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It remains unknown whether the global small vessel disease (SVD) burden predicts post-stroke outcomes.In a prospective multicenter study of 666 ischemic and hemorrhagic stroke patients, we quantified magnetic resonance imaging (MRI)-based SVD markers (lacunes, white matter hyperintensities, microbleeds, perivascular spaces) and explored associations with 6- and 12-month cognitive (battery of 15 neuropsychological tests) and functional (modified Rankin scale) outcomes.A global SVD score (range 0-4) was associated with cognitive impairment; worse performance in executive function, attention, language, and visuospatial ability; and worse functional outcome across a 12-month follow-up. Although the global SVD score did not improve prediction, individual SVD markers, assessed across their severity range, improved the calibration, discrimination, and reclassification of predictive models including demographic, clinical, and other imaging factors.SVD presence and severity are associated with worse cognitive and functional outcomes 12 months after stroke. Assessing SVD severity may aid prognostication for stroke patients.In a multi-center cohort, we explored associations of small vessel disease (SVD) burden with stroke outcomes. SVD burden associates with post-stroke cognitive and functional outcomes. A currently used score of SVD burden does not improve the prediction of poor outcomes. Assessing the severity of SVD lesions adds predictive value beyond known predictors. To add predictive value in assessing SVD in stroke patients, SVD burden scores should integrate lesion severity.

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).

Introduction: Cardiac biomarkers, such as high-sensitivity cardiac troponin T (hs-cTnT), are frequently elevated in ischemic stroke patients but the mechanisms underlying this elevation are insufficiently understood. We determined the presence of cardiac damage, assessed using cardiac magnetic resonance imaging (CMR), in stroke patients with elevated hs-cTnT and brain natriuretic peptide (BNP). Methods: This is a post hoc analysis of the prospective, investigator-initiated, cross-sectional HEart and BRain interfaces in Acute Stroke (HEBRAS) study. All patients underwent the measurement of hs-cTnT and BNP as well as gadolinium-enhanced CMR in the acute phase of ischemic stroke. We performed unadjusted and adjusted logistic regression models to assess the association between hs-cTnT and BNP elevation and the presence of pathological CMR findings. Results: Two hundred and thirty-three stroke patients (median age 67 years, 33% female) were included, of whom 43 (21%) had elevated hs-cTnT and 109 (47%) had elevated BNP. Hundred of the 233 (43%) patients had pathological findings on CMR had focal fibrosis as detected by late-gadolinium enhancement (LGE) in 51 (23%), left-ventricular hypertrophy (LVH) in 38 (16%), reduced LVEF in 32 (14%), and left-atrial dilatation in 34 (15%). After adjustment for potential confounders, both hs-cTnT (adjOR 5.0 (95%CI 2.1–11.7), p Conclusion: Elevated cardiac biomarkers in acute stroke including CMR are strongly associated with pathological findings on CMR. In acute stroke patients, the elevation of cardiac biomarkers may identify patients who require a more thorough cardiology work-up.

BACKGROUND AND PURPOSE A sensitive and frequent clinical sign of a vestibular tone imbalance is the tilt of the perceived subjective visual vertical (SVV). There are no data yet focusing on lesion location at the cortical level as a factor for predicting compensation from the tilt of the SVV. METHODS With modern voxelwise lesion behavior mapping analysis, the present study determines whether lesion location in 23 right-hemispheric cortical stroke patients with an otolith dysfunction could predict the compensation of a vestibular tone imbalance in the chronic stage. RESULTS Our statistical anatomical lesion analysis revealed that lesions of the posterior insular cortex are involved in vestibular otolith compensation. CONCLUSION The insular cortex appears to be a critical anatomical region for predicting a tilt of the SVV as a chronic disorder in stroke patients.

ZusammenfassungDie Durchführung einer oralen Antikoagulation ist bei Patienten mit einer zerebralen Amyloidangiopathie eine therapeutische Herausforderung. Die Assoziation der zerebralen Amyloidangiopathie mit Lobärblutungen, eine hohe Mortalität intrazerebraler Blutungen insbesondere unter oraler Antikoagulation sowie das hohe Rezidivrisiko solcher Blutungen erfordern eine strenge und interdisziplinäre Risiko-Nutzen-Abwägung. Vitamin-K-Antagonisten erhöhen das Risiko für die mit intrazerebralen Blutungen vergesellschaftete Mortalität um 60 % und sollten daher möglichst vermieden bzw. speziellen klinischen Situationen (z. B. mechanischer Aortenklappenersatz) vorbehalten sein. Auch der Einsatz von neuen oralen Antikoagulanzien und Thrombozytenaggregationshemmern bedarf einer strengen Risiko-Nutzen-Abwägung, da auch diese Substanzen das zerebrale Blutungsrisiko erhöhen. Insbesondere bei Patienten mit einer absoluten Arrhyhtmie bei Vorhofflimmern ist der interventionelle Vorhofohrverschluss eine therapeutische Alternative. Darüber hinaus sind weitere klinische Implikationen bei Patienten mit zerebraler Amyloidangiopathie Gegenstand dieser Literaturübersicht, beispielsweise Besonderheiten nach akutem ischämischem Schlaganfall und erforderlicher Sekundärprophylaxe, bei vorherigen intrazerebralen Blutungen und bei Patienten mit kognitiven Defiziten.

OBJECTIVE This study was undertaken to investigate whether high-sensitivity cardiac troponin T (hs-cTnT) is associated with major adverse cardiovascular events (MACE) in patients with minor stroke or transient ischemic attack (TIA), and whether this association differs after risk stratification based on the Age, Blood Pressure, Clinical Features, Duration of Symptoms, Diabetes (ABCD2 ) score. METHODS INSPiRE-TMS was a randomized controlled trial allocating patients with minor stroke or TIA to an intensified support program or conventional care. In this post hoc analysis, participants were categorized using hs-cTnT levels (5th generation; Roche Diagnostics, Manheim, Germany; 99th percentile upper reference limit [URL] = 14ng/l). Vascular risk was stratified using the ABCD2 score (lower risk = 0-5 vs higher risk = 6-7). Cox proportional hazard regression was performed using covariate adjustment and propensity score matching (PSM) for the association between hs-cTnT and MACE (stroke/nonfatal coronary event/vascular death). RESULTS Among 889 patients (mean age = 70 years, 37% female), MACE occurred in 153 patients (17.2%) during a mean follow-up of 3.2 years. hs-cTnT was associated with MACE (9.3%/yr, >URL vs 4.4%/yr, ≤URL, adjusted hazard ratio [HR] = 1.63 [95% confidence interval (CI) = 1.13-2.35], adjusted HR [Q4 vs Q1 ] = 2.57 [95% CI = 1.35-4.97], adjusted HR [log-transformed] = 2.31 [95% CI = 1.37-3.89]). This association remained after PSM (adjusted HR = 1.76 [95% CI = 1.14-2.72]). There was a significant interaction between hs-cTnT and ABCD2 category for MACE occurrence (pinteraction = 0.04). In the lower risk category, MACE rate was 9.5%/yr in patients with hs-cTnT > URL, which was higher than in those ≤URL (3.8%/yr) and similar to the overall rate in the higher risk category. INTERPRETATION hs-cTnT levels are associated with incident MACE within 3 years after minor stroke or TIA and may help to identify high-risk individuals otherwise deemed at lower risk based on the ABCD2 score. If confirmed in independent validation studies, this might warrant intensified secondary prevention measures and cardiac diagnostics in stroke patients with elevated hs-cTnT. ANN NEUROL 2021;90:901-912.

Background:The INSPiRE-TMS trial (Intensified Secondary Prevention Intending a Reduction of Recurrent Events in Transient Ischemic Attack and Minor Stroke Patients) investigated effects of a multicomponent support program in patients with nondisabling stroke or transient ischemic attack. Although secondary prevention targets were achieved more frequently in the intensified care group, no significant differences were seen in rates of recurrent major vascular events. Here, we present the effects on prespecified patient-centered outcomes.Methods:In a multicenter trial, we randomized patients with modifiable risk factors either to the intensified or conventional care alone program. Intensified care was provided by stroke specialists and used feedback and motivational interviewing strategies (≥8 outpatient visits over 2 years) aiming to improve adherence to secondary prevention targets. We measured physical fitness, disability, cognitive function and health-related quality of life by stair-climbing test, modified Rankin Scale, Montreal Cognitive Assessment, and European Quality of Life 5 Dimension 3 Level during the first 3 years of follow-up.Results:Of 2072 patients (mean age: 67.4years, 34% female) assessed for the primary outcome, patient-centered outcomes were collected in 1,771 patients (877 intensified versus 894 conventional care group). Physical fitness improved more in the intensified care group (mean between-group difference in power (Watt): 24.5 after 1 year (95% CI, 5.5–43.5); 36.1 after 2 years (95% CI, 13.1–59.7) and 29.6 (95% CI, 2.0–57.3 after 3 years). At 1 year, there was a significant shift in ordinal regression analysis of modified Rankin Scale in favor of the intensified care group (common odds ratio, 1.23 [95% CI, 1.03–1.47]) but not after 2 (odds ratio, 1.17 [95% CI, 0.96–1.41]) or 3 years (odds ratio, 1.16 [95% CI, 0.95–1.43]) of follow-up. However, Montreal Cognitive Assessment and European Quality of Life 5 Dimension scores showed no improvement in the intensified intervention arm after 1, 2, or 3 years of follow-up.Conclusions:Patients of the intensified care program group had slightly better results for physical fitness and modified Rankin Scale after 1 year, but none of the other patient-centered outcomes was significantly improved.Registration:URL:https://www.clinicaltrials.gov; Unique identifier: NCT01586702.

ispartof: JOURNAL OF NEUROLOGY vol:269 issue:10 pages:5660-5667 ispartof: location:Germany status: published

Background Like other countries in sub-Saharan Africa, Madagascar has a high burden of stroke. The Malagasy population is unique in sharing both African and Asian ancestry. The proportion of ischemic and hemorrhagic stroke types is unknown for this population. Aim Our aim was to establish the proportion of stroke types and known risk factors for the Malagasy population. Methods We conducted a single-center, tertiary-level hospital-based case series. We included all patients with a CT-imaging confirmed stroke who presented at the emergency ward of the study hospital between January 1, 2017, and November 20, 2018. Results Of 223 patients with CT-confirmed stroke, 57.4% (128/223, 95% CI: 51–64%) had an ischemic stroke and 42.6% (95/223, 95% CI: 36–49%) had an intracranial hemorrhage. The majority (89.5%; 85/95, 95% CI: 83–96%) of intracranial hemorrhages were intracerebral; 4.2% (4/95, 95% CI: 0–8%) had a subdural hematoma, 5.3% (5/95, 95% CI: 1–10%) had a subarachnoid hemorrhage, there was one isolated intraventricular hemorrhage (1.1%; 1/95, 95% CI: -1-3%). The prevalence of hypertension among stroke patients was high (86.6%; 187/216, 95% CI: 82–91%). Conclusions Our study is the first to report the proportion of stroke types and known risk factors in Madagascar. We find that the proportion of hemorrhagic strokes was unexpectedly higher than that reported from other countries in sub-Saharan Africa. Our findings highlight the need for a country-specific approach to stroke prevention, treatment, and rehabilitation and provide guidance on public health resource allocation in Madagascar.

Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cerebral small vessel disease derived from its most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older persons with MRI measurements and genome-wide genotyping (n = 41 326), whole-exome sequencing (n = 15 965), or exome chip (n = 5249) data contributed 13 776 and 7079 extreme small vessel disease samples for the genome-wide association study and whole-exome association study, respectively. The genome-wide association study identified significant association of common variants in 11 loci with extreme small vessel disease, of which the chr12q24.11 locus was not previously reported to be associated with any MRI marker of cerebral small vessel disease. The whole-exome association study identified significant associations of extreme small vessel disease with common variants in the 5′ UTR region of EFEMP1 (chr2p16.1) and one probably damaging common missense variant in TRIM47 (chr17q25.1). Mendelian randomization supports the causal association of extensive small vessel disease severity with increased risk of stroke and Alzheimer’s disease. Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. We observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology. Overall, our comprehensive gene-mapping study and preliminary functional evaluation suggests a putative role of TRIM47 in the pathophysiology of cerebral small vessel disease, making it an important candidate for extensive in vivo explorations and future translational work.

Aims We aimed to analyze prevalence and predictors of NOAC off-label under-dosing in AF patients before and after the index stroke. Methods The post hoc analysis included 1080 patients of the investigator-initiated, multicenter prospective Berlin Atrial Fibrillation Registry, designed to analyze medical stroke prevention in AF patients after acute ischemic stroke. Results At stroke onset, an off-label daily dose was prescribed in 61 (25.5%) of 239 NOAC patients with known AF and CHA2DS2-VASc score ≥ 1, of which 52 (21.8%) patients were under-dosed. Under-dosing was associated with age ≥ 80 years in patients on rivaroxaban [OR 2.90, 95% CI 1.05–7.9, P = 0.04; n = 29] or apixaban [OR 3.24, 95% CI 1.04–10.1, P = 0.04; n = 22]. At hospital discharge after the index stroke, NOAC off-label dose on admission was continued in 30 (49.2%) of 61 patients. Overall, 79 (13.7%) of 708 patients prescribed a NOAC at hospital discharge received an off-label dose, of whom 75 (10.6%) patients were under-dosed. Rivaroxaban under-dosing at discharge was associated with age ≥ 80 years [OR 3.49, 95% CI 1.24–9.84, P = 0.02; n = 19]; apixaban under-dosing with body weight ≤ 60 kg [OR 0.06, 95% CI 0.01–0.47, P n = 56], CHA2DS2-VASc score [OR per point 1.47, 95% CI 1.08–2.00, P = 0.01], and HAS-BLED score [OR per point 1.91, 95% CI 1.28–2.84, P Conclusion At stroke onset, off-label dosing was present in one out of four, and under-dosing in one out of five NOAC patients. Under-dosing of rivaroxaban or apixaban was related to old age. In-hospital treatment after stroke reduced off-label NOAC dosing, but one out of ten NOAC patients was under-dosed at discharge. Clinical trial registration NCT02306824.

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.

Background: Elevated high-sensitive cardiac troponin (hs-cTn) can be found in more than 50% of the patients with acute ischemic stroke. The observational TRoponin ELevation in Acute ischemic Stroke (TRELAS) study revealed that about 25% of all stroke patients with elevated troponin had a coronary angiography-detected culprit lesion affording immediate intervention, and about 50% of all patients did not have any obstructive coronary artery disease. Given the risk of procedure-related complications, the identification of stroke patients in urgent need of invasive coronary angiography is desirable. Methods: TRELAS patients were prospectively enrolled into this sub-study. In addition to conventional coronary angiography, a cardiac magnetic resonance imaging (MRI) at 3T was performed during the in-hospital stay after acute ischemic stroke to compare the diagnostic value of both imaging modalities. Results:Nine stroke patients (median age 73 years [range 58–87]; four females; median NIH Stroke Severity score on admission 4 [range 0–6] with elevated hs-cTnT [median 74 ng/L, interquartile range 41–247] on admission) completed cardiac MRI and underwent coronary angiography. The absence of MRI-detected wall motion abnormalities and/or late gadolinium enhancement in 5 stroke patients corresponded with the exclusion of culprit lesions or significant coronary artery disease by coronary angiography. Four patients had abnormal MRI findings, whereof 2 showed evidence of myocardial infarction and in whom coronary angiography demonstrated a >70% stenosis of a coronary artery. Conclusions: The TRELAS sub-study indicates that noninvasive cardiac MRI may provide helpful information to identify stroke patients with or without acute coronary syndrome. Our findings might help to select stroke patients in urgent need of coronary angiography.

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.

BACKGROUND AND PURPOSE: The aim was to study the effect of intravenous alteplase on the development of post-stroke depression (PSD) in acute stroke patients, and to identify predictors of PSD. METHODS: This post hoc analysis included patients with unknown onset stroke randomized to treatment with alteplase or placebo in the WAKE-UP trial (ClinicalTrials.gov number, NCT01525290), in whom a composite end-point of PSD was defined as a Beck Depression Inventory ≥10, medication with an antidepressant, or depression recorded as an adverse event. Multiple logistic regression was used to identify predictors of PSD at 90 days. Structural equation modelling was applied to assess the indirect effect of thrombolysis on PSD mediated by the modified Rankin Scale. RESULTS: Information on the composite end-point was available for 438 of 503 randomized patients. PSD was present in 96 of 224 (42.9%) patients in the alteplase group and 115 of 214 (53.7%) in the placebo group (odds ratio 0.63; 95% confidence interval 0.43-0.94; p = 0.022; adjusted for age and National Institutes of Health Stroke Scale at baseline). Prognostic factors associated with PSD included baseline medication with antidepressants, higher lesion volume, history of depression and assignment to placebo. While 65% of the effect of thrombolysis on PSD were caused directly, 35% were mediated by an improvement of the mRS. CONCLUSIONS: Treatment with alteplase in patients with acute stroke resulted in lower rates of depression at 90 days, which were only partially explained by reduced functional disability. Predictors of PSD including history and clinical characteristics may help in identifying patients at risk of PSD. ispartof: EUROPEAN JOURNAL OF NEUROLOGY vol:28 issue:6 pages:2017-2025 ispartof: location:England status: published

Purpose. Decades of research have explored communication in cerebrovascular diseases by focusing on formulaic expressions (e.g., “Thank you”—“You’re welcome”). This category of utterances is known for engaging primarily right-hemisphere frontotemporal and bilateral subcortical neural networks, explaining why left-hemisphere stroke patients with speech-motor planning disorders often produce formulaic expressions comparatively well. The present proof-of-concept study aims to confirm that using verbal cues derived from formulaic expressions can alleviate word-onset difficulties, one major symptom in apraxia of speech. Methods. In a cross-sectional repeated-measures design, 20 individuals with chronic post-stroke apraxia of speech were asked to produce (i) verbal cues (e.g., /guː/) and (ii) subsequent German target words (e.g., “Tanz”) with critical onsets (e.g., /t/). Cues differed, most notably, in aspects of formulaicity (e.g., stereotyped prompt: /guː/, based on formulaic phrase “Guten Morgen”; unstereotyped prompt: /muː/, based on non-formulaic control word “Mutig”). Apart from systematic variation in stereotypy and communicative-pragmatic embeddedness possibly associated with holistic language processing, cues were matched for consonant-vowel structure, syllable-transition frequency, noun-verb classification, meter, and articulatory tempo. Results. Statistical analyses revealed significant increases in correctly produced word onsets after verbal cues with distinct features of formulaicity (e.g., stereotyped versus unstereotyped prompts: p < 0.001), as reflected in large effect sizes (Cohen’s d ≤ 2.2). Conclusions. The current results indicate that using preserved formulaic language skills can relieve word-onset difficulties in apraxia of speech. This finding is consistent with a dynamic interplay of left perilesional and right intact language networks in post-stroke rehabilitation and may inspire new treatment strategies for individuals with apraxia of speech.

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.

Cardiac troponin is a specific and sensitive biomarker to identify and quantify myocardial injury. Myocardial injury is frequently detected after acute ischemic stroke and strongly associated with unfavorable outcomes. Concomitant acute coronary syndrome is only one of several possible differential diagnoses that may cause elevation of cardiac troponin after stroke. As a result, there are uncertainties regarding the correct interpretation and optimal management of stroke patients with myocardial injury in clinical practice. Elevation of cardiac troponin may occur as part of a ‘Stroke-Heart Syndrome’. The term ‘Stroke-Heart Syndrome’ subsumes a clinical spectrum of cardiac complications after stroke including cardiac injury, dysfunction, and arrhythmia which may relate to disturbances of autonomic function and the brain–heart axis. In this review, we provide an up-to-date overview about prognostic implications, mechanisms, and management of elevated cardiac troponin levels in patients with acute ischemic stroke.

Background Current guidelines recommend measurement of troponin in acute ischemic stroke (AIS) patients. In AIS patients, troponin elevation is associated with increased mortality and worse outcome. However, uncertainty remains regarding the underlying pathophysiology of troponin elevation after stroke, particularly regarding diagnostic and therapeutic consequences. Troponin elevation may be caused by coronary artery disease (CAD) and more precisely acute coronary syndrome (ACS). Both have a high prevalence in stroke patients and contribute to poor outcome. Therefore, better diagnostic algorithms are needed to identify those AIS patients likely to have ACS or other manifestations of CAD. Methods/design The primary goal of the “PRediction of Acute coronary syndrome in acute Ischemic StrokE” (PRAISE) study is to develop a diagnostic algorithm for prediction of ACS in AIS patients. The primary hypothesis will test whether dynamic high-sensitivity troponin levels determined by repeat measurements (i.e., “rise or fall-pattern”) indicate presence of ACS when compared to stable (chronic) troponin elevation. PRAISE is a prospective, multicenter, observational trial with central reading and predefined endpoints guided by a steering committee. Clinical symptoms, troponin levels as well as findings on electrocardiogram, echocardiogram, and coronary angiogram will be recorded and assessed by central academic core laboratories. Diagnosis of ACS will be made by an endpoint adjudication committee. Severe adverse events will be evaluated by a critical event committee. Safety will be judged by a data and safety monitoring board. Follow-up will be conducted at three and twelve months and will record new vascular events (i.e., stroke and myocardial infarction) as well as death, functional and cognitive status. According to sample size calculation, 251 patients have to be included. Discussion PRAISE will prospectively determine the frequency of ACS and characterize cardiac and coronary pathologies in a large, multicenter cohort of AIS patients with troponin elevation. The findings will elucidate the origin of troponin elevation, shed light on its impact on necessary diagnostic procedures and provide data on the safety and diagnostic yield of coronary angiography early after stroke. Thereby, PRAISE will help to refine algorithms and develop guidelines for the cardiac workup in AIS. Trial registration NCT03609385 registered 1st August 2018.

ObjectiveTo explore the utility of serum neurofilament light chain (NfL) as a biomarker for primary and secondary neuroaxonal injury after ischemic stroke (IS) and study its value for the prediction of clinical outcome.MethodsWe used an ultrasensitive single-molecule array assay to measure serum NfL levels in healthy controls (n = 30) and 2 independent cohorts of patients with IS: (1) with serial serum sampling at hospital arrival (n = 196), at days 2, 3, and 7 (n = 89), and up to 6 months post stroke; and (2) with standardized MRI at baseline and at 6 months post stroke, and with cross-sectional serum sampling at 6 months (n = 95). We determined the temporal profile of serum NfL levels, their association with imaging markers of neuroaxonal injury, and with clinical outcome.ResultsPatients with IS had higher serum NfL levels compared with healthy controls starting from admission until 6 months post stroke. Serum NfL levels peaked at day 7 (211.2 pg/mL [104.7–442.6], median [IQR]) and correlated with infarct volumes (day 7: partial r = 0.736, p = 1.5 × 10−15). Six months post stroke, patients with recurrent ischemic lesions on MRI (n = 19) had higher serum NfL levels compared to those without new lesions (n = 76, p = 0.002). Serum NfL levels 6 months post stroke further correlated with a quantitative measure of secondary neurodegeneration obtained from diffusion tensor imaging MRI (r = 0.361, p = 0.001). Serum NfL levels 7 days post stroke independently predicted modified Rankin Scale scores 3 months post stroke (cumulative odds ratio [95% confidence interval] = 2.35 [1.60–3.45]; p = 1.24 × 10−05).ConclusionSerum NfL holds promise as a biomarker for monitoring primary and secondary neuroaxonal injury after IS and for predicting functional outcome.

Lesion volume measurements with magnetic resonance imaging are widely used to assess outcome in rodent models of stroke. In this study, we improved a mathematical framework to correct lesion size for edema which is based on manual delineation of the lesion and hemispheres. Furthermore, a novel MATLAB toolbox to register mouse brain MR images to the Allen brain atlas is presented. Its capability to calculate edema-corrected lesion size was compared to the manual approach. Automated image registration performed equally well in in a mouse middle cerebral artery occlusion model (Pearson r = 0.976, p = 2.265e-11). Information encapsulated in the registration was used to generate maps of edema induced tissue volume changes. These showed discrepancies to simplified tissue models underlying the manual approach. The presented techniques provide biologically more meaningful, voxel-wise biomarkers of vasogenic edema after stroke.

Intracerebral haemorrhage and small vessel ischaemic stroke (SVS) are the most acute manifestations of cerebral small vessel disease, with no established preventive approaches beyond hypertension management. Combined genome-wide association study (GWAS) of these two correlated diseases may improve statistical power to detect novel genetic factors for cerebral small vessel disease, elucidating underlying disease mechanisms that may form the basis for future treatments. Because intracerebral haemorrhage location is an adequate surrogate for distinct histopathological variants of cerebral small vessel disease (lobar for cerebral amyloid angiopathy and non-lobar for arteriolosclerosis), we performed GWAS of intracerebral haemorrhage by location in 1813 subjects (755 lobar and 1005 non-lobar) and 1711 stroke-free control subjects. Intracerebral haemorrhage GWAS results by location were meta-analysed with GWAS results for SVS from MEGASTROKE, using ‘Multi-Trait Analysis of GWAS’ (MTAG) to integrate summary data across traits and generate combined effect estimates. After combining intracerebral haemorrhage and SVS datasets, our sample size included 241 024 participants (6255 intracerebral haemorrhage or SVS cases and 233 058 control subjects). Genome-wide significant associations were observed for non-lobar intracerebral haemorrhage enhanced by SVS with rs2758605 [MTAG P-value (P) = 2.6 × 10(−8)] at 1q22; rs72932727 (P = 1.7 × 10(−8)) at 2q33; and rs9515201 (P = 5.3 × 10(−10)) at 13q34. In the GTEx gene expression library, rs2758605 (1q22), rs72932727 (2q33) and rs9515201 (13q34) are significant cis-eQTLs for PMF1 (P = 1 × 10(−4) in tibial nerve), NBEAL1, FAM117B and CARF (P < 2.1 × 10(−7) in arteries) and COL4A2 and COL4A1 (P < 0.01 in brain putamen), respectively. Leveraging S-PrediXcan for gene-based association testing with the predicted expression models in tissues related with nerve, artery, and non-lobar brain, we found that experiment-wide significant (P < 8.5 × 10(−7)) associations at three genes at 2q33 including NBEAL1, FAM117B and WDR12 and genome-wide significant associations at two genes including ICA1L at 2q33 and ZCCHC14 at 16q24. Brain cell-type specific expression profiling libraries reveal that SEMA4A, SLC25A44 and PMF1 at 1q22 and COL4A1 and COL4A2 at 13q34 were mainly expressed in endothelial cells, while the genes at 2q33 (FAM117B, CARF and NBEAL1) were expressed in various cell types including astrocytes, oligodendrocytes and neurons. Our cross-phenotype genetic study of intracerebral haemorrhage and SVS demonstrates novel genome-wide associations for non-lobar intracerebral haemorrhage at 2q33 and 13q34. Our replication of the 1q22 locus previous seen in traditional GWAS of intracerebral haemorrhage, as well as the rediscovery of 13q34, which had previously been reported in candidate gene studies with other cerebral small vessel disease-related traits strengthens the credibility of applying this novel genome-wide approach across intracerebral haemorrhage and SVS.

BACKGROUND: Central drop foot is a common problem in patients with stroke or multiple sclerosis (MS). For decades, it has been treated with orthotic devices, keeping the ankle in a fixed position. It has been shown recently that semi-implantable functional electrical stimulation (siFES) of the peroneal nerve can lead to a greater gait velocity increase than orthotic devices immediately after being switched on. Little is known, however, about long-term outcomes over 12 months, and the relationship between quality of life (QoL) and gait speed using siFES has never been reported applying a validated tool. We provide here a report of short (3 months) and long-term (12 months) outcomes for gait speed and QoL. METHODS: Forty-five consecutive patients (91% chronic stroke, 9% MS) with central drop foot received siFES (Actigait®). A 10 m walking test was carried out on day 1 of stimulation (T1), in stimulation ON and OFF conditions, and repeated after 3 (T2) and 12 (T3) months. A 36-item Short Form questionnaire was applied at all three time points. RESULTS: We found a main effect of stimulation on both maximum (p

Treatments for acute ischaemic stroke continue to evolve after the superior value of endovascular thrombectomy was confirmed over systemic thrombolysis. Unfortunately, numerous neuroprotective drugs have failed to show benefit in the treatment of acute ischaemic stroke, making the search for new treatments imperative. Increased awareness of the relevance of rigorous preclinical testing, and appropriate selection of study participants, might overcome the barriers to progress in stroke research. Relevant areas of interest include the search for safe and effective treatment strategies that combine neuroprotection reperfusion, better use of advanced brain imaging for patient selection, and wider implementation of prehospital conducted clinical trials. Randomised controlled trials of combination treatments completed within the past 5 years have included growth factors, hypothermia, minocycline, natalizumab, fingolimod, and uric acid; the latter two drugs with alteplase produced encouraging results. Blocking of excitotoxicity is also being reassessed in clinical trials with new approaches, such as the postsynaptic density-95 inhibitor NA-1, or peritoneal dialysis to remove excess glutamate. The findings of these randomised trials are anticipated to improve treatment options and clinical outcomes in of patients with acute stroke., The authors are supported by the Spanish Ministry of Economy and Competence (RETICS-INVICTUS R012/0014).

Background Modifying brain activity using non-invasive, low intensity transcranial electrical brain stimulation (TES) has rapidly increased during the past 20 years. Alternating current stimulation (ACS), for example, has been shown to alter brain rhythm activities and modify neuronal functioning in the visual system. Daily application of transorbital ACS to patients with optic nerve damage induces functional connectivity reorganization, and partially restores vision. While ACS is thought to mainly modify neuronal mechanisms, e.g. changes in brain oscillations that can be detected by EEG, it is still an open question, whether and how it may alter BOLD activity. Objective We evaluated whether transorbital ACS modulates BOLD activity in early visual cortex using high-resolution 7 Tesla functional magnetic resonance imaging (fMRI). Methods In this feasibility study transorbital ACS in the alpha range and sham ACS was applied in a random block design in five healthy subjects for 20 min at 1 mA. Brain activation in the visual areas V1, V2 and V3 were measured using 7 Tesla fMRI-based retinotopic mapping at the time points before (baseline) and after stimulation. In addition, we collected data from one hemianopic stroke patient with visual cortex damage after ten daily sessions with 25–50 min stimulation duration. Results In healthy subjects transorbital ACS increased the activated cortical surface area, decreased the fMRI response amplitude and increased coherence in the visual cortex, which was most prominent in the full field task. In the patient, stimulation improved contrast sensitivity in the central visual field. BOLD amplitudes and coherence values were increased in most early visual areas in both hemispheres, with the most pronounced activation detected during eccentricity testing in retinotopic mapping. Conclusions This feasibility study showed that transorbital ACS modifies BOLD activity to visual stimulation, which outlasts the duration of the AC stimulation. This is in line with earlier neurophysiological findings of increased power in EEG recordings and functional connectivity reorganization in patients with impaired vision. Accordingly, the larger BOLD response area after stimulation can be explained by more coherent activation and lower variability in the activation. Alternatively, increased neuronal activity can also be taken into account. Controlled trials are needed to systematically evaluate the potential of repetitive transorbital ACS to improve visual function after visual pathway stroke and to determine the cause-effect relationship between neural and BOLD activity changes.

Objective— Gut microbiota–dependent metabolites, in particular trimethylamine N -oxide (TMAO), have recently been reported to promote atherosclerosis and thrombosis. Here, we examined for the first time the relation of TMAO and the risk of incident cardiovascular events in patients with recent first-ever ischemic stroke in 2 independent prospective cohorts. Moreover, the link between TMAO and proinflammatory monocytes as a potential contributing factor for cardiovascular risk in stroke patients was studied. Approach and Results— In a first study (n=78), higher TMAO plasma levels were linked with an increased risk of incident cardiovascular events including myocardial infarction, recurrent stroke, and cardiovascular death (fourth quartile versus first quartile; hazard ratio, 2.31; 95% CI, 1.25–4.23; P P P =0.04). A significant correlation was also found between TMAO levels and percentage of proinflammatory intermediate CD14 ++ CD16 + monocytes ( r =0.70; P high monocytes were higher than in the chow-fed control group (choline: 9.2±0.5×10 3 per mL versus control: 6.5±0.5×10 3 per mL; P 3 per mL; P Conclusions— The present study demonstrates for the first time a graded relation between TMAO levels and the risk of subsequent cardiovascular events in patients with recent prior ischemic stroke. Our data support the notion that TMAO-related increase of proinflammatory monocytes may add to elevated cardiovascular risk of patients with increased TMAO levels.

Summary Cardiac complications are a frequent medical problem during the first few days after an ischaemic stroke, and patients present with a broad range of symptoms including myocardial injury, cardiac dysfunction, and arrhythmia, with varying overlap between these three conditions. Evidence from clinical and neuroimaging studies and animal research suggests that these cardiac disturbances share the same underlying mechanisms. Although the exact cascade of events has yet to be elucidated, stroke-induced functional and structural alterations in the central autonomic network, with subsequent dysregulation of normal neural cardiac control, are the assumed pathophysiology. This dysregulation can promote myocardial necrosis, microvascular dysfunction, coronary demand ischaemia, and arrhythmogenesis. These stroke-associated cardiac alterations can be summarised as a distinct so-called stroke–heart syndrome. Independent cohort studies have shown a strong association between this syndrome and unfavourable short-term prognosis; however, long-term consequences, including secondary cardiac events and death, are less well described and specific therapeutic targets are scarce. An integrated view of stroke–heart syndrome will offer opportunities to expedite research and inform clinical decision making.

Supplemental Digital Content is available in the text., Background and Purpose— Structural integrity of the white matter is a marker of cerebral small vessel disease, which is the major cause of vascular dementia and a quarter of all strokes. Genetic studies provide a way to obtain novel insights in the disease mechanism underlying cerebral small vessel disease. The aim was to identify common variants associated with microstructural integrity of the white matter and to elucidate the relationships of white matter structural integrity with stroke, major depressive disorder, and Alzheimer disease. Methods— This genome-wide association analysis included 8448 individuals from UK Biobank—a population-based cohort study that recruited individuals from across the United Kingdom between 2006 and 2010, aged 40 to 69 years. Microstructural integrity was measured as fractional anisotropy- (FA) and mean diffusivity (MD)-derived parameters on diffusion tensor images. White matter hyperintensity volumes (WMHV) were assessed on T2-weighted fluid-attenuated inversion recovery images. Results— We identified 1 novel locus at genome-wide significance (VCAN [versican]: rs13164785; P=3.7×10−18 for MD and rs67827860; P=1.3×10−14 for FA). LD score regression showed a significant genome-wide correlation between FA, MD, and WMHV (FA-WMHV rG 0.39 [SE, 0.15]; MD-WMHV rG 0.56 [SE, 0.19]). In polygenic risk score analysis, FA, MD, and WMHV were significantly associated with lacunar stroke, MD with major depressive disorder, and WMHV with Alzheimer disease. Conclusions— Genetic variants within the VCAN gene may play a role in the mechanisms underlying microstructural integrity of the white matter in the brain measured as FA and MD. Mechanisms underlying white matter alterations are shared with cerebrovascular disease, and inherited differences in white matter microstructure impact on Alzheimer disease and major depressive disorder.

Background The impact of risk factors on poor outcome after ischemic stroke is well known, but estimating the amount of poor outcome attributable to single factors is challenging in presence of multimorbidity. We aim to compare population attributable risk estimates obtained from different statistical approaches regarding their consistency. We use a real-life data set from the PROSCIS study to identify predictors for mortality and functional impairment one year after first-ever ischemic stroke and quantify their contribution to poor outcome using population attributable risks. Methods The PROSpective Cohort with Incident Stroke (PROSCIS) is a prospective observational hospital-based cohort study of patients after first-ever stroke conducted independently in Berlin (PROSCIS-B) and Munich (PROSCIS-M). The association of baseline factors with poor outcome one year after stroke in PROSCIS-B was analysed using multiple logistic regression analysis and population attributable risks were calculated, which were estimated using sequential population attributable risk based on a multiple generalized additive regression model, doubly robust estimation, as well as using average sequential population attributable risk. Findings were reproduced in an independent validation sample from PROSCIS-M. Results Out of 507 patients with available outcome information after 12 months in PROSCIS-B, 20.5% suffered from poor outcome. Factors associated with poor outcome were age, pre-stroke physical disability, stroke severity (NIHSS), education, and diabetes mellitus. The order of risk factors ranked by magnitudes of population attributable risk was almost similar for all methods, but population attributable risk estimates varied markedly between the methods. In PROSCIS-M, incidence of poor outcome and distribution of baseline parameters were comparable. The multiple logistic regression model could be reproduced for all predictors, except pre-stroke physical disability. Similar to PROSCIS-B, the order of risk factors ranked by magnitudes of population attributable risk was almost similar for all methods, but magnitudes of population attributable risk differed markedly between the methods. Conclusions Ranking of risk factors by population impact is not affected by the different statistical approaches. Thus, for a rational decision on which risk factor to target in disease interventions, population attributable risk is a supportive tool. However, population attributable risk estimates are difficult to interpret and are not comparable when they origin from studies applying different methodology. The predictors for poor outcome identified in PROSCIS-B have a relevant impact on mortality and functional impairment one year after first-ever ischemic stroke.

Prediction of functional outcome after stroke based on initial presentation remains an open challenge, suggesting that an important aspect is missing from these prediction models. There exists the notion of a protective mechanism called brain reserve, which may be utilized to understand variations in disease outcome. In this work, we expand the concept of brain reserve (effective reserve) to improve prediction models of functional outcome after acute ischemic stroke (AIS). Consecutive AIS patients with acute brain magnetic resonance imaging (, European Commission. Framework Programme for Research and Innovation. Marie Sklodowska-Curie Actions (Grant 753896), National Institute of Neurological and Communicative Disorders and Stroke (Grant K23NS064052), National Institute of Neurological and Communicative Disorders and Stroke (Grant R01NS082285), National Institute of Neurological and Communicative Disorders and Stroke (Grant R01NS086905)

While the corpus callosum (CC) is important to normal sensorimotor function, its role in motor function after stroke is less well understood. This study examined the relationship between structural integrity of the motor and sensory sections of the CC, as reflected by fractional anisotropy (FA), and motor function in individuals with a range of motor impairment level due to stroke. Fifty-five individuals with chronic stroke (Fugl-Meyer motor score range 14 to 61) and 18 healthy controls underwent diffusion tensor imaging and a set of motor behavior tests. Mean FA from the motor and sensory regions of the CC and from corticospinal tract (CST) were extracted and relationships with behavioral measures evaluated. Across all participants, FA in both CC regions was significantly decreased after stroke (p 39), motor status correlated with FA in the CC but not the CST, while in individuals with relatively greater motor impairment (Fugl-Meyer motor score ≤ 39), motor status correlated with FA in the CST but not the CC. The role interhemispheric motor connections play in motor function after stroke may differ based on level of motor impairment. These findings emphasize the heterogeneity of stroke, and suggest that biomarkers and treatment approaches targeting separate subgroups may be warranted., Highlights • Corpus callosum structural integrity could impact motor function after stroke. • Corpus callosum integrity was decreased and correlated with motor function. • Correlation was strongest in the subgroup with relatively greater motor capacity. • In subgroup with less motor capacity, only CST integrity correlated with motor function.

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 NINDSSiGN, 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 (P55 - 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. (Less)

Stroke in right dorsal anterior insular cortex Is related to myocardial injury.

Background and Purpose— Assessment of cognitive status poststroke is recommended by guidelines but follow-up can often not be done in person. The Telephone Interview of Cognitive Status (TICS) and the Telephone Montreal Cognitive Assessment (T-MoCA) are considered useful screening instruments. Yet, evidence to define optimal cut-offs for mild cognitive impairment (MCI) after stroke is limited. Methods— We studied 105 patients enrolled in the prospective DEDEMAS study (Determinants of Dementia After Stroke; NCT01334749). Follow-up visits at 6, 12, 36, and 60 months included comprehensive neuropsychological testing and the Clinical Dementia Rating scale, both of which served as reference standards. The original TICS and T-MoCA were obtained in 2 separate telephone interviews each separated from the personal visits by 1 week (1 before and 1 after the visit) with the order of interviews (TICS versus T-MoCA) alternating between subjects. Area under the receiver-operating characteristic curves was determined. Results— Ninety-six patients completed both the face-to-face visits and the 2 interviews. Area under the receiver-operating characteristic curves ranged between 0.76 and 0.83 for TICS and between 0.73 and 0.94 for T-MoCA depending on MCI definition. For multidomain MCI defined by multiple-tests definition derived from comprehensive neuropsychological testing optimal sensitivities and specificities were achieved at cut-offs Conclusions— Both the TICS and T-MoCA are valid screening tools poststroke, particularly for multidomain MCI using multiple-test definition.

Patients with anosognosia for visual field defect (AVFD) fail to recognize consciously their visual field defect. There is still unclarity whether specific neural correlates are associated with AVFD. We studied AVFD in 54 patients with acute stroke and a visual field defect. Nineteen percent of this unselected sample showed AVFD. By using modern voxelwise lesion-behaviour mapping techniques we found an association between AVFD and parts of the lingual gyrus, the cuneus as well as the posterior cingulate and corpus callosum. Damage to these regions appears to induce unawareness of visual field defects and thus may play a significant role for conscious visual perception.

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.

Objective: To assess whether statin treatment before or after acute ischemic stroke (AIS) affects the risk of acute intracerebral hemorrhage (ICH), postacute ICH, and mortality within 90 days. Methods: Data were sought from the Virtual International Stroke Trials Archive, an international repository of clinical trials data. Using propensity score matching, we retrospectively compared patients with prior statin treatment and newly initiated statin within 3 days after AIS to patients without statin exposure. Outcomes of interest were acute symptomatic ICH (sICH), any acute ICH, postacute ICH, and mortality during follow-up of 3 months. Results: A total of 8,535 patients (mean age 70 years, 54% male, median baseline NIH Stroke Scale score 13) were analyzed. After propensity score matching, prior statin use was not strongly associated with sICH (adjusted odds ratio [OR] 1.33, 95% confidence interval [CI] 0.83–2.14) or any ICH (adjusted OR 1.35, 95% CI 0.92–1.98). There was no evidence of an interaction between prior statin use and thrombolysis. New initiation of statins was not associated with postacute ICH (adjusted hazard ratio [HR] 1.60, 95% CI 0.70–3.65). There was a signal towards lower 90-day mortality in patients with prior statin use (adjusted HR 0.84, 95% CI 0.70–1.00) and especially early initiation of statins (adjusted HR 0.67, 95% CI 0.46–0.97). Conclusions: Statin use prior to AIS was not associated with early hemorrhagic complications, irrespective of treatment with thrombolysis. New initiation of statin treatment early after AIS did not affect risk of postacute ICH, but might be associated with reduced mortality.

Background and Purpose— Mild cognitive impairment (MCI) is common after stroke and associated with poor outcome. However, the mechanisms underlying poststroke MCI (PS-MCI) are insufficiently understood. We performed amyloid-β positron emission tomography (PET) in a prospective cohort of stroke survivors to determine the role of amyloid pathology in PS-MCI. Methods— We studied 178 consecutive patients enrolled into the prospective DEDEMAS study (Determinants of Dementia After Stroke). Follow-up visits 6 months post stroke included detailed cognitive testing, standardized magnetic resonance imaging, and amyloid-β imaging using flutemetamol ( 18 F) PET. MCI was defined by the modified Petersen criteria. Amyloid-positivity was assessed visually and quantitatively. Fifty-six (31%) patients agreed to undergo PET imaging. Results— Thirty-eight (68%) patients who consented to PET imaging had PS-MCI. Visual assessment revealed amyloid PET positivity in 2 (5%) of the 38 PS-MCI patients and in 2 (11%) of the 18 cognitively healthy stroke survivors. There was no correlation between flutemetamol ( 18 F) standardized uptake value ratios and cognitive scores in the 56 patients. PS-MCI patients had significant cognitive impairments on executive function ( P P P Conclusions— The prevalence of amyloid-pathology in patients with PS-MCI is not increased when compared with cognitively healthy stroke survivors and to recent estimates for cognitively healthy elderly subjects. Factors other than amyloid-pathology likely contribute to the development of PS-MCI. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01334749.

A 76-year-old woman with right-sided tremor-dominant idiopathic Parkinson disease was admitted due to sudden-onset right leg palsy, right hemihypesthesia, and slurred speech but cessation of resting tremor. MRI showed recent infarction in the left thalamus (figure 1). Spatial analysis performed with Lead-DBS software ([www.lead-dbs.org][1]) located the lesion to left ventrolateral and ventroposterior nuclei1 (Jones nomenclature), corresponding to the ventrointermediate nucleus (Walker nomenclature), the typical deep brain stimulation target for tremor. The analysis showed that the (nondecussating) dentatothalamic tract,2 which plays a prominent role in tremor pathophysiology, passes through the lesion (figure 2). [1]: http://www.lead-dbs.org

Apraxia caused by left hemispheric stroke typically impairs skilled sequential movements. After stroke, apraxic patients need to reacquire motor skills by motor learning. The current study assessed for the first time incidental motor sequence learning in apraxic patients. Forty-eight human subjects (henceforth called “patients”) with left hemispheric stroke affecting the middle cerebral artery territory (18 with apraxia and 30 without apraxia) and 17 age-matched healthy controls were tested on a visuomanual serial reaction time task. Subjects performed four blocks consisting of repetitions of a complex six element sequence containing ambiguous pairwise transitions before a new and unfamiliar sequence was introduced in block 5. Reaction time (RT) disadvantages in this fifth block indicated incidental sequence-specific motor learning. The intentional retrieval of the learned motor knowledge was assessed subsequently with a free recall task. Voxel-based lesion-symptom mapping (VLSM) was performed to investigate for the first time the lesion correlates of deficits in learning and retrieving sequential motor knowledge. Despite generally prolonged RTs, apraxic patients showed sequence-specific motor learning as could be observed in nonapraxic patients and healthy controls. However, apraxic patients showed reduced intentional retrieval of the learned sequence. VLSM revealed that impaired intentional retrieval of motor sequence knowledge resulted from dorsal premotor cortex lesions. Apraxic patients showed a dissociation of preserved incidental motor (sequence) learning and deficient intentional retrieval of this incidentally learned motor knowledge. The data suggest that novel approaches for treating apraxia should focus on incidental motor learning, but that automatic rather than intentional retrieval strategies should be enforced.

Background Visual neglect and extinction are two common neurological syndromes in patients with right-hemispheric brain damage. Whether and how these two syndromes are associated or share common neural substrates is still a matter of debate. Methods To address these issues, the authors investigated 56 patients with right-hemispheric stroke with a novel diagnostic test to detect extinction and neglect. In this computerised task, subjects had to respond to target stimuli in uni- and bilateral stimulation conditions with detection probabilities being assessed. A cluster-analytical approach identified 18 patients with neglect and 13 patients with extinction. Statistical lesion-symptom mapping analyses with measures for extinction and neglect were performed. Results Extinction and neglect co-occurred in a subset of patients but were also observed independently from each other, thereby constituting a double dissociation. Lesions within the right inferior parietal cortex were significantly associated with the severity of visual extinction. Visuospatial neglect was related to damage of fronto-parietal brain regions, with parieto-occipital areas affecting line bisection and dorsal fronto-parietal areas affecting cancellation task performance, respectively. Conclusion Quantifying lesion-induced symptoms with this novel paradigm shows that extinction and neglect are dissociable syndromes in patients with right-hemispheric stroke. Furthermore, extinction and neglect can be related to differential neural substrates, with extinction being related to focal brain damage within the right inferior parietal cortex.

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.

Focal ischemia may induce pathological alterations in brain areas distant from the primary lesion. In animal models, exofocal neuron death in the ipsilateral midbrain has been described after occlusion of the middle cerebral artery (MCA). Using sequential magnetic resonance imaging (T2- and diffusion- weighted) at 3 Tesla, we investigated acute ischemic stroke patients on days 1, 2, 6, 8, and 10 after stroke onset. Sixteen consecutive patients who had suffered a stroke involving the caudate nucleus and/or putamen of either hemisphere were recruited into the study. Four additional patients with strokes sparing the caudate nucleus and putamen but encompassing at least one- third of the MCA territory served as controls. Ischemic lesions involving striatal structures resulted in hyperintense lesions in ipsilateral midbrain that emerged between days 6 and 10 after stroke and were not present on the initial scans. In contrast, none of the control stroke patients developed secondary midbrain lesions. Hyperintense lesions in the pyramidal tract or the brain stem caused by degeneration of the corticospinal tract could be clearly distinguished from these secondary midbrain gray matter lesions and were detectable from day 2 after ischemia. Co-registration of high-resolution images with a digitized anatomic atlas revealed localization of secondary lesions primarily in the substantia nigra pars compacta. Apparent diffusion coefficient (ADC) values in the secondary lesions showed a delayed sharp decline through day 10. Normalization of ADC values was observed at late measurements. Taken together, our study demonstrates that striatal infarction elicits delayed degenerative changes in ipsilateral substantia nigra pars compacta.

Transplanted neurons derived from stem cells have been proposed to improve function in animal models of human disease by various mechanisms such as neuronal replacement. However, whether the grafted neurons receive functional synaptic inputs from the recipient's brain and integrate into host neural circuitry is unknown. Here we studied the synaptic inputs from the host brain to grafted cortical neurons derived from human induced pluripotent stem cells after transplantation into stroke-injured rat cerebral cortex. Using the rabies virus-based trans-synaptic tracing method and immunoelectron microscopy, we demonstrate that the grafted neurons receive direct synaptic inputs from neurons in different host brain areas located in a pattern similar to that of neurons projecting to the corresponding endogenous cortical neurons in the intact brain. Electrophysiological in vivo recordings from the cortical implants show that physiological sensory stimuli, i.e. cutaneous stimulation of nose and paw, can activate or inhibit spontaneous activity in grafted neurons, indicating that at least some of the afferent inputs are functional. In agreement, we find using patch-clamp recordings that a portion of grafted neurons respond to photostimulation of virally transfected, channelrhodopsin-2-expressing thalamo-cortical axons in acute brain slices. The present study demonstrates, for the first time, that the host brain regulates the activity of grafted neurons, providing strong evidence that transplanted human induced pluripotent stem cell-derived cortical neurons can become incorporated into injured cortical circuitry. Our findings support the idea that these neurons could contribute to functional recovery in stroke and other conditions causing neuronal loss in cerebral cortex.

Rationale About 20% of stroke patients develop dementia within a few months after their event, but the determinants and mechanisms of poststroke dementia are insufficiently understood. Aims To identify and characterize the determinants of cognitive impairment poststroke. Design Observational prospective study in patients with acute stroke and no prior dementia. Six hundred subjects will be characterized by detailed interview, standardized clinical examinations, biometric measures (intima-media thickness, waist-hip ratio, and ankle-brachial index), multimodal imaging (magnetic resonance imaging, fluorodeoxyglucose-positron emission tomography (FDG-PET), amyloid-positron emission tomography (amyloid-PET), and retinal imaging), analysis of biomarkers derived from blood and cerebrospinal fluid, and detailed cognitive testing at repeat time points. Patients will be followed for five-years with a total of five personal visits and three telephone interviews. Study Outcomes Primary end-point is the occurrence of post-stroke dementia. Secondary end-points include poststroke cognitive impairment–no dementia, stroke recurrence, and death. Predictive factors for poststroke dementia will be identified by multiple Cox proportional-hazards model. Results Baseline characteristics of the first 71 patients (study inclusion between May 2011 and August 2012) are as follows: median age, 70 years (interquartile range, 65–75); female gender, 25 (35%); median National Institutes of Health Stroke Scale at admission, 2 ( 1 – 4 ); and etiological stroke subtypes according to TOAST classification, 15% large artery disease, 18% small vessel disease, 35% cardioembolic, and 32% undetermined or multiple competing etiologies. Discussion This study will provide insights into the mechanisms of poststroke dementia and hold the potential to identify novel diagnostic markers and targets for preventive therapies. The study is registered at http://www.clinicaltrials.gov (NCT01334749) and will be extended as a multicenter study starting 2013.

Unilateral stroke can lead to a disorder of postural balance that manifests as a pushing away toward the contralesional side. It is called "pusher syndrome" (PS). The aims of this study were first to assess the anatomical cortical regions that induce PS and second to clarify whether tilt of the subjective visual vertical (SVV)--a sign of vestibular otolith dysfunction--is associated with PS. Sixty-six patients with acute unilateral strokes (28 left-sided lesions, 38 right-sided lesions) were tested for PS, for tilts of the SVV, for hemineglect and for the anatomical lesion site by magnetic resonance imaging (MRI)-based voxelwise lesion-behavior mapping analysis. Our data indicated no significant voxels; however, there was a trend towards an association between lesions of the posterior part of the insula, the operculum and the superior temporal gyrus--key areas of the multisensory vestibular cortical network--and the extent of pushing in patients with right-sided lesions, whereas the rather anterior part of the insula, the operculum as well as the internal capsule reaching to the lateral thalamus seemed to be involved in PS in left-sided lesion patients. These data might point toward a link between the systems responsible for postural control and for processing vestibular otolith information. These findings indicate that vestibular information might be fundamental in right-sided lesion patients for maintaining body posture in space.

Successful remembering involves both hindering irrelevant information from entering working memory (WM) and actively maintaining relevant information online. Using a voxelwise lesion-behavior brain mapping approach in stroke patients, we observed that lesions of the left basal ganglia render WM susceptible to irrelevant information. Lesions of the right prefrontal cortex on the other hand make it difficult to keep more than a few items in WM. These findings support basal ganglia-prefrontal cortex models of WM whereby the basal ganglia play a gatekeeper role and allow only relevant information to enter prefrontal cortex where this information then is actively maintained in WM.

Background Data of the German population-based cohort SHIP (Study of Health in Pomerania) were analysed to examine treatment rates, antihypertensive substances prescribed, and the proportion of hypertensive study participants reaching target values for blood pressure as well as determinants. Methods The study population was defined using baseline data of the cohort (collected between 1997 and 2001). Participants with blood pressure values ≥140/90 mmHg and/or antihypertensive medication with known hypertension and participants with risk-comorbidity (diabetes, stroke, angina pectoris, and/or myocardial infarction) and blood pressure values ≥130/80 mmHg were included. The analysis of treatment and target values was based on the 5-year follow-up of the cohort (collected between 2002 and 2006). Logistic regression was used to identify determinants for a normotensive blood pressure. Results 3278 SHIP-participants with hypertensive blood pressure values were included (mean age: 55.5 years; SD 13.6, range 21–80 years). The raw hypertension prevalence was 50.9% (N = 1761). 58.7% (N = 1074) of all hypertensive patients reported some form of antihypertensive treatment. Thereof 65.1% (N = 728) received combination therapy. Of the patients without risk-comorbidity, 42.1% (N = 489) reached their target blood pressure values at the time of the 5-year follow-up of the cohort. Of the patients with any risk-comorbidity this proportion was only 21.7% (N = 131). Significant determinants for reaching the target values were being female and having antihypertensive combination therapy. Increasing age, having risk-comorbidities, and obesity were negatively associated with reaching the target values. Conclusions Both the proportion of participants receiving therapy and the number of participants reaching their target blood pressure values are very low. Combination therapy is associated with better blood pressure control as compared to mono therapy. However, even in the subgroup of hypertensive patients under combination therapy only 36% (both patients with and without comorbidity) reach target values.