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OBJECTIVE:To determine whether brain volume is associated with functional outcome after acute ischemic stroke (AIS). PATIENTS AND METHODS:This study was conducted between July 1, 2014, and March 16, 2019. We analyzed cross-sectional data of the multisite, international hospital-based MRI-Genetics Interface Exploration study with clinical brain magnetic resonance imaging obtained on admission for index stroke and functional outcome assessment. Poststroke outcome was determined using the modified Rankin Scale score (0-6; 0 = asymptomatic; 6 = death) recorded between 60 and 190 days after stroke. Demographic characteristics and other clinical variables including acute stroke severity (measured as National Institutes of Health Stroke Scale score), vascular risk factors, and etiologic stroke subtypes (Causative Classification of Stroke system) were recorded during index admission. RESULTS:Utilizing the data from 912 patients with AIS (mean ± SD age, 65.3±14.5 years; male, 532 [58.3%]; history of smoking, 519 [56.9%]; hypertension, 595 [65.2%]) in a generalized linear model, brain volume (per 155.1 cm3) was associated with age (β -0.3 [per 14.4 years]), male sex (β 1.0), and prior stroke (β -0.2). In the multivariable outcome model, brain volume was an independent predictor of modified Rankin Scale score (β -0.233), with reduced odds of worse long-term functional outcomes (odds ratio, 0.8; 95% CI, 0.7-0.9) in those with larger brain volumes. CONCLUSION:Larger brain volume quantified on clinical magnetic resonance imaging of patients with AIS at the time of stroke purports a protective mechanism. The role of brain volume as a prognostic, protective biomarker has the potential to forge new areas of research and advance current knowledge of the mechanisms of poststroke recovery.

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

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: 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.

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.

Objective: Critical illness polyneuropathy (CIP) is a common complication of severe systemic illness treated in intensive care medicine. Ischemic stroke leads to an acute critical injury of the brain with hemiparesis, immunosuppression and subsequent infections, all of which require extended medical treatment. Stroke-induced sarcopenia further contributes to poor rehabilitation and is characterized by muscle wasting and denervation in the paralytic, but also the unaffected limbs. Therefore, we asked whether stroke leads to an additional CIP-like neurodegeneration.Results: Focal brain ischemia was induced in adult mice by 60-minute middle cerebral artery occlusion (MCAo) following reperfusion and led to functional deficits and marked hemispheric brain atrophy. Nerve conduction function and muscle potentials were measured in the ipsilateral sciatic nerve and gastrocnemius and quadriceps muscle with electroneurography/-myography on days 10, 22, 44 after stroke. An additional crush-injury to the sciatic nerve was included in two sham mice as positive control (sham+). We found no differences in nerve conduction function nor spontaneous electromyographic activity between MCAo and sham animals. Sham+ mice developed marked reduction of the motor action potential amplitudes and conduction velocities with pathologic spontaneous activity. In conclusion, we found no peripheral nerve dysfunction/ degeneration as signs of a CIP-like phenotype after MCAo.

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.

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: The best strategy to identify patients with suspected acute ischemic stroke and unknown vessel status (large vessel occlusion) for direct transport to a comprehensive stroke center instead of a nearer primary stroke center is unknown. Methods and Results: We used mathematical modeling to estimate the impact of 10 increasingly complex prehospital triage strategy paradigms on the reduction of population-wide stroke-related disability. The model was applied to suspected acute ischemic stroke patients in (1) abstract geographies, and (2) 3 real-world urban and rural geographies in Germany. Transport times were estimated based on stroke center location and road infrastructure; spatial distribution of emergency medical services calls was derived from census data with high spatial granularity. Parameter uncertainty was quantified in sensitivity analyses. The mothership strategy was associated with a statistically significant population-wide gain of 8 to 18 disability-adjusted life years in the 3 real-world geographies and in most simulated abstract geographies (net gain -4 to 66 disability-adjusted life years). Of the more complex paradigms, transportation of patients with clinically suspected large vessel occlusion based on a dichotomous large vessel occlusion detection scale to the nearest comprehensive stroke center yielded an additional clinical benefit of up to 12 disability-adjusted life years in some rural but not in urban geographies. Triage strategy paradigms based on probabilistic conditional modeling added an additional benefit of 0 to 4 disability-adjusted life years over less complex strategies if based on variable cutoff scores. Conclusions: Variable stroke severity cutoff scores were associated with the highest reduction in stroke-related disability. The mothership strategy yielded better clinical outcome than the drip-'n'-ship strategy in most geographies.

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.

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)

International journal of stroke 12(4), 412-415 (2017). doi:10.1177/1747493016677986, Published by Sage, London

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

Background Atrial fibrillation (AF) is estimated to account for approximately every fifth ischemic stroke. In routine clinical practice, detection of undiagnosed, clinically silent AF represents a major diagnostic challenge, and in up to 30% of patients with ischemic stroke, AF remains undetected. The MonDAFIS study has been designed to quantify the diagnostic yield and clinical relevance of systematic electrocardiogram (ECG) monitoring for patients with acute ischemic stroke during the subsequent in hospital stay. Study Design A prospective randomized multicenter study in 3,470 patients with acute ischemic stroke or transient ischemic attack and without known AF on hospital admission. Over a period of approximately 2 years, patients will be enrolled in about 30 German-certified stroke units and randomized 1:1 to receive either usual stroke unit diagnostic procedures for detection of AF (control group) or usual stroke unit diagnostic procedures plus standardized and centrally analyzed Holter ECG recording for up to 7 days in hospital (intervention group). Results of the ECG core laboratory analysis will be provided to the patients and treating physicians. All patients will be followed up for treatment and cardiovascular outcomes at 6, 12, and 24 months after enrollment. Outcomes The primary outcome of the randomized MonDAFIS study is the proportion of patients who receive anticoagulation therapy 12 months after the index stroke. Secondary outcomes include the number of stroke patients with newly detected AF in hospital and the rate of recurrent stroke, major bleedings, myocardial infarction, or death 6, 12, and 24 months after the index event. MonDAFIS will also explore patient-reported adherence to anticoagulants, the clinical elevance of short atrial tachycardia, or excessive supraventricular ectopic activity as well as cost-effectiveness of prolonged, centrally analyzed ECG recordings. Conclusion MonDAFIS will be the largest study to date to evaluate whether a prolonged and systematic ECG monitoring during the initial in hospital stay has an impact on secondary stroke prevention. In addition, prognosis as well as adherence to medication up to 2 years after the index stroke will be analyzed. The primary results of the MonDAFIS study may have the potential to change the current guidelines recommendations regarding ECG workup after ischemic stroke. (Am Heart J 2016;172:19-25.)

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.

Background Cerebral inflammation is a hallmark of neuronal degeneration. Dipeptidyl peptidase IV, aminopeptidase N as well as the dipeptidyl peptidases II, 8 and 9 and cytosolic alanyl-aminopeptidase are involved in the regulation of autoimmunity and inflammation. We studied the expression, localisation and activity patterns of these proteases after endothelin-induced occlusion of the middle cerebral artery in rats, a model of transient and unilateral cerebral ischemia. Methods Male Sprague-Dawley rats were used. RT-PCR, immunohistochemistry and protease activity assays were performed at different time points, lasting from 2 h to 7 days after cerebral ischemia. The effect of protease inhibitors on ischemia-dependent infarct volumes was quantified 7 days post middle cerebral artery occlusion. Statistical analysis was conducted using the t-test. Results Qualitative RT-PCR revealed these proteases in ipsilateral and contralateral cortices. Dipeptidyl peptidase II and aminopeptidase N were up-regulated ipsilaterally from 6 h to 7 days post ischemia, whereas dipeptidyl peptidase 9 and cytosolic alanyl-aminopeptidase were transiently down-regulated at day 3. Dipeptidyl peptidase 8 and aminopeptidase N immunoreactivities were detected in cortical neurons of the contralateral hemisphere. At the same time point, dipeptidyl peptidase IV, 8 and aminopeptidase N were identified in activated microglia and macrophages in the ipsilateral cortex. Seven days post artery occlusion, dipeptidyl peptidase IV immunoreactivity was found in the perikarya of surviving cortical neurons of the ipsilateral hemisphere, whereas their nuclei were dipeptidyl peptidase 8- and amino peptidase N-positive. At the same time point, dipeptidyl peptidase IV, 8 and aminopeptidase N were targeted in astroglial cells. Total dipeptidyl peptidase IV, 8 and 9 activities remained constant in both hemispheres until day 3 post experimental ischemia, but were increased (+165%) in the ipsilateral cortex at day 7. In parallel, aminopeptidase N and cytosolic alanyl-aminopeptidase activities remained unchanged. Conclusions Distinct expression, localization and activity patterns of proline- and alanine-specific proteases indicate their involvement in ischemia-triggered inflammation and neurodegeneration. Consistently, IPC1755, a non-selective protease inhibitor, revealed a significant reduction of cortical lesions after transient cerebral ischemia and may suggest dipeptidyl peptidase IV, aminopeptidase N and proteases with similar substrate specificity as potentially therapy-relevant targets.

Motor neglect is an impairment in the ability to initiate movement not attributable to muscle weakness. The neural network of this syndrome is not precisely defined. We present the diffusion tensor imaging (DTI)-base tractography findings in an acute stroke patient presenting with isolated motor neglect following infarction in the posterior limb of the internal capsule within the anterior choroidal artery territory. A left-handed 17-year-old woman presented with an acute onset of motor neglect of her left arm. Motor tasks performed with the affected limb were awkward; however, the tasks could be accomplished with effort. Magnetic resonance imaging (MRI) including DTI of the brain were performed. DTI-based tractography extracted the fiber tracts originating from regions of interest placed on the ischemic lesion. MRI revealed an acute ischemic infarction at the posterior part of the posterior limb of the right internal capsule within the territory of the anterior choroidal artery. DTI-based tractography showed fiber tracts projecting from the lesion to the posterior part of the supplementary motor area and some fiber tracts projecting to posterior aspects of the thalamus. DTI-based tractography may be a useful tool for visualizing white matter pathways in vivo following an acute infarction. Our case study supports the notion that fiber tracts connecting the posterior part of the posterior limb of the internal capsule, supplementary motor area, and posterior aspect of the thalamus are key areas of a neural network involved in motor neglect syndrome.

Time to thrombolysis is crucial for outcome in acute ischemic stroke.To determine if starting thrombolysis in a specialized ambulance reduces delays.In the Prehospital Acute Neurological Treatment and Optimization of Medical care in Stroke Study (PHANTOM-S), conducted in Berlin, Germany, we randomly assigned weeks with and without availability of the Stroke Emergency Mobile (STEMO) from May 1, 2011, to January 31, 2013. Berlin has an established stroke care infrastructure with 14 stroke units. We included 6182 adult patients (STEMO weeks: 44.3% male, mean [SD] age, 73.9 [15.0] y; control weeks: 45.2% male, mean [SD] age, 74.3 [14.9] y) for whom a stroke dispatch was activated.The intervention comprised an ambulance (STEMO) equipped with a CT scanner, point-of-care laboratory, and telemedicine connection; a stroke identification algorithm at dispatcher level; and a prehospital stroke team. Thrombolysis was started before transport to hospital if ischemic stroke was confirmed and contraindications excluded.Primary outcome was alarm-to-thrombolysis time. Secondary outcomes included thrombolysis rate, secondary intracerebral hemorrhage after thrombolysis, and 7-day mortality.Time reduction was assessed in all patients with a stroke dispatch from the entire catchment area in STEMO weeks (3213 patients) vs control weeks (2969 patients) and in patients in whom STEMO was available and deployed (1804 patients) vs control weeks (2969 patients). Compared with thrombolysis during control weeks, there was a reduction of 15 minutes (95% CI, 11-19) in alarm-to-treatment times in the catchment area during STEMO weeks (76.3 min; 95% CI, 73.2-79.3 vs 61.4 min; 95% CI, 58.7-64.0; P .001). Among patients for whom STEMO was deployed, mean alarm-to-treatment time (51.8 min; 95% CI, 49.0-54.6) was shorter by 25 minutes (95% CI, 20-29; P .001) than during control weeks. Thrombolysis rates in ischemic stroke were 29% (310/1070) during STEMO weeks and 33% (200/614) after STEMO deployment vs 21% (220/1041) during control weeks (differences, 8%; 95% CI, 4%-12%; P .001, and 12%, 95% CI, 7%-16%; P .001, respectively). STEMO deployment incurred no increased risk for intracerebral hemorrhage (STEMO deployment: 7/200; conventional care: 22/323; adjusted odds ratio [OR], 0.42, 95% CI, 0.18-1.03; P = .06) or 7-day mortality (9/199 vs 15/323; adjusted OR, 0.76; 95% CI, 0.31-1.82; P = .53).Compared with usual care, the use of ambulance-based thrombolysis resulted in decreased time to treatment without an increase in adverse events. Further studies are needed to assess the effects on clinical outcomes.clinicaltrials.gov Identifier: NCT01382862.