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Background: Stroke in UK Biobank (UKB) is ascertained via linkages to coded administrative datasets and self-report. We studied the accuracy of these codes using genetic validation. Methods: We compiled stroke-specific and broad cerebrovascular disease (CVD) code lists (Read V2/V3, ICD-9/-10) for medical settings (hospital, death record, primary care) and self-report. Among 408,210 UKB participants, we identified all with a relevant code, creating 12 stroke definitions based on the code type and source. We performed genome-wide association studies (GWASs) for each definition, comparing summary results against the largest published stroke GWAS (MEGASTROKE), assessing genetic correlations, and replicating 32 stroke-associated loci. Results: The stroke case numbers identified varied widely from 3,976 (primary care stroke-specific codes) to 19,449 (all codes, all sources). All 12 UKB stroke definitions were significantly correlated with the MEGASTROKE summary GWAS results (rg.81-1) and each other (rg.4-1). However, Bonferroni-corrected confidence intervals were wide, suggesting limited precision of some results. Six previously reported stroke-associated loci were replicated using ≥1 UKB stroke definition. Conclusions: Stroke case numbers in UKB depend on the code source and type used, with a 5-fold difference in the maximum case-sample size. All stroke definitions are significantly genetically correlated with the largest stroke GWAS to date. [ABSTRACT FROM AUTHOR]

Objectives: It has been suggested that diffusion tensor imaging (DTI) measures sensitive to white matter (WM) damage may predict future dementia risk not only in cerebral small vessel disease (SVD), but also in mild cognitive impairment. To determine whether DTI measures were associated with cognition cross-sectionally and predicted future dementia risk across the full range of SVD severity, we established the International OPtimising mulTImodal MRI markers for use as surrogate markers in trials of Vascular Cognitive Impairment due to cerebrAl small vesseL disease collaboration which included six cohorts.Methods: Among the six cohorts, prospective data with dementia incidences were available for three cohorts. The associations between six different DTI measures and cognition or dementia conversion were tested. The additional contribution to prediction of other MRI markers of SVD was also determined.Results: The DTI measure mean diffusivity (MD) median correlated with cognition in all cohorts, demonstrating the contribution of WM damage to cognition. Adding MD median significantly improved the model fit compared to the clinical risk model alone and further increased in all single-centre SVD cohorts when adding conventional MRI measures. Baseline MD median predicted dementia conversion. In a study with severe SVD (SCANS) change in MD median also predicted dementia conversion. The area under the curve was best when employing a multimodal MRI model using both DTI measures and other MRI measures.Conclusions: Our results support a central role for WM alterations in dementia pathogenesis in all cohorts. DTI measures such as MD median may be a useful clinical risk predictor. The contribution of other MRI markers varied according to disease severity. [ABSTRACT FROM AUTHOR]

Objective: To systematically investigate causal relationships between obesity and cerebrovascular disease and the extent to which hypertension and hyperglycemia mediate the effect of obesity on cerebrovascular disease.Methods: We used summary statistics from genome-wide association studies for body mass index (BMI), waist-to-hip ratio (WHR), and multiple cerebrovascular disease phenotypes. We explored causal associations with 2-sample Mendelian randomization (MR) accounting for genetic covariation between BMI and WHR, and we assessed what proportion of the association between obesity and cerebrovascular disease was mediated by systolic blood pressure (SBP) and blood glucose levels, respectively.Results: Genetic predisposition to higher BMI did not increase the risk of cerebrovascular disease. In contrast, for each 10% increase in WHR there was a 75% increase (95% confidence interval [CI] = 44-113%) in risk for large artery ischemic stroke, a 57% (95% CI = 29-91%) increase in risk for small vessel ischemic stroke, a 197% increase (95% CI = 59-457%) in risk of intracerebral hemorrhage, and an increase in white matter hyperintensity volume (β = 0.11, 95% CI = 0.01-0.21). These WHR associations persisted after adjusting for genetic determinants of BMI. Approximately one-tenth of the observed effect of WHR was mediated by SBP for ischemic stroke (proportion mediated: 12%, 95% CI = 4-20%), but no evidence of mediation was found for average blood glucose.Interpretation: Abdominal adiposity may trigger causal pathological processes, partially independent from blood pressure and totally independent from glucose levels, that lead to cerebrovascular disease. Potential targets of these pathological processes could represent novel therapeutic opportunities for stroke. ANN NEUROL 2020;87:516-524. [ABSTRACT FROM AUTHOR]

Acute brain ischemia induces a local neuroinflammatory reaction and alters peripheral immune homeostasis at the same time. Recent evidence has suggested a key role of the gut microbiota in autoimmune diseases by modulating immune homeostasis. Therefore, we investigated the mechanistic link among acute brain ischemia, microbiota alterations, and the immune response after brain injury. Using two distinct models of acute middle cerebral artery occlusion, we show by next-generation sequencing that large stroke lesions cause gut microbiota dysbiosis, which in turn affects stroke outcome via immune-mediated mechanisms. Reduced species diversity and bacterial overgrowth of bacteroidetes were identified as hallmarks of poststroke dysbiosis, which was associated with intestinal barrier dysfunction and reduced intestinal motility as determined by in vivo intestinal bolus tracking. Recolonizing germ-free mice with dysbiotic poststroke microbiota exacerbates lesion volume and functional deficits after experimental stroke compared with the recolonization with a normal control microbiota. In addition, recolonization of mice with a dysbiotic microbiome induces a proinflammatory T-cell polarization in the intestinal immune compartment and in the ischemic brain. Using in vivo cell-tracking studies, we demonstrate the migration of intestinal lymphocytes to the ischemic brain. Therapeutic transplantation of fecal microbiota normalizes brain lesion-induced dysbiosis and improves stroke outcome. These results support a novel mechanism in which the gut microbiome is a target of stroke-induced systemic alterations and an effector with substantial impact on stroke outcome. [ABSTRACT FROM AUTHOR]

Magnetization transfer imaging (MTI) can detect microstructural brain tissue changes and may be helpful in determining age-related cerebral damage. We investigated the association between the magnetization transfer ratio (MTR) in gray and white matter (WM) and cognitive functioning in 355 participants of the Austrian stroke prevention family study (ASPS-Fam) aged 38-86 years. MTR maps were generated for the neocortex, deep gray matter structures, WM hyperintensities, and normal appearing WM (NAWM). Adjusted mixed models determined whole brain and lobar cortical MTR to be directly and significantly related to performance on tests of memory, executive function, and motor skills. There existed an almost linear dose-effect relationship. MTR of deep gray matter structures and NAWM correlated to executive functioning. All associations were independent of demographics, vascular risk factors, focal brain lesions, and cortex volume. Further research is needed to understand the basis of this association at the tissue level, and to determine the role of MTR in predicting cognitive decline and dementia. [ABSTRACT FROM AUTHOR]

Background and Aim: Dilated perivascular spaces (dPVS) have previously been associated with aging and hypertension-related cerebral microangiopathy. However, their risk factors, radiological features and clinical relevance have been poorly evaluated in CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy), a unique model to investigate the pathophysiology of ischemic small-vessel disease. The purpose of this study was to investigate these different aspects in a large cohort of patients with this disorder. Methods: Demographic and MRI data of 344 patients from a prospective cohort study were analyzed. The severity of dPVS was evaluated separately in the anterior temporal lobes, subinsular areas, basal ganglia and white matter, using validated semiquantitative scales. Logistic and multiple linear regression models were used to determine the risk factors associated with the severity of dPVS in these different regions and their relationships with cognition, disability and the MRI markers of the disease (white matter hyperintensities (WMH) lacunar infarcts, microbleeds and brain parenchymal fraction (BPF)). Results: The severity of dPVS was found to increase with age regardless of cerebral area (p < 0.001). In contrast with dPVS in other locations, the severity of dPVS in the temporal lobes or subinsular areas was also found strongly and specifically related to the extent of WMH (p < 0.001). Conversely, no significant association was detected with lacunar volume, number of microbleeds or BPF. A high degree of dPVS in the white matter was associated with lower cognitive performances independently of age and other MRI markers of the disease including BPF (p ≤ 0.04). Conclusions: In CADASIL, the progression of the hereditary microangiopathy with aging may promote the dilation of perivascular spaces throughout the whole brain but with variable extent according to cerebral location. In temporal lobes and subinsular areas, dPVS are common MRI features and may share a similar pathogenesis with the extension of WMH during the course of the disease. dPVS may also participate in the development of cognitive decline in this model of small-vessel disease, and their large number in white matter may alert clinicians to a higher risk of cognitive decline in CADASIL. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background In up to 30% of patients with ischemic stroke no definite etiology can be established. A significant proportion of cryptogenic stroke cases may be due to non-stenosing atherosclerotic plaques or low grade carotid artery stenosis not fulfilling common criteria for atherothrombotic stroke. The aim of the CAPIAS study is to determine the frequency, characteristics, clinical and radiological long-term consequences of ipsilateral complicated American Heart Association lesion type VI (AHA-LT VI) carotid artery plaques in patients with cryptogenic stroke. Methods/ design 300 patients (age >49 years) with unilateral DWI-positive lesions in the anterior circulation and non- or moderately stenosing (<70% NASCET) internal carotid artery plaques will be enrolled in the prospective multicenter study CAPIAS. Carotid plaque characteristics will be determined by high-resolution black-blood carotid MRI at baseline and 12 month follow up. Primary outcome is the prevalence of complicated AHA-LT VI plaques in cryptogenic stroke patients ipsilateral to the ischemic stroke compared to the contralateral side and to patients with defined stroke etiology. Secondary outcomes include the association of AHA-LT VI plaques with the recurrence rates of ischemic events up to 36 months, rates of new ischemic lesions on cerebral MRI (including clinically silent lesions) after 12 months and the influence of specific AHA-LT VI plaque features on the progression of atherosclerotic disease burden, on specific infarct patterns, biomarkers and aortic arch plaques. Discussion CAPIAS will provide important insights into the role of non-stenosing carotid artery plaques in cryptogenic stroke. The results might have implications for our understanding of stroke mechanism, offer new diagnostic options and provide the basis for the planning of targeted interventional studies. [ABSTRACT FROM AUTHOR]

Cortical ischemic stroke affecting the precentral “hand knob” area is a rare but well known stroke entity. To date, little is known about the underlying stroke mechanisms and the prognosis. Twenty-nine patients admitted to our service between 2003 and 2007 were included in the study on the basis of an acute ischemic infarct of the cortical “hand knob” area confirmed by diffusion-weighted magnetic resonance imaging with contralateral hand paresis. For all patients clinical, epidemiological as well as imaging data at the time point of admission were analysed retrospectively and follow-up data on all patients was obtained. The majority ( n = 21/72%) had an isolated infarct of the cortical “hand knob” area. In 23 (79%) patients it was a first ever stroke. Ten patients (34%) had ipsilateral extracranial stenosis of the internal carotid artery (ICA), whereas potential cardiac embolic sources were less frequent ( n = 4/14%). No patient exhibited ipsilateral MCA stenosis. All but two patients (93%) had marked atherosclerotic alterations of the ICA. Hypertension was the most prevalent vascular risk factor ( n = 23/79%). At follow-up (mean 25.0 months, range 0.4–47.4 months) no patient had died and only one (3%) experienced a recurrent stroke. The majority of patients (79%) reported improvement of hand paresis, 17 (59%) were asymptomatic (modified Rankin score = 0). Only one patient was significantly disabled due to a recurrent stroke. In conclusion, ischemic infarcts affecting the cortical “hand knob” area are frequently associated with atherosclerotic changes of the carotid artery, suggesting an arterio-arterial thrombembolic stroke mechanism. It mostly reflects first ever ischemic stroke, and follow-up data suggest a rather benign course. [ABSTRACT FROM AUTHOR]

Focal cerebral ischemia leads to the gradual disruption of the extracellular matrix. A key role in the turnover of the extracellular matrix is played by the system of matrix metalloproteinases (MMPs). In this study we describe changes of the MMP inducer protein (EMMPRIN) following experimental cerebral ischemia (induced for 3 h and followed by 24 h reperfusion, suture model) in rats. Extracellular EMMPRIN was measured by Western blot of the ischemic and nonischemic basal ganglia and cortex separately. Compared with the contralateral nonischemic area, the ischemic hemisphere showed a significant increase in EMMPRIN: basal ganglia, 158% ± 4% ( P < 0.05); cortex, 128% ± 25% ( P < 0.05). Immunohistochemistry was used to localize EMMPRIN on cerebral microvessels. EMMPRIN-positive microvascular structures were quantified by automatic morphometric video-imaging analysis and a significant increase in the number of cerebral microvessels staining positive for EMMPRIN in the ischemic basal ganglia was shown. The significant loss of microvascular basal lamina antigen collagen type IV in ischemic cortex and basal ganglia was calculated by Western blot. Measured by gelatin zymography, we demonstrated an MMP-2 and MMP-9 increase in the ischemic brain regions ( P < 0.05). For the first time the MMP activation system EMMPRIN was shown to be relevant in cerebral ischemia. These results raise the possibility that the increased expression of EMMPRIN, the increase in MMPs and the damage of the basal lamina following cerebral ischemia are connected and part of a network of related changes. [ABSTRACT FROM AUTHOR]

Mutations in NOTCH3 are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) an inherited small vessel disease leading to subcortical strokes and dementia. Since the vascular pathology is clearly defined, CADASIL may provide important insights into the mechanisms underlying lacunar infarcts, ischemic white matter changes, and vascular dementia. Evidence from different sources suggests a central role for vascular smooth muscle cells (VSMC) in the pathophysiology of the disease. This article gives a brief overview on the phenotypic spectrum of the disease and discusses some of the relevant disease mechanisms that lead from Notch3 mutations to ischemic infarcts. [Copyright &y& Elsevier]

Summary: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is the most common heritable cause of stroke and vascular dementia in adults. Clinical and neuroimaging features resemble those of sporadic small-artery disease, although patients with CADASIL have an earlier age at onset of stroke events, an increased frequency of migraine with aura, and a slightly variable pattern of ischaemic white-matter lesions on brain MRI. NOTCH3 (Notch homolog 3), the gene involved in CADASIL, encodes a transmembrane receptor primarily expressed in systemic arterial smooth-muscle cells. Pathogenetic mutations alter the number of cysteine residues in the extracellular domain of NOTCH3, which accumulates in small arteries of affected individuals. Functional and imaging studies in cultured cells, genetically engineered mice, and patients with CADASIL have all provided insights into the molecular and vascular mechanisms underlying this disease. A recent multicentre trial in patients with cognitive impairment emphasises the feasibility of randomised trials in patients with CADASIL. In this Review, we summarise the current understanding of CADASIL, a devastating disorder that also serves as a model for the more common forms of subcortical ischaemic strokes and pure vascular dementia. [Copyright &y& Elsevier]

Abstract: Tetracyclines inhibit matrix metalloproteinases (MMPs) and reduce infarction volume following cerebral ischemia. In this thesis an involvement of urokinase could be proven. Cerebral ischemia in rats was induced for 3 h followed by 24 h reperfusion (suture model). Each 6 animals received orally either doxycycline or water. Doxycycline treatment began 10 days before ischemia. MMP-2 and MMP-9 were substantially decreased. The possibility of involvement of the endogenous MMP inhibitors in the MMP inhibiting mechanisms was excluded. The plasminogen activator uPA was significantly decreased by doxycycline indicating an MMP inhibiting mechanism including the plasminogen/plasmin system. In the doxycycline group, this resulted in a decreased damage to the cerebral microvessels and less loss of the basal lamina antigen collagen type IV. Hemoglobin extravasation was also significantly reduced. Our results suggest that doxycycline may have a potential use as an anti-ischemic compound since it provides microvascular protection by inhibiting the plasminogen system. [Copyright &y& Elsevier]

The article discusses how Moyamoya Disease Susceptibility Variant RNF213 p.R4810K Increases the Risk of Ischemic Stroke Attributable to Large-Artery Atherosclerosis. Topics include how Ischemic stroke (IS) is the leading cause of disability and early death in Asia, where large-artery atherosclerosis (LAA) attributable to intracranial stenosis is the predominant etiology.

Abstract: A clinical impact of cognitive reserve (CR) has been demonstrated in Alzheimer''s disease, whereas its role in vascular cognitive impairment (VCI) is largely unknown. In this study, we investigated the impact of CR in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic variant of pure VCI. A total of 247 NOTCH3 mutation carriers from a two-center study were investigated using detailed neuropsychological and neuroimaging protocols. CR was operationalized as years of formal education. Brain pathology was assessed by MRI using normalized brain volume and lacunar lesion volume as proxies. Multivariate analyses were done for each structural measure with scores of processing speed, executive function, and memory as dependent variables. Additional linear regression models were conducted with interaction terms for education × brain volume and education × lacunar lesion volume. Education had an independent impact on cognitive performance in subjects with mild and moderate degrees of brain pathology, whereas there was no significant influence of education on cognition in patients with severe MRI changes. This interaction was found for processing speed, the cognitive domain most impaired in our patients. Our findings demonstrate an interaction of education and brain pathology in regard to cognitive impairment: the effect of education seems most pronounced in early disease stages but may ultimately be overwhelmed by the pathological changes. The results extend the concept of CR to VCI. [Copyright &y& Elsevier]

Abstract: Clinical studies have shown that the treatment of ischemic stroke with hypothermia is promising. In this animal study, we investigated the fate of the microvasculature following focal cerebral ischemia in mice with and without hypothermia. Focal cerebral ischemia was induced by occlusion of the middle cerebral artery (MCAO) (3 h) with an intraluminal filament technique. Eight mice received normothermia (36.5 °C, NT) and eight received hypothermia (32–34 °C, HT) treatment during 24 h of reperfusion. Another six mice represented the sham group. Analysis of the hypothermic group in comparison to the normothermic group revealed a significantly reduced infarct volume (NT: 63.56±4.62 mm3 SEM, HT: 38.09±4.83 mm3 SEM; P <0.01) and showed considerably ameliorated neurological deficits (Garcia-score) after 24 h (P <0.01). In addition, the degradation of the microvascular basal lamina antigen collagen type IV after normothermia was strongly reduced (P <0.05) compared to sham. Hypothermia diminished this effect so that collagen type IV was not significantly reduced compared to sham. Moreover the hemoglobin extravasation was strongly reduced under hypothermic treatment compared to the normothermic group (P <0.01). In the hypothermia group the urokinase plasminogen-activator (uPA) activity (P =0.01) was significantly decreased compared to the normothermia group. Also MMP-9 was significantly reduced (P <0.05) during hypothermic treatment. In conclusion, for the first time we show in mice that hypothermia preserves the microvascular wall structures after ischemia. We have demonstrated that hypothermia protects the basal lamina, reduces the infarct volume and hemorrhage, and reduces proteolytic enzymes. These protective effects in an additional animal model of ischemia and reperfusion strongly recommend hypothermia as a potential beneficial treatment for stroke. [Copyright &y& Elsevier]

Abstract: We describe a novel experimental set-up that allows biochemical, immunohistochemical and morphometric recording of multiple parameters from a single rat brain. The whole brain was cut (coronal sectioning) in a volumetric manner, and 100 cryo-sections (10μm) were collected from the region of infarction. By use of a scalpel to dissect the cryosection, crude brain material was obtained from the cortical and basal ganglia areas of ischemic and non-ischemic hemispheres. Material from four 10μm thick sections of the same animal was pooled. About 30μg protein lysate was extracted per four sections with various lysis buffers; this sufficed for one biochemical or enzymatic test called “micro-Western-blots” or “micro-zymographies”. Scraping brain material from cryosections allows the detection of up to 25 parameters from adjacent brain sections of one single rat brain. Different analysis are possible, we have chosen, e.g. to compare factors affecting the basal lamina of cerebral microvessels like the content of the metalloproteinases-2/-9, their tissue inhibitors, the plasminogen activators, collagen type IV, parameters to test the blood–brain barrier: hemoglobin and the protein of the perfusion solution BSA and the infarction volume. On the basis of these parameters it was possible to compare the interactions of the complex processes in the ischemic brain in the same animal in adjacent sections. Thus, this method increases the validity of data comparisons and reduces significantly the number of animals needed in various experimental settings. [Copyright &y& Elsevier]

Abstract: Both ischemic stroke and peripheral arterial thromboembolism have been described as extraintestinal complications of inflammatory bowel disease. Here, we present the first case with direct cooccurrence of ischemic stroke and peripheral thromboembolism in a 39-year-old patient with Crohn''s disease. A pathophysiological model explaining this cooccurrence as well as the significance of prothrombotic risk factors (“hypercoaguable state”) in the setting of inflammatory bowel disease and stroke are discussed. [Copyright &y& Elsevier]