Τα ΑΕΕ είναι η πρώτη αιτία αναπηρίας και η τρίτη αιτία θανάτου παγκοσμίως. Επίσης οι ασθενείς με ΑΕΕ είναι οι συχνότεροι χρήστες των υπηρεσιών υγείας. Παράλληλα, στη χώρα μας δαπανάται ετησίως το 10% του Ακαθάριστου Εγχώριου Προϊόντος (ΑΕΠ) για την υγεία σε σχέση με το μέσο όρο του 8,9% των χωρών του Οργανισμού Οικονομικής Συνεργασίας και Ανάπτυξης (ΟΟΣΑ). Στόχος της μελέτης είναι η οικονομική αξιολόγηση του ενδο-νοσοκομειακού κόστους ασθενών με οξύ ΑΕΕ στην Ελλάδα καθώς επίσης και ο προσδιορισμός ανεξάρτητων παραγόντων που επηρεάζουν το κόστος νοσηλείας. Καταγράφηκαν δημογραφικά και κλινικά χαρακτηριστικά σε 429 συνεχόμενους ασθενείς με οξύ ΑΕΕ (ισχαιμικό ή αιμορραγικό) που εισήχθησαν σε όλες τις κλινικές του Πανεπιστημιακού Γενικού Νοσοκομείου Πατρών για διάστημα 18 μηνών. Υπολογίσαμε το κόστος, για κάθε ασθενή ατομικά, από την ώρα της εισβολής του ΑΕΕ έως την έξοδό του από το νοσοκομείο. Το κόστος μετρήθηκε σε ευρώ (€) και σύμφωνα με τις πραγματικές δαπάνες του νοσοκομείου. Η μέση ηλικία των ασθενών ήταν 68.9 (±12.7) έτη και η διάρκεια νοσηλείας ήταν 10.9 (±7.9) ημέρες. Οι 345 ασθενείς (80%) είχαν ισχαιμικό ΑΕΕ και 84 (20%) είχαν πρωτοπαθή ενδοεγκεφαλική αιμορραγία. Το άμεσο ενδο-νοσοκομειακό κόστος νοσηλείας όλων των ασθενών με οξύ ΑΕΕ ανήλθε στα 1.551.445,00 € για μια συνολική διάρκεια νοσηλείας 4.674 ημερών (331,9 € ανά ημέρα νοσηλείας). Το μέσο ενδονοσοκομειακό κόστος ανά ασθενή με ΑΕΕ ήταν 3.624,9(±2695.4) €. Το 59% του συνολικού κόστους αποδόθηκε στο κόστος "κλίνης και προσωπικού", (6%) "προ εισαγωγής", (13%) "εργαστηριακό έλεγχο", (6%) "απεικονιστικό έλεγχο", (8%) "αποκλειστική νοσηλευτική φροντίδα", (7%) "φαρμακευτική αγωγή", (0.6%) "θεραπεία αποκατάστασης" και (0.7%) "διάφορα έξοδα". Τα αιμορραγικά ΑΕΕ είχαν σημαντικά μεγαλύτερο κόστος από τα ισχαιμικά ΑΕΕ (μέσο 5305.4 και 3.214,5 €, αντίστοιχα). Μεταξύ των υπότυπων των ισχαιμικών ΑΕΕ το συνολικό μέσο κόστος ήταν σημαντικά χαμηλότερο για τα "κενοτοπιώδη" έμφρακτα (2328.7±1100.2 €). Η διάρκεια νοσηλείας είχε υψηλή συσχέτιση με το συνολικό ενδο-νοσοκομειακό κόστος. Η πολυπαραγοντική γραμμική ανάλυση παλινδρόμησης έδειξε ότι το τμήμα εισαγωγής, η βαρύτητα του ΑΕΕ στην εισαγωγή, ο τύπος του ΑΕΕ και η κατάσταση εξόδου ήταν ανεξάρτητοι παράγοντες του κόστους. Αν επιθυμούμε τη συγκράτηση του νοσοκομειακού κόστους, θα πρέπει να ληφθούν υπόψη πολιτικές διοίκησης που στοχεύουν στη μείωση της διάρκειας νοσηλείας. / Stroke is the first cause of disability and the third cause of death worldwide. Moreover, in the western countries, the stroke patients are the most frequent users of all the health services and the hospital budgets. At the same time, 10% of the Gross Domestic Product (GDP) is annually spent on health in relation with the average 8.9% of the Organisation for Economic Co-operation and Development (OECD) countries. Aim of this study is the economic evaluation on the in-hospital cost of patients with an acute stroke in Greece and the identification of potential independent factors influencing this cost. Demographic and clinical data were recorded on 429 consecutive patients with an acute stroke (ischemic and hemorrhagic), admitted to the University General Hospital of Patras during a period of 18 months. We calculated the cost, individually for each patient, from the stroke onset until the discharge from the hospital. The cost was measured in euro (€), according to the real expenditure of hospital. Mean age was 68.9 (±12.7) years and length of stay (LOS) was 10.9 (±7.9) days. In all, 345 patients (80%) had an ischemic stroke and 84 (20%) had a primary intracerebral hemorrhage. The direct in-hospital cost of all stroke patients, 1.551.445,00 €, accounted for a total hospitalisation of 4.674 days (331.9 € per day in hospital). The mean in-hospital cost per patient was 3.624,9 (±2695.4) €. The 59% of the total cost concerns the cost of "bed and staff", (6%) "pre-hospital cost", (13%) "laboratory investigations", (6%) "imaging investigations", (8%) "supportive nursing", (7%) "medication", (0.6%) "rehabilitation therapy" and (0.7%) "other expenses". Hemorrhagic strokes were significantly more expensive than the ischemic strokes (mean 5305.4 (± 4204.8) € and 3214,5 (±1976.2) € respectively). Amongst ischemic stroke subtypes the mean total cost was significantly lower for lacunar strokes (2328.7 ± 1100.2 €). The length of stay was highly correlated with in-hospital total cost. Multivariate linear regression model showed that the admission ward, stroke severity on admission, stroke type and status discharge were independent predictors of cost. In order to withhold the hospital cost, policies of administration that aiming to the reduction of length of stay should be taken into consideration.

No description available.

We prospectively evaluated 30 consecutive patients with echo-enhanced transcranial color-coded duplexsonography (TCCD) and correlative transfemoral digital subtraction angiography to assess the diagnostic efficacy of echo-enhanced TCCD for evaluation of collateral pathways through the circle of Willis in patients with limited acoustic bone windows and critical symptomatic carotid disease. Echo-enhanced TCCD detected collateral blood flow through the anterior communicating artery in 16 of 18 patients (sensitivity 89%, 95% CI 65–99%) and was false positive in one out of 12 patients without collateral flow (specificity 92%, 95% CI 59–100%). For the posterior communicating artery, sensitivity was 11/14 (79%, 95% CI 49–95%) and specificity was 15/16 (94%, 95% CI 70–100%). Echo-enhanced TCCD enables to study collateral blood flow through the communicating arteries of the circle of Willis with high sensitivity and specificity in patients with obstructions of the internal carotid artery and limited acoustic bone windows. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

One of the most common risk factors for stroke is diabetes. Diabetics are 2 to 4 times more likely to have a stroke and are also significantly more likely to show poor functional recovery. In order to determine why diabetes is associated with poor stroke recovery, we tested the hypotheses that diabetes either exacerbates initial stroke damage, or inhibits neuronal circuit plasticity in surviving brain regions that is crucial for successful recovery. Type 1 diabetes was chemically induced in mice four weeks before receiving a targeted photothrombotic stroke in the right forelimb somatosensory cortex to model a chronic diabetic condition. Following stroke, a subset of diabetic mice were treated with insulin to determine if controlling blood glucose levels could improve stroke recovery. Consistent with previous studies, one behavioural test revealed a progressive improvement in sensory function of the forepaw in non-diabetic mice after stroke. By contrast, diabetic mice treated with and without insulin showed persistent deficits in sensori-motor forepaw function. To determine whether these different patterns of stroke recovery correlated with changes in functional brain activation, forepaw evoked responses in the somatosensory cortex were imaged using voltage sensitive dyes at 1 and 14 weeks after stroke. In both diabetic and non-diabetic mice that did not have a stroke, brief mechanical stimulation of the forepaw evoked a robust and near simultaneous depolarization in the primary (FLS1) and secondary somatosensory (FLS2) cortex. One week after stroke, forepaw-evoked responses had not been remapped in the peri-infarct cortex in both diabetic and non-diabetic mice. Fourteen weeks after stroke, forepaw evoked responses in non-diabetic mice re-emerged in the peri-infarct cortex whereas diabetic mice showed very little activation, reminiscent of the 1 week recovery group. Moreover, controlling hyperglycemia using insulin therapy failed to restore sensory evoked responses in the peri-infarct cortex. In addition to these differences in peri-infarct responsiveness, we discovered that stroke was associated with increased responsiveness in FLS2 of non-diabetic, but not diabetic or insulin treated mice. To determine the importance of FLS2 in stroke recovery, we silenced the FLS2 cortex and found that it re-instated behavioural impairments in stroke recovered mice, significantly more so than naïve mice that still had a functioning FLS1. Collectively, these results indicate that both diabetes and the secondary somatosensory cortex play an important role in determining the extent of functional recovery after ischemic cortical stroke. Furthermore, the fact that insulin therapy after stroke did not normalize functional recovery, suggests that prolonged hyperglycemia (before stroke) may induce pathological changes in the brain’s circulation or nervous system that cannot be easily reversed. / Graduate

La reperfusion complète et précoce est le moyen le plus efficace pour limiter l'extension de l'infarctus cérébral et les séquelles neurologiques. Le traitement de l'infarctus cérébral a été révolutionné par la thrombectomie mécanique intra-artérielle en permettant une recanalisation dans plus de 70% des cas et une réduction significative de la morbidité comparativement à la thrombolyse seule pour le territoire carotidien. Le pronostic des occlusions basilaires reste dramatique et aucun essai n'a démontré le bénéfice de l'approche intra-artérielle à l'heure actuelle. Dans la première partie du travail, nous avons réalisé une méta-analyse sur la thrombectomie par «stent-retriever» des occlusions basilaires, à partir des résultats publiés dans MEDLINE entre novembre 2010 et avril 2014: recanalisation angiographique (TICI≥2b)=81% (IC 95%: 73-87); hémorragie cérébrale symptomatique à 24 heures=4% (IC 95%: 2-8); évolution neurologique favorable (mRS≤2 à 3 mois)=42% (IC 95%: 36-48); mortalité=30% (IC 95%: 25-36). L'approche intra-artérielle ouvre une nouvelle ère thérapeutique, cependant un modèle animal adapté et pertinent est nécessaire pour l'évaluation pré-clinique. Dans la deuxième partie du travail, nous avons caractérisé l'évolution spatio-temporelle précoce de l'infarctus par IRM multimodale dans un modèle d'ischémie cérébrale focale transitoire réalisé par occlusion sélective intra-artérielle de l'artère cérébrale moyenne chez le rat adulte. Une occlusion complète de l'artère cérébrale moyenne proximale était observée dans 75% des 16 rats opérés, et un mismatch diffusion/perfusion dans 77% des cas. Le volume ischémique durant l'occlusion artérielle, définie sur la séquence de diffusion, était de 90±64 mm3 et de 57±67 mm3 à 24 heures sur la séquence T2. La recanalisation artérielle s'associe à une reperfusion tissulaire dans 36% des cas. L'hypoperfusion persistait chez la majorité des animaux 3 heures après recanalisation. L'infarctus était de localisation cortical dans 31%, striatale dans 25%, et cortico-striatale dans 44%. Tous les animaux étaient en vie à 24 heures confirmant le caractère mini-invasif de ce modèle. Bien que la reperfusion sauve incontestablement une partie du parenchyme ischémique, elle s'accompagne également de lésions irréversibles spécifiques, dites de reperfusion, s'ajoutant aux lésions initiales. Limiter l'importance des lésions de reperfusion représente un objectif thérapeutique majeur. Dans la troisième partie, nous avons testé l'effet neuroprotecteur de la Cyclosporine A sur la réduction du volume de l'infarctus cérébral et sur le pronostic clinique. Une procédure d'ischémie reperfusion cérébrale de 60 minutes a été réalisée chez 48 animaux, puis ont été randomisés en quatre groupes (groupe témoin, pré-conditionnement, postconditionnement intraveineux et intra-artériel avec la Cyclosporine A à la dose de 10 mg/kg dans les 30 secondes suivant la reperfusion). Sur les 43 animaux inclus dans l'analyse, il n'a pas été observé de réduction du volume ischémique ni une amélioration du pronostic après injection intraveineuse ou intra-artérielle de Cyclosporine A. La Cyclosporine A ne permet pas non plus de limiter l'extension des lésions de reperfusion au sein de la zone à risque à 24 heures de la reperfusion cérébrale / Early and complete reperfusion is the most effective therapy to limit the extent of brain infarction. The treatment of acute anterior ischemic stroke has been revolutionized by the intra-arterial mechanical thrombectomy allowing a 70% recanalization rate and a significant reduction of morbidity compared with thrombolysis alone. The prognosis of basilar artery occlusion remains catastrophic, and to date any trial has demonstrated the benefit of intra-arterial approach. In the first part of the work, we conducted a systematic review and meta-analysis of all previous studies of stent retriever thrombectomy in basilar artery occlusion patients between November 2010 and April 2014: recanalization (TICI≥2b)=81% (95% CI: 73-87); symptomatic intracranial haemorrhage at 24 hours=4% (95% CI 2-8); favorable neurological outcome (mRS≤2 at 3 months)=42% (95% CI: 36-48); mortality=30%(95% CI 25-36). Intra-arterial approach opens new avenues for the developement of treatments for brain infarction, but a relevant animal model of acute ischemic stroke is required for preclinical evaluation. In the second part of the work, we evaluated the spatiotemporal evolution of cerebral ischemia by sequential multimodal MRI in a new minimally invasive model of transient focal ischemia by selective intra-arterial occlusion of the middle cerebral artery in rat. A complete occlusion of the proximal portion of the middle cerebral artery was observed in 75% of 16 operated rats, and a mismatch diffusion/perfusion in 77% of cases. Acute stroke volume during arterial occlusion was 90±64 mm3 on diffusion-weighted imaging, and 57±67 mm3 at 24 hours on T2-weighted imaging. Recanalization is associated with tissue reperfusion in 36% of cases. The hypoperfusion persisted in the majority of animals 3 hours after recanalization. Brain infarction was cortical in 31%, striatal in 25%, and corticalstriatal in 44% of cases. All animals were alive at 24 hours, confirming the minimally invasive nature of the model. Although reperfusion saves a portion of ischemic tissue, it also carries specific irreversible damage, called reperfusion injury, in addition to initial damage caused by ischemia. Limiting the size of infarction is a major objective. In the third part, we tested the neuroprotective effect of Cyclosporine A in reducing the lesion volume and functional outcome. A total of 48 adult rats underwent the intra-arterial ischemia reperfusion procedure, and were randomly assigned to four treatment groups (control, preconditioning, intravenous and intra-arterial postconditioning with Cyclosporine A). Intravenous or intra arterial injection of Cyclosporine A at reperfusion does not either reduce the volume of stroke or improve the neurological outcome. Administation of Cyclosporin A at reperfusion does not limit the extension of reperfusion injuries within the ischemic risk area at 24 hours

Les mécanismes impliqués dans les troubles cognitifs induits à la suite d’une ischémie cérébrale (IC) demeurent mal compris. En plus du cœur ischémique nécrosé et de la zone de pénombre entourant cette lésion, certaines régions éloignées de la zone ischémique peuvent être fonctionnellement affectées, un phénomène connu sous le nom de «diaschisis». Sachant qu’il existe de fortes interactions fonctionnelles entre l’hippocampe (HPC) et le cortex lors des processus mnésiques, nous avons émis la possibilité que les troubles mnésiques survenant après une IC focale qui préserve l’intégrité de l’HPC, auraient pour origine une perturbation de la connectivité cortico-hippocampique conduisant à un hypofonctionnement hippocampique induit par le phénomène de diaschisis. Afin d’éprouver cette hypothèse, nous avons utilisé le modèle d’occlusion permanente de l'artère cérébrale moyenne chez le rat (OPACM) qui reproduit l’ischémie cérébrale focale humaine. Dans ce modèle, le cortex somato-sensoriel (SS) est endommagé unilatéralement alors que l’intégrité de l’HPC est préservé. Les rats OPACM ont montré une diminution de l’expression du gène c-fos dans l’HPC lors de l'exploration d'un nouvel environnement, indiquant une hypoactivation neuronale. Les rats OPACM ont également présenté une perturbation des mémoires olfactive associative et spatiale lors des tests de transmission sociale de préférence alimentaire (TSPA) et du Barnes maze, respectivement. Afin de confirmer que l’hypofonctionnement hippocampique induit par l’IC résultait d’une réduction des afférences corticales («déactivation») provenant du cortex endommagé, nous avons réalisé des inactivations pharmacologiques spécifiques du cortex SS et ou de l’HPC par injection de lidocaïne ou de CNQX. Ces injections ont induit une hypoactivation hippocampique (réduction du nombre de noyaux Fos-positifs) associée à une perturbation mnésique dans le test de TSPA. L'activité hippocampique chez des rats anesthésiés pendant l’IC ou deux semaines après, ainsi que lors de l’inactivation pharmacologique du cortex SS, a également été examinée par une approche électrophysiologique. Les résultats ont montré une altération de la fréquence d’apparition des «sharp-wave ripples» hippocampiques et révélé une instabilité de la fréquence thêta hippocampique lors de la reperfusion ou deux semaines après IC, ainsi que lors de l’inactivation corticale, suggérant une altération de la dynamique d’interaction entre l’HPC et le cortex. Pris dans leur ensemble, ces résultats identifient le phénomène de diaschisis hippocampique comme un mécanisme crucial impliqué dans l’hypofonctionnement hippocampique et les déficits mnésiques observés après une IC. / The cognitive consequences and the underlying mechanisms leading to cognitive impairments after cerebrovascular occlusive diseases are still unclear. In addition to the infarct zone that suffer the deadly consequence of ischemic stroke, the penumbra surrounding the lesion site and some brain regions more remote to the ischemic areas can be functionally affected by the insult. This phenomenon is referred to as diaschisis. In light of the importance of interactions between hippocampus and cortex during memory processing, we hypothesized that the cognitive impairments observed following focal ischemia could occur in the absence of direct hippocampal insult, possibly via impaired connectivity within cortico-hippocampal networks leading to diaschisis-induced hypofunctioning in specific hippocampal subregions. To examine this possibility, we used the distal middle cerebral artery occlusion (dMCAO) ischemic model in rats which induces restricted cortical infarct in the somatosensory (SS) cortex in the absence of direct hippocampal injury. dMCAO rats exhibited reduced expression of the activity-dependent gene c-fos in the hippocampus when exploring a novel environment, indicating neuronal hypoactivation. Ischemic rats also showed impaired associative olfactory and spatial memory when tested in the social transmission of food preference (STFP) task and the Barnes maze test, respectively. To confirm that the ischemic-induced hippocampal hypofunctioning resulted from reduced afferent inputs (i.e. deactivation) originating in the damaged cortex, we performed region-specific pharmacological inactivation of SS and/or HPC using lidocaine or CNQX. Fos imaging revealed that these treatments induced hippocampal hypoactivation and impaired memory performance as measured in the STFP task. We additionally performed electrophysiological recordings of hippocampal activity in anesthetized rats during acute stroke and two weeks later or after SS cortex inactivation. We found an alteration in the occurrence of sharp-wave ripples associated with instability of theta frequency during reperfusion after stroke and SS cortex inactivation, suggesting an alteration in the dynamics of hippocampal-cortical interactions. Taken collectively, these findings identify hippocampal diaschisis as a crucial mechanism for mediating stroke-induced hippocampal hypofunction and associated memory deficits.

Background: Recent studies showed that the safety and benefit of early intravenous (IV) thrombolysis on favourable outcomes in acute ischemic stroke are also seen in the elderly. Furthermore, it has shown that age increases times for pre- and in-hospital procedures. We aimed to assess the applicability of these findings to telestroke. Methods: We retrospectively analysed 542 of 1659 screened consecutive stroke patients treated with IV thrombolysis in our telestroke network in East-Saxony, Germany from 2007 to 2012. Outcome data were symptomatic intracranial hemorrhage (sICH) by ECASS-2-criteria, survival at discharge and favourable outcome, defined as a modified Rankin scale (mRS) of 0–2 at discharge. Results: Thirty-three percent of patients were older than 80 years (elderly). Being elderly was associated with higher risk of sICH (p¼0.003), less favourable outcomes (p¼0.02) and higher mortality (p¼0.01). Using logistic regression analysis, earlier onsetto-treatment time was associated with favourable outcomes in not elderly patients (adjusted odds ratio (OR) 1.18; 95% CI 1.03–1.34; p¼0.01), and tended to be associated with favourable outcomes (adjusted OR 1.13; 95% CI 0.92–1.38; p¼0.25) and less sICH (adjusted OR 0.88; 95% CI 0.76–1.03; p¼0.11) in elderly patients. Age caused no significant differences in onset-to-doortime (p¼0.25), door-to-treatment-time (p¼0.06) or onset-to-treatment-time (p¼0.29). Conclusion: Treatment time seems to be critical for favourable outcome after acute ischemic stroke in the elderly. Age is not associated with longer delivery times for thrombolysis in telestroke.

Mobilisation in the acute stages of stroke is a complex subject where the nurse must considerseveral confounding variables. There is an insufficient state of evidence around when andhow the first mobilisation should occur after stroke, and there is often uncertainty in thedecision making. The aim was to describe how early mobilisation in the acute stages of stroke affects thepatient’s level of functioning. The method used was a general literature review with an integrated analysis. Results: 17 articles analysing the effect of early mobilisation on nursing-related outcomemeasures, published between 2015–2019, were included in the literature review. Sample,interventions and outcome measures varied between the different articles. Three of the articlesshowed results suggesting that early mobilisation could be negative for the patient’sfunctional outcome after stroke. Among the remaining articles there was an even distributionof positive effects of early mobilisation and results not showing any effect on functionaloutcome. The results of this literature review imply that early mobilisation to some extentmay contribute to improved basic functions as in managing the toilet, dressing and also moreinstrumental features as cooking and driving. Early mobilisation appears to be a safe nursingintervention in most cases, as long as the patient is considered medically stable. The conclusion to be drawn from this literature review is that nurses, through their mainresponsibility for nursing care can influence the patient’s functional outcome through the decisions made regarding the first mobilisation in patients hit by acute stroke. / Mobilisering i akutskedet efter stroke är ett komplext ämne där sjuksköterskan måste ta ställning till ett flertal samverkande faktorer. Evidensläget kring när och hur den första mobiliseringen bör ske efter stroke är otillräckligt, och ofta uppstår en osäkerhet i beslutsfattandet. Syftet var att beskriva hur tidig mobilisering i akutskedet efter stroke påverkar patientens funktionsnivå. Metoden som användes var en allmän litteraturöversikt med integrerad analys. Resultat: 17 artiklar som analyserat effekten av tidig mobilisering på omvårdnadsrelaterade utfallsmått, publicerade från 2015–2019, inkluderades i litteraturöversikten. Urval, interventioner och utfallsmått varierade mellan de olika artiklarna. Tre av artiklarna visade på resultat som talar för att tidig mobilisering skulle kunna vara negativt för patientens funktionsutfall efter stroke. Bland övriga artiklar sågs en jämn fördelning bland positiv effekt av tidig mobilisering och resultat som inte visat någon påverkan på funktionsutfallet. Resultatet i denna litteraturöversikt tyder på att tidig mobilisering i viss mån kan bidra till förbättrade basala funktioner såsom att klara av toalettbesök, på- och avklädning och även mer instrumentella funktioner som att laga mat och köra bil. Tidig mobilisering ter sig vara en säker omvårdnadsåtgärd i de flesta fall, så länge patienten bedöms som medicinskt stabil. Slutsatsen som kan dras av litteraturöversikten är att sjuksköterskan genom sitt huvudansvar för omvårdnad kan påverka patientens funktionsutfall genom de beslut som fattas kring den första mobiliseringen av patienter som drabbats av akut stroke. Ytterligare forskning avseende tidpunkt och mobiliseringens intensitet behövs för att kunna avgöra när och hur den första mobiliseringen skall påbörjas efter att en patient drabbats av stroke.

Background: Rare genetic mutations cause familial early-onset stroke disorders, known as “Mendelian strokes”. The broader relevance of rare mutations in unrelated young stroke patients is uncertain. We hypothesize that rare mutations in known and novel genes are important risk factors for stroke. Methods: Exome sequencing was used to characterize rare disruptive protein-altering mutations in 185 young cases and 185 matched controls from INTERSTROKE, a large and globally representative stroke study. The major objectives were: 1) to precisely define the role of known Mendelian stroke genes and 2) to discover novel gene and pathway associations. Results: A focused assessment of known Mendelian stroke genes revealed a significant contribution from NOTCH3, the causal gene for Cerebral Autosomal Dominant Arteriopathies with Subcortical Infarcts and Leucoencephalopathies (CADASIL). CADASIL mutations were identified in six cases and no controls (P=0.03). The clinical presentation of CADASIL mutation carriers deviated from known symptomatology, consisting of small-vessel ischemic strokes (SVIS) accompanied by secondary features including migraine and depression. A novel role for non-CADASIL NOTCH3 mutations in ICH was also elucidated (OR=2.86; 95% CI, 1.13 to 7.93, P=0.02). Such mutations were present in 22% of ICH cases and 8% of matching controls. An agnostic evaluation of all genes did not reveal any genome-wide significant associations. However, NOTCH3 was among the top ICH genes out of 13,706 tested, and many others were also biologically relevant, notably, AARS2 and NBEAL2. A protective association was identified for the renin angiotensin system (P=8.1x10-4), whereas type II diabetes mellitus was associated with increased risk (P=1.9x10-2). Conclusion: Rare mutations influence risk of early-onset stroke. CADASIL mutations play an important role in unrelated stroke patients. Beyond CADASIL, a novel role was uncovered for other NOTCH3 mutations as common and significant risk factors for ICH. Novel biologically relevant genes and pathways may also affect stroke susceptibility. / Thesis / Master of Science in Medical Sciences (MSMS)

No description available.