Genetic Modifiers of Age at Onset in Carriers of the G206A Mutation in PSEN1 With Familial Alzheimer Disease Among Caribbean Hispanics

Importance  The present study identified potential genetic modifiers that may delay or accelerate age at onset of familial Alzheimer disease (AD) by examining age at onset in PSEN1 mutation carrier families, and further investigation of these modifiers may provide insight into the pathobiology of AD and potential therapeutic measures.

Objective  To identify genetic variants that modify age at onset of AD.

Design, Setting, and Participants  Using a subset of Caribbean Hispanic families that carry thePSEN1 p.G206A mutation, we performed a 2-stage genome study. The mutation carrier families from an ongoing genetic study served as a discovery set, and the cohort of those with LOAD served as a confirmation set. To identify candidate loci, we performed linkage analysis using 5 p.G206A carrier families (n = 56), and we also performed whole-exome association analysis using 31 p.G206A carriers from 26 families. To confirm the genetic modifiers identified from the p.G206A carrier families, we analyzed the GWAS data for 2888 elderly individuals with LOAD. All study participants were Caribbean Hispanics.

Main Outcomes and Measures  Age at onset of AD.

Results  Linkage analysis of AD identified the strongest linkage support at 4q35 (LOD [logarithm of odds] score, 3.69), and the GWAS of age at onset identified variants on 1p13.1, 2q13, 4q25, and 17p11. In the confirmation stage, genewise analysis identified SNX25, PDLIM3, and 3 SH3 domain genes (SORBS2, SH3RF3, and NPHP1) to be significantly associated with LOAD. Subsequent allelic association analysis confirmed SNX25, PDLIM3, and SORBS2 as genetic modifiers of age at onset of EOAD and LOAD and provided modest support for SH3RF3 and NPHP1.

Conclusions and Relevance  Our 2-stage analysis revealed that SNX25, PDLIM3, and SORBS2 may serve as genetic modifiers of age at onset in both EOAD and LOAD.

JAAMA Neurology 2015

Incidence, outcome, risk factors, and long-term prognosis of cryptogenic transient ischaemic attack and ischaemic stroke: a population-based study

Background

A third of transient ischaemic attacks (TIAs) and ischaemic strokes are of undetermined cause (ie, cryptogenic), potentially undermining secondary prevention. If these events are due to occult atheroma, the risk-factor profile and coronary prognosis should resemble that of overt large artery events. If they have a cardioembolic cause, the risk of future cardioembolic events should be increased. We aimed to assess the burden, outcome, risk factors, and long-term prognosis of cryptogenic TIA and stroke.

Methods

In a population-based study in Oxfordshire, UK, among patients with a first TIA or ischaemic stroke from April 1, 2002, to March 31, 2014, we compared cryptogenic events versus other causative subtypes according to the TOAST classification. We compared markers of atherosclerosis (ie, risk factors, coronary and peripheral arterial disease, asymptomatic carotid stenosis, and 10-year risk of acute coronary events) and of cardioembolism (ie, risk of cardioembolic stroke, systemic emboli, and new atrial fibrillation [AF] during follow-up, and minor-risk echocardiographic abnormalities and subclinical paroxysmal AF at baseline in patients with index events between 2010 and 2014).

Findings

Among 2555 patients, 812 (32%) had cryptogenic events (incidence of cryptogenic stroke 0·36 per 1000 population per year, 95% CI 0·23–0·49). Death or dependency at 6 months was similar after cryptogenic stroke compared with non-cardioembolic stroke (23% vs 27% for large artery and small vessel subtypes combined; p=0·26) as was the 10-year risk of recurrence (32% vs 27%; p=0·91). However, the cryptogenic group had fewer atherosclerotic risk factors than the large artery disease (p<0·0001), small vessel disease (p=0·001), and cardioembolic (p=0·008) groups. Compared with patients with large artery events, those with cryptogenic events had less hypertension (adjusted odds ratio [OR] 0·41, 95% CI 0·30–0·56; p<0·0001), diabetes (0·62, 0·43–0·90; p=0·01), peripheral vascular disease (0·27, 0·17–0·45; p<0·0001), hypercholesterolaemia (0·53, 0·40–0·70; p<0·0001), and history of smoking (0·68, 0·51–0·92; p=0·01), and compared with small vessel and cardioembolic subtypes, they had no excess risk of asymptomatic carotid disease (adjusted OR 0·64, 95% CI 0·37–1·11; p=0·11) or acute coronary events (adjusted hazard ratio [HR] 0·76, 95% CI 0·49–1·18; p=0·22) during follow-up. Compared with large artery and small vessel subtypes combined, patients with cryptogenic events also had no excess of minor-risk echocardiographic abnormalities (cryptogenic 37% vs 45%; p=0·18) or paroxysmal AF (6% vs 10%; p=0·17) at baseline or of new AF (adjusted HR 1·23, 0·78–1·95; p=0·37) or presumed cardioembolic events (1·16, 0·62–2·17; p=0·64) during follow-up.

Interpretation

The clinical burden of cryptogenic TIA and stroke is substantial. Although stroke recurrence rates are comparable with other subtypes, cryptogenic events have the fewest atherosclerotic markers and no excess of cardioembolic markers.

Lancet Neurology 2015

Home-based constraint-induced movement therapy for patients with upper limb dysfunction after stroke (HOMECIMT): a cluster-randomised, controlled trial

Background

Constraint-induced movement therapy (CIMT) is recommended for patients with upper limb dysfunction after stroke, yet evidence to support the implementation of CIMT in ambulatory care is insufficient. We assessed the efficacy of home CIMT, a modified form of CIMT that trains arm use in daily activities within the home environment.

Methods

In this parallel, cluster-randomised controlled trial, we selected 71 therapy practices in northern Germany that treat adult patients with upper limb dysfunction after stroke. Practices were stratified by region and randomly allocated by an external biometrician (1:1, block size of four) using a computer-generated sequence. 37 practices were randomly assigned to provide 4 weeks of home CIMT and 34 practices to provide 4 weeks of standard therapy. Eligible patients had mild to moderate impairment of arm function at least 6 months after stroke and a friend or family member willing to participate as a non-professional coach. Patients of both groups received 5 h of professional therapist contact in 4 weeks. In the home CIMT group, therapists used the contact time to instruct and supervise patients and coaches in home CIMT. Patients in the standard therapy group received conventional physical or occupational therapy, but additional home training was not obligatory. All assessments were done by masked outcome assessors at baseline, after 4 weeks of intervention, and at 6 month follow-up. The primary outcomes were quality of movement, assessed by the Motor Activity Log (MAL-QOM, assessor-assisted self-reported), and performance time, assessed by the Wolf Motor Function Test (WMFT-PT, assessor-reported). Primary outcomes were tested hierarchically after 4 weeks of intervention and analysed by intention to treat, using mixed linear models. This trial is registered with ClinicalTrials.gov, NCT01343602.

Findings

Between July 11, 2011, and June 4, 2013, 85 of 156 enrolled patients were assigned home CIMT and 71 patients were assigned standard therapy. 82 (96%) patients in the home CIMT group and 71 (100%) patients in the standard therapy group completed treatment and were assessed at 4 weeks. Patients in both groups improved in quality of movement (MAL-QOM; change from baseline 0·56, 95% CI 0·41–0·71, p<0·0001 for home CIMT vs 0·31, 0·15–0·46, p=0·0003 for standard therapy). Patients in the home CIMT group improved more than patients in the standard therapy group (between-group difference 0·26, 95% CI 0·05–0·46; p=0·0156). Both groups also improved in motor function performance time (WMFT-PT; change from baseline −25·60%, 95% CI −36·75 to −12·49, p=0·0006 for home CIMT vs −27·52%, −38·94 to −13·94, p=0·0004 for standard therapy), but the extent of improvement did not differ between groups (2·65%, −17·94 to 28·40; p=0·8152). Nine adverse events (of which six were serious) were reported in the home CIMT group and ten (of which seven were serious) in the standard therapy group; however, none was deemed related to the study intervention.

Interpretation

Home-based CIMT can enhance the perceived use of the stroke-affected arm in daily activities more effectively than conventional therapy, but was not superior with respect to motor function. Further research is needed to confirm whether home CIMT leads to clinically significant improvements and if so to identify patients that are most likely to benefit.

Lancet Neurology 2015

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

Summary

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.

Lancet Neurology 2015

TPP1 deficiency: Rare cause of isolated childhood-onset progressive ataxia

Neuronal ceroid lipofuscinoses (NCLs) are neurodegenerative disorders characterized by lysosomal ceroid deposition. Historically, NCLs were classified by onset age and electron microscopy abnormalities as infantile, late infantile, juvenile, and adult.^1,2 Molecular techniques have broadened diagnostic subgroups with identification of at least 13 NCL genes (http://www.ucl.ac.uk/ncl/mutation), though categorization remains difficult due to wide-ranging genetic, allelic, and phenotypic heterogeneity.


^{Neurology 2015}

Evidence-based guideline summary: Evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine

Objective: To develop recommendations for the evaluation, diagnosis, prognostication, and treatment of facioscapulohumeral muscular dystrophy (FSHD) from a systematic review and analysis of the evidence.

Methods: Relevant articles were analyzed in accordance with the American Academy of Neurology classification of evidence schemes for diagnostic, prognostic, and treatment studies. Recommendations were linked to the strength of the evidence and other factors.

Results and recommendations: Available genetic testing for FSHD type 1 is highly sensitive and specific. Although respiratory insufficiency occurs rarely in FSHD, patients with severe FSHD should have routine pulmonary function testing. Routine cardiac screening is not necessary in patients with FSHD without cardiac symptoms. Symptomatic retinal vascular disease is very rare in FSHD. Exudative retinopathy, however, is potentially preventable, and patients with large deletions should be screened through dilated indirect ophthalmoscopy. The prevalence of clinically relevant hearing loss is not clear. In clinical practice, patients with childhood-onset FSHD may have significant hearing loss. Because undetected hearing loss may impair language development, screening through audiometry is recommended for such patients. Musculoskeletal pain is common in FSHD and treating physicians should routinely inquire about pain. There is at present no effective pharmacologic intervention in FSHD. Available studies suggest that scapular fixation is safe and effective. Surgical scapular fixation might be cautiously offered to selected patients. Aerobic exercise in FSHD appears to be safe and potentially beneficial. On the basis of the evidence, patients with FSHD might be encouraged to engage in low-intensity aerobic exercises.

Neurology 2015

N-terminal pro–brain natriuretic peptide and abnormal brain aging The AGES–Reykjavik Study

Objective: To investigate the independent association of serum N-terminal fragment of the prohormone natriuretic peptide (NT-proBNP) with structural and functional features of abnormal brain aging in older individuals.

Methods: In this cross-sectional study based on the Age, Gene/Environment Susceptibility (AGES)–Reykjavik Study, we included 4,029 older community-dwelling individuals (born 1907 to 1935) with a measured serum level of NT-proBNP. Outcomes included parenchymal brain volumes estimated from brain MRI, cognitive function measured by tests of memory, processing speed, and executive functioning, and presence of depressive symptoms measured using the Geriatric Depression Scale. In a substudy, cardiac output of 857 participants was assessed using cardiac MRI.

Results: In multivariate analyses, adjusted for sociodemographic and cardiovascular factors, higher levels of NT-proBNP were independently associated with lower total (p < 0.001), gray matter (p < 0.001), and white matter (p = 0.001) brain volumes. Likewise, in multivariate analyses, higher levels of NT-proBNP were associated with worse scores in memory (p = 0.005), processing speed (p = 0.001), executive functioning (p < 0.001), and more depressive symptoms (p = 0.002). In the substudy, the associations of higher NT-proBNP with lower brain parenchymal volumes, impaired executive function and processing speed, and higher depressive symptoms were independent of the level of cardiac output.

Conclusions: Higher serum levels of NT-proBNP, independent of cardiovascular risk factors and a measure of cardiac function, are linked with alterations in brain structure and function. Roles of natriuretic peptides in the process of brain aging need to be further elucidated

Neurology 2015