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Current methods for quantitative assessment of cerebral small vessel disease (CSVD) ignore critical aspects of the disease, namely lesion type and regionality. We developed and tested a new scoring system for CSVD, "regional Cerebral Small Vessel Disease" (rCSVD) based on regional assessment of magnetic resonance imaging (MRI) features.141 patients were retrospectively included with a derivation cohort of 46 consecutive brain MRI exams and a validation cohort of 95 patients with known cerebrovascular disease. We compared the predictive value of rCSVD against existing scoring methods. We determined the predictive value of rCSVD score for all-cause mortality and recurrent strokes.46 (44 male) veteran patients (age: 66-93 years), were included for derivation of the rCSVD score. A non-overlapping validation cohort consisted of 95 patients (89 male; age: 34-91 years) with known cerebrovascular disease were enrolled. Based on ROC analysis with comparison of AUC (Area Under the Curve), "rCSVD" score performed better compared to "total SVD score" and Fazekas score for predicting all-cause mortality (0.75 vs 0.68 vs 0.69; p = 0.046). "rCSVD" and total SVD scores were predictive of recurrent strokes in our validation cohort (p-values 0.004 and 0.001). At a median of 5.1 years (range 2-17 years) follow-up, Kaplan-Meier survival analysis demonstrated an rCSVD score of 2 to be a significant predictor of all-cause-mortality."rCSVD" score can be derived from routine brain MRI, has value in risk stratification of patients at risk of CSVD, and has potential in clinical trials once fully validated in a larger patient cohort.

Inflammation and its myriad pathways are now recognized to play both causal and consequential roles in vascular brain health. From acting as a trigger for vascular brain injury, as evidenced by the COVID-19 pandemic, to steadily increasing the risk for chronic cerebrovascular disease, distinct inflammatory cascades play differential roles in varying states of cerebrovascular injury. New evidence is regularly emerging that characterizes the role of specific inflammatory pathways in these varying states including those at risk for stroke and chronic cerebrovascular injury as well as during the acute, subacute, and repair phases of stroke. Here, we aim to highlight recent basic science and clinical evidence for many distinct inflammatory cascades active in these varying states of cerebrovascular injury. The role of cerebrovascular infections, spotlighted by the severe acute respiratory syndrome coronavirus 2 pandemic, and its association with increased stroke risk is also reviewed. Rather than converging on a shared mechanism, these emerging studies implicate varied and distinct inflammatory processes in vascular brain injury and repair. Recognition of the phasic nature of inflammatory cascades on varying states of cerebrovascular disease is likely essential to the development and implementation of an anti-inflammatory strategy in the prevention, treatment, and repair of vascular brain injury. Although advances in revascularization have taught us that time is brain, targeting inflammation for the treatment of cerebrovascular disease will undoubtedly show us that timing is brain.

Introduction: In 2012, after SAMMPRIS demonstrated worse 30-day outcomes with Wingspan intracranial stent placement for intracranial atherosclerotic disease (ICAD), the FDA narrowed the “on-label” indication to a very specific subset of patients with symptomatic ICAD. The updated criteria require a prior stroke in the territory of the symptomatic vessel based on clinical history. Limitations in the accuracy of diagnosis of clinical stroke may be overcome with the use of MRI to identify any prior stroke - whether clinical or subclinical - which could expand the number of patients who are eligible for stenting. Methods: This was a retrospective analysis of consecutive cases of acute ischemic stroke attributable to ICAD with 50-99% stenosis in the symptomatic vessel from July 2019 - June 2022. MRI FLAIR sequences were reviewed for imaging evidence of prior infarction in the vascular territory of the symptomatic vessel. Subgroup analysis was performed based on stroke location, infarct pattern, degree of stenosis, and premorbid medication use. Results: 73 patients met inclusion criteria. Mean age was 72, and 41% were women. 37 patients (51%) exhibited MRI evidence of prior stroke in the same vascular territory. Of these, only 18/37 (49%) reported a prior clinical stroke. The frequency of prior stroke on MRI was similar with anterior (51%) and posterior (50%) circulation ICAD. Frequency of prior stroke based on infarct pattern was 64% for border zone infarction, 42% for thromboembolism, and 55% for branch atheromatous disease. Of the 31 patients who had degree of stenosis quantified on DSA, the frequency of prior infarction was 63% in patients with 70-99% stenosis versus 48% in those with Conclusions: In patients presenting with acute stroke due to symptomatic ICAD, half exhibit MRI evidence of a prior stroke in the symptomatic arterial territory, and half of these prior strokes are not reported from clinical history. Routine MRI can be a valuable tool to identify prior stroke in the symptomatic territory, which may in turn expand therapeutic options for ICAD.

INTRODUCTION Lowering blood pressure (BP) reduces the risk for cognitive impairment and the progression of cerebral white matter lesions. It is unclear whether hypertension control also influences plasma biomarkers related to Alzheimer's disease and non-disease-specific neurodegeneration. METHODS We examined the effect of intensive (

Glioma stem cells (GSC) exhibit plasticity in response to environmental and therapeutic stress leading to tumor recurrence, but the underlying mechanisms remain largely unknown. Here, we employ single-cell and whole transcriptomic analyses to uncover that radiation induces a dynamic shift in functional states of glioma cells allowing for acquisition of vascular endothelial-like and pericyte-like cell phenotypes. These vascular-like cells provide trophic support to promote proliferation of tumor cells, and their selective depletion results in reduced tumor growth post-treatment in vivo. Mechanistically, the acquisition of vascular-like phenotype is driven by increased chromatin accessibility and H3K27 acetylation in specific vascular genes allowing for their increased expression post-treatment. Blocking P300 histone acetyltransferase activity reverses the epigenetic changes induced by radiation and inhibits the adaptive conversion of GSC into vascular-like cells and tumor growth. Our findings highlight a role for P300 in radiation-induced stress response, suggesting a therapeutic approach to prevent glioma recurrence.

Many neuroprotective and other therapies for treatment of acute ischemic stroke have failed in translation to human studies, indicating a need for more rigorous, multidimensional quality assessment of the totality of preclinical evidence supporting a therapy prior to conducting human trials. A consensus panel of stroke preclinical model and human clinical trial experts assessed candidate items for the translational readiness scale, compiled from prior instruments (STAIR, ARRIVE, CAMARADES, RoB 2) based on importance, reliability, and feasibility. Once constructed, the tool was applied by two independent raters to four current candidate acute stroke therapies, including two pharmacologic agents [nerinetide and trans-sodium crocetinate] and two device interventions [cathodal transcranial direct current stimulation and fastigial nucleus stimulation]. The Preclinical evidence of Readiness In stroke Models Evaluating Drugs and Devices (PRIMED2) assessment tool rates the totality of evidence available from all reported preclinical animal stroke model studies in 11 domains related to diversity of tested animals, time windows, feasibility of agent route of delivery, and robustness of effect magnitude. Within each content domain, clearly operationalized rules assign strength of evidence ratings of 0–2. When applied to the four assessed candidate agents, inter-rater reliability was high (kappa = 0.88), and each agent showed a unique profile of evidentiary strengths and weaknesses. The PRIMED2 assessment tool provides a multidimensional assessment of the cumulative preclinical evidence for a candidate acute stroke therapy on factors judged important for successful basic-to-clinical translation. Further evaluation and refinement of this tool is desirable to improve successful translation of therapies for acute stroke.

Perfusion imaging can risk stratify patients with symptomatic intracranial stenosis. We aim to determine the association between perfusion delay and length of hospital stay (LOS) in symptomatic middle cerebral artery (MCA) stenosis patients.This is a retrospective study of consecutive patients admitted to a comprehensive stroke center over 5 years with ischemic stroke or transient ischemic attack (TIA) within 7 days of symptom onset due to MCA stenosis (50-99%) and underwent perfusion imaging. Patients were divided into three groups: mismatch volume ≥ 15 cc based on T max6 second delay, T max 4-6 second delay, and4 second delay. The outcome was LOS, both as a continuous variable and categorical (≥7 days [prolonged LOS] vs.7 days). We used adjusted regression analyses to determine the association between perfusion categories and LOS.One hundred and seventy eight of 194 patients met the inclusion criteria. After adjusting for age and NIHSS, T max6 second mismatch was associated with prolonged LOS (OR 2.94 95% CI 1.06-8.18; P = .039), but T max 4-6 second was not (OR 1.45 95% CI .46-4.58, P = .528). We found similar associations when LOS was a continuous variable for T max6 second (β coefficient = 2.01, 95% CI .05-3.97, P = .044) and T max 4-6 second (β coefficient = 1.24, 95% CI -.85 to 3.34, P = .244).In patients with symptomatic MCA stenosis, T max6 second perfusion delay is associated with prolonged LOS. Prospective studies are needed to validate our findings.

Background and Purpose: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is associated with an increased rate of cerebrovascular events including ischemic stroke and intracerebral hemorrhage. The mechanisms underlying cerebral endothelial susceptibility and response to SARS-CoV-2 are unknown yet critical to understanding the association of SARS-CoV-2 infection with cerebrovascular events. Methods: Endothelial cells were isolated from human brain and analyzed by RNA sequencing. Human umbilical vein and human brain microvascular cells were used in both monolayer culture and endothelialized within a 3-dimensional printed vascular model of the middle cerebral artery. Gene expression levels were measured by quantitative polymerase chain reaction and direct RNA hybridization. Recombinant SARS-CoV-2 S protein and S protein–containing liposomes were used to measure endothelial binding by immunocytochemistry. Results: ACE2 (angiotensin-converting enzyme-2) mRNA levels were low in human brain and monolayer endothelial cell culture. Within the 3-dimensional printed vascular model, ACE2 gene expression and protein levels were progressively increased by vessel size and flow rates. SARS-CoV-2 S protein–containing liposomes were detected in human umbilical vein endothelial cells and human brain microvascular endothelial cells in 3-dimensional middle cerebral artery models but not in monolayer culture consistent with flow dependency of ACE2 expression. Binding of SARS-CoV-2 S protein triggered 83 unique genes in human brain endothelial cells including upregulation of complement component C3. Conclusions: Brain endothelial cells are susceptible to direct SARS-CoV-2 infection through flow-dependent expression of ACE2. Viral S protein binding triggers a unique gene expression profile in brain endothelia that may explain the association of SARS-CoV-2 infection with cerebrovascular events.

Oligodendrocytes exist in a heterogenous state and are implicated in multiple neuropsychiatric diseases including dementia. Cortical oligodendrocytes are a glial population uniquely positioned to play a key role in neurodegeneration by synchronizing circuit connectivity but molecular pathways specific to this role are lacking. We utilized oligodendrocyte-specific translating ribosome affinity purification and RNA-seq (TRAP-seq) to transcriptionally profile adult mature oligodendrocytes from different regions of the central nervous system. Weighted gene co-expression network analysis reveals distinct region-specific gene networks. Two of these mature myelinating oligodendrocyte gene networks uniquely define cortical oligodendrocytes and differentially regulate cortical myelination (M8) and synaptic signaling (M4). These two cortical oligodendrocyte gene networks are enriched for genes associated with dementia including MAPT and include multiple gene targets of the regulatory microRNA, miR-142-3p. Using a combination of TRAP-qPCR, miR-142-3p overexpression in vitro, and miR-142-null mice, we show that miR-142-3p negatively regulates cortical myelination. In rTg4510 tau-overexpressing mice, cortical myelination is compromised, and tau-mediated neurodegeneration is associated with gene co-expression networks that recapitulate both the M8 and M4 cortical oligodendrocyte gene networks identified from normal cortex. We further demonstrate overlapping gene networks in mature oligodendrocytes present in normal cortex, rTg4510 and miR-142-null mice, and existing datasets from human tauopathies to provide evidence for a critical role of miR-142-3p-regulated cortical myelination and oligodendrocyte-mediated synaptic signaling in neurodegeneration.

BackgroundTargeted eloquence-based tissue reperfusion within the primary motor cortex may have a differential effect on disability as compared with traditional volume-based (thrombolysis in cerebral infarction, TICI) reperfusion after endovascular thrombectomy (EVT) in the setting of acute ischemic stroke (AIS).MethodsWe explored the impact of eloquent reperfusion (ER) within primary motor cortex (PMC) on clinical outcome (modified Rankin Scale, mRS) in AIS patients undergoing EVT. ER-PMC was defined as presence of flow on final digital subtraction angiography (DSA) within four main cortical branches, supplying the PMC (middle cerebral artery (MCA) – precentral, central, postcentral; anterior cerebral artery (ACA) – medial frontal branch arising from callosomarginal or pericallosal arteries) and graded as absent (0), partial (1), and complete (2). Prospectively collected data from two centers were analyzed. Multivariate analysis was conducted to assess the impact of ER-PMC on 90-day disability (mRS) among patients with anterior circulation occlusion who achieved partial reperfusion (TICI 2a and 2b).ResultsAmong the 125 patients who met the study criteria, ER-PMC distribution was: absent (0) in 19/125 (15.2%); partial (1) in 52/125 (41.6%), and complete (2) in 54/125 (43.2%). TICI 2b was achieved in 102/125 (81.6%) and ER-PMC was substantially higher in those patients (PConclusionsEloquent PMC-tissue reperfusion is a key determinant of functional outcome, with a greater impact than volume-based (TICI) degree of partial reperfusion alone. PMC-targeted revascularization among patients with partial reperfusion may further diminish post-stroke disability after EVT.

Background Intracranial atherosclerotic disease (ICAD) is one of the most challenging stroke etiologies, with frequent recurrences despite optimized medical management. Encephaloduroarteriosynangiosis (EDAS) is an indirect revascularization method that produces extra-cranial collaterals to intracranial vessels. We present the results of a phase-II trial of EDAS in intracranial atherosclerotic disease patients. Aims To evaluate the feasibility, safety, and preliminary efficacy of EDAS in intracranial atherosclerotic disease patients. Methods ERSIAS was a prospective objective-performance-criterion trial of EDAS plus intensive medical management (IMM) in intracranial atherosclerotic disease (ICAD) patients failing medical treatment. Primary endpoint was any stroke/death within 30-days post-surgery or stroke in the territory of the qualifying artery beyond 30 days. The primary analysis compared event rates through one year with an objective-performance-criterion based on a 10% reduction from the 20% rate in the intensive medical management arm of the stenting versus aggressive medical management for preventing recurrent stroke in intracranial stenosis trial (SAMMPRIS) in patients with poor collaterals. Event rates through two years were compared with propensity-score-matched (PSM) medically treated patients from SAMMPRIS and the carotid occlusion surgery study (COSS). Results During a median follow-up of 24.5 months, 5 (9.6%) of 52 patients had a primary endpoint event. The primary endpoint rate at one year met the threshold for nonfutility and advancement to phase III (Conclusion ERSIAS phase II provides evidence of safety and strong signals of efficacy of EDAS-plus-intensive medical management, supporting advancement to a seamless phase-IIb/III trial. Clinical Trial Registration URL: https://www.clinicaltrials.gov.NCT01819597 .

Poststroke cognitive impairment and dementia (PSCID) is a major source of morbidity and mortality after stroke worldwide. PSCID occurs as a consequence of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. Cognitive impairment and dementia manifesting after a clinical stroke is categorized as vascular even in people with comorbid neurodegenerative pathology, which is common in elderly individuals and can contribute to the clinical expression of PSCID. Manifestations of cerebral small vessel disease, such as covert brain infarcts, white matter lesions, microbleeds, and cortical microinfarcts, are also common in patients with stroke and likewise contribute to cognitive outcomes. Although studies of PSCID historically varied in the approach to timing and methods of diagnosis, most of them demonstrate that older age, lower educational status, socioeconomic disparities, premorbid cognitive or functional decline, life-course exposure to vascular risk factors, and a history of prior stroke increase risk of PSCID. Stroke characteristics, in particular stroke severity, lesion volume, lesion location, multiplicity and recurrence, also influence PSCID risk. Understanding the complex interaction between an acute stroke event and preexisting brain pathology remains a priority and will be critical for developing strategies for personalized prediction, prevention, targeted interventions, and rehabilitation. Current challenges in the field relate to a lack of harmonization of definition and classification of PSCID, timing of diagnosis, approaches to neurocognitive assessment, and duration of follow-up after stroke. However, evolving knowledge on pathophysiology, neuroimaging, and biomarkers offers potential for clinical applications and may inform clinical trials. Preventing stroke and PSCID remains a cornerstone of any strategy to achieve optimal brain health. We summarize recent developments in the field and discuss future directions closing with a call for action to systematically include cognitive outcome assessment into any clinical studies of poststroke outcome.

Introduction: The real-world evolution of management and outcomes of patients with unruptured cerebral arteriovenous malformations (AVMs) has not been well-delineated following the ARUBA trial findings of no general advantage of initial interventional (surgical/endovascular/radiotherapy) vs initial conservative medical therapy. Methods: We analyzed from 2009-2018 the National Inpatient Sample of all AVM admissions in the United States. Analyses were performed by year and for the dichotomized periods of pre-ARUBA (2009-2013) vs. post-ARUBA (2014-2018). Joinpoint regression models with permutation model selection delineated yearly trends in intervention rate in uAVMs. Results: Among a total of 72,812 uAVMs, 35,420 were in the post-ARUBA and 37,392 in the pre-ARUBA period. Median age was 53.3 in post-ARUBA vs. 51.8 in the pre-ARUBA period (p=0.001) with no difference in female sex, 51.1% vs. 51.8% (p=0.44). The intervention rate was lower in the post- vs -pre-ARUBA period, 29.6% vs. 34.0% (p=0.006) (figure). Interventional rate decreased monotonically by -4.32% in the post-ARUBA period (figure). Among the post-ARUBA AVM patients, compared with pre-ARUBA, there were no differences in odds of in-hospital ischemic stroke [OR 1.05 (0.92-1.20), p=0.45] or in-hospital mortality [OR 0.88 (0.62-1.24), p=0.47] but the odds did increase for combined discharge to a facility or in-hospital mortality [OR 1.14 (1.02-1.28), p=0.020]. In addition, the frequency of admissions for ruptured AVMs accelerated in the post-ARUBA period (figure). Conclusion: Nationwide practice in management of unruptured AVMs changed substantially with the publication of the ARUBA trial, in a durable and increasing manner. Fewer admissions with interventional treatment of unruptured AVMs occurred and a corresponding increase in admission for ruptured AVMs transpired, as expected with a strategy of watchful waiting and treatment only after an index bleeding event.

BACKGROUND AND PURPOSE: Acute leptomeningeal collateral flow is vital for maintaining perfusion to penumbral tissue in acute ischemic stroke caused by large-vessel occlusion. In this study, we aimed to investigate the clinically available indicators of leptomeningeal collateral variability in embolic large-vessel occlusion. MATERIALS AND METHODS: Among prospectively registered consecutive patients with acute embolic anterior circulation large-vessel occlusion treated with thrombectomy, we analyzed 108 patients admitted from January 2015 to December 2019 who underwent evaluation of leptomeningeal collateral status on pretreatment CTA. Clinical characteristics, extent of leukoaraiosis on MR imaging, embolic stroke subtype, time of imaging, occlusive thrombus characteristics, presenting stroke severity, and clinical outcome were collected. The clinical indicators of good collateral status (>50% collateral filling of the occluded territory) were analyzed using multivariate logistic regression analysis. RESULTS: Good collateral status was present in 67 patients (62%) and associated with independent functional outcomes at 3 months. Reduced leukoaraiosis (total Fazekas score, 0–2) was positively related to good collateral status (OR, 9.57; 95% CI, 2.49–47.75), while the cardioembolic stroke mechanism was inversely related to good collateral status (OR, 0.17; 95% CI, 0.02–0.87). In 82 patients with cardioembolic stroke, shorter thrombus length (OR, 0.91 per millimeter increase; 95% CI, 0.82–0.99) and reduced leukoaraiosis (OR, 5.79; 95% CI, 1.40–29.61) were independently related to good collateral status. CONCLUSIONS: Among patients with embolic large-vessel occlusion, reduced leukoaraiosis, noncardiac embolism mechanisms including embolisms of arterial or undetermined origin, and shorter thrombus length in cardioembolism are indicators of good collateral flow.

Background The potential heterogeneity in occlusive thrombi caused by in situ propagation by secondary thrombosis after embolic occlusion could obscure the characteristics of original thrombi, preventing the clarification of a specific thrombus signature for the etiology of ischemic stroke. We aimed to investigate the heterogeneity of occlusive thrombi by pretreatment imaging. Methods Among consecutive stroke patients with acute embolic anterior circulation large vessel occlusion treated with thrombectomy, we retrospectively reviewed 104 patients with visible occlusive thrombi on pretreatment non-contrast computed tomography admitted from January 2015 to December 2018. A region of interest was set on the whole thrombus on non-contrast computed tomography under the guidance of computed tomography angiography. The region of interest was divided equally into the proximal and distal segments and the difference in Hounsfield unit densities between the two segments was calculated. Results Hounsfield unit density in the proximal segment was higher than that in the distal segment (mean difference 4.45; p Conclusions The difference in density between the proximal and distal segments increased as thrombi became longer and decreased as thrombi became older after embolic occlusion. This time/length-dependent thrombus heterogeneity between the two segments is suggestive of secondary thrombosis initially occurring on the proximal side of the occlusion.

We test the hypothesis that endothelial cells adopt an inflammatory phenotype in functionally intact aged human subjects with radiographic evidence of white matter hyperintensity (WMH) suggestive of small cerebrovascular disease. Components of all three complement effector pathways and regulatory proteins were quantified in extracts of plasma endothelial-derived exosomes (EDE) of 11 subjects (age 70–82) with and 15 without evidence of WMH on MRI. Group differences and associations with plasma markers of immune activation (IL6, ICAM1), cognition and neuroimaging were calculated via regression modelling. EDE complement factors within the alternative and classical pathways were found to be higher and regulatory proteins lower in subjects with WMH. EDE levels of some complement components demonstrated significant associations with cognitive slowing and elevated systolic blood pressure. The inhibitor of the membrane attack complex, CD46, showed a significant positive association with cerebral grey matter volume. Plasma inflammatory markers, IL6 and ICAM1, were positively associated with EDE levels of several complement components. These findings provide the first in vivo evidence of the association of endothelial cell inflammation with white matter disease, age-associated cognitive changes, and brain degeneration in functionally normal older individuals. Future endothelial biomarker development may permit recognition of early or preclinical stages of vascular contributions to cognitive impairment and dementia.

Treatment-refractory glioma stem and tumor cells exhibit phenotypic plasticity driving recurrence, but the underlying molecular mechanisms remain to be elucidated. Here, we employed single-cell and whole transcriptomic analyses to discover that radiation induces a dynamic shift in functional states of glioma cells allowing for acquisition of vascular endothelial-like and pericyte-like cell phenotypes. These vascular-like cells provide a trophic niche to promote proliferation of irradiated glioma cells, and their selective depletion results in reduced tumor growth post-treatment in vivo. Mechanistically, the acquisition of vascular-like phenotype is driven by increased chromatin accessibility and H3K27 acetylation in specific vascular gene regions post-treatment. Blocking P300 histone acetyltransferase activity reverses the epigenetic changes induced by radiation, and inhibits the phenotypic transition and tumor growth. Our findings highlight an important role for P300 histone acetyltransferase in treatment-induced plasticity and opens a new therapeutic avenue for preventing glioma recurrence.SignificanceOur study demonstrates that radiation therapy promotes glioma resistance by inducing vascular-like phenotypes in GSC that, in turn, aid in proliferation of the remaining tumor cells. This phenotype switch is mediated by P300 HAT, and inhibition of this enzyme is a potential therapeutic target for preventing glioma recurrence following radiation.

Cerebrovascular events have emerged as a central feature of the clinical syndrome associated with Sars-CoV-2 infection. This increase in infection-related strokes is marked by atypical presentations including stroke in younger patients and a high rate of hemorrhagic transformation after ischemia. A variety of pathogenic mechanisms may underlie this connection. Efforts to identify synergism in the pathophysiology underlying stroke and Sars-CoV-2 infection can inform the understanding of both conditions in novel ways. In this review, the molecular cascades connected to Sars-CoV-2 infection are placed in the context of the cerebral vasculature and in relationship to pathways known to be associated with stroke. Cytokine-mediated promotion of systemic hypercoagulability is suggested while direct Sars-CoV-2 infection of cerebral endothelial cells may also contribute. Endotheliopathy resulting from direct Sars-CoV-2 infection of the cerebral vasculature can modulate ACE2/AT1R/MasR signaling pathways, trigger direct viral activation of the complement cascade, and activate feed-forward cytokine cascades that impact the blood-brain barrier. All of these pathways are already implicated as independent mechanisms driving stroke and cerebrovascular injury irrespective of Sars-CoV-2. Recognizing the overlap of molecular pathways triggered by Sars-CoV-2 infection with those implicated in the pathogenesis of stroke provides an opportunity to identify future therapeutics targeting both Sars-CoV-2 and stroke thereby reducing the impact of the global pandemic.

Background and purpose In symptomatic intracranial atherosclerotic stenosis (ICAS), borderzone infarct pattern and perfusion mismatch are associated with increased risk of recurrent strokes, which may reflect the shared underlying mechanism of hypoperfusion distal to the intracranial atherosclerosis. Accordingly, we hypothesized a correlation between hypoperfusion volumes and ICAS infarct patterns based on the respective underlying mechanistic subtypes. Methods We conducted a retrospective analysis of consecutive symptomatic ICAS cases, acute strokes due to subocclusive (50%-99%) intracranial stenosis. The following mechanistic subtypes were assigned based on the infarct pattern on the diffusion-weighted imaging: Branch occlusive disease (BOD), internal borderzone (IBZ), and thromboembolic (TE). Perfusion parameters, obtained concurrently with the MRI, were studied in each group. Results A total of 42 patients (57% women, mean age 71 ± 13 years old) with symptomatic ICAS received MRI within 24 h of acute presentation. Fourteen IBZ, 11 BOD, and 17 TE patterns were identified. IBZ pattern yielded higher total Tmax > 4 s and Tmax > 6 s perfusion delay volumes, as well as corresponding Tmax > 4 s and Tmax > 6 s mismatch volume, compared to BOD. TE pattern exhibited greater median Tmax > 6 s hypoperfusion delay in volume compared to BOD. In IBZ versus TE, the volume difference between Tmax > 4 s and Tmax > 6 s (Δ Tmax > 4 s - Tmax > 6 s) was substantially greater. Conclusion ICAS infarct patterns, in keeping with their respective underlying mechanisms, may correlate with distinct perfusion profiles.

Background: Perfusion imaging is increasingly used to risk stratify patients with symptomatic intracranial stenosis. Length of hospital stay (LOS) in patients with ischemic stroke is a surrogate marker of increased morbidity. We aim to determine the association between perfusion delay on T max (< 4 sec, 4-6 sec, and > 6 sec) on perfusion weighted imaging and LOS in patients with symptomatic middle cerebral artery (MCA) stenosis. Methods: We included consecutive patients with left MCA stenosis admitted with ischemic stroke or TIA 6 sec delay, mismatch volume ≥ 15 mL based on T max 4-6 sec delay, and neither of the above mismatch patterns. The primary outcome was LOS, both as a continuous variable and categorical (≥ 7 days (prolonged LOS) vs. Results: 179 out of 194 patients met the inclusion criteria; mean age was 70.2 ± 15.4 years, 53.1% were women, median (IQR) NIHSS was 4 (1-9); 83.2% underwent MR perfusion; 38.5% had a mismatch volume ≥ 15 mL based on T max > 6 sec and 31.3% had a mismatch volume ≥ 15 mL based on T max 4-6 sec and the median (IQR) LOS was 4 days (2-8). After adjusting for age and NIHSS, T max > 6 sec mismatch definition was associated with prolonged LOS (OR 2.90 95% CI 1.06-8.18; p=0.039) but T max 4-6 sec definition was not (OR 1.45 95% CI 0.46-4.58, p=0.528), without any interaction based on perfusion imaging modality (p interaction = 0.568). We found similar associations when LOS was considered as a continuous variable for T max > 6 sec (β coefficient=2.01, 95% CI 0.05-3.97, p=0.044) and T max 4-6 sec (β coefficient=1.24, 95% CI -0.85-3.34, p=0.244). In receiver operating curves, the optimal mismatch volume for T max > 6 sec was 10 mL (sensitivity 0.61 and specificity 0.63) whereas for T max 4-6 sec it was 39 mL (sensitivity 0.61 specificity 0.56). Conclusion: In patients with recently symptomatic MCA stenosis, the T max > 6 sec definition for mismatch, but not T max 4-6 sec, is associated with prolonged LOS. Prospective studies are needed to validate our findings and define the optimal mismatch threshold in patients with symptomatic MCA stenosis.

Background and Purpose: Acute leptomeningeal collateral flow is vital to maintain blood perfusion to penumbral tissue in acute ischemic stroke due to large vessel occlusion (LVO). However, the degree of this collateral flow differs among patients. Patient premorbid factors as well as factors caused by the mechanisms of stroke are expected to be associated with this collateral flow. We aimed to investigate the clinical determinants of acute leptomeningeal collateral flow in embolic LVO. Methods: Among consecutive stroke patients caused by acute embolic anterior circulation LVO, we retrospectively reviewed 108 patients who underwent evaluation of acute leptomeningeal collateral status (CS) on pretreatment CTA admitted from January 2015 to December 2019. Both premorbid information including cerebrovascular risk factors and leukoaraiosis evaluated by the total white matter (WM) Fazekas score on MRI, which was calculated as periventricular plus deep WM scores, and stroke related information including stroke subtypes, severity, time course, and occlusive thrombus characteristics were collected. Among thrombus characteristics, thrombus length was measured by tracing the filling defect of contrast on CTA. The clinical determinants of good leptomeningeal CS (> 50% collateral filling of the occluded territory) were analyzed. Results: CS was good in 67 patients (62%). On multivariate logistic regression analysis, cardioembolic stroke subtype was negatively related (OR, 0.170; 95% CI, 0.022-0.868), and mild leukoaraiosis (total WM Fazekas scores of 0-2) was positively related (OR, 9.57; 95% CI, 2.49-47.75) to good CS. On subgroup analysis limited to 82 patients with cardioembolic stroke, shorter thrombus length (OR, 0.913 per mm increase; 95% CI, 0.819-0.999) as well as mild leukoaraiosis (OR, 5.79; 95% CI, 1.40-29.61) were independently related to good CS. Conclusions: Premorbid leukoaraiosis and cardioembolic etiology are determinants of acute leptomeningeal collateral flow in embolic LVO. In addition, thrombus length is also a determinant of collateral flow in cardioembolic LVO. These findings indicate that a combination of chronic cerebrovascular damage and acute embolic mechanisms could determine the degree of leptomeningeal collateral flow.

Background and Purpose: Accurate estimation of ischemic core on baseline imaging has treatment implications in patients with acute ischemic stroke (AIS). Machine learning (ML) algorithms have shown promising results in estimating ischemic core using routine non-contrast CT (NCCT). We used a ML-trained algorithm to quantify ischemic core volume on NCCT and compared the results to concurrent diffusion MRI as the reference standard in patients with AIS. Methods: We analyzed consecutive anterior circulation AIS patients who had baseline (pretreatment) NCCT and MRI (DWI). Ischemic lesion volume was calculated on MRI-DWI using an automated software (Olea Medical SAS, La Ciotat, France). An automatic segmentation approach using a combination of traditional 3D graphics and statistical methods, and ML classification techniques (Brainomix, Oxford, United Kingdom) was used to identify ischemic core voxels on NCCT. Total ischemic core volumes on ML-NCCT and DWI-MR were quantitatively compared by Bland-Altman plots and Pearson correlation. Results: A total of 50 patients (27 female, 23 male, mean age 72.6 years) were included. Baseline imaging was performed within 173 ± 143 minutes (mean ± SD) from symptom onset. The mean time difference between MRI and NCCT was 72 min. The baseline NIHSS was 14, 8-21 (Median, IQR). Algorithm-segmented ischemic core volume detected on NCCT was median 12.7 mL, IQR 3.5-26.0 mL. Ischemic core volume on DWI MRI was median 8.8 mL, IQR 3.2-34.0 mL. ML-NCCT core volumes significantly correlated with DWI MRI core volumes, r =0.61, p p =0.81. For the reperfusion treatment threshold of an ischemic core volume within 70 mL, while no patients would have been excluded using our algorithm, five patients would have been incorrectly dichotomized as having an ischemic volume of Conclusion: This ML-approach accurately quantifies ischemic core volume on NCCT compared to the reference standard of diffusion MRI in patients with AIS.

Background: In patients with symptomatic intracranial atherosclerotic disease (ICAD), borderzone infarct pattern and perfusion mismatch have each been shown to independently predict recurrent strokes, which may reflect the shared underlying mechanism of hypoperfusion distal to the intracranial atherosclerosis. As such, we hypothesized that perfusion volumes and patterns may correlate with various ICAD subtypes. Methods: A retrospective, 5-year analysis of consecutive ICAD patients with perfusion imaging for acute strokes (0-24 hours) due to sub-occlusive (50-99%) stenosis was conducted. The following subtypes were assigned based on the infarct pattern seen on the diffusion-weighted imaging (DWI): perforator, borderzone, and thromboembolic. Core volume on MRI and perfusion parameters on CT or MR perfusion, obtained concurrently or within 12 hours of MR DWI, were studied in each group. Results: 42 patients (57% women, mean age 71±13 years old) with acute strokes received MRI imaging upon initial presentation. 15 were found with borderzone, 12 perforator, and 15 with thromboembolic pattern on DWI. Across all ICAD subtypes, median core volume (ADC p =0.95). Hypoperfusion with Tmax >4s and Tmax >6s delay volumes was significantly higher in the thromboembolic and borderzone infarct patterns compared to the perforator subtype ( Figure 1 ). The volume difference between Tmax >4s and Tmax >6s (Δ Tmax>4s - Tmax>6s) was higher in the borderzone subtype compared to thromboembolism when analyzed pairwise. Conclusion: Core volume in ischemic strokes secondary to symptomatic ICAD is minimal. TMax>4 and TMax>6 parameters vary across the different ICAD patterns, with significantly large Tmax>4 delay volumes in the borderzone profile. Perfusion mapping may further elucidate hemodynamic mechanisms underlying ICAD.

Many neuroprotective and other therapies for treatment of acute ischemic stroke have failed in translation to human studies, indicating a need for more rigorous, multidimensional quality assessment of the totality of preclinical evidence supporting a therapy prior to conducting human trials. A consensus panel of stroke preclinical model and human clinical trial experts assessed candidate items for the translational readiness scale, compiled from prior instruments (STAIR, ARRIVE, CAMARADES, RoB 2) based on importance, reliability, and feasibility. Once constructed, the tool was applied by two independent raters to four current candidate acute stroke therapies, including two pharmacologic agents [nerinetide and trans-sodium crocetinate] and two device interventions [cathodal transcranial direct current stimulation and fastigial nucleus stimulation]. The Preclinical evidence of Readiness In stroke Models Evaluating Drugs and Devices (PRIMED

Intracranial atherosclerotic disease (ICAD) has been characterized by the degree of arterial stenosis and downstream hypoperfusion, yet microscopic derangements of endothelial shear stress at the luminal wall may be key determinants of plaque growth, vascular remodeling and thrombosis that culminate in recurrent stroke. Platelet interactions have similarly been a principal focus of treatment, however, the mechanistic basis of anti-platelet strategies is largely extrapolated rather than directly investigated in ICAD. Platelet FcγRIIa expression has been identified as a potent risk factor in cardiovascular disease, as elevated expression markedly increases the risk of recurrent events. Differential activation of the platelet FcγRIIa receptor may also explain the variable response of individual patients to anti-platelet medications. We review existing data on endothelial shear stress and potential interactions with the platelet FcγRIIa receptor that may alter the evolving impact of ICAD, based on local pathophysiology at the site of arterial stenosis. Current methods for quantification of endothelial shear stress and platelet activation are described, including tools that may be readily adapted to the clinical realm for further understanding of ICAD.

Introduction: The clinical syndrome associated with Sars-CoV-2 infection is associated with an increased rate of cerebrovascular events, predominantly ischemic stroke. Direct viral invasion of the cerebral endothelium could be a significant driver of Sars-CoV-2-mediated stroke through expression of ACE2 and viral entry co-factors including TMPRSS2. Prior work indicates that ACE2 mRNA and protein are expressed in the endothelial cells of the brain, yet the effect of flow-mediated phenomena on ACE2 expression and the susceptibility of human cerebral endothelia to Sars-CoV-2 infection is unknown. Methods: 3D printed models of the human middle cerebral artery were endothelialized with either human umbilical vein endothelial cells (HUVECs) or human brain microvascular endothelial cells (HBMECs). Endothelialized models were subjected to 3D rotational perfusional culture at variable pulsatile flow rates (0-22.5 dynes/cm 2 ). ACE2 and TMPRSS2 expression were measured by Taqman qPCR. Biotinylated recombinant Sars-CoV-2 S protein was used to judge regional vessel binding of virus using confocal microscopy. Results: In 3D models endothelialized with either HUVECs or HBMECs, ACE2 mRNA expression is significantly modulated by vessel diameter and the presence of of flow (15 dynes/cm 2 ) (p2 ) produced further increases in ACE2 expression in both cell types. Gene expression analysis demonstrated no detection of the Sars-CoV-2 viral entry co-factor TMPRSS2 in HBMECs. Flow-mediated ACE2 expression was associated with binding of recombinant Sars-CoV-2 S protein to the vessel wall suggesting direct cerebrovascular susceptibility to Sars-CoV-2. Conclusion: The Sars-CoV-2 cellular receptor ACE2 is expressed by human cerebral endothelia in a flow-dependent manner. Cerebral vessels are susceptible to Sars-CoV-2 infection and bind viral S protein under flow conditions but likely requires unique co-factors for viral entry. Identification of the molecular mechanisms triggered by Sars-CoV-2 infection in brain vasculature can alleviate the burden of stroke associated with COVID-19.

Subcortical white matter ischemic lesions are increasingly recognized to have pathologic overlap in individuals with Alzheimer's disease (AD). The interaction of white matter ischemic lesions with amyloid pathology seen in AD is poorly characterized. We designed a novel mouse model of subcortical white matter ischemic stroke and AD that can inform our understanding of the cellular and molecular mechanisms of mixed vascular and AD dementia. Subcortical white matter ischemic stroke underlying forelimb motor cortex was induced by local stereotactic injection of an irreversible eNOS inhibitor. Subcortical white matter ischemic stroke or sham procedures were performed on human ApoE4-targeted-replacement (TR):5XFAD mice at 8weeks of age. Behavioral tests were done at 7, 10, 15, and 20weeks. A subset of animals underwent 18FDG-PET/CT. At 20weeks of age, brain tissue was examined for amyloid plaque accumulation and cellular changes. Compared with sham E4-TR:5XFAD mice, those with an early subcortical ischemic stroke showed a significant reduction in amyloid plaque burden in the region of cortex overlying the subcortical stroke. Cognitive performance was improved in E4-TR:5XFAD mice with stroke compared with sham E4-TR:5XFAD animals. Iba-1+ microglial cells in the region of cortex overlying the subcortical stroke were increased in number and morphologic complexity compared with sham E4-TR:5XFAD mice, suggesting that amyloid clearance may be promoted by an interaction between activated microglia and cortical neurons in response to subcortical stroke. This novel approach to modeling mixed vascular and AD dementia provides a valuable tool for dissecting the molecular interactions between these two common pathologies.

Background In vitro vascular models for brain aneurysms and acute stroke have been used for training, simulation and research purpose. However, the use of realistic in vitro models for arteriovenous malformation (AVM) have not been reported. Current in vitro AVM models analyzing the efficacy of embolic materials or flow conditions are limited due to a lack of realistic anatomical and dynamic features of complex nidus. Materials and Methods 3D AVM nidus images were extracted and segmented from 3D rotational angiography from a patient. Additional artificial feeders and drainers were attached to the AVM nidus. The inner vascular mold was printed using a plastic 3D printer. The inner mold was coated with silicone and then removed with acetone, leaving a hollow AVM model. Injections of liuid embolic material and 4D flow MRI were performed using the 3D in vitro AVM model. Computational fluid dynamics (CFD) analysis was also performed to compare the flow volume and velocity to 4D flow MRI Results The created in vitro AVM models had realistic representation of nidus vasculature and complexity derived from patients. The injection of liquid embolic material performed in this model replicated real-life treatment conditions. The plug and push technique was successfully simulated to penetratreliquid embolic material into the AVM nidus. The flow data from 4D flow MRI were comparable to CFD analysis. Conclusions An in vitro human brain AVM model with realistic complexities of nidus was successfully manufactured using 3D printing technology. The model demonstrated realistic pliability during the liquid embolic material injection and also feasibility of flow analysis. This in vitro AVM model may represent a valuable tool for simulation, flow research and development of new materials or technique. Disclosures N. Kaneko: None. H. Ullman: None. F. Ali: None. P. Berg: 1; C; German Research Foundation, Federal Ministry of Education and Research within the Forschungscampus STIMULATE. Y. Ooi: None. S. Tateshima: 2; C; Cerenovus, Medtronic, Stryker. G. Colby: 2; C; Medtronic, Microvention, Stryker. Y. Komuro: None. P. Hu: None. V. Szeder: None. M. Nour: None. L. Guo: None. A. Chien: None. F. Vinuela: None. S. Nemoto: None. J. Hinman: None. G. Duckwiler: 1; C; Tarsadia Foundation. 2; C; Medtronic. R. Jahan: None.

The concept of vascular contributions to cognitive impairment and dementia (VCID) derives from more than two decades of research indicating that (1) most older individuals with cognitive impairment have post mortem evidence of multiple contributing pathologies and (2) along with the preeminent role of Alzheimer's disease (AD) pathology, cerebrovascular disease accounts for a substantial proportion of this contribution. Contributing cerebrovascular processes include both overt strokes caused by etiologies such as large vessel occlusion, cardioembolism, and embolic infarcts of unknown source, and frequently asymptomatic brain injuries caused by diseases of the small cerebral vessels. Cerebral small vessel diseases such as arteriolosclerosis and cerebral amyloid angiopathy, when present at moderate or greater pathologic severity, are independently associated with worse cognitive performance and greater likelihood of dementia, particularly in combination with AD and other neurodegenerative pathologies. Based on this evidence, the US National Alzheimer's Project Act explicitly authorized accelerated research in vascular and mixed dementia along with frontotemporal and Lewy body dementia and AD itself. Biomarker development has been consistently identified as a key step toward translating scientific advances in VCID into effective prevention and treatment strategies. Validated biomarkers can serve a range of purposes in trials of candidate interventions, including (1) identifying individuals at increased VCID risk, (2) diagnosing the presence of cerebral small vessel disease or specific small vessel pathologies, (3) stratifying study participants according to their prognosis for VCID progression or treatment response, (4) demonstrating an intervention's target engagement or pharmacodynamic mechanism of action, and (5) monitoring disease progression during treatment. Effective biomarkers allow academic and industry investigators to advance promising interventions at early stages of development and discard interventions with low success likelihood. The MarkVCID consortium was formed in 2016 with the goal of developing and validating fluid- and imaging-based biomarkers for the cerebral small vessel diseases associated with VCID. MarkVCID consists of seven project sites and a central coordinating center, working with the National Institute of Neurologic Diseases and Stroke and National Institute on Aging under cooperative agreements. Through an internal selection process, MarkVCID has identified a panel of 11 candidate biomarker "kits" (consisting of the biomarker measure and the clinical and cognitive data used to validate it) and established a range of harmonized procedures and protocols for participant enrollment, clinical and cognitive evaluation, collection and handling of fluid samples, acquisition of neuroimaging studies, and biomarker validation. The overarching goal of these protocols is to generate rigorous validating data that could be used by investigators throughout the research community in selecting and applying biomarkers to multi-site VCID trials. Key features of MarkVCID participant enrollment, clinical/cognitive testing, and fluid biomarker procedures are summarized here, with full details in the following text, tables, and supplemental material, and a description of the MarkVCID imaging biomarker procedures in a companion paper, "MarkVCID Cerebral small vessel consortium: II. Neuroimaging protocols." The procedures described here address a range of challenges in MarkVCID's design, notably: (1) acquiring all data under informed consent and enrollment procedures that allow unlimited sharing and open-ended analyses without compromising participant privacy rights; (2) acquiring the data in a sufficiently wide range of study participants to allow assessment of candidate biomarkers across the various patient groups who might ultimately be targeted in VCID clinical trials; (3) defining a common dataset of clinical and cognitive elements that contains all the key outcome markers and covariates for VCID studies and is realistically obtainable during a practical study visit; (4) instituting best fluid-handling practices for minimizing avoidable sources of variability; and (5) establishing rigorous procedures for testing the reliability of candidate fluid-based biomarkers across replicates, assay runs, sites, and time intervals (collectively defined as the biomarker's instrumental validity). Participant Enrollment Project sites enroll diverse study cohorts using site-specific inclusion and exclusion criteria so as to provide generalizable validation data across a range of cognitive statuses, risk factor profiles, small vessel disease severities, and racial/ethnic characteristics representative of the diverse patient groups that might be enrolled in a future VCID trial. MarkVCID project sites include both prospectively enrolling centers and centers providing extant data and samples from preexisting community- and population-based studies. With approval of local institutional review boards, all sites incorporate MarkVCID consensus language into their study documents and informed consent agreements. The consensus language asks prospectively enrolled participants to consent to unrestricted access to their data and samples for research analysis within and outside MarkVCID. The data are transferred and stored as a de-identified dataset as defined by the Health Insurance Portability and Accountability Act Privacy Rule. Similar human subject protection and informed consent language serve as the basis for MarkVCID Research Agreements that act as contracts and data/biospecimen sharing agreements across the consortium. Clinical and Cognitive Data Clinical and cognitive data are collected across prospectively enrolling project sites using common MarkVCID instruments. The clinical data elements are modified from study protocols already in use such as the Alzheimer's Disease Center program Uniform Data Set Version 3 (UDS3), with additional focus on VCID-related items such as prior stroke and cardiovascular disease, vascular risk factors, focal neurologic findings, and blood testing for vascular risk markers and kidney function including hemoglobin A1c, cholesterol subtypes, triglycerides, and creatinine. Cognitive assessments and rating instruments include the Clinical Dementia Rating Scale, Geriatric Depression Scale, and most of the UDS3 neuropsychological battery. The cognitive testing requires ≈60 to 90 minutes. Study staff at the prospectively recruiting sites undergo formalized training in all measures and review of their first three UDS3 administrations by the coordinating center. Collection and Handling of Fluid Samples Fluid sample types collected for MarkVCID biomarker kits are serum, ethylenediaminetetraacetic acid-plasma, platelet-poor plasma, and cerebrospinal fluid (CSF) with additional collection of packed cells to allow future DNA extraction and analyses. MarkVCID fluid guidelines to minimize variability include fasting morning fluid collections, rapid processing, standardized handling and storage, and avoidance of CSF contact with polystyrene. Instrumental Validation for Fluid-Based Biomarkers Instrumental validation of MarkVCID fluid-based biomarkers is operationally defined as determination of intra-plate and inter-plate repeatability, inter-site reproducibility, and test-retest repeatability. MarkVCID study participants both with and without advanced small vessel disease are selected for these determinations to assess instrumental validity across the full biomarker assay range. Intra- and inter-plate repeatability is determined by repeat assays of single split fluid samples performed at individual sites. Inter-site reproducibility is determined by assays of split samples distributed to multiple sites. Test-retest repeatability is determined by assay of three samples acquired from the same individual, collected at least 5 days apart over a 30-day period and assayed on a single plate. The MarkVCID protocols are designed to allow direct translation of the biomarker validation results to multicenter trials. They also provide a template for outside groups to perform analyses using identical methods and therefore allow direct comparison of results across studies and centers. All MarkVCID protocols are available to the biomedical community and intended to be shared. In addition to the instrumental validation procedures described here, each of the MarkVCID kits will undergo biological validation to determine whether the candidate biomarker measures important aspects of VCID such as cognitive function. Analytic methods and results of these validation studies for the 11 MarkVCID biomarker kits will be published separately. The results of this rigorous validation process will ultimately determine each kit's potential usefulness for multicenter interventional trials aimed at preventing or treating small vessel disease related VCID.

Background Current in vitro models for human brain arteriovenous malformation (AVM) analyzing the efficacy of embolic materials or flow conditions are limited by a lack of realistic anatomic features of complex AVM nidus. The purpose of this study was to evaluate a newly developed in vitro AVM model for embolic material testing, preclinical training, and flow analysis. Methods Three-dimensional (3D) images of the AVM nidus were extracted from 3D rotational angiography from a patient. Inner vascular mold was printed using a 3D printer, coated with polydimethylsiloxanes, and then was removed by acetone, leaving a hollow AVM model. Injections of liquid embolic material and 4-dimensional (4D) flow magnetic resonance imaging (MRI) were performed using the AVM models. Additionally, computational fluid dynamics analysis was performed to examine the flow volume rate as compared with 4D flow MRI. Results The manufacture of 3D in vitro AVM models delivers a realistic representation of human nidus vasculature and complexity derived from patients. The injection of liquid embolic agents performed in the in vitro model successfully replicated real-life treatment conditions. The model simulated the plug and push technique before penetration of the liquid embolic material into the AVM nidus. The 4D flow MRI results were comparable to computational fluid dynamics analysis. Conclusions An in vitro human brain AVM model with realistic geometric complexities of nidus was successfully created using 3D printing technology. This AVM model offers a useful tool for training of embolization techniques and analysis of hemodynamics analysis, and development of new devices and materials.

Introduction: 3D printed human vascular in vitro models of aneurysms and acute stroke have been utilized for training, simulation and device development. However, there are no realistic in vitro arteriovenous malformation (AVM) models. Current experimental models analyzing the efficacy of embolic materials or flow conditions are limited by their simplistic design, lacking complex AVM nidus anatomic features. The purpose of this study is to develop a new in vitro AVM model for embolic material testing and flow analysis. Methods: 3D images of the AVM nidus were extracted from 3D rotational angiography from a patient. Artificial feeders and drainers were added to the nidus and an inner vascular mold was printed using a 3D printer. The inner mold was coated with polydimethylsiloxanes. The inner plastic mold was removed by acetone, leaving a hollow AVM model. ONYX injection and 4DFlow MRI (Phase Contrast MRA) were performed using the AVM models. In addition, computational fluid dynamics (CFD) analysis was performed to compare flow rate with 4DFlow MRI. Results: An in vitro AVM model with realistic representation of nidus vasculature and complexity was successfully created. Liquid onyx injection performed in the in vitro model successfully replicated real-life treatment conditions. The model effectively simulated plug and push technique before penetration of the ONYX into the AVM nidus. 4DFlow MRI flow rates were similar to the CFD analysis. Conclusions: An in vitro AVM model using 3D printing technology was successfully created. The model demonstrated realistic pliability during ONYX injection. This in vitro AVM model may represent a useful tool for training and development of new materials, and have potential of highly-resolved flow quantifications.

Background: Clot propagation after initial occlusion may increase target thrombus burden and its pathophysiologic basis has not been extensively studied in acute human ischemic stroke. We investigated whether clot characteristics on MRI, catheter angiography, and thrombus histopathology indicated that impaired collaterals may be associated with extension of acute intracranial occlusions via stasis clotting in slow flow arterial segments. Methods: Analysis of consecutive AIS-LVO endovascular thrombectomy patients at 2 academic medical centers with: 1) pretreatment MRI, and 2) retrieved thrombi. GRE MR susceptibility vessel sign presence and extent of ASITN collateral scores were rated by blinded assessors. Extracted clots were fixed in formalin, stained by hematoxylin and eosin, and RBC, WBC and fibrin percent composition quantified by a neuropathologist blinded to clinical details. We evaluated the correlation of collateral grade with clot size by susceptibility vessel sign (SVS) and clot composition by RBC%. Non-parametric values were computed via Spearman correlation. Results: Among the 48 patients, mean age was 71.4 (SD 17.7), 56.3% female, and mean presenting NIHSS was 15.5 (SD 7.41). A susceptibility vessel sign was present in 65%, with mean SVS length 15.6 mm (SD 8.3). Collateral scores were mean 2.3 (SD 1.2). The number of passes per procedure was mean 1.98 (SD 1.30) The presence of a susceptibility vessel sign correlated with higher RBC% in retrieved thrombi (r s =0.36 p=0.011). Worse collateral grades correlated with longer SVS length (r s =-0.50 p=0.004) and greater SVS width (r s =-0.54 p=0.002). Worse collateral grade also trended toward correlation with higher RBC% in retrieved clots (r s =-0.19 p=0.18). Conclusion: Impaired angiographic collaterals are associated with longer RBC-rich thrombi on susceptibility imaging and trend toward association with higher RBC% in retrieved thrombi. These findings support that, in LVO acute ischemic stroke, clot propagation after initial occlusion occurs by stasis clotting accelerated by impaired collaterals.

Introduction: Emboli retrieved from stroke patients undergoing mechanical thrombectomy vastly differ in histopathologic appearance, likely reflecting varying etiologies of stroke. We investigated whether clot components correlated with clinical features and thrombectomy outcomes. Methods: Retrieved thrombi from endovascular thrombectomy in consecutive AIS-LVO patients at 2 academic medical centers were fixed in formalin and sections stained by hematoxylin and eosin. The RBC, WBC and fibrin percentages of the clot were quantified by a neuropathologist blinded to the clinical details. We evaluated the association of these clot components, patient demographic and clinical features, with TICI score (both ordinal and dichotomized at 2c), AOL score, number of thrombectomy passes, and first-pass substantial recanalization (≥TICI 2b result on the first thrombectomy device pass). Non-parametric values were computed via Spearman correlation and pairwise interaction of clinical features was analyzed by ordinal logistic regression. Results: Among the 75 analyzed patients, mean age was 71.4 (SD 17.7), 50.7% were female and presenting NIHSS mean was 16.1 (SD 7.6). Devices employed were stent retrievers in 71% of patients, aspiration in 10%, and both stent retrievers and aspiration in 19%. Number of passes per procedure was mean 2.16 (SD 1.21). Substantial reperfusion (TICI 2B-3) was achieved in 88% and excellent reperfusion (TICI 2C-3) in 44%. In retrieved thrombi, mean RBC% was 44.8% (SD 31.9) and mean fibrin% was 49.8% (SD 31.4). Rates of first-pass substantial reperfusion, final substantial reperfusion, and final excellent reperfusion were homogenous across wide ranges of retrieved thrombus RBC% and fibrin% in correlation analysis. Conclusion: RBC and fibrin composition range widely among retrieved thrombi causing acute ischemic stroke. Current generation thrombectomy devices perform well across a broad range of clot compositions.

Introduction: Recurrent strokes make up 25% of the annual stroke incidence with 10% of the Veteran population suffering a recurrent stroke within 1 year. The role of adherence to a post-stroke medication regimen and its effect on stroke recurrence is unknown. Methods: Veterans evaluated in a vascular neurology specialty clinic from July 2010 to June 2016 underwent a detailed medical chart review and assessment of medication adherence to stroke prevention medications including anti-thrombotic use, anti-coagulants, anti-hypertensives, lipid-lowering therapy, and anti-hyperglycemic therapy. Medication adherence was measured by 90d refill history with >75% medication possession ratio (MPR) indicating adherence. A Framingham Stroke Risk Profile (FSRP) Score was calculated for each patient. Relative risk calculations were generated using a bivariate analysis and means compared via t-test. Results: 162 of 245 patients who were newly referred to the clinic underwent a detailed chart review and medication adherence profile. In this cohort, 93.8% were male and ranged in age between 35-94 years old (mean 69.2±10.2). The mean age of first stroke was 62.9±10.5 and the frequency of recurrent stroke was 26.5% (43 patients). The median time to recurrent stroke was 2.59 years. The average FSRP score for all subjects was 0.087±0.09 and did not differ between those with or without a recurrent stroke (0.103 vs. 0.082, p= 0.18). The rate of medication adherence in all subjects was 69.8% and differed greatly between those without and with a recurrent stroke, 79.0% vs. 44.2%, respectively. Median time to recurrent stroke was 2.59 years in those with MPR >75% and 1.91 years in those with MPR p -value p -value Conclusion: In this high-risk Veteran population, strict adherence with a stroke prevention medication regimen is associated with a lower risk of recurrent stroke. Efforts to measure and encourage medication adherence in patients with prior stroke may reduce the risk of recurrence.

Background and Purpose: Investigation of occlusive thrombus in ischemic stroke is expected to clarify the etiology and mechanism of stroke fueling an optimal treatment strategy. However, in situ propagation due to secondary thrombosis after initial embolic occlusion could obscure the characteristics of initial emboli. Differentiation of the initial embolus and secondary thrombosis using retrieved specimens might be difficult due to fragmentation of whole thrombi. We aimed to investigate the heterogeneity of occlusive thrombi using pretreatment imaging of ischemic stroke. Methods: Among consecutive stroke patients with acute embolic occlusion of the anterior circulation eligible for endovascular reperfusion therapy, we retrospectively reviewed 81 patients who underwent both brain non-contrast CT (NCCT) and CT angiography (CTA) on admission from June 2015 to May 2018. Region of interest (ROI) was set on the whole thrombus on NCCT, which was identified referring to the filling defect on CTA, and the size of thrombus was measured. ROI was then divided equally into proximal and distal segments and Hounsfield Unit (HU) densities of those segments were measured respectively. Difference of HU between proximal and distal segments (ΔHU; HU in proximal segment - HU in distal segment) was calculated and analyzed. Results: HU density on NCCT in proximal segment was higher than in distal segment (mean difference: 3.75, 95% CI: 2.69-4.80, p Conclusions: Density of occlusive thrombi in the proximal segment is higher than in the distal segment. This difference increases as thrombi grow longer and decreases as thrombi get older after embolic occlusion. This time/length-dependent thrombus heterogeneity is suggestive of secondary thrombosis, occurring initially at the proximal side of occlusion.

Introduction: The role of increased CBF after endovascular thrombectomy in post-ischemic hyperperfusion has not been studied in detail. We aimed to investigate the timing of CBF increases on PWI after thrombectomy in association with hemorrhagic transformation. Methods: We analyzed prospectively collected data in consecutive patients treated with endovascular thrombectomy. Inclusion criteria were: (1) patients with ICA or M1 occlusion, and (2) PWI and GRE obtained within 12 hours and 12-48 hours after thrombectomy. We compared each rCBF with early hemorrhage (within 12 hours after thrombectomy), late hemorrhage (12-48 hour) and non-hemorrhage in basal ganglia (BG) and MCA cortical or subcortical (CS) region. In each PWI dataset, ROIs were placed in two slice levels of the BG and three slice levels of the CS region. Results: Fifty-three patients met inclusion criteria. Early BG hemorrhages were noted in 13 patients, with 4 late BG hemorrhage, 8 early CS hemorrhage and 3 late CS hemorrhage. There were no significant differences on rCBF in PWI within 12 hours after thrombectomy between early hemorrhage, late hemorrhage and non-hemorrhage groups. In contrast, rCBF on 12-48 hours PWI in the BG region was significantly higher in the early BG hemorrhage than non-BG hemorrhage (lower BG slice 1.36 vs 1.01, p Conclusions: Most intracerebral hemorrhages after thrombectomy were seen within 12 hours after intervention. A rCBF increase in hemorrhage cases was not seen on PWI within 12 hours after thrombectomy. rCBF increases on PWI 12-48 hours after thrombectomy, however, was associated with post-thrombectomy hemorrhage within 12 hours.