High blood glutamate oxaloacetate transaminase levels are associated with good functional outcome in acute ischemic stroke

The capacity of the blood enzyme glutamate oxaloacetate transaminase (GOT) to remove glutamate from the brain by means of blood glutamate degradation has been shown in experimental models to be an efficient and novel neuroprotective tool against ischemic stroke; however, the beneficial effects of this enzyme should be tested in patients with stroke to validate these results. This study aims to investigate the association of GOT levels in blood with clinical outcome in patients with acute ischemic stroke. In two clinical independent studies, we found that patients with poor outcome show higher glutamate and lower GOT levels in blood at the time of admission. Lower GOT levels and higher glutamate levels were independently associated with poorer functional outcome at 3 months and higher infarct volume. These findings show a clear association between high blood glutamate levels and worse outcome and vice versa for GOT, presumably explained by the capacity of this enzyme to metabolize blood glutamate.

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Abstract P343: Relationship of Infarct Volume to Inflammation and Prognostic Significance in Patients With Acute Ischemic Stroke

Stroke ◽

10.1161/str.52.suppl_1.p343 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Lingling Ding ◽

Zixiao Li ◽

Yongjun Wang

Keyword(s):

Ischemic Stroke ◽

Deep Learning ◽

Acute Ischemic Stroke ◽

Functional Outcome ◽

Acute Inflammation ◽

Infarct Volume ◽

Prognostic Significance ◽

Stroke Recurrence ◽

Vascular Events ◽

Poor Functional Outcome

Background and Purpose: The diffusion weighted imaging (DWI) lesion volumes in acute ischemic stroke (AIS) can be automatically measured using deep learning-based segmentation algorithms. We aim to explore the prognostic significance of artificial intelligence-predicted infarct volume, and the association of markers of acute inflammation with the infarct volume. Methods: 12,598 AIS/TIA patients were included in this analysis. Intarct volume was automatically measured using a U-Net model for acute ischemic stroke lesion segmentation on DWI. Participants were divided into 5 subgroups according to infarct volume. Spearman’s correlations were employed to study the association between infarct volume and markers of acute inflammation. Multivariable logistic regression and Cox proportional hazards model were performed to explore the relationship between infarct volume and the incidence of poor functional outcome (modified Rankin scale score 3-6), stroke recurrence or combined vascular events at 3 months. Results: The U-Net model prediction correlated and agreed well with manual annotation ground truth for infarct volume (r=0.96; P<0.001). There were positive correlations between the infarct volume and markers of acute inflammation (neutrophil [r=0.175; P<0.001], hs-CRP [r=0.180; P<0.001], and IL-6 [r=0.225; P<0.001]). Compared with those without DWI lesions, patients with the largest infarct volume (4th Quartile) were nearly five times more likely to have poor functional outcome (mRS 3-6) (adjusted odds ratio, 4.70; 95% confidence intervals [CI], 3.29-6.72; P for trend<0.001) after adjustment for confounding factors and markers of acute inflammation. The infarct volume category was significantly associated with stroke recurrence (adjusted hazard ratios [HRs], 1.0, 1.43[0.95,2.17], 2.22[1.49,3.29], 2.06[1.40,3.05], 2.26[1.52,3.36]; P for trend<0.001) and combined vascular events(adjusted HRs, 1.0, 1.38[0.92,2.09], 2.25[1.53,3.32], 2.03[1.38,2.98], 2.28[1.54,3.36]; P for trend<0.001). Conclusions: Infarct volume measured automatically by deep learning-based tool was a strong predictor of poor functional outcome as well as stroke recurrence, with the potential for widespread adoption in both research and clinical settings.

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Abstract WMP15: Automated Volumetric Assessment of Infarct Core in Non-Contrast Computed Tomography in Patients With Acute Ischemic Stroke Secondary to Large Vessel Occlusion

Stroke ◽

10.1161/str.51.suppl_1.wmp15 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Alvaro Garcia-Tornel ◽

Matias Deck ◽

Marc Ribo ◽

David Rodriguez-Luna ◽

Jorge Pagola ◽

...

Keyword(s):

Computed Tomography ◽

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Functional Outcome ◽

Infarct Volume ◽

Large Vessel Occlusion ◽

Infarct Core ◽

Vessel Occlusion ◽

Good Functional Outcome ◽

Volumetric Assessment

Introduction: Perfusion imaging has emerged as an imaging tool to select patients with acute ischemic stroke (AIS) secondary to large vessel occlusion (LVO) for endovascular treatment (EVT). We aim to compare an automated method to assess the infarct ischemic core (IC) in Non-Contrast Computed Tomography (NCCT) with Computed Tomography Perfusion (CTP) imaging and its ability to predict functional outcome and final infarct volume (FIV). Methods: 494 patients with anterior circulation stroke treated with EVT were included. Volumetric assessment of IC in NCCT (eA-IC) was calculated using eASPECTS™ (Brainomix, Oxford). CTP was processed using availaible software considering CTP-IC as volume of Cerebral Blood Flow (CBF) <30% comparing with the contralateral hemisphere. FIV was calculated in patients with complete recanalization using a semiautomated method with a NCCT performed 48-72 hours after EVT. Complete recanalization was considered as modified Thrombolysis In Cerebral Ischemia (mTICI) ≥2B after EVT. Good functional outcome was defined as modified Rankin score (mRs) ≤2 at 90 days. Statistical analysis was performed to assess the correlation between EA-IC and CTP-IC and its ability to predict prognosis and FIV. Results: Median eA-IC and CTP-IC were 16 (IQR 7-31) and 8 (IQR 0-28), respectively. 419 patients (85%) achieved complete recanalization, and their median FIV was 17.5cc (IQR 5-52). Good functional outcome was achieved in 230 patients (47%). EA-IC and CTP-IC had moderate correlation between them (r=0.52, p<0.01) and similar correlation with FIV (r=0.52 and 0.51, respectively, p<0.01). Using ROC curves, both methods had similar performance in its ability to predict good functional outcome (EA-IC AUC 0.68 p<0.01, CTP-IC AUC 0.66 p<0.01). Multivariate analysis adjusted by confounding factors showed that eA-IC and CTP-IC predicted good functional outcome (for every 10cc and >40cc, OR 1.5, IC1.3-1.8, p<0.01 and OR 1.3, IC1.1-1.5, p<0.01, respectively). Conclusion: Automated volumetric assessment of infarct core in NCCT has similar performance predicting prognosis and final infarct volume than CTP. Prospective studies should evaluate a NCCT-core / vessel occlusion penumbra missmatch as an alternative method to select patients for EVT.

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Abstract WMP17: Computerized Tomography Perfusion to Characterize Lack of Clinical Improvement After Recanalization in Acute Ischemic Stroke

Stroke ◽

10.1161/str.51.suppl_1.wmp17 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Alvaro Garcia-Tornel ◽

Marta Olive-Gadea ◽

Marc Ribo ◽

David Rodriguez-Luna ◽

Jorge Pagola ◽

...

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Functional Outcome ◽

Infarct Volume ◽

Significant Proportion ◽

Hemorrhagic Transformation ◽

Vessel Occlusion ◽

Clinical Recovery ◽

Good Functional Outcome ◽

Significant Difference

A significant proportion of patients with acute ischemic stroke (AIS) treated with endovascular thrombectomy (EVT) present poor functional outcome despite recanalization. We aim to investigate computed tomography perfusion (CTP) patterns after EVT and their association with outcome Methods: Prospective study of anterior large vessel occlusion AIS patients who achieved complete recanalization (defined as modified Thrombolysis in Cerebral Ischemia (TICI) 2b - 3) after EVT. CTP was performed within 30 minutes post-EVT recanalization (POST-CTP): hypoperfusion was defined as volume of time to maximal arrival of contrast (Tmax) delay ≥6 seconds in the affected territory. Hyperperfusion was defined as visual increase in cerebral blood flow (CBF) and volume (CBV) with advanced Tmax compared with the unaffected hemisphere. Dramatic clinical recovery (DCR) was defined as a decrease of ≥8 points in NIHSS score at 24h or NIHSS≤2 and good functional outcome by mRS ≤2 at 3 months. Results: One-hundred and forty-one patients were included. 49 (34.7%) patients did not have any perfusion abnormality on POST-CTP, 60 (42.5%) showed hypoperfusion (median volume Tmax≥6s 17.5cc, IQR 6-45cc) and 32 (22.8%) hyperperfusion. DCR appeared in 56% of patients and good functional outcome in 55.3%. Post-EVT hypoperfusion was related with worse final TICI, and associated worse early clinical evolution, larger final infarct volume (p<0.01 for all) and was an independent predictor of functional outcome (OR 0.98, CI 0.97-0.99, p=0.01). Furthermore, POST-CTP identified patients with delayed improvement: in patients without DCR (n=62, 44%), there was a significant difference in post-EVT hypoperfusion volume according to functional outcome (hypoperfusion volume of 2cc in good outcome vs 11cc in poor outcome, OR 0.97 CI 0.93-0.99, p=0.04), adjusted by confounding factors. Hyperperfusion was not associated with worse outcome (p=0.45) nor symptomatic hemorrhagic transformation (p=0.55). Conclusion: Hypoperfusion volume after EVT is an accurate predictor of functional outcome. In patients without dramatic clinical recovery, hypoperfusion predicts good functional outcome and defines a “stunned-brain” pattern. POST-CTP may help to select EVT patients for additional therapies.

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Preliminary Application of a Quantitative Collateral Assessment Method in Acute Ischemic Stroke Patients With Endovascular Treatments: A Single-Center Study

Frontiers in Neurology ◽

10.3389/fneur.2021.714313 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ruoyao Cao ◽

Peng Qi ◽

Yun Jiang ◽

Shen Hu ◽

Gengfan Ye ◽

...

Keyword(s):

Ischemic Stroke ◽

Clinical Outcome ◽

Acute Ischemic Stroke ◽

Collateral Circulation ◽

Ct Perfusion ◽

Infarct Volume ◽

Assessment Method ◽

Outcome Evaluation ◽

Analysis Time ◽

Independent Predictive Factor

Objectives: To develop an efficient and quantitative assessment of collateral circulation on time maximum intensity projection CT angiography (tMIP CTA) in patients with acute ischemic stroke (AIS).Methods: Eighty-one AIS patients who underwent one-stop CTA-CT perfusion (CTP) from February 2016 to October 2020 were retrospectively reviewed. Single-phase CTA (sCTA) and tMIP CTA were developed from CTP data. Ischemic core (IC) volume, ischemic penumbra volume, and mismatch ratio were calculated. The Tan scale was used for the qualitative evaluation of collateral based on sCTA and tMIP CTA. Quantitative collateral circulation (CCq) parameters were calculated semi-automatically with software by the ratio of the vascular volume (V) on both hemispheres, including tMIP CTA VCCq and sCTA VCCq. Spearman correlation analysis was used to analyze the correlation of collateral-related parameters with final infarct volume (FIV). ROC and multivariable regression analysis were calculated to compare the significance of the above parameters in clinical outcome evaluation. The analysis time of the observers was also compared.Results: tMIP CTA VCCq (r = 0.61, p < 0.01), IC volume (r = 0.66, p < 0.01), Tan score on tMIP CTA (r = 0.52, p < 0.01) and mismatch ratio (r = 0.60, p < 0.01) showed moderate negative correlations with FIV. tMIP CTA VCCq showed the best prognostic value for clinical outcome (AUC = 0.93, p < 0.001), and was an independent predictive factor of clinical outcome (OR = 0.14, p = 0.009). There was no difference in analysis time of tMIP CTA VCCq among observers (p = 0.079).Conclusion: The quantitative evaluation of collateral circulation on tMIP CTA is associated with clinical outcomes in AIS patients with endovascular treatments.

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Endovascular Treatment Effect Diminishes With Increasing Thrombus Perviousness

Stroke ◽

10.1161/strokeaha.120.033124 ◽

2021 ◽

Author(s):

Manon Kappelhof ◽

Manon L. Tolhuisen ◽

Kilian M. Treurniet ◽

Bruna G. Dutra ◽

Heitor Alves ◽

...

Keyword(s):

Computed Tomography ◽

Ischemic Stroke ◽

Endovascular Treatment ◽

Acute Ischemic Stroke ◽

Functional Outcome ◽

Odds Ratio ◽

Infarct Volume ◽

Treatment Allocation ◽

Common Odds Ratio

Background and Purpose: Thrombus perviousness estimates residual flow along a thrombus in acute ischemic stroke, based on radiological images, and may influence the benefit of endovascular treatment for acute ischemic stroke. We aimed to investigate potential endovascular treatment (EVT) effect modification by thrombus perviousness. Methods: We included 443 patients with thin-slice imaging available, out of 1766 patients from the pooled HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke trials) data set of 7 randomized trials on EVT in the early window (most within 8 hours). Control arm patients (n=233) received intravenous alteplase if eligible (212/233; 91%). Intervention arm patients (n=210) received additional EVT (prior alteplase in 178/210; 85%). Perviousness was quantified by thrombus attenuation increase on admission computed tomography angiography compared with noncontrast computed tomography. Multivariable regression analyses were performed including multiplicative interaction terms between thrombus attenuation increase and treatment allocation. In case of significant interaction, subgroup analyses by treatment arm were performed. Our primary outcome was 90-day functional outcome (modified Rankin Scale score), resulting in an adjusted common odds ratio for a one-step shift towards improved outcome. Secondary outcomes were mortality, successful reperfusion (extended Thrombolysis in Cerebral Infarction score, 2B–3), and follow-up infarct volume (in mL). Results: Increased perviousness was associated with improved functional outcome. After adding a multiplicative term of thrombus attenuation increase and treatment allocation, model fit improved significantly ( P =0.03), indicating interaction between perviousness and EVT benefit. Control arm patients showed significantly better outcomes with increased perviousness (adjusted common odds ratio, 1.2 [95% CI, 1.1–1.3]). In the EVT arm, no significant association was found (adjusted common odds ratio, 1.0 [95% CI, 0.9–1.1]), and perviousness was not significantly associated with successful reperfusion. Follow-up infarct volume (12% [95% CI, 7.0–17] per 5 Hounsfield units) and chance of mortality (adjusted odds ratio, 0.83 [95% CI, 0.70–0.97]) decreased with higher thrombus attenuation increase in the overall population, without significant treatment interaction. Conclusions: Our study suggests that the benefit of best medical care including alteplase, compared with additional EVT, increases in patients with more pervious thrombi.

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Mediation of the Relationship Between Endovascular Therapy and Functional Outcome by Follow-up Infarct Volume in Patients With Acute Ischemic Stroke

JAMA Neurology ◽

10.1001/jamaneurol.2018.3661 ◽

2019 ◽

Vol 76 (2) ◽

pp. 194 ◽

Cited By ~ 16

Author(s):

Anna M. M. Boers ◽

Ivo G. H. Jansen ◽

Scott Brown ◽

Hester F. Lingsma ◽

Ludo F. M. Beenen ◽

...

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Functional Outcome ◽

Endovascular Therapy ◽

Infarct Volume ◽

The Relationship

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Serum YKL-40 Levels Correlate with Infarct Volume, Stroke Severity, and Functional Outcome in Acute Ischemic Stroke Patients

PLoS ONE ◽

10.1371/journal.pone.0051722 ◽

2012 ◽

Vol 7 (12) ◽

pp. e51722 ◽

Cited By ~ 14

Author(s):

Hyun Young Park ◽

Chang-Duk Jun ◽

Se-Jeong Jeon ◽

See-Sung Choi ◽

Hak-Ryul Kim ◽

...

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Functional Outcome ◽

Infarct Volume ◽

Stroke Severity ◽

Stroke Patients

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Abstract WP317: Neutrophil Subtypes and Nets Changes in Diabetes With Acute Ischemic Stroke

Stroke ◽

10.1161/str.51.suppl_1.wp317 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Sanxin Liu ◽

Wei Cai ◽

Mengyan Hu ◽

Zhengqi Lu

Keyword(s):

Flow Cytometry ◽

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Neutrophil Count ◽

Neurological Deficit ◽

Infarct Volume ◽

Immunofluorescence Staining ◽

Neurological Deficit Score ◽

Immunological Mechanisms ◽

The Brain

Objective: Ischemic stroke (AIS) is a globally high-risk cerebrovascular disease. Diabetes can aggravate ischemic stroke, while its mechanism is still unknown, Neutrophils are the first peripheral immune cells that break through the blood-brain barrier and infiltrate the brain after AIS. They have two polarization states of N1 and N2 subtypes. N1 subtype neutrophils can release neutrophil extracellular traps (NETs) containing a large number of pro-inflammatory factors and exacerbate the neuroinflammatory response. This study will explore the immunological mechanisms of diabetes exacerbating ischemic stroke. Methods: Patients with acute ischemic stroke who were admitted to hospital from Jan 2012 to Dec 2018 were collected, compared blood neutrophil count and neutrophil/lymphocyte ratio in diabetic and non-diabetic AIS patients at 1 day; Middle cerebral artery infarction (MCAO) mice was used for animal model of AIS, high-fat diet and STZ-induced type 2 diabetes model. The neurological deficit score, TTC staining, flow cytometry and immunofluorescence staining were used to observe the infarct volume, neutrophil subtypes and NETs changes between AIS with and without diabetes. Results: The neutrophil count of AIS patients with diabetes was higher than that of non-diabetic AIS patients. Animal experiments found that AIS with diabetes increase neurological deficit score and infarct volume. Flow cytometry and immunofluorescence staining found that AIS with diabetes mice can promote neutrophils infiltration into the brain and promote the polarization of neutrophils to N1 subtype and increase NETs formation. Conclusion: Diabetes can promote the neutrophil polarization of N1 subtype which leads to increased NETs formation and exacerbate ischemic stroke.

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Association of follow-up infarct volume with functional outcome in acute ischemic stroke: a pooled analysis of seven randomized trials

Journal of NeuroInterventional Surgery ◽

10.1136/neurintsurg-2017-013724 ◽

2018 ◽

Vol 10 (12) ◽

pp. 1137-1142 ◽

Cited By ~ 26

Author(s):

Anna M M Boers ◽

Ivo G H Jansen ◽

Ludo F M Beenen ◽

Thomas G Devlin ◽

Luis San Roman ◽

...

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Functional Outcome ◽

Imaging Modality ◽

Infarct Volume ◽

Pooled Analysis ◽

Acquisition Time ◽

Anterior Circulation ◽

Multivariable Regression Models

BackgroundFollow-up infarct volume (FIV) has been recommended as an early indicator of treatment efficacy in patients with acute ischemic stroke. Questions remain about the optimal imaging approach for FIV measurement.ObjectiveTo examine the association of FIV with 90-day modified Rankin Scale (mRS) score and investigate its dependency on acquisition time and modality.MethodsData of seven trials were pooled. FIV was assessed on follow-up (12 hours to 2 weeks) CT or MRI. Infarct location was defined as laterality and involvement of the Alberta Stroke Program Early CT Score regions. Relative quality and strength of multivariable regression models of the association between FIV and functional outcome were assessed. Dependency of imaging modality and acquisition time (≤48 hours vs >48 hours) was evaluated.ResultsOf 1665 included patients, 83% were imaged with CT. Median FIV was 41 mL (IQR 14–120). A large FIV was associated with worse functional outcome (OR=0.88(95% CI 0.87 to 0.89) per 10 mL) in adjusted analysis. A model including FIV, location, and hemorrhage type best predicted mRS score. FIV of ≥133 mL was highly specific for unfavorable outcome. FIV was equally strongly associated with mRS score for assessment on CT and MRI, even though large differences in volume were present (48 mL (IQR 15–131) vs 22 mL (IQR 8–71), respectively). Associations of both early and late FIV assessments with outcome were similar in strength (ρ=0.60(95% CI 0.56 to 0.64) and ρ=0.55(95% CI 0.50 to 0.60), respectively).ConclusionsIn patients with an acute ischemic stroke due to a proximal intracranial occlusion of the anterior circulation, FIV is a strong independent predictor of functional outcome and can be assessed before 48 hours, oneither CT or MRI.

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Sustained blood glutamate scavenging enhances protection in ischemic stroke

Communications Biology ◽

10.1038/s42003-020-01406-1 ◽

2020 ◽

Vol 3 (1) ◽

Author(s):

Ahlem Zaghmi ◽

Antonio Dopico-López ◽

María Pérez-Mato ◽

Ramón Iglesias-Rey ◽

Pablo Hervella ◽

...

Keyword(s):

Ischemic Stroke ◽

Infarct Volume ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Treated Group ◽

The Body ◽

Glutamate Oxaloacetate Transaminase ◽

Glutamate Scavenging ◽

Blood Glutamate Scavenging ◽

The Brain

AbstractStroke is a major cause of morbidity, mortality, and disability. During ischemic stroke, a marked and prolonged rise of glutamate concentration in the brain causes neuronal cell death. This study explores the protective effect of a bioconjugate form of glutamate oxaloacetate transaminase (hrGOT), which catalyzes the depletion of blood glutamate in the bloodstream for ~6 days following a single administration. When treated with this bioconjugate, a significant reduction of the infarct volume and a better retention of sensorimotor function was observed for ischemic rats compared to those treated with saline. Moreover, the equivalent dose of native hrGOT yielded similar results to the saline treated group for some tests. Targeting the bioconjugate to the blood-brain-barrier did not improve its performance. The data suggest that the bioconjugates draw glutamate out of the brain by displacing homeostasis between the different glutamate pools of the body.

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