Cerebral collaterals are associated with pre-treatment brain-blood barrier permeability in acute ischemic stroke patients.

INTRODUCTION: To investigate the relationship between collaterals and blood-brain barrier (BBB) permeability on pre-treatment MRI in a cohort of acute ischemic stroke (AIS) patients treated with thrombectomy. METHODS: We conducted a retrospective analysis of the HIBISCUS-STROKE cohort, a single-center observational study that enrolled patients treated with thrombectomy from 2016 to 2022. Dynamic-susceptibility MRIs were post-processed to generate K2 maps with arrival-time correction, which were co-registered with apparent diffusion coefficient (ADC) maps. The 90th percentile of K2 was extracted from the infarct core-defined by an ADC ≤ 620 × 10-6 mm2/s with manual adjustments-and expressed as a percentage change compared to the contralateral white matter. Collaterals were assessed using pre-thrombectomy digital subtraction arteriography with an ASITN/SIR score < 3 defining poor collaterals. RESULTS: Out of 249 enrolled, 101 (40.6%) were included (median age: 72.0 years, 52.5% of males, median NIHSS score at admission: 15.0). Patients with poor collaterals (n = 44) had worse NIHSS scores (median: 16.0 vs 13.0, p = 0.04), larger infarct core volumes (median: 43.7 mL vs 9.5 mL, p < 0.0001), and higher increases in K2 (median: 346.3% vs 152.7%, p = 0.003). They were less likely to achieve successful recanalization (21/44 vs 51/57, p < 0.0001) and experienced more frequent hemorrhagic transformation (16/44 vs 9/57, p = 0.03). On multiple variable analysis, poor collaterals were associated with larger infarct cores (odds ratio (OR) = 1.12, 95% confidence interval (CI): [1.07, 1.17], p < 0.0001) and higher increases in K2 (OR = 6.63, 95% CI: [2.19, 20.08], p = 0.001). CONCLUSION: Poor collaterals are associated with larger infarct cores and increased BBB permeability at admission MRI. CLINICAL RELEVANCE STATEMENT: Poor collaterals are associated with a larger infarct core and increased BBB permeability at admission MRI of AIS patients treated with thrombectomy. These findings may have translational interests for extending thrombolytic treatment eligibility and developing neuroprotective strategies. KEY POINTS: In AIS, collaterals and BBB disruption have been both linked to hemorrhagic transformation. Poor collaterals were associated with larger ischemic cores and increased BBB permeability on pre-treatment MRI. These findings could contribute to hemorrhagic transformation risk stratification, thereby refining clinical decision-making for reperfusion therapies.

More Than 50 Percent Reduction in LDL Cholesterol in Patients With Target LDL <70 mg/dL After a Stroke.

BACKGROUND: Whether a strategy to target an LDL (low-density lipoprotein) cholesterol <70 mg/dL is more effective when LDL is reduced >50% from baseline rather than <50% from baseline has not been investigated. METHODS: The Treat Stroke to Target trial was conducted in France and South Korea in 61 sites between March 2010 and December 2018. Patients with ischemic stroke in the previous 3 months or transient ischemic attack within the previous 15 days and evidence of cerebrovascular or coronary artery atherosclerosis were randomly assigned to a target LDL cholesterol of <70 mg/dL or 100±10 mg/dL, using statin and/or ezetimibe as needed. We used the results of repeated LDL measurements (median, 5 [2-6] per patient) during 3.9 years (interquartile range, 2.1-6.8) of follow-up. The primary outcome was the composite of ischemic stroke, myocardial infarction, new symptoms requiring urgent coronary or carotid revascularization, and vascular death. Cox regression model including lipid-lowering therapy as a time-varying variable, after adjustment for randomization strategy, age, sex, index event (stroke or transient ischemic attack), and time since the index event. RESULTS: Among 2860 patients enrolled, patients in the lower target group who had >50% LDL cholesterol reduction from baseline during the trial had a higher baseline LDL cholesterol and a lower LDL cholesterol achieved as compared to patients who had <50% LDL cholesterol reduction (155±32 and 62 mg/dL versus 121±34 and 74 mg/dL, respectively, P<0.001 for both). In the <70 mg/dL target group, patients with >50% LDL reduction had a significant reduction in the primary outcome as compared to the higher target group (hazard ratio, 0.61 [95% CI, 0.43-0.88]; P=0.007) and patients with <50% LDL reduction from baseline had little reduction (hazard ratio, 0.96 [95% CI, 0.73-1.26]; P=0.75). CONCLUSIONS: In this post hoc analysis of the TST trial, targeting an LDL cholesterol of <70 mg/dL reduced the risk of primary outcome compared with 100±10 mg/dL provided LDL cholesterol reduction from baseline was superior to 50%, thereby suggesting that the magnitude of LDL cholesterol reduction was as important to consider as the target level to achieve. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01252875. URL: https://clinicaltrialsregister.eu; Unique identifier: EUDRACT2009-A01280-57.

Reversibility of Diffusion-Weighted Imaging Lesions in Patients With Ischemic Stroke in the WAKE-UP Trial.

BACKGROUND: Reversibility of the diffusion-weighted imaging (DWI) lesion means that not all of the DWI lesion represents permanently injured tissue. We investigated DWI reversibility and the association with thrombolysis, reperfusion and functional outcome in patients from the WAKE-UP trial (Efficacy and Safety of Magnetic Resonance Imaging-Based Thrombolysis in Wake-Up Stroke). METHODS: In this retrospective analysis of WAKE-UP, a randomized controlled trial (RCT) between September 2012 and June 2017 in Belgium, Denmark, France, Germany, Spain and United Kingdom, a convolutional neural network segmented the DWI lesions (b=1000 s/mm2) at baseline and follow-up (24 hours). We calculated absolute and relative DWI reversibility in 2 ways: first, a volumetric (baseline volume-24-hour volume >0) and second, a voxel-based (part of baseline lesion not overlapping with 24-hour lesion) approach. We additionally defined relative voxel-based DWI-reversibility >50% to account for coregistration inaccuracies. We calculated the odds ratio for reversibility according to treatment arm. We analyzed the association of reversibility with excellent functional outcome (modified Rankin Scale score of 0-1), in a multivariable model. RESULTS: In 363 patients, the median DWI volume was 3 (1-10) mL at baseline and 6 (2-20) mL at follow-up. Volumetric DWI reversibility was present in 19% (69/363) with a median absolute reversible volume of 1 mL (0-2) or 28% (14-50) relatively. Voxel-based DWI reversibility was present in 358/363 (99%) with a median absolute volume of 1 mL (0-2), or 22% (9-38) relatively. In 18% of the patients (67/363), relative voxel-based DWI reversibility >50% was present. Volumetric DWI reversibility and relative voxel-based DWI reversibility >50% was more frequent in patients treated with alteplase versus placebo (OR, 1.86 [95% CI, 1.09-3.17] and OR, 2.03 [95% CI, 1.18-3.50], respectively). Relative voxel-based DWI reversibility >50% was associated with excellent functional outcome (OR, 2.30 [95% CI, 1.17-4.51]). CONCLUSIONS: Small absolute volumes of DWI reversibility were present in a large proportion of randomized patients in the WAKE-UP trial. Reversibility was more often present after thrombolysis.

Intravenous Thrombolysis in Patients With White Matter Hyperintensities in the WAKE-UP Trial.

BACKGROUND: White matter hyperintensities of presumed vascular origin (WMH) are the most prominent imaging feature of cerebral small vessel disease (cSVD). Previous studies suggest a link between cSVD burden and intracerebral hemorrhage and worse functional outcome after thrombolysis in acute ischemic stroke. We aimed to determine the impact of WMH burden on efficacy and safety of thrombolysis in the MRI-based randomized controlled WAKE-UP trial of intravenous alteplase in unknown onset stroke. METHODS: The design of this post hoc study was an observational cohort design of a secondary analysis of a randomized trial. WMH volume was quantified on baseline fluid-attenuated inversion recovery images of patients randomized to either alteplase or placebo in the WAKE-UP trial. Excellent outcome was defined as score of 0-1 on the modified Rankin Scale after 90 days. Hemorrhagic transformation was assessed on follow-up imaging 24-36 hours after randomization. Treatment effect and safety were analyzed by fitting multivariable logistic regression models. RESULTS: Quality of scans was sufficient in 441 of 503 randomized patients to delineate WMH. Median age was 68 years, 151 patients were female, and 222 patients were assigned to receive alteplase. Median WMH volume was 11.4 mL. Independent from treatment, WMH burden was statistically significantly associated with worse functional outcome (odds ratio, 0.72 [95% CI, 0.57-0.92]), but not with higher chances of any hemorrhagic transformation (odds ratio, 0.78 [95% CI, 0.60-1.01]). There was no interaction of WMH burden and treatment group for the likelihood of excellent outcome (P=0.443) or any hemorrhagic transformation (P=0.151). In a subgroup of 166 patients with severe WMH, intravenous thrombolysis was associated with higher odds of excellent outcome (odds ratio, 2.40 [95% CI, 1.19-4.84]) with no significant increase in the rate of hemorrhagic transformation (odds ratio, 1.96 [95% CI, 0.80-4.81]). CONCLUSIONS: Although WMH burden is associated with worse functional outcome, there is no association with treatment effect or safety of intravenous thrombolysis in patients with ischemic stroke of unknown onset. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01525290.

A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke.

BACKGROUND: The use of intensive lipid-lowering therapy by means of statin medications is recommended after transient ischemic attack (TIA) and ischemic stroke of atherosclerotic origin. The target level for low-density lipoprotein (LDL) cholesterol to reduce cardiovascular events after stroke has not been well studied. METHODS: In this parallel-group trial conducted in France and South Korea, we randomly assigned patients with ischemic stroke in the previous 3 months or a TIA within the previous 15 days to a target LDL cholesterol level of less than 70 mg per deciliter (1.8 mmol per liter) (lower-target group) or to a target range of 90 mg to 110 mg per deciliter (2.3 to 2.8 mmol per liter) (higher-target group). All the patients had evidence of cerebrovascular or coronary-artery atherosclerosis and received a statin, ezetimibe, or both. The composite primary end point of major cardiovascular events included ischemic stroke, myocardial infarction, new symptoms leading to urgent coronary or carotid revascularization, or death from cardiovascular causes. RESULTS: A total of 2860 patients were enrolled and followed for a median of 3.5 years; 1430 were assigned to each LDL cholesterol target group. The mean LDL cholesterol level at baseline was 135 mg per deciliter (3.5 mmol per liter), and the mean achieved LDL cholesterol level was 65 mg per deciliter (1.7 mmol per liter) in the lower-target group and 96 mg per deciliter (2.5 mmol per liter) in the higher-target group. The trial was stopped for administrative reasons after 277 of an anticipated 385 end-point events had occurred. The composite primary end point occurred in 121 patients (8.5%) in the lower-target group and in 156 (10.9%) in the higher-target group (adjusted hazard ratio, 0.78; 95% confidence interval, 0.61 to 0.98; P = 0.04). The incidence of intracranial hemorrhage and newly diagnosed diabetes did not differ significantly between the two groups. CONCLUSIONS: After an ischemic stroke or TIA with evidence of atherosclerosis, patients who had a target LDL cholesterol level of less than 70 mg per deciliter had a lower risk of subsequent cardiovascular events than those who had a target range of 90 mg to 110 mg per deciliter. (Funded by the French Ministry of Health and others; Treat Stroke to Target ClinicalTrials.gov number, NCT01252875.).

Brush sign and collateral supply as potential markers of large infarct growth after successful thrombectomy.

OBJECTIVES: To investigate the relationships between brush sign and cerebral collateral status on infarct growth after successful thrombectomy. METHODS: HIBISCUS-STROKE cohort includes acute ischemic stroke patients treated with thrombectomy after MRI triage and undergoing a day-6 MRI including FLAIR images to quantify final infarct volume (FIV). Successful reperfusion was defined as a modified thrombolysis in cerebral infarction score ≥ 2B. Infarct growth was calculated by subtracting FIV from baseline ischemic core after co-registration and considered large (LIG) when > 11.6 mL. Brush sign was assessed on T2*-weighted-imaging and collaterals were assessed using the hypoperfusion intensity ratio, which is the volume of Time-To-Tmax (Tmax) ≥ 10 s divided by the volume of Tmax ≥ 6 s. Good collaterals were defined by a hypoperfusion intensity ratio < 0.4. RESULTS: One hundred and twenty-nine patients were included, of whom 45 (34.9%) had a brush sign and 63 (48.8%) good collaterals. Brush sign was associated with greater infarct growth (p = 0.01) and larger FIV (p = 0.02). Good collaterals were associated with a smaller baseline ischemic core (p < 0.001), larger penumbra (p = 0.04), and smaller FIV (p < 0.001). Collateral status was not significantly associated with brush sign (p = 0.20) or with infarct growth (p = 0.67). Twenty-eight (22.5%) patients experienced LIG. Univariate regressions indicated that brush sign (odds ratio (OR) = 4.8; 95% confidence interval (CI): [1.9;13.3]; p = 0.004) and hemorrhagic transformation (OR = 1.7; 95%CI: [1.2;2.6]; p = 0.04) were predictive of LIG. In multivariate regression, only the brush sign remained predictive of LIG (OR = 5.2; 95%CI: [1.8-16.6], p = 0.006). CONCLUSIONS: Brush sign is a predictor of LIG after successful thrombectomy and cerebral collateral status is not. KEY POINTS: • Few predictors of ischemic growth are known in ischemic stroke patients achieving successful mechanical thrombectomy. • Our results suggest that the brush sign-a surrogate marker of severe hypoperfusion-is independently associated with large ischemic growth (> 11.6 mL) after successful thrombectomy whereas cerebral collateral status does not.

Sex differences in imaging and clinical characteristics of patients from the WAKE-UP trial.

BACKGROUND AND PURPOSE: Sex-based differences in acute ischemic stroke are a well-known phenomenon. We aimed to explore these differences between women and men in the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial. METHODS: We compared baseline demographic and imaging characteristics (visual fluid-attenuated inversion recovery [FLAIR] positivity, relative FLAIR signal intensity, collateral status) between women and men in all screened patients. In randomized patients (i.e., those with diffusion-weighted imaging (DWI)-FLAIR mismatch), we evaluated a modifying role of sex on the treatment effect of alteplase in multivariable logistic regression, with treatment adjusted for National Institute of Health Stroke Scale (NIHSS) score and age. Dependent variables were modified Rankin Scale (mRS) score of 0-1 at 90 days and distribution of mRS scores at 90 days. RESULTS: Of 1362 screened patients, 529 (38.8%) were women. Women were older than men, had higher baseline NIHSS scores and smoked less frequently. FLAIR positivity of the DWI lesion was equally present in women (174/529, 33.1%) and men (273/833, 33.3%; p = 1.00) and other imaging variables also did not differ between the sexes. In a total of 503 randomized patients, of whom 178 were women (35.4%), sex did not modify the treatment effect of alteplase on mRS score 0-1 or on the total distribution of mRS scores. CONCLUSION: As in many other stroke trials, more men than women were included in the WAKE-UP trial, but the presence of a visual DWI-FLAIR mismatch and the relative FLAIR signal intensity did not differ between the sexes. The treatment effect of alteplase was not modified by sex.

Predictors of Early Neurological Improvement and Its Relationship to Thrombolysis Treatment and Long-Term Outcome in the WAKE-UP Study.

INTRODUCTION: The aims of this study were to evaluate the relationship of clinical and imaging baseline factors and treatment on the occurrence of early neurological improvement (ENI) in the WAKE-UP trial of MRI-guided intravenous thrombolysis in unknown onset stroke and to examine the association of ENI with long-term favorable outcome in patients treated with intravenous thrombolysis. METHODS: We analyzed data from all patients with at least moderate stroke severity, reflected by an initial National Institutes of Health Stroke Scale (NIHSS) score ≥4 randomized in the WAKE-UP trial. ENI was defined as a decrease in NIHSS of ≥8 or a decline to zero or 1 at 24 h after initial presentation to the hospital. Favorable outcome was defined as a modified Rankin Scale score of 0-1 at 90 days. We performed group comparison and multivariable analysis of baseline factors associated with ENI and performed mediation analysis to evaluate the effect of ENI on the relationship between intravenous thrombolysis and favorable outcome. RESULTS: ENI occurred in 93 out of 384 patients (24.2%) and was more likely to occur in patients who received treatment with alteplase (62.4% vs. 46.0%, p = 0.009), had smaller acute diffusion-weighted imaging lesion volume (5.51 mL vs. 10.9 mL, p ≤ 0.001), and less often large-vessel occlusion on initial MRI (7/93 [12.1%] versus 40/291 [29.9%], p = 0.014). In multivariable analysis, treatment with alteplase (OR 1.97, 95% confidence interval [CI] 0.954-1.100), lower baseline stroke volume (OR 0.965, 95% CI: 0.932-0.994), and shorter time from symptom recognition to treatment (OR 0.994, 95% CI: 0.989-0.999) were independently associated with ENI. Patients with ENI had higher rates of favorable outcome at 90-day follow-up (80.6% vs. 31.3%, p ≤ 0.001). The occurrence of ENI significantly mediated the association of treatment with a good outcome, with ENI at 24 h explaining 39.4% (12.9-96%) of the treatment effect. CONCLUSION: Intravenous alteplase increases the odds of ENI in patients with at least moderate stroke severity, especially when given early. In patients with large-vessel occlusion, ENI is rarely observed without thrombectomy. ENI represents a good surrogate early marker of treatment effect as more than a third of good outcome at 90 days is explained by ENI at 24 h.

Is the optimal Tmax threshold identifying perfusion deficit volumes variable across MR perfusion software packages? A pilot study.

PURPOSE: Accurate quantification of ischemic core and ischemic penumbra is mandatory for late-presenting acute ischemic stroke. Substantial differences between MR perfusion software packages have been reported, suggesting that the optimal Time-to-Maximum (Tmax) threshold may be variable. We performed a pilot study to assess the optimal Tmax threshold of two MR perfusion software packages (A: RAPID®; B: OleaSphere®) by comparing perfusion deficit volumes to final infarct volumes as ground truth. METHODS: The HIBISCUS-STROKE cohort includes acute ischemic stroke patients treated by mechanical thrombectomy after MRI triage. Mechanical thrombectomy failure was defined as a modified thrombolysis in cerebral infarction score of 0. Admission MR perfusion were post-processed using two packages with increasing Tmax thresholds (≥ 6 s, ≥ 8 s and ≥ 10 s) and compared to final infarct volume evaluated with day-6 MRI. RESULTS: Eighteen patients were included. Lengthening the threshold from ≥ 6 s to ≥ 10 s led to significantly smaller perfusion deficit volumes for both packages. For package A, Tmax ≥ 6 s and ≥ 8 s moderately overestimated final infarct volume (median absolute difference: - 9.5 mL, interquartile range (IQR) [- 17.5; 0.9] and 0.2 mL, IQR [- 8.1; 4.8], respectively). Bland-Altman analysis indicated that they were closer to final infarct volume and had narrower ranges of agreement compared with Tmax ≥ 10 s. For package B, Tmax ≥ 10 s was closer to final infarct volume (median absolute difference: - 10.1 mL, IQR: [- 17.7; - 2.9]) versus - 21.8 mL (IQR: [- 36.7; - 9.5]) for Tmax ≥ 6 s. Bland-Altman plots confirmed these findings (mean absolute difference: 2.2 mL versus 31.5 mL, respectively). CONCLUSIONS: The optimal Tmax threshold for defining the ischemic penumbra appeared to be most accurate at ≥ 6 s for package A and ≥ 10 s for package B. This implies that the widely recommended Tmax threshold ≥ 6 s may not be optimal for all available MRP software package. Future validation studies are required to define the optimal Tmax threshold to use for each package.

Intracranial Hemorrhage in the TST Trial.

BACKGROUND AND PURPOSE: Although statins are effective in secondary prevention of ischemic stroke, they are also associated with an increase risk of intracranial hemorrhage (ICH) in certain conditions. In the TST trial (Treat Stroke to Target), we prespecified an exploration of the predictors of incident ICH. METHODS: Patients with ischemic stroke in the previous 3 months or transient ischemic attack within the previous 15 days and evidence of cerebrovascular or coronary artery atherosclerosis were randomly assigned in a 1:1 ratio to a target LDL (low-density lipoprotein) cholesterol of <70 mg/dL or 100±10 mg/dL, using statin or ezetimibe. RESULTS: Among 2860 patients enrolled, 31 incident ICH occurred over a median follow-up of 3 years (18 and 13 in the lower and higher target group, 3.21/1000 patient-years [95% CI, 2.38-4.04] and 2.32/1000 patient-years [95% CI, 1.61-3.03], respectively). While there were no baseline predictors of ICH, uncontrolled hypertension (HR, 2.51 [95% CI, 1.01-6.31], P=0.041) and being on anticoagulant (HR, 2.36 [95% CI, 1.00-5.62], P=0.047)] during the trial were significant predictors. On-treatment low LDL cholesterol was not a predictor of ICH. CONCLUSIONS: Targeting an LDL cholesterol of <70 mg/dL compared with 100±10 mg/dL in patients with atherosclerotic ischemic stroke nonsignificantly increased the risk of ICH. Incident ICHs were not associated with low LDL cholesterol. Uncontrolled hypertension and anticoagulant therapy were associated with ICH which has important clinical implications. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01252875; EUDRACT identifier: 2009-A01280-57.

Impact of Age on Systemic Inflammatory Profile of Patients With ST-Segment-Elevation Myocardial Infarction and Acute Ischemic Stroke.

BACKGROUND: Aging is associated with a chronic low-grade inflammatory state. This condition may affect the acute inflammatory response involved in ST-segment-elevation myocardial infarction (STEMI) or acute ischemic stroke (AIS). We sought to compare the profile of a set of circulating inflammatory markers between young and older patients admitted for STEMI or AIS. METHODS: HIBISCUS-STEMI (Cohort of Patients to Identify Biological and Imaging Markers of Cardiovascular Outcomes in ST Elevation Myocardial Infarction) and HIBISCUS-STROKE (Cohort of Patients to Identify Biological and Imaging Markers of Cardiovascular Outcomes in Stroke) are 2 cohort studies that enrolled patients with STEMI treated with primary percutaneous coronary intervention in the cardiac intensive care unit of Lyon and patients with AIS treated with mechanical thrombectomy in the Lyon Stroke Center, respectively from 2016 to 2019. Patients were classified as older if they were ≥65 years and as young if they were <65 years. In both cohorts, CRP (C-reactive protein), IL (interleukin)-6, IL-8, IL-10, MCP (monocyte chemoattractant protein), sTNF-RI (soluble tumor necrosis factor receptor I), sST2 (soluble form suppression of tumorigenicity 2), and VCAM-1 (vascular cellular adhesion molecule-1) were measured on serum collected at 5 time points using enzyme-linked immunosorbent assay. A multiple logistic regression model was performed to detect an association between area under the curve of circulating inflammatory markers within the first 48 hours and older age. RESULTS: A total of 260 patients with STEMI and 164 patients with AIS were included. Of them, there were 76 (29%) and 105 (64%) older patients with STEMI and AIS, respectively. Following multivariable analysis, a high area under the curve of IL-6 and sTNF-RI, a low lymphocyte count, and a high neutrophil-lymphocyte ratio at 24 hours were associated with older age in patients with STEMI and AIS. CONCLUSIONS: Older patients had higher IL-6 and sTFN-RI levels within the first 48 hours associated with a lower lymphocyte count and a higher neutrophil-lymphocyte ratio at 24 hours in both cohorts.

Yield of Dual Therapy With Statin and Ezetimibe in the Treat Stroke to Target Trial.

BACKGROUND: In atherosclerotic stroke, lipid-lowering treatment with a target LDL (low-density lipoprotein) cholesterol of <70 compared with 100±10 mg/dL reduced the risk of subsequent cardiovascular events. This post hoc analysis explored the relative effects of the combination of statin and ezetimibe (dual therapy) and statin monotherapy in achieving the lower LDL cholesterol target and in reducing the risk of major vascular events, as compared with the higher target group. METHODS: Patients with ischemic stroke in the previous 3 months or transient ischemic attack within the previous 15 days and evidence of cerebrovascular or coronary artery atherosclerosis were randomly assigned to a target LDL cholesterol of <70 or 100±10 mg/dL, using statin and/or ezetimibe as needed. The primary outcome was the composite of ischemic stroke, myocardial infarction, new symptoms requiring urgent coronary or carotid revascularization, and vascular death. Cox regression model including lipid-lowering therapy as a time varying variable, after adjustment for randomization strategy, age, sex, index event (stroke or transient ischemic attack), and time since the index event. RESULTS: Among 2860 patients enrolled, patients who were on dual therapy during the trial in the lower target group had a higher baseline LDL cholesterol as compared to patients on statin monotherapy (141±38 versus 131±36, respectively, P<0.001). In patients on dual therapy and on statin monotherapy, the achieved LDL cholesterol was 66.2 and 64.1 mg/dL respectively, and the primary outcome was reduced during dual therapy as compared with the higher target group (HR, 0.60 [95% CI, 0.39-0.91]; P=0.016) but not during statin monotherapy (HR, 0.92 [95% CI, 0.70-1.20]; P=0.52), with no significant increase in intracranial bleeding. CONCLUSIONS: In the TST trial (Treat Stroke to Target), targeting an LDL cholesterol of < 70 mg/dL with a combination of statin and ezetimibe compared with 100±10 mg/dL consistently reduced the risk of subsequent stroke. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01252875. URL: clinicaltrialsregister.eu; Unique identifier: EUDRACT2009-A01280-57.

Diffusion-Weighted Imaging and Fluid-Attenuated Inversion Recovery Quantification to Predict Diffusion-Weighted Imaging-Fluid-Attenuated Inversion Recovery Mismatch Status in Ischemic Stroke With Unknown Onset.

BACKGROUND: Visual rating of diffusion-weighted imaging (DWI)-fluid-attenuated inversion recovery (FLAIR) mismatch can be challenging. We evaluated quantification of DWI and FLAIR to predict DWI-FLAIR mismatch status in ischemic stroke. METHODS: In screened patients from the WAKE-UP trial (Efficacy and Safety of Magnetic Resonance Imaging-Based Thrombolysis in Wake-Up Stroke), we retrospectively studied relative DWI (rDWI SI) and FLAIR signal intensity (rFLAIR SI). We defined the optimal mean rFLAIR SI and interquartile range of the rDWI SI in the DWI lesion to predict DWI-FLAIR mismatch status. We investigated agreement between each quantitative parameter and the DWI-FLAIR mismatch and the association between both quantitative parameters. We evaluated the predictive value of the quantitative parameters for excellent functional outcome by logistic regression, adjusted for DWI lesion volume, treatment, age, and National Institutes of Health Stroke Scale score. RESULTS: In the rFLAIR and rDWI SI analysis, 213/369 and 241/421 subjects respectively had a DWI-FLAIR mismatch. A mean rFLAIR SI cutoff of 1.09 and interquartile range rDWI SI cutoff of 0.47 were optimal to predict the DWI-FLAIR mismatch with a sensitivity and specificity of 77% (95% CI, 71%-83%) and 67% (95% CI, 59%-74%), and 76% (95% CI, 70%-81%) and 72% (95% CI, 65%-79%), respectively. For both quantitative parameters, agreement with the DWI-FLAIR mismatch was fair (73%, κ=0.44 [95% CI, 0.35-0.54] for rFLAIR and 74%, κ=0.48 [95% CI, 0.39-0.56] for rDWI). Both quantitative parameters correlated moderately (Pearson R=0.54 [95% CI, 0.46-0.61]; P<0.001, n=367). The interquartile range rDWI SI (n=188), but not the mean rFLAIR SI (n=172), was an independent predictor of excellent functional outcome (odds ratio, 0.67 per 0.1 unit increase of interquartile range rDWI SI, 95% CI, 0.51-0.89, P=0.01). CONCLUSIONS: Agreement between the quantitative and qualitative approach may be insufficient to advocate DWI or FLAIR quantification as alternative for visual rating.

Early effect of thrombolysis on structural brain network organisation after anterior-circulation stroke in the randomized WAKE-UP trial.

The symptoms of acute ischemic stroke can be attributed to disruption of the brain network architecture. Systemic thrombolysis is an effective treatment that preserves structural connectivity in the first days after the event. Its effect on the evolution of global network organisation is, however, not well understood. We present a secondary analysis of 269 patients from the randomized WAKE-UP trial, comparing 127 imaging-selected patients treated with alteplase with 142 controls who received placebo. We used indirect network mapping to quantify the impact of ischemic lesions on structural brain network organisation in terms of both global parameters of segregation and integration, and local disruption of individual connections. Network damage was estimated before randomization and again 22 to 36 h after administration of either alteplase or placebo. Evolution of structural network organisation was characterised by a loss in integration and gain in segregation, and this trajectory was attenuated by the administration of alteplase. Preserved brain network organization was associated with excellent functional outcome. Furthermore, the protective effect of alteplase was spatio-topologically nonuniform, concentrating on a subnetwork of high centrality supported in the salvageable white matter surrounding the ischemic cores. This interplay between the location of the lesion, the pathophysiology of the ischemic penumbra, and the spatial embedding of the brain network explains the observed potential of thrombolysis to attenuate topological network damage early after stroke. Our findings might, in the future, lead to new brain network-informed imaging biomarkers and improved prognostication in ischemic stroke.

Temporal Trend of Transient Ischemic Attack Management over a 10-Year Period: Data from the Rhône County, France.

BACKGROUND: Timely recognition and management of transient ischemic attack (TIA) offer the greatest opportunity to prevent subsequent stroke. But variability of TIA management quality exists across hospitals. Under the impetus of national plans, measures were adopted to improve TIA management, including a structured local pathway. Our objective was to compare TIA management between two periods over 10 years, before and after the implementation of these measures. METHODS: A before-and-after study was conducted with two identical population-based cohort studies in 2006-2007 (AVC69) and 2015-2016 (STROKE69) including all patients with TIA diagnosis over a 7-month period in six public and private hospitals in the Rhône county in France. The primary outcome was the adequate TIA management defined as brain and vessel imaging within 24 h of admission and the prescription of antithrombotic treatment at discharge. RESULTS: We identified 109 patients TIA patients in 2006-2007, and 458 over the same period in 2015-2016. A higher proportion of patients were adequately managed in 2015-2016 compared to 2006-2007 (14/96 [15%] in 2006-2007 vs. 306/452 [68%] in 2015-2016, p < 0.001). This difference was mainly driven by a marked increase of vessel imaging performed within 24 h of admission, most often by computed tomography angiography. Furthermore, patients called more often emergency medical dispatch before admission, were admitted with a shorter delay after symptom onset, and were more likely discharged to home in 2015-2016 compared to 2006-2007. CONCLUSION: Our study demonstrated an increasing rate of adequate TIA management, mainly driven by a marked increase of vessel imaging within 24 h of admission, over a 10-year period in the Rhône county in France.

Simultaneous assessment of microcalcifications and morphological criteria of vulnerability in carotid artery plaque using hybrid 18F-NaF PET/MRI.

BACKGROUND: Previous studies have suggested the role of microcalcifications in plaque vulnerability. This exploratory study sought to assess the potential of hybrid positron-emission tomography (PET)/magnetic resonance imaging (MRI) using 18F-sodium fluoride (18F-NaF) to check simultaneously 18F-NaF uptake, a marker of microcalcifications, and morphological criteria of vulnerability. METHODS AND RESULTS: We included 12 patients with either recently symptomatic or asymptomatic carotid stenosis. All patients underwent 18F-NaF PET/MRI. 18F-NaF target-to-background ratio (TBR) was measured in culprit and nonculprit (including contralateral plaques of symptomatic patients) plaques as well as in other arterial walls. Morphological criteria of vulnerability were assessed on MRI. Mineral metabolism markers were also collected. 18F-NaF uptake was higher in culprit compared to nonculprit plaques (median TBR 2.6 [2.2-2.8] vs 1.7 [1.3-2.2]; P = 0.03) but was not associated with morphological criteria of vulnerability on MRI. We found a positive correlation between 18F-NaF uptake and calcium plaque volume and ratio but not with circulating tissue-nonspecific alkaline phosphatase (TNAP) activity and inorganic pyrophosphate (PPi) levels. 18F-NaF uptake in the other arterial walls did not differ between symptomatic and asymptomatic patients. CONCLUSIONS: 18F-NaF PET/MRI may be a promising tool for providing additional insights into the plaque vulnerability.

Predictors of Outcome After Mechanical Thrombectomy in Stroke Patients Aged ≥85 Years.

BACKGROUND: The effectiveness of mechanical thrombectomy (MT) in elderly stroke patients remains debated. We aimed to describe outcomes and their predictors in a cohort of patients aged ≥ 85 years treated with MT. METHODS: Data from consecutive patients aged ≥ 85 years undergoing MT at two stroke centers between January 2016 and November 2019 were reviewed. Admission National Institutes of Health Stroke Scale (NIHSS), pre-stroke, and 3-month modified Rankin scale (mRS) were collected. Successful recanalization was defined as modified thrombolysis in cerebral ischemia score ≥ 2b. Good outcome was defined as mRS 0-3 or equal to pre-stroke mRS at 3 months. RESULTS: Of 151 included patients, successful recanalization was achieved in 74.2%. At 3 months, 44.7% of patients had a good outcome and 39% had died. Any intracranial hemorrhage (ICH) and symptomatic ICH occurred in 20.3% and 3.6%, respectively. Logistic regression analysis identified lower pre-stroke mRS score (adjusted odds ratio [aOR], 0.52; 95% CI, 0.36-0.76), lower admission NIHSS score (aOR, 0.90; 95% CI, 0.83-0.97), successful recanalization (aOR, 3.65; 95% CI, 1.32-10.09), and absence of ICH on follow-up imaging (aOR, 0.42; 95% CI, 0.08-0.75), to be independent predictors of good outcome. Patients with successful recanalization had a higher proportion of good outcome (45.3% vs 34.3%, p = 0.013) and lower mortality at 3 months (35.8% vs 48.6%, p = 0.006) compared to patients with unsuccessful recanalization. CONCLUSIONS: Among patients aged ≥ 85 years, successful recanalization with MT is relatively common and associated with better 3-month outcome and lower mortality than failed recanalization. Attempting to achieve recanalization in elderly patients using MT appears reasonable.

Co-design and evaluation of a patient-centred transition programme for stroke patients, combining case management and access to an internet information platform: study protocol for a randomized controlled trial - NAVISTROKE.

BACKGROUND: Stroke affects many aspects of life in stroke survivors and their family, and returning home after hospital discharge is a key step for the patient and his or her relatives. Patients and caregivers report a significant need for advice and information during this transition period. Our hypothesis is that, through a comprehensive, individualised and flexible support for patients and their caregivers, a patient-centred post-stroke hospital/home transition programme, combining an Internet information platform and telephone follow-up by a case manager, could improve patients' level of participation and quality of life. METHODS: An open parallel-group randomized trial will be conducted in two centres in France. We will recruit 170 adult patients who have had a first confirmed stroke, and were directly discharged home from the stroke unit with a modified Rankin score ≤3. Intervention content will be defined using a user-centred approach involving patients, caregivers, health-care professionals and social workers. Patients randomized to the intervention group will receive telephonic support by a trained case manager and access to an interactive Internet information platform during the 12 months following their return home. Patients randomized to the control group will receive usual care. The primary outcome is patient participation, measured by the "participation" dimension score of the Stroke Impact Scale 6 months after discharge. Secondary outcomes will include, for patients, quality of life, activation, care consumption, as well as physical, mental and social outcomes; and for caregivers, quality of life and burden. Patients will be contacted within one week after discharge, at 6 and 12 months for the outcomes collection. A process evaluation alongside the study is planned. DISCUSSION: Our patient-centred programme will empower patients and their carers, through individualised and progressive follow-up, to find their way around the range of available healthcare and social services, to better understand them and to use them more effectively. The action of a centralised case manager by telephone and the online platform will make it possible to disseminate this intervention to a large number of patients, over a wide area and even in cases of geographical isolation. TRIAL REGISTRATION: ClinicalTrials NCT03956160 , Posted: May-2019 and Update: September-2021.

Quantitative Assessment of Motor Neglect.

Background and Purpose: We used differential actigraphy as a novel, objective method to quantify motor neglect (a clinical condition whereby patients mimic hemiplegia even in the absence of sensorimotor deficits), whose diagnosis is at present highly subjective, based on the clinical observation of patients' spontaneous motor behavior. Methods: Patients wear wristwatch-like accelerometers, which record spontaneous motor activity of their upper limbs during 24 hours. Asymmetries of motor behavior are then automatically computed offline. On the basis of normal participants' performance, we calculated cutoff scores of left/right motor asymmetry. Results: Differential actigraphy showed contralesional motor neglect in 9 of 35 patients with unilateral strokes, consistent with clinical assessment. An additional patient with clinical signs of motor neglect obtained a borderline asymmetry score. Lesion location in a subgroup of 25 patients was highly variable, suggesting that motor neglect is a heterogenous condition. Conclusions: Differential actigraphy provides an ecological measure of spontaneous motor behavior, and can assess upper limb motricity in an objective and quantitative manner. It thus offers a convenient, cost-effective, and relatively automatized procedure for following-up motor behavior in neurological patients and to assess the effects of rehabilitation.

Stroke Prevention by Anticoagulants in Daily Practice Depending on Atrial Fibrillation Pattern and Clinical Risk Factors.

Background and Purpose: The objective of the study was to assess the effectiveness of individual direct oral anticoagulants versus vitamin K antagonists for primary prevention of stroke (ischemic and hemorrhagic) in routine clinical practice in patients with various clinical risk factors depending on their atrial fibrillation (AF) patterns. Methods: A nested case-referent study was conducted using data from 2 national registries of patients with stroke and AF. Stroke cases with previous history of AF were matched to up to 2 randomly selected referent patients with AF and no stroke. The association of individual anticoagulant use with ischemic or hemorrhagic stroke was studied in patients with or without permanent AF using multivariable conditional logistic models, controlled for clinically significant risk factors and multiple other cardiovascular risk factors. Results: In total, 2586 stroke cases with previous AF and 4810 nonstroke referent patients with AF were retained for the study. Direct oral anticoagulant users had lower odds of stroke of any type than vitamin K antagonist users: the adjusted-matched OR for ischemic stroke were 0.70 (95% CI, 0.50­0.98) for dabigatran, 0.68 (95% CI, 0.53­0.86) for rivaroxaban, and 0.73 (95% CI, 0.52­1.02) for apixaban while for hemorrhagic stroke they were 0.31 (95% CI, 0.14­0.68), 0.64 (95% CI, 0.39­1.06), and 0.70 (95% CI, 0.33­1.49), respectively. The effects of individual direct oral anticoagulants relative to vitamin K antagonists were similar in permanent AF and nonpermanent AF patients. Conclusions: Similar results were observed for each direct oral anticoagulant in real life as those observed in the pivotal clinical trials. The pattern of AF did not affect the outcome.