Translational Stroke Research最新文献

Neonatal arterial ischemic stroke (NAIS) is associated with considerable pediatric morbidity and mortality but lacks effective treatment options compared to adult ischemic stroke, highlighting the need for clinically relevant translational models. This study aimed to develop a novel middle cerebral artery occlusion (MCAO) model in neonatal piglets with high clinical relevance and the opportunity for long-term survival. Piglets were randomly assigned to undergo either MCAO (n = 8) or sham surgery (n = 6). MCAO was achieved by occluding MCAs using 7 mm aneurysm clips via craniotomy. Laser speckle contrast imaging was used to measure changes in relative cerebral blood flow (rCBF) in three cortical regions (anterior cerebral artery territory, penumbra, and ischemic core). Open field testing was performed in a subset of piglets at baseline, at 24 h post-MCAO-induction (MCAOi), and at 48 h post-MCAOi. 2,3,5-triphenyl tetrazolium chloride (TTC) staining was used to identify infarcts at 48 h post-MCAOi. By 10 min post-MCAOi, rCBF had increased approximately 22.4% in the ischemic core compared to immediately post-MCAOi (p < 0.05), with the area of the core as a percentage of the ipsilateral hemisphere decreasing by approximately 38%. Further, piglets in the MCAO group showed increased ipsiversive circling at 24 h and 48 h post-MCAOi compared to pre-surgery as well as higher infarct volumes compared to piglets in the sham group (31.6 ± 17.0%, p < 0.01). Overall, our model creates a reproducible infarct with consistent neuromotor deficits, real-time assessment of rCBF dynamics, and long-term survival, thus offering insights that may inform the development of novel therapies and improve outcomes for patients affected by NAIS.

Collateral circulation (CC) plays a critical role in stroke progression and vascular endothelial growth factor-A (VEGF-A) is a key angiogenic mediator. The aim of the study was to evaluate the association between VEGF-A plasma levels and CC in patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO) who received endovascular therapy (EVT). We conducted a prospective multicentre study of patients with LVO-AIS who received EVT. Blood samples were collected on admission to measure VEGF-A plasma levels. CC was assessed by automated collateral scoring on baseline CT angiography and classified from 0 to 3, later dichotomized into poor (0-1) and good (2-3) CC. Multivariable logistic regression analyses were performed to explore the association between VEGF-A and CC. Included were 290 patients (73.4 ± 13.5 years, 50.0% women), previous mRS median score was 0 (IQR 0-1) and the baseline NIHSS median score was 16 (IQR 9-20). Higher baseline VEGF-A levels were independently associated with better CC (cOR_{x1 log increase of VEGF-A}= 1.83, 95% CI 1.18-2.83; p = 0.007) adjusted for age and known-onset of symptoms < 6 h. A VEGF-A threshold < 14pg/mL identified poor CC with high specificity (75.2%) and was inversely associated with the probability of presenting good CC (aOR = 0.53, 95%CI 0.29-0.96; p = 0.036). No significant association was found between VEGF-A levels and 3-months functional outcome. Circulating VEGF-A levels wereindependently associated with CC status in AIS patients with anterior LVO treated with EVT. While this finding suggests a potential biological link between VEGF-A and collateral function, it should be interpreted as an association rather than a causal relationship.

Pediatric brain arteriovenous malformation (PbAVM) is a potentially life-threatening condition accounting for intracerebral hemorrhage and other neurological complications. Our study aimed to elucidate the relationships between PbAVM angioarchitecture, spatial distribution, and clinical presentation. This retrospective study included all consecutive PbAVMs managed in a tertiary pediatric center (2007-2023). We performed a hierarchical clustering based on quantitative imaging data and constructed a 3D MRI-based atlas. We derived and analyzed clusters for initial presentation, clinical parameters (cure, recurrent bleeding, proliferation/recurrence, seizures) and location. We included 245 pediatric brain arteriovenous malformations in 234 patients (74.8% ruptured, mean age 9.9±4 years). Hierarchical clustering delineated three clusters of PbAVMs. Cluster 1 included ruptured small slow flow PbAVMs (n = 162, 82% ruptured). Cluster 2 included ruptured and epileptic fast flow PbAVMs (n = 69, 53% ruptured, 23% epileptic), more frequently located within the right thalamus. Cluster 3 included giant PbAVMs (n = 14, 21.5% ruptured, 57% epileptic), more frequently located within the left posterior insula and right premotor area. Cluster 2 PbAVMs achieved lower rate of exclusion than Cluster 1 (HR_cure=0.34±0.23, p = 3.7.10^- 6). Cluster 3 exhibited null complete exclusion, more frequent recurrent bleeding (HR_rupture=6.83±0.61, p = 0.001) and proliferation over time (HR_{proliferation}=11.1±0.49, p = 1.10^- 6). The probabilistic analyses showed association between PbAVMs within primary motor cortex and epileptic presentation, PbAVMs within right thalamus and neurological deficit at presentation, and PbAVMs within left parietal lobe and headaches. We identified three clusters (small slow flow, fast flow, giant) of PbAVMs that demonstrated unique initial presentation, clinical course, outcomes and spatial distribution.

Moyamoya disease (MMD) is a chronic cerebrovascular disorder characterised by the progressive stenosis of bilateral internal carotid arteries, predominantly affecting East Asian populations. Recent advances in RNA expression studies have provided insights into the molecular underpinnings of MMD. This study aims to aggregate transcriptomic data to identify the top differentially expressed genes (DEGs) across published studies and elucidate biological pathways associated with MMD. We conducted a systematic search of the PubMed and Embase databases, identifying 15 transcriptomic studies involving RNA transcriptome-wide analyses of 177 MMD patients. Following preprocessing of significantly upregulated and downregulated Genes, we performed biological pathway enrichment analysis to identify DEGs between MMD patients and control. Additionally, Gene-transcription factor and Gene-drug interaction analyses were conducted to explore potential therapeutic repurposing. Our analysis revealed 98 upregulated and 37 downregulated DEGs (Bonferroni-adjusted p-values < 0.05) significantly associated with MMD. In peripheral blood cells (PBCs), upregulated pathways were predominantly associated with mitotic kinetochore assembly and response to axon injury, while downregulated pathways were linked to cellular response to brain-derived neurotrophic factor (BDNF) and extracellular matrix organization. In vascular tissues, mitotic pathways were notably upregulated, whereas the regulation of cell proliferation and blood circulation pathways were suppressed. Gene-drug interaction analysis highlighted MI-773 and MLN 8237 as potential MMD therapy. This study identifies distinct biological pathways that are dysregulated in key tissues of MMD patients. Given the current limited treatment options for MMD, our findings offer potential biomarkers for risk stratification and novel therapeutic targets that could pave the way for improved management of this debilitating disease.

Rates of recurrent strokes have remained relatively unchanged over the past couple decades, highlighting a need for advancements in secondary prevention of stroke recurrence. This study utilizes the Blood And Clot Thrombectomy Registry And Collaboration (BACTRAC) tissue bank to identify proteomic and demographic differences in recurrent ischemic stroke patients. Blood samples were collected during mechanical thrombectomy of large-vessel occlusion ischemic strokes. Plasma levels for 184 inflammatory and cardiometabolic proteins were measured in systemic blood and intracranial blood from the infarction area. Differences between recurrent and first-stroke patients were analyzed using Fisher's Exact Test for categorical variables and Student's independent samples t tests or Welch's t tests for continuous variables. Proteins were divided into systemic and intracranial proteins, and independent samples t tests were performed with a False Discovery Rate of 5.0%. Significant variables were used in multiple logistic regression. There were 20 patients in the prior stroke group and 121 in the first stroke group. The prior stroke group had a significantly higher percentage of females (80.0% vs 50.4%, p = 0.016) and lower rate of hyperlipidemia comorbidity (10.5% vs 35.5%, p = 0.034). Two systemic proteins were significantly higher in those with a prior stroke: CCL14 and FGF-19. Multiple logistic regression found higher levels of CCL14 and FGF-19 to be predictive of a stroke being recurrent. Along with other demographics, these proteins could provide a predictive model to identify patients with risk of recurrent ischemic strokes. Serum CCL14 and FGF-19 levels are easily accessible biomarkers, making them possible therapeutic targets for recurrent stroke prevention.

Connexin 43 (Cx43), particularly its truncated isoform GJA1-20 k, has shown promise in mitigating neuronal injury through mitochondrial regulation. This study aimed to investigate the therapeutic potential of astrocyte-derived extracellular vesicles (EVs) enriched with GJA1-20 k (Exo-GJA1-20 k) for treating traumatic brain injury (TBI). Primary astrocytes were isolated and transfected with an adeno-associated viral vector to overexpress GJA1-20 k. EVs were extracted and characterized using nanoparticle tracking analysis and Western blotting. A controlled cortical impact (CCI) model of TBI was established in mice, followed by daily administration of Exo-GJA1-20 k via tail vein injections. Mitochondrial function, neuroinflammation, pyroptosis, and cognitive outcomes were evaluated through molecular assays, histological staining, and behavioral tests, including the Morris Water Maze and open field tests. Exo-GJA1-20 k treatment significantly improved mitochondrial quality control by enhancing mitophagy and reducing mitochondrial dysfunction. Pyroptosis, driven by the NLRP3 inflammasome, was notably suppressed, with significant reductions in NLRP3, ASC, and IL-1β expression levels. Behavioral analyses revealed enhanced cognitive performance, as evidenced by shorter escape latencies in the Morris Water Maze and reduced anxiety-like behaviors in the open field test in Exo-GJA1-20 k-treated mice compared to controls. Importantly, the therapeutic effects of Exo-GJA1-20 k were diminished in Pink1-knockout mice, underscoring the dependence on Pink1-mediated mitophagy. This study demonstrates that Exo-GJA1-20 k exerts neuroprotective effects by modulating the mitophagy-NLRP3 inflammasome axis, alleviating neuroinflammation, and mitigating cognitive deficits in a TBI model. These findings propose a novel therapeutic strategy for addressing TBI-induced neuronal damage and underscore the potential of EV-based therapies for treating neurological disorders.

Stroke is a leading cause of disability worldwide, often resulting in persistent motor, cognitive, and emotional impairments. While the hippocampus and amygdala play critical roles in post-stroke behavioral changes, specific neuronal alterations and prolonged glial responses within these regions across different stroke types remain unclear. This study investigates the behavioral, neuronal, and glial effects of subarachnoid hemorrhage (SAH), transient middle cerebral artery occlusion (tMCAO), and photothrombotic stimulation (PTS) in mice. SAH and tMCAO models exhibited significant motor deficits, spatial and recognition memory impairments, and increased anxiety- and depressive-like behaviors, whereas the PTS model showed similar motor and cognitive impairments but lacked affective (anxiety- and depressive-like) behavioral changes. Immunohistochemical analysis revealed increased overlap of tyrosine hydroxylase (TH, a dopaminergic marker) process with NeuN (a neuronal marker) in the dentate gyrus (DG) of SAH and tMCAO mice, highlighting region-specific vulnerability to ischemic damage in the hippocampus. In the amygdala, elevated overlap of TH⁺ process with NeuN in SAH and tMCAO mice suggests enhanced dopaminergic involvement in emotional dysregulation. In contrast, the PTS model did not exhibit any changes in overlap of TH⁺ process with NeuN in either the hippocampus or amygdala, consistent with the absence of affective behavioral deficits. Additionally, SAH and tMCAO models exhibited persistent astrocytic and microglial activation in the amygdala, characterized by increased intensity and density without significant morphological changes, indicative of a chronic inflammatory response. The PTS model also showed increased microglial intensity and density without overt morphological changes, suggesting a more moderate, possibly subclinical inflammatory response. These findings highlight the differential effects of stroke models on behavior, neuronal populations, and glial responses in limbic regions. The pronounced dopaminergic and glial alterations in SAH and tMCAO may underlie post-stroke emotional and cognitive disturbances.

The aim of this study is to investigate the association of neutrophil extracellular traps (NETs) markers with clinical and radiological outcomes in acute ischemic stroke (AIS) patients undergoing endovascular thrombectomy (EVT) and assess the effect of periprocedural heparin during EVT on NETs markers and their association with outcomes. From 198 AIS patients included in the MRCLEAN-MED trial, randomized to receive EVT with (N = 104) or without (N = 94) low-dose unfractionated heparin (5000 IU bolus followed by 500 IU/h for 6 h, n = 104), blood samples were collected at baseline, 1 h, and 24 h post-reperfusion. NETs markers (MPO-DNA, histone-DNA, citrullinated histone H3 [CitH3]) were measured in blood samples, and their associations with stroke severity (National Institutes of Health Stroke Scale [NIHSS] score at 24 h post-reperfusion), long-term functional outcome (modified Rankin Scale [mRS] score at 90-day), and final infarct size (5-7 days) were assessed in EVT and heparin + EVT-treated patients using logistic regression, linear regression, and Pearson's correlation. Histone-DNA levels at 1 h post-heparin + EVT, but not EVT alone, were positively associated with final infarct size. Histone-DNA levels at 24 h post-heparin + EVT were negatively associated with infarct size mRS and NIHSS, while baseline CitH3 was positively correlated with NIHSS at 24 h post-EVT. Interaction analysis showed that the association between histone-DNA levels at 24 h and NIHSS at 24 h was different in the two treatment groups. No further associations were observed. At 1 h post-heparin + EVT, the histone-DNA levels were independently associated with larger infarct size, while at 24 h, histone-DNA linked to improved outcomes post-heparin + EVT and baseline-CitH3 to worse outcomes post-EVT, suggesting heparin may attenuate histone-DNA's effect on outcome.

Chronic cerebral hypoperfusion due to anterior circulation stenosis contributes to cognitive decline. This study examined whether preoperative human urinary kallidinogenase (HUK) administration improves outcomes following percutaneous transluminal angioplasty with stenting (PTAS). In this prospective non-randomized controlled trial, 128 patients with severe anterior circulation stenosis were included in the HUK and control groups, respectively. The primary endpoint was change in Mini-Mental State Examination (MMSE) score at 90 days. Secondary outcomes included changes in Montreal Cognitive Assessment (MoCA) and National Institutes of Health Stroke Scale (NIHSS) scores, perfusion parameters, and inflammatory biomarkers. Propensity score adjustments addressed selection bias. Besides mechanical revascularization by PTAS, HUK pretreatment improved cognitive recovery (ΔMMSE, 5 vs. 2; adjusted p < 0.01) and domain-specific gains in memory, calculation/attention, language, and visuospatial function. HUK significantly promoted postoperative mean transit time (MTT) reduction (1.8 ± 1.3 vs. 0.9 ± 0.6, adjusted p < 0.01), indicating enhanced microcirculatory flow. HUK attenuated ΔIL-6 (18.6 ± 16.2 vs. 26 ± 18, adjusted p = 0.03) and amplified ΔIL-10 (2 ± 0.9 vs. 0.4 ± 0.2, adjusted p < 0.01). Baseline TNF-α predicted cognitive recovery (OR = 0.7, p = 0.03). Safety profiles were comparable (9.4% vs. 10.9% complications, p > 0.05), with no mortality. Collectively, adjunctive HUK administration before PTAS in patients with anterior circulation stenosis was associated with greater cognitive improvement and enhanced microvascular hemodynamics, potentially through anti-inflammatory and perfusion-modulating effects. Larger randomized controlled trials are warranted to validate these associations and elucidate the underlying mechanisms.Trial registration: Chinese Clinical Trial Registry. URL: https://www.chictr.org.cn/ ; unique identifier: ChiCTR2100053351.

Recent studies have shown that the glymphatic system plays a crucial role in driving hyperacute edema after ischemic stroke. This has sparked interest in understanding how this system changes in later phases of ischemic stroke. In this study, we utilized cisternal contrast-enhanced magnetic resonance imaging (CE-MRI) and immunofluorescence staining to investigate glymphatic system alterations at subacute and chronic phases of ischemic stroke. Middle cerebral artery occlusion (MCAO) for 90 min in Sprague-Dawley rats was used to mimic ischemic stroke. A total of 20 rats were randomly divided into four groups: sham group, MCAO 1-week group, MCAO 2-week group, and MCAO 2-month group. Our results showed the glymphatic system was spatially and temporally heterogeneously impaired in the peri-infarct area at subacute phase, even lasting for chronic phase. Specially, we found retention of contrast after cisternal CE-MRI in the infarct core and peri-infarct area at subacute phase of ischemic stroke, which corresponded to the distribution of microglia/macrophages. Our results indicated that ischemic stroke contributed to long-term glymphatic impairment and waste retention, and cisternal CE-MRI delayed enhancement could reflect the retention of waste and activation of microglia/macrophages in this process. These findings suggest cisternal CE-MRI might be a useful tool for investigating the interaction between the glymphatic system and microglia/macrophages in waste clearance and neuroinflammation after brain insult.