Nigel Leigh

Cognitive impairment in patients with multiple system atrophy and progressive supranuclear palsy

This article reports the severity and profile of neuropsychological impairment on a prevalent cohort of patients with a clinical diagnosis of either multiple system atrophy (n=372) or progressive supranuclear palsy (n=311) from the Neuroprotection and Natural History in Parkinson Plus Syndromes cohort. The Dementia Rating Scale and Frontal Assessment Battery were used to assess global cognition and executive dysfunction. For the Dementia Rating Scale impairment was observed in approximately 57% of the progressive supranuclear palsy group and 20% of the multiple system atrophy group. In the former, impairment in a single cognitive domain was observed in 40%, with the same number showing impairment in multiple domains, while in the latter the figures were 28.6 and 13.5%, respectively. On the Frontal Assessment Battery, impairment was observed in 62.0% of patients with progressive supranuclear palsy and 31.8% of those with multiple system atrophy. Although the progressive supranuclear palsy group performed worse overall, the cognitive profiles of the two groups on the Dementia Rating Scale subscales were identical, with the main impairment of the Initiation and Perseveration subscale. The impaired patients in the two groups were largely indistinguishable, qualitatively and quantitatively. Impairment was associated with greater age and clinical disability in both groups and was evident even in the early stages (22% in multiple system atrophy and 50% in progressive supranuclear palsy). Where a pathological diagnosis was available, the original clinical diagnosis was confirmed in the majority of cases, including those with significant cognitive impairment. The rate of impairment in those with a confirmed pathological diagnosis was comparable to that of the sample as a whole. These results demonstrate, in the largest prospectively recruited cohort of patients with progressive supranuclear palsy and multiple system atrophy studied to date, the existence of a cognitive profile similar to that previously reported in idiopathic Parkinsons disease. The results indicate a high level of cognitive impairment associated with progressive supranuclear palsy, but also point to comparable dysfunction in a substantial proportion of the patients with multiple system atrophy. Significant cognitive impairment appears consistent with a diagnosis of multiple system atrophy, even early in the disease, with important implications for diagnosis, research and management.

Phase II/III randomized trial of TCH346 in patients with ALS

Background: TCH346 exerts antiapoptotic effects by binding to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and blocking the apoptotic pathway in which GAPDH is involved. Apoptosis is considered to be a key pathogenic mechanism in neurodegenerative diseases including ALS. Methods: Patients were randomly assigned in a double-blind fashion to receive either placebo or one of four doses of TCH346 (1.0, 2.5, 7.5, or 15 mg/day) administered orally once daily for at least 24 weeks. The primary outcome measure was the rate of change in the revised ALS functional rating scale (ALSFRS-R). The trial design included a 16-week lead-in phase to determine each patients rate of disease progression. The between treatment comparison was adjusted for the individual pretreatment rates of progression. The study was powered to detect a 25% reduction in the rate of decline of the ALSFRS-R as compared with placebo. Secondary outcome measures included survival, pulmonary function, and manual muscle testing (MMT). Results: Five hundred ninety-one patients were enrolled at 42 sites in Europe and North America. There were no differences in baseline variables. There were no significant differences between placebo and active treatment groups in the mean rate of decline of the ALSFRS-R or in the secondary outcome measures (survival, pulmonary function, and MMT). Conclusion: The trial revealed no evidence of a beneficial effect of TCH346 on disease progression in patients with ALS.

An MND/ALS phenotype associated with C9orf72 repeat expansion: Abundant p62-positive, TDP-43-negative inclusions in cerebral cortex, hippocampus and cerebellum but without associated cognitive decline

The transactive response DNA binding protein (TDP‐43) proteinopathies describe a clinico‐pathological spectrum of multi‐system neurodegeneration that spans motor neuron disease/amyotrophic lateral sclerosis (MND/ALS) and frontotemporal lobar degeneration (FTLD). We have identified four male patients who presented with the clinical features of a pure MND/ALS phenotype (without dementia) but who had distinctive cortical and cerebellar pathology that was different from other TDP‐43 proteinopathies. All patients initially presented with weakness of limbs and respiratory muscles and had a family history of MND/ALS. None had clinically identified cognitive decline or dementia during life and they died between 11 and 32 months after symptom onset. Neuropathological investigation revealed lower motor neuron involvement with TDP‐43‐positive inclusions typical of MND/ALS. In contrast, the cerebral pathology was atypical, with abundant star‐shaped p62‐immunoreactive neuronal cytoplasmic inclusions in the cerebral cortex, basal ganglia and hippocampus, while TDP‐43‐positive inclusions were sparse. This pattern was also seen in the cerebellum where p62‐positive, TDP‐43‐negative inclusions were frequent in granular cells. Western blots of cortical lysates, in contrast to those of sporadic MND/ALS and FTLD‐TDP, showed high p62 levels and low TDP‐43 levels with no high molecular weight smearing. MND/ALS‐associated SOD1, FUS and TARDBP gene mutations were excluded; however, further investigations revealed that all four of the cases did show a repeat expansion of C9orf72, the recently reported cause of chromosome 9‐linked MND/ALS and FTLD. We conclude that these chromosome 9‐linked MND/ALS cases represent a pathological sub‐group with abundant p62 pathology in the cerebral cortex, hippocampus and cerebellum but with no significant associated cognitive decline.

A longitudinal study of diffusion tensor MRI in ALS

In this study, we investigated whether diffusion tensor MRI (DTI) could detect progressive corticospinal tract degeneration in amyotrophic lateral sclerosis (ALS) and whether changes in diffusion variables reflected clinical deterioration. Twenty‐three ALS patients and 25 healthy volunteers underwent whole brain DTI. Patients and a subset (n = 12) of controls returned for a second scan. Clinical measures of disease severity were assessed in the ALS group. Changes in fractional anisotropy (FA) and mean diffusivity (MD) were measured along the corticospinal tract using a region of interest approach. Adequate DTI data were available in 11 ALS patients and 11 controls at two time points. FA and MD differed significantly between ALS patients and controls at both time points, but neither changed significantly over time, while global measures of disease severity in patients increased with time. Although we confirmed that DTI detects corticospinal tract damage in ALS, there were no significant changes in diffusion measures over time. The sensitivity of DTI may be improved by advanced data analysis techniques, although the high dropout rate suggests that use of MRI as a biomarker in ALS may be restricted to earlier stages of disease.

Meta-analysis of vascular endothelial growth factor variations in amyotrophic lateral sclerosis: increased susceptibility in male carriers of the −2578AA genotype

Background: Targeted delivery of the angiogenic factor, vascular endothelial growth factor (VEGF), to motor neurons prolongs survival in rodent models of amyotrophic lateral sclerosis (ALS), while mice expressing reduced VEGF concentrations develop motor neuron degeneration reminiscent of ALS, raising the question whether VEGF contributes to the pathogenesis of ALS. An initial association study reported that VEGF haplotypes conferred increased susceptibility to ALS in humans, but later studies challenged this initial finding. Methods and findings: A meta-analysis was undertaken to critically reappraise whether any of the three common VEGF gene variations (−2578C/A, −1154G/A and −634G/C) increase the risk of ALS. Over 7000 subjects from eight European and three American populations were included in the analysis. Pooled odds ratios were calculated using fixed-effects and random-effects models, and four potential sources of heterogeneity (location of disease onset, gender, age at disease onset and disease duration) were assessed. After correction, none of the genotypes or haplotypes was significantly associated with ALS. Subgroup analysis by gender revealed, however, that the −2578AA genotype, which lowers VEGF expression, increased the risk of ALS in males (OR = 1.46 males vs females; 95% CI = 1.19 to 1.80; p = 7.8 10E-5), even after correction for publication bias and multiple testing. Conclusions: This meta-analysis does not support the original conclusion that VEGF haplotypes increase the risk of ALS in humans, but the significant association of the low-VEGF −2578AA genotype with increased susceptibility to ALS in males reappraises the link between reduced VEGF concentrations and ALS, as originally revealed by the fortuitous mouse genetic studies.

A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis

Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (∼90%) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN (the International Consortium on Amyotrophic Lateral Sclerosis Genetics). We analysed a total of 13 225 individuals, 6100 cases and 7125 controls for almost 7 million single-nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 with P = 1.11 × 10(-8); OR 0.82) that was validated when combined with genotype data from a replication cohort (P = 8.62 × 10(-9); OR 0.833) of 4656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P = 7.69 × 10(-9); OR 1.16). Finally, we estimated the contribution of common variation to heritability of sporadic ALS as ∼12% using a linear mixed model accounting for all SNPs. Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci.

Management of respiration in MND/ALS patients: An evidence based review

This systematic review comprises an objective appraisal of the evidence in regard to the management of respiration in patients with motor neuron disease (MND/ALS). Studies were identified through computerised searches of 32 databases. Internet searches of websites of drug companies and MND/ALS research web sites, ‘snow balling’ and hand searches were also employed to locate any unpublished study or other ‘grey literature’ on respiration and MND/ALS. Since management of MND/ALS involves a number of health professionals and care workers, searches were made across multiple disciplines. No time frame was imposed on the search in order to increase the probability of identifying all relevant studies, although there was a final limit of March 2005. Recommendations for patient and carer‐based guidelines for the clinical management of respiration for MND/ALS patients are suggested on the basis of qualitative analyses of the available evidence. However, these recommendations are based on current evidence of best practice, which largely comprises observational research and clinical opinion. There is a clear need for further evidence, in particular randomised and non‐randomised controlled trials on the effects of non‐invasive ventilation and additional larger scale cohort studies on the issues of initial assessment of respiratory symptoms, and management and timing of interventions.

Survival of patients with ALS following institution of enteral feeding is related to pre‐procedure oximetry: A retrospective review of 98 patients in a single centre

A retrospective review was carried out on the influence of pre‐procedure respiratory assessment on survival of patients with amyotrophic lateral sclerosis (ALS) requiring nutritional support with either a gastrostomy or a nasogastric feeding tube. Over a five‐year period 98 patients (49 male, 49 female; median age 61 years, range 26–86 years) with ALS were referred for enteral feeding with either radiological inserted gastrostomy (RIG), percutaneous endoscopic gastrostomy (PEG) or nasogastric tube (NG). Case notes review was performed to record patient age, sex, pre‐procedure respiratory assessment, method of enteral feeding and survival post‐procedure. Kaplan‐Meier survival curves were constructed for each group, with Cox regression analyses performed in order to establish the effect of each variable on outcome. Median survival (with 95% confidence intervals) following RIG, PEG and NG was 6.31 months (4.58–8.04 months), 7.13 months (4.81–9.45 months) and 0.95 months (0.00–2.77 months), respectively. The survival advantage between RIG and PEG was not statistically significant (p = 0.50), but for NG versus RIG and PEG groups combined, there was a significant difference (p = 0.03). For patients with normal overnight oximetry, median survival was 8.54 months (3.88–13.21 months), compared to 4.80 months (1.20–8.39 months) in the abnormal oximetry group (p = 0.03; relative risk 1.97). It is concluded that RIG and PEG are equivalent in terms of post‐procedure survival. Abnormal oximetry prior to the procedure is a significant indicator of post‐procedure survival.

Cyclin-dependent kinase-5 is associated with lipofuscin in motor neurones in amyotrophic lateral sclerosis

We have studied the distribution of cyclin dependent kinase-5 (cdk-5) within spinal cord in sporadic and two superoxide dismutase type 1 (SOD1) familial cases of amyotrophic lateral sclerosis (ALS). Although most neurofilament accumulations in ALS motor neurones did not appear to contain high levels of cdk-5, intense cdk-5 immunoreactivity was observed in perikarya of degenerating neurones in many ALS cases. Here, cdk-5 co-localised with lipofuscin. Co-localisation of cdk-5 with lipofuscin was also observed in some aged non-affected controls although this labelling was less intense than the ALS cases. The biogenesis of lipofuscin is believed to be linked to oxidative stress and oxidative stress and free radical damage have been suggested to be part of the pathogenic process of ALS, possibly involving apoptotic mechanisms. cdk-5 has recently been associated with apoptosis. These observations suggest a role for cdk-5 in the pathogenesis of ALS.

Safety and efficacy of diaphragm pacing in patients with respiratory insufficiency due to amyotrophic lateral sclerosis (DiPALS): a multicentre, open-label, randomised controlled trial.

BACKGROUND Non-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. METHODS We 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. FINDINGS Between 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. INTERPRETATION Addition 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. FUNDING The National Institute for Health Research Health Technology Assessment Programme; the Motor Neurone Disease Association of England, Wales, and Northern Ireland.