Translational Stroke Research最新文献

Our study aimed to investigate the factors associated with residual cavernous sinus extra-axial cavernous hemangiomas (ECHs) progression after surgery. This retrospective study consecutively included patients of cavernous sinus ECHs with incomplete lesion resection from February 2012 to January 2024. The progression of the lesions was defined as new lesions or a growth of residual lesion (≥ 10% increase in volume). Cox regression analysis was used to determine factors associated with residual lesion progression. Kaplan-Meier analysis was conducted to estimate the cumulative incidence of residual lesion progression. Sixty patients were included in this study. During the follow-up, there were 31 (51.7%) residual lesions underwent progression, whereas 29 (48.3%) patients were nonprogressive. Multivariate Cox analysis showed that the homogeneous enhancement lesion was correlated with the residual lesion progression (HR, 8.17 [95% CI, 1.03-64.58]; p = 0.046). Kaplan-Meier survival analysis indicated that the rate of homogeneous enhancement lesion progression (3.7 per 10 person-years) was significantly higher than that of the heterogeneous enhancement group (0.5 per 10 person-years; p = 0.019). Fourteen of the 31 patients with lesion progression underwent radiotherapy, and all of them experienced control over the progression of their lesions. This study found that end-of-treatment residual lesions are not rare in patients with cavernous sinus ECHs and the MRI feature is helpful to predict the progression of residual lesions.

Electroencephalogram (EEG) during pinprick stimulation has the potential to unveil neural mechanisms underlying sensorimotor impairments post-stroke. A proof-of-concept study explored event-related peak pinprick amplitude and oscillatory responses in healthy controls and in people with acute and subuacute motor and sensorimotor stroke, their relationship, and to what extent EEG somatosensory responses can predict sensorimotor impairment. In this study, 26 individuals participated, 10 people with an acute and early subacute sensorimotor stroke, 6 people with an acute and early subacute motor stroke, and 10 age-matched controls. Pinpricks were applied to the dorsa of the impaired hand to collect somatosensory evoked potentials. Time(-frequency) analyses of somatosensory evoked potential (SEP) data at electrodes C3 and C4 explored peak pinprick amplitude and oscillatory responses across the three groups. Also, in stroke, (sensori-)motor impairments were assessed with the Fugl Meyer Assessment Upper Extremity (FMA) and Erasmus modified Nottingham Sensory Assessment (EmNSA) at baseline and 7 to 14 days later. Mixed model analyses were used to address objectives. It was demonstrated that increased beta desynchronization magnitude correlated with milder motor impairments (R²_adjusted = 0.213), whereas increased beta resynchronization and delta power were associated to milder somatosensory impairment (R²_adjusted = 0.550). At the second session, larger peak-to-peak SEP amplitude and beta band resynchronization at baseline were related to greater improvements in EMNSA and FMA scores, respectively, in the sensorimotor stroke group. These findings highlight the potential of EEG combined with somatosensory stimuli to differentiate between sensorimotor and motor impairments in stroke, offering preliminary insights into both diagnostic and prognostic aspects of upper limb recovery.

Ischemic stroke is a worldwide disease with high mortality and morbidity. Kv7/KCNQ channels are key modulators of neuronal excitability and microglia function, and activation of Kv7/KCNQ channels has emerged as a potential therapeutic avenue for ischemic stroke. In the present study, we focused on a new Kv7/KCNQ channel opener QO-83 on the stroke outcomes and its therapeutic potential. Transient or distal middle cerebral artery occlusion model was established with C57 mouse to evaluate the role of QO-83. Solitary dose of QO-83 contributes to the microglia inhibition and fibrotic scar mitigation post stroke. QO83 shows prominent effect on reducing infarction area, alleviating cerebral edema, maintaining blood-brain barrier integrity, and enhancing neurogenesis. Single-nucleus RNA sequencing unveils neuroprotection and specific microglial subclusters influenced by QO-83. More importantly, QO83 shows promise in enhancing survival rates with dose dependence. Notably, these protective effects extend beyond the 4-6 h post-reperfusion window. Additionally, continuous dosing of QO-83 correlates with enhanced cognition. In conclusion, this study highlights QO-83 as a protective agent against ischemic brain injury, showcasing its multifaceted effects and potential as a therapeutic strategy.

To investigate corticospinal tract (CST) injury and remodeling in patients with basal ganglia intracerebral hemorrhage (ICH) and explore the characterization capabilities of the corresponding parameters. In this prospective study, baseline, scale, and diffusion-weighted imaging (DWI) data were collected from patient cohorts. Participants were stratified into favorable (0-3 points) and unfavorable (4-6 points) prognosis groups, based on Modified Rankin Scale (mRS) after 3-6 months. The analysis of DWI data was conducted employing FSL and DSI Studio software to compare CST injury between the prognosis groups and CST remodeling features. A partial correlation model was deployed to elucidate the characterization capability of CST-related parameters. Additionally, logistic regression analysis was applied to identify factors significantly influencing prognosis. A total of 65 patients were enrolled with a mean age of 53.52 years and a median hematoma volume of 23.60 ml. The 44 patients were classified within the favorable prognosis group, demonstrating a statistically significant difference in their lower mean age (P = 0.002). Additionally, 10 patients underwent DWI review with a mean age of 50.30 years and a median hematoma volume of 18.56 ml. The investigation uncovered evidence of CST damage versus remodeling at the group level, respectively, with statistical significance (FDR-corrected P < 0.05, 10,000 permutations). The fractional anisotropy (FA) ratio in the internal capsule region exhibited moderate correlation with motor function (r = 0.507, P < 0.001) and the 3- to 6-month mRS scores (r =  - 0.318, P < 0.013). Furthermore, binary logistic regression analysis identified the FA rate in the internal capsule as a significant influencing factor of prognosis (odds ratio = 1.027, 95% confidence interval = 1.003-1.052, P = 0.025). Basal ganglia ICH can coincide with injury to the CST, which could undergo repair over time. Additionally, the FA ratio of the internal capsule is a potential biomarker to characterize residual motor function and provide prognostic information.

Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) polymorphisms are known risk factors for vascular diseases due to the impact on folate metabolism dysfunction and homocysteine (Hcy) accumulation. This study aimed to investigate the association between folate metabolism risk and hemorrhagic risk in moyamoya disease (MMD). In this prospective study, we enrolled 350 MMD patients with complete genotype data for MTHFR and MTRR. Patients were divided into non-hemorrhagic and hemorrhagic MMD groups. Folate metabolism risk was classified into three levels according to genotype configurations. We analyzed the association between folate metabolism risk and hemorrhagic risk in MMD. Furthermore, the association between folate metabolism risk, collateral circulation, and periventricular anastomosis (PA) was assessed. In vitro experiments were conducted on HBMECs to explore the potential mechanism. TT genotype and T allele in MTHFR C677T were significantly associated with a lower risk of hemorrhage, whereas AC genotype and C allele in MTHFR A1298C were significantly linked to a higher risk of hemorrhage. Patients with high folate metabolism risk exhibited a significantly decreased risk of hemorrhage compared to those with low folate metabolism risk. Further analyses demonstrated that high folate metabolism risk was significantly correlated with poor collateral circulation and PA dilation and elevated levels of Hcy. In vitro experiments showed that increased Hcy levels significantly inhibited the proliferation, migration, and tube formation of HBMECs. This study identified a significant negative correlation between folate metabolism risk and hemorrhagic risk in MMD. URL: http://www.chictr.org.cn . Unique identifier: ChiCTR2200061889.

Microcirculatory dysfunction is an important pathophysiology mechanism of early brain injury after aneurysmal subarachnoid hemorrhage (aSAH), which contributes to poor outcomes. The study was performed in Beijing Tiantan Hospital from October 2020 to July 2023. Patients with aSAH who underwent computed tomographic perfusion (CTP) within 24 h after ictus were enrolled prospectively. The peak time of arterial inflow (PTA), peak time of venous outflow (PTV), total venous outflow time (TVT), and difference value of arteriovenous peak time (DV) were collected from the time-density curve of CTP. Primary outcome was 3-month unfavorable functional outcome (modified Rankin Scale score of 4-6). Secondary outcomes included 3-month all-cause death and delayed cerebral ischemia. Multivariable logistic regression analysis and restricted cubic splines were performed to explore the relationship between cerebral hemodynamic parameters and outcomes. We also assessed the prognostic performance of incorporating hemodynamic parameters into previous nomogram models for 3-month poor clinical outcomes. A total of 612 patients were enrolled, among whom the mean age was 56.9 ± 12.3 years old and 391 (63.9%) were female. On multivariable analysis, prolonged TVT could significantly predict 3-month poor functional outcome (adjusted OR 1.074, 95%CI 1.013-1.139), while prolonged PTA was an independent predictor of 3-month all-cause death (adjusted OR 1.293, 95%CI 1.099-1.521). The addition of TVT or PTA to previous nomogram models led to improvements in C-statistics, net reclassification (NRI), and integrated discrimination improvement (IDI). Our study underscores the vital role of arterial inflow and venous outflow in sustaining microcirculation during the acute phase after aSAH, thereby offering new directions for future investigations into therapeutic targets.

Spontaneous intracranial artery dissection (sIAD) is the leading cause of stroke in young individuals. Identifying high-risk sIAD cases that exhibit symptoms and are likely to progress is crucial for treatment decision-making. This study aimed to develop a model relying on circulating biomarkers to discriminate symptomatic sIADs. The study prospectively collected sIAD tissues and corresponding serums from January 2020 to December 2022 as the discovery cohort. Symptomatic sIADs were defined as those with mass effect, hemorrhagic, or ischemic stroke. A stratification model was developed using the machine-learning algorithm within the derivation cohort (a cross-sectional cohort including from January 2018 to August 2022) and validated within the validation cohort (a longitudinal cohort including from January 2017 to April 2023). In the discovery cohort (n = 10, 5 symptomatic), analyses of tissues and serums revealed 15 proteins and 2 cytokines with significance between symptomatic and asymptomatic sIADs. Among these biomarkers, six proteins and one cytokine, participating in the immune response and inflammatory-related pathways, have a good consistency in expression level between sIAD tissues and serums. In the derivation cohort (n = 181, 77 symptomatic), a model incorporating these 7 biomarkers was highly discriminative of symptomatic sIADs (area under curve [AUC], 0.95). This model performed well in predicting the occurrence of sIAD-related symptoms in the validation cohort (n = 84, 26 symptomatic) with an AUC of 0.88. This study revealed seven circulating biomarkers of symptomatic sIAD and provided a high-accuracy model relying on these circulating biomarkers to identify symptomatic sIADs, which may aid in clinical decision-making for sIADs.

The role of chromatin biology and epigenetics in disease progression is gaining increasing recognition. Genes that escape X chromosome inactivation (XCI) can impact neuroinflammation through epigenetic mechanisms. Our previous study has suggested that the X escapee genes Kdm6a and Kdm5c are involved in microglial activation after stroke in aged mice. However, the underlying mechanisms remain unclear. We hypothesized that Kdm6a/5c demethylate H3K27Me3/H3K4Me3 in microglia, respectively, and mediate the transcription of interferon regulatory factor 5 (IRF5) and IRF4, leading to microglial pro-inflammatory responses and exacerbated stroke injury. Aged (17-20 months) Kdm6a/5c microglial conditional knockout (CKO) female mice (one allele of the gene) were subjected to a 60-min middle cerebral artery occlusion (MCAO). Gene floxed females (two alleles) and males (one allele) were included as controls. Infarct volume and behavioral deficits were quantified 3 days after stroke. Immune responses including microglial activation and infiltration of peripheral leukocytes in the ischemic brain were assessed by flow cytometry. Epigenetic modification of IRF5/4 by Kdm6a/5c was analyzed by CUT&RUN assay. The demethylation of H3K27Me3 by kdm6a increased IRF5 transcription; meanwhile, Kdm5c demethylated H3K4Me3 to repress IRF5. Both Kdm6a^fl/fl and Kdm5c^fl/fl mice had worse stroke outcomes compared to fl/y and CKO mice. Gene floxed females showed more robust expression of CD68 in microglia and elevated brain and plasma levels of IL-1β or TNF-α, after stroke. We concluded that IRF5 signaling plays a critical role in mediating the deleterious effect of Kdm6a, whereas Kdm5c's effect is independent of IRF5.

Perihematomal edema (PHE) significantly aggravates secondary brain injury in patients with intracerebral hemorrhage (ICH), yet its detailed mechanisms remain elusive. Neutrophil extracellular traps (NETs) are known to exacerbate neurological deficits and worsen outcomes after stroke. This study explores the potential role of NETs in the pathogenesis of brain edema following ICH. The rat ICH model was created, immunofluorescence and Western blot were used to examine neutrophil accumulation, NET markers citrullinated histone H3 (CitH3) and myeloperoxidase (MPO), tight junction proteins (ZO-1 and Occludin), Aquaporin-4 (AQP4), matrix metalloproteinase-9 (MMP-9), and ERK phosphorylation (p-ERK) in brain tissues surrounding the hematoma. TUNEL staining and behavioral tests were employed to evaluate neuronal apoptosis and neurological dysfunction, while blood-brain barrier (BBB) permeability and brain edema were also measured by Evans blue and brain water content. Furthermore, the molecular mechanisms related to NETs-induced PHE were investigated using NETs, ERK, MMP-9 and AQP4 regulators, respectively. Ly6G⁺ neutrophils surrounding the hematoma developed NETs within 3 days post-ICH. NETs decreased tight junction proteins, destroyed BBB integrity, promoted brain edema, increased neuronal apoptosis, and exacerbated neurological deficits. Conversely, inhibition of NETs mitigated PHE, reduced neuronal apoptosis, and improved neurological functions. Mechanistically, NET-induced PHE was originated from impairment of BBB tight junction via ERK/MMP9 pathway, coupled with ERK-mediated AQP4 downregulation in perihematomal regions. These findings elucidated the effects of NETs on PHE, which offered promising insights for targeting NETs to relieve brain edema and secondary brain injury post-ICH.