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Find video protocols related to scientific articles indexed in Pubmed.
Changing outcome in inflammatory neuropathies: Rasch-comparative responsiveness.
Neurology
PUBLISHED: 11-08-2014
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We performed responsiveness comparison between the patient-reported Inflammatory Rasch-built Overall Disability Scale (I-RODS) and the widely used clinician-reported Inflammatory Neuropathy Cause and Treatment-Overall Neuropathy Limitation Scale (INCAT-ONLS) in patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and immunoglobulin M-monoclonal gammopathy of undetermined significance related polyneuropathy (IgM-MGUSP).
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Analysis of amyotrophic lateral sclerosis as a multistep process: a population-based modelling study.
Lancet Neurol
PUBLISHED: 10-07-2014
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Amyotrophic lateral sclerosis shares characteristics with some cancers, such as onset being more common in later life, progression usually being rapid, the disease affecting a particular cell type, and showing complex inheritance. We used a model originally applied to cancer epidemiology to investigate the hypothesis that amyotrophic lateral sclerosis is a multistep process.
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Exome-wide Rare Variant Analysis Identifies TUBA4A Mutations Associated with Familial ALS.
Neuron
PUBLISHED: 09-16-2014
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Exome sequencing is an effective strategy for identifying human disease genes. However, this methodology is difficult in late-onset diseases where limited availability of DNA from informative family members prohibits comprehensive segregation analysis. To overcome this limitation, we performed an exome-wide rare variant burden analysis of 363 index cases with familial ALS (FALS). The results revealed an excess of patient variants within TUBA4A, the gene encoding the Tubulin, Alpha 4A protein. Analysis of a further 272 FALS cases and 5,510 internal controls confirmed the overrepresentation as statistically significant and replicable. Functional analyses revealed that TUBA4A mutants destabilize the microtubule network, diminishing its repolymerization capability. These results further emphasize the role of cytoskeletal defects in ALS and demonstrate the power of gene-based rare variant analyses in situations where causal genes cannot be identified through traditional segregation analysis.
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Prognostic factors for the course of functional status of patients with ALS: a systematic review.
J. Neurol.
PUBLISHED: 09-13-2014
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The progressive course of amyotrophic lateral sclerosis (ALS) results in an ever-changing spectrum of the care needs of patients with ALS. Knowledge of prognostic factors for the functional course of ALS may enhance clinical prediction and improve the timing of appropriate interventions. Our objective was to systematically review the evidence regarding prognostic factors for the rate of functional decline of patients with ALS, assessed with versions of the ALS Functional Rating Scale (ALSFRS). Two reviewers independently assessed the methodological quality of the thirteen included studies using the Quality in Prognosis Studies (QUIPS) tool. The overall quality of evidence for each prognostic factor was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, considering risk of bias, imprecision, inconsistency, indirectness, and publication bias. The quality of evidence for the prognostic value of age at onset, site of onset, time from symptom onset to diagnosis, and ALSFRS-Revised baseline score was low, mainly due to the limited data and inconsistency of results in the small number of studies included. The prognostic value of initial rate of disease progression, age at diagnosis, forced vital capacity, frontotemporal dementia, body mass index, and comorbidity remains unclear. We conclude that the current evidence on prognostic factors for functional decline in ALS is insufficient to allow the development of a prediction tool that can support clinical decisions. Given the limited data, future prognostic studies may need to focus on factors that have a predictive value for a decline in ALSFRS(-R) domain scores, preferably based on internationally collected and shared data.
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Clonality of anti-GM1 IgM antibodies in multifocal motor neuropathy and the Guillain-Barré syndrome.
J. Neurol. Neurosurg. Psychiatr.
PUBLISHED: 08-25-2014
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Multifocal motor neuropathy (MMN) and the Guillain-Barré syndrome (GBS) are immune-mediated motor neuropathies with antibodies against the ganglioside GM1. In GBS, these antibodies are induced by molecular mimicry, but in MMN their origin is elusive.
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A post hoc analysis of subgroup outcomes and creatinine in the phase III clinical trial (EMPOWER) of dexpramipexole in ALS.
Amyotroph Lateral Scler Frontotemporal Degener
PUBLISHED: 08-15-2014
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Our objective was to compare the phase II and phase III (EMPOWER) studies of dexpramipexole in ALS and evaluate potential EMPOWER responder subgroups and biomarkers based on significant inter-study population differences. In a post hoc analysis, we compared the baseline population characteristics of both dexpramipexole studies and analyzed EMPOWER efficacy outcomes and laboratory measures in subgroups defined by significant inter-study differences. Results showed that, compared with phase II, the proportion of El Escorial criteria (EEC) definite participants decreased (p = 0.005), riluzole use increased (p = 0.002), and mean symptom duration increased (p = 0.037) significantly in EMPOWER. Baseline creatinine (p < 0.001) and on-study creatinine change (p < 0.001) correlated significantly with ALSFRS-R in EMPOWER. In the EMPOWER subgroup defined by EEC-definite ALS, riluzole use, and < median symptom duration (15.3 months), dexpramipexole-treated participants had reduced ALSFRS-R slope decline (p = 0.015), decreased mortality (p = 0.011), and reduced creatinine loss (p = 0.003). In conclusion, significant differences existed between the phase II and EMPOWER study populations in ALS clinical trials of dexpramipexole. In a post hoc analysis of EMPOWER subgroups defined by these differences, potential clinical benefits of dexpramipexole were identified in the subgroup of riluzole-treated, short-symptom duration, EEC-definite ALS participants. Creatinine loss correlated with disease progression and was reduced in dexpramipexole-treated participants, suggesting it as a candidate biomarker.
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Bulbar muscle MRI changes in patients with SMA with reduced mouth opening and dysphagia.
Neurology
PUBLISHED: 08-13-2014
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We performed a study in patients with proximal spinal muscular atrophy (SMA) to determine the prevalence of reduced maximal mouth opening (MMO) and its association with dysphagia as a reflection of bulbar dysfunction and visualized the underlying mechanisms using MRI.
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Cortical thickness in ALS: towards a marker for upper motor neuron involvement.
J. Neurol. Neurosurg. Psychiatr.
PUBLISHED: 08-13-2014
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Examine whether cortical thinning is a disease-specific phenomenon across the spectrum of motor neuron diseases in relation to upper motor neuron (UMN) involvement.
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Prefrontal involvement related to cognitive impairment in progressive muscular atrophy.
Neurology
PUBLISHED: 07-30-2014
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To examine brain activation patterns during verbal fluency performance in patients with progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS).
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Subcortical structures in amyotrophic lateral sclerosis.
Neurobiol. Aging
PUBLISHED: 06-12-2014
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The aim of this study was to assess the involvement of deep gray matter, hippocampal subfields, and ventricular changes in patients with amyotrophic lateral sclerosis (ALS). A total of 112 ALS patients and 60 healthy subjects participated. High-resolution T1-weighted images were acquired using a 3T MRI scanner. Thirty-nine patients underwent a follow-up scan. Volumetric and shape analyses of subcortical structures were performed, measures were correlated with clinical parameters, and longitudinal changes were assessed. At baseline, reduced hippocampal volumes (left: p = 0.007; right: p = 0.011) and larger inferior lateral ventricles (left: p = 0.013; right: p = 0.041) were found in patients compared to healthy controls. Longitudinal analyses demonstrated a significant decrease in volume of the right cornu ammonis 2/3 and 4/dentate gyrus and left presubiculum (p = 0.002, p = 0.045, p < 0.001), and a significant increase in the ventricular volume in the lateral (left: p < 0.001; right: p < 0.001), 3rd (p < 0.001) and 4th (p = 0.001) ventricles. Larger ventricles were associated with a lower ALSFRS-R score (p = 0.021). In conclusion, ALS patients show signs of neurodegeneration of subcortical structures and ventricular enlargement. Subcortical involvement is progressive and correlates with clinical parameters, highlighting its role in the neurodegenerative process in ALS.
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Prior medical conditions and the risk of amyotrophic lateral sclerosis.
J. Neurol.
PUBLISHED: 06-12-2014
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Sporadic amyotrophic lateral sclerosis (ALS) is believed to be a complex disease in which multiple exogenous and genetic factors interact to cause motor neuron degeneration. Elucidating the association between medical conditions prior to the first symptoms of ALS could lend support to the theory that specific subpopulations are at risk of developing ALS and provide new insight into shared pathogenic mechanisms. We performed a population-based case-control study in the Netherlands, including 722 sporadic ALS patients and 2,268 age and gender matched controls. Data on medical conditions and use of medication were obtained through a structured questionnaire. Multivariate analyses showed that hypercholesterolemia (OR 0.76, 95 % CI 0.63-0.92, P = 0.006), the use of statins (OR 0.45, 95 % CI 0.35-0.59, P = 1.86 × 10(-9)) or immunosuppressive drugs (OR 0.26, 95 % CI 0.08-0.86, P = 0.03) were associated with a decreased risk of ALS. Head trauma was associated with an increased ALS susceptibility (OR 1.95, 95 % CI 1.11-3.43, P = 0.02). No association was found with autoimmune diseases, cancer, psychiatric disorders or cardiovascular diseases, or survival. The lower frequency of hypercholesterolemia and less use of statins in ALS patients indicate a favorable lipid profile prior to symptom onset in at least a subpopulation of ALS. Prior head trauma is a risk factor for ALS and the significantly lower use of immunosuppressive drugs in ALS patients could suggest a protective effect. The identification of specific subpopulations at risk for ALS may provide clues towards possible pathogenic mechanisms.
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C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: a genome-wide meta-analysis.
Ann. Neurol.
PUBLISHED: 06-10-2014
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Substantial clinical, pathological, and genetic overlap exists between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 inclusions have been found in both ALS and FTD cases (FTD-TDP). Recently, a repeat expansion in C9orf72 was identified as the causal variant in a proportion of ALS and FTD cases. We sought to identify additional evidence for a common genetic basis for the spectrum of ALS-FTD.
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The provision of assistive devices and home adaptations to patients with ALS in the Netherlands: patients' perspectives.
Amyotroph Lateral Scler Frontotemporal Degener
PUBLISHED: 06-05-2014
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The timely provision of assistive devices and home adaptations (ADHA) is crucial in the management of patients with amyotrophic lateral sclerosis (ALS) in order to maintain their independence and relieve their caregivers. Our objective was to study the experiences of patients with ALS during the process of procuring ADHA. We sent a cross-sectional questionnaire survey addressing issues concerning the application for and provision process of ADHA to 239 patients with ALS registered at one of the three tertiary academic diagnostic centres within the Netherlands ALS Centre. One hundred and fifty-nine (89%) of the 179 responding patients (response rate 75%) had experience with the procurement process and 93 (58%) of them indicated problems in obtaining ADHA. The most reported problems were delay (42%) and the authorities' lack of disease knowledge (24%). Patients viewed these issues as the most prominent requiring improvement. In conclusion, the main problems perceived by patients indicate that increasing awareness of ALS and promoting a proactive attitude among ALS care professionals towards the application for ADHA may contribute positively to the quality of ALS care.
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The verbal fluency index: Dutch normative data for cognitive testing in ALS.
Amyotroph Lateral Scler Frontotemporal Degener
PUBLISHED: 05-27-2014
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Executive dysfunction occurs in 30-50% of amyotrophic lateral sclerosis (ALS) patients and is most frequently assessed with the verbal fluency test. The verbal fluency index (VFI) has been developed to correct for slowness of speech in ALS, and reflects the average thinking time per word. However, its use as a marker of cognitive impairment is hindered by the absence of valid norm scores. Therefore, we provide normative data for the VFI.
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Euthanasia and physician-assisted suicide in amyotrophic lateral sclerosis: a prospective study.
J. Neurol.
PUBLISHED: 04-06-2014
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The objective of this study is to determine if quality of care, symptoms of depression, disease characteristics and quality of life of patients with amyotrophic lateral sclerosis (ALS) are related to requesting euthanasia or physician-assisted suicide (EAS) and dying due to EAS. Therefore, 102 ALS patients filled out structured questionnaires every 3 months until death and the results were correlated with EAS. Thirty-one percent of the patients requested EAS, 69 % of whom eventually died as a result of EAS (22 % of all patients). Ten percent died during continuous deep sedation; only one of them had explicitly requested death to be hastened. Of the patients who requested EAS, 86 % considered the health care to be good or excellent, 16 % felt depressed, 45 % experienced loss of dignity and 42 % feared choking. These percentages do not differ from the number of patients who did not explicitly request EAS. The frequency of consultations of professional caregivers and availability of appliances was similar in both groups. Our findings do not support continuous deep sedation being used as a substitute for EAS. In this prospective study, no evidence was found for a relation between EAS and the quality and quantity of care received, quality of life and symptoms of depression in patients with ALS. Our study does not support the notion that unmet palliative care needs are related to EAS.
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Analysis of the KIFAP3 gene in amyotrophic lateral sclerosis: a multicenter survival study.
Neurobiol. Aging
PUBLISHED: 03-08-2014
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Sporadic amyotrophic lateral sclerosis is a multifactorial disease of environmental and genetic origin. In a previous large multicenter genome wide study, common genetic variation in the Kinesin-Associated Protein 3 (KIFAP3) gene (rs1541160) was reported to have a significant effect on survival in amyotrophic lateral sclerosis patients. However, this could not be replicated in 3 smaller independent cohorts. We conducted a large multicenter multivariate survival analysis (n = 2362) on the effect of genetic variation in rs1541160. The previously reported beneficial genotype did not show a significant improvement in survival in this patient group.
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MMN: from immunological cross-talk to conduction block.
J. Clin. Immunol.
PUBLISHED: 03-07-2014
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Multifocal motor neuropathy (MMN) is a rare inflammatory neuropathy characterized by progressive, asymmetric distal limb weakness and conduction block (CB). Clinically MMN is a pure motor neuropathy, which as such can mimic motor neuron disease. GM1-specific IgM antibodies are present in the serum of approximately half of all MMN patients, and are thought to play a key role in the immune pathophysiology. Intravenous immunoglobulin (IVIg) treatment has been shown to be effective in MMN in five randomized placebo-controlled trials. Despite long-term treatment with intravenous immunoglobulin (IVIg), which is efficient in the majority of patients, slowly progressive axonal degeneration and subsequent muscle weakness cannot be fully prevented. In this review, we will discuss the current understanding of the immune pathogenesis underlying MMN and how this may cause CB, available treatment strategies and future therapeutic targets.
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Chronic idiopathic axonal polyneuropathy and vitamin B6: a controlled population-based study.
J. Peripher. Nerv. Syst.
PUBLISHED: 03-03-2014
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Vitamin B6 intoxication can result in a sensory ataxic neuropathy, but the association with a milder predominantly sensory or sensorimotor phenotype in chronic idiopathic axonal polyneuropathy (CIAP) remains unclear. A total of 381 patients with CIAP and 140 healthy controls were prospectively included. In a standardized fashion the use of vitamin B6 containing supplements and vitamin B6 levels were compared between patients and controls. On follow-up, patients were questioned about cessation of supplement use and the impact on the symptoms of polyneuropathy. Vitamin B6 levels in patients (median: 99?nmol/l, range: 38-2,967?nmol) were not significantly higher than in controls (median: 109?nmol/l, range: 41-2,373?nmol/l, p?=?0.58), nor were daily dose, cumulative dose or duration of supplement use. However, more patients (31%) than controls (22%) used vitamin B6 containing supplements (odds ratio [OR] 1.7, 95% confidence interval [CI] 1.0-2.7, p?=?0.032). Follow-up of patients confirming the cessation of supplements showed slow progression of symptoms in 64%, stabilization in 26%, and regression in 10%. On the basis of our prospective case-control study and review of the literature, an association between CIAP and vitamin B6 exposure or elevated vitamin B6 levels appears unlikely.
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Fc? receptor IIIA genotype is associated with rituximab response in antimyelin-associated glycoprotein neuropathy.
J. Neurol. Neurosurg. Psychiatr.
PUBLISHED: 01-31-2014
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Treatment with anti-B cell antibody rituximab may ameliorate the disease course in a subgroup of patients with polyneuropathy associated with IgM monoclonal gammopathy. Polymorphisms of leukocyte IgG receptors (Fc?R) that influence efficiency of antibody-dependent cell-mediated cytotoxicity determine rituximab efficacy in patients with lymphoma and autoimmune disease.
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Prevalence, specificity and functionality of anti-ganglioside antibodies in neuropathy associated with IgM monoclonal gammopathy.
J. Neuroimmunol.
PUBLISHED: 01-23-2014
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IgM antibodies against gangliosides and their complexes were studied in sera from 54 patients with polyneuropathy and IgM monoclonal gammopathy (IgM-PNP) without anti-MAG antibodies. Anti-ganglioside antibodies were found in 19 (35%) patients. Five (9%) patients had antibodies against ganglioside complexes. IgM antibodies against gangliosides activated complement in vitro. Light chain usage was restricted to kappa or lambda in most, but not all patients. In conclusion, anti-ganglioside antibodies in IgM-PNP are common, display pathogenic properties and do not always arise from a monoclonal B cell proliferation.
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Correlation between structural and functional connectivity impairment in amyotrophic lateral sclerosis.
Hum Brain Mapp
PUBLISHED: 01-21-2014
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterized by progressive loss of motor function. While the pathogenesis of ALS remains largely unknown, imaging studies of the brain should lead to more insight into structural and functional disease effects on the brain network, which may provide valuable information on the underlying disease process. This study investigates the correlation between changes in structural connectivity (SC) and functional connectivity (FC) of the brain network in ALS. Structural reconstructions of the brain network, derived from diffusion weighted imaging (DWI), were obtained from 64 patients and 27 healthy controls. Functional interactions between brain regions were derived from resting-state fMRI. Our results show that (i) the most structurally affected connections considerably overlap with the most functionally impaired connections, (ii) direct connections of the motor cortex are both structurally and functionally more affected than connections at greater topological distance from the motor cortex, and (iii) there is a strong positive correlation between changes in SC and FC averaged per brain region (r?=?0.44, P?
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No mutations in hnRNPA1 and hnRNPA2B1 in Dutch patients with amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy.
Neurobiol. Aging
PUBLISHED: 01-02-2014
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Inclusion body myopathy (IBM) associated with Paget disease of the bone, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), sometimes called IBMPFD/ALS or multi system proteinopathy, is a rare, autosomal dominant disorder characterized by progressive degeneration of muscle, brain, motor neurons, and bone with prominent TDP-43 pathology. Recently, 2 novel genes for multi system proteinopathy were discovered; heterogenous nuclear ribonucleoprotein (hnRNP) A1 and A2B1. Subsequently, a mutation in hnRNPA1 was also identified in a pedigree with autosomal dominant familial ALS. The genetic evidence for ALS and other neurodegenerative diseases is still insufficient. We therefore sequenced the prion-like domain of these genes in 135 familial ALS, 1084 sporadic ALS, 68 familial FTD, 74 sporadic FTD, and 31 sporadic IBM patients in a Dutch population. We did not identify any mutations in these genes in our cohorts. Mutations in hnRNPA1 and hnRNPA2B1 prove to be a rare cause of ALS, FTD, and IBM in the Netherlands.
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Pharmacokinetics of intravenous immunoglobulin in multifocal motor neuropathy.
J. Neurol. Neurosurg. Psychiatr.
PUBLISHED: 12-11-2013
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Multifocal motor neuropathy (MMN) is often responsive to treatment with intravenous immunoglobulin (IVIg), but the optimal dose and intervals of IVIg maintenance treatment have not been established. Increase in IgG concentration (?IgG) after IVIg infusion has recently been identified as determinant of outcome in Guillain-Barré syndrome. ?IgG may therefore represent a potentially useful biomarker to optimise IVIg dosing in patients with MMN.
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Multimodal tract-based analysis in ALS patients at 7T: A specific white matter profile?
Amyotroph Lateral Scler Frontotemporal Degener
PUBLISHED: 12-10-2013
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Our objective was to explore the value of additional MR contrasts in elucidating the decrease in fractional anisotropy (FA) as has been observed in the corticospinal tracts (CST) of patients with amyotrophic lateral sclerosis (ALS). Eleven patients and nine healthy control subjects were scanned at 3T and 7T MRI. Whole brain and tract specific comparison was performed of both diffusion weighted (3T), quantitative T1 (qT1), magnetization transfer ratio (MTR) and amide proton transfer weighted (APTw) imaging (7T). Results of whole brain comparison using histogram analyses showed no significant differences between patients and controls. Measures along the CST showed a significantly reduced FA together with a significantly increased diffusivity perpendicular to the tract direction in patients compared to controls. In addition, patients showed a small but significant increase in MTR values within the right CST. No significant changes were observed in qT1 and APTw values. In conclusion, our findings, based on a multimodal approach, revealed that the decrease in FA is most probably caused by an increased diffusivity perpendicular to the CST. This diffusivity profile, together with the increase in MTR is inconsistent with demyelination but consistent with an increase of free liquid spins in the white matter tissue.
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Cluster RCT of case management on patients quality of life and caregiver strain in ALS.
Neurology
PUBLISHED: 11-27-2013
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To study the effect of case management on quality of life, caregiver strain, and perceived quality of care (QOC) in patients with amyotrophic lateral sclerosis (ALS) and their caregivers.
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A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis.
Hum. Mol. Genet.
PUBLISHED: 11-20-2013
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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 3,959 newly genotyped Italian individuals (1,982 cases, 1,977 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 analyzed a total of 13,225 individuals, 6,100 cases and 7,125 controls for almost 7 million single nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 P=1.11 x 10(-8); OR 0.82) that was validated when combined with genotype data from a replication cohort (P=8.62 x 10(-9); OR 0.833) of 4,656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P=7.69 x 10(-9); OR 1.16). Finally, we have 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.
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No evidence for shared genetic basis of common variants in multiple sclerosis and amyotrophic lateral sclerosis.
Hum. Mol. Genet.
PUBLISHED: 11-13-2013
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Genome-wide association studies have been successful in identifying common variants that influence the susceptibility to complex diseases. From these studies, it has emerged that there is substantial overlap in susceptibility loci between diseases. In line with those findings, we hypothesized that shared genetic pathways may exist between multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). While both diseases may have inflammatory and neurodegenerative features, epidemiological studies have indicated an increased co-occurrence within individuals and families. To this purpose, we combined genome-wide data from 4088 MS patients, 3762 ALS patients and 12 030 healthy control individuals in whom 5 440 446 single-nucleotide polymorphisms (SNPs) were successfully genotyped or imputed. We tested these SNPs for the excess association shared between MS and ALS and also explored whether polygenic models of SNPs below genome-wide significance could explain some of the observed trait variance between diseases. Genome-wide association meta-analysis of SNPs as well as polygenic analyses fails to provide evidence in favor of an overlap in genetic susceptibility between MS and ALS. Hence, our findings do not support a shared genetic background of common risk variants in MS and ALS.
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Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial.
Lancet Neurol
PUBLISHED: 09-23-2013
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In a phase 2 study, dexpramipexole (25-150 mg twice daily) was well tolerated for up to 9 months and showed a significant benefit at the high dose in a combined assessment of function and mortality in patients with amyotrophic lateral sclerosis. We aimed to assess efficacy and safety of dexpramipexole in a phase 3 trial of patients with familial or sporadic disease.
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Systematic identification of trans eQTLs as putative drivers of known disease associations.
Nat. Genet.
PUBLISHED: 08-14-2013
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Identifying the downstream effects of disease-associated SNPs is challenging. To help overcome this problem, we performed expression quantitative trait locus (eQTL) meta-analysis in non-transformed peripheral blood samples from 5,311 individuals with replication in 2,775 individuals. We identified and replicated trans eQTLs for 233 SNPs (reflecting 103 independent loci) that were previously associated with complex traits at genome-wide significance. Some of these SNPs affect multiple genes in trans that are known to be altered in individuals with disease: rs4917014, previously associated with systemic lupus erythematosus (SLE), altered gene expression of C1QB and five type I interferon response genes, both hallmarks of SLE. DeepSAGE RNA sequencing showed that rs4917014 strongly alters the 3 UTR levels of IKZF1 in cis, and chromatin immunoprecipitation and sequencing analysis of the trans-regulated genes implicated IKZF1 as the causal gene. Variants associated with cholesterol metabolism and type 1 diabetes showed similar phenomena, indicating that large-scale eQTL mapping provides insight into the downstream effects of many trait-associated variants.
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Taking a risk: a therapeutic focus on ataxin-2 in amyotrophic lateral sclerosis?
Trends Mol Med
PUBLISHED: 07-15-2013
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by the loss of lower and upper motor neurons leading to progressive muscle weakness and respiratory insufficiency. No treatment is currently available to cure ALS. Recent progress has led to the identification of several novel genetic determinants of this disease, including repeat expansions in the ataxin-2 (ATXN2) gene. Ataxin-2 is mislocalized in ALS patients and represents a relatively common susceptibility gene in ALS, making it a promising therapeutic target. In this review, we summarize genetic and pathological data implicating ataxin-2 in ALS, discuss potential disease mechanisms linked to altered ataxin-2 localization or function, and propose potential strategies for therapeutic intervention in ALS based on ataxin-2.
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Association study of common genetic variants and HIV-1 acquisition in 6,300 infected cases and 7,200 controls.
PLoS Pathog.
PUBLISHED: 07-01-2013
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Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6 × 10(-11)). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5?32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size.
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DeepSAGE reveals genetic variants associated with alternative polyadenylation and expression of coding and non-coding transcripts.
PLoS Genet.
PUBLISHED: 06-01-2013
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Many disease-associated variants affect gene expression levels (expression quantitative trait loci, eQTLs) and expression profiling using next generation sequencing (NGS) technology is a powerful way to detect these eQTLs. We analyzed 94 total blood samples from healthy volunteers with DeepSAGE to gain specific insight into how genetic variants affect the expression of genes and lengths of 3-untranslated regions (3-UTRs). We detected previously unknown cis-eQTL effects for GWAS hits in disease- and physiology-associated traits. Apart from cis-eQTLs that are typically easily identifiable using microarrays or RNA-sequencing, DeepSAGE also revealed many cis-eQTLs for antisense and other non-coding transcripts, often in genomic regions containing retrotransposon-derived elements. We also identified and confirmed SNPs that affect the usage of alternative polyadenylation sites, thereby potentially influencing the stability of messenger RNAs (mRNA). We then combined the power of RNA-sequencing with DeepSAGE by performing a meta-analysis of three datasets, leading to the identification of many more cis-eQTLs. Our results indicate that DeepSAGE data is useful for eQTL mapping of known and unknown transcripts, and for identifying SNPs that affect alternative polyadenylation. Because of the inherent differences between DeepSAGE and RNA-sequencing, our complementary, integrative approach leads to greater insight into the molecular consequences of many disease-associated variants.
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Deciphering amyotrophic lateral sclerosis: what phenotype, neuropathology and genetics are telling us about pathogenesis.
Amyotroph Lateral Scler Frontotemporal Degener
PUBLISHED: 05-18-2013
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Amyotrophic lateral sclerosis (ALS) is characterized phenotypically by progressive weakness and neuropathologically by loss of motor neurons. Phenotypically, there is marked heterogeneity. Typical ALS has mixed upper motor neuron (UMN) and lower motor neuron (LMN) involvement. Primary lateral sclerosis has predominant UMN involvement. Progressive muscular atrophy has predominant LMN involvement. Bulbar and limb ALS have predominant regional involvement. Frontotemporal dementia has significant cognitive and behavioral involvement. These phenotypes can be so distinctive that they would seem to have differing biology. However, they cannot be distinguished, at least neuropathologically or genetically. In sporadic ALS (SALS), they are mostly characterized by ubiquitinated cytoplasmic inclusions of TDP-43. In familial ALS (FALS), where phenotypes are indistinguishable from SALS and similarly heterogeneous, each mutated gene has its own genetic and molecular signature. Overall, since the same phenotypes can have multiple causes including different gene mutations, there must be multiple molecular mechanisms causing ALS - and ALS is a syndrome. Since, however, multiple phenotypes can be caused by one single gene mutation, a single molecular mechanism can cause heterogeneity. What the mechanisms are remain unknown, but active propagation of the pathology neuroanatomically seems to be a principal component. Leading candidate mechanisms include RNA processing, cell-cell interactions between neurons and non-neuronal neighbors, focal seeding from a misfolded protein that has prion-like propagation, and fatal errors introduced during neurodevelopment of the motor system. If fundamental mechanisms could be identified and understood, ALS therapy could rationally target progression and stop the disease - a goal that seems increasingly achievable.
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ALS-associated mutations in FUS disrupt the axonal distribution and function of SMN.
Hum. Mol. Genet.
PUBLISHED: 05-15-2013
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Mutations in the RNA binding protein fused in sarcoma/translated in liposarcoma (FUS/TLS) cause amyotrophic lateral sclerosis (ALS). Although ALS-linked mutations in FUS often lead to a cytosolic mislocalization of the protein, the pathogenic mechanisms underlying these mutations remain poorly understood. To gain insight into these mechanisms, we examined the biochemical, cell biological and functional properties of mutant FUS in neurons. Expression of different FUS mutants (R521C, R521H, P525L) in neurons caused axonal defects. A protein interaction screen performed to explain these phenotypes identified numerous FUS interactors including the spinal muscular atrophy (SMA) causing protein survival motor neuron (SMN). Biochemical experiments showed that FUS and SMN interact directly and endogenously, and that this interaction can be regulated by FUS mutations. Immunostaining revealed co-localization of mutant FUS aggregates and SMN in primary neurons. This redistribution of SMN to cytosolic FUS accumulations led to a decrease in axonal SMN. Finally, cell biological experiments showed that overexpression of SMN rescued the axonal defects induced by mutant FUS, suggesting that FUS mutations cause axonal defects through SMN. This study shows that neuronal aggregates formed by mutant FUS protein may aberrantly sequester SMN and concomitantly cause a reduction of SMN levels in the axon, leading to axonal defects. These data provide a functional link between ALS-linked FUS mutations, SMN and neuronal connectivity and support the idea that different motor neuron disorders such as SMA and ALS may be caused, in part, by defects in shared molecular pathways.
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Genome-wide association analyses in Han Chinese identify two new susceptibility loci for amyotrophic lateral sclerosis.
Nat. Genet.
PUBLISHED: 04-05-2013
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To identify susceptibility genes for amyotrophic lateral sclerosis (ALS), we conducted a genome-wide association study (GWAS) in 506 individuals with sporadic ALS and 1,859 controls of Han Chinese ancestry. Ninety top SNPs suggested by the current GWAS and 6 SNPs identified by previous GWAS were analyzed in an independent cohort of 706 individuals with ALS and 1,777 controls of Han Chinese ancestry. We discovered two new susceptibility loci for ALS at 1q32 (CAMK1G, rs6703183, Pcombined = 2.92 × 10(-8), odds ratio (OR) = 1.31) and 22p11 (CABIN1 and SUSD2, rs8141797, Pcombined = 2.35 × 10(-9), OR = 1.52). These two loci explain 12.48% of the overall variance in disease risk in the Han Chinese population. We found no association evidence for the previously reported loci in the Han Chinese population, suggesting genetic heterogeneity of disease susceptibility for ALS between ancestry groups. Our study identifies two new susceptibility loci and suggests new pathogenic mechanisms of ALS.
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Protein aggregation in amyotrophic lateral sclerosis.
Acta Neuropathol.
PUBLISHED: 03-30-2013
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the aggregation of ubiquitinated proteins in affected motor neurons. Recent studies have identified several new molecular constituents of ALS-linked cellular aggregates, including FUS, TDP-43, OPTN, UBQLN2 and the translational product of intronic repeats in the gene C9ORF72. Mutations in the genes encoding these proteins are found in a subgroup of ALS patients and segregate with disease in familial cases, indicating a causal relationship with disease pathogenesis. Furthermore, these proteins are often detected in aggregates of non-mutation carriers and those observed in other neurodegenerative disorders, supporting a widespread role in neuronal degeneration. The molecular characteristics and distribution of different types of protein aggregates in ALS can be linked to specific genetic alterations and shows a remarkable overlap hinting at a convergence of underlying cellular processes and pathological effects. Thus far, self-aggregating properties of prion-like domains, altered RNA granule formation and dysfunction of the protein quality control system have been suggested to contribute to protein aggregation in ALS. The precise pathological effects of protein aggregation remain largely unknown, but experimental evidence hints at both gain- and loss-of-function mechanisms. Here, we discuss recent advances in our understanding of the molecular make-up, formation, and mechanism-of-action of protein aggregates in ALS. Further insight into protein aggregation will not only deepen our understanding of ALS pathogenesis but also may provide novel avenues for therapeutic intervention.
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Serum IgG levels in IV immunoglobulin treated chronic inflammatory demyelinating polyneuropathy.
J. Neurol. Neurosurg. Psychiatr.
PUBLISHED: 03-28-2013
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To determine the variability of serum IgG in patients with chronic inflammatory demyelinating polyneuropathy (CIDP).
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Characterization of FUS mutations in amyotrophic lateral sclerosis using RNA-Seq.
PLoS ONE
PUBLISHED: 03-02-2013
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting in severe muscle weakness and eventual death by respiratory failure. Although little is known about its pathogenesis, mutations in fused in sarcoma/translated in liposarcoma (FUS) are causative for familial ALS. FUS is a multifunctional protein that is involved in many aspects of RNA processing. To elucidate the role of FUS in ALS, we overexpressed wild-type and two mutant forms of FUS in HEK-293T cells, as well as knocked-down FUS expression. This was followed by RNA-Seq to identify genes which displayed differential expression or altered splicing patterns. Pathway analysis revealed that overexpression of wild-type FUS regulates ribosomal genes, whereas knock-down of FUS additionally affects expression of spliceosome related genes. Furthermore, cells expressing mutant FUS displayed global transcription patterns more similar to cells overexpressing wild-type FUS than to the knock-down condition. This observation suggests that FUS mutants do not contribute to the pathogenesis of ALS through a loss-of-function. Finally, our results demonstrate that the R521G and R522G mutations display differences in their influence on transcription and splicing. Taken together, these results provide additional insights into the function of FUS and how mutations contribute to the development of ALS.
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Structural brain network imaging shows expanding disconnection of the motor system in amyotrophic lateral sclerosis.
Hum Brain Mapp
PUBLISHED: 03-01-2013
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Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease, which primarily targets the motor system. The structural integrity of the motor network and the way it is embedded in the overall brain network is essential for motor functioning. We studied the longitudinal effects of ALS on the brain network using diffusion tensor imaging and questioned whether over time an increasing number of connections become involved or whether there is progressive impairment of a limited number of connections. The brain network was reconstructed based on "whole brain" diffusion tensor imaging data. We examined: (1) network integrity in 24 patients with ALS at baseline (T = 1) and at a more advanced stage of the disease (T = 2; interval 5.5 months) compared with a group of healthy controls and (2) progressive brain network impairment comparing patients at two time-points in a paired-analysis. These analyses demonstrated an expanding subnetwork of affected brain connections over time with a central role for the primary motor regions (P-values T = 1 0.003; T = 2 0.001). Loss of structural connectivity mainly propagated to frontal and parietal brain regions at T = 2 compared with T = 1. No progressive impairment of the initially affected (motor) connections could be detected. The main finding of this study is an increasing loss of network structure in patients with ALS. In contrast to the theory of ALS solely affecting a fixed set of primary motor connections, our findings show that the network of impaired connectivity is expanding over time. These results are in support of disease spread along structural brain connections. Hum Brain Mapp, 2013. © 2013 Wiley-Periodicals, Inc.
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Controversies and priorities in amyotrophic lateral sclerosis.
Lancet Neurol
PUBLISHED: 02-19-2013
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Two decades after the discovery that 20% of familial amyotrophic lateral sclerosis (ALS) cases were linked to mutations in the superoxide dismutase-1 (SOD1) gene, a substantial proportion of the remainder of cases of familial ALS have now been traced to an expansion of the intronic hexanucleotide repeat sequence in C9orf72. This breakthrough provides an opportunity to re-evaluate longstanding concepts regarding the cause and natural history of ALS, coming soon after the pathological unification of ALS with frontotemporal dementia through a shared pathological signature of cytoplasmic inclusions of the ubiquitinated protein TDP-43. However, with profound clinical, prognostic, neuropathological, and now genetic heterogeneity, the concept of ALS as one disease appears increasingly untenable. This background calls for the development of a more sophisticated taxonomy, and an appreciation of ALS as the breakdown of a wider network rather than a discrete vulnerable population of specialised motor neurons. Identification of C9orf72 repeat expansions in patients without a family history of ALS challenges the traditional division between familial and sporadic disease. By contrast, the 90% of apparently sporadic cases and incomplete penetrance of several genes linked to familial cases suggest that at least some forms of ALS arise from the interplay of multiple genes, poorly understood developmental, environmental, and age-related factors, as well as stochastic events.
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Lifetime physical activity and the risk of amyotrophic lateral sclerosis.
J. Neurol. Neurosurg. Psychiatr.
PUBLISHED: 02-16-2013
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It has been hypothesised that physical activity is a risk factor for developing amyotrophic lateral sclerosis (ALS), fuelled by observations that professional soccer players and Gulf War veterans are at increased risk. In a population based study, we determined the relation between physical activity and risk of sporadic ALS, using an objective approach for assessing physical activity.
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The Combined Assessment of Function and Survival (CAFS): a new endpoint for ALS clinical trials.
Amyotroph Lateral Scler Frontotemporal Degener
PUBLISHED: 01-17-2013
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Our objective was to describe a new endpoint for amyotrophic lateral sclerosis (ALS), the Combined Assessment of Function and Survival (CAFS). CAFS ranks patients clinical outcomes based on survival time and change in the ALS Functional Rating Scale-Revised (ALSFRS-R) score. Each patients outcome is compared to every other patients outcome, assigned a score, and the summed scores are ranked. The mean rank score for each treatment group can then be calculated. A higher mean CAFS score indicates a better group outcome. Historically, ALS clinical trials have assessed survival and function as independent endpoints. Combined endpoints have been used in other diseases to decrease the confounding effect of mortality on analysis of functional outcomes. We explored the application of a similar approach in ALS, the CAFS endpoint, which was used as a pre-specified secondary analysis in a phase II study of dexpramipexole. Those results and some hypothetical examples based on modeling exercises are presented here. CAFS is the primary endpoint of a dexpramipexole phase III study in ALS. In conclusion, the CAFS is a robust statistical tool for ALS clinical trials and appropriately accounts for and weights mortality in the analysis of function.
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Increased paternal age and the influence on burden of genomic copy number variation in the general population.
Hum. Genet.
PUBLISHED: 01-13-2013
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Genomic copy number variations (CNVs) and increased parental age are both associated with the risk to develop a variety of clinical neuropsychiatric disorders such as autism, schizophrenia and bipolar disorder. At the same time, it has been shown that the rate of transmitted de novo single nucleotide mutations is increased with paternal age. To address whether paternal age also affects the burden of structural genomic deletions and duplications, we examined various types of CNV burden in a large population sample from the Netherlands. Healthy participants with parental age information (n = 6,773) were collected at different University Medical Centers. CNVs were called with the PennCNV algorithm using Illumina genome-wide SNP array data. We observed no evidence in support of a paternal age effect on CNV load in the offspring. Our results were negative for global measures as well as several proxies for de novo CNV events in this unique sample. While recent studies suggest de novo single nucleotide mutation rate to be dominated by the age of the father at conception, our results strongly suggest that at the level of global CNV burden there is no influence of increased paternal age. While it remains possible that local genomic effects may exist for specific phenotypes, this study indicates that global CNV burden and increased fathers age may be independent disease risk factors.
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Gene expression profile of SOD1-G93A mouse spinal cord, blood and muscle.
Amyotroph Lateral Scler Frontotemporal Degener
PUBLISHED: 01-08-2013
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The exact pathway leading to neuron death and muscle atrophy in amyotrophic lateral sclerosis (ALS) has not yet been elucidated. Gene expression profile of spinal cord, blood and muscle could provide signalling pathways and systemic alterations useful for future biomarker development. In our study we compared whole genome expression profiles of lumbar spinal cord with peripheral blood and tibialis anterior muscle in 16 mutant SOD1-G93A mice and 15 wild-type littermates. In SOD1-G93A mice, 11 genes were significantly differentially expressed in spinal cord, and 16 genes in blood, while much larger transcriptional changes were noted in muscle (1745 genes significant; six overlapping with spinal cord (0.3%)) probably due to muscle atrophy. Overlap with spinal cord was enriched for significant genes in blood (six of 16 overlapping with spinal cord (37.5%)). Three genes were significantly down-regulated in all three tissues, and were closely related to mitochondrial function. Furthermore, clustering the significant genes in spinal cord and in blood, but not in muscle, could identify the SOD1-G93A mice. We conclude that blood gene expression profile overlapped with profile of spinal cord, allowing differentiation of SOD1-G93A mice from wild-type littermates. Blood gene expression profiling may be a promising biomarker for ALS patients.
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Meta-analysis of gene expression profiling in amyotrophic lateral sclerosis: a comparison between transgenic mouse models and human patients.
Amyotroph Lateral Scler Frontotemporal Degener
PUBLISHED: 01-04-2013
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The exact pathogenic cascade leading to motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is unknown. Gene expression profiles of ALS-affected spinal cord and motor neurons have been well established in mice and man. We provide a meta-analysis of the reported significant gene lists of gene expression studies in ALS, and compare results between mouse models and human post mortem tissue. In total, 12 articles met inclusion criteria. Twenty-nine genes were found to be differentially expressed at least twice in studies using human post mortem tissue, enriched for the functions immune response, apoptosis and protein metabolism. In mouse studies, 86 genes were reported at least two times and were enriched for immune response, lysosome, metal ion binding and mitochondrion. Next, all differentially expressed genes from the mouse studies were translated to human homologous genes. Seventy-four differentially expressed genes in mouse tissue were also found to be differentially expressed in human tissue. In conclusion, evidence was found for shared dysfunction in protein turnover in the ubiquitin-proteasome system. Differential expression of Cathepsin B and D, GFAP and SERPINA3 was repeatedly found to be significant in both the mouse model and ALS patients.
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Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis.
Ann. Neurol.
PUBLISHED: 12-23-2011
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Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both ALS and PD.
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Modifying the Medical Research Council grading system through Rasch analyses.
Brain
PUBLISHED: 12-20-2011
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The Medical Research Council grading system has served through decades for the evaluation of muscle strength and has been recognized as a cardinal feature of daily neurological, rehabilitation and general medicine examination of patients, despite being respectfully criticized due to the unequal width of its response options. No study has systematically examined, through modern psychometric approach, whether physicians are able to properly use the Medical Research Council grades. The objectives of this study were: (i) to investigate physicians ability to discriminate among the Medical Research Council categories in patients with different neuromuscular disorders and with various degrees of weakness through thresholds examination using Rasch analysis as a modern psychometric method; (ii) to examine possible factors influencing physicians ability to apply the Medical Research Council categories through differential item function analyses; and (iii) to examine whether the widely used Medical Research Council 12 muscles sum score in patients with Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy would meet Rasch models expectations. A total of 1065 patients were included from nine cohorts with the following diseases: Guillain-Barré syndrome (n?=?480); myotonic dystrophy type-1 (n?=?169); chronic inflammatory demyelinating polyradiculoneuropathy (n?=?139); limb-girdle muscular dystrophy (n?=?105); multifocal motor neuropathy (n?=?102); Pompes disease (n?=?62) and monoclonal gammopathy of undetermined related polyneuropathy (n?=?8). Medical Research Council data of 72 muscles were collected. Rasch analyses were performed on Medical Research Council data for each cohort separately and after pooling data at the muscle level to increase category frequencies, and on the Medical Research Council sum score in patients with Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy. Disordered thresholds were demonstrated in 74-79% of the muscles examined, indicating physicians inability to discriminate between most Medical Research Council categories. Factors such as physicians experience or illness type did not influence these findings. Thresholds were restored after rescoring the Medical Research Council grades from six to four options (0, paralysis; 1, severe weakness; 2, slight weakness; 3, normal strength). The Medical Research Council sum score acceptably fulfilled Rasch model expectations after rescoring the response options and creating subsets to resolve local dependency and item bias on diagnosis. In conclusion, a modified, Rasch-built four response category Medical Research Council grading system is proposed, resolving clinicians inability to differentiate among its original response categories and improving clinical applicability. A modified Medical Research Council sum score at the interval level is presented and is recommended for future studies in Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy.
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Drug treatment for spinal muscular atrophy types II and III.
Cochrane Database Syst Rev
PUBLISHED: 12-14-2011
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Spinal muscular atrophy (SMA) is caused by degeneration of anterior horn cells, which leads to progressive muscle weakness. Children with SMA type II do not develop the ability to walk without support and have a shortened life expectancy, whereas children with SMA type III develop the ability to walk and have a normal life expectancy. There are no known efficacious drug treatments that influence the disease course of SMA. This is an update of a review first published in 2009.
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Drug treatment for spinal muscular atrophy type I.
Cochrane Database Syst Rev
PUBLISHED: 12-14-2011
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Spinal muscular atrophy (SMA) is caused by degeneration of anterior horn cells of the spinal cord, which leads to progressive muscle weakness. Children with SMA type I will never be able to sit without support and usually die by the age of two years. There are no known efficacious drug treatments that influence the course of the disease. This is an update of a review first published in 2009.
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Palliative care in amyotrophic lateral sclerosis: a review of current international guidelines and initiatives.
BMJ Support Palliat Care
PUBLISHED: 12-01-2011
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Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative condition. Optimal management requires a palliative approach from diagnosis with emphasis on patient autonomy, dignity and quality of life.
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Multifocal motor neuropathy: diagnosis, pathogenesis and treatment strategies.
Nat Rev Neurol
PUBLISHED: 11-22-2011
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Multifocal motor neuropathy (MMN) is a rare inflammatory neuropathy characterized by slowly progressive, asymmetric distal limb weakness without sensory loss. The clinical presentation of MMN may mimic amyotrophic lateral sclerosis, other variants of motor neuron disease, or chronic inflammatory demyelinating polyneuropathy with asymmetric onset. Differentiation is important, as these diseases differ in prognosis and treatment. The electrophysiological finding of conduction block in the absence of abnormalities in sensory nerves is the hallmark of MMN, but can be difficult to detect. Intravenous immunoglobulin is efficacious in most patients, but long-term maintenance therapy does not prevent slowly progressive axonal degeneration. Moreover, cyclophosphamide, although effective, has substantial adverse effects, and the efficacy of other immunosuppressive drugs, including rituximab, is not established. The underlying pathological mechanisms of MMN are unclear, but IgM autoantibodies against the ganglioside GM1 may cause changes in nodal and perinodal structures that compromise nerve conduction. Further elucidation of the disease mechanisms may ultimately lead to improved treatment strategies. In this Review, we discuss the diagnostic criteria for MMN, and provide an update on the current understanding of MMN pathogenesis. We also describe available treatments and promising new therapeutic strategies.
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Multifocal motor neuropathy is not associated with genetic variation in PTPN22, BANK1, Blk, FCGR2B, CD1A/E, and TAG-1 genes.
J. Peripher. Nerv. Syst.
PUBLISHED: 10-19-2011
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The contribution of genetic heterogeneity to the pathogenesis of multifocal motor neuropathy (MMN) has not been elucidated. We investigated frequencies of single nucleotide polymorphisms (SNPs) in the candidate genes protein tyrosine phosphatase, non-receptor type 22 (PTPN22), B-cell scaffold protein with ankyrin repeats (BANK1), B lymphocyte kinase (Blk), and Fc gamma receptor class IIB (FCGR2B), which have been found to be associated with other autoimmune diseases, CD1A and CD1E, important for antigen presentation of glycolipids, and transient axonal glycoprotein 1 (TAG-1), which is associated with responsiveness to intravenous immunoglobulin in patients with chronic inflammatory demyelinating polyneuropathy. SNP frequencies were determined by means of TaqMan SNP genotyping assay and direct sequencing of candidate genes in 92 Dutch patients with MMN and 1152 healthy controls. SNP frequencies did not differ between patients and controls (all p-values >0.15) and disease characteristics were not associated with SNP genotypes. Our results suggest that allelic variation in these genes does not play a major role in determining MMN susceptibility.
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Clinical diagnosis and management of amyotrophic lateral sclerosis.
Nat Rev Neurol
PUBLISHED: 10-11-2011
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results in progressive loss of bulbar and limb function. Patients typically die from respiratory failure within 3 years of symptom onset. The incidence of ALS in Europe is 2-3 cases per 100,000 individuals in the general population, and the overall lifetime risk of developing the disease is 1:400. ALS is familial in 5% of cases, and shows a Mendelian pattern of inheritance. ALS is recognized to overlap with frontotemporal dementia. Diagnosis is made on clinical grounds, using internationally recognized consensus criteria, after exclusion of conditions that can mimic ALS. The Revised ALS Functional Rating Scale is currently the most widely used assessment tool; scores are used to predict survival, and have been employed extensively in clinical trials. Riluzole remains the only effective drug, and extends the average survival of patients by 3-6 months. Optimal treatment is based on symptom management and preservation of quality of life, provided in a multidisciplinary setting. The discovery of further effective disease-modifying therapies remains a critical need for patients with this devastating condition.
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Structural MRI reveals cortical thinning in amyotrophic lateral sclerosis.
J. Neurol. Neurosurg. Psychiatr.
PUBLISHED: 09-29-2011
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Amyotrophic lateral sclerosis (ALS) is a fatal disease characterised by combined upper and lower motor neuron degeneration. An early and accurate diagnosis is important for patient care and might facilitate the search for a more effective therapy. MRI was used to study the whole cortical mantle, applying an unbiased surface based approach to identify a marker of upper motor neuron involvement in ALS.
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Associated autoimmune diseases in patients with multifocal motor neuropathy and their family members.
J. Neurol.
PUBLISHED: 09-07-2011
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Multifocal motor neuropathy (MMN) is a rare immune-mediated disorder and is characterized by male predominance, the presence of serum anti-GM1 IgM antibodies in up to half of all patients, responsiveness to intravenous immunoglobulins (IVIg) and an increased frequency of HLA type HLA-DRB1*15. The aim of this study was to assess whether the frequency of autoimmune diseases (AID) is increased in patients with MMN and their first-degree family members, since this would indicate that MMN shares pathogenic mechanisms with other AID. We conducted a case-control study using questionnaires to evaluate the prevalence of AID in MMN and controls, and their first-degree relatives. Questionnaires from 81 MMN patients (417 first-degree relatives) and 438 controls (2,377 first-degree relatives) were analyzed. Overall prevalence of AID was higher in MMN patients (11%) than in controls (5%) (OR 2.4, 95% CI 1.1-5.5, p = 0.037). Type 1 diabetes, Hashimotos thyroid disease, and celiac disease were significantly more prevalent in family members of patients than controls. The presence of an additional AID was not associated with age at MMN onset, disease duration, titer of serum anti-GM1 IgM antibodies or HLA type HLA-DRB1*15. The higher frequency of AID in patients with MMN indicates a common autoimmune diathesis.
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VCP mutations in familial and sporadic amyotrophic lateral sclerosis.
Neurobiol. Aging
PUBLISHED: 08-30-2011
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Mutations in the valosin-containing protein (VCP) gene were recently reported to be the cause of 1%-2% of familial amyotrophic lateral sclerosis (ALS) cases. VCP mutations are known to cause inclusion body myopathy (IBM) with Pagets disease (PDB) and frontotemporal dementia (FTD). The presence of VCP mutations in patients with sporadic ALS, sporadic ALS-FTD, and progressive muscular atrophy (PMA), a known clinical mimic of inclusion body myopathy, is not known. To determine the identity and frequency of VCP mutations we screened a cohort of 93 familial ALS, 754 sporadic ALS, 58 sporadic ALS-FTD, and 264 progressive muscular atrophy patients for mutations in the VCP gene. Two nonsynonymous mutations were detected; 1 known mutation (p.R159H) in a patient with familial ALS with several family members suffering from FTD, and 1 mutation (p.I114V) in a patient with sporadic ALS. Conservation analysis and protein prediction software indicate the p.I114V mutation to be a rare benign polymorphism. VCP mutations are a rare cause of familial ALS. The role of VCP mutations in sporadic ALS, if present, appears limited.
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Common variants at VRK2 and TCF4 conferring risk of schizophrenia.
Hum. Mol. Genet.
PUBLISHED: 07-26-2011
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Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.09, P = 1.9 × 10(-9)] and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 × 10(-9)).
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European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene.
Hum. Mol. Genet.
PUBLISHED: 07-12-2011
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Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 × 10(-11). SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidneys ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the urogenous contact hypothesis that urine production and voiding frequency modify the risk of UBC.
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UNC13A is a modifier of survival in amyotrophic lateral sclerosis.
Neurobiol. Aging
PUBLISHED: 07-05-2011
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A large genome-wide screen in patients with sporadic amyotrophic lateral sclerosis (ALS) showed that the common variant rs12608932 in gene UNC13A was associated with disease susceptibility. UNC13A regulates the release of neurotransmitters, including glutamate. Genetic risk factors that, in addition, modify survival, provide promising therapeutic targets in ALS, a disease whose etiology remains largely elusive. We examined whether UNC13A was associated with survival of ALS patients in a cohort of 450 sporadic ALS patients and 524 unaffected controls from a population-based study of ALS in The Netherlands. Additionally, survival data were collected from individuals of Dutch, Belgian, or Swedish descent (1767 cases, 1817 controls) who had participated in a previously published genome-wide association study of ALS. We related survival to rs12608932 genotype. In both cohorts, the minor allele of rs12608932 in UNC13A was not only associated with susceptibility but also with shorter survival of ALS patients. Our results further corroborate the role of UNC13A in ALS pathogenesis.
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Impaired structural motor connectome in amyotrophic lateral sclerosis.
PLoS ONE
PUBLISHED: 06-25-2011
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Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease selectively affecting upper and lower motor neurons. Patients with ALS suffer from progressive paralysis and eventually die on average after three years. The underlying neurobiology of upper motor neuron degeneration and its effects on the complex network of the brain are, however, largely unknown. Here, we examined the effects of ALS on the structural brain network topology in 35 patients with ALS and 19 healthy controls. Using diffusion tensor imaging (DTI), the brain network was reconstructed for each individual participant. The connectivity of this reconstructed brain network was compared between patients and controls using complexity theory without--a priori selected--regions of interest. Patients with ALS showed an impaired sub-network of regions with reduced white matter connectivity (p?=?0.0108, permutation testing). This impaired sub-network was strongly centered around primary motor regions (bilateral precentral gyrus and right paracentral lobule), including secondary motor regions (bilateral caudal middle frontal gyrus and pallidum) as well as high-order hub regions (right posterior cingulate and precuneus). In addition, we found a significant reduction in overall efficiency (p?=?0.0095) and clustering (p?=?0.0415). From our findings, we conclude that upper motor neuron degeneration in ALS affects both primary motor connections as well as secondary motor connections, together composing an impaired sub-network. The degenerative process in ALS was found to be widespread, but interlinked and targeted to the motor connectome.
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Symptoms of activity-induced weakness in peripheral nervous system disorders.
J. Peripher. Nerv. Syst.
PUBLISHED: 06-23-2011
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Activity-induced weakness was reported in multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyneuropathy (CIDP). This was attributed to activity-dependent conduction block (CB) arising in demyelinated axons. It is not known if activity-induced weakness is common, nor if it is specific for MMN and CIDP. We, therefore, carried out an investigation by questionnaire in 64 MMN patients, 52 CIDP patients, 48 progressive spinal muscular atrophy (PSMA) patients, and 30 normal subjects. Subjects were asked if they experienced an increase in weakness when performing 10 common tasks. The percentage of tasks causing activity-induced weakness was higher in the patient groups than in the normal subjects (p < 0.001). The risk of activity-induced weakness exceeding that in normal subjects was sixfold higher for each patient group when adjusted for sex, age, and a fatigue score. With further adjustment for scores of weakness and axon loss, no significant differences were found between the patient groups. In conclusion, activity-induced weakness is frequently reported in MMN and CIDP. It is, however, not specific for these neuropathies as PSMA patients reported it to the same extent.
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Population based epidemiology of amyotrophic lateral sclerosis using capture-recapture methodology.
J. Neurol. Neurosurg. Psychiatr.
PUBLISHED: 05-27-2011
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Variation in the incidence rate in epidemiological studies on amyotrophic lateral sclerosis (ALS) may be due to a small population size and under ascertainment of patients. The previously reported incidence decline in the elderly and a decrease in the male:female ratio in postmenopausal age groups have yet to be confirmed.
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Effects of aerobic exercise therapy and cognitive behavioural therapy on functioning and quality of life in amyotrophic lateral sclerosis: protocol of the FACTS-2-ALS trial.
BMC Neurol
PUBLISHED: 05-03-2011
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Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder affecting motor neurons in the spinal cord, brainstem and motor cortex, leading to muscle weakness. Muscle weakness may result in the avoidance of physical activity, which exacerbates disuse weakness and cardiovascular deconditioning. The impact of the grave prognosis may result in depressive symptoms and hopelessness. Since there is no cure for ALS, optimal treatment is based on symptom management and preservation of quality of life (QoL), provided in a multidisciplinary setting. Two distinctly different therapeutic interventions may be effective to improve or preserve daily functioning and QoL at the highest achievable level: aerobic exercise therapy (AET) to maintain or enhance functional capacity and cognitive behavioural therapy (CBT) to improve coping style and cognitions in patients with ALS. However, evidence to support either approach is still insufficient, and the underlying mechanisms of the approaches remain poorly understood. The primary aim of the FACTS-2-ALS trial is to study the effects of AET and CBT, in addition to usual care, compared to usual care alone, on functioning and QoL in patients with ALS.
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Novel optineurin mutations in sporadic amyotrophic lateral sclerosis patients.
Neurobiol. Aging
PUBLISHED: 03-23-2011
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Optineurin (OPTN) mutations have been reported in a cohort of Japanese patients with familial (FALS) and sporadic (SALS) amyotrophic lateral sclerosis. In Caucasian patients, OPTN mutations have been identified in FALS patients, but were not detected in a cohort of 95 SALS patients. Moreover, single nucleotide polymorphisms (SNPs) in OPTN that could raise amyotrophic lateral sclerosis (ALS) susceptibility have not been investigated. Therefore, we screened a large Dutch cohort of 1191 patients with SALS, 94 patients with FALS, and 1415 control subjects for mutations and SNPs in OPTN. We identified 1 novel nonsense mutation (Q165X) and 1 unreported missense mutation (Q454E) in individual SALS patients. These patients demonstrated rapid disease progression with an average survival of 24.5 months. No heterozygous or homozygous OPTN mutations were identified in our cohort of FALS patients. SNP analysis did not reveal significant differences between ALS patients and control subjects. Therefore, variations in OPTN appear to be a rare cause of rapidly progressive SALS in the Netherlands.
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Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2, REL, and CARD9.
Hepatology
PUBLISHED: 03-09-2011
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Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts. Both environmental and genetic factors contribute to its pathogenesis. To further clarify its genetic background, we investigated susceptibility loci recently identified for ulcerative colitis (UC) in a large cohort of 1,186 PSC patients and 1,748 controls. Single nucleotide polymorphisms (SNPs) tagging 13 UC susceptibility loci were initially genotyped in 854 PSC patients and 1,491 controls from Benelux (331 cases, 735 controls), Germany (265 cases, 368 controls), and Scandinavia (258 cases, 388 controls). Subsequently, a joint analysis was performed with an independent second Scandinavian cohort (332 cases, 257 controls). SNPs at chromosomes 2p16 (P-value 4.12 × 10(-4) ), 4q27 (P-value 4.10 × 10(-5) ), and 9q34 (P-value 8.41 × 10(-4) ) were associated with PSC in the joint analysis after correcting for multiple testing. In PSC patients without inflammatory bowel disease (IBD), SNPs at 4q27 and 9q34 were nominally associated (P < 0.05). We applied additional in silico analyses to identify likely candidate genes at PSC susceptibility loci. To identify nonrandom, evidence-based links we used GRAIL (Gene Relationships Across Implicated Loci) analysis showing interconnectivity between genes in six out of in total nine PSC-associated regions. Expression quantitative trait analysis from 1,469 Dutch and UK individuals demonstrated that five out of nine SNPs had an effect on cis-gene expression. These analyses prioritized IL2, CARD9, and REL as novel candidates.
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Upper and extra-motoneuron involvement in early motoneuron disease: a diffusion tensor imaging study.
Brain
PUBLISHED: 02-28-2011
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Motoneuron disease is a term encompassing three phenotypes defined largely by the balance of upper versus lower motoneuron involvement, namely amyotrophic lateral sclerosis, primary lateral sclerosis and progressive muscular atrophy. However, neuroradiological and pathological findings in these phenotypes suggest that degeneration may exceed the neuronal system upon which clinical diagnosis is based. To further delineate the phenotypes within the motoneuron disease spectrum, this controlled study assessed the upper- and extra-motoneuron white matter involvement in cohorts of patients with motoneuron disease phenotypes shortly after diagnosis by comparing diffusion tensor imaging data of the different cohorts to those of healthy controls and directly between the motoneuron disease phenotypes (n?=?12 for each cohort). Furthermore, we acquired follow-up data 6 months later to evaluate fractional anisotropy changes over time. Combined use of diffusion tensor tractography of the corticospinal tract and whole-brain voxel-based analysis allowed for comparison of the sensitivity of these techniques to detect white matter involvement in motoneuron disease. The voxel-based analysis demonstrated varying extents of white matter involvement in different phenotypes of motoneuron disease, albeit in quite similar anatomical locations. In general, fractional anisotropy reductions were modest in progressive muscular atrophy and most extensive in primary lateral sclerosis. The most extensive patterns of fractional anisotropy reduction were observed over time in the voxel-based analysis, indicating progressive extra-motor white matter degeneration in limb- and bulbar onset amyotrophic lateral sclerosis and in progressive muscular atrophy. The observation of both upper motor and extra-motoneuron involvement in all phenotypes of motoneuron disease shortly after diagnosis suggests that these are all part of a single spectrum of multisystem neurodegenerative disease. Voxel-based analysis was more sensitive to detect longitudinal changes than diffusion tensor tractography of the corticospinal tract. Voxel-based analyses may be particularly valuable in the evaluation of motor and extra-motor white matter involvement in the early symptomatic stages of motoneuron disease, and for monitoring the spread of pathology over time.
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Trans-eQTLs reveal that independent genetic variants associated with a complex phenotype converge on intermediate genes, with a major role for the HLA.
PLoS Genet.
PUBLISHED: 02-24-2011
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For many complex traits, genetic variants have been found associated. However, it is still mostly unclear through which downstream mechanism these variants cause these phenotypes. Knowledge of these intermediate steps is crucial to understand pathogenesis, while also providing leads for potential pharmacological intervention. Here we relied upon natural human genetic variation to identify effects of these variants on trans-gene expression (expression quantitative trait locus mapping, eQTL) in whole peripheral blood from 1,469 unrelated individuals. We looked at 1,167 published trait- or disease-associated SNPs and observed trans-eQTL effects on 113 different genes, of which we replicated 46 in monocytes of 1,490 different individuals and 18 in a smaller dataset that comprised subcutaneous adipose, visceral adipose, liver tissue, and muscle tissue. HLA single-nucleotide polymorphisms (SNPs) were 10-fold enriched for trans-eQTLs: 48% of the trans-acting SNPs map within the HLA, including ulcerative colitis susceptibility variants that affect plausible candidate genes AOAH and TRBV18 in trans. We identified 18 pairs of unlinked SNPs associated with the same phenotype and affecting expression of the same trans-gene (21 times more than expected, P<10(-16)). This was particularly pronounced for mean platelet volume (MPV): Two independent SNPs significantly affect the well-known blood coagulation genes GP9 and F13A1 but also C19orf33, SAMD14, VCL, and GNG11. Several of these SNPs have a substantially higher effect on the downstream trans-genes than on the eventual phenotypes, supporting the concept that the effects of these SNPs on expression seems to be much less multifactorial. Therefore, these trans-eQTLs could well represent some of the intermediate genes that connect genetic variants with their eventual complex phenotypic outcomes.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.