Acute Infarct Volume Research Articles

Abstract WP321: Novel Therapeutic Potential of Intestinal Organoids Secretomes for Cerebrovascular Stroke

Background: Our recent studies show that transplants of intestine epithelial stem cells (IESCs) promote acute and long term recovery after stroke in middle-aged rats. To improve the translational potential of this therapy, we investigated whether injections of the IESC conditioned media (CM) would be similarly effective in improving acute and chronic stroke outcomes. Methods: Conditioned media was collected intestinal organoids culture from young animals and processed for proteomic and tropic factors analysis. CM efficacy was tested in middle-aged male and female rats assigned to the following groups: Control (sham), stroke+vehicle injection, or stroke+IESC-CM treatment. Middle cerebral artery occlusion (MCAo) was induced by Endothelin-1 (vasoconstrictor). Conditioned media was injected ip (CMip) 4h/24h/48h after stroke. In the acute phase, infarct volume, sensorimotor function and serum levels of the gut permeability markers were measured 4d post stroke. Long term (4 weeks after stroke) depressive-like behavior was assessed by the Social Interaction test, and cognitive performance by the Novel object Recognition test and Barnes maze test. Results: Proteomic analysis of CM showed elevated levels of small peptide growth factors ad large matrix molecules. IESC-CMip treatment significantly improved acute stroke outcomes and reduced gut permeability in middle-aged hosts of either sex. In long term study, vehicle-treated MCAo animals showed depressive-like behaviors compared to their pre-stroke behaviors. In contrast, stroke animals that received IESC secretome were no different from their pre stroke performance and were similar sham (no-stroke) animals. In cognition assesments. MCAo+vehicle animals showed poor ability to discriminate the novel object and displayed impaired learning and recall on the Barnes maze. MCAo animals that received IESC secretome did not show significant improved during the Barnes learning trials, but retrieval (memory recall) performance was improved and significantly different from the vehicle group. Conclusion: Overall, these data show that IESC secretome derived from a healthy young animal can significantly improve acute stroke outcomes and specific aspects of cognitive performance.

Abstract 97: Acute Ischemic Stroke Despite Anticoagulant Use: The Neuro-AFib Study

Background: Acute ischemic stroke (AIS) admissions in patients with atrial fibrillation (AF) using anticoagulants (AIS-despite-AC) are commonly seen in stroke units but data on their frequency, causes, and outcomes are scarce. Methods: The Neuro-AFib study is a multicenter effort geared toward elucidating the causes and consequences of strokes in a contemporary AF cohort. Detailed clinical, laboratory and multimodal imaging data from known AF patients consecutively admitted to 20 stroke centers with an IS between 1/2018-12/2019 were used to define characteristics of AIS-despite-AC and compared to AIS-off-AC. Results: Out of 4456 patients with known AF prior to the AIS, 2051 (46%) were using anticoagulants. Patients who had AIS-despite-AC were younger (76.8 + 11 vs 77.8 + 12, p=0.007), had higher mean CHA 2 DS 2 -VASc scores (4.57 + 1.7 vs 4.21 + 1.7, p<0.001), and they were more likely to have permanent AF (23.5% vs 19.6%, p=0.002) and a past-history of stroke/TIA (36% vs 25%, p<0.001) when compared to non-AC group. Chronic embolic (non-lacunar) infarcts on imaging were more common among AIS-despite-AC (34.5% vs 26.7%, p<0.001). Acute large vessel occlusion (LVO) was common among AIS-despite-AC (48%). The pattern of the acute infarcts (numbers, embolic features) was not different. The calculated acute infarct volume was large (34ml) and mean NIHSS was 10.4 for AIS-despite-AC. Intravenous thrombolysis was used much less commonly for AIS-despite-AC (10.5% vs 32.1%, p<0.001). Symptomatic carotid disease was suspected in 2.4%, a hypercoagulable condition in 5.7%, whereas acute lacunar infarct was found in 6.5% of all patients. Death or significant disability (mRS 3-5) at hospital discharge were common in AIS on vs off AC (70.6% vs 75.2%, p<0.001). Conclusions: Based on a large multicenter cohort, AF patients who have AIS-despite-AC have higher AF load and risk scores, most don't have a concurrent etiology and they are more likely to have recurrent embolic events. The stroke severity, common presence of LVO, infarct size, and poor outcomes are alarming features, and most patients are unable to receive thrombolysis because of AC use. Overall, detection of AF patients at risk of AIS-despite-AC and development of specific preventive modalities should be priorities.

Abstract 006: Glenzocimab Is Associated With Less Haemorrhagic Transformation Using Artificial Intelligence Imaging In Mechanical Thrombectomy Patients

Introduction Lesion volume measurement provides an objective and quantitative assessment of stroke severity and it is often used as a surrogate endpoint of clinical outcome in therapeutic trials. ACTIMIS (NCT03803007) was a randomized phase 1b/2a clinical trial evaluating glenzocimab, a monoclonal antibody fragment targeting platelet receptor glycoprotein VI, versus placebo in patients with acute ischemic stroke treated by thrombolysis alone or associated with mechanical thrombectomy (MT), both subgroups being well balanced. Primary analysis demonstrated a significant reduction in intracranial hemorrhage occurrence stroke‐related mortality and a trend towards reduction in severe disability. In this sub‐analysis, Artificial Intelligence (AI) imaging biomarkers were used to assess efficacy of glenzocimab in the subgroup undergoing MT in the pooled phase 1b (dose escalation) and phase 2a (dose confirmation) studies. Methods In the phase 1b study, patients were randomized to an escalating dose of glenzocimab or placebo (4:1, n=12 per group, 125mg, 250mg, 500mg, 1000mg). In the phase 2 dose confirmation study, patients were randomized (1:1) with 1000mg glenzocimab or placebo. CT scan or MRI was acquired at baseline with CT at 24 hours and MRI at 7 days (CT if MRI not available) for safety and efficacy analysis, respectively. Baseline and follow up imaging were processed using Brainomix software (Oxford, UK). AI output was reviewed for accuracy by an expert clinician (DC) blinded to treatment allocation. Results Of 166 patients in the trial, 81 patients underwent MT and had follow up non‐contrast CT imaging available at 24 hours (48 glenzocimab, 33 placebo) and 72 had Day‐7 imaging (47 glenzocimab, 25 placebo). Day‐7 imaging was available for 8 fewer placebo patients and 1 glenzocimab patient than at 24 hours. All except 2 patients (1 placebo, 1 glenzocimab) with missing data at Day‐7 died during the study. Multivariate regression modelling showed a significant interaction between patients undergoing MT and receiving glenzocimab. Glenzocimab had a greater effect on reducing the risk of haemorrhagic transformation in the MT subgroup (exploratory p=0.001). Presenting acute infarct volume was similar between glenzocimab and placebo arms (mean [SD]; 16.27mL [30.2] vs. 19.62mL [28.98], non‐significant). There was a significantly smaller volume of haemorrhagic transformation in the glenzocimab group at 24 hours compared to placebo (1.83mL [6.59] vs 33.46mL [75.07], exploratory p<0.01) and a trend towards smaller volume of ischemic injury in the glenzocimab group (52.32mL [82.07] vs 62.93mL [79.4]). Similar significant trend at Day‐7 for haemorrhagic transformation was seen but less marked due to the unbalanced loss to follow up at Day‐7 (2.99mL [12.35] vs 4.19mL [10.83], exploratory p<0.05). Conclusion Glenzocimab reduces likelihood of haemorrhagic transformation in patients undergoing MT. Haemorrhage volumes were smaller in the glenzocimab group and encouragingly there was a trend to smaller volumes of ischemic injury. There was a greater drop‐out rate in the placebo group between 24 hours and Day‐7, which resulted in a smaller difference in haemorrhagic volumes at Day‐7. Those results, which are to be further analysed in ACTIMIS overall population of AIS patients, could highlight glenzocimab mechanism in the reperfusion injury mitigation.

White Matter Hyperintensity Volume and Poststroke Cognition: An Individual Patient Data Pooled Analysis of 9 Ischemic Stroke Cohort Studies.

White matter hyperintensities (WMH) are associated with cognitive dysfunction after ischemic stroke. Yet, uncertainty remains about affected domains, the role of other preexisting brain injury, and infarct types in the relation between WMH burden and poststroke cognition. We aimed to disentangle these factors in a large sample of patients with ischemic stroke from different cohorts. We pooled and harmonized individual patient data (n=1568) from 9 cohorts, through the Meta VCI Map consortium (www.metavcimap.org). Included cohorts comprised patients with available magnetic resonance imaging and multidomain cognitive assessment <15 months poststroke. In this individual patient data meta-analysis, linear mixed models were used to determine the association between WMH volume and domain-specific cognitive functioning (Z scores; attention and executive functioning, processing speed, language and verbal memory) for the total sample and stratified by infarct type. Preexisting brain injury was accounted for in the multivariable models and all analyses were corrected for the study site as a random effect. In the total sample (67 years [SD, 11.5], 40% female), we found a dose-dependent inverse relationship between WMH volume and poststroke cognitive functioning across all 4 cognitive domains (coefficients ranging from -0.09 [SE, 0.04, P=0.01] for verbal memory to -0.19 [SE, 0.03, P<0.001] for attention and executive functioning). This relation was independent of acute infarct volume and the presence of lacunes and old infarcts. In stratified analyses, the relation between WMH volume and domain-specific functioning was also largely independent of infarct type. In patients with ischemic stroke, increasing WMH volume is independently associated with worse cognitive functioning across all major domains, regardless of old ischemic lesions and infarct type.

Abstract TP85: Clinical And Imaging Biomarkers Of Ageing And Stroke Severity, And Their Interaction With Clinical Outcomes

Outcomes following endovascular thrombectomy (EVT) for large vessel occlusion stroke remain variable. Clinical predictors include presenting NIHSS and age, surrogate metrics of stroke severity and pre-stroke brain health, respectively. Imaging biomarkers can also predict outcome, but prognostic models typically only include biomarkers of acute stroke severity. This study aimed at exploring how incorporating both imaging biomarkers of stroke severity and brain frailty, automatically derived from routine imaging, impacts outcome prediction following successful EVT. In this single-center retrospective study of 215 patients presenting with anterior circulation stroke, we evaluated prognostic significance of automated analysis outputs from e-Stroke. Acute ischemic volume (AIV) and e-ASPECTS were used to define stroke severity. Cerebral atrophy was used as a marker of brain frailty. Models incorporating imaging biomarkers, clinical features, procedural factors, and combinations of these were evaluated using multivariate regression models predicting mRS 0-2 at 30 and 90-days, NIHSS improvement, mortality and sICH. Incorporation of brain atrophy into models negated the effect of age on patient outcome. The interaction of stroke severity with age was similar to that of infarct volume and brain atrophy. Models incorporating age, presenting NIHSS, AIV, atrophy, reperfusion status and time to recanalization outperformed clinical models at predicting NIHSS improvement (ROC AUC 0.81 and 0.57, respectively) and 90-day mRS. Combinations of imaging and clinical features were superior for predicting any outcome compared with clinical or imaging features in isolation. Models incorporating automated image analysis of acute infarct volume and atrophy outperform models based solely on clinical characteristics for predicting short- and long-term outcome following EVT. Atrophy as a marker of brain frailty is associated with poorer long-term outcomes and negates the effect of age in multivariate models. AIV tempers the effect of intervention on early neurological improvement. Better understanding the relationship between stroke severity and baseline health status may improve patient selection strategies for reperfusion therapies.

Depressive symptoms due to stroke are strongly predicted by the volume and location of the cerebral infarction, white matter hyperintensities, hypertension, and age: A precision nomothetic psychiatry analysis

ObjectivesTo delineate the effects of white matter hyperintensities (WMHs) as measured by Fluid-attenuated inversion recovery (FLAIR) and infarction volume as measured by Diffusion-weighted imaging (DWI) on post-stroke depression symptoms. MethodsBaseline National Institutes of Health Stroke Score (NIHSS) and Modified Rankin Scale (mRS) scores, and FLAIR and DWI MRIs to assess WMHs and acute infarct volumes, respectively, were assessed in 47 patients (≥55 years) with acute ischemic stroke and 17 normal controls. The Montgomery–Åsberg Depression Rating Scale (MDRS) was assessed three months after the stroke. ResultsThe MADRS score was significantly increased in stroke patients as compared with normal controls. The MADRS scale is not unidimensional and cannot be used as an accurate indicator of depression severity in stroke patients. Three months after stroke, key depressive (sadness and inability to feel) and concentration-tension symptoms, and lassitude are significantly predicted by the infarct volume. Right side infarction strongly predicts key depressive symptoms and left side infarction strongly predicts concentration-tension and lassitude scores. Total WMHs significantly predict key depressive and concentration-tension symptoms, and lassitude, with these effects being mediated by right and left DWI stroke volumes and associated disabilities. ConclusionsInteractions between age, hypertension, a chronic atherosclerotic process, and acute stroke account for the onset of key depressive symptoms three months after the acute infarct. Chronic and acute neuro-immune and neuro-oxidative stress pathways associated with the formation of WMHs and acute stroke may explain the incidence of post-stroke key depressive and concentration-tension symptoms, and lassitude.

Abstract TP18: Progressive White Matter Degeneration After Ischemic Stroke

Background: White matter degeneration after ischemic stroke may herald post-stroke cognitive decline. FLAIR white matter hyperintensity (WMH) reflects tissue injury and accumulates around the infarct and in remote regions. But WMH volumetry is insensitive to regional or short-term progression. We compared WMH volumetry to a voxel-wise approach for detecting FLAIR WMH change longitudinally after stroke. Methods: Ischemic stroke patients enrolled in an observational cohort study underwent serial MRI acutely, at 1 month and every 3 months thereafter. Patients with 6 to 12-month follow-ups were included. WMH lesion volumes were automatically segmented on serial FLAIR MRI. In the hemisphere contralateral to the infarct from 30 days onward, we compared longitudinal change in WMH volume to a voxel-wise regression of FLAIR signal change over time. We used T1 images as an intermediate to nonlinearly align serial FLAIR images to individual templates. FLAIR intensities were normalized, corrected for local expansion/contraction, and smoothed. Within voxels identified as lesion at any timepoint, significant WMH change was determined relative to the normal appearing white matter and converted to a percentage of the intracranial volume. Results: 22 ischemic stroke patients (mean age 73 ± 8 years, NIHSS 4 ± 4, infarct volume 10.3 ± 23 cc) had on average 3 follow-ups over 343 days. In the non-stroke hemisphere, volumetry revealed lesion growth in 12. Mean lesion increase was 0.01 ± 0.20% per year. In voxel-wise analysis 15 patients had increasing FLAIR signal. Intensity increased in mean 0.11 ± 0.23% of intracranial voxels. Lesion growth was associated with the volume of voxel-wise signal increase (Beta = 0.51, p = 0.018). In the stroke hemisphere, progressive WMH expansion of peri-infarct tissue, consistent with Wallerian degeneration, was present in 10 patients. WMH regression, consistent with atrophy and infarct cavitation, was present in 14. Stroke hemisphere WMH expansion was associated with initial NIHSS (B = 0.58, p = 0.0086) while regression was associated with acute infarct volume (B = 0.80, p &lt; 0.001). Conclusions: Voxel-wise longitudinal WMH analysis detects progressive white matter degradation and regional variation continuing 30 days after stroke.

Phenotype Shifting in Astrocytes Account for Benefits of Intra-Arterial Selective Cooling Infusion in Hypertensive Rats of Ischemic Stroke

The translational failure of neuroprotective therapies in stroke may be influenced by the mismatch of existing comorbidities between animal models and patients. Previous studies found that single-target neuroprotective agents reduced infarction in Sprague–Dawley but not in spontaneously hypertensive rats. It is of great interest to explore whether multi-target neuroprotectants and stroke models with comorbidities should be used in further translational researches. Ischemic stroke was induced in normotensive or hypertensive rats by 90- or 120-min middle cerebral artery occlusion (MCAO) and reperfusion. Intra-Arterial Selective Cooling Infusion (IA-SCI) was started at the onset of reperfusion for 30 minutes. Acute neurological deficits, infarct volumes, gene expression and markers of A1-like and A2-like astrocytes were evaluated. In further analysis, TNFα and IL-1α were administrated intracerebroventricularly, phenotype shifting of astrocytes and infarct volumes were assessed. Normobaric oxygen treatment, as a negative control, was also assessed in hypertensive rats. IA-SCI led to similar benefits in normotensive rats with 120-min MCAO and hypertensive rats with both 90-min and 120-min MCAO, including mitigated functional deficit and reduced infarct volumes. IA-SCI shifted astrocyte phenotypes partly by downregulating A1-like astrocytes and upregulating A2-like astrocytes in both RNA and protein levels. Upregulated A1-type astrocyte markers levels, induced by intracerebroventricular injection of TNFα and IL-1α, were closely related to increased infarct volumes in hypertensive rats, despite receiving IA-SCI treatment. In addition, infarct volumes and A1/A2-like genes were not affected by normobaric oxygen treatment. IA-SCI reduced infarction in both normotensive and hypertensive rats. Our results demonstrated the neuroprotective effects of IA-SCI in hypertensive rats may be related with phenotype shifting of astrocytes.

Abstract P317: White Matter Hyperintensity Lesion Burden Modulates Functional Outcome After Acute Ischemic Stroke

Introduction: As a radiographic signature of end-stage small vessel disease, white matter hyperintensity (WMH) burden impacts recovery and outcomes after acute ischemic stroke (AIS). In this study, we sought to investigate the effect of WMH volume (WMHv) on stroke severity and functional outcomes independent of the infarct size and topography. Methods: We analyzed 503 AIS patients with MRI data obtained on admission for index stroke enrolled in the multi-center MRI-GENIE study (cohort 1), followed by validation of the findings in an independent single-site study of 555 AIS patients (cohort 2). Stroke severity (NIHSS score) at index stroke and the long-term outcome (3-6 months mRS score) were modeled via Bayesian linear regression. Models included WMHv, age, sex, a 10-dimensional spatial ischemic lesion representation, acute infarct (DWI) volume, and common vascular risk factors (hypertension, diabetes mellitus, atrial fibrillation, coronary artery disease). Results: Cohorts did not differ significantly in major clinical characteristics [cohort 1: age: 65.0±14.6, 41% female, NIHSS: 5.5±5.4, mRS: 1(iqr 2); cohort 2: age: 65.0±14.8, 38% female, NIHSS: 5.0±6.0, mRS: 1(iqr 3), p &gt;0.05 for all comparisons]. WMHv did not substantially affect AIS severity ( Fig A ); in contrast, it emerged as an independent predictor of functional outcome in both datasets ( Fig B ). Conclusions: When accounted for AIS lesion topography and stroke volume, total WMH lesion burden did not appear to modulate initial stroke severity but was associated with worse functional post-stroke outcomes. Future studies are needed to explore potential origins of these detrimental effects of pre-existing WMH burden on recovery after AIS.

White Matter Acute Infarct Volume After Thrombectomy for Anterior Circulation Large Vessel Occlusion Stroke is Associated with Long Term Outcomes

ObjectivesDespite the proven efficacy of endovascular thrombectomy (EVT) for large vessel occlusion stroke, over half treated remain functionally disabled or die. Infarct topography may have implications for prognostication, patient selection, and the development of tissue-specific neuroprotective agents. We sought to quantify white matter injury in anterior circulation acute infarcts post-EVT to understand its significance and identify its determinants. Materials and MethodsDemographics, history, presentations, and outcomes for consecutive patients treated with EVT were recorded in a prospectively maintained database at a single center. Acute infarct masks were coregistered to standard space. Standard atlases of white matter, cortex, and basal ganglia were used to determine region-specific infarct volumes. Results167 individuals were identified with median age 69 years and 53% women. 85% achieved adequate reperfusion (TICI 2b-3) after EVT; 43% achieved 90-day functional independence (mRS 0-2). Median infarct volumes were 45cc (IQR 18-122) for total, 17cc (6-49) for white matter, 21cc (4-53) for cortex, and 5cc (1-8) for basal ganglia. The odds of 90-day mRS 0-2 were reduced in patients with larger white matter infarct volume (cc, OR=0.89, 95%CI=0.81-0.96), independent of cortex infarct volume, basal ganglia infarct volume, age, NIHSS, and TICI 2b-3 reperfusion. Reperfusion-to-MRI time was associated with white matter infarct volume (hr, β=0.119, p=0.017), but not cortical or basal ganglia infarct volume. ConclusionsThese data quantitatively describe region-specific infarct volumes after EVT and suggest the clinical relevance of white matter infarct volume as a predictor of long-term outcomes. Further study is warranted to examine delayed white matter infarction and the significance of specific white matter tracts.

Characterizing spatiotemporal progression and prediction of infarct lesion volumes in experimental acute ischemia using quantitative perfusion and diffusion imaging

PurposeThis study was conducted to explore the diagnostic value of arterial spin labeling (ASL) combined with diffusion weighted imaging (DWI) in characterizing the spatiotemporal progression of infarct lesions in a rabbit middle cerebral artery occlusion (MCAO) model and predicting the acute cerebral infarction (ACI) volume. Materials and methodsForty-two male rabbits (2.9 ± 0.2 kg body weight) were used in this experimental study. Animals were initially anesthetized by intravenous injection of uratan. There were seven experimental groups with six rabbits in each group. The apparent diffusion coefficient (ADC) and cerebral blood flow (CBF) thresholds were established in the control group (n = 6), which were sacrificed at 12 h, stained for infarct volume, and imaged at each time point. ResultsThe normal ADC and CBF were estimated as 0.90 ± 0.03 × 10−3 mm2/s and 0.68 ± 0.06 mL g−1 min−1, respectively. The viability thresholds of ADC and CBF yielding the lesion volumes (LVs) at 3 h, which best approximated the 2,3,5-triphenyltetrazolium chloride (TTC) infarct volumes at 12 h, were 0.52 ± 0.02 × 10−3 mm2/s (42.2 ± 3% reduction) and 0.33 ± 0.09 mL g−1 min−1 (51.0 ± 11% reduction), respectively. The temporal evolution of the ADC- and CBF-defined LVs showed a significant perfusion/diffusion mismatch up to 1 h (p = 0.001). ConclusionADC values and ACI volumes were positively correlated, while CBF was negatively correlated, which is supposed to be a reference for predicting ACI volume.

Reliability and Reproducibility of the Diameters Method in Rapid Determination of Acute Infarct Volume in Magnetic Resonance Diffusion-Weighted Imaging

Background: In acute ischemic stroke, diffusion-weighted imaging (DWI) volume is an independent predictive factor of poor outcome and an exclusion criterion for thrombolytic treatment. A simplified diameters method (ABC/2, orthogonal diameter [OD], and the maximum diameter [MD]) was proposed to replace the conventional measuring method and overcome the tedious and time-consuming defects, but its accuracy remains to be determined. Objective: The objective of this study is to clarify the reliability and reproducibility of the diameter-based estimations in the infarct volume in DWI (Vol-DWI) measured by automated software. Methods: Data of 316 patients with acute ischemic stroke who underwent MRI within 72 h at Jinling Hospital were retrospectively reviewed. Subgroup analysis by the location (cortex, white matter and deep gray nuclei, and combined) and volume (<70 and >70 mL) of cerebral infarction was evaluated. Relationship and consistency between the diameters methods and Vol-DWI were determined using Spearman rank correlation, Wilcoxon signed-rank test, and Bland-Altman plots. The OD and MD thresholds indicating infarct size >15, 70, and 100 mL were determined by generating receiver-operating characteristic (ROC) curves. Interobserver reliability was established using intraclass correlation coefficient and Bland-Altman plot. Results: There was a strong positive correlation between the diameters and the Vol-DWI (ABC/2: r = 0.992, OD: r = 0.984, MD: r = 0.970, p < 0.001). Infarct volumes measured using the ABC/2 formula were significantly lower than those measured with Vol-DWI (Wilcoxon signed-rank test, z = 6.476, p < 0.001). Bland-Altman plot showed that the agreement of the volume <70 mL group, and white matter and deep gray nuclei groups was better than that of the other subgroups. For infarct volumes >15, 70, and 100 mL, the cutoff value for the MD was identified at 5, 6.9, and 8.4 cm, and the OD was identified at 12.47, 26.4, and 36.4 cm², respectively, with a sensitivity and specificity >90%. Conclusions: The MD method was the best for achieving a rapid and excellent interobserver reliability for estimating infarct volume. Both OD and MD methods can quickly screen patients suitable for recanalization treatment and predict poor prognosis through threshold evaluation.

Higher level of acute serum VEGF and larger infarct volume are more frequently associated with post-stroke cognitive impairment

Serum vascular endothelial growth factor (VEGF) and infarct volume detected by brain imaging have been associated with stroke outcome. However, the relationship of these two variables with post-stroke cognitive impairment (PSCI) remains unclear. We aimed to investigate the association between acute serum VEGF levels and infarct volume with PSCI in ischemic stroke patients. Fifty-six first-ever ischemic stroke patients who were hospitalized in Dr. Sardjito General Hospital Yogyakarta, Indonesia were prospectively recruited. Serum VEGF level was taken on day 5 of stroke onset and measured by ELISA. Infarct volume was calculated manually from head CT scan by expert radiologist. PSCI was assessed after 3 months follow up by using Montreal Cognitive Assessment-Indonesian version (MoCA-INA). We performed a ROC curve analysis to determine the cut-off point of VEGF level and infarct volume. Multivariate logistic regression analysis was performed to measure the contribution of VEGF level and infarct volume to PSCI after controlling covariates (demographic and clinical data). The mean age of PSCI and non-PSCI patients was 61.63% ± 8.47 years and 58.67% ± 9.01 years, respectively (p = 0.221). No differences observed for vascular risk factors, infarct location, and NIHSS in both groups. Multivariate logistic regression showed that patients with higher VEGF level alone (≥519.8 pg/ml) were 4.99 times more likely to have PSCI than those with lower VEGF level (OR = 4.99, 95% CI = 1.01-24.7, p = 0.048). In addition, patients with larger infarct volume alone (≥0.054 ml) were also more frequently associated with PSCI (OR = 7.71, 95% CI = 1.39-42.91, p = 0.019). Acute ischemic stroke patients with higher serum VEGF level (≥519.8 pg/ml) and larger infarct volume (≥0.054 ml) were more likely to have PSCI 3 months after stroke. These findings may contribute to predict PSCI earlier and thus better prevention strategy could be made.

Rapamycin Induces an eNOS (Endothelial Nitric Oxide Synthase) Dependent Increase in Brain Collateral Perfusion in Wistar and Spontaneously Hypertensive Rats.

Rapamycin is a clinically approved mammalian target of rapamycin inhibitor that has been shown to be neuroprotective in animal models of stroke. However, the mechanism of rapamycin-induced neuroprotection is still being explored. Our aims were to determine if rapamycin improved leptomeningeal collateral perfusion, to determine if this is through eNOS (endothelial nitric oxide synthase)-mediated vessel dilation and to determine if rapamycin increases immediate postreperfusion blood flow. Wistar and spontaneously hypertensive rats (≈14 weeks old, n=22 and n=15, respectively) were subjected to ischemia by middle cerebral artery occlusion (90 and 120 minutes, respectively) with or without treatment with rapamycin at 30-minute poststroke. Changes in middle cerebral artery and collateral perfusion territories were measured by dual-site laser Doppler. Reactivity to rapamycin was studied using isolated and pressurized leptomeningeal anastomoses. Brain injury was measured histologically or with triphenyltetrazolium chloride staining. In Wistar rats, rapamycin increased collateral perfusion (43±17%), increased reperfusion cerebral blood flow (16±8%) and significantly reduced infarct volume (35±6 versus 63±8 mm3, P<0.05). Rapamycin dilated leptomeningeal anastomoses by 80±9%, which was abolished by nitric oxide synthase inhibition. In spontaneously hypertensive rats, rapamycin increased collateral perfusion by 32±25%, reperfusion cerebral blood flow by 44±16%, without reducing acute infarct volume 2 hours postreperfusion. Reperfusion cerebral blood flow was a stronger predictor of brain damage than collateral perfusion in both Wistar and spontaneously hypertensive rats. Rapamycin increased collateral perfusion and reperfusion cerebral blood flow in both Wistar and comorbid spontaneously hypertensive rats that appeared to be mediated by enhancing eNOS activation. These findings suggest that rapamycin may be an effective acute therapy for increasing collateral flow and as an adjunct therapy to thrombolysis or thrombectomy to improve reperfusion blood flow.

Impact of slice thickness on clinical utility of automated Alberta Stroke Program Early Computed Tomography Scores.

The clinical utility of electronically derived ASPECTS (e-ASPECTS) to quantify signs of acute ischemic infarction could be demonstrated in multiple studies. Here, we aim to clinically validate the impact of CT slice thickness (ST) on the performance of e-ASPECTS software. A consecutive series of n = 258 patients (06/2016 and 01/2019) with middle cerebral artery occlusion and subsequent treatment with mechanical thrombectomy was analyzed. The e-ASPECTS score and acute infarct volumes were calculated from baseline non-contrast CT with a software using 1-mm slice thickness (ST) (defined as ground truth) and axial reconstructions with 2-10-mm ST and correlated with baseline stroke severity (NIHSS) as well as clinical outcome (mRS) using logistic regressions. In comparison with the ground truth, significant differences were seen in e-ASPECTS scores with ST > 6mm (p ≤ 0.031) and infarct volumes with ST > 4mm (p ≤ 0.001). There was a significant correlation of lower e-ASPECTS and higher acute infarct volumes with increasing baseline NIHSS values for all ST (p ≤ 0.001, respectively), with values derived from 1mm yielding the highest correlation for both parameters (rho, - 0.38 and 0.31, respectively). Similarly, lower e-ASPECTS and higher acute infarct volumes from all ST were significantly associated with poor outcome after 90days (p ≤ 0.05, respectively) with values derived from 1-mm ST yielding the highest effects for both parameters (OR, 0.69 [95% CI 0.50-0.88] and 1.27 [95% CI 1.10-1.50], respectively). The e-ASPECTS software generates robust values for e-ASPECTS and acute infarct volumes when using ST ≤ 4mm with ST = 1mm yielding the best performance for predicting baseline stroke severity and clinical outcome after 90days. • Clinical utility of automatically derived ASPECTS from computed tomography scans was shown in patients with acute ischemic stroke and treatment with mechanical thrombectomy. • Thin slices (= 1mm) had the highest clinical utility in comparison with thicker slices (2-10mm) by having the strongest correlation with baseline stroke severity and independent effects on clinical outcome after 90days. • Automatically calculated acute infarct volumes possess clinical utility beyond ASPECTS and should be considered in future studies.

Abstract 180: Women Have Higher Neurological Severity and Worse Functional Outcome Than Men With Similar Infarct Volume and Leukoaraiosis Burden

Background: Women, compared with men, tend to have worse functional outcome after stroke. The gender effect is not fully explained by age, pre-stroke dependency, and stroke severity. We hypothesized that it might be due to different prognostic impacts of stroke-related brain lesions in women vs. men. Objective: To investigate if the effects of acute infarct volume and white matter hyperintensity (WMH) volume on initial stroke severity and 3-month functional outcome are modified by gender. Methods: This prospective study included 6748 patients with acute ischemic stroke (&lt;1-week) recruited (May 2011 to February 2013) consecutively from 11 academic stroke centers. The volumes (% of brain parenchyma) of acute infarct and WMH were measured in all patients by using diffusion-weighted magnetic resonance images (MRIs) and fluid-attenuated inversion recovery MRIs. Multivariable analyses were performed to test gender-related interactions in the relationship of MR lesion (infarct or WMH) volume (quartiles) with admission NIH stroke scale (NIHSS) score or 3-month modified Rankin scale (mRS) score, after adjusting for relevant covariates. Results: Women, compared with men, were older (mean 72 vs. 65, p&lt;0.01), and had more risk factors, a higher admission NIHSS score (median 4 vs. 3; p&lt;0.01), and a higher WMH volume (median 0.98% vs. 0.74%, p&lt;0.01). Acute infarct volume was not different between the two groups (median 0.15% vs. 0.16%, p=0.27), however its impact on the NIHSS score was greater in women than in men (adjusted analysis, p&lt;0.01). At 3 months, women had worse functional outcome than men (mRS&gt;2: adjusted OR [95%], 1.36 [1.09-1.69]). The association of WMH volume with 3-month mRS score was significantly modified by gender (p-for-interaction=0.049), with the WMH effect being greater in women (adjusted ORs of the highest vs. lowest quartile for the worse outcome: 2.47 in women vs. 1.51 in men). Conclusion: Women, compared with men, are probably more susceptible to the adverse effects of infarct volume and WMH volume on stroke severity and functional outcome.

Abstract WMP84: Effects of a New Thrombolytic Compound DC007d in Acute Brain Tissue Damage After Focal Embolic Stroke in Rats

Background and Purpose: DC007D is a novel small molecule designed to have thrombolytic and free radical scavenging activities. In this study, we aimed to test the potential neuroprotective effects of DC007D in embolic clot model of focal ischemic stroke in rats. Methods: All animals received intravenous infusion of either saline, 10 mg/kg DC007D or 10 mg/kg tPA at each experimental time point (1.5, 3 and 4.5 hrs after stroke, respectively). In first set of experiments, animals were treated at 1.5-hr after stroke. We performed a time course of multi-parametric MRI analysis including perfusion, diffusion and T2 relaxation. Brain infarction size and swelling rate were measured by TTC staining at 24 hrs after stroke. Next, in 3- and 4.5-hrs treatment experiments, we examined acute brain infarct volume, brain swelling rate, hemorrhagic transformation, neurological deficits. Additionally, we also tested potentially direct neuroprotection effects of DC007D in a mechanical filament pMCAO rat model. Lastly, the effect of DC007D in tPA activity in vitro, INR, and serum levels of tPA and PAI-1 activities in vivo at 24 hrs after stroke were assessed and compared. Results: Both tPA and DC007D treated at 1.5 hrs after stroke reduced hypoperfused area, diffusion, T2 lesion size and TTC-stained infarction. When treated at 3 hrs after stroke, DC007D had significantly better therapeutic effects in reducing brain infarction size, swelling rate and hemorrhagic transformation compared to conventional tPA treatment group. When treated at 4.5 hrs after stroke, both tPA and DC007D had no effects in brain infarction. However, tPA, but not DC007D, significantly increased brain swelling and intracerebral hemorrhagic transformation compared to saline controls. Our experimental results also showed that DC007D failed to have direct neuroprotection in the mechanical pMCAO rat model. Lastly, DC007D did not interfere tPA activity in vitro, and also did not significantly alter INR, serum levels of tPA and PAI-1 activities post stroke in vivo. Conclusions: DC007D is neuroprotective to embolic focal stroke of rats, likely via tPA/PAI-1 activity independent thrombolytic mechanism. It might be developed as a new and novel thrombolytics or adjunct for tPA thrombolytic reperfusion therapy.

History of Migraine and Volume of Brain Infarcts: The Italian Project on Stroke at Young Age (IPSYS).

Background and PurposeMigraine has been shown to increase cerebral excitability, promote rapid infarct expansion into tissue with perfusion deficits, and result in larger infarcts in animal models of focal cerebral ischemia. Whether these effects occur in humans has never been properly investigated. MethodsIn a series of consecutive patients with acute ischemic stroke, enrolled in the setting of the Italian Project on Stroke at Young Age, we assessed acute as well as chronic infarct volumes by volumetric magnetic resonance imaging, and compared these among different subgroups identified by migraine status. ResultsA cohort of 591 patients (male, 53.8%; mean age, 37.5±6.4 years) qualified for the analysis. Migraineurs had larger acute infarcts than non-migraineurs (median, 5.9 cm3 [interquartile range (IQR), 1.4 to 15.5] vs. 2.6 cm3 [IQR, 0.8 to 10.1], P<0.001), and the largest volumes were observed in patients with migraine with aura (median, 9.0 cm3 [IQR, 3.4 to 16.6]). In a linear regression model, migraine was an independent predictor of increased log (acute infarct volumes) (median ratio [MR], 1.64; 95% confidence interval [CI], 1.22 to 2.20), an effect that was more prominent for migraine with aura (MR, 2.92; 95% CI, 1.88 to 4.54). ConclusionsThese findings reinforce the experimental observation of larger acute cerebral infarcts in migraineurs, extend animal data to human disease, and support the hypothesis of increased vulnerability to ischemic brain injury in people suffering migraine.

Abstract TP185: Acute Infarct Location and Volume Predicts Rehab Outcomes After Ischemic Stroke

Objective: We evaluated the association between acute infarct location and volume with outcome measures during inpatient rehabilitation facility (IRF) in ischemic stroke patients. Methods: Between 2012 and 2014, we prospectively enrolled consecutive acute ischemic stroke (AIS) patients admitted from a Comprehensive Stroke Center and followed to an IRF in Chicago, Illinois. Their lesion locations and infarct volumes were calculated. The Functional Independence Measure (FIM) measure was extracted. We analyzed the association between acute infarct characteristics and functional measures using adjusted Spearman’s correlation. Results: Among 162 AIS patients (mean age 67.6 years, 48.1% male, 58.6% Caucasian), the median FIM was 52 (IQR 36-62). In adjusted analysis, patients with larger infarct volumes in the left basal ganglia ( r s =-0.44, p=0.02) and frontal lobe ( r s =-0.35, p=0.04) had lower FIM scores. Conclusions and Relevance: There is a strong association between acute infarct volume and specific locations and subsequent FIM scores assessed during AIF. Our findings indicate that functional outcomes can be predicted earlier using index stroke imaging, opening opportunities for targeted rehabilitation.

Abstract WMP116: Acute Infarct Volume in Childhood Stroke Can Be Accurately Estimated by Modelling Contraction of Chronic Infarction

Introduction: Arterial ischemic stroke (AIS) occurs in 1-2 children/100,000/year. Most children have neurologic deficits post-AIS, but the influence of infarct volume on neurologic outcome is understudied. While acute infarct volume {best measured as a percentage of total brain volume infarcted (%aTBVi) in the growing brain} likely predicts outcome, acute scans are not always available in children. Chronic infarct volumes are underestimated by direct measurement due to contraction. A method for estimating acute infarct volumes from chronic scans is needed. We developed and compared the reliability of three methods for estimating the %aTBVi from values measured on chronic images. Methods: A retrospective IRB-approved study studying children (age 1 month-17 years) with AIS enrolled 158 patients. Those with acute (&lt;3 days) and chronic (&gt;90 days) MRIs were manually segmented by a pediatric neuroradiologist. Method 1 (direct method, used as control) estimated %aTBVi by measuring chronic infarct volume (cVI) and dividing by total brain volume. Method 2 (OFC method) estimated %aTBVi by subtracting the total non-infarcted brain volume from an extrapolated total brain volume based on orbitofrontal circumference (OFC). Method 3 (contraction method, Figure 1) used a regression model to apply a correction factor to the direct measurement of cVI that was then divided by total brain volume to estimate %aTBVi. Intraclass correlation compared estimated %aTBVi of the three methods to the gold standard %aTBVi calculated from manual segmentation of acute scans. Results: Inclusion criteria were met by 86 patients. The control direct method had excellent reliability (ICC 0.79), although it was exceeded by the contraction method (Figure 1, ICC=0.86), while the OFC method reliability was poor (ICC=0.42). Conclusion: %aTBVi is reliably estimated in children with AIS with only chronic imaging via the contraction method.