Current Neurovascular Research - Volume 21, Issue 3, 2024

Cerebral Small Vessel Disease (CSVD) has not been systematically studied in patients with Transient Global Amnesia (TGA). We aimed to investigate the CSVD burden in patients with TGA and its relationship with TGA recurrence.

We retrospectively examined 69 patients diagnosed with TGA in a single center between January 2015 and November 2023. The overall CSVD burden and single CSVD imaging markers, including enlarged perivascular spaces in the hippocampus (H-EPVS), were measured in each patient and compared with those in 69 age- and sex-matched healthy controls. Multivariate logistic regression was performed to determine independent predictors of recurrence.

Of the 69 included patients, 40 (58%) were female, and the median age was 67 years (range 42-83 years). Twenty-one patients (30.4%) showed dot-like hippocampal hyperintensities on diffusion-weighted imaging (DWI). The mean follow-up was 51 months. Sixteen patients (23.2%) experienced TGA recurrence. The burden of overall CSVD, lacunes, WMH, EPVS, and extensive H-EPVS was higher in TGA patients than in controls. TGA patients who experienced recurrence had a heavier overall CSVD burden, lower frequency of hippocampal DWI hyperintensities, and longer follow-up duration than those who had with single episode. In the multivariate analysis, only follow-up duration was an independent predictor of TGA recurrence.

The overall CSVD burden and extensive H-EPVS burden were higher in patients with TGA than healthy controls. Follow-up duration but not overall CSVD burden may predict TGA recurrence.

Although Endovascular Thrombectomy (EVT) significantly improves the prognosis of Acute Ischemic Stroke (AIS) patients with large vessel occlusion, the mortality rate remains higher. This study aimed to construct and validate a nomogram for predicting 90-day all-cause mortality in AIS patients with large vessel occlusion and who have undergone EVT.

AIS patients with large vessel occlusion in the anterior circulation who underwent EVT from May 2017 to December 2022 were included. 430 patients were randomly split into a training group (N=302) and a test group (N=128) for the construction and validation of our nomogram. In the training group, multivariate logistic regression analysis was performed to determine the predictors of 90-day all-cause mortality. The C-index, calibration plots, and decision curve analysis were applied to evaluate the nomogram performance.

Multivariate logistic regression analysis revealed neurological deterioration during hospitalization, age, baseline National Institutes of Health Stroke Scale (NIHSS) score, occlusive vessel location, malignant brain edema, and Neutrophil-to-lymphocyte Ratio (NLR) as the independent predictors of 90-day all-cause mortality (all p ≤ 0.039). The C-index of the training and test groups was 0.891 (95%CI 0.848-0.934) and 0.916 (95% CI: 0.865-0.937), respectively, showing the nomogram to be well distinguished. The Hosmer-Lemeshow goodness-of-fit test revealed the p-values for both the internal and external verification datasets to be greater than 0.5.

Our nomogram has incorporated relevant clinical and imaging features, including neurological deterioration, age, baseline NIHSS score, occlusive vessel location, malignant brain edema, and NLR ratio, to provide an accurate and reliable prediction of 90-day all-cause mortality in AIS patients undergoing EVT.

A rupture of the intracranial aneurysm is frequently complicated, with an increase of intracranial pressure (ICP) requiring conservative and/or surgical treatment. We analyzed the risk factors related to the duration of pathologic ICP increase and the relationship between ICP burden and the outcome of subarachnoid hemorrhage (SAH).

Consecutive cases with aneurysmal SAH treated at our institution between 01/2003 and 06/2016 were eligible for this study. Different admission variables were evaluated to predict the duration of ICP increase >20 mmHg in univariate and multivariate analyses. The association of the ICP course with SAH outcome parameters (risk of cerebral infarction, in-hospital mortality, and unfavorable outcome at 6 months defined as modified Rankin scale >3) was adjusted for major outcome-relevant confounders.

Of 820 SAH patients, 378 individuals (46.1%) developed at least one ICP increase requiring conservative and/or surgical management after aneurysm treatment (mean duration: 1.76 days, range: 1 - 14 days). In the multivariable linear regression analysis, patients’ age (unstandardized coefficient [UC]=-0.02, p <0.0001), World Federation of Neurosurgical Societies (WFNS) grade 4-5 at admission (UC=0.71, p <0.004), regular medication with the angiotensin-converting enzyme (ACE) inhibitors (UC=-0.61, p =0.01), and presence of intracerebral hemorrhage (UC=0.59, p =0.002) were associated with the duration of ICP increase. In turn, patients with longer ICP elevations were at higher risk for cerebral infarction (adjusted odds ratio [aOR]=1.32 per-day-increase, p <0.0001), in-hospital mortality (aOR=1.30, p <0.0001) and unfavorable outcome (aOR=1.43, p <0.0001). SAH patients who underwent primary decompressive craniectomy (DC) showed shorter periods of ICP increase than patients with a secondary decompression (mean: 2.8 vs 4.9 days, p <0.0001).

The duration of ICP increase after aneurysm rupture is a strong outcome predictor and is related to younger age and higher initial severity of SAH. Further analysis of the factors impacting the course of ICP after SAH is essential for the optimization of ICP management and outcome improvement.

CI/R, characterized by ischemic injury following abrupt reestablishment of blood flow, can cause oxidative stress, mitochondrial dysfunction, and apoptosis. We used oxygen-glucose deprivation/reoxygenation (OGD/R) induced injury in HT22 and primary mouse cortical neurons (MCN) as a model for CI/R.

This study investigates the role of miR-188-5p in hippocampal neuron cell injury associated with Cerebral Ischemia-Reperfusion (CI/R).

HT22 and MCN cells were induced by OGD/R to construct an in vitro model of CI/R. Cell apoptosis and proliferation were assessed using flow cytometry and the Cell Counting Kit-8 (CCK8). ELISA was conducted to measure the levels of IL-1β, IL-6, and TNF-α. Moreover, the interaction between miR-188-5p and IL6ST was investigated using dual luciferase assay, the expression of miR-188-5p, Bax, cleaved-caspase3, IL-6, Bcl-2, IL-1β, TNF-α, IL6ST, NFκB, NLRP3 and STAT3 was evaluated using RT-qPCR or Western blot, and immunofluorescence was used to analyze the co-expression of p-STAT3 and NLRP3 in neuronal cells.

OGD/R reduced proliferation and miR-188-5p levels and increased IL6ST expression, inflammation, and apoptosis in HT22 and MCN cells. Moreover, miR-188-5p was found to bind to IL6ST. Mimics of miR-188-5p reduced apoptosis, lowered the expression of cleaved-caspase3 and Bax proteins, and elevated Bcl-2 protein expression in cells treated with OGD/R. Overexpression of miR-188-5p decreased the levels of NLRP3 and p-STAT3 in the OGD/R group. Furthermore, the overexpression of miR-188-5p reduced IL6ST, p-NFκB/NFκB, p-STAT3/STAT3, and NLRP3 proteins in OGD/R, and these effects could be reversed by IL6ST overexpression.

Mimics of miR-188-5p were found to inhibit inflammation and the STAT3/NLRP3 pathway via IL6ST, thereby ameliorating injury in HT22 and MCN cells treated with OGD/R in the context of CI/R.

Adherens junction in the blood-labyrinth barrier is largely unexplored because it is traditionally thought to be less important than the tight junction. Since increasing evidence indicates that it actually functions upstream of tight junction adherens junction may potentially be a better target for ameliorating the leakage of the blood-labyrinth barrier under pathological conditions such as acoustic trauma.

This study was conducted to investigate the pathogenesis of the disruption of adherens junction after acoustic trauma and explore potential therapeutic targets.

Critical targets that regulated the disruption of adherens junction were investigated by techniques such as immunofluorescence and Western blotting in C57BL/6J mice.

Upregulation of Vascular Endothelial Growth Factor (VEGF) and downregulation of Pigment Epithelium-derived Factor (PEDF) coactivated VEGF-PEDF/VEGF receptor 2 (VEGFR2) signaling pathway in the stria vascularis after noise exposure. Downstream effector Src kinase was then activated to degrade VE-cadherin and dissociate adherens junction, which led to the leakage of the blood-labyrinth barrier. By inhibiting VEGFR2 or Src kinase, VE-cadherin degradation and blood-labyrinth barrier leakage could be attenuated, but Src kinase represented a better target to ameliorate blood-labyrinth barrier leakage as inhibiting it would not interfere with vascular endothelium repair, neurotrophy and pericytes proliferation mediated by upstream VEGFR2.

Src kinase may represent a promising target to relieve noise-induced disruption of adherens junction and hyperpermeability of the blood-labyrinth barrier.

The impact of low platelet count on outcomes in patients with Acute Ischemic Stroke (AIS) undergoing Mechanical Thrombectomy (MT) is still unclear. In this study we have further explored the effect of thrombocytopenia on the safety and efficacy of MT in patients with anterior circulation Large Vessel Occlusion (LVO) stroke.

Patients with AIS who underwent MT at our center between June 2015 and November 2021 were examined. Based on the platelet count recorded on admission patients were divided into two groups: those with thrombocytopenia (<150 × 10⁹/L) and those without thrombocytopenia (≥ 150 × 10⁹/L). Symptomatic Intracranial Hemorrhage (sICH) was the primary safety outcome. The efficacy outcome was functional independence defined as a 90-day modified Rankin Scale (mRS) score of 0-2. Multivariate logistic regression models were used to determine the risk factors for post-procedure sICH and 90-day functional outcomes.

Among 302 patients included in the study, thrombocytopenia was detected in 111 (36.8%) cases. Univariate analysis showed age, the proportion of atrial fibrillation, the rates of sICH, 90-day poor outcomes, and mortality to be higher in patients with thrombocytopenia (all p <0.05). Multivariable analysis showed thrombocytopenia to be independently associated with a higher rate of sICH (OR 2.022, 95% CI 1.074-3.807, p =0.029) however, thrombocytopenia did not affect the 90-day functional outcomes (OR 1.045, 95% CI 0.490-2.230, p = 0.909) and mortality (OR 1.389, 95% CI 0.467– 4.130 p = 0.554).

Thrombocytopenia may increase the risk of sICH but not affect the 90-day functional outcomes and mortality in patients with AIS treated with MT.

Interleukin-6 (IL-6) plays an important role   in   the   pathophysiology   of atherosclerosis. This study aimed to determine whether IL-6 is a crucial biomarker associated with Multiple Acute Infarctions (MAIs), which indicate   an   important   stroke   mechanism of artery-to-artery embolism with a high risk of stroke recurrence in symptomatic Intracranial Atherosclerotic Disease (sICAD). We tested the association between circulating IL-6 levels and the presence of MAIs in a prospective population-based registry.

We included 1,919 patients with sICAD and baseline IL-6 levels from the Third China National Stroke Registry for the current analysis, The baseline IL-6 was centrally measured at Beijing Tiantan Hospital, Images of the brain parenchyma and vascular structures were digitized and then blindly and independently read by two groups of trained readers, The recruited patients were divided into 3 groups according to IL-6 tertiles, The relationship between baseline IL-6 tertile levels and the presence of MAIs was modeled using multivariate logistic regression.

Compared to patients in the first IL-6 tertile those in the second and third tertiles demonstrated a significantly higher proportion of MAIs. The odds ratios were 1.81 [95% Confidence Interval (CI), 1.42-2.30] for the second versus first tertile and 2.15 (95% CI 1.66-2.79) for the third versus first tertile, The proportion of patients with MAIs increased with rising IL-6 tertiles observed at 59.3%, 71.6% and 76.4% for the first, second and third tertiles, respectively (P for trend < 0.001). The association between higher IL-6 tertiles and increased proportion of MAIs was also present in subgroups defined by age < 65 years, age ≥ 65 years, male, and high-sensitivity C-reactive Protein (hs-CRP) ≥ 2 mg/L. Furthermore, a significant interaction was detected for the hs-CRP subgroup (P = 0.038). In sensitivity analyses, the positive correlation between IL-6 levels and the proportion of MAIs remained consistent.

In patients with sICAD, higher IL-6 levels were associated with an increased proportion of MAIs. IL-6 could be used as a biomarker and a potential therapeutic target for future atherosclerosis treatment and prevention in patients with sICAD.

Neutrophil-To-Albumin Ratio (NAR) is a novel inflammatory biomarker. However, the potential prognostic value of NAR in acute ischemic stroke (AIS) remains unclear. This study aimed to evaluate whether NAR levels correlated with the 3-month modified Rankin scale (mRS) in patients with AIS.

AIS patients were included in this retrospective study. NAR was calculated as the ratio of absolute neutrophil count to serum albumin level. Logistic regression analyses were used to investigate the effect of NAR on 3-month mRS of AIS. The predictive values of NAR, albumin level, and neutrophil count were compared utilizing receiver operating characteristic (ROC) curves. Moreover, subgroup analyses and interaction tests were conducted to evaluate the consistency of NAR’s effect on AIS prognosis.

Of the 780 patients included, 403 (51.67%) had a poor clinical outcome (mRS 3-6) at 3 months. NAR was independently correlated to 3-month poor functional outcome after adjusting for confounders (Odds ratios (OR), 9.34; 95% confidence intervals (CI), 1.09 to 80.13; p =0.0417). Subgroup analysis showed a relative effect consistent with the overall population results, and no statistical interactions were found in the subgroups (all p for interaction > 0.05). The ROC curve showed that the prognosis-related cutoff value for NAR was 0.123, with corresponding specificity and sensitivity of 53.55% and 63.94%, respectively. When comparing the predictive power, NAR (0.590; 95%CI 0.549–0.630) exhibited the highest area under the curve (AUC) of ROC compared to neutrophils (0.584; 95%CI 0.543–0.624) and albumin (0.540; 95%CI 0.500–0.581).

There is a positive relationship between NAR levels and 3-month poor functional outcomes in AIS patients, supporting the potential of NAR as a readily available and economic serum biomarker for the early identification of AIS prognosis. Further studies are required to validate the prognostic value and clinical utility of the NAR.

END (Early Neurologic Deterioration) significantly elevates the risk of morbidity and mortality. While numerous studies have investigated END following hemorrhagic transformation post-thrombolysis in acute cerebral infarction research on END without hemorrhagic transformations in patients with acute cerebral infarction due to non-cardiogenic embolism remains scarce.

This study aimed to elucidate the impact of PCSK9 inhibitors on early neurological deterioration (END) in patients with acute non-cardioembolism cerebral infarction without hemorrhagic transformation post-intravenous thrombolysis. Additionally it aimed to identify risk factors associated with END in patients suffering from this type of stroke.

The objective of this study is to investigate the effect of PCSK9 inhibitors on early neurologic deterioration (END) in patients with acute non-cardiogenic cerebral infarction without hemorrhagic transformation after intravenous thrombolysis and identify associated risk factors for END in this patient population.

In this retrospective case-control study the data of consecutive patients who underwent intravenous thrombolysis after AIS (acute ischemic stroke) without hemorrhagic transformation during hospitalization at the Stroke Center of The Fifth Affiliated Hospital of Sun Yat-sen University between January 2018 to February 2023 were retrieved and assessed. An increase of >2 in the National Institutes of Health Stroke Scale (NIHSS) within 7 days after admission was defined as END.

This study included 250 patients (56 males 22.4%) they were 63.344±12.901 years old. There were 41 patients in the END group and 209 in the non-END group. The usage rate of PCSK9 inhibitors was significantly different between the END group and non-END group (29.268% vs 58.852% P<0.001). The White blood cell count (WBC) and homocysteine levels showed a significant difference between the two groups (all P<0.05). Patients not using PCSK9 inhibitors (OR=0.282 95%CI: 0.127-0.593) and white blood cell count (OR=1.197, 95%CI: 1.085-1.325) were independently associated with END. Receiver-operating characteristic curve analysis suggested that the sensitivity specificity and area under the curve for PCSK9 inhibitors used for END were 88.9%, 80.7% and 0.648 respectively.

The use of PCSK9 inhibitors can reduce the incidence of early neurological deterioration in patients with acute non-cardioembolism and non-hemorrhagic transformation after intravenous thrombolysis.

Glioblastoma multiforme (GBM) is an aggressive type of brain tumor that is difficult to remove surgically. Research suggests that substances from saffron, namely crocetin and crocin, could be effective natural treatments, showing abilities to kill cancer cells.

Our study focused on evaluating the effects of crocetin on glioma using the U87 cell line. We specifically investigated how crocetin affects the survival, growth, and spread of glioma cells, exploring its impact at concentrations ranging from 75-150 μM. The study also included experiments combining crocetin with the chemotherapy drug Temozolomide (TMZ) to assess potential synergistic effects.

Crocetin significantly reduced the viability, proliferation, and migration of glioma cells. It achieved these effects by decreasing the levels of Matrix Metallopeptidase 9 (MMP-9) and Ras homolog family member A (RhoA), proteins that are critical for cancer progression. Additionally, crocetin inhibited the formation of cellular structures necessary for tumor growth. It blocked multiple points of the Ak Strain Transforming (AKT) signaling pathway, which is vital for cancer cell survival. This treatment led to increased cell death and disrupted the cell cycle in the glioma cells. When used in combination with TMZ, crocetin not only enhanced the reduction of cancer cell growth but also promoted cell death and reduced cell replication. This combination therapy further decreased levels of high mobility group box 1 (HMGB1) and Receptor for Advanced Glycation End-products (RAGE), proteins linked to inflammation and tumor progression. It selectively inhibited certain pathways involved in the cellular stress response without affecting others.

Our results underscore the potential of crocetin as a treatment for glioma. It targets various mechanisms involved in tumor growth and spread, offering multiple avenues for therapy. Further studies are essential to fully understand and utilize crocetin’s benefits in treating glioma.