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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.

Hereditary disorders of voluntary motor neurons are individually relatively uncommon, but have the potential to provide significant insights into motor neuron function in general and into the mechanisms underlying the more common form of sporadic Amyotrophic Lateral Sclerosis. Recently, mutations in a number of novel genes have been associated with Lower Motor Neuron (HSPB1, HSPB8, GARS, Dynactin), Upper Motor Neuron (Spastin, Atlastin, Paraplegin, HSP60, KIF5A, NIPA1) or mixed ALS-like phenotypes (Alsin, Senataxin, VAPB, BSCL2). In comparison to sporadic ALS these conditions are usually associated with slow progression, but as experience increases, a wide variation in clinical phenotype has become apparent. At the molecular level common themes are emerging that point to areas of specific vulnerability for motor neurons such as axonal transport, endosomal trafficking and RNA processing. We review the clinical and molecular features of this diverse group of genetically determined conditions and consider the implications for the broad group of motor neuron diseases in general.

SummaryBackgroundNon-invasive ventilation is part of the standard of care for treatment of respiratory failure in patients with amyotrophic lateral sclerosis (ALS). The NeuRx RA/4 Diaphragm Pacing System has received Humanitarian Device Exemption approval from the US Food and Drug Administration for treatment of respiratory failure in patients with ALS. We aimed to establish the safety and efficacy of diaphragm pacing with this system in patients with respiratory muscle weakness due to ALS.MethodsWe undertook a multicentre, open-label, randomised controlled trial at seven specialist ALS and respiratory centres in the UK. Eligible participants were aged 18 years or older with laboratory supported probable, clinically probable, or clinically definite ALS; stable riluzole treatment for at least 30 days; and respiratory insufficiency. We randomly assigned participants (1:1), via a centralised web-based randomisation system with minimisation that balanced patients for age, sex, forced vital capacity, and bulbar function, to receive either non-invasive ventilation plus pacing with the NeuRx RA/4 Diaphragm Pacing System or non-invasive ventilation alone. Patients, carers, and outcome assessors were not masked to treatment allocation. The primary outcome was overall survival, defined as the time from randomisation to death from any cause. Analysis was by intention to treat. This trial is registered, ISRCTN number 53817913.FindingsBetween Dec 5, 2011, and Dec 18, 2013, we randomly assigned 74 participants to receive either non-invasive ventilation alone (n=37) or non-invasive ventilation plus diaphragm pacing (n=37). On Dec 18, 2013, the Data Monitoring and Ethics Committee (DMEC) recommended suspension of recruitment on the basis of overall survival figures. Randomly assigned participants continued as per the study protocol until June 23, 2014, when the DMEC advised discontinuation of pacing in all patients. Follow-up assessments continued until the planned end of the study in December, 2014. Survival was shorter in the non-invasive ventilation plus pacing group than in the non-invasive ventilation alone group (median 11·0 months [95% CI 8·3–13·6] vs 22·5 months [13·6–not reached]; adjusted hazard ratio 2·27, 95% CI 1·22–4·25; p=0·009). 28 (76%) patients died in the pacing group and 19 (51%) patients died in the non-invasive ventilation alone group. We recorded 162 adverse events (5·9 events per person-year) in the pacing group, of which 46 events were serious, compared with 81 events (2·5 events per person-year) in the non-invasive ventilation alone group, of which 31 events were serious.InterpretationAddition of diaphragm pacing to standard care with non-invasive ventilation was associated with decreased survival in patients with ALS. Our results suggest that diaphragmatic pacing should not be used as a routine treatment for patients with ALS in respiratory failure.FundingThe National Institute for Health Research Health Technology Assessment Programme; the Motor Neurone Disease Association of England, Wales, and Northern Ireland.

Spinal muscular atrophy is an autosomal recessive disease of motor neurone degeneration which shows a variable phenotype. Two candidate genes show deletions in affected subjects but with no distinction between different forms of the disease. We report an unusual family in which mild and severe SMA coexists and patients are deleted for the SMN gene. The father is affected with late onset SMA; therefore this family shows pseudodominant inheritance. When typed using closely linked flanking markers the severely affected son does not share the same haplotype as his sib, who is deleted for SMN but shows no signs yet of SMA. This supports the hypothesis that differences in SMA phenotype can be explained by a multiple allele model.

The impact of Parkinson's disease (PD) dementia is substantial and has major functional and socioeconomic consequences. Early prediction of future cognitive impairment would help target future interventions. The Montreal Cognitive Assessment (MoCA), the Mini-Mental State Examination (MMSE), and fluency tests were administered to 486 patients with PD within 3.5 years of diagnosis, and the results were compared with those from 141 controls correcting for age, sex, and educational years. Eighteen-month longitudinal assessments were performed in 155 patients with PD. The proportion of patients classified with normal cognition, mild cognitive impairment (MCI), and dementia varied considerably, depending on the MoCA and MMSE thresholds used. With the MoCA total score at screening threshold, 47.7%, 40.5%, and 11.7% of patients with PD were classified with normal cognition, MCI, and dementia, respectively; by comparison, 78.7% and 21.3% of controls had normal cognition and MCI, respectively. Cognitive impairment was predicted by lower education, increased age, male sex, and quantitative motor and non-motor (smell, depression, and anxiety) measures. Longitudinal data from 155 patients with PD over 18 months showed significant reductions in MoCA scores, but not in MMSE scores, with 21.3% of patients moving from normal cognition to MCI and 4.5% moving from MCI to dementia, although 13.5% moved from MCI to normal; however, none of the patients with dementia changed their classification. The MoCA may be more sensitive than the MMSE in detecting early baseline and longitudinal cognitive impairment in PD, because it identified 25.8% of those who experienced significant cognitive decline over 18 months. Cognitive decline was associated with worse motor and non-motor features, suggesting that this reflects a faster progressive phenotype. © 2014 The Authors. International Parkinson and Movement Disorder Society published by Wiley Periodicals, Inc.

Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder characterized by loss of spinal cord motor neurons, muscle atrophy and infantile death or severe disability. It is caused by severe reduction of the ubiquitously expressed survival motor neuron (SMN) protein, owing to loss of the SMN1 gene. This would be completely incompatible with survival without the presence of a quasi-identical duplicated gene, SMN2, specific to humans. SMN2 harbours a silent point mutation that favours the production of transcripts lacking exon 7 and a rapidly degraded non-functional SMNΔ7 protein, but from which functional full length SMN protein is produced at very low levels (∼10%). Since the seminal discovery of the SMA-causing gene in 1995, research has focused on the development of various SMN replacement strategies culminating, in December 2016, in the approval of the first precise molecularly targeted therapy for SMA (nusinersen), and a pivotal proof of principle that therapeutic antisense oligonucleotide (ASO) treatment can effectively target the central nervous system (CNS) to treat neurological and neuromuscular disease. Nusinersen is a steric block ASO that binds the SMN2 messenger RNA and promotes exon 7 inclusion and thus increases full length SMN expression. Here, we consider the implications of this therapeutic landmark for SMA therapeutics and discuss how future developments will need to address the challenges of delivering ASO therapies to the CNS, with appropriate efficiency and activity, and how SMN-based therapy should be used in combination with complementary strategies to provide an integrated approach to treat CNS and peripheral pathologies in SMA.