there was no progression to frontotemporal dementia. Tongue wasting and fasciculations, …

BackgroundThere is a paucity of reliable markers of disease activity and progression in ALS. Better biomarkers would also reduce clinical trial duration and cost by providing more sensitive measures of target engagement. Cortical hyperexcitability with transcranial magnetic stimulation, while promising, has not yet been clinically translatable. Multimodal correlation of cortical hyperexcitability could yield more robust composite biomarkers.MethodsThis project applies multimodal non-invasive neuroimaging (MRI, MEG) and neurophysiol- ogy (TMS) to explore cortical hyperexcitability in ALS. 11 affected ALS patients, 9 age matched healthy controls and 13 asymptomatic relatives at-risk of inheriting the disease-causing C9orf72 hexanucleotide repeat expansion were studied. MRI findings are reported here (diffusion-tensor imaging [DTI], functional MRI and MR spectroscopy).ResultsRight cortical activation with contralateral finger movement was significantly increased in patients (p = 0.04), while right cortical de-activation with ipsilateral movement was lost (p = 0.01). N-acetyl-aspar- tate (p=0.04) and glutamate (p = 0.01) are significantly reduced in patients. At-risk relatives occupy an intermediate profile.DiscussionBilateral motor cortex hyperexcitability was found in ALS. Asymmetry in task-related activa- tion is consistent with previously reported loss of cortical inhibition in early ALS. Integration of multimodal imaging and neurophysiological data could explain variable phenotype and disease mechanisms in ALS.eedmond@gmail.com

Richard Christopher David Greenhall devoted the whole of his professional life as a neurologist to working exclusively in the NHS. Never one for pushing himself forward, he was the sort of full time consultant who provides the rock on which the NHS stands, totally dedicated to his clinical service and to his patients. Richard was a Birmingham boy of Welsh heritage who after leaving King Edward’s School went up to Cambridge in 1962, initially to read natural sciences, although he soon switched to medicine. After clinical training at St Thomas’ Hospital in London, and junior hospital doctor posts in Oxford, Bristol, and London, he started training in neurology under Bryan Matthews in Oxford. Completing his DM thesis in 1975, he flirted …

Despite the intense research focus on the molecular and cellular mechanisms of motor neuron degeneration using models based on specific genetic mutations, there are good reasons to consider amyotrophic lateral sclerosis (ALS) as a ‘system degeneration’, which arises through multiple biological triggers. ALS experts generally agree that loss of function has a clinically focal onset and a non-random pattern of spread, which favours the ‘vulnerable network’ hypothesis, in which the degenerative process propagates through compartmentalised anatomical and functional networks.1 Furthermore, evidence from neuropathological studies suggests that the burden of TDP-43 proteinopathy reflects an orderly progression of spread through anatomically contiguous pathways.2 All of which raises the critical question of the nature of the anatomical substrate of …

Increased serum neurofilament is associated with CNS axonal loss from a range of causes. We assessed its potential as a minimally-invasive indicator of active CNS pathology in those with neurological symptoms.GP referrals to the Neurology Rapid Access Clinic (RAC) at the John Radcliffe Hospital, Oxford were approached to take part. Informed consent was taken under a local Research Ethics Committee-approved protocol. Serum was taken prior to clinical assessment and tested for phosphorylated neurofilament heavy chain (pNFH) using a commercial ELISA (Euroimmun, Germany). Participants were followed up for final diagnosis.The 62 participants had a range of symptoms, with final diagnoses including migraine, functional, neurodegenerative and inflammatory conditions. Receiver Operating Curve analysis defined cut-off levels based on serum pNfH levels in healthy controls and patients with motor neurone disease measured as part of an independent local biomarker study. pNFH levels in the ‘pathological’ range were associated with serious underlying pathology in several RAC referrals. Ongoing analysis of the cohort will be presented.Alongside clinical reasoning, serum pNFH may have significant value for the improved triage of those presenting to primary care with neurological symptoms. Further study in larger populations, including healthy individuals, is now warranted.

Therapeutic options for the fatal neurodegenerative disorder ALS are urgently needed. Trials rely on blunt outcome measures such as survival because of a lack of objective markers of disease activity and progression. The C9orf72 hexanucleotide repeat expansion (HRE) is associated with 10% of all cases of ALS, bringing the near-future prospect of oligonucleotide therapeutic trials.The development of biomarkers will reduce trial duration and cost by providing more sensitive measures of disease-slowing and/or evidence of target engagement. ALS is consistently associated with cortical hyperexcitability (CE), based on transcranial magnetic paired stimulation (TMS) to induce short-interval cortical inhibition (SICI). This project builds on the potential shown by non-invasive neuroimaging to provide biomarkers in ALS. We develop functional neuroimaging biomarkers that reflect the phenomenon of CE, including markers of pre-symptomatic pathology.Affected ALS patients carrying the C9orf72 HRE and a group of asymptomatic carriers are studied using a combined functional MRI (FMRI and MRS) and neurophysiological (MEG) readout. This study offers novel non-invasive biomarkers based on a consistent neurophysiological mechanism in ALS to advance therapeutic development

BACKGROUND: Concomitant REM sleep behaviour disorder (RBD) is commonly observed in patients with Parkinson's disease (PD). Although the brainstem structures responsible for the symptoms of RBD correspond to the premotor stages of PD, the association of RBD with motor and non-motor features in early PD remains unclear. METHODS: The study evaluated 475 patients with PD within 3.5 years of diagnosis for the presence of probable RBD (pRBD) using the REM Sleep Behaviour Disorder Screening Questionnaire (RBDSQ). A neurologist and a trained research nurse carried out evaluation of each participant blinded to the results of the RBDSQ. Standardised rating scales for motor and non-motor features of PD, as well as health-related quality of life measures, were assessed. Multiple linear and logistic regression analyses were used to determine the relationship between pRBD and a variety of outcomes, controlling for confounding factors. RESULTS: The overall frequency of pRBD was 47.2% (95% CI 42.7% to 51.9%). None of the patients had a previous diagnosis of RBD. Patients with PD and concomitant pRBD did not differ on motor phenotype and scored comparably on the objective motor scales, but reported problems with motor aspects of daily living more frequently. Adjusted for age, sex, disease duration and smoking history, pRBD was associated with greater sleepiness (p=0.001), depression (p=0.001) and cognitive impairment (p=0.006). CONCLUSIONS: pRBD is common and under-recognised in early PD. It is associated with increased severity and frequency of non-motor features, poorer subjective motor performance and a greater impact on health-related quality of life.

The progression of motor neurone disease (MND) is currently irreversible, and the grave implications of diagnosis naturally fuels concern among neurologists over missing a potential mimic disorder. There is no diagnostic test for MND but in reality there are few plausible mimics in routine clinical practice. In the presence of a progressive pure motor disorder, signs such as florid fasciculations, bilateral tongue wasting, the 'split hand', head drop, emotionality, and cognitive or behavioural impairment carry high positive predictive value. MND is clinically heterogeneous, however, with some important chameleon-like presentations and considerable variation in clinical course. Lack of confidence about the scope of such variation, or an approach to diagnosis emphasising investigations over clinical common sense, has the potential to exacerbate diagnostic delay in MND and impede timely planning of the care which is essential to maximising quality of life.

Background Amyotrophic lateral sclerosis (ALS) appears to be a sporadic disorder in 95% of cases. Although few personal characteristics associated with developing ALS are known, identification of those at risk is essential to any vision of early intervention. There is persistent anecdotal observation that those with ALS are premorbidly physically ‘fitter’, although such observations are susceptible to bias. Hospital admission for coronary heart disease (CHD) might serve as an objective marker of reduced cardiovascular fitness. Methods A record linkage study of two large databases of hospital admissions, the Oxford Record Linkage Study (ORLS) and an English national record linkage dataset of Hospital Episode Statistics was undertaken. The ratio of the rate of ALS in people without a record of CHD to that in those with a record of CHD was calculated, factoring out premature death in both cohorts. Similar analysis for Parkinson9s disease (PD) and multiple sclerosis (MS) was undertaken. Results In the English population, the rate ratio for ALS in the non-CHD cohort, compared with the CHD cohort, was 1.14 (95% CI 1.05 to 1.22); for PD it was 0.95 (95% CI 0.93 to 0.98); and for MS 0.95 (95% CI 0.88 to 1.04). The ORLS data yielded similar findings. Conclusions Those without a record of CHD were at modestly higher risk of ALS, but not for PD or MS. This lends support to the assertion that ALS arises within a population who may have relatively higher levels of cardiovascular fitness.

INTRODUCTION The patient presenting with weakness and wasting of one limb, usually the arm, can be a considerable diagnostic challenge for the neurologist. While the spectre of the amyotrophic lateral sclerosis form of motor neuron disease (ALS/MND) is often in the clinician’s mind, there is also a significant differential diagnosis to be considered. While this article discusses a number of well-known conditions that should be in the differential diagnosis, I will focus particularly on a lesser known condition, Hirayama’s Disease (also known as Sobue Disease in North America), that is only rarely seen in European populations and may therefore be less familiar to neurologists outside Japan and India. Monomelic amyotrophy or ‘juvenile non-progressive amyotrophy of the upper limb’ is rarely encountered in the general neurology clinics but it may be under diagnosed. Previously thought to be restricted to Japan and South Asia, it is now clear that this condition does

Background We and others have demonstrated marked abnormalities of mitochondrial and lysosomal function in peripheral tissue of patients with familial Parkinson’s disease (fPD). Aim The aim of this project was to determine whether similar changes can also be detected in subgroups of patients with sporadic PD (sPD). Methods Fibroblast cultures were established from 100 sPD patients and 50 age matched controls and assessed for mitochondrial membrane potential (MMP), intracellular ATP levels, mitochondrial morphology and number of lysosomes. Subsequent validation assays included mitochondrial complex assays, Western blot analysis for mitochondrial complex proteins, LAMP2 staining and cathepsin D/lysosomal activity. Results 12/100 sPD patients had ATP levels 2 SD lower than the mean ATP of controls with an overall increase in mitochondrial area and count in the sPD cohort (p 2 SD higher than the average of controls (>154%), but CathepsinD/lysosomal activity was decreased. Treatment with ursodeoxycholic acid (UDCA) improved mitochondrial function, but not lysosomal impairment in sPD patient tissue with combined impairment of mitochondrial and lysosomal function. Conclusion The detection of distinct pathogenic mechanisms in individual patients with sPD may help for future disease-stratification.

Despite significant advances in basic research, the treatment of degenerative diseases of the nervous system remains one of the greatest challenges for translational medicine. The childhood onset motor neuron disorder spinal muscular atrophy (SMA) has been viewed as one of the more tractable targets for molecular therapy, due to our detailed understanding of the molecular genetic basis of the disease. In SMA, inactivating mutations in the SMN1 gene can be partially compensated for by limited expression of SMN protein from a variable number of copies of the SMN2 gene, which provides both a molecular explanation for phenotypic severity and a target for therapy. The advent of the first tailored molecular therapy for SMA, nusinersin, based on modulating the splicing behaviour of the SMN2 gene, is the first treatment which significantly alters the natural history of motor neuron degeneration. This will change the landscape for diagnosis, clinical management and future therapeutic trials in SMA, and has implications for the molecular therapy of other neurological diseases.

Two candidate genes (NAIP and SMN) have recently been reported for childhood onset spinal muscular atrophy (SMA). Although affected subjects show deletions of these genes, these deletions can lead to either a very mild or a severe phenotype. We have analysed a large number of clinically well defined patients, carriers, and normal controls to assess the frequency and extent of deletions encompassing both of these genes. A genotype analysis indicates that more extensive deletions are seen in the severe form of SMA than in the milder forms. In addition, 1 center dot 9% of phenotypically normal carriers are deleted for the NAIP gene; no carriers were deleted for the SMN gene. Our data suggest that deletions in both of these genes, using the currently available assays, are associated with both a severe and very mild phenotype.

Background Guidelines caution against percutaneous endoscopic gastrostomy (PEG) in MND patients with forced vital capacity (FVC) below 50% predicted. However, radiological approaches (RIG) may be equally challenging in patients with advanced disease, and less reliable. Objectives To review Oxford MND Centre PEG patient characteristics, including the introduction of a risk stratification tool to identify those vulnerable to sedation-related complications, in whom a procedural adaptation was undertaken. Methods MND patients undergoing PEG insertion over the last four years were analysed. Cases stratified as higher risk underwent insertion in a semi-supine position, by a consultant gastroenterologist and experienced team using reduced sedation, and with intra-operative nasal non-invasive ventilation available. Results PEG was undertaken in 107 patients. All were successful in terms of immediate placement and recovery. Four deaths occurred within one month of insertion. Across the entire cohort one third had pre-procedure FVC Conclusions PEG can be safely performed in MND patients with advanced respiratory involvement. Screening and procedural adaptation for higher risk cases is associated with lower sedative doses.

Background Amyotrophic lateral sclerosis (ALS) is a progressive and usually fatal neurodegenerative disease. Survival from diagnosis varies considerably. Several prognostic factors are known, including site of onset (bulbar or limb), age at symptom onset, delay from onset to diagnosis and the use of riluzole and non-invasive ventilation (NIV). Clinicians and patients would benefit from a practical way of using these factors to provide an individualised prognosis. Methods 575 consecutive patients with incident ALS from a population-based registry in South-East England register for ALS (SEALS) were studied. Their survival was modelled as a two-step process: the time from diagnosis to respiratory muscle involvement, followed by the time from respiratory involvement to death. The effects of predictor variables were assessed separately for each time interval. Findings Younger age at symptom onset, longer delay from onset to diagnosis and riluzole use were associated with slower progression to respiratory involvement, and NIV use was associated with lower mortality after respiratory involvement, each with a clinically significant effect size. Riluzole may have a greater effect in younger patients and those with longer delay to diagnosis. A patient's survival time has a roughly 50% chance of falling between half and twice the predicted median. Interpretation A simple and clinically applicable graphical method of predicting an individual patient's survival from diagnosis is presented. The model should be validated in an independent cohort, and extended to include other important prognostic factors.

Population registries, uncontaminated by the referral bias seen in clinic based case series, show that approximately 5% of amyotrophic lateral sclerosis (ALS) cases are familial.1 At most, only 30% of these cases are explained by mutations in the small number of currently identified ALS related genes, including SOD1, TDP-43 and FUS.2–4 The era of Mendelian genetics for the common neurodegenerative diseases is fast drawing to a close. There are very few large families left to collect and the sun is setting on linkage studies. It is unlikely that there is another gene which explains as many familial cases as SOD1 (approximately 20%). The potentially numerous and diverse gene defects responsible for the remaining 70% of familial ALS cases will likely be identified in the future by large scale ‘deep sequencing’ projects, either through targeting genes in specific pathways or by whole genome sequencing. There is a widespread and entirely reasonable assumption that the remaining 95% of ALS cases, which are classified as ‘sporadic’, are caused by a mixture of genetic and environmental effects, and that ALS is therefore a ‘complex’ disease like diabetes and stroke. However, in the case of ALS this is still a hypothesis and the most interesting area of uncertainty is not whether the totality of ALS has a genetic component, which it clearly does because we can identify genetic mutations in patients with familial disease and in a few cases with sporadic disease, but whether there is a subpopulation of sporadic ALS cases in which the genetic contribution is minimal or even …

Background Focality of onset and spread of pathology in MND are poorly understood. Biomarkers are needed to improve diagnosis and therapeutic monitoring, but must accurately reflect the inherent clinical and prognostic heterogeneity. Diffusion tensor imaging (DTI) is a sensitive MRI application for the noninvasive detection of white matter pathology. Methods High-field cerebral DTI was applied in an unbiased whole-brain analysis across a group of 24 unselected heterogeneous MND patients, and well-matched healthy controls. Patients were scored for clinical upper motor neurone (UMN) involvement, and disability (using the revised ALS Functional Rating Scale, ALSFRS-R). Results A consistent reduction in fractional anisotropy (FA) was demonstrated in the central corpus callosum (CC) of the MND patients, and correlated with disability. A separate whole-brain analysis in relation to UMN involvement highlighted the corticospinal tract (CST). Conclusions Corpus callosum FA is a promising biomarker for the heterogeneous syndrome of MND, and may provide a clue to the topographical spread of disease. FA reduction was related to disability, and did not simply reflect UMN involvement, which supports the inclusion of those subjects with apparently LMN/UMN-only phenotypes within one syndrome. The exquisite delineation of the CST in whole-brain analysis of FA in relation to clinical UMN involvement provided validation of both DTI and a “bedside score” as markers of UMN neuronal damage in MND.

Background Case-control studies to identify risk factors for MND suffer from the intractable problem of recall bias, and have provided conflicting results. There is a persistent anecdotal observation that MND patients arise from a ‘fitter’ population. Such a physical profile might then be reflected in a reduced incidence of coronary heart disease (CHD) prior to the development of MND. Methods A record-linkage study of a large national database of hospital admissions was undertaken. The ratio of the rate of MND in people without a record of CHD, to the rate in people with a record of CHD was calculated, factoring out premature death in the non-CHD and CHD cohorts. Similar analysis for Parkinson9s disease (PD) and multiple sclerosis (MS) was undertaken. Results Those without a record of CHD were at higher risk of ALS than those with CHD (rate ratio 1.14; 95% CI 1.05 to 1.22). The higher risk was not found for PD (0.95; 95% CI 0.93 to 0.98) or MS (0.95; 95% CI 0.88 to 1.04). Discussion This study provides indirect support for the assertion that MND arises in a cardiovascularly fitter population. It has been proposed that greater physical activity might trigger MND, perhaps through oxidative stress. An alternative formulation might be that fitness in part reflects a distinct motor system architecture which, whilst associated with improved physical performance in youth, may be inherently vulnerable to the stochastic events of ageing.

Background MND is a multiple system neurodegenerative disorder sharing clinicopathological features with frontotemporal dementia. The normal saccade generating network has overlap with cortical regions consistently involved in MND, and the relative sparing of brainstem nuclear oculomotor functions makes eye-tracking a uniquely practical way to explore this extramotor pathology. Meyhods ALS (n=31) and PLS patients (n=5) and age-similar healthy controls (n=26) were tested using the EyeLink® eye-tracker. The tasks included a prosaccade (“look towards”), antisaccade (“look away”), word and picture-cued visual search tasks, and an oculomotor version of the Trail-making test. Results Both antisaccade latency and error rates were markedly increased in both ALS and PLS patient groups compared to controls (p Conclusions Eye-tracking has significant potential as an objective, quantifiable biomarker of extramotor pathology in MND. The antisaccade task has attraction as a non-invasive diagnostically supportive biomarker that could be adapted to a portable saccadometer for routine clinical use.

The OPDC will focus on understanding the earliest pathological pathways in Parkinson9s disease (PD). Scientists with strengths in genetics and genomics, transgenic rodent PD models, in vivo neuroanatomy and neuropharmacology of the basal ganglia, magnetic resonance imaging (MRI), and analysis of protein biomarkers, will work closely with experts in clinical epidemiology and neurology of PD. We will identify causal genetic variants within pathways leading to PD from bioinformatics analyses of large-scale genomics projects. Variants will be characterised by resequencing genes in a clinical cohort of 2000 PD patients, 300 at-risk individuals and 300 age-matched controls. Induced pluripotent stem cells generated from individuals harbouring susceptibility variants will be differentiated into dopaminergic neurones. Genetic variant effects on genome-wide transcription/cellular dopamine homeostasis will identify best candidates to use in improved rodent models. BAC transgenesis will be used to express causal variants at physiologically-relevant levels preserving temporal and spatial expression. New models will be analysed for earliest changes of dopamine neuropharmacology compared to midbrain MRI. Biomarker studies on microRNAs/proteins will correlate blood/CSF findings with neuroanatomical alterations. This will lead to improved methods of earlier diagnosis of PD, identify new molecular targets for therapy, and generate improved models for testing neuroprotective treatments.

Background The majority of cases of amyotrophic lateral sclerosis (ALS) start in late adult life and are characterised by TDP-43 positive ubiquitinated inclusions. Juvenile ALS is a rare but important exception with regard to age of onset and underlying neuropathology, which is TDP-43 negative, but characterised by basophilic inclusions on H+E stain. Methods We identified four patients with juvenile ALS with basophilic inclusions, characterised the neuropathology and performed genetic analyses. Results Motor symptoms began between age 17 and 22, with rapid disease progression without dementia. No family history was identified. Basophilic inclusions were present in all cases and were immunoreactive for various RNA binding proteins, most prominently FUS (fused in sarcoma), but negative for TDP-43. A wide range of FUS deposits was identified in glia and neuronal cytoplasm and nuclei. This was accompanied by disintegration of Nissl substance, ultrastructurally in keeping with aggregation of fragmented rough endoplasmic reticulum. Although no patient had a family history, FUS mutations were found in all three cases with available DNA, one of which was novel. Conclusion Juvenile ALS with basophilic inclusions is a FUS proteinopathy caused by mutations in FUS , suggesting that altered RNA metabolism is pivotal in disease pathogenesis.

Motor neurone disease (MND) is a disorder with a complex aetiology, marked phenotypic variability and malignant progression. Our research program is multidisciplinary and takes place within the Division of Medical Sciences which is one of the most significant concentrations of neuroscience researchers anywhere in the world. Basic neurobiological research has a focus on the role of RNA trafficking and transport using cell culture, mouse models and gene and protein expression analysis to identify the key pathways relevant to motor neurone degeneration. With neuropathology we study comparative neuropathology in human autopsy samples and mouse models. Oxford has a broad community of researchers interested in neurodegeneration, including a number of MRC Units and the Department of Physiology, Anatomy and Genetics, the highest ranked preclinical department in the country. BioMOx is a longitudinal study to identify biomarkers in MND to improve early diagnosis and understand disease progression using high-field MRI techniques including diffusion tensor imaging at the world-leading FMRIB Centre. Biosamples are analysed with high throughput proteomics and the same group of patients will ultimately progress to post mortem. We also have a strong links with epidemiologists at the University Department of Public Health. This all takes place within a leading UK MND clinical centre which attracts patients from across South and Central England. http://www.oxfordmnd.net

Background The Trail Making Test (TMT) is a two-part written tool for detecting executive dysfunction. Part A consists of joining a “trail” of ascending numbers, which serves as a control for a second more challenging Part B where the “trail” alternates between ascending numbers and alphabetical letters. The time taken for completion of each is recorded. Executive dysfunction is common in patients with MND but detection using neuropsychological tests is often confounded by motor involvement (dominant upper limb weakness for the TMT). We sought to design a hands-free TMT using eye-tracking equipment, and to compare it with the standard written version. Methods A pilot study of 10 healthy volunteers was undertaken. A head-mounted Eyelink® eye-tracking device was used in conjunction with a visual display of the trails. There was an interval of 1 week between testing each version of the TMT. The B:A ratio of time in seconds for each task was used as the reliability outcome measure to standardise across the two different paradigms. Results A correlation coefficient of 0.6 was found between written and visual TMTs. Conclusions It is possible to perform the TMT using a hands-free, eye-tracking method which shows reasonable reliability in comparison with the written version. A larger control group is now being studied, with increased visual feedback during the testing process in an effort to improve reliability before application to MND and other dysexecutive patient groups.