Stroke Infarct Volume Research Articles

Time of day dependent reduction in stroke infarct volume by the Reverb agonist SR9009 in mice

Time of day dependent reduction in stroke infarct volume by the Reverb agonist SR9009 in mice

MRI-based Quantitative Collateral Assessment in Acute Stroke : AComparison with Single-phase CTA in Drip-and-ship Patients with Serial Imaging.

In acute ischemic stroke with large-vessel occlusion (LVO), collateral assessment with single-phase computed tomography angiography (CTA) might underestimate pial collateral supply in aconsiderable proportion of patients. We aimed to compare time-resolved magnetic resonance imaging (MRI)-based quantitative collateral mapping to conventional collateral imaging with CTA. This retrospective single-center study covering aperiod of 6years (2012-2018) included drip-and-ship LVO patients who underwent MR imaging after initial imaging evaluation with CT. For MRI-based collateral assessment, T2*-weighted time series from perfusion-weighted imaging (PWI) were processed to compute aquantitative collateral vessel index (CVIPWI) based on the magnitude of signal variance across the entire acquisition time. CTA-based collateral scores (Tan and Maas) and CVIPWI were investigated in terms of inter-modality associations between collateral measures, as well as their relationships with stroke severity, infarct volume and early functional outcome. The final analysis included n = 56patients (n = 31female, mean age69.9 ± 14.21 years). No significant relationship was found between MR-based quantitative collateral supply (CVIPWI) and CT-based collateral scores (r = -0.00057, p = 0.502 and r = -0.124, p = 0.797). In contrast to CVIPWI, CTA-based collateral scores showed no significant relationship with clinical stroke severity and infarct volume. While MR-based CVIPWI was independently associated with favorable early functional outcome in multivariate analysis (OR 1.075, 95% CI 1.001-1.153, p = 0.046), CTA-based collateral scores were not significantly associated with outcome. Since collateral scores based on single-phase CTA do not accurately reflect infarct progression and might underestimate pial collateralization in arelevant proportion of patients, they are not associated with early functional outcome in LVO patients. In contrast, CVIPWI represents arobust imaging parameter of collateral supply and is independently associated with functional outcome.

Orosomucoid 2 is an endogenous regulator of neuronal mitochondrial biogenesis and promotes functional recovery post-stroke

Development of functional recovery therapies is critical to reduce the global impact of stroke as the leading cause of long-term disability. Our previous studies found that acute-phase protein orosomucoid (ORM) could provide an up to 6 h therapeutic time window to reduce infarct volume in acute ischemic stroke by improving endothelial function. However, its role in neurons and functional recovery post-stroke remains largely unknown. Here, we showed that exogenous ORM administration with initial injection at 0.5 h (early) or 12 h (delayed) post-MCAO daily for consecutive 7 days significantly decreased infarct area, improved motor and cognitive functional recovery, and promoted mitochondrial biogenesis after MCAO. While neuron-specific knockout of ORM2, a dominant subtype of ORM in the brain, produced opposite effects which could be rescued by exogenous ORM. In vitro, exogenous ORM protected SH-SY5Y cells from OGD-induced damage and promoted mitochondrial biogenesis, while endogenous ORM2 deficiency worsened these processes. Mechanistically, inactivation of CCR5 or AMPK eliminated the protective effects of ORM on neuronal damage and mitochondrial biogenesis. Taken together, our findings demonstrate that ORM, mainly ORM2, is an endogenous regulator of neuronal mitochondrial biogenesis by activating CCR5/AMPK signaling pathway, and might act as a potential therapeutic target for the functional recovery post-stroke.

Constructing machine learning models based on non-contrast CT radiomics to predict hemorrhagic transformation after stoke: a two-center study.

Machine learning (ML) models were constructed according to non-contrast computed tomography (NCCT) images as well as clinical and laboratory information to assess risk stratification for the occurrence of hemorrhagic transformation (HT) in acute ischemic stroke (AIS) patients. A retrospective cohort was constructed with 180 AIS patients who were diagnosed at two centers between January 2019 and October 2023 and were followed for HT outcomes. Patients were analyzed for clinical risk factors for developing HT, infarct texture features were extracted from NCCT images, and the radiomics score (Rad-score) was calculated. Then, five ML models were established and evaluated, and the optimal ML algorithm was used to construct the clinical, radiomics, and clinical-radiomics models. Receiver operating characteristic (ROC) curves were used to compare the performance of the three models in predicting HT. Based on the outcomes of the AIS patients, 104 developed HT, and the remaining 76 had no HT. The HT group consisted of 27 hemorrhagic infarction (HI) and 77 parenchymal-hemorrhage (PH). Patients with HT had a greater neutrophil-to-lymphocyte ratio (NLR), baseline National Institutes of Health Stroke Scale (NIHSS) score, infarct volume, and Rad-score and lower Alberta stroke program early CT score (ASPECTS) (all p < 0.01) than patients without HT. The best ML algorithm for building the model was logistic regression. In the training and validation cohorts, the AUC values for the clinical, radiomics, and clinical-radiomics models for predicting HT were 0.829 and 0.876, 0.813 and 0.898, and 0.876 and 0.957, respectively. In subgroup analyses with different treatment modalities, different infarct sizes, and different stroke time windows, the assessment accuracy of the clinical-radiomics model was not statistically meaningful (all p > 0.05), with an overall accuracy of 79.5%. Moreover, this model performed reliably in predicting the PH and HI subcategories, with accuracies of 82.9 and 92.9%, respectively. ML models based on clinical and NCCT radiomics characteristics can be used for early risk evaluation of HT development in AIS patients and show great potential for clinical precision in treatment and prognostic assessment.

Detection of early neurological deterioration using a quantitative electroencephalography system in patients with large vessel occlusion stroke after endovascular treatment

BackgroundEarly neurological deterioration (END) is a serious complication in patients with large vessel occlusion (LVO) stroke. However, modalities to monitor neurological function after endovascular treatment (EVT) are lacking. This study...

Evaluating Serum Copeptin as a Promising Biomarker for Predicting Acute Ischaemic Stroke Severity: A Hospital-Based Study on Strokes.

Stroke is the second cause of mortality and the foremost leading cause of disability globally. Many potential biomarkers have been described to contribute to prognosticating the severity in the acute phase of stroke as well as help with risk stratification. Copeptin, an inactive peptide that is produced in an equimolar ratio to arginine vasopressin and adequately mirrors an individual's stress response to acute illnesses like acute ischaemic stroke as evidenced by elevated or increasing levels is being explored in this study to determine its relationship with acute stroke severity and infarct size on admission. This is a cross-sectional study of 80 neuroimaging-confirmed acute ischaemic patients who presented within seven days of symptom onset and 80 control subjects. The ischaemic stroke cases had stroke severity and infarct volume determined on admission by the National Institute of Health Stroke Scale (NIHSS) and neuroimaging (brain CT/MRI). A baseline serum copeptin level was measured in the study subjects. Spearman correlation and Kruskal Wallis test were used to determine the relationship between serum copeptin level with admission NIHSS and infarct size respectively. The receiver operating characteristic (ROC) curve was calculated to determine the sensitivity and specificity of copeptin to predict severity and outcome. The mean age of the study group was 61.3 ± 12.7 years with 55.0% males and 45.0% females. The serum level of copeptin was significantly higher in the stroke cases with a median of 28.6 pmol/L (interquartile range (IQR)- 15.4-31.6 pmol/L) versus 8.8 pmol/L (IQR- 3.2- 10.7 pmol/L) among the stroke-free controls (p= 0.001) at a statistically significant level. There was a weak correlation between copeptin and NIHSS calculated at admission to measure stroke severity (r- 0.02, p= 0.873). Patients with infarct sizes in the fourth quartile (infarct sizes greater than 18.78 cm3) had higher copeptin levels, though this was not statistically significant (H= 2.88; p= 0.410). Admission serum copeptin did not show a statistically significant prognostic value in predicting stroke severity and mortality in stroke patients who presented within seven days of symptomonset with an area under curve (AUC) of 0.51 (95% CI: 0.36-0.65; p= 0.982). In this study, copeptin was higher among the stroke cases compared with the stroke-free controls which suggests a significant prognostic value in risk stratification in the acute phase of stroke; however, this did not significantly correlate with stroke severity and thus warrants further study in this field to elucidate it's fascinating potential as a prognostic biomarker (especially in the acute period) as this may enable allocation of a better-focused therapy for stroke patients.

Association between Transient-Continuous Hypotension during Mechanical Thrombectomy for Acute Ischemic Stroke and Final Infarct Volume in Patients with Proximal Anterior Circulation Large Vessel Occlusion.

Background/Objectives: Periprocedural blood pressure changes in stroke patients with a large vessel occlusion are a known modifiable risk factor of unfavorable treatment outcomes. We aimed to evaluate the association between pre-revascularization hypotension and the final infarct volume. Methods: In our retrospective analysis, we included 214 consecutive stroke patients with an anterior circulation large vessel occlusion that underwent mechanical thrombectomy under general anesthesia. Noninvasively obtained blood pressure values prior to symptomatic vessel recanalization were analyzed as a predictor of post-treatment infarct size. Linear logistic regression models adjusted for predefined factors were used to investigate the association between blood pressure parameters and the final infarct volume. Results: In our cohort, higher baseline systolic blood pressure (aβ = 8.32, 95% CI 0.93-15.7, p = 0.027), its maximal absolute drop (aβ = 6.98, 95% CI 0.42-13.55, p = 0.037), and >40% mean arterial pressure decrease (aβ = 41.77, CI 95% 1.93-81.61, p = 0.040) were independently associated with higher infarct volumes. Similarly, continuous hypotension measured as intraprocedural cumulative time spent below either 100 mmHg (aβ = 3.50 per 5 min, 95% CI 1.49-5.50, p = 0.001) or 90 mmHg mean arterial pressure (aβ = 2.91 per 5 min, 95% CI 0.74-5.10, p = 0.010) was independently associated with a larger ischemia size. In the subgroup analysis of 151 patients with an M1 middle cerebral artery occlusion, two additional factors were independently associated with a larger ischemia size: systolic blood pressure maximal relative drop and >40% drop from pretreatment value (aβ = 1.36 per 1% lower than baseline, 95% CI 0.04-2.67, p = 0.043, and aβ = 43.01, 95% CI 2.89-83.1, p = 0.036, respectively). No associations between hemodynamic parameters and post-treatment infarct size were observed in the cohort of intracranial internal carotid artery occlusion. Conclusions: In patients with ischemic stroke due to a proximal middle cerebral artery occlusion, higher pre-thrombectomy treatment systolic blood pressure is associated with a larger final infarct size. In patients treated under general anesthesia, hypotension prior to the M1 portion of middle cerebral artery recanalization is independently correlated with the post-treatment infarct volume. In this group, every 5 min spent below the mean arterial pressure threshold of 100 mmHg is associated with a 4 mL increase in ischemia volume on a post-treatment NCCT. No associations between blood pressure and final infarct volume were present in the subgroup of patients with an intracranial internal carotid artery occlusion.

Abstract 138: Platelet RIPK1 Promotes Platelet Activation And Aggregation In Arteriolar Thrombosis And Ischemic Stroke

Receptor-interacting protein Ser/Thr kinase 1 (RIPK1) is a molecular switch for inflammation and cell death in nucleated cells, and its function is controlled by phosphorylation at the Ser166 residue. However, it is unknown whether RIPK1 regulates platelet function in arterial thrombosis. Intravital microscopy using megakaryocyte-specific Ripk1 conditional knockout (CKO) mice ( Ripk1 fl/fl;Pf4-cre ) revealed that platelet Ripk1 promoted platelet thrombus formation at sites of laser-induced cremaster arteriolar thrombosis. Deletion of platelet Ripk1 prolonged the time to occlusion in FeCl 3 -induced carotid arterial thrombosis without affecting tail bleeding times. Further, compared to wild-type (WT) mice, Ripk1 CKO mice exhibited improved neurological deficits and reduced infarct volume in ischemic stroke induced by transient middle cerebral artery occlusion. Flow cytometry and aggregation assays showed that deletion of platelet Ripk1 reduced P-selectin exposure, αIIbβ3 integrin activation, and platelet aggregation induced by thrombin, collagen-related peptides (CRP), and U46619, but not ADP. Pretreatment of Ripk1-null platelets with ADP rescued the aggregation defect. Treatment of platelets with Nec-1s, a RIPK1 inhibitor that blocks RIPK1-Ser166 phosphorylation, did not affect platelet activation and aggregation. Instead, RIPK1-Ser320/321 was rapidly phosphorylated in thrombin- or CRP-stimulated human and mouse platelets. Treatment of platelets with an inhibitor of phospholipase C, p38, or MAPK-activated protein kinase 2 (MK2), but not a protein kinase C inhibitor, decreased RIPK1-Ser320/321 phosphorylation after thrombin or CRP stimulation, implying that the p38-MK2 axis phosphorylates RIPK1-Ser320/321. Using a genetic approach in human megakaryoblastic MEG-01 cells, we found that RIPK1 knockdown reduced granule secretion from stimulated MEG-01 cells, which was rescued by overexpressing WT RIPK1, but not mutant RIPK1-Ser320Ala, in the RIPK1 knockdown MEG-01 cells. These results suggest that platelet RIPK1 enhances granule secretion during platelet activation through p38-MK2-mediated phosphorylation of RIPK1-Ser320/321, thereby contributing to the pathology of thrombotic disease.

A low bleeding risk thrombolytic agent: citPA5.

Alteplase is a cornerstone thrombolytic agent in clinical practice but presents a potential bleeding risk. Stroke patients need pre-screening to exclude haemorrhagic stroke before using alteplase. In this study, we develop a new thrombolytic agent citPA5, characterized by an enhanced safety profile and minimal bleeding tendency. A clot lysis agent, named citPA5, is developed based on rtPA with point mutations to completely suppress its proteolytic activity in the absence of fibrin. In the presence of fibrin, citPA5 exhibited significantly higher fibrinolytic activity (a 15.8-fold increase of kcat/Km). Furthermore, citPA5 showed resistance to endogenous fibrinolysis inhibitor, PAI-1, resulting in enhanced potency. In a series of safety evaluation experiments, including thrombelastography assay, mice tail bleeding assay, and a murine intracerebral haemorrhage (ICH) model, citPA5 did not cause systemic bleeding or worsen ICH compared with alteplase. This highlights the low risk of bleeding associated with citPA5. Finally, we found that citPA5 effectively improved cerebral blood flow and reduced infarct volume in a carotid embolism-induced stroke model. This clot lysis agent, citPA5, not only exhibits a low risk of bleeding but also demonstrates highly effective thrombolysis capabilities. As a result, citPA5 shows great potential for administration prior to the classification of stroke types, making it possible for use in ambulances at the onset of stroke when symptoms are identified. The findings presented in this study also suggest that this strategy could be applied to develop a new generation of fibrinolytic drugs that offer greater safety and specificity in targeting fibrin.

Potensi Citicoline sebagai Terapi Neuroproteksi dan Neuroregenerasi pada Stroke Iskemik Akut

Ischemic stroke, caused by a blockage in the brain’s blood vessels, is a critical emergency that requires immediate treatment. This study examined the efficacy of citicoline as an adjunct therapy to improve outcomes in acute ischemic stroke. A comprehensive search of four databases (Cochrane Library, ScienceDirect, PubMed, and Google Scholar) was conducted, identifying a total of 5265 articles. Three clinical trials were selected for critical appraisal. Agarwal demonstrated a larger reduction in stroke infarct volume in the citicoline group (4.22 cm3) compared to the placebo group (2.63 cm3) (p=0.483). On day 90, the citicoline group exhibited superior results in mRS scores of 0-2 (p=0.732), NIHSS scores of 0-2 (p=0.934), Barthel index ≥95 (p=0.564), and patient mortality (p=0.468). Seifaddini’s study revealed improved peak systolic velocity and mean arterial flow velocity in the cerebrovascular system. Enrico’s study showed improved mean short afferent latency inhibition in the cholinergic circuits of the citicoline group (p=0.004). Citicoline proves effective as an adjuvant neuroprotective and neuroregenerative therapy for acute ischemic stroke.

Pharmacological Inhibition of LRRK2 Exhibits Neuroprotective Activity in Mouse Photothrombotic Stroke Model.

Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of Parkinson's disease (PD). Interestingly, recent studies have reported an increased risk of stroke in patients with PD harboring LRRK2 mutations, but there is no evidence showing the functional involvement of LRRK2 in stroke. Here, we found that LRRK2 kinase activity was significantly induced in the Rose-Bengal (RB) photothrombosis-induced stroke mouse model. Interestingly, stroke infarct volumes were significantly reduced, and neurological deficits were diminished by pharmacological inhibition of LRRK2 kinase activity using MLi-2, a brain-penetrant LRRK2 kinase inhibitor. Immunohistochemical analysis showed p-LRRK2 level in stroke lesions, co-localizing with mitophagy-related proteins (PINK, Parkin, LC3B, cytochrome c), suggesting their involvement in stroke progression. Overlapping p-LRRK2 with cytochrome c/TUNEL/JC-1 (an indicator of mitochondrial membrane potential) puncta in RB photothrombosis indicated LRRK2-induced mitochondrial apoptosis, which was blocked by MLi-2. These results suggest that pharmacological inhibition of LRRK2 kinase activity could attenuate mitochondrial apoptosis, ultimately leading to neuroprotective potential in stroke progression. In conclusion, LRRK2 kinase activity might be neuro-pathogenic due to impaired mitophagy in stroke progression, and pharmacological inhibition of LRRK2 kinase activity could be beneficial in reducing the risk of stroke in patients with LRRK2 mutations.

Abstract TP96: Association Between Infarct Volume, Neighborhood-Level Deprivation, and Outcomes in Pediatric Stroke

Introduction: Recent studies in adults have reported an association between neighborhood-level deprivation, infarct volume and outcome. However, this is yet to be investigated in pediatric arterial ischemic stroke (AIS). Our study aimed to assess the relationship between neighborhood-level deprivation, infarct volume, and neurological outcome in children diagnosed with AIS. Methods: We conducted a study of a consecutive cohort of children aged &amp;gt; 28 days-18 years and diagnosed with AIS between 2004 and 2019 at a comprehensive stroke center. Patient demographic, clinical characteristics and neighborhood material deprivation data including household income, parental educational attainment, the proportion of single-parent families, and housing quality were collected. Lesion volumes were determined by conducting semi-automatic segmentation of diffusion-weighted MRI brain scans at stroke presentation. Neurological outcome was assessed using the Pediatric Stroke Outcome Measure Severity Classification System wherein poor outcome was defined as moderate-to-severe deficit at 18 months post-stroke. Wilcoxon rank sum test was conducted. Results: Seventy-two patients were included in the study (62% male, median age of stroke onset 6.1 years [IQR 1.0-12.7]). 39% of patients were White, 72% lived in an urban region, and 64% in highly deprived neighborhoods. 70% of patients arrived within 6 hours from onset of stroke. Cardiac disease and other risk factors including infection and head trauma represented the most common risk factor. 55% presented with moderate stroke severity (as per the PedNIHSS). Median lesion volume was 14 cm 3 (IQR 2-51) and a mean infarct volume of 3% was reported. Race, rurality, and neighborhood-level material deprivation were not significantly associated with either percent infarct volume or neurological outcome; however, percent infarct volume was significantly associated with neurological outcome at 18 months post-stroke (W = 79, p = 0.025). Conclusion: Our study findings confirm the relationship between infarct volume and pediatric AIS outcomes. Future multi-center studies are warranted to further understand the interplay between material deprivation, infarct volume, and post-AIS neurological outcomes in children.

Abstract TP199: Prominent Laterality of the Posterior Cerebral Artery on MR Angiography Before Mechanical Thrombectomy in Patients With the Middle Cerebral Artery Occlusion Predicts Long-Term Functional Outcome

Background and Purpose: Well-developed collateral flow is reported to be associated with a reduction of infarct volume, successful reperfusion, and better functional outcome in acute ischemic stroke (AIS). Relatively increased visualization of posterior cerebral artery (PCA) ipsilateral to the ischemic lesion on MR angiography (MRA), a sign of prominent PCA laterality (PCAL), represents the development of collateral flow from PCA to middle cerebral artery (MCA) territory. However, the prognostic value of PCAL on functional outcome in AIS patients having MCA occlusion and undergoing mechanical thrombectomy, is not well known. Methods: We retrospectively reviewed initial MRA scans of pre-morbidly independent patients treated with mechanical thrombectomy for M1-segment occlusion from September 2017 to May 2022. PCAL was defined as better visualization of ipsilateral PCA, compared to contralateral PCA, by one or more segments on MRA. We divided patients into two groups, those presenting PCAL and not, and compared the background characteristics, in-hospital management, and functional outcome between the two groups. Factors associated with favorable outcome (mRS score 0-2) at 3 months after onset were assessed using multivariate logistic regression analysis. Results: In total, 172 patients (76 female [44%], median age 77 [IQR 74.5-78.0] years, median NIHSS score 16 [15-18]) were included. Of these, 86 patients (50%) presented PCAL on initial MRA. There is no significant difference between the two groups in age, sex, major vascular risk factors, NIHSS on admission, DWI-ASPECTS, onset-to-recanalization time (OTR), and preclinical modified Rankin scale. Multivariate logistic regression analysis showed an adjusted odds ratio of 2.11 for a favorable outcome in patients with PCAL (95% CI: 0.986 to 4.53, P=0.054). When focused on the cases with OTR &gt;6 hours (n=53), PCAL was independently associated with favorable outcome (OR 5.77, 95% CI: 1.28 to 26.0, P=0.022). Conclusion: PCAL on initial MRA in patients with M1-segment occlusion predicts favorable long-term functional outcome after mechanical thrombectomy, especially in the case taking longer time from onset to recanalization.

Possible Influence of Ethnicity on Computed Tomography Perfusion Parameter Thresholds in Acute Ischaemic Stroke

Introduction: Tissue at risk, as estimated by CT perfusion utilizing Tmax+6, correlates with final infarct volume (FIV) in acute ischaemic stroke (AIS) without reperfusion. Tmax thresholds are derived from Western ethnic populations but not from ethnic Asian populations. We aimed to investigate the influence of ethnicity on Tmax thresholds. Methods: From a clinical-imaging registry of Australian and Indonesian stroke patients, we selected a participant subgroup with the following inclusion criteria: AIS under 24 h and absence of reperfusion therapy. Clinical data included demographics, time metrics, stroke severity, pre-morbid, and 3-month Modified Rankin Score. Baseline computed tomography perfusion and MRI <72 h were performed. Volumes of Tmax utilizing different thresholds and FIVs were calculated. Spearman correlation was used to evaluate relationship involving ordinal variables and calculate the optimal Tmax threshold against FIV in both populations. Results: Two hundred patients were included in the study sample, 100 in Jakarta and 100 in Geelong. The median National Institutes of Health Stroke Scale (IQR) were 6 (3–11) and 3 (1–5), respectively. The median Tmax+6 (IQR) was 0 (0–46.5) in Jakarta group and 0 (0–7.5) in Geelong group. The median FIV (IQR) was 0 (0–30.5) and 0 (0–5.5). Tmax+8 s in Jakarta population against FIV showed Spearman’s coefficient ρ = 0.72, representing the optimal Tmax threshold. Tmax+6 s showed Spearman’s coefficient ρ = 0.51 against FIV in the Geelong population. Conclusion: Tmax thresholds approximating FIV were possibly different in the Asian when compared with the non-Asian populations. Future studies are required to extend and confirm the validity of our findings.

Exosomal circCNOT6L Regulates Astrocyte Apoptotic Signals Induced by Hypoxia Exposure Through miR99a-5p/SERPINE1 and Alleviates Ischemic Stroke Injury.

Circular RNAs are involved in intervention strategies for treating ischemic stroke (IS). However, circCNOT6L (hsa_circ_0006168) has not yet been reported in IS. Thus, we aimed to explore the potential role of circCNOT6L and its molecular mechanism in IS. In this study, we first found that the expression of both exosomal circCNOT6L (P = 0.0006) and plasma circCNOT6L (P = 0.0054) was down-regulated in IS patients compared with controls. Clinically, a negative correlation was observed between the relative expression level of circCNOT6L and the National Institutes of Health Stroke Scale (NIHSS) score and infarct volume of the brain. Simultaneously, the relative expression level of circCNOT6L was negatively associated with multiple risk factors for IS, such as mean platelet volume (MPV), red cell distribution width (RDW), very low-density lipoprotein (VLDL), and serum potassium, whereas it was positively correlated with high-density lipoprotein (HDL). In vitro, circCNOT6L silencing blocked cell viability and proliferation, while it promoted cell apoptosis of astrocytes undergoing oxygen-glucose deprivation/reperfusion (OGD/R) treatment. Mechanistically, the RNA antisense purification (RAP) assay and luciferase reporter assay revealed that circCNOT6L acts as a miRNA sponge to absorb miR-99a-5p and then regulates the expression of serine proteinase inhibitor (SERPINE1). In the further rescue experiment, overexpressing SERPINE1 could rescue the cell apoptotic signals due to circCNOT6L depletion. In conclusion, CircCNOT6L attenuated the cell apoptotic signal of astrocytes via the miR99a-5p/SERPINE1 axis and then alleviated injury after hypoxia induced by ischemic stroke.

The multiple roles of lysophosphatidic acid in vascular disease and atherosclerosis.

To explore the multiple roles that lysophosphatidic acid (LPA) plays in vascular disease and atherosclerosis. A high-fat high-cholesterol diet decreases antimicrobial activity in the small intestine, which leads to increased levels of bacterial lipopolysaccharide in the mucus of the small intestine and in plasma that increase systemic inflammation, and enhance dyslipidemia and aortic atherosclerosis. Decreasing LPA production in enterocytes reduces the impact of the diet. LPA signaling inhibits glucagon-like peptide 1 secretion, promotes atherosclerosis, increases vessel permeability and infarct volume in stroke, but protects against abdominal aortic aneurysm formation and rupture. Acting through the calpain system in lymphatic endothelial cells, LPA reduces the trafficking of anti-inflammatory Treg lymphocytes, which enhances atherosclerosis. Acting through LPA receptor 1 in cardiac lymphatic endothelial cells and fibroblasts, LPA enhances hypertrophic cardiomyopathy. LPA plays multiple roles in vascular disease and atherosclerosis that is cell and context dependent. In some settings LPA promotes these disease processes and in others it inhibits the disease process. Because LPA is so ubiquitous, therapeutic approaches targeting LPA must be as specific as possible for the cells and the context in which the disease process occurs.

Increased plasma levels of circPTP4A2 and circTLK2 are associated with stroke injury.

Accumulating studies have shown that circulating circular RNAs (circRNAs) represent novel biomarkers for many human diseases. We investigated whether plasma circPTP4A2 and circTLK2 levels are associated with stroke severity, infarct volume, stroke etiology, and functional outcome in acute ischemic stroke (AIS) patients. We applied quantitative real-time PCR (qPCR) to measure plasma circPTP4A2 and circTLK2 levels of 236 AIS patients within 72 h of symptoms onset and 136 healthy controls. We further assessed the National Institutes of Health Stroke Scale (NIHSS), infarct size, the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification and the 90-day modified Rankin scale (mRS) for each patient. At admission, plasma circPTP4A2 and circTLK2 levels in patients with moderate to severe stroke were significantly higher compared to those with mild stroke. Logistic regression and receiver-operating characteristic (ROC) curve analyses indicated that they might function as predictive biomarkers for moderate to severe stroke. We also observed a medium positive correlation between these two circRNAs and NIHSS. Plasma circPTP4A2 and circTLK2 levels were slight positively correlated with cerebral infarct volume only in anterior circulation infarction (ACI) patients. Levels of both circPTP4A2 and circTLK2 were closely related with large artery atherosclerosis (LAA) stroke. Moreover, changes within 7 days after admission in circPTP4A2 and circTLK2 were able to predict unfavorable clinical outcome 90 days after AIS. These results demonstrate that plasma circPTP4A2 and circTLK2 strongly correlated with severity, subtypes and prognosis of AIS, and they could serve as promising biomarkers.

Integrated Photoacoustic, Ultrasound, and Angiographic Tomography (PAUSAT) for NonInvasive Whole-Brain Imaging of Ischemic Stroke.

Presented here is an experimental ischemic stroke study using our newly developed noninvasive imaging system that integrates three acoustic-based imaging technologies: photoacoustic, ultrasound, and angiographic tomography (PAUSAT). Combining these three modalities helps acquire multi-spectral photoacoustic tomography (PAT) of the brain blood oxygenation, high-frequency ultrasound imaging of the brain tissue, and acoustic angiography of the cerebral blood perfusion. The multi-modal imaging platform allows the study of cerebral perfusion and oxygenation changes in the whole mouse brain after stroke. Two commonly used ischemic stroke models were evaluated: the permanent middle cerebral artery occlusion (pMCAO) model and the photothrombotic (PT) model. PAUSAT was used to image the same mouse brains before and after a stroke and quantitatively analyze both stroke models. This imaging system was able to clearly show the brain vascular changes after ischemic stroke, including significantly reduced blood perfusion and oxygenation in the stroke infarct region (ipsilateral) compared to the uninjured tissue (contralateral). The results were confirmed by both laser speckle contrast imaging and triphenyltetrazolium chloride (TTC) staining. Furthermore, stroke infarct volume in both stroke models was measured and validated by TTC staining as the ground truth. Through this study, we have demonstrated that PAUSAT can be a powerful tool in noninvasive and longitudinal preclinical studies of ischemic stroke.

Diffusion-weighted Imaging and Arterial Spin Labeling for Prediction of Cerebral Infarct Volume in Acute Atherothrombotic Stroke.

This study aims to investigate the usefulness of diffusion-weighted imaging (DWI) and arterial spin labeling (ASL) for predicting final infarct volume in patients with acute atherothrombotic subtype cerebral infarction (AT-type stroke). The data of 77 patients with AT-type stroke were retrospectively analyzed. ASL and DWI values of minimum apparent diffusion coefficient (min ADC), mean ADC (mean ADC), minimum cerebral blood flow (min CBF), and mean CBF (mean CBF) of the infarction lesions were measured. Changes in cerebral infarction volume (ΔVolume) were determined by DWI reexamination on the 7th day after onset. Correlations of ADC and CBF with Δ Volume were analyzed. Receiver operating characteristic (ROC) curve analysis was used to determine the usefulness of ADC and CBF values for predicting final infarct volume. There was a significant difference in the distribution of the ΔVolume in AT-type stroke (P<0.0001). The ADC and min CBF values were negatively correlated with the infarct ΔVolume (P<0.05); mean CBF and ΔCBF were not correlated with ΔVolume. When min ADC was ≤0.303 × 10-3 mm2/s, min CBF 1.5 ≤2.415 mL/100 g/min, or min CBF2.5 ≤4.25 mL/100 g/min, ΔVolume was likely to be large. The ROC curve showed the highest predictive value for min ADC and min CBF. Distinctive patterns of quantitative ADC and CBF can be used as a simple and rapid method for predicting change in infarction volume in AT-type stroke.

GAS6/sAXL ratio correlates with National Institutes of Health Stroke Scale (NIHSS) and infarction size in patients with acute ischemic stroke

Background &amp; Objective: Ischemic stroke is the leading cause of death and long-term disability worldwide. In patients with ischemic stroke, both cell loss and inflammation are observed. GAS6/sAXL signaling is effective in both inflammation and clearance of dead/dying cells. This study investigated the GAS6/sAXL pathway and its role in patients with acute stroke. Specifically, we evaluated whether GAS6/sAXL was associated with stroke severity and infarct volume. Methods: This study involved 53 patients with acute ischemic stroke (AIS) and 49 healthy controls. GAS6 and sAXL proteins were collected in the first 24 hours in the acute stroke. NIHSS scores, GCS, and demographic data of the patients at the time of admission to the hospital were recorded. The infarct area was calculated using cranial magnetic resonance imaging. Results: Mean age of the patients was 64±12 years, 60% were female. HDL was lower in AIS group (40.5±13.01 mg/dl) than in the control group (55.4±14.9 mg/ dl) (p&lt;0.05). The GAS6 levels of patients with ischemic stroke (30.58 [1.58-162.33] ng/dL) were significantly lower than the control group (83.33 [10.71-181.96] ng/dL) (p &lt; 0.001). There was a significant difference in the GAS6/sAXL ratio between the AIS (8.60 [0.55-48] ng/mL) and control groups (14.78 [1.82-53.71] ng/mL) (p &lt; 0.001). The serum GAS6 level and MR infarct area was positively correlated (r = 0.381 p = 0.005). The GAS6/sAXL ratio was positively correlated with the NIHSS and infarct area (p = 0.004). The GAS6/sAXL ratio and GCS showed a negative correlation (p = 0.001). Conclusion: Plasma GAS6 levels were positively correlated with infarct size, and the GAS6/sAXL ratio was positively correlated with the NIHSS score and infarct area in patients with AIS. Plasma GAS levels and GAS6/sAXL ratio can be used as an indicator of severity of AIS.