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PurposeThis study aimed to evaluate the perfomance of Siemens Healthineers’ StrokeSegApp performance in automatically segmenting diffusion and perfusion lesions in patients with acute ischemic stroke and to assess its clinical utility in guiding mechanical thrombectomy decisions.MethodsThis retrospective study used MRI data of acute ischemic stroke patients from the prospective observational single-center 1000Plus study, acquired between September 2008 and June 2013 (clinicaltrials.org; NCT00715533) and manually segmented by radiologists as the ground truth. The performance of the StrokeSegApp was compared against this ground truth using the dice similarity coefficient (DSC) and Bland–Altman plots. The study also evaluated the application’s ability to recommend mechanical thrombectomy based on DEFUSE 2 and 3 trial criteria.ResultsThe StrokeSegApp demonstrated a mean DSC of 0.60 (95% CI: 0.57–0.63; n = 241) for diffusion deficit segmentation and 0.80 (95% CI: 0.76–0.85; n = 56) for perfusion deficit segmentation. The mean volume deviation was 0.49 mL for diffusion lesions and −7.69 mL for perfusion lesions. Out of 56 subjects meeting DEFUSE 2/3 criteria in the cohort, it correctly identified mechanical thrombectomy candidates with a sensitivity of 82.1% (95% CI: 63.1–93.9%) and a specificity of 96.4% (95% CI: 81.7–99.9%).ConclusionThe Siemens Healthineers’ StrokeSegApp provides accurate automated segmentation of ischemic stroke lesions, comparable to human experts as well as similar commercial software, and shows potential as a reliable tool in clinical decision-making for stroke treatment.

Abstract Background Blood-brain barrier (BBB) alterations may contribute to AD pathology through various mechanisms, including impaired amyloid-β (Aβ) clearance and neuroinflammation. Soluble platelet-derived growth factor receptor beta (sPDGFRβ) has emerged as a potential biomarker for BBB integrity. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) offers a direct assessment of BBB permeability. However, the relationship between BBB dysfunction, cognitive impairment, and AD pathology remains unclear, with inconsistent findings in the literature. Methods We conducted a cross-sectional study using data from the DELCODE and DESCRIBE cohorts to investigate BBB dysfunction in participants with normal cognition (NC), mild cognitive impairment (MCI), and AD dementia. BBB function was assessed using DCE-MRI and sPDGFRβ levels in cerebrospinal fluid and AD biomarkers Aβ and tau were measured. In a subset of patients, the CSF/plasma-ratio of albumin (QAlb) as a standard marker of BBB integrity and markers of neuroinflammation were analyzed. Results 91 participants (NC: 44, MCI: 21, AD: 26) were included in the analysis. The average age was 74.4 years, 42% were female. Increased hippocampal BBB disruption was observed in the AD-group (Ktrans: 0.55 × 10− 3 min− 1 ± 0.74 × 10− 3 min− 1) but not the MCI-group (Ktrans: 0.177 × 10− 3 min− 1 ± 0.22 × 10− 3 min− 1), compared to the NC group (Ktrans: 0.19 × 10− 3 min− 1 ± 0.37 × 10− 3 min− 1, p

Background Atrial fibrillation detected after stroke (AFDAS) is considered to be a distinct entity influenced by cardiogenic and neurogenic factors. We hypothesized that patients with AFDAS have larger stroke lesions than patients without atrial fibrillation (AF) and with known AF (KAF). Methods and Results Consecutive patients with magnetic resonance imaging–confirmed acute ischemic stroke admitted to a university hospital between October 2020 and January 2023 were prospectively registered. We categorized patients as AFDAS, no AF or KAF upon hospital discharge. We manually segmented diffusion‐weighted imaging lesions to determine lesion volume. We analyzed 1420 patients (median age, 78; 47.2% women, median National Institutes of Health Stroke Scale score, 3; median hospital stay, 5 days). Of these, 81 had AFDAS (5.7%), 329 had KAF (23.2%) and 1010 had no AF (71.1%). Lesion volume was larger in patients with AFDAS (median, 5.4 mL [interquartile range, 1.0–21.6]) compared with patients with no AF and KAF (median, 0.7 [interquartile range,0.2–4.4] and 2.0 [interquartile range,0.3–11.1] mL, respectively; both P6.5 mL) were more likely to be diagnosed with AFDAS compared with the lowest quartile (

Abstract Thalamic aphasia results from focal thalamic lesions that cause dysfunction of remote but functionally connected cortical areas due to language network perturbation. However, specific local and network-level neural substrates of thalamic aphasia remain incompletely understood. Using lesion symptom mapping, we demonstrate that lesions in the left ventrolateral and ventral anterior thalamic nucleus are most strongly associated with aphasia in general and with impaired semantic and phonemic fluency and complex comprehension in particular. Lesion network mapping (using a normative connectome based on fMRI data from 1000 healthy individuals) reveals a Thalamic aphasia network encompassing widespread left-hemispheric cerebral connections, with Broca’s area showing the strongest associations, followed by the superior and middle frontal gyri, precentral and paracingulate gyri, and globus pallidus. Our results imply the critical involvement of the left ventrolateral and left ventral anterior thalamic nuclei in engaging left frontal cortical areas, especially Broca’s area, during language processing.

Abstract 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-Aβ42/Aβ40 (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.

IntroductionThe 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.MethodsA 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.ResultsAdding 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).ConclusionTraining 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.

PurposeAutomated 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.MethodsRetrospective, 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.Results108 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 (β = −0.68, p

BackgroundAccurate prediction of clinical outcomes in individual patients following acute stroke is vital for healthcare providers to optimize treatment strategies and plan further patient care. Here, we use advanced machine learning (ML) techniques to systematically compare the prediction of functional recovery, cognitive function, depression, and mortality of first-ever ischemic stroke patients and to identify the leading prognostic factors.MethodsWe predicted clinical outcomes for 307 patients (151 females, 156 males; 68 ± 14 years) from the PROSpective Cohort with Incident Stroke Berlin study using 43 baseline features. Outcomes included modified Rankin Scale (mRS), Barthel Index (BI), Mini-Mental State Examination (MMSE), Modified Telephone Interview for Cognitive Status (TICS-M), Center for Epidemiologic Studies Depression Scale (CES-D) and survival. The ML models included a Support Vector Machine with a linear kernel and a radial basis function kernel as well as a Gradient Boosting Classifier based on repeated 5-fold nested cross-validation. The leading prognostic features were identified using Shapley additive explanations.ResultsThe ML models achieved significant prediction performance for mRS at patient discharge and after 1 year, BI and MMSE at patient discharge, TICS-M after 1 and 3 years and CES-D after 1 year. Additionally, we showed that National Institutes of Health Stroke Scale (NIHSS) was the top predictor for most functional recovery outcomes as well as education for cognitive function and depression.ConclusionOur machine learning analysis successfully demonstrated the ability to predict clinical outcomes after first-ever ischemic stroke and identified the leading prognostic factors that contribute to this prediction.

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).

Background and Purpose: In the setting of acute ischemic stroke, increased blood-brain barrier permeability (BBBP) as a sign of injury is believed to be associated with increased risk of poor outcome. Pre-clinical studies show that selected serum biomarkers including C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFα), matrix metallopeptidases (MMP), and vascular endothelial growth factors (VEGFs) may play a role in BBBP post-stroke. In the subacute phase of stroke, increased BBBP may also be caused by regenerative mechanisms such as vascular remodeling and therefore may improve functional recovery. Our aim was to investigate the evolution of BBBP in ischemic stroke using contrast-enhanced (CE) magnetic resonance imaging (MRI) and to analyze potential associations with blood-derived biomarkers as well as functional recovery in subacute ischemic stroke patients.Methods: This is an exploratory analysis of subacute ischemic stroke patients enrolled in the BAPTISe study nested within the randomized controlled PHYS-STROKE trial (interventions: 4 weeks of aerobic fitness training vs. relaxation). Patients with at least one CE-MRI before (v1) or after (v2) the intervention were eligible for this analysis. The prevalence of increased BBBP was visually assessed on T1-weighted MR-images based on extent of contrast-agent enhancement within the ischemic lesion. The intensity of increased BBBP was assessed semi-quantitatively by normalizing the mean voxel intensity within the region of interest (ROI) to the contralateral hemisphere (“normalized CE-ROI”). Selected serum biomarkers (high-sensitive CRP, IL-6, TNF-α, MMP-9, and VEGF) at v1 (before intervention) were analyzed as continuous and dichotomized variables defined by laboratory cut-off levels. Functional outcome was assessed at 6 months after stroke using the modified Rankin Scale (mRS).Results: Ninety-three patients with a median baseline NIHSS of 9 [IQR 6–12] were included into the analysis. The median time to v1 MRI was 30 days [IQR 18–37], and the median lesion volume on v1 MRI was 4 ml [IQR 1.2–23.4]. Seventy patients (80%) had increased BBBP visible on v1 MRI. After the trial intervention, increased BBBP was still detectable in 52 patients (74%) on v2 MRI. The median time to v2 MRI was 56 days [IQR 46–67]. The presence of increased BBBP on v1 MRI was associated with larger lesion volumes and more severe strokes. Aerobic fitness training did not influence the increase of BBBP evaluated at v2. In linear mixed models, the time from stroke onset to MRI was inversely associated with normalized CE-ROI (coefficient −0.002, Standard Error 0.007, p < 0.01). Selected serum biomarkers were not associated with the presence or evolution of increased BBBP. Multivariable regression analysis did not identify the occurrence or evolution of increased BBBP as an independent predictor of favorable functional outcome post-stroke.Conclusion: In patients with moderate-to-severe subacute stroke, three out of four patients demonstrated increased BBB permeability, which decreased over time. The presence of increased BBBP was associated with larger lesion volumes and more severe strokes. We could not detect an association between selected serum biomarkers of inflammation and an increased BBBP in this cohort. No clear association with favorable functional outcome was observed.Trial registration: NCT01954797.

Organic-diffusive gradients in thin-film samplers (o-DGT), were developed and applied for accumulation of estrogen and estrogen-like compounds on a XAD18 resin and deployed in situ in the effluents of Beijing Gaobeidian Wastewater Treatment Plant (GWWTP) and Brussels North Wastewater Treatment Plant as well as in several aquatic systems in Belgium, including the Zenne River, the Belgian Oostende Harbor and the North Sea. Estrogenic compounds accumulate on the XAD18 resin and the estrogenic activity of the resin extract was measured with the Estrogen Responsive Elements-Chemically Activated LUciferase gene eXpression (ERE-CALUX) bioassay. With this result and by applying Fick's diffusion law, it is possible to calculate the estrogenic activity in the aquatic system, if the diffusion boundary layer (DBL) is known or negligible compared to the hydrogel diffusive layer thickness. The DBL thickness in our study varied from 0.010 to 0.023 cm and ignoring the DBL thickness would for instance, underestimate the estrogenic activity by 10–20%. Estrogenic activities in the secondary effluent of GWWTP were the highest (29 ± 4 ng E2-equivalents L−1), while the lowest level was found at the Belgian Oostende Harbor (0.05 ± 0.01 ng E2-equivalents L−1). Comparable estrogenic activities in water samples measured by o-DGT and grab sampling were obtained, confirming that o-DGT can be efficiently used in various aquatic systems. The advantage of our sampling and measuring method is that very low, time averaged estrogenic activities can be determined, with a minimum of sample treatment. The risk of sample contamination is very low as well as the cost of the whole analytical procedure. Keywords: Estrogenic activity, o-DGT, CALUX, DBL, Effluent, Sea water

In this study, an AhR-responsive reporter-gene cell-based bioassay CALUX was used to assess the biological potency of dioxins and dioxin-like PCBs (dl-PCBs) in top soil samples collected from a former airbase (A-So) and remote regions from urban and agricultural areas in Thua Thien Hue, Vietnam. In top soil collected from A-So airbase, Bioanalytical EQuivalent (BEQ) concentrations of up to 2700 pg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) per g dry weight (pg BEQ-TCDD g−1 dw) were assessed. Interestingly, while BEQ values for dl-PCBs were found to be up to 13 pg BEQ-TCDD g−1 dw, the dl-PCB activity was not detected in all the hotspot sample extracts. In contrasts, BEQ values for dioxin like compounds from remote regions were much lower and occasionally below the quantification limits of the method. The BEQ activities obtained in this study have a similar trend to the WHO-TEQ results for the samples collected in the A-So airbase. However, BEQ values were higher than those of TEQ, probably reflecting the presence of additional AhR ligands and/or possible non-additive interactions in the sample mixture. This study confirms that after more than 60 years, a strong residual pollution of PCDD/Fs remains on this former air base following the use and storage of Agent Orange during the Vietnam War, raising a health risk for populations exposed in this area because livestock animals graze there.

Objectives: To evaluate the impact of resting-state functional MRI scan length on the diagnostic accuracy, image quality and lesion volume estimation of BOLD delay maps used for brain perfusion assessment in acute ischemic stroke.Methods: Sixty-three acute ischemic stroke patients received a 340 s resting-state functional MRI within 24 h of stroke symptom onset. BOLD delay maps were calculated from the full scan and four shortened versions (68 s, 136 s, 204 s, 272 s). The BOLD delay lesions on these maps were compared in terms of spatial overlap and volumetric agreement with the lesions derived from the full scans and with time-to-maximum (Tmax) lesions derived from DSC-MRI in a subset of patients (n = 10). In addition, the interpretability and quality of these maps were compared across different scan lengths using mixed models.Results: Shortened BOLD delay scans showed a small volumetric bias (ranging from 0.05 to 5.3 mL; between a 0.13% volumetric underestimation and a 7.7% overestimation relative to the mean of the volumes, depending on scan length) compared to the full scan. Decreased scan length was associated with decreased spatial overlap with both the BOLD delay lesions derived from the full scans and with Tmax lesions. Only the two shortest scan lengths (68 and 136 s) were associated with substantially decreased interpretability, decreased structure clarity, and increased noisiness of BOLD delay maps.Conclusions: BOLD delay maps derived from resting-state fMRI scans lasting 272 and 204 s provide sufficient diagnostic quality and adequate assessment of perfusion lesion volumes. Such shortened scans may be helpful in situations where quick clinical decisions need to be made.

Recent studies have suggested that both cardiac magnetic resonance (MR) and multidetector computed tomography (MDCT) can quantify aortic regurgitation (AR) by planimetry of the anatomical regurgitant orifice (ARO). However, this measurement was not compared with quantitative assessment of AR such as the effective regurgitant orifice (ERO) by proximal isosurface area (PISA) transthoracic echocardiography (TTE) or phase contrast MR. In 42 patients (34 men, age 54 +/- 11 years) we compared planimetered ARO by MDCT and MR with ERO and regurgitant volume by PISA TTE and phase contrast MR. ARO by MDCT (r = 0.87, p < 0.001) and MR (r = 0.81, p < 0.001) correlated highly with ERO by TTE. However, ARO by MDCT (27 +/- 15 mm(2), p < 0.001), but not by MR (23 +/- 13 mm(2), p = 0.58), were larger than PISA ERO (22 +/- 11 mm(2)). ARO by MDCT (r = 0.78, p < 0.001; r = 0.85, p < 0.001) and MR (r = 0.85, p < 0.001; r = 0.87 p < 0.001) correlated well with regurgitant volume by PISA and phase contrast MR. Both MDCT (small ka, Cyrillic = 0.80, p < 0.001) and MR (small ka, Cyrillic = 0.84, p < 0.001) demonstrated excellent agreement in correctly assessing the mechanisms of AR, i.e. aortic root dilatation (type I), cusp prolapse (type II) and restrictive cusp motion (type III), using surgical inspection as a reference. Measurement of ARO by both MDCT and MR allows accurate quantitative assessment of AR. Both techniques can also accurately determine the mechanism of AR. [ABSTRACT FROM AUTHOR]

Background: Collateral circulation in ischemic stroke patients plays an important role in infarct evolution und assessing patients' eligibility for endovascular treatment. By means of dynamic susceptibility contrast MRI, we aimed to investigate the effects of reperfusion, recanalization, and collateral flow on clinical and imaging outcomes after stroke.Methods: Retrospective analysis of 184 patients enrolled into the prospective observational 1000Plus study (clinicaltrials.org NCT00715533). Inclusion criteria were vessel occlusion on baseline MR-angiography, imaging within 24 h after stroke onset and follow-up perfusion imaging. Baseline Higashida score using subtracted dynamic MR perfusion source images was used to quantify collateral flow. The influence of these variables, and their interaction with vessel recanalization, on clinical and imaging outcomes was assessed using robust linear regression.Results: Ninety-eight patients (53.3%) showed vessel recanalization. Higashida score (p = 0.002), and recanalization (p = 0.0004) were independently associated with reperfusion. However, we found no evidence that the association between Higashida score and reperfusion relied on recanalization status (p = 0.2). NIHSS on admission (p < 0.0001) and recanalization (p = 0.001) were independently associated with long-term outcome at 3 months, however, Higashida score (p = 0.228) was not.Conclusion: Higashida score and recanalization were independently associated with reperfusion, but the association between recanalization and reperfusion was similar regardless of collateral flow quality. Recanalization was associated with long-term outcome. DSC-based measures of collateral flow were not associated with long-term outcome, possibly due to the complex dynamic nature of collateral recruitment, timing of imaging and the employed post-processing.

Introduction: In WAKE-UP (Efficacy and Safety of MRI-based Thrombolysis in Wake-Up Stroke), patients with an acute stroke of unknown onset time were randomized to treatment with intravenous alteplase or placebo, guided by MRI.Methods: In this exploratory post-hoc secondary analysis we compared clinical and imaging data, as well as treatment effects and safety of intravenous thrombolysis between patients with infra- vs. supratentorial stroke.Results: Forty-eight out of 503 randomized patients (9.5%) presented with a stroke involving the cerebellum or brainstem. Patients with infratentorial stroke were younger compared to patients with supratentorial stroke (mean age 60 vs. 66 years), more frequently male (85 vs. 62%), and less severely affected (median NIHSS 4.5 vs. 6.0). There was no heterogeneity for treatment effect between supratentorial (OR 1.67 95% CI 1.11–2.51) and infratentorial (OR 1.31 95% CI 0.41–4.22) sub-groups (test for interaction p = 0.70). In patients with infratentorial stroke, favorable outcome [a score of 0–1 on the modified Rankin scale (mRS) at 90 days] was observed in 12/22 patients (54.5%) in the alteplase group and in 13/25 patients (52.0%) in the placebo group (p = 0.59). The primary safety endpoint (death or mRS 4–6 at day 90) occurred in three patients of the alteplase group (13.6%) and three patients in the placebo group (12.0%); p = 0.74.Discussion: WAKE-UP was underpowered for demonstrating treatment effect in subgroup analyses however, based on our current results, there is no evidence to recommend withholding MRI-guided thrombolysis in patients with unknown onset stroke of infratentorial localization.

Purpose: Perfusion magnetic resonance imaging (P-MRI) is part of the mismatch concept employed for therapy decisions in acute ischemic stroke. Using dynamic susceptibility contrast (DSC) MRI the time-to-maximum (Tmax) parameter is quite popular, but its inconsistently defined computation, arterial input function (AIF) selection, and the applied deconvolution method may introduce bias into the assessment. Alternatively, parameter free methods, namely, standardized time-to-peak (stdTTP), zf-score, and standardized-zf (stdZ) are also available, offering consistent calculation procedures without the need of an AIF or deconvolution.Methods: Tmax was compared to stdTTP, zf-, and stdZ to evaluate robustness of infarct volume estimation in 66 patients, using data from two different sites and MR systems (i.e., 1.5T vs. 3T; short TR (= 689 ms) vs. medium TR (= 1,390 ms); bolus dose 0.1 or 0.2 ml/kgBW, respectively).Results: Quality factors (QF) for Tmax were 0.54 ± 0.18 (sensitivity), 0.90 ± 0.06 (specificity), and 0.87 ± 0.05 (accuracy). Though not significantly different, best specificity (0.93 ± 0.05) and accuracy (0.90 ± 0.04) were found for stdTTP with a sensitivity of 0.56 ± 0.17. Other tested parameters performed not significantly worse than Tmax and stdTTP, but absolute values of QFs were slightly lower, except for zf showing the highest sensitivity (0.72 ± 0.16). Accordingly, in ROC-analysis testing the parameter performance to predict the final infarct volume, stdTTP and zf showed the best performance. The odds for stdTTP to obtain the best prediction of the final infarct size, was 6.42 times higher compared to all other parameters (odds-ratio test; p = 2.2*10–16).Conclusion: Based on our results, we suggest to reanalyze data from large cohort studies using the parameters presented here, particularly stdTTP and zf-score, to further increase consistency of perfusion assessment in acute ischemic stroke.

The functional organization of the brain can be represented as a low-dimensional space that reflects its macroscale hierarchy. The dimensions of this space, described as connectivity gradients, capture the similarity of areas' connections along a continuous space. Studying how pathological perturbations with known effects on functional connectivity affect these connectivity gradients provides support for their biological relevance. Previous work has shown that localized lesions cause widespread functional connectivity alterations in structurally intact areas, affecting a network of interconnected regions. By using acute stroke as a model of the effects of focal lesions on the connectome, we apply the connectivity gradient framework to depict how functional reorganization occurs throughout the brain, unrestricted by traditional definitions of functional network boundaries. We define a three-dimensional connectivity space template based on functional connectivity data from healthy controls. By projecting lesion locations into this space, we demonstrate that ischemic strokes result in dimension-specific alterations in functional connectivity over the first week after symptom onset. Specifically, changes in functional connectivity were captured along connectivity Gradients 1 and 3. The degree of functional connectivity change was associated with the distance from the lesion along these connectivity gradients (a measure of functional similarity) regardless of the anatomical distance from the lesion. Together, these results provide support for the biological validity of connectivity gradients and suggest a novel framework to characterize connectivity alterations after stroke. Keywords: Connectivity gradients, Intrinsic functional connectivity, Diaschisis, Resting-state fMRI, Connectome, Diffusion embedding

In acute ischemic stroke the status of collateral circulation is a critical factor in determining outcome. We propose a less invasive alternative to digital subtraction angiography for evaluating collaterals based on dynamic-susceptibility contrast magnetic resonance imaging.Perfusion maps of Tmax and cerebral blood flow (CBF) were created for 35 patients with baseline occlusion of a major cerebral artery. Volumes of hypoperfusion were defined as having a Tmax delay of > 4 seconds (Tmax4s) and > 6 seconds (Tmax6s) and a CBF drop below 80% of healthy, contralateral tissue. For each patient a ratio between the volume of the CBF and the Tmax based perfusion deficit was calculated. Associations with collateral status and radiological outcome were assessed with the Mann-Whitney-U test, uni- and multivariable logistic regression analyses as well as area under the receiver-operator-characteristic (ROC) curve.The CBF/Tmax volume ratios were significantly associated with bad collateral status in crude logistic regression analysis as well as with adjustment for NIHSS at admission and baseline infarct volume (OR = 2.5 95% CI[1.2-5.4] p = 0.020 for CBF/Tmax 4s volume ratio and OR = 1.6 95% CI[1.0-2.6] p = 0.031 for CBF/Tmax6s volume ratio). Moreover, the ratios were significantly correlated to final infarct size (Spearman's rho = 0.711 and 0.619, respectively for the CBF/Tmax4s volume ratio and CBF/Tmax6s volume ration, all p

Background: The main safety aspect in the use of stroke thrombolysis and in clinical trials of new pharmaceutical or interventional stroke therapies is the incidence of hemorrhagic transformation (HT) after treatment. The computed tomography (CT)-based classification of the European Cooperative Acute Stroke Study (ECASS) distinguishes four categories of HTs. An HT can range from a harmless spot of blood accumulation to a symptomatic space-occupying parenchymal bleeding associated with a massive deterioration of symptoms and clinical prognosis. In magnetic resonance imaging (MRI) HTs are often categorized using the ECASS criteria although this classification has not been validated in MRI. We developed MRI-specific criteria for the categorization of HT and sought to assess its diagnostic reliability in a retrospective study. Methods: Consecutive acute ischemic stroke patients, who had received a 3-tesla MRI before and 12-36 h after thrombolysis, were screened retrospectively for an HT of any kind in post-treatment MRI. Intravenous tissue plasminogen activator was given to all patients within 4.5 h. HT categorization was based on a simultaneous read of 3 different MRI sequences (fluid-attenuated inversion recovery, diffusion-weighted imaging and T2* gradient-recalled echo). Categorization of HT in MRI accounted for the various aspects of the imaging pattern as the shape of the bleeding area and signal intensity on each sequence. All data sets were independently categorized in a blinded fashion by 3 expert and 3 resident observers. Interobserver reliability of this classification was determined for all observers together and for each group separately by calculating Kendall's coefficient of concordance (W). Results: Of the 186 patients screened, 39 patients (21%) had an HT in post-treatment MRI and were included for the categorization of HT by experts and residents. The overall agreement of HT categorization according to the modified classification was substantial for all observers (W = 0.79). The degrees of agreement between experts (W = 0.81) and between residents (W = 0.87) were almost perfect. For the distinction between parenchymal hematoma and hemorrhagic infarction, the interobserver agreement was almost perfect for all observers taken together (W = 0.82) as well as when experts (W = 0.82) and residents (W = 0.91) were analyzed separately. Conclusion: The ECASS CT classification of HT was successfully adapted for usage in MRI. It leads to a substantial to almost perfect interobserver agreement and can be used for safety assessment in clinical trials.

OBJECTIVES:To assess the sensitivity of stimulated echo acquisition mode diffusion weighted imaging (STEAM-DWI) to ischemic stroke in comparison to echo-planar imaging diffusion weighted imaging (EPI-DWI) in the infratentorial compartment. METHODS:Fifty-seven patients presenting with clinical features of infratentorial stroke underwent STEAM-DWI, high-resolution EPI-DWI (HR-DWI, 2.5 mm slice thickness) and low-resolution EPI-DWI (LR-DWI, 5 mm slice thickness). Four readers assessed the presence of ischemic lesions and artifacts. Agreement between sequences and interobserver agreement on the presence of ischemia were calculated. The sensitivities of the DWI sequences were calculated in 45 patients with a confirmed diagnosis of infratentorial stroke. RESULTS:Median time from symptom onset to imaging was 24 hours. STEAM-DWI agreed with LR-DWI in 89.5% of cases (kappa = 0.72, p

BackgroundIn order to select patients most likely to benefit for thrombolysis and to predict patient outcome in acute ischemic stroke, the volumetric assessment of the infarcted tissue is used. However, infarct volume estimation on Diffusion weighted imaging (DWI) has moderate interrater variability despite the excellent contrast between ischemic lesion and healthy tissue. In this study, we compared volumetric measurements of DWI hyperintensity to a simple maximum orthogonal diameter approach to identify thresholds indicating infarct size >70 ml and >100 ml.MethodsPatients presenting with ischemic stroke with an NIHSS of ≥ 8 were examined with stroke MRI within 24 h after symptom onset. For assessment of the orthogonal DWI lesion diameters (od-values) the image with the largest lesion appearance was chosen. The maximal diameter of the lesion was determined and a second diameter was measured perpendicular. Both diameters were multiplied. Od-values were compared to volumetric measurement and od-value thresholds identifying a lesion size of > 70 ml and > 100 ml were determined. In a selected dataset with an even distribution of lesion sizes we compared the results of the od value thresholds with results of the ABC/2 and estimations of lesion volumes made by two resident physicians.ResultsFor 108 included patients (53 female, mean age 71.36 years) with a median infarct volume of 13.4 ml we found an excellent correlation between volumetric measures and od-values (r2 = 0.951). Infarct volume >100 ml corresponds to an od-value cut off of 42; > 70 ml corresponds to an od-value of 32. In the compiled dataset (n = 50) od-value thresholds identified infarcts > 100 ml / > 70 ml with a sensitivity of 90%/ 93% and with a specificity of 98%/ 89%. The od-value offered a higher accuracy in identifying large infarctions compared to both visual estimations and the ABC/2 method.ConclusionThe simple od-value enables identification of large DWI lesions in acute stroke. The cutoff of 42 is useful to identify large infarctions with volume larger than 100 ml. Further studies can analyze the therapeutic utility of this new method.Trail registrationClinicalTrials.org NCT00715533.

There is an ongoing debate whether stroke patients presenting with minor or moderate symptoms benefit from thrombolysis. Up until now, stroke severity on admission is typically measured with the NIHSS, and subsequently used for treatment decision.Acute MRI lesion volume assessment can aid in therapy decision for iv-tPA in minor stroke.We analysed 164 patients with NIHSS 0-7 from a prospective stroke MRI registry, the 1000+ study (clinicaltrials.org NCT00715533). Patients were examined in a 3 T MRI scanner and either received (n = 62) or did not receive thrombolysis (n = 102). DWI (diffusion weighted imaging) and PI (perfusion imaging) at admission were evaluated for diffusion - perfusion mismatch. Our primary outcome parameter was final lesion volume, defined by lesion volume on day 6 FLAIR images.The association between t-PA and FLAIR lesion volume on day 6 was significantly different for patients with smaller DWI volume compared to patients with larger DWI volume (interaction between DWI and t-PA: p = 0.021). Baseline DWI lesion volume was dichotomized at the median (0.7 ml): final lesion volume at day 6 was larger in patients with large baseline DWI volumes without t-PA treatment (median difference 3, IQR -0.4-9.3 ml). Conversely, in patients with larger baseline DWI volumes final lesion volumes were smaller after t-PA treatment (median difference 0, IQR -4.1-5 ml). However, this did not translate into a significant difference in the mRS at day 90 (p = 0.577).Though this study is only hypothesis generating considering the number of cases, we believe that the size of DWI lesion volume may support therapy decision in patients with minor stroke.Clinicaltrials.org NCT00715533.

Systemic thrombolysis in acute ischemic stroke is restricted to the 4.5 h time window. Many patients are excluded from this treatment because symptom onset is unknown. Magnetic resonance imaging (MRI) studies have shown that stroke patients presenting with acute supra-tentorial diffusion-weighted imaging (DWI) lesions that do not have matching lesions on fluid attenuated inversion recovery (FLAIR) are likely to be within a 4.5 hour time window. This study examines the DWI-FLAIR mismatch in infra-tentorial stroke.This was a retrospectively conducted substudy of the "1000+" study; a prospective, single-center observational study (http://clinicaltrials.gov; NCT00715533). Fifty-six patients with infra-tentorial stroke confirmed by MRI and known symptom onset who underwent the scan within 24 h after symptom onset were analysed. Two neurologists blinded to clinical information separately rated the DWI lesion visibility on FLAIR. Lesion volume, relative signal intensities of DWI and relative apparent diffusion coefficient values were determined.Regarding baseline characteristics our study population had a median age of 66 years, a median time from symptom onset to MRI of 616.5 minutes, a median NIHSS of 3 and a median DWI lesion volume of 0.26 ml. A negative FLAIR allocated patients to a time window under 4.5 h correctly with a sensitivity of 55% and a specificity of 61%, a positive predictive value of 44% and a negative predictive value of 71%. FLAIR positivity decreased with age (p = 0.018), and showed no significant correlation to lesion volume (p = 0.145).In our study the DWI-FLAIR-Mismatch does not help to reliably identify patients within 4.5 h of symptom onset in acute ischemic infra-tentorial stroke. Thus therapeutical decisions based on the DWI-FLAIR mismatch estimation of time from onset cannot be recommended in patients with infra-tentorial stroke.

Mucosal vaccination appears to be suitable to protect against SARS-CoV-2 infection. In this study, we tested an intranasal mucosal vaccine candidate for COVID-19 that consisted of a cationic liposome containing a trimeric SARS-CoV-2 spike protein and CpG-ODNs, a Toll-like receptor 9 agonist, as an adjuvant. In vitro and in vivo experiments indicated the absence of toxicity following the intranasal administration of this vaccine formulation. First, we found that subcutaneous or intranasal vaccination protected hACE-2 transgenic mice from infection with the wild-type (Wuhan) SARS-CoV-2 strain, as shown by weight loss and mortality indicators. However, when compared with subcutaneous administration, the intranasal route was more effective in the pulmonary clearance of the virus and induced higher neutralizing antibodies and anti-S IgA titers. In addition, the intranasal vaccination afforded protection against gamma, delta, and omicron virus variants of concern. Furthermore, the intranasal vaccine formulation was superior to intramuscular vaccination with a recombinant, replication-deficient chimpanzee adenovirus vector encoding the SARS-CoV-2 spike glycoprotein (Oxford/AstraZeneca) in terms of virus lung clearance and production of neutralizing antibodies in serum and bronchial alveolar lavage (BAL). Finally, the intranasal liposomal formulation boosted heterologous immunity induced by previous intramuscular vaccination with the Oxford/AstraZeneca vaccine, which was more robust than homologous immunity.

Activated hepatic stellate cells (HSCs) play a key role in hepatic fibrosis and, thus, build the "soil" for hepatocarcinogenesis. Furthermore, HSCs are known to promote the progression of hepatocellular carcinoma (HCC), but the molecular mechanisms are only incompletely understood. Recently, we newly described the expression of bone morphogenetic protein 13 (BMP13) by HSCs in fibrotic liver tissue. In addition, BMP13 has mostly been studied in the context of cartilage and bone repair, but not in liver disease or cancer. Thus, we aimed to analyze the expression and function of BMP13 in HCC. Expression analyses revealed high BMP13-expression in activated human HSCs, but not in human HCC-cell-lines. Furthermore, analysis of human HCC tissues showed a significant correlation between BMP13 and α-smooth muscle actin (α-SMA), and immunofluorescence staining confirmed the co-localization of BMP13 and α-SMA, indicating activated HSCs as the cellular source of BMP13 in HCC. Stimulation of HCC cells with recombinant BMP13 increased the expression of the inhibitors of differentiation 1 ( ID1 ) and 2 ( ID2 ), which are known targets of BMP-signaling and cell-cycle promotors. In line with this, BMP13-stimulation caused an induced SMAD 1/5/9 and extracellular signal-regulated kinase (ERK) phosphorylation, as well as reduced expression of cyclin-dependent kinase inhibitors 1A ( CDKN1A ) and 2A ( CDKN2A ). Furthermore, stimulation with recombinant BMP13 led to increased proliferation and colony size formation of HCC cells in clonogenicity assays. The protumorigenic effects of BMP13 on HCC cells were almost completely abrogated by the small molecule dorsomorphin 1 (DMH1), which selectively blocks the intracellular kinase domain of ALK2 and ALK3, indicating that BMP13 acts via these BMP type I receptors on HCC cells. In summary, this study newly identifies stroma-derived BMP13 as a potential new tumor promotor in HCC and indicates this secreted growth-factor as a possible novel therapeutic target in HCC.

Osteoarthritis (OA) is a highly prevalent disease and a major health burden. Its development and progression are influenced by factors such as age, obesity or joint overuse. As a whole organ disease OA affects not only cartilage, bone and synovium but also ligaments, fatty or nervous tissue surrounding the joint. These joint tissues interact with each other and understanding this interaction is important in developing novel treatments. To incorporate and study these interactions in OA research, several co-culture models have evolved. They combine two or more cell types or tissues and investigate the influence of amongst others inflammatory or degenerative stimuli seen in OA. This review focuses on co-cultures and the differential processes occurring in a given tissue or cell as a consequence of being combined with another joint cell type or tissue, and/or the extent to which a co-culture mimics the in vivo processes. Most co-culture models depart from synovial lining and cartilage culture, but also fat pad and bone have been included. Not all of the models appear to reflect the postulated in vivo OA pathophysiology, although some of the discrepancies may indicate current assumptions on this process are not entirely valid. Systematic analysis of the mutual influence the separate compartments in a given model exert on each other and validation against in vivo or ex vivo observation is still largely lacking and would increase their added value as in vitro OA models., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Muenzebrock, Kersten, Alblas, Garcia and Creemers.)

Virus-like particles (VLPs) are a versatile, safe, and highly immunogenic vaccine platform. Recently, there are developmental vaccines targeting SARS-CoV-2, the causative agent of COVID-19. The COVID-19 pandemic affected humanity worldwide, bringing out incomputable human and financial losses. The race for better, more efficacious vaccines is happening almost simultaneously as the virus increasingly produces variants of concern (VOCs). The VOCs Alpha, Beta, Gamma, and Delta share common mutations mainly in the spike receptor-binding domain (RBD), demonstrating convergent evolution, associated with increased transmissibility and immune evasion. Thus, the identification and understanding of these mutations is crucial for the production of new, optimized vaccines. The use of a very flexible vaccine platform in COVID-19 vaccine development is an important feature that cannot be ignored. Incorporating the spike protein and its variations into VLP vaccines is a desirable strategy as the morphology and size of VLPs allows for better presentation of several different antigens. Furthermore, VLPs elicit robust humoral and cellular immune responses, which are safe, and have been studied not only against SARS-CoV-2 but against other coronaviruses as well. Here, we describe the recent advances and improvements in vaccine development using VLP technology.