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Cerebral white matter hyperintensities (WMH) have been associated with subclinical atherosclerosis including coronary artery calcification (CAC). However, previous studies on this association are limited by only cross-sectional analysis. We aimed to explore the relationship between WMH and CAC in elderly individuals both cross-sectionally and longitudinally. The study population consisted of elderly stroke- and dementia-free participants from the community-based Austrian Stroke Prevention Family Study (ASPFS). WMH volume and CAC levels (via Agatston score) were analyzed at baseline and after a 6-year follow-up period. Of 324 study participants (median age: 68 years), 115 underwent follow-up. Baseline WMH volume (median: 4.1 cm 3 ) positively correlated with baseline CAC levels in multivariable analysis correcting for common vascular risk factors (p = 0.010). While baseline CAC levels were not predictive for WMH progression (p = 0.447), baseline WMH volume was associated CAC progression (median Agatston score progression: 27) in multivariable analysis (ß = 66.3 ± 22.3 [per cm 3 ], p = 0.004). Ten of 11 participants (91%) with severe WMH (Fazekas Scale: 3) at baseline showed significant CAC progression > 100 during follow-up. In this community-based cohort of elderly individuals, WMH were associated with CAC and predictive of its progression over a 6-year follow-up. Screening for coronary artery disease might be considered in people with more severe WMH., (© 2024. The Author(s).)

Background: Several blood biomarkers have been identified as predictors for poor outcome after ischemic stroke. However, recent studies mainly focused on single or experimental biomarkers and considered rather short follow-up intervals limiting their value for daily clinical practice. We, therefore, aimed to compare various clinical routine blood biomarkers for their predictive value on post-stroke mortality over a 5-year follow-up period., Patients and Methods: This data analysis of a prospective single-center study included all consecutive ischemic stroke patients admitted to the stroke unit of our university hospital over a 1-year period. Various blood biomarkers of inflammation, heart failure, metabolic disorders, and coagulation were analyzed from standardized routine blood samples collected within 24 h of hospital admission. All patients underwent a thorough diagnostic workup and were followed for 5 years post-stroke., Results: Of 405 patients (mean age: 70.3 years), 72 deceased (17.8%) during the follow-up period. While various routine blood biomarkers were associated with post-stroke mortality in univariable analyses, only NT-proBNP remained an independent predictor (adjusted odds ratio 5.1; 95% CI 2.0-13.1; p  < 0.001) for death after stroke. NT-proBNP levels ⩾794 pg/mL ( n  = 169, 42%) had a sensitivity of 90% for post-stroke mortality with a negative predictive value of 97% and was additionally associated with cardioembolic stroke and heart failure (each p  ⩽ 0.05)., Conclusion: NT-proBNP represents the most relevant routine blood-based biomarker for the prediction of long-term mortality after ischemic stroke. Increased NT-proBNP levels indicate a vulnerable subgroup of stroke patients in which early and thorough cardiovascular assessment and consistent follow-ups could improve outcome after stroke.

Impaired kidney function is associated with structural brain changes and cognitive dysfunction. In the aging kidney, hemodynamic and structural alterations reduce the glomerular filtration rate (eGFR). Little is known about differences between men and women regarding decline of kidney function and brain damage. In this community-based study, we assessed associations between the eGFR, focal and diffuse brain abnormalities and cognitive functions. Sex-specific effects were analyzed by interaction terms eGFR x sex on brain structure and cognition. Interactive effects were assessed using mixed-models -stratified by sex. Overall, 196 women and 129 men (median age 68 years and mean eGFR 73.8±14.9 ml/min/1.73m 2 ) were included. Significant associations existed between eGFR and cortical volume (β: 1.53E-04; SE: 6.72E-05; p=0.023 for neocortex). Sex exerted a significant interactive effect. Only in men, eGFR related to cortical volumes of all lobes and of deep gray matter structures (p= 0.001 for total gray matter, p=0.0004 for neocortex). In the whole group eGFR was not associated with cognition, but men with lower eGFR performed worse on tests for executive function, which, after FDR correction, was not significant. We conclude, that in community-dwelling middle-aged and elderly individuals, reduced eGFR relates to brain volume loss in men but not in women.

Background: The circle of Willis (COW) is part of the brain collateral system. The absence of COW segments may affect functional outcome in patients with ischaemic stroke undergoing endovascular therapy., Methods: In 182 patients in the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution 2 Study and the CT Perfusion to Predict Response to Recanalisation in Ischaemic Stroke Project, COW anatomy was evaluated on postinterventional magnetic resonance angiography. The absence of the posterior communicating artery or the first segments of posterior or anterior cerebral arteries ipsilateral to the ischaemic infarction was rated as an incomplete COW. Logistic regression was applied to evaluate an association with the patients' modified Rankin scale (mRS) at 90 days after stroke RESULTS: An incomplete ipsilateral COW was not predictive of the patients' mRS at 90 days after stroke. Significant associations were shown for the patients' baseline National Institutes of Health Stroke Scale (NIHSS), age and reperfusion status. The effect size suggests that a significant association of an incomplete COW with the mRS at 90 days may be obtained in cohorts of more than 3000 patients., Conclusions: Compared with the established predictors NIHSS, age and reperfusion status, an incomplete COW is not associated with functional outcome after endovascular therapy., Competing Interests: Competing interests: SC performs consulting work for iSchemaView; GWA is a consultant of iSchemaView and has an equity interest in iSchemaView., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Worldwide, 2 million patients aged 18-50 years suffer a stroke each year, and this number is increasing. Knowledge about global distribution of risk factors and aetiologies, and information about prognosis and optimal secondary prevention in young stroke patients are limited. This limits evidence-based treatment and hampers the provision of appropriate information regarding the causes of stroke, risk factors and prognosis of young stroke patients., Methods and Analysis: The Global Outcome Assessment Life-long after stroke in young adults (GOAL) initiative aims to perform a global individual patient data meta-analysis with existing data from young stroke cohorts worldwide. All patients aged 18-50 years with ischaemic stroke or intracerebral haemorrhage will be included. Outcomes will be the distribution of stroke aetiology and (vascular) risk factors, functional outcome after stroke, risk of recurrent vascular events and death and finally the use of secondary prevention. Subgroup analyses will be made based on age, gender, aetiology, ethnicity and climate of residence., Ethics and Dissemination: Ethical approval for the GOAL study has already been obtained from the Medical Review Ethics Committee region Arnhem-Nijmegen. Additionally and when necessary, approval will also be obtained from national or local institutional review boards in the participating centres. When needed, a standardised data transfer agreement will be provided for participating centres. We plan dissemination of our results in peer-reviewed international scientific journals and through conference presentations. We expect that the results of this unique study will lead to better understanding of worldwide differences in risk factors, causes and outcome of young stroke patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Interactions between cerebral small vessel disease (CSVD) and renal dysfunction (RD) have been reported, but previous studies were mostly retrospective and limited to measurements of estimated glomerular filtration rate (eGFR). In this prospective, longitudinal study of patients with CSVD-related recent small subcortical infarcts (RSSI), we aimed at a comprehensive exploration of markers of early RD and their association with microvascular brain damage. We investigated 101 stroke patients (mean age: 60.2 ± 10.7 years) with an MRI-confirmed RSSI who underwent follow-up brain MRI 15 months post-stroke. Besides serum creatinine and eGFR, we assessed urinary Albumin-Creatinine Ratio and fibroblast growth factor-23 (FGF-23). RD was classified according to recent Kidney Disease: Improving Global Outcomes criteria. We identified 24 patients with RD, only six patients revealed an eGFR <60 mL/min/1.73 m². RSSI patients with RD more often had severe white matter hyperintensities (WMH, 58% vs. 36%, p = 0.04). CSVD progression was not dependent on RD. However, patients in the highest FGF-23 quartile more frequently had new microangiopathic lesions on follow-up MRI (50% vs. 21%, p = 0.03). Early RD was found in a quarter of RSSI patients and associated with WMH severity, but not CSVD progression. High FGF-23 indicates an increased risk for ongoing microvascular brain damage, warranting further studies.

Background and Purpose- Occult atrial fibrillation (AF) causes a relevant proportion of initially cryptogenic stroke (CS), but prolonged rhythm monitoring is difficult to apply to all such patients. We hypothesized that blood biomarkers indicating heart failure (NT-proBNP [N-terminal pro-brain natriuretic peptide]) and hypercoagulability (D-dimer, AT-III [antithrombin-III]) were associated with AF-related stroke and could serve to predict the likelihood of AF detection in CS patients early on. Methods- Over a 1-year period, we prospectively applied a defined etiologic work-up to all ischemic stroke patients admitted to our stroke unit. If no clear stroke cause was detected (CS), patients underwent extended in-hospital cardiac rhythm monitoring (≥72 hours). Blood to determine biomarker levels was drawn within 24 hours after admission. Results- Of 429 patients, 103 had AF-related stroke. Compared with noncardiac stroke patients (n=171), they had higher NT-proBNP (1867 versus 263 pg/ml) and D-dimer levels (1.1 versus 0.6 µg/ml), and lower AT-III concentration (89% versus 94%). NT-proBNP ≥505 pg/ml distinguished AF-related from noncardiac stroke with a sensitivity of 93% and a specificity of 72%. D-dimer and AT-III cutoffs had lower sensitivities (61% and 53%) and specificities (58% and 69%) for AF-related stroke. Of all initially 143 CS patients, 14 were diagnosed with AF during in-hospital monitoring. The preidentified NT-proBNP cutoff ≥505 pg/ml correctly predicted AF in 12 of them (86%, negative predictive value: 98%), while D-dimer and AT-III cutoffs were noncontributory. Conclusions- This study supports the association of NT-proBNP and to a lesser extent of hypercoagulation markers with AF-related stroke. NT-proBNP seems helpful in selecting CS patients for immediate extended cardiac rhythm monitoring to detect occult AF whereby levels <505 pg/ml seem to have a high-negative predictive value.

Background and Purpose- Several risk factors are known to increase mid- and long-term mortality of ischemic stroke patients. Information on predictors of early stroke mortality is scarce but often requested in clinical practice. We therefore aimed to develop a rapidly applicable tool for predicting early mortality at the stroke unit. Methods- We used data from the nationwide Austrian Stroke Unit Registry and multivariate regularized logistic regression analysis to identify demographic and clinical variables associated with early (≤7 days poststroke) mortality of patients admitted with ischemic stroke. These variables were then used to develop the Predicting Early Mortality of Ischemic Stroke score that was validated both by bootstrapping and temporal validation. Results- In total, 77 653 ischemic stroke patients were included in the analysis (median age: 74 years, 47% women). The mortality rate at the stroke unit was 2% and median stay of deceased patients was 3 days. Age, stroke severity measured by the National Institutes of Health Stroke Scale, prestroke functional disability (modified Rankin Scale >0), preexisting heart disease, diabetes mellitus, posterior circulation stroke syndrome, and nonlacunar stroke cause were associated with mortality and served to build the Predicting Early Mortality of Ischemic Stroke score ranging from 0 to 12 points. The area under the curve of the score was 0.879 (95% CI, 0.871-0.886) in the derivation cohort and 0.884 (95% CI, 0.863-0.905) in the validation sample. Patients with a score ≥10 had a 35% (95% CI, 28%-43%) risk to die within the first days at the stroke unit. Conclusions- We developed a simple score to estimate early mortality of ischemic stroke patients treated at a stroke unit. This score could help clinicians in short-term prognostication for management decisions and counseling.

Background and Purpose- Hemodynamic changes following mechanical thrombectomy for large vessel occlusion stroke could be associated with complications and might affect prognosis. We investigated postinterventional middle cerebral artery blood flow on transcranial duplex sonography (TCD) and its prognostic value for anterior large vessel occlusion stroke patients. Methods- We identified all ischemic stroke patients who had undergone mechanical thrombectomy for anterior circulation large vessel occlusion from 2010 onwards. Postinterventional middle cerebral artery flow was graded according to the sonographic Thrombolysis in Brain Ischemia score and related to patient outcome stratified by the angiographic Thrombolysis in Cerebral Infarction reperfusion status. Results- Of 215 large vessel occlusion stroke patients, 193 patients (90%) showed successful angiographic recanalization (Thrombolysis in Cerebral Infarction grade 2b-3). Of those, 69 (36%) patients had abnormal sonographic middle cerebral artery blood flow (Thrombolysis in Brain Ischemia grade 0-4) within 72 hours after mechanical thrombectomy, which was an independent predictor for poor 90-day outcome. Conclusions- TCD indicates abnormal middle cerebral artery hemodynamics in a substantial proportion of patients with angiographically defined successful mechanical thrombectomy of the anterior cerebral circulation. Such changes are associated with poor short-term outcome.

Primary intracerebral haemorrhage and lacunar ischaemic stroke are acute manifestations of progressive cerebral microvascular disease. Current paradigms suggest atherosclerosis is a chronic, dynamic, inflammatory condition precipitated in response to endothelial injury from various environmental challenges. Myeloperoxidase plays a central role in initiation and progression of vascular inflammation, but prior studies linking myeloperoxidase with stroke risk have been inconclusive. We hypothesized that genetic determinants of myeloperoxidase levels influence the development of vascular instability, leading to increased primary intracerebral haemorrhage and lacunar stroke risk. We used a discovery cohort of 1409 primary intracerebral haemorrhage cases and 1624 controls from three studies, an extension cohort of 12 577 ischaemic stroke cases and 25 643 controls from NINDS-SiGN, and a validation cohort of 10 307 ischaemic stroke cases and 29 326 controls from METASTROKE Consortium with genome-wide genotyping to test this hypothesis. A genetic risk score reflecting elevated myeloperoxidase levels was constructed from 15 common single nucleotide polymorphisms identified from prior genome-wide studies of circulating myeloperoxidase levels (P < 5 × 10-6). This genetic risk score was used as the independent variable in multivariable regression models for association with primary intracerebral haemorrhage and ischaemic stroke subtypes. We used fixed effects meta-analyses to pool estimates across studies. We also used Cox regression models in a prospective cohort of 174 primary intracerebral haemorrhage survivors for association with intracerebral haemorrhage recurrence. We present effects of myeloperoxidase elevating single nucleotide polymorphisms on stroke risk per risk allele, corresponding to a one allele increase in the myeloperoxidase increasing genetic risk score. Genetic determinants of elevated circulating myeloperoxidase levels were associated with both primary intracerebral haemorrhage risk (odds ratio, 1.07, P = 0.04) and recurrent intracerebral haemorrhage risk (hazards ratio, 1.45, P = 0.006). In analysis of ischaemic stroke subtypes, the myeloperoxidase increasing genetic risk score was strongly associated with lacunar subtype only (odds ratio, 1.05, P = 0.0012). These results, demonstrating that common genetic variants that increase myeloperoxidase levels increase risk of primary intracerebral haemorrhage and lacunar stroke, directly implicate the myeloperoxidase pathway in the pathogenesis of cerebral small vessel disease. Because genetic variants are not influenced by environmental exposures, these results provide new support for a causal rather than bystander role for myeloperoxidase in the progression of cerebrovascular disease. Furthermore, these results support a rationale for chronic inflammation as a potential modifiable stroke risk mechanism, and suggest that immune-targeted therapies could be useful for treatment and prevention of cerebrovascular disease., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background and Purpose: Dysphagia is a common stroke symptom and leads to serious complications such as aspiration and pneumonia. Early dysphagia screening can reduce these complications. In many hospitals, dysphagia screening is performed by speech-language therapists who are often not available on weekends/holidays, which results in delayed dysphagia assessment., Methods: We trained the nurses of our neurological department to perform formal dysphagia screening in every acute stroke patient by using the Gugging Swallowing Screen. The impact of a 24/7 dysphagia screening (intervention) over swallowing assessment by speech-language therapists during regular working hours only was compared in two 5-month periods with time to dysphagia screening, pneumonia rate, and length of hospitalization as outcome variables., Results: Overall, 384 patients (mean age, 72.3±13.7 years; median National Institutes of Health Stroke Scale score of 3) were included in the study. Both groups (pre-intervention, n=198 versus post-intervention, n=186) were comparable regarding age, sex, and stroke severity. Time to dysphagia screening was significantly reduced in the intervention group (median, 7 hours; range, 1-69 hours) compared with the control group (median, 20 hours; range, 1-183; P =0.001). Patients in the intervention group had a lower rate of pneumonia (3.8% versus 11.6%; P =0.004) and also a reduced length of hospital stay (median, 8 days; range, 2-40 versus median, 9 days; range, 1-61 days; P =0.033)., Conclusions: 24/7 dysphagia screening can be effectively performed by nurses and leads to reduced pneumonia rates. Therefore, empowering nurses to do a formal bedside screening for swallowing dysfunction in stroke patients timely after admission is warranted whenever speech-language therapists are not available., (© 2017 American Heart Association, Inc.)

Background and Purpose: We evaluated whether basilar dolichoectasia is associated with markers of cerebral small vessel disease in younger transient ischemic attack and ischemic stroke patients., Methods: We used data from the SIFAP1 study (Stroke in Young Fabry Patients), a large prospective, hospital-based, screening study for Fabry disease in young (<55 years) transient ischemic attack/stroke patients in whom detailed clinical data and brain MRI were obtained, and stroke subtyping with TOAST classification (Trial of ORG 10172 in Acute Stroke Treatment) was performed., Results: Dolichoectasia was found in 508 of 3850 (13.2%) of patients. Dolichoectasia was associated with older age (odds ratio per decade, 1.26; 95% confidence interval, 1.09-1.44), male sex (odds ratio, 1.96; 95% confidence interval, 1.59-2.42), and hypertension (odds ratio, 1.39; 95% confidence interval, 1.13-1.70). Dolichoectasia was more common in patients with small infarctions (33.9% versus 29.8% for acute lesions, P =0.065; 29.1% versus 16.5% for old lesions, P <0.001), infarct location in the brain stem (12.4% versus 6.9%, P <0.001), and in white matter (27.8% versus 21.1%, P =0.001). Microbleeds (16.3% versus 4.7%, P =0.001), higher grades of white matter hyperintensities ( P <0.001), and small vessel disease subtype (18.1% versus 12.4%, overall P for differences in TOAST ( P =0.018) were more often present in patients with dolichoectasia., Conclusions: Dolichoectasia is associated with imaging markers of small vessel disease and brain stem localization of acute and old infarcts in younger patients with transient ischemic attack and ischemic stroke., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00414583., (© 2017 American Heart Association, Inc.)

Background and Purpose: A patent foramen ovale (PFO) is disproportionately prevalent in patients with cryptogenic stroke. Without alternative explanations, it is frequently considered to be causative. A detailed stratification of these patients may improve the identification of incidental PFO., Methods: We investigated the PFO prevalence in 3497 transient ischemic attack and ischemic stroke patients aged 18 to 55 years in the prospective multicenter SIFAP1 study (Stroke in Young Fabry Patients 1) using the ASCO classification. Patients without an obvious cause for transient ischemic attack/stroke (ASCO 0) were divided into subgroups with and without vascular risk factors (ASCO 0+ and 0-). In addition, we looked for PFO-related magnetic resonance imaging lesion patterns., Results: PFO was identified in 25% of patients. Twenty percent of patients with a definite or probable cause of transient ischemic attack/stroke (≥1 grade 1 or 2 ASCO criterion; n=1769) had a PFO compared with 29% of cryptogenic stroke patients (ASCO 0 and 3; n=1728; P<0,001); subdivision of cryptogenic strokes revealed a PFO in 24% of 978 ASCO 3 patients (n.s. versus ASCO 1 and 2) and a higher prevalence of 36% in 750 ASCO 0 cases (P<0.001 versus ASCO 3 and versus ASCO 1 and 2). PFO was more commonly observed in ASCO 0- (n=271) than in ASCO 0+ patients (n=479; 48 versus 29%; P<0.001). There was no PFO-associated magnetic resonance imaging lesion pattern., Conclusions: Cryptogenic stroke patients demonstrate a heterogeneous PFO prevalence. Even in case of less conclusive diseases like nonstenotic arteriosclerosis, patients should preferentially be considered to have a non-PFO-mediated stroke., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00414583., (© 2016 American Heart Association, Inc.)

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 <55 years) with stroke in whom cardiovascular risk factors and family history of stroke were obtained and detailed stroke subtyping was performed., 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., (© 2015 American Heart Association, Inc.)