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BackgroundPlatelets and von Willebrand factor (vWF) are key components of acute ischemic stroke (AIS) emboli. We aimed to investigate the CD42b (platelets)/vWF expression, its association with stroke etiology and the impact these components may have on the clinical/procedural parameters.MethodsCD42b/vWF immunostaining was performed on 288 emboli collected as part of the multicenter STRIP Registry. CD42b/VWF expression and distribution were evaluated. Student’s t-test and χ2test were performed as appropriate.ResultsThe mean CD42b and VWF content in clots was 44.3% and 21.9%, respectively. There was a positive correlation between platelets and vWF (r=0.64, pConclusionsThe vWF level and CD42b/vWF distribution pattern in emboli were correlated with AIS etiology and revascularization outcome. Platelet content was associated with response to thrombolysis.

BackgroundProper identification of infarct extent is crucial for thrombectomy and prognostication. We sought to study the frequency and topographic aspects of those cases in which CT perfusion (CTP) misses a core lesion that is present on initial non-contrast CT (NCCT).MethodsA review was carried out of a prospectively collected database of endovascular patients with anterior circulation large vessel occlusion strokes from January 2014 to November 2018. Patients with an e-ASPECTS ResultsIn total, 629 patients were analyzed of which 161 (25.6%) had a TMC. On univariate analysis, TMC was associated with isolated deep middle cerebral artery (MCA) strokes (77.6% vs 56.6%, pConclusionsCTP may completely fail to detect ischemic core in as many as 25% of cases, especially in isolated deep MCA strokes. Technical refinements of the post-processing algorithms are therefore warranted. TMC infarcts may have a lower risk of reperfusion hemorrhage, potentially due to greater preservation of the neurovascular unit structure in face of delayed recovery of cerebral blood flow.

Bioisosteric H/F or CH

Neurodegenerative diseases are multifactorial disorders characterized by protein misfolding, oxidative stress, and neuroinflammation, finally resulting in neuronal loss and cognitive dysfunctions. Nowadays, an attractive strategy to improve the classical treatments is the development of multitarget-directed molecules able to synergistically interact with different enzymes and/or receptors. In addition, an interesting tool to refine personalized therapies may arise from the use of bioactive species able to modify their activity as a result of light irradiation. To this aim, we designed and synthesized a small library of cinnamic acid-inspired isomeric compounds with light modulated activity able to inhibit acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B), with remarkable selectivity over butyrylcholinesterase (BChE) and MAO-A, which have been investigated as the enzyme targets related to Alzheimer's disease (AD). The inhibitory activities were evaluated for the pure E-diastereomers and the E/Z-diastereomer mixtures, obtained upon UV irradiation. Molecular docking studies were carried out to rationalize the differences in the inhibition potency of the E and Z diastereomers of the best performing analogue 1c. Our preliminary findings may open-up the way for developing innovative multitarget photo-switch drugs against neurodegenerative diseases.

Background and Purpose: Despite the lower rates of good outcomes and higher mortality in elderly patients, age does not modify the treatment effect of mechanical thrombectomy for large vessel occlusion strokes. We aimed to study whether racial background influences the outcome after mechanical thrombectomy in the elderly population. Methods: We reviewed a prospectively maintained database of patients with acute ischemic stroke treated with mechanical thrombectomy from October 2010 through June 2020 to identify all consecutive patients with age ≥80 years and anterior circulation large vessel occlusion strokes. The patients were categorized according to their race as Black and White. Univariable and multivariable analyses were performed to define the predictors of 90-day modified Rankin Scale and mortality in the overall population and in each race separately. Results: Among 2241 mechanical thrombectomy, a total of 344 patients (median [interquartile range]; age 85 [82–88] years, baseline National Institutes of Health Stroke Scale score of 19 [15–23], Alberta Stroke Program Early CT Score 9 [7–9], 69.5% females) were eligible for the analysis. White patients (n=251; 73%) had significantly lower median body mass index (25.37 versus 26.89, P =0.04) and less frequent hypertension (78.9% versus 90.3%, P =0.01) but more atrial fibrillation (64.5% versus 44.1%, P =0.001) compared with African Americans (n=93; 27%). Other clinical, imaging, and procedural characteristics were comparable between groups. The rates of symptomatic intracerebral hemorrhage, 90-day modified Rankin Scale score of 0 to 2, and mortality were comparable among both groups. On multivariable analysis, race was neither a predictor of 90-day modified Rankin Scale score of 0 to 2 (White race: odds ratio, 0.899 [95% CI, 0.409–1.974], P =0.79) nor 90-day mortality (White race: odds ratio, 1.368; [95% CI, 0.715–2.618], P =0.34). Conclusions: In elderly patients undergoing mechanical thrombectomy for acute ischemic stroke, there was no racial difference in terms of outcome.

BackgroundCompositional and structural features of retrieved clots by thrombectomy can provide insight into improving the endovascular treatment of ischemic stroke. Currently, histological analysis is limited to quantification of compositions and qualitative description of the clot structure. We hypothesized that heterogeneous clots would be prone to poorer recanalization rates and performed a quantitative analysis to test this hypothesis.MethodsWe collected and did histology on clots retrieved by mechanical thrombectomy from 157 stroke cases (107 achieved first-pass effect (FPE) and 50 did not). Using an in-house algorithm, the scanned images were divided into grids (with sizes of 0.2, 0.3, 0.4, 0.5, and 0.6 mm) and the extent of non-uniformity of RBC distribution was computed using the proposed spatial heterogeneity index (SHI). Finally, we validated the clinical significance of clot heterogeneity using the Mann–Whitney test and an artificial neural network (ANN) model.ResultsFor cases with FPE, SHI values were smaller (0.033 vs 0.039 for grid size of 0.4 mm, P=0.028) compared with those without. In comparison, the clot composition was not statistically different between those two groups. From the ANN model, clot heterogeneity was the most important factor, followed by fibrin content, thrombectomy techniques, red blood cell content, clot area, platelet content, etiology, and admission of intravenous tissue plasminogen activator (IV-tPA). No statistical difference of clot heterogeneity was found for different etiologies, thrombectomy techniques, and IV-tPA administration.ConclusionsClot heterogeneity can affect the clot response to thrombectomy devices and is associated with lower FPE. SHI can be a useful metric to quantify clot heterogeneity.

Introduction: Expediting notification of lesions in acute ischemic stroke (AIS) is critical. Limited availability of experts to assess such lesions and delays in large vessel occlusion (LVO) recognition can negatively affect outcomes. Artificial intelligence (AI) may aid LVO recognition and treatment. This study aims to evaluate the performance of an AI-based algorithm for LVO detection in AIS. Methods: Retrospective analysis of a database of AIS patients admitted in a single center between 2014 and 2019. Vascular neurologists graded computed tomography angiographies (CTAs) for presence and site of LVO. Studies were analyzed by the Viz-LVO Algorithm® version 1.4 – neural network programmed to detect occlusions from the internal carotid artery terminus (ICA-T) to the Sylvian fissure. Comparisons between human versus AI-based readings were done by test characteristic analysis and Cohen’s kappa. Primary analysis included ICA-T and/or middle cerebral artery (MCA)-M1 LVOs versus non-LVOs/more distal occlusions. Secondary analysis included MCA-M2 occlusions. Results: 610 CTAs were analyzed. The AI algorithm rejected 2.5% of the CTAs due to poor quality, which were excluded from the analysis. Viz-LVO identified ICA-T and MCA-M1 LVOs with a sensitivity of 87.6%, specificity of 88.5%, and accuracy of 87.9% (AUC 0.88, 95% CI: 0.85–0.92, p < 0.001). Cohen’s kappa was 0.74. In the secondary analysis, the algorithm yielded a sensitivity of 80.3%, specificity of 88.5%, and accuracy of 82.7%. The mean run time of the algorithm was 2.78 ± 0.5 min. Conclusion: Automated AI reading allows for fast and accurate identification of LVO strokes with timely notification to emergency teams, enabling quick decision-making for reperfusion therapies or transfer to specialized centers if needed.

Hansch-type regression analysis enables the derivation of quantitative structure-activity relationship (QSAR) equations correlating bioactivity data with physicochemical parameters accounting for hydrophobicity, electronic properties, and steric effects of molecules or functional groups (substituents). Two datasets of MAO A and B inhibitors were enrolled in prototypical workflows employing multiparametric stepwise regression analysis, which includes linear and nonlinear (generally quadratic) terms. The optimal choice of variables (and/or combinations thereof) along with statistical validation yielded two robust equations describing MAO B potency and B/A selectivity, which included three and one parameter(s), respectively, and explained more than 80% of y-variance (r

Background Three randomized clinical trials have reported similar safety and efficacy for contact aspiration and stent-retriever thrombectomy. Aim We aimed to determine whether the combined technique (stent-retriever + contact aspiration) was superior to stent-retriever alone as first-line thrombectomy strategy in a patient cohort where balloon guide catheter was universally used. Methods A prospectively maintained mechanical thrombectomy database from January 2018 to December 2019 was reviewed. Patients were included if they had anterior circulation proximal occlusion ischemic stroke (intracranial ICA or MCA-M1/M2 segments) and underwent stent-retriever alone thrombectomy or stent-retriever + contact aspiration as first-line therapy. The primary outcome was the first-pass effect (mTICI2c-3). Secondary outcomes included modified first-pass effect (mTICI2b-3), successful reperfusion (mTICI2b-3) prior to and after any rescue strategy, and 90-day functional independence (mRS ≤ 2). Safety outcomes included rate of parenchymal hematoma type-2 and 90-day mortality. Sensitivity analyses were performed after dividing the overall cohort according to first-line modality into two matched groups. Results A total of 420 patients were included in the analysis (mean age 64.4 years; median baseline NIHSS 16 (11–21)). As compared to first-line stent-retriever alone, first-line stent-retriever + contact aspiration resulted in similar rates of first-pass effect (53% vs. 51%, adjusted odds ratio (aOR) 1.122, 95%CI (0.745–1.691), p = 0.58), modified first-pass effect (63% vs. 60.4%, aOR1.250, 95%CI (0.782–2.00), p = 0.35), final successful reperfusion (97.6% vs. 98%, p = 0.75), and higher chances of successful reperfusion prior to any rescue strategy (81.8% vs. 72.5%, aOR 2.033, 95%CI (1.209–3.419), p = 0.007). Functional outcome and safety measures were comparable between both groups. Likewise, the matched analysis (148 patient-pairs) demonstrated comparable results for all clinical and angiographic outcomes except for significantly higher rates of successful reperfusion prior to any rescue strategies with the first-line stent-retriever + contact aspiration treatment (81.8% vs. 73.6%, aOR 1.881, 95%CI (1.039–3.405), p = 0.037). Conclusions Our findings reinforce the findings of ASTER-2 trial in that the first-line thrombectomy with a combined technique did not result in increased rates of first-pass reperfusion or better clinical outcomes. However, the addition of contact aspiration after initial stent-retriever failure might be beneficial in achieving earlier reperfusion.

BackgroundSeveral animal studies have demonstrated that mechanical thrombectomy (MT) for acute ischemic stroke (AIS) may cause vessel wall injury (VWI). However, the histological changes in human cerebral arteries following MT are difficult to determine.ObjectiveTo investigate the occurrence of VWI during MT by histological and immunohistochemical evaluation of AIS clots.MethodsAs part of the multicenter STRIP registry, 277 clots from 237 patients were analyzed using Martius Scarlett Blue stain and immunohistochemistry for CD34 (endothelial cells) and smooth muscle actin (smooth muscle cells).ResultsMT devices used were aspiration catheters (100 cases), stentriever (101 cases), and both (36 cases). VWI was found in 33/277 clots (12%). There was no significant correlation between VWI and MT device. The degree of damage varied from grade I (mild intimal damage, 24 clots), to grade II (relevant intimal and subintimal damage, 3 clots), and III (severe injury, 6 clots). VWI clots contained significantly more erythrocytes (p=0.006*) and less platelets/other (p=0.005*) than non-VWI clots suggesting soft thrombus material.Thrombolysis correlated with a lower rate of VWI (p=0.04*). VWI cases showed a significantly higher number of passes (2 [1–4] vs 1 [1–3], p=0.028*) and poorer recanalization outcome (p=0.01*) than cases without VWI.ConclusionsHistological markers of VWI were present in 12% of AIS thrombi, suggesting that VWI might be related to MT. VWI was associated with soft thrombus consistency, higher number of passes and poorer revascularization outcome. There was no significant correlation between VWI and MT device.

Background and aim Mechanical thrombectomy (MT) for large vessel occlusion often requires multiple passes to retrieve the entire thrombus load. In this multi-institutional study we sought to examine the composition of thrombus fragments retrieved with each pass during MT. Methods Patients who required multiple passes during thrombectomy were included. Histopathological evaluation of thrombus fragments retrieved from each pass was performed using Martius Scarlet Blue staining and the composition of each thrombus component including RBC, fibrin and platelet was determined using image analysis software. Results 154 patients underwent MT and 868 passes was performed which resulted in 263 thrombus fragments retrieval. The analysis of thrombus components per pass showed higher RBC, lower fibrin and platelet composition in the pass 1 and 2 when compared to pass 3 and passes 4 or more combined (P values 0.05). Similarly, when each composition of thrombus fragments retrieved in pass 3 and passes 4 or more combined were compared with each other, no significant difference was noted (P values >0.05). Conclusion Our findings confirm that thrombus fragments retrieved with each pass differed significantly in histological content. Fragments in the first passes were associated with lower fibrin and platelet composition compared to fragments retrieved in passes three and four or higher. Also, thrombus fragments retrieved after failed pass were associated with higher fibrin and platelet components.

BackgroundPatients with large vessel occlusion stroke (LVOS) and a low Alberta Stroke Program Early CT Score (ASPECTS) are often not offered endovascular therapy (ET) as they are thought to have a poor prognosis.ObjectiveTo compare the outcomes of patients with low and high ASPECTS undergoing ET based on baseline infarct volumes.MethodsReview of a prospectively collected endovascular database at a tertiary care center between September 2010 and March 2020. All patients with anterior circulation LVOS and interpretable baseline CT perfusion (CTP) were included. Subjects were divided into groups with low ASPECTS (0–5) and high ASPECTS (6-10) and subsequently into limited and large CTP-core volumes (cerebral blood flow 30% >70 cc). The primary outcome measure was the difference in rates of 90-day good outcome as defined by a modified Rankin Scale (mRS) score of 0 to 2 across groups.Results1248 patients fit the inclusion criteria. 125 patients had low ASPECTS, of whom 16 (12.8%) had a large core (LC), whereas 1123 patients presented with high ASPECTS, including 29 (2.6%) patients with a LC. In the category with a low ASPECTS, there was a trend towards lower rates of functional independence (90-day modified Rankin Scale (mRS) score 0-2) in the LC group (18.8% vs 38.9%, p=0.12), which became significant after adjusting for potential confounders in multivariable analysis (aOR=0.12, 95% CI 0.016 to 0.912, p=0.04). Likewise, LC was associated with significantly lower rates of functional independence (31% vs 51.9%, p=0.03; aOR=0.293, 95% CI 0.095 to 0.909, p=0.04) among patients with high ASPECTS.ConclusionsOutcomes may vary significantly in the same ASPECTS category depending on infarct volume. Patients with ASPECTS ≤5 but baseline infarct volumes ≤70 cc may achieve independence in nearly 40% of the cases and thus should not be excluded from treatment.

BackgroundWe retrospectively evaluated the composition of retrieved clots from ischemic stroke patients to study the association between histological composition and stroke etiologyMethodsConsecutive patients enrolled in the Stroke Thromboembolism Registry of Imaging and Pathology (STRIP) were included in this study. All patients underwent mechanical thrombectomy and retrieved clots were sent to a central core lab for processing. Histological analysis was performed using martius scarlet blue (MSB) staining, and quantification for red blood cells (RBCs), white blood cells (WBCs), fibrin and platelets was performed using Orbit Image Software. A Wilcoxon test was used for continuous variables and χ2test for categorical variables.Results1350 patients were included in this study. The overall rate of Thrombolysis In Cerebral Infarction (TICI) 2c/3 was 68%. 501 patients received tissue plasminogen activator (tPA) (37%). 267 patients (20%) had a large artery atherosclerosis (LAA) source, 662 (49%) a cardioembolic (CE) source, 301 (22%) were cryptogenic, and the remainder had other identifiable sources including hypercoagulable state or dissection. LAA thrombi had a higher mean RBC density (46±23% vs 42±22%, p=0.01) and a lower platelet density (24±18% vs 27±18%, p=0.03) than CE thrombi. Clots from dissection patients had the highest mean RBC density (50±24%) while clots from patients with a hypercoagulable state had the lowest mean RBC density (26±21%).ConclusionsOur study found statistically significant but clinically insignificant differences between clots of CE and LAA etiologies. Future studies should emphasize molecular, proteomic and immunohistochemical characteristics to determine links between clot composition and etiology.

BackgroundThe optimal anesthesia management for patients with stroke undergoing mechanical thrombectomy (MT) during the COVID-19 pandemic has become a matter of controversy. Some recent guidelines have favored general anesthesia (GA) in patients perceived as high risk for intraprocedural conversion from sedation to GA, including those with dominant hemispheric occlusions/aphasia or baseline National Institutes of Health Stroke Scale (NIHSS) score >15. We aim to identify the rate and predictors of conversion to GA during MT in a high-volume center where monitored anesthesia care (MAC) is the default modality.MethodsA retrospective review of a prospectively maintained MT database from January 2013 to July 2020 was undertaken. Analyses were conducted to identify the predictors of intraprocedural conversion to GA. In addition, we analyzed the GA conversion rates in subgroups of interest.ResultsAmong 1919 MT patients, 1681 (87.6%) started treatment under MAC (median age 65 years (IQR 55–76); baseline NIHSS 16 (IQR 11–21); 48.4% women). Of the 1677 eligible patients, 26 (1.6%) converted to GA including 1.4% (22/1615) with anterior and 6.5% (4/62) with posterior circulation strokes. The only predictor of GA conversion was posterior circulation stroke (OR 4.99, 95% CI 1.67 to 14.96, P=0.004). The conversion rates were numerically higher in right than in left hemispheric occlusions (1.6% vs 1.2%; OR 1.37, 95% CI 0.59 to 3.19, P=0.47) and in milder than in more severe strokes (NIHSS ≤15 vs >15: 2% vs 1.2%; OR 0.62, 95% CI 0.28 to 1.36, P=0.23).ConclusionsOur study showed that the overall rate of conversion from MAC to GA during MT was low (1.6%) and, while higher in posterior circulation strokes, it was not predicted by either hemispheric dominance or stroke severity. Caution should be given before changing clinical practice during moments of crisis.

Nature-inspired, bridged polycyclic molecules share low similarity with currently available drugs, containing preferentially planar and/or achiral moieties. This "Escape from Flatland" scenario, aimed at exploring pharmacological properties of atypical molecular scaffolds, finds interest in synthetic routes leading to tridimensional-shaped molecules. Herein we report on the synthesis of N-bridged cyclopenta[a]indene derivatives, achieved through microwave-assisted thermal rearrangement of allene 3-benzazecines with high diastereoselectivity. The biological evaluation disclosed selective inhibition of human acetylcholinesterase or butyrylcholinesterase, depending on the substitution around the molecular core, which was rationalized by means of docking simulations. The most potent BChE inhibitor 31 was effective in neuroprotection from glutamatergic excitotoxicity and displayed low intrinsic cytotoxicity and good brain penetration. Overall, compound 31 and its close congeners 34 and 35 acted as multitarget agents addressing different biological events involved in neurodegeneration, particularly in the progression of Alzheimer's disease.

Different Mannich base derivatives have been studied with the aim of addressing the poor aqueous solubility of the recently disclosed 6-phenethyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one (1), a human butyrylcholinesterase inhibitor (hBChE, IC50 13 nM) and protective agent in NMDA-induced neurotoxicity, in in vivo assays. The N-(4-methylpiperazin-1-yl)methyl derivative 2 c showed a 50-fold increase in solubility in pH 7.4-buffered solution, high stability in serum and (half-life >24 h) and rapid (

BackgroundThe first-pass effect (FPE) has emerged as a key metric for efficacy in mechanical thrombectomy (MT). The hyperdense vessel sign (HDVS) on non-contrast head CT (NCCT) indicates a higher clot content of red blood cells.ObjectiveTo assess whether the HDVS could serve as an imaging biomarker for guiding first-line device selection in MT.MethodsA prospective MT database was reviewed for consecutive patients with anterior circulation large vessel occlusion stroke who underwent thrombectomy with stent retriever (SR) or contact aspiration (CA) as first-line therapy between January 2012 and November 2018. Pretreatment NCCT scans were evaluated for the presence of HDVS. The primary outcome was FPE (modified Thrombolysis in Cerebral Infarction score 2c/3). The primary analysis was the interaction between HDVS and thrombectomy modality on FPE. Secondary analyses aimed to evaluate the predictors of FPE.ResultsA total of 779 patients qualified for the analysis. HDVS and FPE were reported in 473 (60.7%) and 286 (36.7%) patients, respectively. The presence of HDVS significantly modified the effect of thrombectomy modality on FPE (p=0.01), with patients with HDVS having a significantly higher rate of FPE with a SR (41.3% vs 22.2%, p=0.001; adjusted OR 2.11 (95% CI 1.20 to 3.70), p=0.009) and non-HDVS patients having a numerically better response to CA (41.4% vs 33.9%, p=0.28; adjusted OR 0.58 (95% CI 0.311 to 1.084), p=0.088). Age (OR 1.01 (95% CI 1.00 to 1.02), p=0.04) and balloon guide catheter (OR 2.08 (95% CI 1.24 to 3.47), p=0.005) were independent predictors of FPE in the overall population.ConclusionOur data suggest that patients with HDVS may have a better response to SRs than CA for the FPE. Larger confirmatory prospective studies are warranted.

BackgroundFirst pass reperfusion (FPR) has been established as a key performance metric in mechanical thrombectomy (MT). The impact of FPR may be more relevant in fast progressors. We aim to study the impact of baseline Alberta Stroke Program Early CT Score (ASPECTS) on non-contrast CT and hypoperfusion intensity ratio (HIR) on CT perfusion on clinical outcomes after FPR.MethodsA prospective MT database was reviewed for patients with isolated occlusion of the intracranial internal carotid artery and/or middle cerebral artery M1 segment who underwent MT with complete reperfusion (modified Thrombolyis in Cerebral Infarction score 2c–3) from January 2012 to May 2019. The overall population was divided into ASPECTS >7 versus ≤7 and the subgroup of patients with baseline CT perfusion was divided into HIR ResultsA total of 436 patients were included in the analyses. FPR was achieved in 254 (58.3%) patients. ASPECTS modified the effect of FPR on clinical outcomes, with FPR predicting good outcomes in patients with ASPECTS ≤7 (46% vs 29%, adjusted OR 3.748; 95% CI 1.590 to 8.838, p=0.003) while no significant effect was detected in those with ASPECTS >7 (62.3% vs 53.1%, adjusted OR 1.372; 95% CI 0.798 to 2.358, p=0.25). Similarly, FPR predicted good outcomes in patients with HIR ≥0.3 (54.8% vs 41.9%, adjusted OR 2.204; 95% CI 1.148 to 4.233, p=0.01) but not in those with HIR ConclusionsThe impact of FPR on functional outcomes is highly dependent on baseline imaging characteristics, with a more prominent influence in patients presenting with lower ASPECTS and/or higher HIR.

Background and Purpose Infarct growth rate (IGR) in acute ischemic stroke is highly variable. We sought to evaluate impact of symptom-reperfusion time on outcomes in patients undergoing mechanical thrombectomy (MT). Methods A prospectively maintained database from January,2012-August,2020 was reviewed. All patients with isolated MCA-M1 occlusion who achieved complete reperfusion(mTICI2C-3), had a witnessed symptom onset and follow-up MRI were included. IGR was calculated as final infarct volume (FIV)(ml)/symptom onset to reperfusion time(hours) and was dichotomized according to the median value into slow-(SP) versus fast-progressors (FP). The primary analysis aimed to evaluate the impact of symptom-reperfusion time on 90-day mRS in SP and FP. Secondary analysis was performed to identify predictors of IGR. Results A total of 137 patients were eligible for analysis. Mean age was 63 ± 15.4 years and median IGR was 5.13ml/hour. SP(n = 69) had higher median ASPECTS, lower median rCBFConclusions The impact of symptom-reperfusion time on outcomes significantly varies across slow-versus fast-progressors. ASPECTS, collateral score, rCBF

Background As compared to single-phase CTA (sCTA), multi-phase CTA (mCTA) has been shown to more accurately estimate collateral flow in acute ischemic stroke (AIS). We sought to determine the characterization of poor collaterals across the three different phases of the mCTA. We also attempted to establish the optimal arterio-venous contrast timing parameters on sCTA that would prevent false positive reads of poor collateral status. Methods We retrospectively screened consecutive patients admitted for possible thrombectomy from February 2018 to June 2019. Only cases with intracranial internal carotid artery (ICA) or main trunk of the middle cerebral artery (MCA) occlusion and both baseline mCTA and CT Perfusion available were included. Mean Hounsfield units (HU) of torcula and torcula/patent ICA ratio were used for the arterio-venous timing analysis. Results Of the 105 patients included, 35 (34%) received IV-tPA treatment and 65 (61.9%) underwent mechanical thrombectomy. A total of 20 patients (19%) had poor collaterals on the third-phase CTA (ground-truth). The first-phase CTA often underestimated collateral score (37/105 [35%], p Conclusion A dual-phase CTA is significantly similar to a mCTA assessment of collateral score and may be applied at community-based centers. Absolute or relative thresholds for torcula opacification may be used to identify poor bolus-scan timing thus preventing erroneous assumptions of poor collaterals on sCTA.

Background Intra-procedural characterization of stroke thromboemboli might guide mechanical thrombectomy (MT) device choice to improve recanalization rates. Electrochemical impedance spectroscopy (EIS) has been used to characterize various biological tissues in real time but has not been used in thrombus. Objective To perform a feasibility study of EIS analysis of thrombi retrieved by MT to evaluate: (1) the ability of EIS and machine learning to predict red blood cell (RBC) percentage content of thrombi and (2) to classify the thrombi as “RBC-rich” or “RBC-poor” based on a range of cutoff values of RBC. Methods ClotbasePilot was a multicentric, international, prospective feasibility study. Retrieved thrombi underwent histological analysis to identify proportions of RBC and other components. EIS results were analyzed with machine learning. Linear regression was used to evaluate the correlation between the histology and EIS. Sensitivity and specificity of the model to classify the thrombus as RBC-rich or RBC-poor were also evaluated. Results Among 514 MT,179 thrombi were included for EIS and histological analysis. The mean composition in RBC of the thrombi was 36% ± 24. Good correlation between the impedance-based prediction and histology was achieved (slope of 0.9, R2 = 0.53, Pearson coefficient = 0.72). Depending on the chosen cutoff, ranging from 20 to 60% of RBC, the calculated sensitivity for classification of thrombi ranged from 77 to 85% and the specificity from 72 to 88%. Conclusion Combination of EIS and machine learning can reliably predict the RBC composition of retrieved ex vivo AIS thrombi and then classify them into groups according to their RBC composition with good sensitivity and specificity.

A set of twenty-five thioxanthene-9-one and xanthene-9-one derivatives, that were previously shown to inhibit cholinesterases (ChEs) and amyloid β (Aβ40) aggregation, were evaluated for the inhibition of tau protein aggregation. All compounds exhibited a good activity, and eight of them (5–8, 10, 14, 15 and 20) shared comparable low micromolar inhibitory potency versus Aβ40 aggregation and human acetylcholinesterase (AChE), while inhibiting human butyrylcholinesterase (BChE) even at submicromolar concentration. Compound 20 showed outstanding biological data, inhibiting tau protein and Aβ40 aggregation with IC50 = 1.8 and 1.3 μM, respectively. Moreover, at 0.1–10 μM it also exhibited neuroprotective activity against tau toxicity induced by okadoic acid in human neuroblastoma SH-SY5Y cells, that was comparable to that of estradiol and PD38. In preliminary toxicity studies, these interesting results for compound 20 are somewhat conflicting with a narrow safety window. However, compound 10, although endowed with a little lower potency for tau and Aβ aggregation inhibition additionally demonstrated good inhibition of ChEs and rather low cytotoxicity. Compound 4 is also worth of note for its high potency as hBChE inhibitor (IC50 = 7 nM) and for the three order of magnitude selectivity versus hAChE. Molecular modelling studies were performed to explain the different behavior of compounds 4 and 20 towards hBChE. The observed balance of the inhibitory potencies versus the relevant targets indicates the thioxanthene-9-one derivatives as potential MTDLs for AD therapy, provided that the safety window will be improved by further structural variations, currently under investigation.

Multitarget directed ligands (MTDLs) represent a promising frontier in tackling the complexity of multifactorial pathologies. The synergistic inhibition of monoamine oxidase B (MAO B) and acetylcholinesterase (AChE) is believed to provide a potentiated effect in the treatment of Alzheimer's disease. Among previously reported micromolar or sub-micromolar coumarin-bearing dual inhibitors, compound

Given recent evidence suggesting the clot composition may be associated with revascularization outcomes and stroke etiology, clot composition research has been a topic of growing interest. It is currently unclear what effect, if any, pre-thrombectomy thrombolysis has on clot composition. Understanding this association is important as it is a potential confounding variable in clot composition research. We retrospectively evaluated the composition of retrieved clots from ischemic stroke patients who did and did not receive pre-treatment tPA to study the effect of tPA on clot composition.Consecutive patients enrolled in the Stroke Thromboembolism Registry of Imaging and Pathology (STRIP) were included in this study. All patients underwent mechanical thrombectomy and retrieved clots were sent to a central core lab for processing. Histological analysis was performed using Martius Scarlett Blue (MSB) staining and area of the clot was also measured on the gross photos. Student's t test was used for continuous variables and chi-squared test for categorical variables.A total of 1430 patients were included in this study. Mean age was 68.4±13.5 years. Overall rate of TICI 2c/3 was 67%. A total of 517 patients received tPA (36%) and 913 patients did not (64%). Mean RBC density for the tPA group was 42.97±22.62% compared to 42.80±23.18% for the non-tPA group (P=0.89). Mean WBC density for the tPA group was 3.74±2.60% compared to 3.42±2.21% for the non-tPA group (P=0.012). Mean fibrin density for the tPA group was 26.52±15.81% compared to 26.53±15.34% for the non-tPA group (P=0.98). Mean platelet density for the tPA group was 26.22±18.60% compared to 26.55±19.47% for the non-tPA group (P=0.75). tPA group also had significantly smaller clot area compared to non-tPA group.Our study 1430 retrieved emboli and ischemic stroke patients shows no interaction between tPA administration and clot composition. These findings suggest that tPA does not result in any histological changes in clot composition.

BackgroundCarotid webs (CaW) are now recognized as a cause of ischemic stroke in young patients. The thromboembolic potential appears related to the CaW’s morphology and consequent impact on local flow dynamics. We aim to evaluate the reliability of different measurement methods for the quantification of CaW and their relationship to symptomatic status, presence of large vessel occlusion stroke (LVOS), clot burden and final infarct volume.MethodsThis was a retrospective analysis of the local comprehensive stroke center CaW database (September 2014–July 2019). CT angiograms (CTAs) were reviewed independently by two raters, blinded to the clinical information and laterality of the stroke/transient ischemic attack. CaW were quantified with 1-D (length), 2-D (area) and 3-D (volume) measurements via Osirix software. Final infarct volume was calculated on MRI. Patients with superimposed CaW thrombus and no repeat imaging were excluded.ResultsForty-eight CaW (37 symptomatic and 11 contralateral/asymptomatic) in 38 patients were included. Mean age (±SD) was 48.7 (±8.5) years, 78.9% were women and 77.1% were black. Inter-rater agreement was 0.921 (p2(p=0.35) and median volume was 15.0 versus 10.6 mm3(pConclusionCaW dimension quantification (1-D, 2-D and 3-D) is highly reproducible. Linear and volumetric measurements were more strongly associated with symptoms. The impact of CaW size on the presence of LVOS, clot burden and final infarct volume is unclear.

Aim: Enamino 3-benzazecine compounds, incorporating the C6-C8 allene system, were synthesized and evaluated in vitro as inhibitors of P-glycoprotein (P-gp) and/or multidrug resistance-associated protein 1 (MRP1), two efflux pumps mainly connected with multidrug resistance (MDR) in cancer cells. Results & methodology: Most of the synthesized compounds were selective P-gp inhibitors in Calcein-AM uptake assay. Structure–activity relationships (SARs) pointed out that CO2Me derivatives are more potent than acetyl derivatives, and 10,11-dimethoxy compounds are five to tenfold more potent inhibitors than the respective unsubstituted compounds, and that the P-gp inhibition potency is mainly related to volume parameters. Conclusion: Nanomolar P-gp inhibitors, such as 23 (IC50 = 4.2 nM), restored the antiproliferative activity of doxorubicin in multidrug-resistant cells. The observed activities showed that 3-benzazecine-based compounds may be promising MDR reversers.

Background and Purpose: There is a robust relationship between the duration of ischemia and functional outcomes after mechanical thrombectomy. Higher number of mechanical thrombectomy passes strongly correlate with lower chances of favorable outcomes. Indeed, previous studies have suggested that after multiple passes the procedure may be futile. However, using uncontrolled thresholds to define thrombectomy futility might be misleading. We aim to compare the outcome of successful reperfusion after 4 to 5 passes and ≥6 passes with those of failed reperfusion. Methods: A prospectively acquired mechanical thrombectomy database from January 2012 to October 2019 was reviewed. Patients were included if they had intracranial internal carotid artery or middle cerebral artery-M1/M2 occlusions and either achieved successful reperfusion after ≥4 passes or failed reperfusion. Reperfused patients (mTICI2b-3) were divided into 2 subgroups; (1) 4 to 5 passes and (2) ≥6 passes. Each subgroup was compared with a matched group of mechanical thrombectomy failure (mTICI0-2a). The primary outcome was the shift in the degree of disability at 90-day as measured by the modified Rankin Scale. Results: A total of 273 patients were included. As compared with matched failed reperfusion patients (n=62), those reperfused after 4 to 5 passes (n=62) had a favorable shift in the overall modified Rankin Scale score distribution (adjusted odds ratio, 3.992 [95% CI, 1.807–8.512], P =0.001] and higher rates of functional independence (31% versus 8.9%, P =0.004, adjusted odds ratio; 9.860 [95% CI, 2.323–41.845], P =0.002) at 90 days. Similarly, when compared with a matched group of failed reperfusion (n=42), patients reperfused after ≥6 passes (n=42) demonstrated a favorable shift in the overall modified Rankin Scale score distribution (adjusted odds ratio, 2.640 [95% CI, 1.073–6.686], P =0.037) and had higher rates of functional independence (36.8% vs 11.1%, P =0.004, adjusted odds ratio, 5.392 [95% CI, 1.185–24.530], P =0.029) at 90 day. Rates of parenchymal hematoma type-2 and 90-day mortality were comparable in the reperfused and nonreperfused groups. Conclusions: Achieving reperfusion despite multiple passes leads to improved outcomes compared with failed procedures. Arbitrary uncontrolled thresholds for a maximum number of passes to predict futile recanalization may lead to inappropriate early termination of procedures.

Introduction: Final infarct volume (FIV) is a commonly used imaging endpoint in stroke trials. The aim of this study was to investigate the potential of an automated masking pipeline (Brain Intensity AbNormality Classification Algorithm - BIANCA) on detecting ischemic stroke lesions of follow-up imaging on patients with acute ischemic stroke. Methods: Patients were retrospectively selected from a prospectively acquired mechanical thrombectomy (MT) database from January to July 2019, and were included if they had a follow-up magnetic resonance imaging DWI within 72h from procedure available. Masks were generated on B1000 imaging by clinical research stroke personnel and then compared with volumes delineated by a fully automated supervised method for lesion detection, based on a k-nearest neighbor (k-NN) algorithm. Results: Seventy patients were included. Human FIV measurements mean was comparable with BIANCA [67.7±73.2 vs 71.8±67 (p Conclusion: The automated masking pipeline measurement showed to behighlysimilar to a standardized protocol of FIV estimation at a busy neuroendovascular center and could be used in trials with large numbers of patients.

Introduction: We aimed to compare the perfusion parametric maps and the determination of predicted ischemic core between three automated CT perfusion software packages: RAPID (IschemaView), Viz CTP (Viz.ai) and e-Mismatch (Brainomix). Methods: Retrospectively review of a prospective database spanning September 2018-November 2019 with the following inclusion criteria: 1) acute large vessel occlusion strokes (LVOS) involving the intracranial internal carotid artery or proximal middle cerebral artery (M1 segment), 2) available CTP images, 3) final complete/near-complete endovascular reperfusion (eTICI2c-3) and 4) follow-up imaging with final infarct volume (FIV) assessment. Results: A total of 242 cases were included. There was a strong correlation for rCBFs =0.844, ps =0.833, p6s were observed between RAPID and Viz CTP (r s =0.892, ps =0.752, ps =0.637, ps =0.601, ps =0.605, p10ml within 6 hours from stroke onset) was identified in 10 (15.9%) RAPID, 15 (23.8%) Viz CTP and 3 (4.7%) e-Mismatch cases. Conclusion: The key CTP parameters for the RAPID, Viz CTP and e-Mismatch packages strongly correlate. CTP predictability of final infarct volume remains moderate and requires further evaluation.

Background and Purpose: The e-Stroke Suite software (Brainomix, Oxford, United Kingdom) is a tool designed for the automated quantification of The Alberta Stroke Program Early CT Score and ischemic core volumes on noncontrast computed tomography (NCCT). We sought to compare the prediction of postreperfusion infarct volumes and the clinical outcomes across NCCT e-Stroke software versus RAPID (IschemaView, Menlo Park, CA) computed tomography perfusion measurements. Methods: All consecutive patients with anterior circulation large vessel occlusion stroke presenting at a tertiary care center between September 2010 and November 2018 who had available baseline infarct volumes on both NCCT e-Stroke Suite software and RAPID CTP as well as final infarct volume (FIV) measurements and achieved complete reperfusion (modified Thrombolysis in Cerebral Infarction scale 2c-3) post-thrombectomy were included. The associations between estimated baseline ischemic core volumes and FIV as well as 90-day functional outcomes were assessed. Results: Four hundred seventy-nine patients met inclusion criteria. Median age was 64 years (55–75), median e-Stroke and computed tomography perfusion ischemic core volumes were 38.4 (21.8–58) and 5 (0–17.7) mL, respectively, whereas median FIV was 22.2 (9.1–56.2) mL. The correlation between e-Stroke and CTP ischemic core volumes was moderate (R=0.44; P P P 6 hours) treatment windows. Multivariate analysis showed that both e-Stroke software NCCT baseline ischemic core volume (adjusted odds ratio, 0.98 [95% CI, 0.97–0.99]) and RAPID CTP ischemic core volume (adjusted odds ratio, 0.98 [95% CI, 0.97–0.99]) were independently and comparably associated with good outcome (modified Rankin Scale score of 0–2) at 90 days. Conclusions: NCCT e-Stroke Suite software performed similarly to RAPID CTP in assessing postreperfusion FIV and functional outcomes for both early- and late-presenting patients. NCCT e-Stroke volumes seems to represent a viable alternative in centers where access to advanced imaging is limited. Moreover, the future development of fusion maps of NCCT and CTP ischemic core estimates may improve upon the current performance of these tools as applied in isolation.

Nature-inspired, bridged polycyclic molecules share low similarity with currently available drugs, containing preferentially planar and/or achiral moieties. This "Escape from Flatland" scenario, aimed at exploring pharmacological properties of atypical molecular scaffolds, finds interest in synthetic routes leading to tridimensional-shaped molecules. Herein we report on the synthesis of

Thirty-six novel indole-containing compounds, mainly 3-(2-phenylhydrazono) isatins and structurally related 1H-indole-3-carbaldehyde derivatives, were synthesized and assayed as inhibitors of beta amyloid (A&beta, ) aggregation, a hallmark of pathophysiology of Alzheimer&rsquo, s disease. The newly synthesized molecules spanned their IC50 values from sub- to two-digit micromolar range, bearing further information into structure-activity relationships. Some of the new compounds showed interesting multitarget activity, by inhibiting monoamine oxidases A and B. A cell-based assay in tau overexpressing bacterial cells disclosed a promising additional activity of some derivatives against tau aggregation. The accumulated data of either about ninety published and thirty-six newly synthesized molecules were used to generate a pharmacophore hypothesis of antiamyloidogenic activity exerted in a wide range of potencies, satisfactorily discriminating the &lsquo, active&rsquo, compounds from the &lsquo, inactive&rsquo, (poorly active) ones. An atom-based 3D-QSAR model was also derived for about 80% of &lsquo, compounds, i.e., those achieving finite IC50 values lower than 100 &mu, M. The 3D-QSAR model (encompassing 4 PLS factors), featuring acceptable predictive statistics either in the training set (n = 45, q2 = 0.596) and in the external test set (n = 14, r2ext = 0.695), usefully complemented the pharmacophore model by identifying the physicochemical features mainly correlated with the A&beta, anti-aggregating potency of the indole and isatin derivatives studied herein.

Background and purpose The baseline characteristics of patients with symptomatic carotid web (CaW) are unclear. We investigate demographic and cerebrovascular risk factors in patients with this overlooked stroke etiology. Methods We identified consecutive patients diagnosed with symptomatic CaW at a comprehensive stroke center from July 2014-December 2018. These patients were matched at a 1:4 ratio (based on age and NIHSS scores) to create a control group of acute ischemic stroke (AIS) patients with non-CaW etiologies from the local GetWithTheGuidelines stroke database. Results Thirty patients with symptomatic CaW were compared to 120 AIS patients with non-CaW etiologies. Symptomatic CaW patients were more likely to be female (73.3 vs. 44.2%; p = 0.004) and black (86.7 vs. 64.2%; p = 0.02). Symptomatic CaWs patients had a fewer absolute number of modifiable cerebrovascular risk factors (1.7±1.1 vs. 2.5±1.2; p = 0.002), lower rates of hypertension (43.4 vs. 63.3%; p = 0.04), and a more favorable lipid profile with lower average LDL (89.5±30.3 vs. 111.2±43.7 mg/dL; p = 0.01) and higher average HDL (47.9±11.3 vs. 42.2±13.8 mg/dL; p = 0.01) as compared to strokes with non-CaW etiology. Symptomatic CaW patients were more likely to have a large vessel occlusion (80.0 vs. 51.7%; p = 0.005), despite similar e-ASPECTS between the groups (8.1±2.1 vs. 8.3±2.2; p = 0.30). On multivariable analysis, symptomatic CaW was an independent predictor of independence at discharge (OR 3.72; 95%CI 1.27–10.94). Conclusion A gender and racial predilection of symptomatic CaWs may exist as females and blacks were were found to be more likely affected. Symptomatic CaW patients have a more benign cerebrovascular risk factor profile corroborating the proposed mechanism of local stasis and thromboembolism. Despite presenting more commonly with LVO, symptomatic CaW was associated with good functional outcome, warranting further studies.