No description available.

Vitronectin (VTN) is a blood protein produced mainly by the liver. We show that VTN leaks from the bloodstream into the injury site and neighboring subventricular zone (SVZ) following ischemic stroke (middle cerebral artery occlusion, MCAO) in adult mice. MCAO is known to increase neurogenesis after stroke. VTN inhibits this response in females, but not in males, as shown by ~70% more stroke-induced SVZ neurogenesis in female VTN−/− mice at 14 d. In female VTN−/− mice, stroke-induced expression of interleukin-6 (IL-6) at 24 h was reduced in the SVZ. The closely related leukemia inhibitory factor (LIF) or pro-neurogenic ciliary neurotrophic factor (CNTF) were not affected. The female-specific effect of VTN on IL-6 expression was not due to sex hormones, as shown by ovariectomy and castration. IL-6 injection next to the SVZ reversed the MCAO-induced increase in neurogenesis seen in VTN−/− mice. Our in vitro and vivo data suggest that plasma VTN activates focal adhesion kinase (FAK) in the SVZ following MCAO, which reduces IL-6 expression in astrocytes but increases it in other cells such as microglia/macrophages. Inducible conditional astrocytic FAK deletion increased MCAO-induced IL-6 expression in females at 24 h and blocked MCAO-induced neurogenesis at 14 d, confirming a key detrimental role of IL-6. Collectively, these data suggest that leakage of VTN into the SVZ reduces the neurogenic response to stroke in female mice by promoting IL-6 expression. Reducing VTN or VTN signaling may be an approach to promote neurogenesis for neuroprotection and cell replacement after stroke in females.

Balali_Pargol_MSc thesis_Neuroscience department_2023Sep / Background: Cerebral microbleeds are asymptomatic neuroimaging markers of small vessel disease (SVD), visualized as small hypointensities on blood-sensitive magnetic resonance imaging (MRI) sequences. Patients with ischemic stroke and microbleeds are at a higher risk of future ischemic stroke and intracranial hemorrhage. Antithrombotic therapies, the mainstay treatment of secondary stroke prevention, are associated with an increased risk of bleeding. This raises concerns surrounding the net benefit of antithrombotic therapies in these hemorrhage-prone patients. The overarching aim of this thesis is to determine the safety of antithrombotic treatments in patients with hemorrhage-prone SVD marked by microbleeds on MRI or prior intracerebral hemorrhage (ICH). I aimed to characterize the association between baseline microbleeds and the risk of future clinical outcomes in patients with ischemic stroke and whether there exists treatment effect modification of different anticoagulants on clinical outcomes according to microbleeds presence, location, and number. Methods: We performed post hoc analyses on two multicenter previously conducted randomized trials in patients with non-cardioembolic ischemic stroke. For the PACIFIC-STROKE trial, we used multivariable regression models to determine the contribution of microbleeds to the risk of new microbleeds, hemorrhagic transformation (HT), ischemic stroke, intracranial hemorrhage, and death. We assessed the treatment effect of asundexian, a factor XIa inhibitor, vs. placebo on these clinical outcomes, stratified by microbleeds presence, location, and number. I was trained on standardized rating of microbleeds on MRI, achieved excellent interrater reliability, and rated all DATAS-II participant MRIs. I used multivariable logistic regression models to identify the association between microbleeds and HT and 90-day excellent functional outcome. I assessed the interaction between treatment with dabigatran, a direct thrombin inhibitor, vs. aspirin and microbleeds for these outcomes. Separately, I performed a review of the literature and wrote an editorial discussing the optimum timing of antiplatelet re-initiation after ICH. Results: The PACIFIC-STROKE post hoc analyses showed that microbleeds are associated with a 1.6-fold and 4.4-fold higher risk of HT and new microbleeds, respectively. The DATAS-II exploratory analyses demonstrated no association between the risk of outcomes and microbleeds presence. We found no interaction between treatment assignment and microbleed presence for any of the clinical outcomes investigated in either of these studies. Based on the totality of evidence, we concluded that early resumption of antiplatelets in ICH survivors is likely to be safe. Conclusion: Our findings do not support existing concerns surrounding the use of anticoagulants in patients with acute ischemic stroke and microbleeds on MRI, nor for the early resumption of antiplatelets in ICH survivors. / Thesis / Master of Science (MSc) / Diseases of small brain blood vessels can lead to strokes due to blockage or bleeding. Small, asymptomatic brain bleeds on MRIs (microbleeds) are common among affected patients. Patients with clot-induced stroke and microbleeds have a higher risk of both types of strokes. Blood thinners are standard treatments to prevent future clotting events after clot-induced stroke. However, their potential to increase the risk of brain bleeding has raised concerns regarding their use in patients with microbleeds or bleeding-induced stroke. We assessed information from two large, previously completed randomized trials to evaluate the safety of strong blood thinners (anticoagulants) in patients with clot-induced stroke and microbleeds. Additionally, we evaluated the risk vs. benefit of restarting milder blood thinners (antiplatelets) early after bleeding-induced stroke. Bleeding was more prevalent in patients with microbleeds; however, the effect of the anticoagulants tested on bleeding outcomes was not modified by microbleed presence. Overall, our findings suggest that blood thinners are safe in patients with clot-induced stroke and microbleeds, and that early resumption of antiplatelets seems safe in patients with bleeding-induced stroke.

Stroke is a devastating neurological disease with limited treatment opportunities. Recent advances in understanding the underlying pathogenesis of cerebral ischemia support the involvement of multiple biochemical pathways in the development of the ischemic injury. The work reported in this thesis was undertaken to investigate the hypothesis that fenamate NSAIDs have neuroprotective properties against ischemic stroke and to explore the underlying mechanisms for any efficacy. Fenamates are non-selective inhibitors of cyclooxygenases. In addition, fenamates are antagonists of non-selective cation channels, subtype-selective modulators of GABA A receptors, weak inhibitors of glutamate receptors and activators of some potassium channels, all potentially important in the pathogenesis of ischemic stroke. Mefenamic acid, a prototype fenamate, administered by intracerebroventricular (ICV) infusion, reduced the ischemic brain damage and edema volume in the middle cerebral artery occlusion model in male rats. Consistent with these results, systemic administration of mefenamic acid, by multiple intravenous injections, also reduced the ischemic damage and edema volume measured by morphometric analysis and as a function of brain water content. These are the first set of experiments to demonstrate a significant neuroprotective effect of a fenamate against an in vivo model of ischemic stroke. In vitro , mefenamic acid was also shown to reduce glutamate-evoked cell death ( excitotoxicity ) in a concentration-dependent manner in cultured embryonic rat hippocampal neurons. Similarly, selected other fenamates also reduced excitotoxicity in the rank order (from highest): mefenamic acid > flufenamic acid ≥ meclofenamic acid > niflumic acid supporting the idea that this is a drug class action. Three pharmacological properties of fenamates, cyclooxygenase inhibition, GABA A receptor modulation and potassium channel activation were investigated as the potential mechanism(s) for the neuroprotective effects of mefenamic acid against excitotoxicity. The experimental results suggest that these are not the primary mechanisms for neuroprotective effects of mefenamic acid against glutamate-evoked cell death. Collectively, these data support the hypothesis that fenamate NSAIDs are neuroprotective against experimental models of cerebral ischemia and suggest they should be further investigated as potential pharmacological treatments for stroke.

Yes / Endothelial dysfunction and damage underlie cerebrovascular disease and ischemic stroke. We undertook corneal confocal microscopy (CCM) to quantify corneal endothelial cell and nerve morphology in 146 patients with an acute ischemic stroke and 18 age-matched healthy control participants. Corneal endothelial cell density was lower (P<0.001) and endothelial cell area (P<0.001) and perimeter (P<0.001) were higher, whilst corneal nerve fbre density (P<0.001), corneal nerve branch density (P<0.001) and corneal nerve fbre length (P=0.001) were lower in patients with acute ischemic stroke compared to controls. Corneal endothelial cell density, cell area and cell perimeter correlated with corneal nerve fber density (P=0.033, P=0.014, P=0.011) and length (P=0.017, P=0.013, P=0.008), respectively. Multiple linear regression analysis showed a signifcant independent association between corneal endothelial cell density, area and perimeter with acute ischemic stroke and triglycerides. CCM is a rapid non-invasive ophthalmic imaging technique, which could be used to identify patients at risk of acute ischemic stroke. / Qatar National Research Fund Grant BMRP20038654

No description available.

Paroxysmal Atrial fibrillation (AF) is often clinically silent and may be missed by the usual diagnostic workup after ischemic stroke. We aimed to determine whether shape characteristics of ischemic stroke lesions can be used to predict AF in stroke patients without known AF at baseline. Lesion shape quantification on brain MRI was performed in selected patients from the intervention arm of the Impact of standardized MONitoring for Detection of Atrial Fibrillation in Ischemic Stroke (MonDAFIS) study, which included patients with ischemic stroke or TIA without prior AF. Multiple morphologic parameters were calculated based on lesion segmentation in acute brain MRI data. Multivariate logistic models were used to test the association of lesion morphology, clinical parameters, and AF. A stepwise elimination regression was conducted to identify the most important variables. A total of 755 patients were included. Patients with AF detected within 2 years after stroke (n=86) had a larger overall oriented bounding box (OBB) volume (p=0.003) and a higher number of brain lesion components (p=0.008) than patients without AF. In the multivariate model, OBB volume (OR 1.72, 95%CI 1.29–2.35, p<0.001), age (OR 2.13, 95%CI 1.52–3.06, p<0.001), and female sex (OR 2.45, 95%CI 1.41–4.31, p=0.002) were independently associated with detected AF. Ischemic lesions in patients with detected AF after stroke presented with a more dispersed infarct pattern and a higher number of lesion components. Together with clinical characteristics, these lesion shape characteristics may help in guiding prolonged cardiac monitoring after stroke.

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No description available.