Cathal Walsh

Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study

Summary Background Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of upper and lower motor neurons, associated with frontotemporal dementia (FTD) in about 14% of incident cases. We assessed the frequency of the recently identified C9orf72 repeat expansion in familial and apparently sporadic cases of ALS and characterised the cognitive and clinical phenotype of patients with this expansion. Methods A population-based register of patients with ALS has been in operation in Ireland since 1995, and an associated DNA bank has been in place since 1999. 435 representative DNA samples from the bank were screened using repeat-primed PCR for the presence of a GGGGCC repeat expansion in C9orf72. We assessed clinical, cognitive, behavioural, MRI, and survival data from 191 (44%) of these patients, who comprised a population-based incident group and had previously participated in a longitudinal study of cognitive and behavioural changes in ALS. Findings Samples from the DNA bank included 49 cases of known familial ALS and 386 apparently sporadic cases. Of these samples, 20 (41%) cases of familial ALS and 19 (5%) cases of apparently sporadic ALS had the C9orf72 repeat expansion. Of the 191 patients for whom phenotype data were available, 21 (11%) had the repeat expansion. Age at disease onset was lower in patients with the repeat expansion (mean 56·3 [SD 8·3] years) than in those without (61·3 [10·6] years; p=0·043). A family history of ALS or FTD was present in 18 (86%) of those with the repeat expansion. Patients with the repeat expansion had significantly more co-morbid FTD than patients without the repeat (50% vs 12%), and a distinct pattern of non-motor cortex changes on high-resolution 3 T magnetic resonance structural neuroimaging. Age-matched univariate analysis showed shorter survival (20 months vs 26 months) in patients with the repeat expansion. Multivariable analysis showed an increased hazard rate of 1·9 (95% 1·1–3·7; p=0·035) in those patients with the repeat expansion compared with patients without the expansion Interpretation Patients with ALS and the C9orf72 repeat expansion seem to present a recognisable phenotype characterised by earlier disease onset, the presence of cognitive and behavioural impairment, specific neuroimaging changes, a family history of neurodegeneration with autosomal dominant inheritance, and reduced survival. Recognition of patients with ALS who carry an expanded repeat is likely to be important in the context of appropriate disease management, stratification in clinical trials, and in recognition of other related phenotypes in family members. Funding Health Seventh Framework Programme, Health Research Board, Research Motor Neuron, Irish Motor Neuron Disease Association, The Motor Neurone Disease Association of Great Britain and Northern Ireland, ALS Association.

Prediction of conversion from mild cognitive impairment to Alzheimer's disease dementia based upon biomarkers and neuropsychological test performance

The current study tested the accuracy of primary MRI and cerebrospinal fluid (CSF) biomarker candidates and neuropsychological tests for predicting the conversion from mild cognitive impairment (MCI) to Alzheimers disease (AD) dementia. In a cross-validation paradigm, predictor models were estimated in the training set of AD (N = 81) and elderly control subjects (N = 101). A combination of CSF t-tau/Aβ(1-4) ratio and MRI biomarkers or neuropsychological tests (free recall and trail making test B (TMT-B)) showed the best statistical fit in the AD vs. HC comparison, reaching a classification accuracy of up to 64% when applied to the prediction of MCI conversion (3.3-year observation interval, mean = 2.3 years). However, several single-predictor models showed a predictive accuracy of MCI conversion comparable to that of any multipredictor model. The best single predictors were right entorhinal cortex (prediction accuracy = 68.5% (95% CI (59.5, 77.4))) and TMT-B test (prediction accuracy 64.6% (95% CI (55.5, 73.4%))). In conclusion, short-term conversion to AD is predicted by single marker models to a comparable degree as by multimarker models in amnestic MCI subjects.

Addition of brain and carotid imaging to the ABCD² score to identify patients at early risk of stroke after transient ischaemic attack: a multicentre observational study.

BACKGROUND The ABCD² score improves stratification of patients with transient ischaemic attack by early stroke risk. We aimed to develop two new versions of the score: one that was based on preclinical information and one that was based on imaging and other secondary care assessments. METHODS We analysed pooled data from patients with clinically defined transient ischaemic attack who were investigated while in secondary care. Items that contribute to the ABCD² score (age, blood pressure, clinical weakness, duration, and diabetes), other clinical variables, carotid stenosis, and abnormal acute diffusion-weighted imaging (DWI) were recorded and were included in multivariate logistic regression analysis of stroke occurrence at early time intervals after onset of transient ischaemic attack. Scores based on the findings of this analysis were validated in patients with transient ischaemic attack from two independent population-based cohorts. FINDINGS 3886 patients were included in the study: 2654 in the derivation sample and 1232 in the validation sample. We derived the ABCD³ score (range 0-9 points) by assigning 2 points for dual transient ischaemic attack (an earlier transient ischaemic attack within 7 days of the index event). C statistics (which indicate discrimination better than chance at >0·5) for the ABCD³ score were 0·78 at 2 days, 0·80 at 7 days, 0·79 at 28 days, and 0·77 at 90 days, compared with C statistics for the ABCD² score of 0·71 at 2 days (p=0·083), 0·71 at 7 days (p=0·012), 0·71 at 28 days (p=0·021), and 0·69 at 90 days (p=0·018). We included stenosis of at least 50% on carotid imaging (2 points) and abnormal DWI (2 points) in the ABCD³-imaging (ABCD³-I) score (0-13 points). C statistics for the ABCD³-I score were 0·90 at 2 days (compared with ABCD² score p=0·035), 0·92 at 7 days (p=0·001), 0·85 at 28 days (p=0·028), and 0·79 at 90 days (p=0·073). The 90-day net reclassification improvement compared with ABCD² was 29·1% for ABCD³ (p=0·0003) and 39·4% for ABCD³-I (p=0·034). In the validation sample, the ABCD³ and ABCD³-I scores predicted early stroke at 7, 28, and 90 days. However, discrimination and net reclassification of patients with early stroke were similar with ABCD³ compared with ABCD². INTERPRETATION The ABCD³-I score can improve risk stratification after transient ischaemic attack in secondary care settings. However, use of ABCD³ cannot be recommended without further validation. FUNDING Health Research Board of Ireland, Irish Heart Foundation, and Irish National Lottery.

A Frailty Instrument for primary care: findings from the Survey of Health, Ageing and Retirement in Europe (SHARE)

BackgroundA frailty paradigm would be useful in primary care to identify older people at risk, but appropriate metrics at that level are lacking. We created and validated a simple instrument for frailty screening in Europeans aged ≥50. Our study is based on the first wave of the Survey of Health, Ageing and Retirement in Europe (SHARE, http://www.share-project.org), a large population-based survey conducted in 2004-2005 in twelve European countries.MethodsSubjects: SHARE Wave 1 respondents (17,304 females and 13,811 males). Measures: five SHARE variables approximating Frieds frailty definition. Analyses (for each gender): 1) estimation of a discreet factor (DFactor) model based on the frailty variables using LatentGOLD®. A single DFactor with three ordered levels or latent classes (i.e. non-frail, pre-frail and frail) was modelled; 2) the latent classes were characterised against a biopsychosocial range of Wave 1 variables; 3) the prospective mortality risk (unadjusted and age-adjusted) for each frailty class was established on those subjects with known mortality status at Wave 2 (2007-2008) (11,384 females and 9,163 males); 4) two web-based calculators were created for easy retrieval of a subjects frailty class given any five measurements.ResultsFemales: the DFactor model included 15,578 cases (standard R2 = 0.61). All five frailty indicators discriminated well (p < 0.001) between the three classes: non-frail (N = 10,420; 66.9%), pre-frail (N = 4,025; 25.8%), and frail (N = 1,133; 7.3%). Relative to the non-frail class, the age-adjusted Odds Ratio (with 95% Confidence Interval) for mortality at Wave 2 was 2.1 (1.4 - 3.0) in the pre-frail and 4.8 (3.1 - 7.4) in the frail. Males: 12,783 cases (standard R2 = 0.61, all frailty indicators had p < 0.001): non-frail (N = 10,517; 82.3%), pre-frail (N = 1,871; 14.6%), and frail (N = 395; 3.1%); age-adjusted OR (95% CI) for mortality: 3.0 (2.3 - 4.0) in the pre-frail, 6.9 (4.7 - 10.2) in the frail.ConclusionsThe SHARE Frailty Instrument has sufficient construct and predictive validity, and is readily and freely accessible via web calculators. To our knowledge, SHARE-FI represents the first European research effort towards a common frailty language at the community level.

Rate of familial amyotrophic lateral sclerosis: a systematic review and meta-analysis

Background The population rate of familial amyotrophic lateral sclerosis (FALS) is frequently reported as 10%. However, a systematic review and meta-analysis of the true population based frequency of FALS has never been performed. Method A Medline literature review identified all original articles reporting a rate of FALS. Studies were grouped according to the type of data presented and examined for sources of case ascertainment. A systematic review and meta-analysis of reported rates of FALS was then conducted to facilitate comparison between studies and calculate a pooled rate of FALS. Results 38 papers reported a rate of FALS. Thirty-three papers were included in analysis and the rate of FALS for all studies was 4.6% (95% CI 3.9% to 5.5%). Restricting the analysis to prospective population based registry data revealed a rate of 5.1% (95% CI 4.1% to 6.1%). The incidence of FALS was lower in southern Europe. There was no correlation between rate of FALS and reported SOD1 mutation rates. Conclusion The rate of FALS among prospective population based registries is 5.1% (CI 4.1 to 6.1%), and not 10% as is often stated. Further detailed prospective population based studies of familial ALS are required to confirm this rate.

The impact of cognitive training and mental stimulation on cognitive and everyday functioning of healthy older adults: A systematic review and meta-analysis

This systematic review and meta-analysis investigates the impact of cognitive training and general mental stimulation on the cognitive and everyday functioning of older adults without known cognitive impairment. We examine transfer and maintenance of intervention effects, and the impact of training in group versus individual settings. Thirty-one randomised controlled trials were included, with 1806 participants in cognitive training groups and 386 in general mental stimulation groups. Meta-analysis results revealed that compared to active controls, cognitive training improved performance on measures of executive function (working memory, p=0.04; processing speed, p<0.0001) and composite measures of cognitive function (p=0.001). Compared to no intervention, cognitive training improved performance on measures of memory (face-name recall, p=0.02; immediate recall, p=0.02; paired associates, p=0.001) and subjective cognitive function (p=0.01). The impact of cognitive training on everyday functioning is largely under investigated. More research is required to determine if general mental stimulation can benefit cognitive and everyday functioning. Transfer and maintenance of intervention effects are most commonly reported when training is adaptive, with at least ten intervention sessions and a long-term follow-up. Memory and subjective cognitive performance might be improved by training in group versus individual settings.

The attitudes and practices of general practitioners regarding dementia diagnosis in Ireland

The diagnosis of dementia poses difficulties for general practitioners (GPs) particularly when access to specialist diagnostic services is delayed. Ireland is soon to witness an increase in numbers of people presenting with dementia, yet little is known about the service needs of GPs when attempting to diagnose dementia.

Self-efficacy for managing dementia may protect against burden and depression in Alzheimer's caregivers

Background: Self-efficacy is the belief that one can perform a specific task or behaviour and is a modifiable attribute which has been shown to influence health behaviours. Few studies have examined the relationship between self-efficacy for dementia-related tasks and symptoms of burden and depression in caregivers. Methods: Eighty four patient/caregiver dyads with Alzheimers disease were recruited through a memory clinic. Patient function, cognition and neuropsychiatric symptoms were assessed together with caregiver burden, personality, depressive symptoms, coping strategies and self-efficacy for completing tasks related to dementia care. Results: 33% (28) of caregivers reported significant depressive symptoms (CES-D ≥ 10). In multivariate analyses, caregiver burden was predicted by self-efficacy for symptom management, neuroticism, patient function and neuropsychiatric symptoms while caregiver depression was predicted by self-efficacy for symptom management, caregiver educational level, neuroticism, emotion-focused coping, dysfunctional coping and patient function. In patients with moderate to severe impairment (MMSE ≤ 20), self-efficacy for symptom management behaved as a mediator between patient neuropsychiatric symptoms and symptoms of burden and depression in caregivers. Conclusions: Further longitudinal investigation is warranted to determine if self-efficacy might be usefully considered a target in future interventional studies to alleviate symptoms of burden and depression in Alzheimers caregivers.

'Neurophobia'--attitudes of medical students and doctors in Ireland to neurological teaching.

(i) To determine whether neurology is the medical specialty with which Irish students and doctors have most difficulty, (ii) appraise attitudes towards how neurology is taught, and (iii) suggest ways teaching might be improved. A questionnaire on medical teaching was given to 457 medical students and junior doctors in Ireland. Perceived difficulties with neurology compared with seven other medical specialties were analysed. Other aspects of teaching were assessed including why neurology is perceived as difficult and ways teaching could be improved. Neurology was perceived as the most difficult of the eight medical specialties assessed. Participants felt they learned most at bedside tutorials with surprisingly few learning online. Neurology was perceived as difficult because of insufficient exposure to the subject, lack of teaching, and perceived complexity. Neurology teaching could be improved by increasing the number of bedside tutorials and by greater exposure to neurological patients for the students in clinical training. Medical students and doctors find neurology difficult. The teaching of neurology is reported as moderate to poor. The reasons for this are wide ranging but an emphasis on increased numbers of tutorials and greater integration of pre‐clinical neurology to clinical years would improve teaching.

A mixed treatment comparison of the efficacy of anti-TNF agents in rheumatoid arthritis for methotrexate non-responders demonstrates differences between treatments: a Bayesian approach

Background A number of tumour necrosis factor α (TNFα) antagonists (anti-TNFα) are available to treat rheumatoid arthritis. All of these have demonstrated considerable efficacy in placebo controlled trials, but few head-to-head comparisons exist to date. This works objective is to estimate the relative efficacy among licensed anti-TNFs in patients who have had an inadequate response to methotrexate (MTX). Different outcome measures are used to highlight the advantages of continuous measures in such analyses. Methods A systematic review identified randomised controlled trials comparing the efficacy of licensed anti-TNFα agents with placebo at 24 weeks in patients who have had an inadequate response to MTX. Relative efficacy was estimated using Bayesian mixed treatment comparison (MTC) models. Three different outcome measures were used: RR of achieving an American College of Rheumatology (ACR) 20 and ACR50 response and the percentage improvement in Health Assessment Questionnaire (HAQ) score. Results 16 published trials were included in the analysis. All anti-TNFs show considerably improved efficacy over placebo. The MTC results also provide evidence of some differences in efficacy of the TNFα antagonists. Etanercept appears superior to infliximab and golimumab, and certolizumab to infliximab and adalimumab. ACR results indicate improved efficacy of certolizumab over golimumab. On HAQ analysis, adalimumab, certolizumab, etanercept and golimumab appear superior to infliximab, and etanercept shows improved efficacy compared with adalimumab. Conclusions There are differences in efficacy among the TNFα antagonists. In a MTC, a continuous outcome measure has more strength to detect such differences than a binomial outcome measure because of its enhanced sensitivity to change.