Translational Stroke Research最新文献

Kynurenine pathway has been linked to several cardiovascular diseases, but their specific associations with stroke risk remain elusive. This study aimed to explore the associations between kynurenine pathway metabolites and the subsequent risk of stroke. A case-control study nested in a community-based cohort (n = 16,113) was performed between 2013 and 2018. A total of 412 incident stroke cases and 412 controls matched by age and sex were included. Plasma levels of kynurenine pathway metabolites, including tryptophan, kynurenine, kynurenic acid (KA), 3-hydroxykynurenine (3-HK), 3-hydroxy anthranilic acid (3-HAA), anthranilic acid (AA), and xanthurenic acid (XA), were measured by ultrahigh performance liquid chromatography-tandem mass spectrometry. Conditional logistic regression analyses were used to calculate odds ratios (ORs) and their 95% confidence intervals (CIs) between these biomarkers and stroke risk. After adjustment for body mass index, current smoking, marital status, estimated glomerular filtration rate, and physical activity, the corresponding OR for the highest versus lowest quintile of XA was 0.56 (95% CI: 0.36-0.89, P trend = 0.018) for total stroke risk and 0.48 (95% CI:0.28-0.81, P trend = 0.015) for ischemic stroke risk, respectively. No significant association was observed between plasma tryptophan, kynurenine, KA, 3-HK, 3-HAA, or AA and stroke risk. Our novel findings indicate an inverse association of plasma XA with the risk of total stroke and ischemic stroke in the general population. These findings highlight the potential of plasma XA as a valuable biomarker for assessing stroke risk and developing targeted prevention strategies.

Circadian organization of blood pressure (BP) is increasingly recognized as a determinant of vascular risk, but its role in acute ischemic stroke (AIS) remains undefined. We investigated whether early circadian BP phenotypes derived from high-frequency monitoring predict short- and long-term outcomes after AIS. In a prospective cohort of 529 patients with AIS, BP was recorded-noninvasively or via arterial line-during the first 72 h. Circadian parameters were extracted using cosinor analysis, and exploratory clustering was applied to identify recurrent BP patterns. Associations with early neurological deterioration (END), symptomatic intracerebral hemorrhage (sICH), 90-day functional outcome, mortality, and 1-year major adverse cardiovascular events (MACE) were assessed using multivariable logistic and Cox regression. Three distinct circadian BP phenotypes emerged: Steady-High (sustained elevation with blunted nocturnal decline), Disrupted-Rhythmicity (loss of amplitude and irregular oscillation), and Partial-Recovery (initial disorganization with progressive re-entrainment). Subtype-specific vulnerabilities were observed. In embolic stroke of undetermined source (ESUS), disrupted rhythmicity was associated with higher risk of END (adjusted OR 2.8, 95% CI 1.2-6.4). In cardioembolic stroke, circadian disorganization was linked to greater risk of sICH after reperfusion (adjusted OR 3.1, 95% CI 1.1-8.7). In large-artery atherosclerosis, the Steady-High phenotype predicted poor 90-day outcome (adjusted OR 2.2, 95% CI 1.0-4.6). Lacunar stroke showed relative preservation of circadian organization, with the lowest prevalence of adverse phenotypes. Across the cohort, Partial-Recovery was associated with the most favorable outcomes. High-frequency 72-hour BP monitoring combined with exploratory, data-driven clustering revealed reproducible circadian BP patterns with subtype-specific prognostic relevance in AIS. These findings suggest that circadian BP profiling may help inform individualized hemodynamic management in acute stroke.

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.