Translational Stroke Research最新文献

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.

Hyperthermia within the first 24 h following ischemic stroke (IS) has been associated with poor outcomes. We sought to determine whether blood-brain barrier (BBB) permeability contributes to the relationship between hyperthermia and early infarct growth (EIG). A retrospective analysis was conducted on a prospective stroke biobank. EIG was defined as the percentage difference between the initial volume (mL) determined by the diffusion-weighted imaging at admission and the volume (mL) from the control CT image on the 4 th-7 th day. Hyperthermia was defined as an axillary body temperature ≥ 37.5 °C within the first 24 h. Soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) serum levels were measured by ELISA. One-hundred and two (19.7%) patients showed EIG from a cohort of 519 patients (45.6% females). Linear correlation was observed for axillar body temperature and EIG (Pearson's r = 0.46; p < 0.001). sTWEAK serum levels showed a c-statistic of 0.74 (95% CI: 0.69-0.79), with an optimal cut-off point > 3000 pg/mL for EIG prediction. Moreover, microalbuminuria levels strongly correlated with sTWEAK levels (Pearson's r = 0.75; p < 0.001). In the multivariate analysis for EIG was observed an independent association with hyperthermia (adjusted OR 24.21; 95% CI: 12.03-39.12), sTWEAK levels > 3000 pg/mL (adjusted OR 16.43; 95% CI: 3.71-72.70), leukoaraiosis (adjusted OR 10.42; 95% CI: 2.68-39.08), and microalbuminuria (adjusted OR 1.02; 95% CI: 1.00-1.12). In our cohort, hyperthermia was independently associated with EIG after IS. The fact that microalbuminuria, leukoaraiosis, and sTWEAK were also associated with EIG suggests a relationship with increased BBB permeability.

Stereotactic radiosurgery (SRS) is a non-invasive treatment option for brain arteriovenous malformations (bAVMs). However, SRS cures are delayed, making it less favorable for higher risk ruptured bAVMs (rbAVMs) than unruptured (ubAVMs). This systematic review and meta-analysis explores the long-term outcomes of SRS-focused protocols for rbAVMs and ubAVMs. This study adhered to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines. Literature search was conducted using PubMed, Ovid Medline, Scopus, and hand-search on January 30th, 2025. The inclusion criteria encompassed studies: distinguishing cohorts by rupture status, reporting post-SRS outcomes, and without overlapping series. Pooled analysis was performed from 24 articles using DerSimonian-Laird random effects models. Subgroup and meta-regression analyses were also conducted. All analyses were performed using R. For rbAVMs, the pooled rupture, obliteration, and mortality rates were 7.14% (95% CI: 5.76%-8.64%), 65.0% (95% CI: 57.2%-72.4%), and 0.87% (95% CI: 0.00%-5.14%), respectively, and for ubAVMs, 6.13% (95% CI: 4.71%-7.69%), 59.5% (95% CI: 51.3%-67.3%), and 0.89% (95% CI: 0.00%-3.82%), respectively. Subgroup meta-analyses of rupture rates and obliteration rates showed no significant differences based on prior treatments (Q = 2.47, p = 0.48; Q = 4.34, p = 0.23; respectively) or volume-staging protocols (Q = 4.90, p = 0.18; Q = 1.12, p = 0.77, respectively). Meta-regression analysis for rbAVMs demonstrated a positive correlation between intranidal aneurysms and rupture rate (p < 0.05, R² = 100%), an inverse correlation between Spetzler-Martin (SM) grade I-II bAVMs and obliteration rate (p < 0.05, R² = 68.6%), and a positive correlation between SM grade III-V bAVMs and obliteration rate (p < 0.05, R² = 68.0%). Meta-regression analysis for ubAVMs demonstrated an inverse correlation between eloquent-region lesions and rupture rate (p < 0.05, R² = 31.3%), and surprisingly a positive correlation between mean age and obliteration rate (p < 0.05, R² = 23.8%). SRS-focused studies show similar long-term outcomes regardless of rupture status, but presence of underlying factors indicates the need for individualized risk-benefit analysis.

Ischemic stroke, the second leading cause of death worldwide and the leading cause of long-term disabilities, presents a significant global health challenge, particularly in aging populations where the risk and severity of cerebrovascular events are significantly increased. The aftermath of stroke involves neuronal loss in the infarct core and reactive astrocyte proliferation, disrupting the neurovascular unit, especially in aged brains. Restoring the balance between neurons and non-neuronal cells within the perilesional area is crucial for post-stroke recovery. The aged post-stroke brain mounts a fulminant proliferative astroglial response, leading to gliotic scarring that prevents neural regeneration. While countless therapeutic techniques have been attempted for decades with limited success, alternative strategies aim to transform inhibitory gliotic tissue into an environment conducive to neuronal regeneration and axonal growth through genetic conversion of astrocytes into neurons. This concept gained momentum following discoveries that in vivo direct lineage reprogramming in the adult mammalian brain is a feasible strategy for reprogramming non-neuronal cells into neurons, circumventing the need for cell transplantation. Recent advancements in glial cell reprogramming, including transcription factor-based methods with factors like NeuroD1, Ascl1, and Neurogenin2, as well as small molecule-induced reprogramming and chemical induction, show promise in converting glial cells into functional neurons. These approaches leverage the brain's intrinsic plasticity for neuronal replacement and circuit restoration. However, applying these genetic conversion therapies in the aged, post-stroke brain faces significant challenges, such as the hostile inflammatory environment and compromised regenerative capacity. There is a critical need for safe and efficient delivery methods, including viral and non-viral vectors, to ensure targeted and sustained expression of reprogramming factors. Moreover, addressing the translational gap between preclinical successes and clinical applications is essential, emphasizing the necessity for robust stroke models that replicate human pathophysiology. Ethical considerations and biosafety concerns are critically evaluated, particularly regarding the long-term effects and potential risks of genetic reprogramming. By integrating recent research findings, this comprehensive review provides an in-depth understanding of the current landscape and future prospects of genetic conversion therapy for ischemic stroke rehabilitation, highlighting the potential to enhance personalized stroke management and regenerative strategies through innovative approaches.

Ischemic stroke disrupts protein homeostasis in brain cells, causes endoplasmic reticulum (ER) stress, and consequently activates the unfolded protein response (UPR). The primary function of UPR activation is to help cells restore ER function, thereby promoting cell survival. A major adaptive UPR branch is mediated by activating transcription factor 6 (ATF6). We previously provided experimental evidence that activation of ATF6 signaling in neurons improves short-term outcome after both transient and permanent stroke. However, the effect of ATF6 activation in astrocytes on stroke outcome remains undetermined, and critically, the long-term therapeutic potential of targeting this UPR branch in permanent stroke has not been evaluated. The current study aimed to address these two critical unknowns. First, using conditional knock-in mice in which functional short-form ATF6 (sATF6) is specifically expressed in astrocytes, we demonstrated that astrocytic ATF6 activation modestly improved outcome after permanent stroke. Then, our pharmacokinetic analysis indicated that compound AA147, an ATF6-specific activator, can cross the blood-brain barrier. Lastly, we found that post-stroke treatment with AA147 had no significant beneficial effect on short-term outcome, but improved long-term functional recovery in both young and aged mice after permanent stroke. Together with previous findings, our data support the notion that the ATF6 pathway is a promising target for stroke therapy.

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.

The Woven EndoBridge (WEB) device has become a prominent treatment for wide-neck bifurcation intracranial aneurysms since its FDA approval in 2018. However, the impact of anticoagulant therapy on its efficacy and patient outcomes remains underexplored. This study aims to evaluate the effects of postoperative anticoagulant use on aneurysm occlusion, retreatment rates, and functional outcomes following WEB device implantation. This retrospective multicenter study included 457 patients treated with the WEB device across 10 academic institutions in the United States between January 2012 and June 2024. Patients were categorized based on postoperative anticoagulant use: 91 patients (19.9%) received anticoagulants, while 366 patients (80.1%) did not. Propensity score matching (PSM) was employed to control for potential confounders, resulting in 316 matched patients (229 non-anticoagulant and 87 anticoagulant). After PSM, the anticoagulant group had lower rates of excellent functional outcomes (mRS 0-1: 73% vs. 85%, p = 0.026) and higher mortality rates (6.7% vs. 3.7%, p = 0.33), though the latter difference was not statistically significant. No significant differences in the last follow-up adequate occlusion were observed between the two groups (p = 0.7). However, patients in the anticoagulant group had lower major device compaction (> 50%) (4.9% vs. 12%, p = 0.12) and retreatment rates (4.6% vs. 12%, p = 0.045). Postoperative anticoagulant use is associated with poor functional outcomes and higher tendency for higher mortality rate. No significant differences in the last follow-up adequate occlusion rate were observed between the anticoagulant group and non-anticoagulant group. However, patients in the anticoagulant group had lower major compaction and retreatment rates. These findings suggest that the WEB mechanism of occlusion is more complex than what have been hypothesized and highlight the need for individualized management strategies to optimize outcomes in patients requiring anticoagulation post-WEB. Further studies are needed.

Introduction: Neuroinflammation may contribute to outcomes following subarachnoid haemorrhage (SAH). Human cerebrospinal fluid (CSF) cytokine data is limited and its relationship with systemic inflammation is unknown. This study compares the inflammatory responses in CSF and plasma compartments, and their associations with outcome.

Methods: Ten cytokines were measured in CSF and plasma from 98 SAH patients and 18 control patients. Outcome was assessed with the modified Rankin scale (mRS) and Subarachnoid Haemorrhage Outcome Tool (SAHOT) at days 7, 28, 90 and 180. Regression analyses and principal component analysis (PCA) were performed.

Results: Median levels of all CSF cytokines and plasma IL-6 were higher in SAH patients than controls (p < 0.001). Plasma IL-6 peaked earlier (3 days after SAH) than CSF cytokines (7-9 days after SAH). On day 7, CSF levels were greater than plasma levels for all cytokines (p < 0.001). There was no correlation between individual cytokines in the plasma and CSF. Only plasma IL-6 levels correlated with long-term outcome (mRS (p = 0.009) and SAHOT (p = 0.007) at day 180), accounting for WFNS and blood volume. Seven principal components of cytokines had an eigenvalue greater than 1. Only the first plasma principal component (dominated by IL-6, IL-8, IL-12, IL-13, and TNF-α) was associated with outcomes (p < 0.05). Mediation analysis suggested the effects of WFNS and blood volume on outcome were not mediated by IL-6 or this principal component.

Conclusion: SAH provokes an inflammatory response in CSF and plasma. The response pattern is different and distinct in each compartment. Each compartment's relationship with outcomes differ, suggesting separate roles in SAH pathophysiology. Plasma IL-6 is independently associated with outcomes.

Ischemic stroke is a significant global public health issue that impacts health burdens across various regions. This study analyzed data from the Global Burden of Disease Study 2021 to assess the incidence, mortality, and disability-adjusted life years (DALYs) associated with ischemic stroke worldwide and across different Socio-demographic Index (SDI) regions. Using joinpoint regression and age-period-cohort (APC) models, we examined trends in disease burden and made projections for 2022 to 2035. As of 2021, approximately 7,804,449 (95% UI, 6,719,760-8,943,692) individuals were affected by ischemic stroke, resulting in 3,591,499 (95% UI, 3,213,281-3,888,327) deaths and 70,357,912 (95% UI, 64,329,576-76,007,063) DALYs. These numbers represent increases of 88.0%, 55.0%, and 52.4% since 1990. Despite these increases, age-standardized incidence, mortality, and DALYs rates are declining, with annual percentage change rates (AAPC) of - 0.578%, - 0.927%, and - 14.372%, consistent across all SDI regions. The global rates of IS are influenced by age, period, and cohort, showing increased rates with age but declining over time, particularly in high SDI regions. Major risk factors include hypertension, environmental pollution, and low-density lipoprotein cholesterol (LDL-C). Projections indicate that by 2035, incidence, mortality, and DALYs will rise among those aged 45 and above, while decreasing for those under 35. This highlights the urgent need for preventive and therapeutic strategies targeting ischemic stroke, particularly for individuals over 45, while addressing the impact of major risk factors in high-burden regions.