Translational Stroke Research最新文献

This study investigated the therapeutic potential of skin-derived precursor Schwann cells (SKP-SCs) for secondary brain injury following intracerebral hemorrhage (ICH) and its underlying mechanisms. An ICH model was established in mice via intrastriatal autologous blood injection. SKP-SCs were administered intranasally 24 h post-ICH, with the AKT inhibitor GDC0068 used for intervention. Results demonstrated that transplanted SKP-SCs survived peri-hematomally, significantly improved short- and long-term neurological function, reduced brain tissue damage and neuronal apoptosis, preserved blood-brain barrier integrity, and suppressed microglial/macrophage activation and neutrophil infiltration. Mechanistically, SKP-SCs exerted neuroprotection by activating the PI3K/AKT/FOXO3a signaling pathway. In conclusion, intranasal SKP-SC transplantation alleviates ICH-induced deficits and secondary injury via this pathway, representing a promising therapeutic strategy during the acute phase following ICH.

Clarifying the critical lesion regions of poststroke cognitive impairment (PSCI) could improve the understanding of how anatomical locations and functional networks jointly influence the manifestation of cognitive deficits. Lesion-symptom and lesion network analyses are performed to identify the anatomical sites and functional networks related to specific cognitive functions. The multidomain cognitive statuses and the focal brain lesions of 83 patients with PSCI were recorded during the acute poststroke period (< 2 weeks). Multivariate lesion-symptom mapping was performed to identify risk regions, i.e., lesion sites associated with worse cognitive deficits; functional lesion network mapping was performed to identify risk networks, i.e., brain networks connected to risk regional peaks. Lesion-symptom mapping analysis identified several brain regions where lesions were significantly correlated with neurological deficit, general cognitive impairment, visuospatial dysfunction, and executive dysfunction. Various types of cognitive deficits presented diverse risk region distribution patterns with different peaks. Functional lesion network mapping demonstrated that networks connected to peak risk regions for neurological deficit and general cognitive impairment were mostly similar to the default network (DN), whereas the risk network for visuospatial and executive dysfunctions was the somatomotor network (SN). Functional imaging measurements directly from PSCI patients revealed that intranetwork functional connections within the limbic network, which is functionally similar to the DN, were stably reduced in all patients, and intranetwork functional connections in the SN exhibited the same pattern. Although the decreases did not present the network preference observed in lesion network mapping, these results still support the concept that lesions to specific nodes of the DN or SN are associated with the cognitive deficits that constitute PSCI.

A gap in developing novel preclinical treatment strategies for ischemic stroke is predicting long-term outcome in experimental stroke models early during ischemia to reduce heterogeneity and sample size. Besides saving costs through improved risk stratification, reducing the number of animals is a requirement of the 3Rs principle. In this secondary analysis, we analyzed 28 Sprague-Dawley rats of a prospective data base that underwent 90-minute filament-occlusion of the middle cerebral artery (MCAO) to assess the predictive power of early variables at 30, 60, and 90 min after occlusion. The animals were sacrificed after 72 h. Infarct sizes were determined by hematoxylin staining. In a minimally invasive fashion, we recorded cerebral blood flow (CBF) with laser-Doppler flowmetry and direct current (DC)/alternating current-electrocorticography (ECoG) with epidural Ag/AgCl electrodes. Both CBF and ECoG markers correlated with the cortical infarct volumes. Multiclass receiver operating characteristic analysis identified the best predictors of three risk classes, and Spearman's rank correlation was used to explore relationships between ECoG and CBF. The slope of the CBF transients in response to spreading depolarization (SD) was the best biomarker at all time points, while the DC integral was the best epidural biomarker. Both correlated negatively at all time points (ρ < -0.68). In summary, we have found that early risk stratification during MCAO in rats is possible using minimally invasive biomarkers. This would enable, in particular, the early sorting out of animals with a low risk of cortical infarction in neuroprotection studies, where these animals typically distort the statistical results.

Background: Moyamoya syndrome (MMS) associated with sickle cell disease (SCD) is a severe vasculopathy that significantly increases stroke risk. While cerebral revascularization is increasingly considered in this population, concerns about perioperative safety and long-term outcomes have limited its use in clinical practice.

Methods: We conducted a multicenter, retrospective cohort study of 553 patients with MMS who underwent surgical revascularization across 13 centers. Patients were grouped by SCD status (SCD-MMS vs. moyamoya disease (MMD)). Primary outcomes included perioperative stroke, perioperative complications, and functional status at discharge. Secondary outcomes included length of stay, and follow-up stroke.

Results: Of 553 patients, 32 (5.8%) had SCD. There were no significant differences in overall perioperative stroke (OR 1.05, 95% CI 0.19 to 5.54), symptomatic perioperative stroke (OR 0.94, 95% CI 0.09 to 8.94), perioperative complications (OR 1.66, 95% CI 0.47 to 5.86), or follow-up stroke (OR 0.88, 95% CI 0.17 to 4.55). Functional outcomes at discharge were similarly favorable in both groups (mRS 0-1: OR 0.84, 95% CI 0.29 to 2.40). SCD was associated with a longer hospital stay (beta 2.78 days, 95% CI 0.60 to 4.96).

Conclusion: Surgical revascularization for MMS in patients with SCD does not confer additional procedural risk and yields outcomes comparable to those of patients without SCD. These findings support the role of bypass surgery as a viable treatment option in this high-risk population.

Ischemic stroke is a common and devastating disease that imposes a huge burden on global health and the economy. Mitochondrial dysfunction is a key feature of cerebral ischemia-reperfusion injury (CIRI). Mitochondrial transplantation, an emerging neuroprotective strategy that introduces exogenous mitochondria into a living organism, has shown great potential in various neurological diseases. However, significant challenges persist, including the lack of standardized dosing regimens and unclear mechanisms regarding long-term mitochondrial engraftment. While initial clinical trials have demonstrated the safety of this approach, the field is currently at a pivotal juncture requiring rigorous translation from preclinical success to proven clinical efficacy. This review summarizes the in vitro and in vivo research findings on mitochondrial transplantation in stroke models, with the aim of providing a basis for the clinical translation of this technology.

Unruptured intracranial aneurysms (IAs) are highly prevalent in the general population and there is an unmet need for radiological surrogates for the assessment of an increased risk of rupture. High turnover of type I collagen, i.e. abundant proportions of newly synthesized, immature collagen, has been linked to structural instability of the IA wall. This study aimed to test a newly synthesized positron emission tomography tracer that could selectively visualize immature type I collagen in human IAs as a marker for structural instability and thereby increased rupture risk. Following the synthesis of [⁶⁸Ga]Ga-NODA-GA-PEG₁-collagelin, in vitro and ex vivo analyses of collagen, nonhuman tissue and human IAs were performed. Patients undergoing microsurgical repair for unruptured and ruptured IAs were prospectively included in this cross-sectional, single-center study. After safe IA clipping and IA excision, cryosections of IAs were incubated with the tracer, and signal intensity was quantified via autoradiography. To differentiate immature from mature collagen, polarization microscopy was performed after picrosirius red staining. Our study showed that the synthesized tracer [⁶⁸Ga]Ga-NODA-GA-PEG₁-collagelin bound specifically to type I collagen in vitro and in rat tail tendon ex vivo. We included 25 patients with 25 IAs (12 unruptured, 13 ruptured). The tracer preferentially labeled immature type I collagen in human IAs ex vivo: Regions with high tracer uptake correlated with areas rich in immature collagen, as identified by polarization microscopy (r = 0.40, P = 0.002). [⁶⁸Ga]Ga-NODA-GA-PEG₁-collagelin could serve as a complementary, noninvasive molecular imaging tool for personalized assessment of IA instability, but animal studies are required before in vivo use of [⁶⁸Ga]Ga-NODA-GA-PEG₁-collagelin in humans.

To explore the association of lipid accumulation product (LAP) with 3-month functional outcome and etiologic subtypes in patients with acute ischemic stroke. Patients with acute ischemic stroke admitted from July 1, 2020, to June 30, 2022 were enrolled in this study. Initial neurological severity was assessed by the National Institutes of Health Stroke Scale (NIHSS) at admission. Functional outcome was evaluated by the modified Rankin Scale (mRS) at 3 months after ischemic stroke onset. Etiologic subtypes were determined according to the method reported in the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. LAP was calculated by a well-established formula and analyzed by quartiles (Q1-Q4). Multivariate logistic regression analysis was conducted to evaluate the association of LAP quartiles with 3-month functional outcome and etiologic subtypes in patients with acute ischemic stroke. A total of 431 patients with acute ischemic stroke were included in this study. After adjusting for several confounding factors, compared with those in the LAP-Q1 group, patients in LAP-Q3 and LAP-Q4 group had a reduced association with poor 3-month functional outcome [odds ratio (OR): 0.038, 95% confidence interval (CI): 0.004-0.339; OR: 0.014, 95% CI: 0.001-0.158]. Furthermore, patients in LAP-Q3 and LAP-Q4 group showed an increased association with Small-artery occlusion (SAO) subtype (OR: 1.919, 95% CI: 1.075-3.425; OR: 2.322, 95% CI: 1.265-4.262). Elevated LAP levels were associated with favorable 3-month functional outcome in patients with acute ischemic stroke, supporting the concept of the "obesity-stroke paradox". Concurrently, patients with elevated LAP levels were more likely to experience SAO as the etiological subtype of their stroke.

The prognostic implications of Alberta Stroke Program Early CT Score (ASPECTS) subscores in patients with large-core ischemic stroke undergoing endovascular thrombectomy (EVT) remain uncertain. We hypothesized that specific ASPECTS regions substantially influence functional outcomes after EVT and therefore sought to identify which individual subscores are associated with outcome and whether any of them account for the association between total ASPECTS and functional outcomes. We retrospectively analyzed patients with large-core ischemic stroke (ASPECTS ≤ 5) who underwent EVT. Multivariate logistic regression identified factors associated with functional outcomes, and mediation analysis assessed whether specific ASPECTS subscores explains the effect of total ASPECTS on outcomes. Among 295 patients (median ASPECTS 4), 49.2% had a median mRS score of 3 at 3 months. Internal capsule (IC) involvement was the only subscore significantly associated with worse outcomes, including ordinal mRS shift (Odds ratio 2.03 [ 95% confidence interval 1.19‒3.46], P = 0.009), mRS ≥ 4 (3.01 [1.45‒6.24], P = 0.003), and mRS ≥ 3 (2.24 [1.03‒4.87], P = 0.042). Mediation analysis showed that IC involvement explained 50.6% of the total ASPECTS effect on outcomes. Patients with IC lesions showing reversal on follow-up imaging had a significantly lower risk of poor outcomes (0.28 [0.09-0.80], P = 0.018). IC involvement independently predicts poor outcomes after EVT for large-core stroke and substantially explains the effect of total ASPECTS on prognosis.