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Amyotrofische Laterale Sclerose (ALS) is een verwoestende ziekte die wordt gekenmerkt door de selectieve neurodegeneratie van motorische neuronen in de motorische cortex, hersenstam en ruggenmerg die leidt tot verlamming en de dood meestal binnen drie jaar na ontstaan van de ziekte. De meeste gevallen zijn sporadisch (SALS) terwijl erfelijke of familiaire vormen (FALS) slechts verantwoordelijk zijn voor een klein percentage. Mutaties in verschillende genen zijn geïdentificeerd in FALS waarvan het superoxide dismutase 1 gen (SOD1) het meest uitgebreid bestudeerd is. Net als in andere complexe ziekten wordt gedacht dat genetische variatie een belangrijke rol speelt in de pathogenese van SALS. Waarschijnlijk is het samenspel van genetische factoren, veroudering en milieu-invloeden verantwoordelijk voor susceptibiliteit van deze aandoening. Verder wordt ook verondersteld dat genetische achtergrond ook het ziekteverloop kan beïnvloeden. Genetische associatie studies bij de mens, evenals genetische en/of farmaceutische screeningen in diermodellen worden uitgevoerd om de genetische component in ALS te identificeren. We beschrijven hier een klein diermodel voor ALS waarbij overexpressie van mutant SOD1 axonale abnormaliteiten induceerde in motorische neuronen van zebravis embryo’s. Het fenotype was motorneuron specifiek, zeer stereotyp in presentatie en is gemakkelijk te kwantificeren. Bovendien wijzigden gekende factoren het fenotype op een vergelijkbare wijze als in knaagdier modellen voor ALS. Dit model zal het mogelijk maken om grootschalige screeningen uit te voeren om factoren te vinden met een rol in motorneurobiologie, ALS in het bijzonder. Twee onafhankelijke genetische studies identificeerden een rol voor Elongator Proteïne 3 (ELP3) in motorneurobiologie. ELP3 is onderdeel van een groter complex, de Elongator. Holo-Elongator bestaat uit zes subeenheden die opgedeeld kunnen worden in twee subcomplexen: kern-Elongator (ELP1, ELP2 en ELP3) en een kleiner deel (bestaande uit ELP4, ELP5 en ELP6). Elongator en ELP3 in het bijzonder hebben meerdere functies in RNA verwerking. Het is betrokken bij acetylatie van histonen, RNA elongatie, wijziging van tRNA-Wobble-nucleosiden alsook exocytose. In een genetische associatiestudie bleken varianten in ELP3 geassocieerd te zijn met ALS. Expressie van ELP in hersenen van personen met genotypen geassocieerd met ‘bescherming’ tegen ALS was aanzienlijk hoger. Een mutagenese screening in Drosophila suggereerde dat gedaalde niveaus van ELP3 geassocieerd waren met abnormale axonale projecties. Knock-down van ELP3 in zebravis resulteerde in abnormaliteiten in axonale uitgroei. Overexpressie van ELP3 in zebravis embryo’s verbeterde de axonale defecten van motorische neuronen geïnduceerd door injectie van mutant SOD1. Deze bevindingen suggereren dat ELP3 neuroprotectief zou kunnen zijn voor (motor)neuronen en vermindering van ELP3 als een risicofactor kan fungeren voor (motor)neuronale aandoeningen. Het exacte werkingsmechanisme moet nog worden opgehelderd. Potentieel kan ELP3 een nog onbekend cytoplasmatisch substraat acetyleren of één of meerdere mechanismen in RNA verwerking beïnvloeden, en daardoor interfereren met motorneuronale functie en overleving. Tenslotte beschrijven we een nieuwe mutatie in TARDBP, een onlangs beschreven nieuw gen betrokken bij zowel FALS als SALS. In ons cohort van FALS patiënten zijn mutaties in SOD1 verantwoordelijk voor 35% van alle gevallen en mutaties in TARDBP slechts in een minderheid van FALS (3%). Amyotrophic Lateral Sclerosis (ALS) is a devastating disease which is characterized by the selective neurodegeneration of motor neurons in the motor cortex, brainstem and spinal cord which results in paralysis and death usually within three years of disease onset. Most cases are sporadic (SALS) whilst inherited or familial forms (FALS) account for only a small percentage. Different disease causing mutated genes have been identified in FALS of which superoxide dismutase 1 (SOD1) has been most extensively studied. As in other complex diseases, genetic variation is thought to play a role in the pathogenesis of SALS. Probably it acts in concert with other risk factors as ageing and environmental influences, determining disease susceptibility. Furthermore, genetic variation is also believed to be able to modify the disease course. Genetic association studies in humans as well as genetic and/or chemical screenings in animal models are being performed in order to identify the genetic component in ALS. We here describe a small animal model for ALS which will enable large scale genetic and chemical screening. Overexpression of mutant SOD1 induced a motor neuron axonopathy in the zebrafish embryo. The phenotype is motor neuron specific, very stereotypic in appearance, and is easy to score quantitatively and in sufficient numbers to allow high-powered statistics. Moreover, known modifying factors influenced the phenotype similar as in rodent models for ALS. This model will enable large scale screening for modifying factors in motor neuron diseases, ALS in particular. Two independent genetic studies identified Elongator Protein 3 (ELP3) to be involved in motor neurobiology. ELP3 is part of a larger complex, the Elongator. Holo-Elongator is a six-subunit complex composed of two subcomplexes: core-Elongator (ELP1, ELP2 and ELP3) and a smaller component (composed of ELP4, ELP5 and ELP6). The Elongator and ELP3 in particular have several functions in RNA processing. It is involved in histone acetylation, RNA elongation, modification of tRNA wobble nucleosides and exocytosis. In a human association study variants in ELP3 were shown to be associated with ALS. Additionally in human brain of individuals with genotypes associated with protection for ALS, levels of ELP3 were significantly higher. A mutagenesis screen in Drosophila also suggested decreased levels of ELP3 to be associated with abnormal axonal projections. Knock down of ELP3 in zebrafish resulted in defects in axonal outgrowth. Interestingly, overexpression of ELP3 rescued the motor neuronal axonopathy induced by mutant SOD1. These findings suggest increasing ELP3 to be beneficial for (motor) neurons and reduction in ELP3 to be a risk factor for (motor) neuronal diseases. The exact mechanism of action needs to be elucidated. Potentially ELP3 can acetylate yet unknown cytoplasmic substrates or influences one or more mechanisms in RNA processing, thereby affecting motor neuronal function and survival. Finally, we identified a new mutation in TARDBP by sequencing this recently described gene involved in both FALS and SALS. In our cohort of FALS patients SOD1 mutations are responsible for 35% of all cases, whilst TARDBP was only identified in a minority of FALS (3%) in this population.

Academic collection --- 616.8 --- 612.8 --- Neurology. Neuropathology. Nervous system --- Nervous system. Sensory organs --- Theses

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Background Acute ischemic stroke (AIS) is a prevalent disease with a large mortality, morbidity and socioeconomic cost. Current treatment of AIS in the acute phase focusses on revascularization strategies. Due to a short window of opportunity and stringent inclusion criteria, only a small number of patients can benefit from these reperfusion therapies. Although neuroprotective strategies could theoretically be a meaningful intervention, possibly even in the prehospital setting, studies have been disappointing. Preclinical studies have shown that remote ischemic conditioning (RIC), i.e. induction of intermittent ischemia, typically applied to the limbs, may reduce infarct volume and improves neurological deficits in experimental stroke. Aim The aim of this study is to describe and summarize all the clinical evidence on the efficacy and safety of RIC in the treatment of AIS. Methods A study of the literature on RIC and AIS was conducted on Pubmed, EMBASE, Web of science core collection and Cochrane central databases. The included randomized controlled trials (RCT) were assessed for methodological quality, and outcomes reported on efficacy and safety summarized and analyzed in a narrative analysis. Data on frequency of stroke recurrence and favorable clinical outcome, defined as the percentage of patients with modified Rankin Score (mRS) ≤ 1 at day 90, were extracted and pooled in a quantitative meta-analysis. Relative risks with 95% confidence intervals were calculated. Data was pooled with a random-effect model and presented as a forest plot. I² was used to assess for heterogeneity. Results We included 16 published RCT’s and 15 ongoing trials in our study. All the evidence suggests that RIC is a safe intervention, even if administered in combination with revascularization techniques. Outcomes reported on efficacy were not unambiguous. 14 RCT’s were included for meta-analysis. The total relative risk for favorable clinical outcome at 90 days was 1.25 (95%CI 0.98-1.58, P=0.07, N=8, n=780, I²=66%) in favor of RIC treatment. The total relative risk for stroke recurrence was 0.39 (95%CI 0.21-0.72, P=0.003, N=10, n=539, I²=0%) in favor of RIC treatment. Subgroup analysis revealed that a more extensive RIC regimen produces more favorable results with regard to functional and neurological functioning. Conclusion In this meta-analysis, we found low-quality evidence that RIC may have a beneficial effect on functional outcome and reduces stroke recurrence. RIC proves to be a safe intervention. The large heterogeneity in timing, number, duration, or repetition of RIC limits the ability to draw definitive conclusions on efficacy and propose a treatment regimen. Larger RCT’s are warranted.

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In een oogopslag: We bepalen de rol van fysieke activiteit in primaire en secundaire beroertepreventie door vergelijking van gepubliceerde artikels. Doel: De rol van fysieke activiteit in beroertepreventie is controversieel door tekort aan literatuur en grote heterogeniteit. Deze studie tracht op basis van de beschikbare literatuur, de rol van fysieke activiteit in primaire en secundaire beroertepreventie aan te tonen. Methode: We zochten naar wetenschappelijke literatuur via de databases PubMed, Scopus, Web of Science, Trip medical database en Embase. Meta-analyses met random-effect models gebruikten we om de rol van fysieke activiteit in primaire beroertepreventie aan te tonen. Bovendien schreven we een review die de rol van fysieke activiteit beschrijft in secundaire beroertepreventie. Resultaten: Van de 340 geraadpleegde studies, voldeden zestien studies aan criteria voor meta-analyses ter bepaling van de rol van fysieke activiteit in primaire beroertepreventie. In vergelijking met lage fysieke activiteit, verlaagt het beoefenen van matige en hoge fysieke activiteit het risico op een beroerte met respectievelijk 10% (RR = 0,90; CI: 0,85 – 0,95; p < 0,0001) en 20% (RR = 0,80; CI: 0,76 – 0,85; p < 0,00001). We includeerden vijf studies in review ter bepaling van de rol van fysieke activiteit in secundaire beroertepreventie. Het risico op een recurrente beroerte neemt omgekeerd evenredig toe met het beoefenen van fysieke activiteit. Conclusie: Fysieke activiteit speelt een significante rol in zowel primaire als secundaire preventie van beroertes. Naargelang minder beroertes optreden bij patiënten die fysieke activiteit beoefenen, moedigen we dit doorgaans aan. Sleutelwoorden: beroerte; primaire preventie; secundaire preventie; fysieke activiteit

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Background Acute ischemic stroke is one of the leading causes for death and disability. The usage of alteplase as a thrombolytic agent for acute treatment in strokes was approved by the Food and Drug Administration (FDA) in 1995, and by the European Medical Agency (EMA) in 2002. Currently, alteplase is the only thrombolytic agent that is recommended for clinical use. However, several clinical trials demonstrated promising results applying other thrombolytic agents. Objectives This review aims to summarize the evolution of thrombolysis for the treatment of an acute ischemic stroke starting from the National Institute of Neurological Disorder and Stroke (NINDS) trial published in 1995 until the recent publication of the Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND) trial in May 2019. Methods The medical database PubMed was screened for eligible articles in June 2019. The following keywords were used: ‘acute cerebrovascular accident’, ‘stroke’, ‘acute ischemic stroke’, ‘thrombolysis’, tissue plasminogen activator’ and ‘thrombolytic therapy. Only clinical trials published between January 1995 and June 2019 were selected. Results Initially the time window for administering thrombolysis in acute ischemic stroke was only 3 hours after onset of ischemia. Patients were selected based on clinical criteria, baseline computed tomography (CT) scan and elapsed time since stroke onset. After publication of the results from the European Cooperative Acute Stroke Study (ECASS) III, the window was extended to 4,5 hours after stroke onset. Following studies focused on the use of neuroimaging criteria to identify patients who can still benefit from reperfusion beyond 4,5 hours after stroke onset although they do not comply with the criteria mentioned above. The MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial proved that in patients with a mismatch between diffusion weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) suggestive of stroke onset within 4,5 hours thrombolysis is effective and safe. Recently the EXTEND trial proved that patients having a favourable core-perfusion profile qualify for thrombolysis up to 9 hours after the onset of ischemia. At this moment alteplase is the only approved thrombolytic agent for treatment of an acute ischemic stroke. Tenecteplase shows a similar effectivity and safety as alteplase, but several trials are still in progress. The desmoteplase trials, focusing on larger time windows could not demonstrate a significant benefit, which was probably due to underpowering. Conclusion Thrombolysis in acute ischemic stroke is possible until 4,5 hours after stroke onset based on clinical criteria and a baseline CT scan. When patients present after this time window treatment might still be possible based on neuroimaging criteria.

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Cerebral small vessel disease (SVD) refers to a variety of pathological processes affecting the small vessels of the brain. It is an important cause of strokes and age-related cognitive decline and disability. The majority of cerebral small vessel diseases are sporadic and are very prevalent in the elderly population. Rare monogenic causes have also been discovered causing a typical clinical picture at a relatively younger age. In this narrative review, we summarize the known monogenic causes of SVD: CADASIL, autosomal dominant small vessel disease, CARASAL, PADMAL, RVCL-S, FOXC1 deletion-related angiopathy, COL4A1 and COL4A2-related angiopathies, CARASIL and Fabry’s disease. We classified these syndromes according to inheritance pattern and describe the responsible gene defect, clinical picture and imaging characteristics. We also describe a practical approach to the diagnosis of patients with SVD of presumed monogenetic etiology.