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Apraxia of speech is a motor speech disorder that occurs after lesions to the left cerebral hemisphere, most often concomitant with aphasia. It requires specific approaches in the study of its physiological and neuroanatomical basis and special expertise in clinical care. Knowing its prevalence in patients with aphasia after stroke is therefore relevant for planning specific resources in clinical research and in health care provision. Systematic studies of the frequency of this condition are lacking. We examined the frequency of apraxia of speech in a representative sample of 156 patients with chronic post-stroke aphasia. Three experts classified the patients' speech by best-practice auditory-perceptual methods. Bayesian hierarchical models were fitted to obtain probability distributions for prevalence estimates. A prior distribution was calculated in two steps, including Bayesian models for published frequency data (step 1) and prevalence estimates from experienced clinicians (step 2). Separate models were fitted for different severity ranges. Overall, a prevalence rate of .44 [.30, .58] was obtained. When only moderate and severe cases were taken into account, the rate was .35 [.23, .49]. After a further restriction to only severe impairment, prevalence dropped to .22 [.12, .34]. Patients identified with apraxia of speech had suffered more severe strokes according to clinical criteria and had more severe aphasias. The presence of apraxia of speech was predicted by the articulation/prosody and syntax rating scales of the Aachen Aphasia Test. Lower prevalence estimates published earlier are probably biased by low sensitivity of assessment instruments for mild speech impairment.

Background White matter hyperintensities (WMH) are the result of cerebral small vessel disease and may increase the risk of cognitive impairment (CI), recurrent stroke, and depression. We aimed to explore the association between selected cerebrovascular risk factors (CVRF) and WMH load as well as the effect of increased WMH burden on recurrent vascular events, CI, and depression in first-ever ischemic stroke patients. Methods 431 from the PROSpective Cohort with Incident Stroke (PROSCIS) were included; Age-Related White Matter Changes (ARWMC) score was used to assess WMH burden on FLAIR. The presence of CVRF (defined via blood pressure, body-mass-index, and serological markers of kidney dysfunction, diabetes mellitus, and hyperlipoproteinemia) was categorized into normal, borderline, and pathological profiles based on commonly used clinical definitions. The primary outcomes included recurrent vascular events (combined endpoint of recurrent stroke, myocardial infarction and/or death), CI 3 years post-stroke, and depression 1-year post-stroke. Results There was no clear association between CVRF profiles and WMH burden. High WMH lesion load (ARWMC score ≥ 10) was found to be associated with CI (adjusted OR 1.05 [95% CI 1.00–1.11]; p p = 0.18). WMH burden was not associated with depression 1-year post stroke (adjusted OR 0.72 [95% CI 0.31–1.64]; p = 0.44). Conclusion Higher WMH burden was associated with a significant decline in cognition 3 years post-stroke in this cohort of first-ever stroke patients.

Background Although of high individual and socioeconomic relevance, a reliable prediction model for the prognosis of juvenile stroke (18–55 years) is missing. Therefore, the study presented in this protocol aims to prospectively validate the discriminatory power of a prediction score for the 3 months functional outcome after juvenile stroke or transient ischemic attack (TIA) that has been derived from an independent retrospective study using standard clinical workup data. Methods PREDICT-Juvenile-Stroke is a multi-centre (n = 4) prospective observational cohort study collecting standard clinical workup data and data on treatment success at 3 months after acute ischemic stroke or TIA that aims to validate a new prediction score for juvenile stroke. The prediction score has been developed upon single center retrospective analysis of 340 juvenile stroke patients. The score determines the patient’s individual probability for treatment success defined by a modified Rankin Scale (mRS) 0–2 or return to pre-stroke baseline mRS 3 months after stroke or TIA. This probability will be compared to the observed clinical outcome at 3 months using the area under the receiver operating characteristic curve. The primary endpoint is to validate the clinical potential of the new prediction score for a favourable outcome 3 months after juvenile stroke or TIA. Secondary outcomes are to determine to what extent predictive factors in juvenile stroke or TIA patients differ from those in older patients and to determine the predictive accuracy of the juvenile stroke prediction score on other clinical and paraclinical endpoints. A minimum of 430 juvenile patients ( Discussion The juvenile stroke prediction score has the potential to enable personalisation of counselling, provision of appropriate information regarding the prognosis and identification of patients who benefit from specific treatments. Trial registration The study has been registered at https://drks.de on March 31, 2022 (DRKS00024407).

The field of medical and population genetics in stroke is moving at a rapid pace and has led to unanticipated opportunities for discovery and clinical applications. Genome-wide association studies have highlighted the role of specific pathways relevant to etiologically defined subtypes of stroke and to stroke as a whole. They have further offered starting points for the exploration of novel pathways and pharmacological strategies in experimental systems. Mendelian randomization studies continue to provide insights in the causal relationships between exposures and outcomes and have become a useful tool for predicting the efficacy and side effects of drugs. Additional applications that have emerged from recent discoveries include risk prediction based on polygenic risk scores and pharmacogenomics. Among the topics currently moving into focus is the genetics of stroke outcome. While still at its infancy, this field is expected to boost the development of neuroprotective agents. We provide a brief overview on recent progress in these areas.

AimsAssessing whether modifiable risk factors are causally associated with reduced stroke risk is important in planning public health measures, but determining causality can be difficult in epidemiological data. Leveraging large-scale genetic data in a technique known as Mendelian randomisation, we aimed to determine whether modifiable lifestyle factors including educational attainment, smoking, and body mass index are causal risk factors for ischaemic stroke and its different subtypes and haemorrhagic stroke.Methods and ResultsWe performed two-sample and multivariable Mendelian randomization to assess the causal effect of twelve lifestyle factors on risk of stroke and whether these effects are independent. We found genetic predisposition to increased number of years of education to be inversely associated with ischaemic, large-artery, and small-vessel stroke, as well as with intracerebral haemorrhage. Genetic predisposition to ever smoking regularly, higher body mass index (BMI), and higher waist-hip ratio are also associated with ischaemic and large-artery stroke. Additionally, we found that the effects of education, BMI, and smoking on ischaemic stroke to be independent of each other.ConclusionGenetic predisposition to higher educational attainment can reduce the risk of ischaemic, large-artery, and small-vessel stroke, while genetic predisposition to smoking and higher anthropometry measures can increase the risk of these stroke subtypes. This suggests that lifestyle modification addressing these risk factors will reduce stroke risk.

Background: Elevated triglyceride and glucose levels are associated with an increased cardiovascular disease risk including ischemic stroke. It is not known whether the response to a combined oral triglyceride and glucose challenge after ischemic stroke improves identification of patients with increased risk for recurrent vascular events. Methods: The prospective, observational Berlin “Cream&Sugar” study was conducted at 3 different university hospital sites of the Charité–Universitätsmedizin Berlin, Germany, between January 24, 2009 and July 31, 2017. Patients with first-ever ischemic stroke were recruited 3 to 7 days after stroke. An oral triglyceride tolerance test (OTTT) and consecutive blood tests before (t 0 ) as well as 3 (t 1 ), 4 (t 2 ), and 5 hours (t 3 ) after OTTT were performed in fasting patients. An oral glucose tolerance test was performed in all nondiabetic patients 3 hours after the start of OTTT. Outcomes of the study were recurrent fatal or nonfatal stroke as well as a composite vascular end point including stroke, transient ischemic attack, myocardial infarction, coronary revascularization, and cardiovascular death assessed 1 year after stroke. Cox regression models were used to estimate hazard ratios and corresponding 95% CIs between patients with high versus low levels of triglyceride and glucose levels. Results: Overall 755 patients were included; 523 patients completed OTTT and 1-year follow-up. Patients were largely minor strokes patients with a median National Institutes of Health Stroke Scale score of 1 (0–3). Comparing highest versus lowest quartiles of triglyceride levels, neither fasting (adjusted hazard ratio t0 , 1.24 [95% CI, 0.45–3.42]) nor postprandial triglyceride levels (adjusted hazard ratio t3 , 0.44 [95% CI, 0.16–1.25]) were associated with recurrent stroke. With regard to recurrent vascular events, results were similar for fasting triglycerides (adjusted hazard ratio t0 , 1.09 [95% CI, 0.49–2.43]), however, higher postprandial triglyceride levels were significantly associated with a lower risk for recurrent vascular events (adjusted hazard ratio t3 , 0.42 [95% CI, 0.18–0.95]). No associations were observed between fasting and post–oral glucose tolerance test blood glucose levels and recurrent vascular risk. All findings were irrespective of the diabetic status of patients. Conclusions: In this cohort of patients with first-ever‚ minor ischemic stroke, fasting triglyceride or glucose levels were not associated with recurrent stroke at one year after stroke. However, higher postprandial triglyceride levels were associated with a lower risk of recurrent vascular events which requires further validation in future studies. Overall, our results do not support the routine use of a combined OTTT/oral glucose tolerance test to improve risk prediction for recurrent stroke.

Poststroke cognitive impairment and dementia (PSCID) is a major source of morbidity and mortality after stroke worldwide. PSCID occurs as a consequence of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. Cognitive impairment and dementia manifesting after a clinical stroke is categorized as vascular even in people with comorbid neurodegenerative pathology, which is common in elderly individuals and can contribute to the clinical expression of PSCID. Manifestations of cerebral small vessel disease, such as covert brain infarcts, white matter lesions, microbleeds, and cortical microinfarcts, are also common in patients with stroke and likewise contribute to cognitive outcomes. Although studies of PSCID historically varied in the approach to timing and methods of diagnosis, most of them demonstrate that older age, lower educational status, socioeconomic disparities, premorbid cognitive or functional decline, life-course exposure to vascular risk factors, and a history of prior stroke increase risk of PSCID. Stroke characteristics, in particular stroke severity, lesion volume, lesion location, multiplicity and recurrence, also influence PSCID risk. Understanding the complex interaction between an acute stroke event and preexisting brain pathology remains a priority and will be critical for developing strategies for personalized prediction, prevention, targeted interventions, and rehabilitation. Current challenges in the field relate to a lack of harmonization of definition and classification of PSCID, timing of diagnosis, approaches to neurocognitive assessment, and duration of follow-up after stroke. However, evolving knowledge on pathophysiology, neuroimaging, and biomarkers offers potential for clinical applications and may inform clinical trials. Preventing stroke and PSCID remains a cornerstone of any strategy to achieve optimal brain health. We summarize recent developments in the field and discuss future directions closing with a call for action to systematically include cognitive outcome assessment into any clinical studies of poststroke outcome.

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.

Background and ObjectivesHuman genetic studies support a key role of interleukin-6 (IL-6) in the pathogenesis of ischemic stroke. However, there are only limited data from observational studies exploring circulating IL-6 levels as a risk factor for ischemic stroke. We set out to perform a systematic review and meta-analysis of aggregate data on cohort studies to determine the magnitude and shape of the association between circulating IL-6 levels and risk of incident ischemic stroke in the general population.MethodsFollowing the PRISMA guidelines, we systematically screened the PubMed search engine from inception to March 2021 for population-based prospective cohort studies exploring the association between circulating IL-6 levels and risk of incident ischemic stroke. We pooled association estimates for ischemic stroke risk with random-effects models and explored nonlinear effects in dose–response meta-analyses. Risk of bias was assessed with the Newcastle-Ottawa Scale (NOS). We used funnel plots and trim-to-fill analyses to assess publication bias.ResultsWe identified 11 studies (n = 27,411 individuals; 2,669 stroke events) meeting our eligibility criteria. Mean age of all included participants was 60.5 years and 54.8% were female. Overall, quality of the included studies was high (median 8 out of 9 NOS points, interquartile range 7–9). In meta-analyses, 1 SD increment in circulating log-transformed IL-6 levels was associated with a 19% increase in risk of incident ischemic stroke over a mean follow-up of 12.4 years (relative risk 1.19; 95% confidence interval 1.10 to 1.28). A dose–response meta-analysis showed a linear association between circulating IL-6 levels and ischemic stroke risk. There was only moderate heterogeneity and the results were consistent in sensitivity analyses restricted to studies of low risk of bias and studies fully adjusting for demographic and vascular risk factors. The results also remained stable following adjustment for publication bias.DiscussionHigher circulating IL-6 levels in community-dwelling individuals are associated with higher long-term risk of incident ischemic stroke in a linear pattern and independently of conventional vascular risk factors. Along with findings from genetic studies and clinical trials, these results provide additional support for a key role of IL-6 signaling in ischemic stroke.

Background: Observational studies suggest an association of stroke with cardiac traits beyond atrial fibrillation, the leading source of cardioembolism. However, controversy remains regarding a causal role of these traits in stroke pathogenesis. Here, we leveraged genetic data to systematically assess associations between cardiac traits and stroke risk using a Mendelian Randomization framework. Methods: We studied 66 cardiac traits including cardiovascular diseases, magnetic resonance imaging–derived cardiac imaging, echocardiographic imaging, and electrocardiographic measures, as well as blood biomarkers in a 2-sample Mendelian Randomization approach. Genetic predisposition to each trait was explored for associations with risk of stroke and stroke subtypes in data from the MEGASTROKE consortium (40 585 cases/406 111 controls). Using multivariable Mendelian Randomization, we adjusted for potential pleiotropic or mediating effects relating to atrial fibrillation, coronary artery disease, and systolic blood pressure. Results: As expected, we observed strong independent associations between genetic predisposition to atrial fibrillation and cardioembolic stroke and between genetic predisposition to coronary artery disease as a proxy for atherosclerosis and large-artery stroke. Our data-driven analyses further indicated associations of genetic predisposition to both heart failure and lower resting heart rate with stroke. However, these associations were explained by atrial fibrillation, coronary artery disease, and systolic blood pressure in multivariable analyses. Genetically predicted P-wave terminal force in V1, an electrocardiographic marker for atrial cardiopathy, was inversely associated with large-artery stroke. Conclusions: Available genetic data do not support substantial effects of cardiac traits on the risk of stroke beyond known clinical risk factors. Our findings highlight the need to carefully control for confounding and other potential biases in studies examining candidate cardiac risk factors for stroke.

The Apolipoprotein E (APOE) gene polymorphism (rs429358 and rs7412) shows a well-established association with lipid profiles, but its effect on cardiovascular disease is still conflicting. Therefore, we examined the association of different APOE alleles with common carotid artery intima-media thickness (CCA-IMT), carotid plaques, incident myocardial infarction (MI) and stroke. We analyzed data from 3327 participants aged 20–79 years of the population-based Study of Health in Pomerania (SHIP) from Northeast Germany with a median follow-up time of 14.5 years. Linear, logistic, and Cox-regression models were used to assess the associations of the APOE polymorphism with CCA-IMT, carotid plaques, incident MI and stroke, respectively. In our study, the APOE E2 allele was associated with lower CCA-IMT at baseline compared to E3 homozygotes (β: − 0.02 [95% CI − 0.04, − 0.004]). Over the follow-up, 244 MI events and 218 stroke events were observed. APOE E2 and E4 allele were not associated with incident MI (E2 HR: 1.06 [95% CI 0.68, 1.66]; E4 HR: 1.03 [95% CI 0.73, 1.45]) and incident stroke (E2 HR: 0.79 [95% CI 0.48, 1.30]; E4 HR: 0.96 [95% CI 0.66, 1.38]) in any of the models adjusting for potential confounders. However, the positive association between CCA-IMT and incident MI was more pronounced in E2 carriers than E3 homozygotes. Thus, our study suggests that while APOE E2 allele may predispose individuals to lower CCA-IMT, E2 carriers may be more prone to MI than E3 homozygotes as the CCA-IMT increases. APOE E4 allele had no effect on CCA-IMT, plaques, MI or stroke.

Ischemic stroke etiology remains undetermined in 30% of cases. We explored the genetic architecture of stroke classified as undetermined to test if mechanisms and risk factors underlying large-artery atherosclerotic (LAAS), cardioembolic (CES), and small-vessel stroke (SVS) contribute to its pathogenesis.We analyzed genome-wide data from 16,851 ischemic stroke cases and 32,473 controls. Using polygenic risk scores for LAAS, CES, and SVS, we assessed the genetic overlap with stroke of undetermined source and used pairwise genomewide association study (GWAS-PW) to search for shared loci. We then applied Mendelian randomization (MR) to identify potentially causal risk factors of stroke of undetermined source.Genetic risk for LAS, CES, and SVS was associated with stroke of undetermined source pointing to overlap in their genetic architecture. Pairwise analyses revealed 19 shared loci with LAAS, 2 with CES, and 5 with SVS that have been implicated in atherosclerosis-related phenotypes. Genetic liability to both carotid atherosclerosis and atrial fibrillation was associated with stroke of undetermined source, but the association with atrial fibrillation was attenuated after excluding cases with incomplete diagnostic workup. MR analyses showed effects of genetically determinants of blood pressure, diabetes, waist-to-hip ratio, inflammatory pathways (IL-6 signaling, MCP-1/CCL2 levels), and factor XI levels on stroke of undetermined source.Stroke of undetermined source shares genetic and vascular risk factors with other stroke subtypes, especially LAAS, thus highlighting the diagnostic limitations of current subtyping approaches. The potentially causal associations with carotid atherosclerosis and atherosclerotic risk factors might have implications for prevention strategies targeting these mechanisms. ANN NEUROL 2022;91:640-651.

After ischemic stroke, there is a significant burden of cardiovascular complications, both in the acute and chronic phase. Severe adverse cardiac events occur in 10% to 20% of patients within the first few days after stroke and comprise a continuum of cardiac changes ranging from acute myocardial injury and coronary syndromes to heart failure or arrhythmia. Recently, the term stroke–heart syndrome was introduced to provide an integrated conceptual framework that summarizes neurocardiogenic mechanisms that lead to these cardiac events after stroke. New findings from experimental and clinical studies have further refined our understanding of the clinical manifestations, pathophysiology, and potential long‐term consequences of the stroke–heart syndrome. Local cerebral and systemic mediators, which mainly involve autonomic dysfunction and increased inflammation, may lead to altered cardiomyocyte metabolism, dysregulation of (tissue‐resident) leukocyte populations, and (micro‐) vascular changes. However, at the individual patient level, it remains challenging to differentiate between comorbid cardiovascular conditions and stroke‐induced heart injury. Therefore, further research activities led by joint teams of basic and clinical researchers with backgrounds in both cardiology and neurology are needed to identify the most relevant therapeutic targets that can be tested in clinical trials.

Complicated nonstenosing carotid artery plaques (CAPs) are an under-recognized cause of stroke.The purpose of this study was to determine whether complicated CAP ipsilateral to acute ischemic anterior circulation stroke (icCAP) are associated with recurrent ischemic stroke or transient ischemic attack (TIA).The CAPIAS (Carotid Plaque Imaging in Acute Stroke) multicenter study prospectively recruited patients with ischemic stroke restricted to the territory of a single carotid artery. Complicated (AHA-lesion type VI) CAP were defined by multisequence, contrast-enhanced carotid magnetic resonance imaging obtained within 10 days from stroke onset. Recurrent events were assessed after 3, 12, 24, and 36 months. The primary outcome was recurrent ischemic stroke or TIA.Among 196 patients enrolled, 104 patients had cryptogenic stroke and nonstenosing CAP. During a mean follow-up of 30 months, recurrent ischemic stroke or TIA occurred in 21 patients. Recurrent events were significantly more frequent in patients with icCAP than in patients without icCAP, both in the overall cohort (incidence rate [3-year interval]: 9.50 vs 3.61 per 100 patient-years; P = 0.025, log-rank test) and in patients with cryptogenic stroke (10.92 vs 1.82 per 100 patient-years; P = 0.003). The results were driven by ipsilateral events. A ruptured fibrous cap (HR: 4.91; 95% CI: 1.31-18.45; P = 0.018) and intraplaque hemorrhage (HR: 4.37; 95% CI: 1.20-15.97; P = 0.026) were associated with a significantly increased risk of recurrent events in patients with cryptogenic stroke.Complicated CAP ipsilateral to acute ischemic anterior circulation stroke are associated with an increased risk of recurrent ischemic stroke or TIA. Carotid plaque imaging identifies high-risk patients who might be suited for inclusion into future secondary prevention trials. (Carotid Plaque Imaging in Acute Stroke [CAPIAS]; NCT01284933).

Background Myocardial injury as indicated by cardiac troponin elevation is associated with poor prognosis in acute stroke patients. Coronary angiography (CAG) is the diagnostic gold-standard to rule-out underlying obstructive coronary artery disease (CAD) in these patients. However, weighing risks and benefits of coronary angiography (CAG) against each other is particularly challenging, because stroke patients undergoing CAG may have a higher risk for secondary intracranial bleeding. Current guidelines remain vague. Thus, the aim of this study was to analyze frequency of pathological findings of CAG and associated clinical factors. Methods We analyzed indications and frequency of CAG performed in acute ischemic stroke patients in clinical routine in two European tertiary care hospitals from 2011 to 2018. All data were obtained retrospectively. Multiple logistic regression analyses were performed to identify variables associated with absence of obstructive coronary artery disease defined as presence of at least one coronary vessel stenosis ≥ 50%. Results A total of 139 AIS patients underwent CAG. Frequent indications for CAG were suspected acute coronary syndrome (N = 114) or scheduled cardiac surgery (N = 25). Acute coronary stenting was applied in 51/139 patients. Among patients with suspected acute coronary syndrome, no obstructive CAD was found in 27/114 patients. Absence of obstructive CAD was associated with insular cortex lesions, no clinical symptoms for ACS, less than three cardiovascular risk factors, younger age and normal wall motion. Conclusion Several variables suggest absence of CAD in AIS patients and may help in clinical decision making in stroke patients with myocardial injury.

This study sought to prospectively evaluate the prevalence, risk factors, and short-term major clinical outcomes of mobile thrombus detected on transvenous leads in patients undergoing lead extraction.The prevalence and clinical significance of thrombus on transvenous leads in patients undergoing lead extraction is not well characterized.Consecutive patients undergoing transvenous lead extraction for noninfectious indications were enrolled. Preoperative transesophageal echocardiograms were performed prospectively for all patients to examine for mobile thrombus. Anticoagulation was not started for thrombus unless other indications were present. Clinical endpoints of mortality and cardiovascular morbidity (symptomatic pulmonary embolism, myocardial infarction, or cerebrovascular accident) were assessed at a minimum of 2-month follow-up.A total of 108 patients underwent lead extraction for noninfectious indications. Lead thrombi were detected in 20 (18.5%) patients and all were

ObjectiveTo investigate the relationship between baseline white matter hyperintensities (WMH) in patients with ischemic stroke and long-term risk of dementia, functional impairment, recurrent stroke, and mortality.MethodsFollowing the Meta-analysis of Observational Studies in Epidemiology and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO protocol: CRD42018092857), we systematically searched Medline and Scopus for cohort studies of ischemic stroke patients examining whether MRI- or CT-assessed WMH at baseline are associated with dementia, functional impairment, recurrent stroke, and mortality at 3 months or later poststroke. We extracted data and evaluated study quality with the Newcastle–Ottawa scale. We pooled relative risks (RR) for the presence and severity of WMH using random-effects models.ResultsWe included 104 studies with 71,298 ischemic stroke patients. Moderate/severe WMH at baseline were associated with increased risk of dementia (RR 2.17, 95% confidence interval [CI] 1.72–2.73), cognitive impairment (RR 2.29, 95% CI 1.48–3.54), functional impairment (RR 2.21, 95% CI 1.83–2.67), any recurrent stroke (RR 1.65, 95% CI 1.36–2.01), recurrent ischemic stroke (RR 1.90, 95% CI 1.26–2.88), all-cause mortality (RR 1.72, 95% CI 1.47–2.01), and cardiovascular mortality (RR 2.02, 95% CI 1.44–2.83). The associations followed dose-response patterns for WMH severity and were consistent for both MRI- and CT-defined WMH. The results remained stable in sensitivity analyses adjusting for age, stroke severity, and cardiovascular risk factors, in analyses of studies scoring high in quality, and in analyses adjusted for publication bias.ConclusionsPresence and severity of WMH are associated with substantially increased risk of dementia, functional impairment, stroke recurrence, and mortality after ischemic stroke. WMH may aid clinical prognostication and the planning of future clinical trials.

Rationale: Proinflammatory cytokines have been identified as potential targets for lowering vascular risk. Experimental evidence and Mendelian randomization suggest a role of MCP-1 (monocyte chemoattractant protein-1) in atherosclerosis and stroke. However, data from large-scale observational studies are lacking. Objective: To determine whether circulating levels of MCP-1 are associated with risk of incident stroke in the general population. Methods and Results: We used previously unpublished data on 17 180 stroke-free individuals (mean age, 56.7±8.1 years; 48.8% men) from 6 population-based prospective cohort studies and explored associations between baseline circulating MCP-1 levels and risk of any stroke, ischemic stroke, and hemorrhagic stroke during a mean follow-up interval of 16.3 years (280 522 person-years at risk; 1435 incident stroke events). We applied Cox proportional-hazards models and pooled hazard ratios (HRs) using random-effects meta-analyses. After adjustments for age, sex, race, and vascular risk factors, higher MCP-1 levels were associated with increased risk of any stroke (HR per 1-SD increment in ln-transformed MCP-1, 1.07; 95% CI, 1.01–1.14). Focusing on stroke subtypes, we found a significant association between baseline MCP-1 levels and higher risk of ischemic stroke (HR, 1.11 [1.02–1.21]) but not hemorrhagic stroke (HR, 1.02 [0.82–1.29]). The results followed a dose-response pattern with a higher risk of ischemic stroke among individuals in the upper quartiles of MCP-1 levels as compared with the first quartile (HRs, second quartile: 1.19 [1.00–1.42]; third quartile: 1.35 [1.14–1.59]; fourth quartile: 1.38 [1.07–1.77]). There was no indication for heterogeneity across studies, and in a subsample of 4 studies (12 516 individuals), the risk estimates were stable after additional adjustments for circulating levels of IL (interleukin)-6 and high-sensitivity CRP (C-reactive protein). Conclusions: Higher circulating levels of MCP-1 are associated with increased long-term risk of stroke. Our findings along with genetic and experimental evidence suggest that MCP-1 signaling might represent a therapeutic target to lower stroke risk.Visual Overview: An online visual overview is available for this article.

Background Functional outcome post-stroke depends on time to recanalization. Effect of in-hospital delay may differ in patients directly admitted to a comprehensive stroke center and patients transferred via a primary stroke center. We analyzed the current door-to-groin time in Germany and explored its effect on functional outcome in a real-world setting. Methods Data were collected in 25 stroke centers in the German Stroke Registry-Endovascular Treatment a prospective, multicenter, observational registry study including stroke patients with large vessel occlusion. Functional outcome was assessed at three months by modified Rankin Scale. Association of door-to-groin time with outcome was calculated using binary logistic regression models. Results Out of 4340 patients, 56% were treated primarily in a comprehensive stroke center and 44% in a primary stroke center and then transferred to a comprehensive stroke center (“drip-and-ship” concept). Median onset-to-arrival at comprehensive stroke center time and door-to-groin time were 103 and 79 min in comprehensive stroke center patients and 225 and 44 min in primary stroke center patients. The odds ratio for poor functional outcome per hour of onset-to-arrival-at comprehensive stroke center time was 1.03 (95%CI 1.01–1.05) in comprehensive stroke center patients and 1.06 (95%CI 1.03–1.09) in primary stroke center patients. The odds ratio for poor functional outcome per hour of door-to-groin time was 1.30 (95%CI 1.16–1.46) in comprehensive stroke center patients and 1.04 (95%CI 0.89–1.21) in primary stroke center patients. Longer door-to-groin time in comprehensive stroke center patients was associated with admission on weekends (odds ratio 1.61; 95%CI 1.37–1.97) and during night time (odds ratio 1.52; 95%CI 1.27–1.82) and use of intravenous thrombolysis (odds ratio 1.28; 95%CI 1.08–1.50). Conclusion Door-to-groin time was especially relevant for outcome of comprehensive stroke center patients, whereas door-to-groin time was much shorter in primary stroke center patients. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03356392 . Unique identifier NCT03356392

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials., White matter hyperintensities (WMH) are a common brain-imaging feature of cerebral small vessel disease. Here, the authors carry out a GWAS and followup analyses for WMH-volume, implicating several variants with potential for risk stratification and drug targeting.

The ‘Stroke Complications after Traumatic Experiences and Stress’ (SATURN) study was designed to investigate the effects of a prior traumatic event on PTSD symptoms triggered by a subsequent stroke. First-ever ischemic stroke patients were surveyed 9–13 months after hospitalization at the Charite University Medical Center. Stroke-induced PTSD symptoms were measured using the Impact of Event Scale-revised (IES-R). Prior traumatization together with past PTSD symptoms was assessed retrospectively with the Brief Trauma Questionnaire (BTQ) and the 7-item Short Screening Scale for PTSD. Depressive symptoms were assessed with the Beck Depression Inventory (BDI-II). The Short Form (SF)-36 was used to evaluate physical and mental health outcomes. We received 258 responses from 636 eligible patients (~41%). Based on respondents' scores on the IES-R, the prevalence of probable PTSD due to the stroke event was 11% in our sample. Female sex and younger age were associated with more severe PTSD symptoms. Psychological endpoints did not differ between patients who denied prior trauma exposure and those who reported earlier trauma exposure but denied subsequent PTSD symptoms. However, a history of trauma exposure in tandem with endorsing subsequent PTSD symptoms was linked with significantly increased post-stroke PTSD and depressive symptoms together with decreased psychological well-being. Self-reported physical health did not differ across groups. Younger age, being a woman, and having developed PTSD symptoms in the aftermath of a prior trauma were associated with adverse psychological outcomes after stroke.

Background and Purpose—Our study aim was to estimate risk of incident stroke based on levels of hs-cTn (high-sensitivity cardiac troponin), a specific biomarker indicating myocardial injury, in the general population, patients with atrial fibrillation, and patients with previous stroke.Methods—Embase, PubMed, and Web of Science were searched until March 14, 2019 to identify relevant articles. Randomized controlled trials and cohort studies assessing the risk of incident stroke based on hs-cTn were eligible. Pooled adjusted hazard ratios including 95% CI were calculated using a random-effects model due to study heterogeneity per population, coding of hs-cTn (categorical/continuous data), per hs-cTn subunit (T or I), for low risk of bias, and for all-cause and ischemic stroke separately.Results—We included 17 articles with 96 702 participants. In studies conducted in the general population (n=12; 77 780 participants), the pooled adjusted hazard ratio for incident stroke was 1.25 (CI, 1.10–1.40) for high versus low hs-cTn (as defined by included studies) during an average follow-up of 1 to 20 years (median 10). When categorical data were used, this was increased to 1.58 (CI, 1.26–1.90). The results were robust when accounting for stroke classification (all-cause stroke/ischemic stroke), hs-cTn subunit, risk of bias, and coding of hs-cTn. In patients with atrial fibrillation (4 studies; 18 725 participants), the pooled adjusted hazard ratio for incident stroke was 1.95 (CI, 1.29–2.62) for high versus low hs-cTn. Due to lack of data (one study, 197 participants), no meta-analysis could be performed in patients with previous stroke.Conclusions—This meta-analysis suggests that hs-cTn can be regarded as a risk marker for incident stroke, with different effect size in different subgroups. More research about the association between hs-cTn and incident stroke in high-risk populations is needed, especially in patients with history of ischemic stroke.

Background and Purpose— The study goal was to investigate the prevalence of pregnancy complications and pregnancy loss in women before, during, and after young ischemic stroke/transient ischemic attack. Methods— In the FUTURE study (Follow-Up of Transient Ischemic Attack and Stroke Patients and Unelucidated Risk Factor Evaluation), a prospective young stroke study, we assessed the occurrence of pregnancy, miscarriages, and pregnancy complications in 223 women aged 18 to 50 years with a first-ever ischemic stroke/transient ischemic attack. Pregnancy complications (gestational hypertension, diabetes mellitus, preeclampsia, and hemolysis, elevated liver enzymes, low platelet count syndrome) were assessed before, during, and after stroke using standardized questionnaires. Primary outcome was occurrence of pregnancy complications and the rate of pregnancy loss compared with the Dutch population. Secondary outcome was the risk of recurrent vascular events after stroke, stratified by a history of hypertensive disorder in pregnancy. Results— Data were available for 213 patients. Mean age at event was 39.6 years (SD=7.8) and mean follow-up 9.5 years (SD=8.5). Miscarriages occurred in 35.2% and fetal death in 6.2% versus 13.5% and 0.9% in the Dutch population, respectively ( P P P P P =0.62). Conclusions— When compared with the general population, women with young stroke show higher rates of pregnancy loss throughout their lives. Also, after stroke, nulliparous women more frequently experienced serious pregnancy complications.

Background and Purpose— The National Institutes of Health Stroke Scale (NIHSS) correlates with presence of large anterior vessel occlusion (LAVO). However, the application of the full NIHSS in the prehospital setting to select patients eligible for treatment with thrombectomy is limited. Therefore, we aimed to evaluate the prognostic value of simple clinical selection strategies. Methods— Data from the Safe Implementation of Thrombolysis in Stroke International Stroke Thrombolysis Registry (January 2012–May 2014) were analyzed retrospectively. Patients with complete breakdown of NIHSS scores and documented vessel status were included. We assessed the association of prehospital stroke scales and NIHSS symptom profiles with LAVO (internal carotid artery, carotid-terminus or M1-segment of the middle cerebral artery). Results— Among 3505 patients, 23.6% (n=827) had LAVO. Pathological finding on the NIHSS item best gaze was strongly associated with LAVO (adjusted odds ratio 4.5, 95% confidence interval 3.8–5.3). All 3 face–arm–speech–time test (FAST) items identified LAVO with high sensitivity. Addition of the item best gaze to the original FAST score (G-FAST) or high scores on other simplified stroke scales increased specificity. The NIHSS symptom profiles representing total anterior syndromes showed a 10-fold increased likelihood for LAVO compared with a nonspecific clinical profile. If compared with an NIHSS threshold of ≥6, the prehospital stroke scales performed similarly or even better without losing sensitivity. Conclusions— Simple modification of the face–arm–speech–time score or evaluating the NIHSS symptom profile may help to stratify patients’ risk of LAVO and to identify individuals who deserve rapid transfer to comprehensive stroke centers. Prospective validation in the prehospital setting is required.

The incidence of stroke and dementia are diverging across the world, rising for those in low- and middle-income countries and falling in those in high-income countries. This suggests that whatever factors cause these trends are potentially modifiable. At the population level, neurological disorders as a group account for the largest proportion of disability-adjusted life years globally (10%). Among neurological disorders, stroke (42%) and dementia (10%) dominate. Stroke and dementia confer risks for each other and share some of the same, largely modifiable, risk and protective factors. In principle, 90% of strokes and 35% of dementias have been estimated to be preventable. Because a stroke doubles the chance of developing dementia and stroke is more common than dementia, more than a third of dementias could be prevented by preventing stroke. Developments at the pathological, pathophysiological, and clinical level also point to new directions. Growing understanding of brain pathophysiology has unveiled the reciprocal interaction of cerebrovascular disease and neurodegeneration identifying new therapeutic targets to include protection of the endothelium, the blood-brain barrier, and other components of the neurovascular unit. In addition, targeting amyloid angiopathy aspects of inflammation and genetic manipulation hold new testable promise. In the meantime, accumulating evidence suggests that whole populations experiencing improved education, and lower vascular risk factor profiles (e.g., reduced prevalence of smoking) and vascular disease, including stroke, have better cognitive function and lower dementia rates. At the individual levels, trials have demonstrated that anticoagulation of atrial fibrillation can reduce the risk of dementia by 48% and that systolic blood pressure lower than 140 mmHg may be better for the brain. Based on these considerations, the World Stroke Organization has issued a proclamation, endorsed by all the major international organizations focused on global brain and cardiovascular health, calling for the joint prevention of stroke and dementia. This article summarizes the evidence for translation into action.

Oral anticoagulation (OAC) substantially reduces stroke risk in patients with atrial fibrillation (AF) at risk for stroke. Whether non-vitamin K-dependent oral anticoagulants (NOACs) improve OAC use in stroke prevention requires investigation.To investigate temporal trends of OAC use in patients with known AF pre-stroke, we retrospectively analyzed records of 6,803 stroke patients admitted in 2003-2004 (n=1,496), 2008-2010 (n=1,638) or 2013-2015 (n=3,669) to the Charité-Universitätsmedizin Berlin, Germany. Adjusted regression models were used to identify factors associated with OAC use.Of 1,209 AF patients (mean age 79 years, 55.9% female) with given indication for OAC according to the CHADS2/CHA2DS2-VASc score, 484 (40.0%) were anticoagulated prior to the index stroke, 458 (37.9%) received antiplatelets and 236 (19.5%) had no antithrombotic medication. Compared to 2003-2004 and 2008-2010, there was a higher rate of pre-admission OAC in 2013-2015 (28.2% vs. 49.6%, p

Stroke, a leading cause of long-term disability and death worldwide, has a heritable component. Recent gene discovery efforts have expanded the number of known single-gene disorders associated with stroke and have linked common variants at approximately 35 genetic loci to stroke risk. These discoveries have highlighted novel mechanisms and pathways implicated in stroke related to large artery atherosclerosis, cardioembolism, and small vessel disease, and defined shared genetic influences with related vascular traits. Genetics has also successfully established causal relationships with risk factors and holds promise for prioritising targets for exploration in clinical trials. Genome-wide polygenic scores enable the identification of high-risk individuals before the emergence of vascular risk factors. Challenges ahead include a better understanding of rare variants and ancestral differences for integration of genetics into precision medicine, integration with other omics data, uncovering the genetic factors that govern stroke recurrence and stroke outcome, and the conversion of genetic discoveries to novel therapies.

Objective To evaluate the associations of a polygenic risk score and healthy lifestyle with incident stroke. Design Prospective population based cohort study. Setting UK Biobank Study, UK. Participants 306 473 men and women, aged 40-73 years, recruited between 2006 and 2010. Main outcome measure Hazard ratios for a first stroke, estimated using Cox regression. A polygenic risk score of 90 single nucleotide polymorphisms previously associated with stroke was constructed at P

ObjectiveTo investigate the prognostic relevance of cortical superficial siderosis (cSS) in patients with cerebral amyloid angiopathy (CAA).MethodsA total of 302 patients fulfilling clinical and imaging criteria for probable or possible CAA were enrolled into a prospective, multicenter cohort study and followed for 12 months. cSS was assessed on T2*/susceptibility-weighted imaging MRI. The predefined primary composite endpoint was incident stroke or death in patients with cSS compared to those without. Secondary analyses included cerebrovascular events and functional outcome measured by the modified Rankin Scale (mRS). Multiple regression analysis was performed to adjust for possible confounders.ResultscSS prevalence was 40%. The primary endpoint occurred more frequently in patients with cSS (22%, 27/121) compared to those without (8%, 15/181, p = 0.001). Rates of CAA-related incident intracranial hemorrhage were 17% (cSS) and 4% (no cSS, p = 0.0003). The proportion of patients being functionally independent (mRS 0–2) 12 months from baseline were 59% (cSS) and 82% (no cSS, p = 0.00002). Presence of cSS was associated with the primary endpoint (adjusted odds ratio [OR] 1.2, 95% confidence interval [CI] 1.1–1.3, p = 0.0005), incident intracranial hemorrhage (adjusted OR 1.2, 95% CI 1.1–1.3, p = 0.0003), and less favorable outcome as assessed by the mRS (common OR 1.9, 95% CI 1.2–3.1, p = 0.009). Similar results were obtained in analyses restricted to patients with probable CAA and to patients with disseminated cSS (all p < 0.005).ConclusionsPatients with cSS and suspected CAA are at high risk for CAA-related incident intracranial hemorrhage and poor functional outcome. Both the presence and extent of cSS have prognostic relevance and may influence clinical decision-making.

Aims Therapeutic oral anticoagulation on hospital admission reduces morbidity and mortality after acute ischaemic stroke in patients with atrial fibrillation (AF). The underlying mechanism is not fully understood. In order to assess the impact of INR-level on admission on stroke volume, lesion pattern and the frequency of intracranial arterial occlusion, we analysed serial MRI measurements in AF patients suffering acute ischaemic stroke. Methods and results This subgroup analysis of the prospective '1000Plus' study included patients with acute ischaemic stroke and known AF or a first episode of AF in hospital. All patients underwent serial brain magnetic resonance imaging. Stroke patients were categorized as follows: Group1, phenprocoumon intake, international normalized ratio (INR) ≥1.7 on admission, no thrombolysis; Group2, INR

ObjectiveTo identify promising blood-based biomarkers and novel etiologic pathways of disease risk, we applied an untargeted serum metabolomics profiling in a community-based prospective study of ischemic stroke (IS).MethodsIn 3,904 men and women from the Atherosclerosis Risk In Communities study, Cox proportional hazard models were used to estimate the association of incident IS with the standardized level of 245 fasting serum metabolites individually, adjusting for age, sex, race, field center, batch, diabetes, hypertension, current smoking status, body mass index, and estimated glomerular filtration rate. Validation of results was carried out in an independent sample of 114 IS cases and 112 healthy controls.ResultsSerum levels of 2 long-chain dicarboxylic acids, tetradecanedioate and hexadecanedioate, were strongly correlated (r = 0.88) and were associated with incident IS after adjusting for covariates (hazard ratio [95% confidence interval (CI)] 1.11 [1.06–1.16] and 1.12 [1.07–1.17], respectively; p < 0.0001). Analyses by IS subtypes suggested that these associations were specific to cardioembolic stroke (CES). Associations of tetradecanedioate and hexadecanedioate with IS were independently confirmed (odds ratio [95% CI] 1.76 [1.21; 2.56] and 1.60 [1.11; 2.32], respectively).ConclusionTwo serum long-chain dicarboxylic acids, metabolic products of ω-oxidation of fatty acids, were associated with IS and CES independently of known risk factors. Pathways related to intracellular hexadecanedioate synthesis or those involved in its clearance from the circulation may mediate IS risk. These results highlight the potential of metabolomics to discover novel circulating biomarkers for stroke and to unravel novel pathways for IS and its subtypes.

The effects of intravenous thrombolysis (IVT) in ischemic stroke are time dependent.1,2 Because of delays in conventional stroke workup, previous randomized IVT trials were unable to include patients with onset-to-treatment time (OTT) ≤60 minutes of symptom onset. With the invention of computed tomography–equipped mobile stroke units (MSUs), a relevant proportion of patients treated on such ambulances receive IVT within this ultraearly time window.3 In this study, we assessed the effects of IVT on 3-month functional outcome and mortality in different OTT intervals, including the first hour after onset, using a pooled analysis of 2 prospective prehospital and in-hospital registries in Berlin/Germany.4 Methods of patient inclusion and documentation in the 2 registries were described elsewhere4 (URL: http://www.clinicaltrials.gov. Unique identifier: NCT02358772). Briefly, all patients admitted through emergency medical services who received IVT between February 5, 2011, and March 5, 2015, were included in the registries. The prehospital registry included patients thrombolysed in an MSU and admitted to the nearest stroke unit thereafter. Intra-arterial treatment was optional in patients with occlusion of proximal intracranial arteries in both cohorts. The in-hospital registry comprised patients receiving IVT at Charite-Universitatsmedizin, Campus Benjamin Franklin. We excluded patients with nonstroke diagnosis, IVT without known exact (witnessed) time of onset, denial/withdrawal of informed consent for follow-up, missing 3-month follow-up, or incomplete documentation of data used in the multivariable analyses. For the pooled analyses of time-to-treatment effects, we included …

Background and Purpose— Selective serotonin-reuptake inhibitors (SSRIs) impair platelet function and have been linked to a higher risk of spontaneous intracerebral hemorrhage—an association that may be augmented by oral anticoagulants (OAC). We aimed to assess whether preadmission treatment with SSRIs in patients with acute ischemic stroke is associated with post-thrombolysis symptomatic intracerebral hemorrhage (sICH) and functional outcome. Methods— A multicenter retrospective analysis was conducted in prospective registries of patients treated by thrombolysis within 4.5 hours of stroke onset. The association between preadmission treatment with SSRIs and sICH (ECASS II definition [European Cooperative Acute Stroke Study]) or unfavorable 3-month outcome (modified Rankin Scale >2) was assessed by logistic regression, taking into account potential interaction with concomitant use of antithrombotics. Results— Six thousand two hundred forty-two patients were included (mean age, 70.1±14.0 years; median National Institutes of Health Stroke Scale, 9 [5–16]). Preadmission treatment with SSRIs was present in 4.3% (n=266) of patients. Overall, SICH rate was 3.9% (95% confidence interval [CI], 3.5%–4.4%; n=244), and SSRI use was not significantly associated with sICH in unadjusted (odds ratio [OR], 1.28; 95% CI, 0.72–2.27) or adjusted (OR, 1.30; 95% CI, 0.71–2.40) analysis. However, there was a significant interaction of concomitant use of OACs (international normalized ratio P =0.01). SICH was significantly more frequent in patients taking both OAC and SSRI (23.1%; 95% CI, 8.2%–50.3%) than in patients taking OAC but not SSRI (adjusted OR, 9.04; 95% CI, 1.95–41.89). Preadmission use of SSRI was associated with unfavorable 3-month outcome (unadjusted OR, 1.90; 95% CI, 1.48–2.46; adjusted OR, 1.59; 95% CI, 1.15–2.19). Conclusions— Preadmission treatment with SSRIs was not significantly associated with an increased risk of post-thrombolysis sICH in this cohort study. However, subgroup analysis suggested an increased risk of sICH in patients taking both SSRI and OAC. Preadmission treatment with SSRIs was associated with unfavorable outcome, which may reflect the prognostic significance of prestroke depression.

Background Depression is a risk factor for stroke and mortality but whether this also holds into old age is uncertain. We therefore studied the association of depression with the risk for non-fatal stroke and all-cause mortality in very old age. Methods A representative sample of 3085 primary care patients aged ≥75 years were serially assessed during a 6-year follow-up. The relation between depression (Geriatric Depression Scale >6, n=261) and relevant covariates including vascular risk factors and disease, functional and mild cognitive impairment and ApoE genotype on primary care givers information of incident stroke (n=209) and mortality (n=647) were assessed by Cox regression and by competing risk regressions. Results Depression was not independently associated with incident stroke in fully adjusted models that treated death as the competing event (subdistribution hazard ratio=0.80, 95% confidence interval=0.47 to 1.36). The risk associated with depression was similar for men and women, and for age groups 75–79, 80–84 and ≥85 years. In contrast, depression increased all-cause mortality rates, even after adjusting for a range of confounders (hazard ratio=1.31, 95% confidence interval=1.03 to 1.67). Limitations We have no information on past depressive episodes and cause of death. Conclusions In contrast to reports in younger populations, depression does not appear to increase stroke risk among the old and very old, but continuous to be a risk factor for all-cause mortality.

Summary Previous cross-sectional studies regarding the association of restless legs syndrome (RLS) with cardiovascular morbidity are controversial. Our aim was to evaluate prospectively the relationship of cardiovascular risk factors and vascular diseases with incident RLS in the general population. The results are from two prospective population-based cohort studies: the Dortmund Health Study (n = 1312, median follow-up of 2.1 years) and the Study of Health in Pomerania (n = 4308, median follow-up of 5.0 years). RLS status was assessed twice according to the minimal criteria. Diabetes, hypertension, myocardial infarction and stroke, as well as currently taken medications, were assessed as self-reports. Body mass index and serum total cholesterol were also measured. The independent risks associated with each outcome were estimated by multivariable logistic regression models adjusted for comorbidities and behavioural factors. Obesity was an independent risk factor of incident RLS in the Dortmund Health Study, and higher body mass index was an independent risk factor in both studies. Diabetes, hypertension and hypercholesterolaemia were independent predictors of incident RLS in the Study of Health in Pomerania. The vascular comorbidity index, defined by the number of concurrent cardiovascular risk factors and vascular diseases, showed a positive association with incident RLS in both studies. RLS at baseline was not a significant predictor of any subsequent cardiovascular risk factors and/or vascular diseases in any of the studies. Cardiovascular risk factors and diseases predict the subsequent development of RLS in the general population. The presence of RLS is not a significant risk factor of cardiovascular morbidity.

Stroke incidence rates have decreased in developed countries over the past 40 years, but trends vary across populations. We investigated whether age-and-sex-specific stroke incidence rates and associated risk factors as well as preventive medication use have changed in Rotterdam in the Netherlands during the last two decades. The study was part of the Rotterdam Study, a large population-based cohort study among elderly people. Participants were 10,994 men and women aged 55-94 years who were stroke-free at baseline. Trends were calculated by comparing the 1990 subcohort (n = 7516; baseline 1990-1993) with the 2000 subcohort (n = 2883; baseline 2000-2001). Poisson regression was used to calculate incidence rates and incidence rate ratios in age-and-sex-specific strata. We further compared the prevalence of stroke risk factors and preventive medication use in the two subcohorts. In the 1990 subcohort 467 strokes occurred during 45,428 person years; in the 2000 subcohort 115 strokes occurred in 18,356 person years. Comparing the subcohorts, incidence rates decreased by 34% in men, but remained unchanged in women. Blood pressure levels increased between 1990 and 2000, whereas the proportion of current cigarette smokers decreased in men, but not in women. There was a strong increase in medication use for treatment of stroke risk factors across all age categories in both sexes. Our findings suggest that in Rotterdam between 1990 and 2008 stroke incidence rates have decreased in men but not in women.

Insulin resistance, which plays a key role in the development of diabetes mellitus, is a putative modifiable risk factor for stroke. The aim of this study was to investigate if markers of insulin resistance were associated with risk of stroke in the general elderly population. This study was part of the large population-based Rotterdam Study and included 5,234 participants who were aged 55 years or older and stroke free and diabetes free at baseline (1997-2001). Fasting insulin levels and homeostasis model assessment for insulin resistance were used as markers for insulin resistance. Cox regression was used to determine associations between insulin resistance markers and stroke risk, adjusted for age, sex, and potential confounders. During 42,806 person-years of follow-up (median: 8.6 years), 366 first-ever strokes occurred, of which 225 were cerebral infarctions, 42 were intracerebral hemorrhages, and 99 were unspecified strokes. Fasting insulin levels were not associated with risk of any stroke, cerebral infarction, or intracerebral hemorrhage. Homeostasis model assessment for insulin resistance, which almost perfectly correlated with fasting insulin levels, was also not associated with risk of stroke or stroke subtypes. In conclusion, in this population-based cohort study among nondiabetic elderly, insulin resistance markers were not associated with risk of stroke or any of its subtypes.

Stroke incidence in hemodialysis patients is up to 10 times greater than in the general population and is associated with a worse prognosis. Factors influencing stroke risk by subtype and subsequent prognosis are poorly described in the literature.Retrospective single-center cohort study.2,384 established maintenance hemodialysis patients at a single center from January 1, 2002, to June 1, 2009.Patient demographics, comorbid conditions.Incidence of acute stroke (International Classification of Diseases, 9th Revision codes 430, 431, 432.9, 433.1, and 434.1 with evidence of compatible neuroimaging), patient survival.Cumulative patient survival, incidence of acute fatal and nonfatal stroke.127 strokes occurred during 9,541 total patient-years of follow-up. First (incident) stroke occurred at a rate of 14.9/1,000 patient years (95% CI, 12.2-17.9) with a predominance of ischemic compared with hemorrhagic subtypes (11.2 vs 3.7/1,000 patient-years). 54% of hemorrhagic strokes occurred in patients of South Asian ethnicity compared with ischemic strokes, which occurred predominantly in white patients (45% of events). Diabetes mellitus (HR, 1.92; 95% CI, 1.29-2.85; P = 0.001) and prior cerebrovascular disease (HR, 4.54; 95% CI, 3.07-6.72; P < 0.001) were independently associated with incident cerebrovascular accident on multivariate analysis. Acute stroke was associated with worse patient survival (HR, 3.26; 95% CI, 2.47-4.30; P < 0.001) and overall 1-year mortality of 24%, which was significantly worse in patients with hemorrhagic events (39% vs 19% mortality for ischemic subtypes). Serum albumin level >3.5 g/L (HR, 0.38; 95% CI, 0.19-0.76; P = 0.007) and C-reactive protein level >3.0 mg/l (HR, 1.36; 95% CI, 1.12-1.64; P = 0.002) influenced survival after stroke on multivariate analysis.Retrospective analysis of data cannot prove causality.The high incidence of stroke in hemodialysis patients is associated with high mortality, especially hemorrhagic subtypes. Strict management of hypertension, better appreciation of hemodialysis anticoagulation, and large-scale interventional studies are urgently required to direct prevention and treatment of this significant disease.

Background and Purpose— Multiple methods to detect paroxysmal atrial fibrillation (pAF) in patients with acute stroke are available. However, it is unknown which approaches are currently used in clinical routine and guidelines remain vague to the extent of cardiac monitoring. We characterize diagnostic efforts for pAF detection on German stroke units (SU). Methods— A standardized anonymous questionnaire was sent to all clinical leads of certified SUs in Germany. The questionnaire focused on basic characteristics of SUs, procedures to detect AF, and estimates on AF detection. Results— One hundred seventy-nine SU leads participated (response rate 71.6%). All patients undergo continuous bedside ECG monitoring. A percentage of 77.6 SUs initiate additional 24-hour Holter ECG in >50% of patients without known AF. Patients with transient ischemic attack are monitored significantly shorter than patients with ischemic stroke. Independent of SU type or size, 67.6% of leads assumed to fail detecting pAF in 5% to 20% of patients. In cryptogenic stroke, additional ECG monitoring is recommended by 90.2% but only 13.8% of SUs perform routine ECG follow-up visits. The use of implanted event recorders is low (1–10 patients/y by 60.7% of SUs; 28.1%: no use). A percentage of 83.9 do not use external event recorders. Conclusions— Our survey demonstrates substantial heterogeneity among German SUs on diagnostic work-up for pAF. Future prospective multicenter studies should systematically evaluate the impact of different methods to uncover pAF.

OBJECTIVES: Multimorbidity is a risk factor for incident restless legs syndrome (RLS). In this relationship, the potential role of known genetic risk loci for RLS has not been studied. Our aim was to evaluate whether carriers of specific RLS risk alleles have higher comorbidity burden than noncarriers. DESIGN: Two independent, population-based cohort studies in Germany: the Dortmund Health Study (DHS) and the Study of Health in Pomerania (SHIP). SETTING AND PARTICIPANTS: Age-stratified, random samples drawn from the respective population registers. DHS included 1,312 subjects and SHIP included 4,308 subjects. MEASUREMENTS: RLS status was assessed according to the RLS standard minimal criteria. A comorbidity index was calculated by summing the scores of the following conditions: diabetes, hypertension, myocardial infarction, obesity, stroke, cancer, renal disease, anemia, depression, thyroid disease, and migraine. Thirteen single nucleotide polymorphisms (SNP) previously associated with elevated risk of RLS were genotyped. Analyses were carried out on the pooled sample of the two studies. RESULTS: The mean age was 50.4+/-15.9 y, and the proportion of women was 51.4%. The mean number of comorbid conditions was 1.5+/-1.3. In multivariable regression, the mean number of comorbidities was not significantly different between carriers of any of the RLS risk alleles and noncarriers either in the total pooled sample or in those having RLS symptoms. CONCLUSIONS: Based on these results it is unlikely that known genetic risk factors for RLS would lead to increased multimorbidity.

IMPORTANCE: The prevalence of cardiometabolic multimorbidity is increasing. OBJECTIVE: To estimate reductions in life expectancy associated with cardiometabolic multimorbidity. DESIGN, SETTING, AND PARTICIPANTS: Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689 300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128 843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499 808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates. EXPOSURES: A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI). MAIN OUTCOMES AND MEASURES: All-cause mortality and estimated reductions in life expectancy. RESULTS: In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy. CONCLUSIONS AND RELEVANCE: Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.

Background and Purpose— Family history of stroke is an established risk factor for stroke. We evaluated whether family history of stroke predisposed to certain stroke subtypes and whether it differed by sex in young patients with stroke. Methods— We used data from the Stroke in Fabry Patients study, a large prospective, hospital-based, screening study for Fabry disease in young patients (aged Results— A family history of stroke was present in 1578 of 4232 transient ischemic attack and ischemic stroke patients (37.3%). Female patients more often had a history of stroke in the maternal lineage ( P =0.027) than in the paternal lineage. There was no association with stroke subtype according to Trial of Org 10172 in Acute Stroke Treatment nor with the presence of white matter disease on brain imaging. Patients with dissection less frequently reported a family history of stroke (30.4% versus 36.3%; P =0.018). Patients with a parental history of stroke more commonly had siblings with stroke (3.6% versus 2.6%; P =0.047). Conclusions— Although present in about a third of patients, a family history of stroke is not specifically related to stroke pathogenic subtypes in patients with young stroke. Young women with stroke more often report stroke in the maternal lineage. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00414583.

Background: Population-based data, which continuously monitors time trends in stroke epidemiology are limited. We investigated the incidence of pathological and etiological stroke subtypes over a 16 year time period. Methods: Data were collected within the Erlangen Stroke Project (ESPro), a prospective, population-based stroke register in Germany covering a total study population of 105,164 inhabitants (2010). Etiology of ischemic stroke was classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. Results: Between January 1995 and December 2010, 3,243 patients with first-ever stroke were documented. The median age was 75 and 55% were females. The total stroke incidence decreased over the 16 year study period in men (Incidence Rate Ratio 1995-1996 vs. 2009-2010 (IRR) 0.78; 95% CI 0.58-0.90) but not in women. Among stroke subtypes, a decrease in ischemic stroke incidence (IRR 0.73; 95% CI 0.57-0.93) and of large artery atherosclerotic stroke (IRR 0.27; 95% CI 0.12-0.59) was found in men and an increase of stroke due to small artery occlusion in women (IRR 2.33; 95% CI 1.39-3.90). Conclusions: Variations in time trends of pathological and etiological stroke subtypes were found between men and women that might be linked to gender differences in the development of major vascular risk factors in the study population.

Background Control of modifiable cardiovascular disease (CVD) risk factors has substantially reduced CVD mortality, but risk factor levels in populations may change and need continuous monitoring. This study aims to provide current estimates of the prevalence of these risk factors in Germany according to sex and history of coronary heart disease (CHD) or stroke. Methods The analyses were based on data from the German Health Interview and Examination Survey for Adults (DEGS1; age 40–79 years, n = 5101), which is a cross-sectional population-based examination survey. CVD risk factors were defined according to recommendations in the European Guidelines on Cardiovascular Disease Prevention in Clinical Practice 2012. Results The mean age was 57 years and 52 % were female; 493 participants had prior CHD and 163 participants a prior stroke. The overall prevalence of behavioural risk factors ranged from 17.9 % for high risk alcohol consumption to 90 % for low vegetable intake. Blood pressure ≥ 140/90 mmHg was found in 21 % and 69 % had total cholesterol ≥ 5.0 mmol/l. Only 16 % met the targets for five behavioural factors combined (smoking, physical activity, fruit intake, alcohol intake and obesity), 13 % of those with and 16 % of those without CHD or stroke. The prevalences of most behavioural risk factors were higher among men compared to women. Conclusions There is a high prevention potential from modifiable cardiovascular risk factors in the general population aged 40–79 years in Germany and among those with prior CHD or stroke. Risk factors are often co-occurring, are interrelated and require combined educational, behavioral, medical and policy approaches. Electronic supplementary material The online version of this article (doi:10.1186/s12889-015-1929-5) contains supplementary material, which is available to authorized users.

The ENDOSTROKE registry aims to accompany the spreading use of endovascular stroke treatment (EVT) in academic and non-academic hospitals. This analysis focuses on preprocedural imaging, patient handling and referral, as well as on different treatment modalities in mechanical recanalization.Data for this study were from observational registry study in 12 stroke centers in Germany and Austria with online assessment of prespecified variables concerning endovascular stroke therapy.Data from 734 patients undergoing EVT were analyzed. Preferred imaging modality prior to EVT was CT (83 %) and CTA (78 %). In 95 %, EVT was performed under general anesthesia. In 55 % of patients, a combination of intravenous (IV) thrombolysis and EVT was used, followed by pure EVT (25 %), intra-arterial (IA) thrombolysis plus EVT (13 %) and IV + IA thrombolysis plus EVT (7 %). Intrahospital time delay until start of EVT was 91 and 99 min in anterior and vertebrobasilar circulation stroke, respectively. Average duration of EVT was 60 min. Overall thrombolysis in myocardial infarction grade 2/3 recanalization rate was 85 %. Stent retrievers were used in 75 %, being associated with higher recanalization rates than non-stent retrievers. Hemorrhagic complications (symptomatic and asymptomatic) occurred in 12 %. Overall vessel occlusion time was approximately 60 min longer in patients being referred from a primary care hospital for EVT.This study gives an overview of procedure-related factors in current EVT practice. It gives estimates on preprocedural imaging modalities, periprocedural handling, and treatment combinations used for EVT. Patient referral for EVT from primary care hospitals is associated with longer vessel occlusion times.

Objective: To evaluate total antioxidant capacity of the diet, measured by the ferric-reducing antioxidant power (FRAP) assay, in relation to risks of dementia and stroke, as well as key structural brain volumes, in the elderly. Methods: We prospectively studied 5,395 participants in the Rotterdam Study, aged 55 years and older, who were dementia free and provided dietary information at study baseline; 5,285 individuals were also stroke free at baseline, and 462 were dementia and stroke free at the time of an MRI brain scan 5 years after baseline. Dietary data were ascertained using a semiquantitative food-frequency questionnaire, and combined with food-specific FRAP measurements from published tables; this information was aggregated across the diet to obtain “dietary FRAP scores.” Multivariable-adjusted Cox proportional hazard models were used to estimate relative risks of dementia and stroke, and multivariable-adjusted linear regression was used to estimate mean differences in structural brain volumes, across tertiles of dietary FRAP scores. Results: During a median 13.8 years of follow-up, we identified approximately 600 cases each of dementia and stroke. In multivariable-adjusted models, we observed no associations between dietary FRAP scores and risk of dementia ( p trend = 0.3; relative risk = 1.12, 95% confidence interval = 0.91–1.38, comparing the highest vs lowest FRAP tertiles) or risk of stroke ( p trend = 0.3; relative risk = 0.91, 95% confidence interval = 0.75–1.11, comparing extreme FRAP tertiles); results were similar across subtypes of these outcomes. Dietary FRAP scores were unrelated to brain tissue volumes as well. Conclusions: Total antioxidant capacity of the diet, measured by dietary FRAP scores, does not seem to predict risks of major neurologic diseases.

These EFNS guidelines on the molecular diagnosis of channelopathies, including epilepsy and migraine, as well as stroke, and dementia are designed to summarize the possibilities and limitations of molecular genetic techniques and to provide diagnostic criteria for deciding when a molecular diagnostic work-up is indicated.To collect data about planning, conditions, and performance of molecular diagnosis of these disorders, a literature search in various electronic databases was carried out and original papers, meta-analyses, review papers, and guideline recommendations were reviewed.The best level of evidence for genetic testing recommendation (B) can be found for a small number of syndromes, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, severe myoclonic epilepsy of infancy, familial recurrent hemorrhages, familial Alzheimer's disease, and frontotemporal lobar degeneration. Good practice points can be formulated for a number of other disorders.These guidelines are provisional, and the future availability of molecular genetic epidemiological data about the neurogenetic disorders under discussion in our article will allow improved recommendation with an increased level of evidence.