Characterization of Gene Expression Phenotype in Amyotrophic Lateral Sclerosis Monocytes

Abstract

Importance  Amyotrophic lateral sclerosis (ALS) is a common adult-onset neurodegenerative disease characterized by selective loss of upper and lower motor neurons. Patients with ALS have persistent peripheral and central inflammatory responses including abnormally functioning T cells and activated microglia. However, much less is known about the inflammatory gene profile of circulating innate immune monocytes in these patients.

Objective  To characterize the transcriptomics of peripheral monocytes in patients with ALS.

Design, Setting, and Participants  Monocytes were isolated from peripheral blood of 43 patients with ALS and 22 healthy control individuals. Total RNA was extracted from the monocytes and subjected to deep RNA sequencing, and these results were validated by quantitative reverse transcription polymerase chain reaction.

Main Outcomes and Measures  The differential expressed gene signatures of these monocytes were identified using unbiased RNA sequencing strategy for gene expression profiling.

Results  The demographics between the patients with ALS (mean [SD] age, 58.8 [1.57] years; 55.8% were men and 44.2% were women; 90.7% were white, 4.65% were Hispanic, 2.33% were black, and 2.33% were Asian) and control individuals were similar (mean [SD] age, 57.6 [2.15] years; 50.0% were men and 50.0% were women; 90.9% were white, none were Hispanic, none were black, and 9.09% were Asian). RNA sequencing data from negative selected monocytes revealed 233 differential expressed genes in ALS monocytes compared with healthy control monocytes. Notably, ALS monocytes demonstrated a unique inflammation-related gene expression profile, the most prominent of which, including IL1B, IL8, FOSB, CXCL1, and CXCL2, were confirmed by quantitative reverse transcription polymerase chain reaction (IL8, mean [SE], 1.00 [0.18]; P = .002; FOSB, 1.00 [0.21]; P = .009; CXCL1, 1.00 [0.14]; P = .002; and CXCL2, 1.00 [0.11]; P = .01). Amyotrophic lateral sclerosis monocytes from rapidly progressing patients had more proinflammatory DEGs than monocytes from slowly progressing patients.

Conclusions and Relevance  Our data indicate that ALS monocytes are skewed toward a proinflammatory state in the peripheral circulation and may play a role in ALS disease progression, especially in rapidly progressing patients. This increased inflammatory response of peripheral immune cells may provide a potential target for disease-modifying therapy in patients with ALS.

JAMA Neurology 2017

Clinical Aspects of Glucose Transporter Type 1 Deficiency Information From a Global Registry

Abstract

Importance  Case reports regularly document unique or unusual aspects of glucose transporter type 1 deficiency (G1D). In contrast, population studies from which to draw global inferences are lacking. Twenty-five years after the earliest case reports, this deficiency still particularly affects treatment and prognostic counseling.

Objective  To examine the most common features of G1D.

Design, Setting, and Participants  In this study, data were collected electronically from 181 patients with G1D through a web-based, worldwide patient registry from December 1, 2013, through December 1, 2016. The study used several statistical methods tailored to address the age at onset of various forms of G1D, associated manifestations, natural history, treatment efficacy, and diagnostic procedures. These factors were correlated in a predictive mathematical model designed to guide prognosis on the basis of clinical features present at diagnosis.

Results  A total of 181 patients with G1D were included in the study (92 [50.8%] male and 89 female [49.2%]; median age, 9 years; age range, 0-65 years). As previously known, a relatively large variety of common phenotypes are characteristic of the G1D syndrome, including movement disorders, absence epilepsy (typical and atypical), and myoclonic and generalized epilepsies. The 3 main novel results are (1) the feasibility of effective dietary therapies (such as the modified Atkins diet) other than the ketogenic diet, (2) the relatively frequent occurrence (one-fourth of cases) of white matter magnetic resonance imaging abnormalities, and (3) the favorable effect of early diagnosis and treatment regardless of treatment modality and mutation type. In fact, the most important factor that determines outcome is age at diagnosis, as reflected in a predictive mathematical model.

Conclusions and Relevance  The results reveal several changing notions in the approach to G1D syndrome diagnosis and treatment, such as the perceived absolute requirement for a ketogenic diet, the assumed lack of structural brain defects, and the potential existence of genotype-phenotype correlations, all of which are contested by the registry data.

JAMA Neurology 2017

Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer's disease.

Abstract

Premature termination codon (PTC) mutations in the ATP-Binding Cassette, Sub-Family A, Member 7 gene (ABCA7) have recently been identified as intermediate-to-high penetrant risk factor for late-onset Alzheimer's disease (LOAD). High variability, however, is observed in downstream ABCA7 mRNA and protein expression, disease penetrance, and onset age, indicative of unknown modifying factors. Here, we investigated the prevalence and disease penetrance of ABCA7 PTC mutations in a large early onset AD (EOAD)-control cohort, and examined the effect on transcript level with comprehensive third-generation long-read sequencing. We characterized the ABCA7 coding sequence with next-generation sequencing in 928 EOAD patients and 980 matched control individuals. With MetaSKAT rare variant association analysis, we observed a fivefold enrichment (p = 0.0004) of PTC mutations in EOAD patients (3%) versus controls (0.6%). Ten novel PTC mutations were only observed in patients, and PTC mutation carriers in general had an increased familial AD load. In addition, we observed nominal risk reducing trends for three common coding variants. Seven PTC mutations were further analyzed using targeted long-read cDNA sequencing on an Oxford Nanopore MinION platform. PTC-containing transcripts for each investigated PTC mutation were observed at varying proportion (5-41% of the total read count), implying incomplete nonsense-mediated mRNA decay (NMD). Furthermore, we distinguished and phased several previously unknown alternative splicing events (up to 30% of transcripts). In conjunction with PTC mutations, several of these novel ABCA7 isoforms have the potential to rescue deleterious PTC effects. In conclusion, ABCA7 PTC mutations play a substantial role in EOAD, warranting genetic screening of ABCA7 in genetically unexplained patients. Long-read cDNA sequencing revealed both varying degrees of NMD and transcript-modifying events, which may influence ABCA7 dosage, disease severity, and may create opportunities for therapeutic interventions in AD.

Acta Neuropathologica 2017

Tremor stability index: a new tool for differential diagnosis in tremor syndromes

Abstract

Misdiagnosis among tremor syndromes is common, and can impact on both clinical care and research. To date no validated neurophysiological technique is available that has proven to have good classification performance, and the diagnostic gold standard is the clinical evaluation made by a movement disorders expert. We present a robust new neurophysiological measure, the tremor stability index, which can discriminate Parkinson’s disease tremor and essential tremor with high diagnostic accuracy. The tremor stability index is derived from kinematic measurements of tremulous activity. It was assessed in a test cohort comprising 16 rest tremor recordings in tremor-dominant Parkinson’s disease and 20 postural tremor recordings in essential tremor, and validated on a second, independent cohort comprising a further 50 tremulous Parkinson’s disease and essential tremor recordings. Clinical diagnosis was used as gold standard. One hundred seconds of tremor recording were selected for analysis in each patient. The classification accuracy of the new index was assessed by binary logistic regression and by receiver operating characteristic analysis. The diagnostic performance was examined by calculating the sensitivity, specificity, accuracy, likelihood ratio positive, likelihood ratio negative, area under the receiver operating characteristic curve, and by cross-validation. Tremor stability index with a cut-off of 1.05 gave good classification performance for Parkinson’s disease tremor and essential tremor, in both test and validation datasets. Tremor stability index maximum sensitivity, specificity and accuracy were 95%, 95% and 92%, respectively. Receiver operating characteristic analysis showed an area under the curve of 0.916 (95% confidence interval 0.797–1.000) for the test dataset and a value of 0.855 (95% confidence interval 0.754–0.957) for the validation dataset. Classification accuracy proved independent of recording device and posture. The tremor stability index can aid in the differential diagnosis of the two most common tremor types. It has a high diagnostic accuracy, can be derived from short, cheap, widely available and non-invasive tremor recordings, and is independent of operator or postural context in its interpretation.

Brain 2017

Cognitive reserve and TMEM106B genotype modulate brain damage in presymptomatic frontotemporal dementia: a GENFI study

Abstract

Frontotemporal dementia is a heterogeneous neurodegenerative disorder with around a third of cases having autosomal dominant inheritance. There is wide variability in phenotype even within affected families, raising questions about the determinants of the progression of disease and age at onset. It has been recently demonstrated that cognitive reserve, as measured by years of formal schooling, can counteract the ongoing pathological process. The TMEM106B genotype has also been found to be a modifier of the age at disease onset in frontotemporal dementia patients with TDP-43 pathology. This study therefore aimed to elucidate the modulating effect of environment (i.e. cognitive reserve as measured by educational attainment) and genetic background (i.e. TMEM106B polymorphism, rs1990622 T/C) on grey matter volume in a large cohort of presymptomatic subjects bearing frontotemporal dementia-related pathogenic mutations. Two hundred and thirty-one participants from the GENFI study were included: 108 presymptomatic MAPT, GRN, and C9orf72 mutation carriers and 123 non-carriers. For each subject, cortical and subcortical grey matter volumes were generated using a parcellation of the volumetric T1-weighted magnetic resonance imaging brain scan. TMEM106B genotyping was carried out, and years of education recorded. First, we obtained a composite measure of grey matter volume by graph-Laplacian principal component analysis, and then fitted a linear mixed-effect interaction model, considering the role of (i) genetic status; (ii) educational attainment; and (iii) TMEM106B genotype on grey matter volume. The presence of a mutation was associated with a lower grey matter volume (P = 0.002), even in presymptomatic subjects. Education directly affected grey matter volume in all the samples (P = 0.02) with lower education attainment being associated with lower volumes. TMEM106B genotype did not influence grey matter volume directly on its own but in mutation carriers it modulated the slope of the correlation between education and grey matter volume (P = 0.007). Together, these results indicate that brain atrophy in presymptomatic carriers of common frontotemporal dementia mutations is affected by both genetic and environmental factors such that TMEM106B enhances the benefit of cognitive reserve on brain structure. These findings should be considered in evaluating outcomes in future disease-modifying trials, and support the search for protective mechanisms in people at risk of dementia that might facilitate new therapeutic strategies.

Brain 2017

Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial

Summary

Background

The calcitonin gene-related peptide (CGRP) pathway is important in migraine pathophysiology. We assessed the efficacy and safety of erenumab, a fully human monoclonal antibody against the CGRP receptor, in patients with chronic migraine.

Methods

This was a phase 2, randomised, double-blind, placebo-controlled, multicentre study of erenumab for adults aged 18–65 years with chronic migraine, enrolled from 69 headache and clinical research centres in North America and Europe. Chronic migraine was defined as 15 or more headache days per month, of which eight or more were migraine days. Patients were randomly assigned (3:2:2) to subcutaneous placebo, erenumab 70 mg, or erenumab 140 mg, given every 4 weeks for 12 weeks. Randomisation was centrally executed using an interactive voice or web response system. Patients, study investigators, and study sponsor personnel were masked to treatment assignment. The primary endpoint was the change in monthly migraine days from baseline to the last 4 weeks of double-blind treatment (weeks 9–12). Safety endpoints were adverse events, clinical laboratory values, vital signs, and anti-erenumab antibodies. The efficacy analysis set included patients who received at least one dose of investigational product and completed at least one post-baseline monthly measurement. The safety analysis set included patients who received at least one dose of investigational product. The study is registered with ClinicalTrials.gov, number NCT02066415.

Findings

From April 3, 2014, to Dec 4, 2015, 667 patients were randomly assigned to receive placebo (n=286), erenumab 70 mg (n=191), or erenumab 140 mg (n=190). Erenumab 70 mg and 140 mg reduced monthly migraine days versus placebo (both doses −6·6 days vs placebo −4·2 days; difference −2·5, 95% CI −3·5 to −1·4, p<0·0001). Adverse events were reported in 110 (39%) of 282 patients, 83 (44%) of 190 patients, and 88 (47%) of 188 patients in the placebo, 70 mg, and 140 mg groups, respectively. The most frequent adverse events were injection-site pain, upper respiratory tract infection, and nausea. Serious adverse events were reported by seven (2%), six (3%), and two (1%) patients, respectively; none were reported in more than one patient in any group or led to discontinuation. 11 patients in the 70 mg group and three in the 140 mg group had anti-erenumab binding antibodies; none had anti-erenumab neutralising antibodies. No clinically significant abnormalities in vital signs, laboratory results, or electrocardiogram findings were identified. Of 667 patients randomly assigned to treatment, 637 completed treatment. Four withdrew because of adverse events, two each in the placebo and 140 mg groups.

Interpretation

In patients with chronic migraine, erenumab 70 mg and 140 mg reduced the number of monthly migraine days with a safety profile similar to placebo, providing evidence that erenumab could be a potential therapy for migraine prevention. Further research is needed to understand long-term efficacy and safety of erenumab, and the applicability of this study to real-world settings.

Lancet Neurology 2017

Safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 spinal muscular atrophy: a randomised, double-blind, placebo-controlled phase 2 trial

Summary

Background

Spinal muscular atrophy (SMA) is a progressive motor neuron disease causing loss of motor function and reduced life expectancy, for which limited treatment is available. We investigated the safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 SMA.

Methods

This randomised, double-blind, placebo-controlled, phase 2 study was done in 22 neuromuscular care centres in Belgium, France, Germany, Italy, Netherlands, Poland, and the UK. Safety and efficacy of olesoxime were assessed in patients aged 3–25 years with genetically confirmed type 2 or non-ambulatory type 3 SMA. A centralised, computerised randomisation process allocated patients (2:1 with stratification by SMA type and centre) to receive olesoxime (10 mg/kg per day) in an oral liquid suspension or placebo for 24 months. Patients, investigators assessing outcomes, and sponsor study personnel were masked to treatment assignment. The primary outcome measure was change from baseline compared with 24 months between the two treatment groups in functional domains 1 and 2 of the Motor Function Measure (MFM D1 + D2) assessed in the full analysis population. A shorter, 20-item version of the MFM, which was specifically adapted for young children, was used to assess patients younger than 6 years. Safety was assessed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT01302600.

Findings

The trial was done between Nov 18, 2010, and Oct 9, 2013. Of 198 patients screened, 165 were randomly assigned to olesoxime (n=108) or placebo (n=57). Five patients in the olesoxime group were not included in the primary outcome analysis because of an absence of post-baseline assessments. The change from baseline to month 24 on the primary outcome measure was 0·18 for olesoxime and −1·82 for placebo (treatment difference 2·00 points, 96% CI −0·25 to 4·25, p=0·0676). Olesoxime seemed to be safe and generally well tolerated, with an adverse event profile similar to placebo. The most frequent adverse events in the olesoxime group were pyrexia (n=34), cough (n=32), nasopharyngitis (n=25), and vomiting (n=25). There were two patient deaths (one in each group), but these were not deemed to be related to the study treatment.

Interpretation

Olesoxime was safe at the doses studied, for the duration of the trial. Although the primary endpoint was not met, secondary endpoints and sensitivity analyses suggest that olesoxime might maintain motor function in patients with type 2 or type 3 SMA over a period of 24 months. Based on these results, olesoxime might provide meaningful clinical benefits for patients with SMA and, given its mode of action, might be used in combination with other drugs targeting other mechanisms of disease, although additional evidence is needed.

Lancet Neurology 2017

Pregabalin use early in pregnancy and the risk of major congenital malformations

ABSTRACT

Objective: To assess whether first-trimester exposure to pregabalin is associated with an increased risk of major congenital malformations, as recently suggested in a pregnancy registry study.

Methods: We performed a cohort study nested in the US Medicaid Analytic eXtract (MAX). The study population included 1,323,432 pregnancies resulting in a live-born infant between 2000 and 2010. We examined the risk of major congenital malformations among infants born to women exposed to pregabalin during the first trimester compared with women unexposed to anticonvulsants. We used propensity score fine stratification to control for >50 potential confounders, and we estimated relative risks (RRs) and 95% confidence intervals (CIs) in generalized linear models. The analyses were replicated in the Truven Health MarketScan Commercial Database (MarketScan). Pooled estimates based on the adjusted RR produced in MAX, MarketScan, and the previous registry study were calculated.

Results: Of 477 infants exposed to pregabalin during the first trimester in MAX, 28 (5.9%) had malformations compared to 3.3% in nonexposed infants. The crude RR of major congenital malformations for pregabalin was 1.80 (95% CI 1.26–2.58). After propensity score adjustment, the RR moved to 1.16 (95% CI 0.81–1.67). Restriction to pregabalin monotherapy and sensitivity analyses produced similar results. The adjusted RR for major congenital malformations for the 174 infants exposed in MarketScan was 1.03 (95% CI 0.56–1.90). The pooled RR was 1.33 (95% CI 0.83–2.15) for pregabalin any use and 1.02 (95% CI 0.69–1.51) for pregabalin monotherapy.

Conclusions: Findings did not confirm the suggested teratogenic effects of pregabalin, although they cannot rule out the possibility of a small effect.

Neurology 2017

Vagotomy and Parkinson disease A Swedish register–based matched-cohort study

ABSTRACT

Objective: To examine whether vagotomy decreases the risk of Parkinson disease (PD).

Methods: Using data from nationwide Swedish registers, we conducted a matched-cohort study of 9,430 vagotomized patients (3,445 truncal and 5,978 selective) identified between 1970 and 2010 and 377,200 reference individuals from the general population individually matched to vagotomized patients by sex and year of birth with a 40:1 ratio. Participants were followed up from the date of vagotomy until PD diagnosis, death, emigration out of Sweden, or December 31, 2010, whichever occurred first. Vagotomy and PD were identified from the Swedish Patient Register. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs) using Cox models stratified by matching variables, adjusting for country of birth, chronic obstructive pulmonary disease, diabetes mellitus, vascular diseases, rheumatologic disease, osteoarthritis, and comorbidity index.

Results: A total of 4,930 cases of incident PD were identified during 7.3 million person-years of follow-up. PD incidence (per 100,000 person-years) was 61.8 among vagotomized patients (80.4 for truncal and 55.1 for selective) and 67.5 among reference individuals. Overall, vagotomy was not associated with PD risk (HR 0.96, 95% CI 0.78–1.17). However, there was a suggestion of lower risk among patients with truncal vagotomy (HR 0.78, 95% CI 0.55–1.09), which may be driven by truncal vagotomy at least 5 years before PD diagnosis (HR 0.59, 95% CI 0.37–0.93). Selective vagotomy was not related to PD risk in any analyses.

Conclusions: Although overall vagotomy was not associated the risk of PD, we found suggestive evidence for a potential protective effect of truncal, but not selective, vagotomy against PD development.

Neurology 2017

Randomized controlled trial of deutetrabenazine for tardive dyskinesia The ARM-TD study

ABSTRACT

Objective: To determine the efficacy and safety of deutetrabenazine as a treatment for tardive dyskinesia (TD).

Methods: One hundred seventeen patients with moderate to severe TD received deutetrabenazine or placebo in this randomized, double-blind, multicenter trial. Eligibility criteria included an Abnormal Involuntary Movement Scale (AIMS) score of ≥6 assessed by blinded central video rating, stable psychiatric illness, and stable psychoactive medication treatment. Primary endpoint was the change in AIMS score from baseline to week 12. Secondary endpoints included treatment success at week 12 on the Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change.

Results: For the primary endpoint, deutetrabenazine significantly reduced AIMS scores from baseline to week 12 vs placebo (least-squares mean [standard error] −3.0 [0.45] vs −1.6 [0.46], p = 0.019). Treatment success on CGIC (48.2% vs 40.4%) favored deutetrabenazine but was not significant. Deutetrabenazine and placebo groups showed low rates of psychiatric adverse events: anxiety (3.4% vs 6.8%), depressed mood/depression (1.7% vs 1.7%), and suicidal ideation (0% vs 1.7%, respectively). In addition, no worsening in parkinsonism, as measured by the Unified Parkinson's Disease Rating Scale motor subscale, was noted from baseline to week 12 in either group.

Conclusions: In patients with TD, deutetrabenazine was well tolerated and significantly reduced abnormal movements.

Classification of evidence: This study provides Class I evidence that in patients with TD, deutetrabenazine reduces AIMS scores.

Neurology 2017

Body mass index and outcome after revascularization for symptomatic carotid artery stenosis

ABSTRACT

Objective: To determine whether the obesity paradox exists in patients who undergo carotid artery stenting (CAS) or carotid endarterectomy (CEA) for symptomatic carotid artery stenosis.

Methods: We combined individual patient data from 2 randomized trials (Endarterectomy vs Angioplasty in Patients with Symptomatic Severe Carotid Stenosis and Stent-Protected Angioplasty vs Carotid Endarterectomy) and 3 centers in a third trial (International Carotid Stenting Study). Baseline body mass index (BMI) was available for 1,969 patients and classified into 4 groups: <20, 20–<25, 25–<30, and ≥30 kg/m². Primary outcome was stroke or death, investigated separately for the periprocedural and postprocedural period (≤120 days/>120 days after randomization). This outcome was compared between different BMI strata in CAS and CEA patients separately, and in the total group. We performed intention-to-treat multivariable Cox regression analyses.

Results: Median follow-up was 2.0 years. Stroke or death occurred in 159 patients in the periprocedural (cumulative risk 8.1%) and in 270 patients in the postprocedural period (rate 4.8/100 person-years). BMI did not affect periprocedural risk of stroke or death for patients assigned to CAS (p_trend = 0.39) or CEA (p_trend = 0.77) or for the total group (p_trend = 0.48). Within the total group, patients with BMI 25–<30 had lower postprocedural risk of stroke or death than patients with BMI 20–<25 (BMI 25–<30 vs BMI 20–<25; hazard ratio 0.72; 95% confidence interval 0.55–0.94).

Conclusions: BMI is not associated with periprocedural risk of stroke or death; however, BMI 25–<30 is associated with lower postprocedural risk than BMI 20–<25. These observations were similar for CAS and CEA.

Neurology 2017

Effect of a long-term intensive lifestyle intervention on prevalence of cognitive impairment

ABSTRACT

Objective: To assess whether an average of 10 years of lifestyle intervention designed to reduce weight and increase physical activity lowers the prevalence of cognitive impairment among adults at increased risk due to type 2 diabetes and obesity or overweight.

Methods: Central adjudication of mild cognitive impairment and probable dementia was based on standardized cognitive test battery scores administered to 3,802 individuals who had been randomly assigned, with equal probability, to either the lifestyle intervention or the diabetes support and education control. When scores fell below a prespecified threshold, functional information was obtained through proxy interview.

Results: Compared with control, the intensive lifestyle intervention induced and maintained marked differences in weight loss and self-reported physical activity throughout follow-up. At an average (range) of 11.4 (9.5–13.5) years after enrollment, when participants' mean age was 69.6 (54.9–87.2) years, the prevalence of mild cognitive impairment and probable dementia was 6.4% and 1.8%, respectively, in the intervention group, compared with 6.6% and 1.8%, respectively, in the control group (p = 0.93). The lack of an intervention effect on the prevalence of cognitive impairment was consistent among individuals grouped by cardiovascular disease history, diabetes duration, sex, and APOE ε4 allele status (all p ≥ 0.50). However, there was evidence (p = 0.03) that the intervention effect ranged from benefit to harm across participants ordered from lowest to highest baseline BMI.

Conclusions: Ten years of behavioral weight loss intervention did not result in an overall difference in the prevalence of cognitive impairment among overweight or obese adults with type 2 diabetes.

Neurology 2017

Endovascular therapy for ischemic stroke Save a minute—save a week

ABSTRACT

Objective: To quantify the patient lifetime benefits gained from reduced delays in endovascular therapy for acute ischemic stroke.

Methods: We used observational prospective data of consecutive stroke patients treated with IV thrombolysis in Helsinki (1998–2014; n = 2,474) to describe distributions of age, sex, stroke severity, onset-to-treatment times, and 3-month modified Rankin Scale (mRS) in routine clinical practice. We used treatment effects by time of endovascular therapy in large vessel occlusion over and above thrombolysis as reported by the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) study to model the shift in 3-month mRS distributions with reducing treatment delays. From the 3-month outcomes we derived patient-expected lifetimes and cumulative long-term disability with incremental treatment delay reductions.

Results: Each minute saved in onset-to-treatment time granted on average 4.2 days of extra healthy life, with a 95% prediction interval 2.3–5.4. Women gained slightly more than men due to their longer life expectancies. Patients younger than 55 years with severe strokes of NIH Stroke Scale score above 10 gained more than a week per each minute saved. In the whole cohort, every 20 minutes decrease in treatment delays led to a gain of average equivalent of 3 months of disability-free life.

Conclusions: Small reductions in endovascular delays lead to marked health benefits over patients' lifetimes. Services need to be optimized to reduce delays to endovascular therapy.

Neurology 2017

Autologous hematopoietic stem cell transplantation in multiple sclerosis A meta-analysis

ABSTRACT

Objective: To summarize the evidence on immunoablative therapy followed by autologous hematopoietic stem cell transplantation (aHSCT) to manage severe and treatment-refractory multiple sclerosis (MS).

Methods: We collected all the published studies of aHSCT in any form of MS from 1995 to 2016, carefully excluding reports that were updated in subsequent studies. Endpoints were transplant-related mortality (TRM), rate of disease progression, and no evidence of disease activity (NEDA) status. A weighted metaregression based on a Poisson model was run, assessing whether there were study-specific characteristics with an effect on TRM and progression.

Results: Fifteen studies including 764 transplanted patients were pooled in the meta-analysis. The pooled estimate of TRM was 2.1% (95% confidence interval [CI] 1.3%–3.4%). TRM was higher in older studies (p = 0.014) and in studies with a lower proportion of patients with relapsing-remitting MS (RRMS) (p = 0.028). A higher baseline Expanded Disability Status Scale (p = 0.013) was also significantly associated with a higher TRM. Pooled rate of progression was 17.1% at 2 years (95% CI 9.7%–24.5%) and 23.3% (95% CI 16.3%–31.8%) at 5 years. Lower 2-year progression rate was significantly associated with higher proportions of patients with RRMS (p = 0.004). The pooled proportion of NEDA patients at 2 years was 83% (range 70%–92%) and at 5 years was 67% (range 59%–70%).

Conclusions: The emerging evidence on this therapeutic approach in MS indicates that the largest benefit/risk profile form this therapeutic approach can be obtained in patients with aggressive MS with a relapsing-remitting course and who have not yet accumulated a high level of disability.

Neurology 2017

A rare variant in TOR1A exon 5 associated with isolated dystonia in southwestern Chinese

ABSTRACT

Background: TOR1A has been proposed as an important genetic factor in early-onset isolated dystonia. Variants located in the 3′ untranslated region of TOR1A are of particular importance because they may influence gene expression, although related studies are limited. The objectives of the present study focused on variants in the TOR1A 3′ untranslated region.

Methods: The last exon of TOR1A was sequenced in 229 cases with isolated dystonia and in 210 controls. In addition, 471 controls were tested to determine the frequency of the variants in the 3′ untranslated region.

Results: Except for c.904_906delGAG, 3 rare sequence variants (NM_000113.2:c.*454T>A, NM_000113.2:c.860C>A [rs766483672], and NM_000113.2:c.*302T>A [rs563498119]) were found only in the patients. The c.*302T>A variant was located in the conserved region of the human microRNA (hsa-miR-494) binding site. A luciferase reporter assay showed that c.*302T>A significantly altered gene expression.

Conclusions: Population frequencies, computational analyses, and function experiments in this study implied that c.*302T>A is associated with dystonia.

Movement Disorders 2017

The dizzy patient: don't forget disorders of the central vestibular system

Vertigo and dizziness are among the most common complaints in neurology clinics, and they account for about 13% of the patients entering emergency units. In this Review, we focus on central vestibular disorders, which are mostly attributable to acute unilateral lesions of the bilateral vestibular circuitry in the brain. In a tertiary interdisciplinary outpatient dizziness unit, central vestibular disorders, including vestibular migraine, comprise about 25% of the established diagnoses. The signs and symptoms of these disorders can mimic those of peripheral vestibular disorders with sustained rotational vertigo. Bedside examinations, such as the head impulse test and ocular motor testing to determine spontaneous and gaze-evoked nystagmus or skew deviation, reliably differentiate central from peripheral syndromes. We also consider disorders of 'higher vestibular functions', which involve more than one sensory modality as well as cognitive domains (for example, orientation, spatial memory and navigation). These disorders include hemispatial neglect, the room tilt illusion, pusher syndrome, and impairment of spatial memory and navigation associated with hippocampal atrophy in cases of peripheral bilateral vestibular loss.

Nature Reviews Neurology 2017

Evaluation of Amyloid Protective Factors and Alzheimer Disease Neurodegeneration Protective Factors in Elderly Individuals

Abstract

Importance  While amyloid and neurodegeneration are viewed together as Alzheimer disease pathophysiology (ADP), the factors that influence amyloid and AD-pattern neurodegeneration may be considerably different. Protection from these ADP factors may be important for aging without significant ADP.

Objective  To identify the combined and independent protective factors for amyloid and AD-pattern neurodegeneration in a population-based sample and to test the hypothesis that “exceptional agers” with advanced ages do not have significant ADP because they have protective factors for amyloid and neurodegeneration.

Design, Setting, and Participants  This cohort study conducted a prospective analysis of 942 elderly individuals (70-≥90 years) with magnetic resonance imaging and Pittsburgh compound B–positron emission tomography scans enrolled in the Mayo Clinic Study of Aging, a longitudinal population-based study of cognitive aging in Olmsted County, Minnesota. We operationalized “exceptional aging” without ADP by considering individuals 85 years or older to be without significant evidence of ADP.

Main Outcomes and Measures  We evaluated predictors including demographics, APOE, intellectual enrichment, midlife risk factors (physical inactivity, obesity, smoking, diabetes, hypertension, and dyslipidemia), and the total number of late-life cardiac and metabolic conditions. We used multivariate linear regression models to identify the combined and independent protective factors for amyloid and AD-pattern neurodegeneration. Using a subsample of the cohort 85 years of age or older, we computed Cohen d–based effect size estimations to compare the quantitative strength of each predictor variable in their contribution with exceptional aging without ADP.

Results  The study participants included 423 (45%) women and the average age of participants was 79.7 (5.9) years. Apart from demographics and the APOE genotype, only midlife dyslipidemia was associated with amyloid deposition. Obesity, smoking, diabetes, hypertension, and cardiac and metabolic conditions, but not intellectual enrichment, were associated with greater AD-pattern neurodegeneration. In the 85 years or older cohort, the Cohen d results showed small to moderate effects (effect sizes > 0.2) of several variables except job score and midlife hypertension in predicting exceptional aging without ADP.

Conclusions and Relevance  The protective factors that influence amyloid and AD-pattern neurodegeneration are different. “Exceptional aging” without ADP may be possible with a greater number of protective factors across the lifespan but warrants further investigation.

JAMA Neurology 2017