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    ABSTRACT: The problem of distinguishing causes from effects is not a trivial one, as illustrated by the science fiction writer Isaac Asimov in a novel dedicated to an imaginary compound with surprising "chronochemistry" properties. The problem is particularly important when trying to establish the etiology of diseases. Here, we discuss how the problem reflects on our understanding of disease using two specific examples: Alzheimer's disease (AD) and Friedreich's ataxia (FRDA). We show how the fibrillar aggregates observed in AD were first denied any interest, then to assume a central focus, and to finally recess to be considered the dead-end point of the aggregation pathway. This current view is that the soluble aggregates formed along the aggregation pathway rather than the mature amyliod fiber are the causes of disease, Similarly, we illustrate how the identification of causes and and effects have been important in the study of FRDA. This disease has alternatively been considered as the consequence of oxidative stress, iron precipitation or reduction of iron-sulfur cluster protein context. We illustrate how new tools have recently been established which allow us to follow the development of the disease. We hope that this review may inspire similar studies in other scientific disciplines.
    Frontiers in Molecular Neuroscience 03/2014; 7:20. DOI:10.3389/fnmol.2014.00020
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    ABSTRACT: Migraine headaches are a common comorbidity in Rolandic Epilepsy (RE) and familial aggregation of migraine in RE families suggests a genetic basis not mediated by seizures. We performed a genome-wide linkage analysis of the migraine phenotype in 38 families with RE to localize potential genetic contribution, with a follow-up in an additional 21 families at linked loci. We used two-point and multipoint LOD (logarithm of the odds) score methods for linkage, maximized over genetic models. We found evidence of linkage to migraine at chromosome 17q12-22 (multipoint HLOD 4.40 (heterogeneity LOD), recessive, 99% penetrance), replicated in the second dataset (HLOD 2.61); and suggestive evidence at 1q23.1-23.2, centering over the FHM2 locus (2PT LOD 3.00, MP HLOD 2.52). Sanger sequencing in 14 migraine-affected individuals found no coding mutations in the FHM2 gene ATP1A2. There was no evidence of pleiotropy for migraine and either reading or speech disorder, or the electroencephalographic endophenotype of RE when the affected definition was redefined as those with migraine or the comorbid phenotype, and pedigrees re-analyzed for linkage.
    Genes Brain and Behavior 11/2013; DOI:10.1111/gbb.12110
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    ABSTRACT: The GGGGCC (G4C2) intronic repeat expansion within C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Intranuclear neuronal RNA foci have been observed in ALS and FTD tissues, suggesting that G4C2 RNA may be toxic. Here, we demonstrate that the expression of 383 and 723 G4C2 repeats form intranuclear RNA foci that initiate apoptotic cell death in neuronal cell lines and zebrafish embryos. The foci colocalize with a subset of RNA binding proteins, including SF2, SC35, and hnRNP-H in transfected cells. Only hnRNP-H binds directly to G4C2 repeats following RNA immunoprecipitation, and only hnRNP-H colocalizes with 70% of G4C2 RNA foci detected in C9ORF72 mutant ALS and FTD brain tissues. We show that expanded G4C2 repeats are potently neurotoxic and bind hnRNP-H and other RNA binding proteins. We propose that RNA toxicity and protein sequestration may disrupt RNA processing and contribute to neurodegeneration.
    Cell Reports 11/2013; 5(5):1178-86. DOI:10.1016/j.celrep.2013.10.049
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    ABSTRACT: To investigate if Magnetoencephalography (MEG) can add non-redundant information to guide implantation sites for intracranial recordings (IR). The contribution of MEG to intracranial recording planning was evaluated in 12 consecutive patients assessed pre-surgically with MEG followed by IR. Primary outcome measures were the identification of focal seizure onset in IR and favorable surgical outcome. Outcome measures were compared to those of 12 patients matched for implantation type in whom non-invasive pre-surgical assessment suggested clear hypotheses for implantation (non-MEG group). In the MEG group, non-invasive assessment without MEG was inconclusive, and MEG was then used to further help identify implantation sites. In all MEG patients, at least one virtual MEG electrode generated suitable hypotheses for the location of implantations. No differences in outcome measures were found between non-MEG and MEG groups. Although the MEG group included more complex patients, it showed similar percentage of successful implantations as the non-MEG group. This suggests that MEG can contribute to identify implantation sites where standard methods failed.
    Brain Topography 11/2013; 27(1). DOI:10.1007/s10548-013-0330-x
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disease of motor neurons, resulting in worsening weakness of voluntary muscles until death from respiratory failure occurs after about 3 years. Although great advances have been made in our understanding of the genetic causes of ALS, the contribution of environmental factors has been more difficult to assess. Large-scale studies of the clinical patterns of ALS, individual histories preceding the onset of ALS, and the rates of ALS in different populations and groups have led to improved patient care, but have not yet revealed a replicable, definitive environmental risk factor. In this Review, we outline what is currently known of the environmental and genetic epidemiology of ALS, describe the current state of the art with respect to the different types of ALS, and explore whether ALS should be considered a single disease or a syndrome. We examine the relationship between genetic and environmental risk factors, and propose a disease model in which ALS is considered to be the result of environmental risks and time acting on a pre-existing genetic load, followed by an automatic, self-perpetuating decline to death.
    Nature Reviews Neurology 10/2013; 9(11). DOI:10.1038/nrneurol.2013.203
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    ABSTRACT: Post-extubation dysphagia is a common and serious problem. The presence of neuromuscular disease at the time of intubation is likely to increase this. Until recently, the prevalence and the association with length of intubation had not been clarified. Results published in this journal suggest that 93% of extubated patients with neuromuscular disease had post-extubation dysphagia, which in 33% of cases was considered severe. The number of days ventilated was the single predictor of severe dysphagia and a consequent prolonged hospital stay. Further work to build on these results to unravel the complex interplay between disease, trauma, and other unknown factors will be required.
    Critical care (London, England) 10/2013; 17(5):194. DOI:10.1186/cc12762
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    ABSTRACT: Deep brain stimulation (DBS) of the thalamus is an emerging surgical option for people with medically refractory epilepsy that is not suitable for resective surgery, or in whom surgery has failed. Our main aim was to evaluate the efficacy of bilateral centromedian thalamic nucleus (CMN) DBS for seizure control in generalized epilepsy and frontal lobe epilepsy with a two-center, single-blind, controlled trial. Participants were adults with refractory generalized or frontal lobe epilepsy. Seizure diaries were kept by patients/carers prospectively from enrollment. The baseline preimplantation period was followed by a control period consisting of a blind stimulation-OFF phase of at least 3 months, a 3-month blind stimulation-ON phase, and a 6-month unblinded stimulation-ON phase. The control period was followed by an unblinded long-term extension phase with stimulation-ON in those patients in whom stimulation was thought to be effective. Eleven patients were recruited at King's College Hospital (London, United Kingdom United Kingdom) and at University Hospital La Princesa (Madrid, Spain). Among the five patients with frontal lobe epilepsy, only one patient had >50% improvement in seizure frequency during the blind period. In the long-term extension phase, two patients with frontal lobe epilepsy had >50% improvement in seizure frequency. All six patients with generalized epilepsy had >50% improvement in seizure frequency during the blind period. In the long-term extension phase, five of the six patients showed >50% improvement in the frequency of major seizures (one became seizure free, one had >99% improvement, and three had 60-95% reduction in seizure frequency). Among patients with generalized epilepsy, the DBS implantation itself appears to be effective, as two patients remained seizure free during 12 and 50 months with DBS OFF, and the remaining four had 50-91% improvement in the initial 3 months with DBS OFF. DBS implantation and stimulation of the CMN appears to be a safe and efficacious treatment, particularly in patients with refractory generalized epilepsy. CMN stimulation was not as effective in frontal lobe epilepsy, which requires further studies. DBS of the CMN should be considered as a treatment option, particularly in patients with refractory generalized epilepsy syndromes.
    Epilepsia 09/2013; 54(10). DOI:10.1111/epi.12352
  • Movement Disorders 09/2013; 28(10). DOI:10.1002/mds.25517
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    Neuromuscular Disorders 08/2013; 23(12). DOI:10.1016/j.nmd.2013.08.006
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    ABSTRACT: Multimodal CT or MR imaging may be helpful in guiding reperfusion therapy for stroke. However, access to multimodal imaging may frequently be limited. We hypothesised that certain clinical and non-enhanced CT (NECT) findings at initial assessment can potentially predict mismatch on CT perfusion (CTP) in patients with acute ischaemic stroke. We undertook an analysis of prospectively collected clinical and imaging data of consecutive patients with anterior circulation ischaemic stroke who underwent CTP during their initial assessment. NECT was read for early ischaemic change as measured by the Alberta Stroke Program Early CT Score (ASPECTS), and for hyperdense middle cerebral artery sign (HMCAS). CTP images were evaluated for mismatch. Independent clinical and imaging predictors of a CTP mismatch were identified using stepwise logistic regression. Of the 202 patients, 92 (46%) demonstrated a mismatch, 23 (11%) a matched deficit, and 87 (43%) no perfusion deficit. HMCAS on NECT (OR 13.65, 95% CI 6.04-30.81, p<0.001), female gender (OR 2.37, 95% CI 1.19-4.72, p=0.015), atrial fibrillation (OR 2.05, 95% CI 1.02-4.11, p=0.044), and absence of a history of hypertension (OR 0.46, 95% CI 0.22-0.96, p=0.037) were independent predictors of a CTP mismatch. HMCAS had 58% sensitivity, 91% specificity, 84% positive predictive value and 72% negative predictive value. A HMCAS on the initial NECT is associated with a high probability of mismatch in acute ischaemic stroke, and may identify patients most likely to benefit from recanalisation treatments when access to multimodal CT or MR facilities is limited.
    Journal of the neurological sciences 08/2013; 334(1-2). DOI:10.1016/j.jns.2013.07.002
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