SIRT6 prevent chronic cerebral hypoperfusion induced cognitive impairment by remodeling mitochondrial dynamics in a STAT5-PGAM5-Drp1 dependent manner.

Vascular dementia (VaD) is a prevalent form of dementia resulting from chronic cerebral hypoperfusion (CCH). However, the pathogenic mechanisms of VaD and corresponding therapeutic strategies are not well understood. Sirtuin 6 (SIRT6) has been implicated in various biological processes, including cellular metabolism, DNA repair, redox homeostasis, and aging. Nevertheless, its functional relevance in VaD remains unexplored. In this study, we utilized a bilateral common carotid artery stenosis (BCAS) mouse model of VaD to investigate the role of SIRT6. We detected a significant decrease in neuronal SIRT6 protein expression following CCH. Intriguingly, neuron-specific ablation of Sirt6 in mice exacerbated neuronal damage and cognitive deficits after CCH. Conversely, treatment with MDL-800, an agonist of SIRT6, effectively mitigated neuronal loss and facilitated neurological recovery. Mechanistically, SIRT6 inhibited excessive mitochondrial fission by suppressing the CCH-induced STAT5-PGAM5-Drp1 signaling cascade. Additionally, the gene expression of monocyte SIRT6 in patients with asymptomatic carotid stenosis showed a correlation with cognitive outcomes, suggesting translational implications in human subjects. Our findings provide the first evidence that SIRT6 prevents cognitive impairment induced by CCH, and mechanistically, this protection is achieved through the remodeling of mitochondrial dynamics in a STAT5-PGAM5-Drp1-dependent manner.

Electroacupuncture improves cognitive impairment after ischemic stroke based on regulation of mitochondrial dynamics through SIRT1/PGC-1α pathway.

In recent years, the mechanism of acupuncture in the treatment of post-stroke cognitive impairment (PSCI) has not been fully elucidated. The balance between mitochondrial fission and fusion is important for PSCI. Our previous research demonstrated that electroacupuncture can improve learning and memory in middle cerebral artery ischemia reperfusion (MCAO/R) rats. However, the specific mechanism by which electroacupuncture improves learning and memory in MCAO/R rats by regulating mitochondrial fission and fusion needs to be further investigated. The MCAO/R rats was developed using the line-bolt method. The rats were randomly divided into sham-operated (Sham), model (MCAO/R), electroacupuncture (MCAO/R + EA) and sham-electroacupuncture (MCAO/R + sham EA) groups. Investigating the effects of EA on the expression of Sirtuin1 (SIRT1), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), Optic atrophy 1R + (OPA1) and Dynamin-related protein 1 (DRP1) in hippocampal neurons and on the morphology and function of hippocampal neurons and mitochondria. EA was able to reduce neurologic deficit scores and cerebral infarct volume and improve new object discrimination in MCAO/R rats, but there were no significant changes in these indices in the sham-electroacupuncture group. Moreover, EA increased the expression of SIRT1, PGC-1α, and OPA1 in hippocampal tissues, inhibited the expression of DRP1, attenuated neuronal and mitochondrial damage, and reduced mitochondrial fragmentation. The mechanism by which EA improves learning memory deficits in MCAO/R rats may be related to the inhibition of SIRT1/PGC-1α expression, the enhancement of mitochondrial fusion and the obstruction of its fission, and the reduction of hippocampal neuronal damage.

Smartphone pupillometry for detection of cerebral vasospasm after aneurysmal subarachnoid hemorrhage.

OBJECTIVES: Vasospasm is a complication of aneurysmal subarachnoid hemorrhage (aSAH) that can change the trajectory of recovery and is associated with morbidity and mortality. Earlier detection of vasospasm could improve patient outcomes. Our objective is to evaluate the accuracy of smartphone-based quantitative pupillometry in the detection of radiographic vasospasm and delayed cerebral ischemia (DCI) after aSAH. MATERIALS AND METHODS: We prospectively collected pupillary light reflex (PLR) parameters from patients with aSAH admitted to a neurocritical care unit at a single hospital twice daily using quantitative smartphone pupillometry recordings. PLR parameters included: Maximum pupil diameter, minimum pupil diameter, percent change in pupil diameter, latency in beginning of pupil constriction to light, mean constriction velocity, maximum constriction velocity, and mean dilation velocity. Two-tailed t-tests for independent samples were performed to determine changes in average concurrent PLR parameter values between the following comparisons: (1) patients with and without radiographic vasospasm (defined by angiography with the need for endovascular intervention) and (2) patients with and without DCI. RESULTS: 49 subjects with aSAH underwent 323 total PLR recordings. For PLR recordings taken with (n=35) and without (n=241) radiographic vasospasm, significant differences were observed in MIN (35.0 ± 7.5 pixels with vasospasm versus 31.6 ± 6.2 pixels without; p=0.002). For PLR recordings taken with (n=43) and without (n=241) DCI, significant differences were observed in MAX (48.9 ± 14.3 pixels with DCI versus 42.5 ± 9.2 pixels without; p<0.001). CONCLUSIONS: Quantitative smartphone pupillometry has the potential to be used to detect radiographic vasospasm and DCI after aSAH.

ß-hydroxybutyrate and ischemic stroke: roles and mechanisms.

Stroke is a significant global burden, causing extensive morbidity and mortality. In metabolic states where glucose is limited, ketone bodies, predominantly ß-hydroxybutyrate (BHB), act as alternative fuel sources. Elevated levels of BHB have been found in the ischemic hemispheres of animal models of stroke, supporting its role in the pathophysiology of cerebral ischemia. Clinically, higher serum and urinary BHB concentrations have been associated with adverse outcomes in ischemic stroke, highlighting its potential utility as a prognostic biomarker. In both animal and cellular models, exogenous BHB administration has exhibited neuroprotective effects, reduction of infarct size, and improvement of neurological outcomes. In this review, we focus on the role of BHB before and after ischemic stroke, with an emphasis on the therapeutic potential and mechanisms of ketone administration after ischemic stroke.

Advancing diagnostic precision of delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage: The potential for a vasospasm index score on perfusion imaging to detect vasospasm.

BACKGROUND: The occurrence of delayed cerebral ischemia and vasospasm following aneurysmal subarachnoid hemorrhage (aSAH) results in high morbidity and mortality, but the diagnosis remains challenging. This study aimed to identify neuroimaging perfusion parameters indicative of delayed cerebral ischemia in patients with suspected vasospasm. METHODS: This is a case-control study. Cases were adult aSAH patients who underwent magnetic resonance perfusion or computed tomography perfusion (CTP) imaging ≤ 24 h before digital subtraction angiography performed for vasospasm diagnosis and treatment. Controls were patients without aSAH who underwent CTP. Quantitative perfusion parameters at different thresholds, including Tmax 4-6-8-10 s delay, cerebral blood flow and cerebral blood volume were measured and compared between cases and controls. The Vasospasm Index Score was calculated as the ratio of brain volume with time-to-max (Tmax) delay > 6 s over volume with Tmax > 4 s. RESULTS: 54 patients with aSAH and 119 controls without aSAH were included. Perfusion parameters with the strongest prediction of vasospasm on cerebral angiography were the combination of the Vasospasm Index Score (Tmax6/Tmax4) + CBV ≤ 48 % (area under the curve value of 0.85 [95 % CI 0.78-0.91]) with a sensitivity of 63 % and specificity of 95 %. CONCLUSION: The Vasospasm Index Score in combination with CBV ≤ 48 % on cerebral perfusion imaging reliably identified vasospasm as the cause of DCI on perfusion imaging.

Risk factors for epilepsy following arterial ischemic stroke childhood: A retrospective cohort study.

AIM: PSE is reported more frequently in childhood than in adults. In this study, we aimed to investigate potential risk factors for the development of post-stroke epilepsy (PSE) in children with arterial ischemic stroke (AIS). MATERIAL METHODS: The current retrospective cohort study included the medical records of 50 pediatric participants (aged 29 days to 18 years) diagnosed with AIS at a university hospital between January 2006 and December 2023. All information of the patients who were followed for at least two years for the development of PSE after AIS was entered into the hospital database and recorded in a pre-designed questionnaire. Acute symptomatic seizures were defined as seizures occurring within 7 days after stroke. Two or more late seizures occurring after the acute period (>7 days) were classified as PSE. The incidence of PSE and potential risk factors were investigated. RESULTS: After AIS, more than half of the patients (58 %) developed acute seizures and almost one-third (38 %) developed PSE. Risk factors associated with the development of PSE, very early seizures (within the first six hours), high stroke severity, cortical lesions, neurological deficits and low serum vitamin D levels were detected (p = 0.05, p = 0.036, p = 0.011, p < 0.001, p < 0.001, respectively). CONCLUSION: Seizures within the first six hours, high stroke severity, and neurological deficits are important risk factors for the development of PSE in children. Knowing the potential risk factors of PSE may be helpful for clinicians to identify high-risk patients. It can also contribute to treatment decision-making and post-discharge follow-up planning.

Delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage- areas at risk.

Delayed cerebral ischemia is a major neurological complication of aneurysmal subarachnoid hemorrhage. Its unpredictable course and potentially unfavorable outcome draw attention to clinicians to improve the methods for its prediction, prevention, and diagnosis. The computed tomography perfusion (CTP) technique of the brain is one of the promising methods for revealing brain areas endangered by cerebral vasospasm and delayed cerebral ischemia.

Mangiferin alleviated poststroke cognitive impairment by modulating lipid metabolism in cerebral ischemia/reperfusion rats.

INTRODUCTION: Mangiferin is a Chinese herbal extract with multiple biological activities. Mangiferin can penetrate the blood‒brain barrier and has potential in the treatment of nervous system diseases. These findings suggest that mangiferin protects the neurological function in ischemic stroke rats by targeting multiple signaling pathways. However, little is known about the effect and mechanism of mangiferin in alleviating poststroke cognitive impairment. METHODS: Cerebral ischemia/reperfusion (I/R) rats were generated via middle cerebral artery occlusion. Laser speckle imaging was used to monitor the cerebral blood flow. The I/R rats were intraperitoneally (i.p.) injected with 40 mg/kg mangiferin for 7 consecutive days. Neurological scoring, and TTC staining were performed to evaluate neurological function. Behavioral experiments, including the open field test, elevated plus maze, sucrose preference test, and novel object recognition test, were performed to evaluate cognitive function. Metabolomic data from brain tissue with multivariate statistics were analyzed by gas chromatography‒mass spectrometry and liquid chromatography‒mass spectrometry. RESULTS: Mangiferin markedly decreased neurological scores, and reduced infarct areas. Mangiferin significantly attenuated anxiety-like and depression-like behaviors and enhanced learning and memory in I/R rats. According to the metabolomics results, 13 metabolites were identified to be potentially regulated by mangiferin, and the differentially abundant metabolites were mainly involved in lipid metabolism. CONCLUSIONS: Mangiferin protected neurological function and relieved poststroke cognitive impairment by improving lipid metabolism abnormalities in I/R rats.

CTP for the Screening of Vasospasm and Delayed Cerebral Ischemia in Aneurysmal SAH: A Systematic Review and Meta-analysis.

BACKGROUND: Delayed cerebral ischemia and vasospasm are the most common causes of late morbidity following aneurysmal SAH, but their diagnosis remains challenging. PURPOSE: This systematic review and meta-analysis investigated the diagnostic performance of CTP for detection of delayed cerebral ischemia and vasospasm in the setting of aneurysmal SAH. DATA SOURCES: Studies evaluating the diagnostic performance of CTP in the setting of aneurysmal SAH were searched on the Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Cochrane Clinical Answers, Cochrane Methodology Register, Ovid MEDLINE, EMBASE, American College of Physicians Journal Club, Database of Abstracts of Reviews of Effects, Health Technology Assessment, National Health Service Economic Evaluation Database, PubMed, and Google Scholar from their inception to September 2023. STUDY SELECTION: Thirty studies were included, encompassing 1786 patients with aneurysmal SAH and 2302 CTP studies. Studies were included if they compared the diagnostic accuracy of CTP with a reference standard (clinical or radiologic delayed cerebral ischemia, angiographic spasm) for the detection of delayed cerebral ischemia or vasospasm in patients with aneurysmal SAH. The primary outcome was accuracy for the detection of delayed cerebral ischemia or vasospasm. DATA ANALYSIS: Bivariate random effects models were used to pool outcomes for sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio. Subgroup analyses for individual CTP parameters and early-versus-late study timing were performed. Bias and applicability were assessed using the modified QUADAS-2 tool. DATA SYNTHESIS: For assessment of delayed cerebral ischemia, CTP demonstrated a pooled sensitivity of 82.1% (95% CI, 74.5%-87.8%), specificity of 79.6% (95% CI, 73.0%-84.9%), positive likelihood ratio of 4.01 (95% CI, 2.94-5.47), and negative likelihood ratio of 0.23 (95% CI, 0.12-0.33). For assessment of vasospasm, CTP showed a pooled sensitivity of 85.6% (95% CI, 74.2%-92.5%), specificity of 87.9% (95% CI, 79.2%-93.3%), positive likelihood ratio of 7.10 (95% CI, 3.87-13.04), and negative likelihood ratio of 0.16 (95% CI, 0.09-0.31). LIMITATIONS: QUADAS-2 assessment identified 12 articles with low risk, 11 with moderate risk, and 7 with a high risk of bias. CONCLUSIONS: For delayed cerebral ischemia, CTP had a sensitivity of >80%, specificity of >75%, and a low negative likelihood ratio of 0.23. CTP had better performance for the detection of vasospasm, with sensitivity and specificity of >85% and a low negative likelihood ratio of 0.16. Although the accuracy offers the potential for CTP to be used in limited clinical contexts, standardization of CTP techniques and high-quality randomized trials evaluating its impact are required.

The Association of Epileptic Seizures after Acute Ischemic Stroke with Cerebral Cortical Involvement and Electroencephalographic Changes.

Background and objectives: while acute ischemic stroke is the leading cause of epilepsy in the elderly population, data about its risk factors have been conflicting. Therefore, the aim of our study is to determine the association of early and late epileptic seizures after acute ischemic stroke with cerebral cortical involvement and electroencephalographic changes. Materials and methods: a prospective cohort study in the Hospital of the Lithuanian University of Health Sciences Kaunas Clinics Department of Neurology was conducted and enrolled 376 acute ischemic stroke patients. Data about the demographical, clinical, radiological, and encephalographic changes was gathered. Patients were followed for 1 year after stroke and assessed for late ES. Results: the incidence of ES was 4.5%, the incidence of early ES was 2.7% and the incidence of late ES was 2.4%. The occurrence of early ES increased the probability of developing late ES. There was no association between acute cerebral cortical damage and the occurrence of ES, including both early and late ES. However, interictal epileptiform discharges were associated with the occurrence of ES, including both early and late ES.

Cerebrospinal fluid volume as an early radiological factor for clinical course prediction after aneurysmal subarachnoid hemorrhage. A pilot study.

BACKGROUND: The pathological mechanisms following aneurysmal subarachnoid hemorrhage (SAH) are poorly understood. Limited clinical evidence exists on the association between cerebrospinal fluid (CSF) volume and the risk of delayed cerebral ischemia (DCI) or cerebral vasospasm (CV). In this study, we raised the hypothesis that the amount of CSF or its ratio to hemorrhage blood volume, as determined from non-contrast Computed Tomography (NCCT) images taken on admission, could be a significant predictor for CV and DCI. METHODS: The pilot study included a retrospective analysis of NCCT scans of 49 SAH patients taken shortly after an aneurysm rupture (33 males, 16 females, mean age 56.4 ± 15 years). The SynthStrip and Slicer3D software tools were used to extract radiological factors - CSF, brain, and hemorrhage volumes from the NCCT images. The "pure" CSF volume (VCSF) was estimated in the range of [-15, 15] Hounsfield units (HU). RESULTS: VCSF was negatively associated with the risk of CV occurrence (p = 0.0049) and DCI (p = 0.0069), but was not associated with patients' outcomes. The hemorrhage volume (VSAH) was positively associated with an unfavorable outcome (p = 0.0032) but was not associated with CV/DCI. The ratio VSAH/VCSF was positively associated with, both, DCI (p = 0.031) and unfavorable outcome (p = 0.002). The CSF volume normalized by the brain volume showed the highest characteristics for DCI prediction (AUC = 0.791, sensitivity = 0.80, specificity = 0.812) and CV prediction (AUC = 0.769, sensitivity = 0.812, specificity = 0.70). CONCLUSION: It was demonstrated that "pure" CSF volume retrieved from the initial NCCT images of SAH patients (including CV, Non-CV, DCI, Non-DCI groups) is a more significant predictor of DCI and CV compared to other routinely used radiological biomarkers. VCSF could be used to predict clinical course as well as to personalize the management of SAH patients. Larger multicenter clinical trials should be performed to test the added value of the proposed methodology.

Sepsis compromises post-ischemic stroke neurological recovery and is associated with sex differences.

AIMS: Infection is a complication after stroke and outcomes vary by sex. Thus, we investigated if sepsis affects brain from ischemic stroke and sex involvement. MAIN METHODS: Male and female Wistar rats, were submitted to middle cerebral artery occlusion (MCAO) and after 7 days sepsis to cecal ligation and perforation (CLP). Infarct size, neuroinflammation, oxidative stress, and mitochondrial activity were quantified 24 h after CLP in the prefrontal cortex and hippocampus. Survival and neurological score were assessed up to 15 days after MCAO or 8 days after CLP (starting at 2 h after MCAO) and memory at the end. KEY FINDINGS: CLP decreased survival, increased neurological impairments in MCAO females. Early, in male sepsis following MCAO led to increased glial activation in the brain structures, and increased TNF-α and IL-1ß in the hippocampus. All groups had higher IL-6 in both tissues, but the hippocampus had lower IL-10. CLP potentiated myeloperoxidase (MPO) in the prefrontal cortex of MCAO male and female. In MCAO+CLP, only male increased MPO and nitrite/nitrate in hippocampus. Males in all groups had protein oxidation in the prefrontal cortex, but only MCAO+CLP in the hippocampus. Catalase decreased in the prefrontal cortex and hippocampus of all males and females, and MCAO+CLP only increased this activity in males. Female MCAO+CLP had higher prefrontal cortex complex activity than males. In MCAO+CLP-induced long-term memory impairment only in females. SIGNIFICANCE: The parameters evaluated for early sepsis after ischemic stroke show a worse outcome for males, while females are affected during long-term follow-up.

Association of early seizures after ischemic stroke with diffusion-weighted imaging-alberta stroke program early CT score (DWI-ASPECTS) and neutrophil-to-lymphocyte ratio.

BACKGROUND: Post-stroke seizure (PSS) is a common considerable complication of acute ischemic stroke (AIS). Early risk assessment can clinical practitioners to plan effective prevention and management. We aimed to determine whether assessing Diffusion-Weighted Imaging-Alberta Stroke Program Early CT Score (DWI-ASPECTS), and neutrophil indices allows for identifying patients at risk of PSS. METHODS: This prospective study included AIS patients with cortical involvement admitted to a single academic center between January 2020 to October 2023. For all included subjects, DWI-Brain MRI, blood neutrophils, and platelet counts were obtained and the DWI-ASPECTS score was calculated. Then, the patients were followed up for 6 months in terms of PSS occurrence. Based on the occurrence of PSS, patients were divided into two groups of PSS and non-PSS. For analysis, imaging and laboratory data were compared between two groups. Logistic regression was applied to determine the relationship between DWI-ASPECTS and neutrophil indices, with early PSS. Finally, the sensitivity and specificity of these variables for PSS were estimated. RESULTS: A total of 309 were included in the final statistical analysis. DWI-ASPECT and neutrophil-to-lymphocyte ratio (NLR) were significantly associated with early PSS with OR of 0.74 and OR of 1.13, respectively (P < 0.05). Further analysis showed that, a combination of DWI-ASPECTS, NLR had an area under the curve (AUC) of 0.72 for predicting the occurrence of early PSS. CONCLUSION: DWI-ASPECTS and NLR are associated with the occurrence of early PSS after cortical ischemic stroke. A combination of these predictors had higher sensitivity and specificity for PSS rather than each factor alone. These findings may be helpful for determining the risk of PSS if validated in future studies.

Systemic immune-inflammation index is associated with cardiac complications following acute ischemic stroke: A retrospective single-center study.

BACKGROUND: Stroke-induced heart syndrome is a feared complication of ischemic stroke, that is commonly encountered and has a strong association with unfavorable prognosis. More research is needed to explore underlying mechanisms and inform clinical decision making. This study aims to explore the relationship between the early systemic immune-inflammation (SII) index and the cardiac complications after acute ischemic stroke. METHODS: Consecutive patients with acute ischemic stroke were prospectively collected from January 2020 to August 2022 and retrospectively analyzed. We included subjects who presented within 24 hours after symptom onset and were free of detectable infections or cancer on admission. SII index [(neutrophils × platelets/ lymphocytes)/1000] was calculated from laboratory data at admission. RESULTS: A total of 121 patients were included in our study, of which 24 (19.8 %) developed cardiac complications within 14 days following acute ischemic stroke. The SII level was found higher in patients with stroke-heart syndrome (p<.001), which was an independent predictor of stroke-heart syndrome (adjusted odds ratio 5.089, p=.002). CONCLUSION: New-onset cardiovascular complications diagnosed following a stroke are very common and are associated with early SII index.

The Relationship Between Composite Inflammatory Ratios and Complications of Massive Ischaemic Stroke.

OBJECTIVE: To investigate the relationship between complications of massive cerebral infarction (MCI) and composite inflammatory ratios. STUDY DESIGN: A case-control study. Place and Duration of the Study: Department of Neurology, Affiliated Hospital of Putian University, Putian, China, from January 2019 to November 2021. METHODOLOGY: Eighty-two patients with MCI underwent blood tests within 24 hours of admission. Complications such as cerebral herniation, haemorrhage transformation (HT), and stroke-associated pneumonia (SAP) were evaluated based on imaging examinations. The prognosis was assessed using the modified Rankin Scale score (mRS) at discharge. RESULTS: Among the 82 patients, the cerebral herniation group had higher levels of systemic immune inflammation index (SII) and neutrophil-to-lymphocyte ratio (NLR) compared to the non-cerebral herniation group. MCI patients who developed HT had higher levels of SII, NLR, mean platelet volume/platelet (MPV/PLT), and platelet-to-lymphocyte ratio (PLR). The SAP group had higher levels of MPV/PLT and NLR compared to the non-SAP group. The poor prognosis group had higher SII and NLR levels but a lower lymphocyte-to-monocyte ratio (LMR) compared to the good prognosis group. CONCLUSION: NLR showed high accuracy in predicting complications and the short-term prognosis of MCI. SII was linked to cerebral herniation, HT, and the short-term prognosis of MCI. MPV/PLT was found to be related to SAP and HT caused by MCI. LMR may act as a protective factor for the short-term prognosis of MCI. KEY WORDS: Massive cerebral infarction, Neutrophil-to-lymphocyte ratio, Systemic immune inflammation index, Prognosis.

Personalised stroke evaluation and management: tailoring individualised patient care for hereditary haemorrhagic telangiectasia.

SummaryHereditary haemorrhagic telangiectasia (HHT) has an estimated prevalence of 1 in 5000-8000 individuals globally with pulmonary arteriovenous malformations (PAVMs) affecting approximately 15%-50% of HHT patients. Ischaemic stroke is a known complication of PAVMs that affects ≤30% of patients with PAVMs. Studies have shown that patients with PAVMs have ischaemic stroke a decade earlier than routine stroke. The predominant mechanism of ischaemic stroke in HHT patients is paradoxical embolism due to PAVMs, but most HHT-related PAVMs are asymptomatic. Additionally, HHT is often underdiagnosed in patients and poses a challenge to physicians due to its rarity. We present a case of a patient with ischaemic stroke who was subsequently diagnosed with HHT and found to have a PAVM on further evaluation. This case highlights the importance of using an individualised patient-centred stroke evaluation and screening for PAVMs in patients who had a stroke with possible or suspected HHT and definite HHT.

ADAMTS13 deficiency exacerbates neuroinflammation by targeting matrix metalloproteinase-9 in ischemic brain injury.

Our design aimed to explore the potential involvement of matrix metalloproteinase-9 (MMP-9) in the inflammatory response associated with acute ischemic stroke (AIS). We also aimed to preliminarily examine the potential impact of a disintegrin-like and metalloprotease with thrombospondin type I repeats-13 (ADAMTS13) on MMP-9 in AIS. We conducted oxygen-glucose deprivation models of microglia cells and mice models of AIS with middle cerebral artery occlusion (MCAO). We assessed the expression pattern of MMP-9 with western blotting (WB) and real-time quantitative PCR both in vivo and in vitro. MMP-9 downregulation was achieved by using ACE inhibitors such as trandolapril. For the MCAO model, we used ADAMTS13-deficient mice. We then evaluated the related neurological function scores, cerebral edema and infarct volume. The levels of inflammation-related proteins, such as COX2 and iNOS, were assessed using WB, and the expression of inflammatory cytokines was measured via enzyme-linked immuno sorbent assay in vivo. Our findings indicated that MMP-9 was up-regulated while ADAMTS13 was down-regulated in the MCAO model. Knockdown of MMP-9 reduced both inflammation and ischemic brain injury. ADAMTS13 prevented brain damage, improved neurological function and decreased the inflammation response in mice AIS models. Additionally, ADAMTS13 alleviated MMP-9-induced neuroinflammation in vivo. It showed that ADAMTS13 deficiency exacerbated ischemic brain injury through an MMP-9-dependent inflammatory mechanism. Therefore, the ADAMTS13-MMP-9 axis could have therapeutic potential for the treatment of AIS.

Beam narrowing test: a motor index of post-stroke motor evaluation in an aged rat model of cerebral ischemia.

Each year, 15 million people worldwide suffer from strokes. Consequently, researchers face increasing pressure to develop reliable behavioural tests for assessing functional recovery after a stroke. Our aim was to establish a new motor performance index that can be used to evaluate post-stroke recovery in both young and aged animals. Furthermore, we validate the proposed procedure and recommend the necessary number of animals for experimental stroke studies. Young (n = 20) and aged (n = 27) Sprague-Dawley rats were randomly assigned to receive either sham or stroke surgery. The newly proposed performance index was calculated for the post-stroke acute, subacute and chronic phases. The advantage of using our test over current tests lies in the fact that the newly proposed motor index test evaluates not only the performance of the unaffected side in comparison to the affected one but also assesses overall performance by taking into account speed and coordination. Moreover, it reduces the number of animals needed to achieve a statistical power of 80%. This aspect is particularly crucial when studying aged rodents. Our approach can be used to monitor and assess the effectiveness of stroke therapies in experimental models using aged animals.

Leukocyte counts and ratios as potential predictors of large vessel occlusion in acute ischemic stroke: A retrospective cohort study.

Leukocyte counts and ratios are independent biomarkers to determine the severity and prognosis of acute ischemic stroke (AIS). In AIS, the connection between leukocytes and large vessel occlusion (LVO) is uncertain. This study aims to determine the relationship between the existence of LVO and leukocyte counts and ratios on admission to AIS. Patients were retrospectively evaluated within six hours of AIS starting between January 2019 and April 2023. On admission, blood specimens were collected, and leukocyte subtype counts were promptly analyzed. Computed tomography or digital subtraction angiography were utilized to verify the existence of LVO. Regression analysis and receiver operating characteristic (ROC) curves were employed to investigate the connections between the counts and ratios of leukocytes and the existence of LVO, as well as the discriminatory ability of these variables in predicting LVO. Total white blood cell (WBC) count, neutrophil count, and neutrophil-to-lymphocyte ratio (NLR) were substantially higher in the LVO existence group compared to the LVO absence group, whereas the ratio of eosinophils to neutrophils (ENR × 102) was lower (P < .001, respectively). Significant associations were observed between total WBC counts, neutrophil counts, NLR, and ENR × 102 and the existence of LVO (P < .001, respectively). Total WBC counts, neutrophil counts, NLR, and ENR × 102 had respective areas under the curves (AUC) of 0.730, 0.748, 0.704, and 0.680 for identifying LVO. Our results show that in AIS patients, the existence of LVO is independently associated with elevated total WBC and neutrophil counts, high NLR, and low ENR × 102 levels. Neutrophil and total WBC counts, as well as NLR and levels of ENR × 102, may serve as potential biomarkers for predicting LVO. Neuroinflammation, based on the existence of LVO, should be given particular attention in future investigations.

Glucose Control and Risk of Symptomatic Intracerebral Hemorrhage Following Thrombolysis for Acute Ischemic Stroke: A SHINE Trial Analysis.

BACKGROUND AND OBJECTIVES: Baseline hyperglycemia is associated with worse outcomes in acute ischemic stroke (AIS), including higher risk of symptomatic intracerebral hemorrhage (sICH) following treatment with thrombolysis. Prospective data are lacking to inform management of post-thrombolysis hyperglycemia. In a prespecified analysis from the Stroke Hyperglycemia Insulin Network Effort (SHINE) trial of hyperglycemic stroke management, we hypothesized that post-thrombolysis hyperglycemia is associated with a higher risk of sICH. METHODS: Hyperglycemic AIS patients <12 hours onset were randomized to intensive insulin (target range 80-130 mg/dL) vs standard sliding scale (80-179 mg/dL) over a 72-hour period, stratified by treatment with thrombolysis. Three board-certified vascular neurologists independently reviewed all sICH events occurring within 7 days, defined by neurologic deterioration of ≥4 points on the NIH Stroke Scale (NIHSS). Associations between blood glucose control and sICH were analyzed using logistic regression accounting for NIHSS, age, systolic blood pressure, onset to thrombolysis time, and endovascular therapy (odds ratios [OR], 95% CI). Additional analysis compared patients in a high-risk group (age older than 60 years and NIHSS ≥8) vs all others. Categorical variables and outcomes were compared using the χ2 test (p < 0.05). RESULTS: Of 1151 SHINE participants, 725 (63%) received thrombolysis (median age 65 years, 46% women, 29% Black, 18% Hispanic). The median NIHSS was 7, baseline blood glucose was 187 (interquartile range 153-247) mg/dL, and 80% were diabetic. Onset to thrombolysis time was 2.2 hours (1.6-2.9). Post-thrombolysis sICH occurred in 3.6% (3.0% intensive vs 4.3% standard glucose control, OR 1.10, 0.60-2.01, p = 0.697). In the first 12 hours, every 10 mg/dL higher glucose increased the odds of sICH (OR 1.08, 1.03-1.14, p = 0.004), and a greater proportion of glucose measures in the normal range (80-130 mg/dL) decreased the odds of sICH (0.89, 0.80-0.99, p = 0.030). These associations were strongest in the high-risk group (age older than 60 years and NIHSS ≥8). DISCUSSION: In this prespecified analysis from the SHINE trial, intensive insulin therapy was not associated with a reduced risk of post-thrombolysis sICH compared with standard sliding scale. However, early post-thrombolysis hyperglycemia was associated with a higher risk of sICH overall, particularly in older patients with more severe strokes. Further prospective research is warranted to address the risk of sICH in hyperglycemic stroke patients undergoing endovascular therapy. TRIAL REGISTRATION INFORMATION: NCT01369069.