Validation of a simple clinical tool for screening of acute lacunar stroke-A substudy of the WAKE-UP trial.

INTRODUCTION: Lacunar stroke represents around a quarter of all ischemic strokes; however, their identification with computed tomography in the hyperacute setting is challenging. We aimed to validate a clinical score to identify lacunar stroke in the acute setting, independently, with data from the WAKE-UP trial using magnetic resonance imaging. METHODS: We analyzed data from the WAKE-UP trial and extracted Oxfordshire Community Stroke Project (OCSP) classification. Lacunar score was defined by National Institutes of Health Stroke Scale (NIHSS) < 7 and OCSP lacunar syndrome. Assessment of lacunar infarct by two independent investigators was blinded to clinical data. We calculated sensitivity, specificity, negative and positive predictive value (NPV and PPV, respectively) of lacunar score. RESULTS: We included 503 patients in the analysis, mean (±SD) age 65.2 (±11.6) years, 325 (65%) males, median (IQR) NIHSS = 6 (4-9); 108 (22%) lacunar infarcts were identified on magnetic resonance (MR), patients fulfilling lacunar score criteria were 120 (24%), of which 47 (44%) had a lacunar infarct. Lacunar score was negative in 322 (82%) of patients without lacunar infarct. Patients with lacunar score had lower NIHSS (4 vs 7, p < 0.001), higher systolic (157 vs 151 mmHg, p = 0.001) and diastolic (86 vs 83 mmHg, p = 0.013) blood pressure and smaller infarct volume (2.4 vs 9.5 mL, p < 0.001). Performance of lacunar score was as follows: sensitivity 0.44; specificity 0.82; PPV 0.39; NPV 0.84; and accuracy 0.73. Assuming a prevalence of lacunar stroke of 13%, PPV lowered to 0.30 but NPV was 0.90. Lacunar score performed better for supratentorial lacunar infarcts. CONCLUSION: Lacunar score had a very good specificity and NPV for screening of lacunar stroke. Implementation of this simple tool into clinical practice may help hyperacute management and guide patient selection in clinical trials. DATA ACCESS STATEMENT: Data supporting the results of this paper are available upon reasonable request to the corresponding author.

Imaging of Amyloid-Related Imaging Abnormalities (ARIA). / Bildgebung von Amyloid-related Imaging Abnormalities (ARIA).

Patients with Alzheimer's disease (AD) can now be treated with monoclonal antibodies aiming at clearing amyloid plaques from the brain parenchyma. Weeks after initiation of this drug therapy, patients may develop so-called amyloid-related imaging abnormalities (ARIA) on MRI. ARIA comprise vasogenic edema and leptomeningeal effusions (ARIA-E) as well as microbleeds and superficial hemosiderosis (ARIA-H). The prevalence is drug- and dose-dependent (up to 40 % of patients), the apolipoprotein E4 variant and concomitant cerebral amyloid angiopathy (CAA) increase the risk. With regard to MRI characteristics, ARIA strongly resembles the so-called inflammatory subtype of CAA (CAA-ri). While patients with CAA-ri are typically detected due to symptoms such as headaches, lethargy, confusion, and rarely epileptic seizures, around 20 % of ARIA patients show symptoms. Management of ARIA is not yet clearly established. In asymptomatic patients, discontinuation of the drug might be sufficient. KEY POINTS: · Amyloid-related imaging abnormalities (ARIA) occur in around 20 % of patients who are treated with monoclonal antibodies against amyloid ß.. · There are 2 types: ARIA-E (edema effusion) und ARIA-H (hemorrhage).. · Depending on the severity, therapy with monoclonal antibodies is either interrupted or finished.. CITATION FORMAT: · Urbach H, Linn J, Hattingen E et al. Imaging of Amyloid-Related Imaging Abnormalities (ARIA). Fortschr Röntgenstr 2024; 196: 363 - 369.

Validation of 3- and 5-point severity scales to assess ARIA-E.

INTRODUCTION: Anti-amyloid-ß (Aß) monoclonal antibodies (mAbs) offer the promise of disease modification and are emerging treatment options in Alzheimer's disease. Anti-Aß mAbs require brain magnetic resonance imaging (MRI) examinations to detect anti-amyloid-induced amyloid-related imaging abnormalities (ARIA), important adverse drug reactions associated with some anti-Aß mAbs currently available in the United States and in clinical development. We present a simple rating system for ARIA-edema (ARIA-E) that can assess severity on a 3- or 5-point scale based upon a single linear measurement of the largest area of lesion, and dissemination in space, termed the 3-point Severity Scale of ARIA-E (SSAE-3) and the 5-point Severity Scale of ARIA-E (SSAE-5), respectively. METHODS: MRI results were collected from 75 participants from the SCarlet RoAD (NCT01224106) and Marguerite RoAD (NCT02051608) studies of gantenerumab. Three neuroradiologists experienced with the detection of ARIA-E were selected to read all cases independently. One rater was then chosen for a second read to assess intra-reader reproducibility. RESULTS: The three raters had high agreement in identifying and grading ARIA-E. The Cohen/Fleiss kappa (κ) scores (95% confidence interval [CI]) for the inter- and intra-reader comparisons for SSAE-3 and SSAE-5 were 0.79 (0.70-1.00), 0.94 (0.94-1.00), 0.73 (0.66-1.00), and 0.90 (0.90-1.00), respectively. DISCUSSION: Our study suggests that SSAE-3 and SSAE-5 are valid ARIA-E rating scales for use in routine clinical practice by experienced radiologists in specialized settings. The application of these scales in everyday use in clinical practice will support the expansion of anti-Aß mAbs as a treatment option for people living with Alzheimer's disease. Highlights: A simple rating scale is needed to rate severity of amyloid-related imaging abnormalities-edema (ARIA-E) in both research and clinical settings.The 3- and 5-point Severity Scales of ARIA-E (SSAE-3/-5) have good inter- and intra-reader agreement.The SSAE-3/-5 have been used in most major Alzheimer's disease (AD) trials to date and are suitable for large-scale use in routine clinical practice, which may help support the expansion of anti-amyloid antibodies as treatment options for AD.

A deep learning analysis of stroke onset time prediction and comparison to DWI-FLAIR mismatch.

INTRODUCTION: When time since stroke onset is unknown, DWI-FLAIR mismatch rating is an established technique for patient stratification. A visible DWI lesion without corresponding parenchymal hyperintensity on FLAIR suggests time since onset of under 4.5 h and thus a potential benefit from intravenous thrombolysis. To improve accuracy and availability of the mismatch concept, deep learning might be able to augment human rating and support decision-making in these cases. METHODS: We used unprocessed DWI and coregistered FLAIR imaging data to train a deep learning model to predict dichotomized time since ischemic stroke onset. We analyzed the performance of Group Convolutional Neural Networks compared to other deep learning methods. Unlabeled imaging data was used for pre-training. Prediction performance of the best deep learning model was compared to the performance of four independent junior and senior raters. Additionally, in cases deemed indeterminable by human raters, model ratings were used to augment human performance. Post-hoc gradient-based explanations were analyzed to gain insights into model predictions. RESULTS: Our best predictive model performed comparably to human raters. Using model ratings in cases deemed indeterminable by human raters improved rating accuracy and interrater agreement for junior and senior ratings. Post-hoc explainability analyses showed that the model localized stroke lesions to derive predictions. DISCUSSION: Our analysis shows that deep learning based clinical decision support has the potential to improve the accessibility of the DWI-FLAIR mismatch concept by supporting patient stratification.

Detection of brain lesions after catheter ablation depends on imaging criteria: insights from AXAFA-AFNET 5 trial.

AIMS: Left atrial catheter ablation is well established in patients with symptomatic atrial fibrillation (AF) but associated with risk of embolism to the brain. The present analysis aims to assess the impact of diffusion-weighted imaging (DWI) slice thickness on the rate of magnetic resonance imaging (MRI)-detected ischaemic brain lesions after ablation. METHODS AND RESULTS: AXAFA-AFNET 5 trial (NCT02227550) participants underwent MRI using high-resolution (hr) DWI (slice thickness: 2.5-3 mm) and standard DWI (slice thickness: 5-6 mm) within 3-48 h after ablation. In 321 patients with analysable brain MRI (mean age 64 years, 33% female, median CHA2DS2-VASc 2), hrDWI detected at least one acute brain lesion in 84 (26.2%) patients and standard DWI in 60 (18.7%; P < 0.01) patients. High-resolution diffusion-weighted imaging detected more lesions compared to standard DWI (165 vs. 104; P < 0.01). The degree of agreement for lesion confirmation using hrDWI vs. standard DWI was substantial (κ = 0769). Comparing the proportion of DWI-detected lesions, lesion distribution, and total lesion volume per patient, there was no difference in the cohort of participants undergoing MRI at 1.5 T (n = 52) vs. 3 T (n = 269). CONCLUSION: The pre-specified AXAFA-AFNET 5 sub-analysis revealed significantly increased rates of MRI-detected acute brain lesions using hrDWI instead of standard DWI in AF patients undergoing ablation. In comparison to DWI slice thickness, MRI field strength had a no significant impact in the trial. Comparing the varying rates of ablation-related MRI-detected brain lesions across previous studies has to consider these technical parameters. Future studies should use hrDWI, as feasibility was demonstrated in the multicentre AXAFA-AFNET 5 trial.

Automated acute ischemic stroke lesion delineation based on apparent diffusion coefficient thresholds.

Purpose: Automated lesion segmentation is increasingly used in acute ischemic stroke magnetic resonance imaging (MRI). We explored in detail the performance of apparent diffusion coefficient (ADC) thresholding for delineating baseline diffusion-weighted imaging (DWI) lesions. Methods: Retrospective, exploratory analysis of the prospective observational single-center 1000Plus study from September 2008 to June 2013 (clinicaltrials.org; NCT00715533). We built a fully automated lesion segmentation algorithm using a fixed ADC threshold (≤620 × 10-6 mm2/s) to delineate the baseline DWI lesion and analyzed its performance compared to manual assessments. Diagnostic capabilities of best possible ADC thresholds were investigated using receiver operating characteristic curves. Influential patient factors on ADC thresholding techniques' performance were studied by conducting multiple linear regression. Results: 108 acute ischemic stroke patients were selected for analysis. The median Dice coefficient for the algorithm was 0.43 (IQR 0.20-0.64). Mean ADC values in the DWI lesion (ß = -0.68, p < 0.001) and DWI lesion volumes (ß = 0.29, p < 0.001) predicted performance. Optimal individual ADC thresholds differed between subjects with a median of ≤691 × 10-6 mm2/s (IQR ≤660-750 × 10-6 mm2/s). Mean ADC values in the DWI lesion (ß = -0.96, p < 0.001) and mean ADC values in the brain parenchyma (ß = 0.24, p < 0.001) were associated with the performance of individual thresholds. Conclusion: The performance of ADC thresholds for delineating acute stroke lesions varies substantially between patients. It is influenced by factors such as lesion size as well as lesion and parenchymal ADC values. Considering the inherent noisiness of ADC maps, ADC threshold-based automated delineation of very small lesions is not reliable.

Deep learning-based segmentation of brain parenchyma and ventricular system in CT scans in the presence of anomalies.

Introduction: The automatic segmentation of brain parenchyma and cerebrospinal fluid-filled spaces such as the ventricular system is the first step for quantitative and qualitative analysis of brain CT data. For clinical practice and especially for diagnostics, it is crucial that such a method is robust to anatomical variability and pathological changes such as (hemorrhagic or neoplastic) lesions and chronic defects. This study investigates the increase in overall robustness of a deep learning algorithm that is gained by adding hemorrhage training data to an otherwise normal training cohort. Methods: A 2D U-Net is trained on subjects with normal appearing brain anatomy. In a second experiment the training data includes additional subjects with brain hemorrhage on image data of the RSNA Brain CT Hemorrhage Challenge with custom reference segmentations. The resulting networks are evaluated on normal and hemorrhage test casesseparately, and on an independent test set of patients with brain tumors of the publicly available GLIS-RT dataset. Results: Adding data with hemorrhage to the training set significantly improves the segmentation performance over an algorithm trained exclusively on normally appearing data, not only in the hemorrhage test set but also in the tumor test set. The performance on normally appearing data is stable. Overall, the improved algorithm achieves median Dice scores of 0.98 (parenchyma), 0.91 (left ventricle), 0.90 (right ventricle), 0.81 (third ventricle), and 0.80 (fourth ventricle) on the hemorrhage test set. On the tumor test set, the median Dice scores are 0.96 (parenchyma), 0.90 (left ventricle), 0.90 (right ventricle), 0.75 (third ventricle), and 0.73 (fourth ventricle). Conclusion: Training on an extended data set that includes pathologies is crucial and significantly increases the overall robustness of a segmentation algorithm for brain parenchyma and ventricular system in CT data, also for anomalies completely unseen during training. Extension of the training set to include other diseases may further improve the generalizability of the algorithm.

Enhanced diagnostic workup increases pathological findings in patients with acute ischaemic stroke: results of the prospective HEBRAS study.

BACKGROUND: Stroke aetiology remains cryptogenic in a relevant proportion of patients with acute ischaemic stroke (AIS). We assessed whether enhanced diagnostic workup after AIS yields a higher rate of prespecified pathological findings compared with routine diagnostic care in-hospital. METHODS: Hospitalised patients with AIS were prospectively enrolled in the investigator-initiated observational HEart and BRain Interfaces in Acute Ischaemic Stroke (HEBRAS) study at the Charité, Berlin, Germany. Patients with AIS without known atrial fibrillation (AF) underwent cardiovascular MR imaging (CMR), MR-angiography of the aortic arch and prolonged Holter-ECG monitoring on top of routine diagnostic care. RESULTS: Among 356 patients with AIS (mean age 66 years, 37.6% female), enhanced workup yielded a higher rate of prespecified pathological findings compared with routine care (17.7% vs 5.3%; p<0.001). Consequently, fewer patients were classified as cryptogenic after enhanced diagnostic workup (38.5% vs 45.5%, p<0.001). Routine care included echocardiography in 228 (64.0%) patients. CMR was successfully performed in 292 (82.0%) patients and revealed more often a prespecified pathological finding compared with routine echocardiography (16.1% vs 5.3%). Furthermore, study-related ECG monitoring (median duration 162 hours (IQR 98-210)) detected AF in 16 (4.5%) patients, while routine monitoring (median duration 51 hours (IQR 34-74)) detected AF in seven (2.0%) patients. CONCLUSIONS: Enhanced diagnostic workup revealed a higher rate of prespecified pathological findings in patients with AIS compared with routine diagnostic care and significantly reduced the proportion of patients with cryptogenic stroke. TRIAL REGISTRATION NUMBER: NCT02142413.

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.

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.

Exploring the ATN classification system using brain morphology.

BACKGROUND: The NIA-AA proposed amyloid-tau-neurodegeneration (ATN) as a classification system for AD biomarkers. The amyloid cascade hypothesis (ACH) implies a sequence across ATN groups that patients might undergo during transition from healthy towards AD: A-T-N-➔A+T-N-➔A+T+N-➔A+T+N+. Here we assess the evidence for monotonic brain volume decline for this particular (amyloid-conversion first, tau-conversion second, N-conversion last) and alternative progressions using voxel-based morphometry (VBM) in a large cross-sectional MRI cohort. METHODS: We used baseline data of the DELCODE cohort of 437 subjects (127 controls, 168 SCD, 87 MCI, 55 AD patients) which underwent lumbar puncture, MRI scanning, and neuropsychological assessment. ATN classification was performed using CSF-Aß42/Aß40 (A+/-), CSF phospho-tau (T+/-), and adjusted hippocampal volume or CSF total-tau (N+/-). We compared voxel-wise model evidence for monotonic decline of gray matter volume across various sequences over ATN groups using the Bayesian Information Criterion (including also ROIs of Braak stages). First, face validity of the ACH transition sequence A-T-N-➔A+T-N-➔A+T+N-➔A+T+N+ was compared against biologically less plausible (permuted) sequences among AD continuum ATN groups. Second, we evaluated evidence for 6 monotonic brain volume progressions from A-T-N- towards A+T+N+ including also non-AD continuum ATN groups. RESULTS: The ACH-based progression A-T-N-➔A+T-N-➔A+T+N-➔A+T+N+ was consistent with cognitive decline and clinical diagnosis. Using hippocampal volume for operationalization of neurodegeneration (N), ACH was most evident in 9% of gray matter predominantly in the medial temporal lobe. Many cortical regions suggested alternative non-monotonic volume progressions over ACH progression groups, which is compatible with an early amyloid-related tissue expansion or sampling effects, e.g., due to brain reserve. Volume decline in 65% of gray matter was consistent with a progression where A status converts before T or N status (i.e., ACH/ANT) when compared to alternative sequences (TAN/TNA/NAT/NTA). Brain regions earlier affected by tau tangle deposition (Braak stage I-IV, MTL, limbic system) present stronger evidence for volume decline than late Braak stage ROIs (V/VI, cortical regions). Similar findings were observed when using CSF total-tau for N instead. CONCLUSION: Using the ATN classification system, early amyloid status conversion (before tau and neurodegeneration) is associated with brain volume loss observed during AD progression. The ATN system and the ACH are compatible with monotonic progression of MTL atrophy. TRIAL REGISTRATION: DRKS00007966, 04/05/2015, retrospectively registered.

New Cerebral Microbleeds After Catheter-Based Structural Heart Interventions: An Exploratory Analysis.

Background Cerebral microbleeds (CMBs) are increasingly recognized as "covert" brain lesions indicating increased risk of future neurological events. However, data on CMBs in patients undergoing catheter-based structural heart interventions are scarce. Therefore, we assessed occurrence and predictors of new CMBs in patients undergoing catheter-based left atrial appendage closure and percutaneous mitral valve repair using the MitraClip System. Methods and Results We conducted an exploratory analysis using data derived from 2 prospective, observational studies. Eligible patients underwent cerebral magnetic resonance imaging (3 Tesla) examinations and cognitive tests (using the Montreal Cognitive Assessment) before and after catheter-based left atrial appendage closure and percutaneous mitral valve repair. Forty-seven patients (53% men; median age, 77 years) were included. New CMBs occurred in 17 of 47 patients (36%) following catheter-based structural heart interventions. Occurrences of new CMBs did not differ significantly between patients undergoing catheter-based left atrial appendage closure and percutaneous mitral valve repair (7/25 versus 10/22; P=0.348). In univariable analysis, longer procedure time was significantly associated with new CMBs. Adjustment for heparin attenuated this association (adjusted odds ratio [per 30 minutes]: 1.77 [95% CI, 0.92-3.83]; P=0.090). Conclusions New CMBs occur in approximately one-third of patients after catheter-based left atrial appendage closure and percutaneous mitral valve repair using the MitraClip System. Our data suggest that longer duration of the procedure may be a risk factor for new CMBs. Future studies in larger populations are needed to further investigate their clinical relevance. Clinical Trial Registration German Clinical Trials Register: DRKS00010300 (https://drks.de/search/en/trial/DRKS00010300); ClinicalTrials.gov : NCT03104556 (https://clinicaltrials.gov/ct2/show/NCT03104556?term=NCT03104556&draw=2&rank=1).

Reproducibility of cerebral perfusion measurements using BOLD delay.

BOLD delay is an emerging, noninvasive method for assessing cerebral perfusion that does not require the use of intravenous contrast agents and is thus particularly suited for longitudinal monitoring. In this study, we assess the reproducibility of BOLD delay using data from 136 subjects with normal cerebral perfusion scanned on two separate occasions with scanners, sequence parameters, and intervals between scans varying between subjects. The effects of various factors on the reproducibility of BOLD delay, defined here as the differences in BOLD delay values between the scanning sessions, were investigated using a linear mixed model. Reproducibility was additionally assessed using the intraclass correlation coefficient of BOLD delay between sessions. Reproducibility was highest in the posterior cerebral artery territory. The mean BOLD delay test-retest difference after accounting for the aforementioned factors was 1.2 s (95% CI = 1.0 to 1.4 s). Overall, BOLD delay shows good reproducibility, but care should be taken when interpreting longitudinal BOLD delay changes that are either very small or are located in certain brain regions.

Patient-Reported Quality of Life After Intravenous Alteplase for Stroke in the WAKE-UP Trial.

BACKGROUND AND OBJECTIVES: Intravenous alteplase improves functional outcome after acute ischemic stroke. However, little is known about the effects on self-reported health-related quality of life (HRQoL). METHODS: WAKE-UP was a multicenter, randomized, placebo-controlled trial of MRI-guided intravenous alteplase in stroke with unknown onset time. HRQoL was assessed using the EuroQol five-dimensional questionnaire (EQ-5D) at 90 days, comprising the EQ-5D index and the EQ visual analogue scale (VAS). Functional outcome was assessed by the modified Rankin Scale (mRS). We calculated the effect of treatment on EQ-5D index and EQ VAS using multiple linear regression models. Mediation analysis was performed on stroke survivors to explore the extent to which the effect of alteplase on HRQoL was mediated by functional outcome. RESULTS: Among 490 stroke survivors, the EQ-5D index was available for 452 (92.2%), of whom 226 (50%) were assigned to treatment with alteplase and 226 (50%) to placebo. At 90 days, mean EQ-5D index was higher, reflecting a better health state, in patients randomized to treatment with alteplase than with placebo (0.75 vs 0.67) with an adjusted mean difference of 0.07 (95% CI 0.02-0.12, p = 0.005). In addition, mean EQ VAS was higher with alteplase than with placebo (72.6 vs 64.9), with an adjusted mean difference of 7.6 (95% CI 3.9-11.8, p < 0.001). Eighty-five percent of the total treatment effect of alteplase on the EQ-5D index was mediated using the mRS score while there was no significant direct effect. By contrast, the treatment effect on the EQ VAS was mainly through the direct pathway (60%), whereas 40% was mediated by the mRS. DISCUSSION: Assessment of patient-reported outcome measures reveals a potential benefit of intravenous alteplase for HRQoL beyond improvement of functional outcome. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov number, NCT01525290; EudraCT number, 2011-005906-32.

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.

Comparing ARIA-E severity scales and effects of treatment management thresholds.

Introduction: Amyloid-related imaging abnormalities-edema (ARIA-E) is associated with anti-amyloid beta monoclonal antibody treatment. ARIA-E severity may be assessed using the Barkhof Grand Total Scale (BGTS) or the 3- or 5-point Severity Scales of ARIA-E (SSAE-3/SSAE-5). We assessed inter- and intra-reader correlations between SSAE-3/5 and BGTS. Methods: Magnetic resonance imaging scans were collected from 75 participants in the SCarlet RoAD and Marguerite RoAD studies. Three neuroradiologists reviewed scans at baseline and at follow-up. Concordance in dichotomized ARIA-E ratings was assessed for a range of BGTS thresholds. Results: SSAE-3/5 scores correlated with BGTS scores, with high inter-reader intraclass correlation coefficients across all scales. There was high agreement in dichotomized ratings for SSAE-3 > 1 versus BGTS > 3 for all readers (accuracy 0.85-0.93) and between pairs of readers. Discussion: SSAE-3/5 showed high degrees of correlation with BGTS, potentially allowing seamless transition from the BGTS to SSAE-3/5 for ARIA-E management.

Anatomical labeling of intracranial arteries with deep learning in patients with cerebrovascular disease.

Brain arteries are routinely imaged in the clinical setting by various modalities, e.g., time-of-flight magnetic resonance angiography (TOF-MRA). These imaging techniques have great potential for the diagnosis of cerebrovascular disease, disease progression, and response to treatment. Currently, however, only qualitative assessment is implemented in clinical applications, relying on visual inspection. While manual or semi-automated approaches for quantification exist, such solutions are impractical in the clinical setting as they are time-consuming, involve too many processing steps, and/or neglect image intensity information. In this study, we present a deep learning-based solution for the anatomical labeling of intracranial arteries that utilizes complete information from 3D TOF-MRA images. We adapted and trained a state-of-the-art multi-scale Unet architecture using imaging data of 242 patients with cerebrovascular disease to distinguish 24 arterial segments. The proposed model utilizes vessel-specific information as well as raw image intensity information, and can thus take tissue characteristics into account. Our method yielded a performance of 0.89 macro F1 and 0.90 balanced class accuracy (bAcc) in labeling aggregated segments and 0.80 macro F1 and 0.83 bAcc in labeling detailed arterial segments on average. In particular, a higher F1 score than 0.75 for most arteries of clinical interest for cerebrovascular disease was achieved, with higher than 0.90 F1 scores in the larger, main arteries. Due to minimal pre-processing, simple usability, and fast predictions, our method could be highly applicable in the clinical setting.