Translational Stroke Research最新文献

Vascular inflammation is involved in the pathophysiology of post-stroke cognitive impairment. We aimed to assess whether blood-based biomarkers of inflammation and endothelial dysfunction, such as interleukin 6 (IL-6), vascular cell adhesion molecule (VCAM-1), and tumor necrosis factor-alpha (TNF-α), are associated with cognitive function over time in a prospective cohort of first-ever ischemic stroke patients. Data were obtained from the Prospective Cohort with Incident Stroke Berlin (NCT01363856). Cognitive function was assessed with the Telephone Interview for Cognitive Status-modified (TICS-m) at 1 to 3 years of follow-up. Associations of baseline levels of IL-6, VCAM-1, and TNF-α with cognitive function over time were estimated using a linear mixed model adjusted for demographics, education, vascular risk factors, stroke severity, ischemic stroke subtype, and severity of white matter hyperintensity. We included 570 patients with mild-to-moderate ischemic stroke and baseline data on biomarker levels. The mean age was 67 (± 12 SD), 38.6% were female, and the median National Institutes of Health Stroke Scale (NIHSS) was 2 (IQR 1-4). Frequency of cognitive impairment defined as TICS-m score ≤ 31 was 21.9% at year one, 15.4% at year two, and 11.6% at year three. Higher log-transformed levels of IL-6 and VCAM-1 were associated with lower TICS-m scores over time in the adjusted linear mixed model including white matter hyperintensity burden (IL-6: β = -2.0, 95% CI -3.3 to -0.7, p = 0.003; VCAM-1: β = -4.1, 95% CI -7.3 to -1.0, p = 0.01). In patients with mild-to-moderate first-ever ischemic stroke, higher baseline levels of IL-6 and VCAM-1 were associated with lower Telephone Interview for Cognitive Status-modified during 3 years of follow-up.ClinicalTrials.gov Identifier: NCT01363856.

The accurate identification of acute ischemic stroke (AIS) etiology is fundamental for its management. Midregional pro-atrial natriuretic peptide (MR-proANP) shows potential as a biomarker of cardioembolic (CE) etiology. We aimed to review and synthesize all data on the association between MR-proANP and CE stroke. Articles were searched in Scopus, Web of Science, and Medline databases up to March 2025. Search terms included the free-text words to identify "stroke" and "MR-pro-ANP" and the Mesh term "Stroke." A meta-analysis was performed using the random-effects model. ROBINS-E Tool was used for quality assessment. Eight studies were included, from which six evaluated the association between MR-proANP and CE etiology in patients with AIS and two evaluated MR-proANP levels in the general population and their association with the risk of future CE stroke. All studies were consistent in describing significantly higher levels of MR-proANP in patients with CE stroke when compared to non-CE stroke. Four studies were included in the meta-analysis, confirming a significant association between MR-proANP and CE etiology (OR 6.04, 95% CI 2.79-13.07). Also, MR-proANP showed moderate to high discriminative ability in identifying CE strokes, significantly improving the discriminative capacity of clinical models, and a strong association with atrial fibrillation (AF). Finally, higher MR-proANP levels were associated with an increased risk of future CE stroke. MR-proANP circulating levels were consistently associated with CE etiology of ischemic stroke, improving the discriminative ability of clinical models, suggesting a role for this biomarker in the accurate classification of AIS etiology.

Neurofilament light chain (NfL) and brain glial fibrillary acidic protein (GFAP) are promising markers for cerebral vascular damage. We aimed to evaluate if increased serum NfL and GFAP were associated with cerebral small vessel disease (CSVD) markers among the nondemented middle-to-old aged population. We included participants from the Shunyi Study who had serum NfL and GFAP measurements. Cerebral microbleeds (CMBs), lacunes, perivascular space (PVS) white matter hyperintensities volume (WMHV), and brain parenchymal fraction (BPF) were measured. Cross-sectional and longitudinal associations between CSVD imaging markers and NfL levels were evaluated using multivariable-adjusted models. We included 848 nondemented participants (mean age: 55.5 ± 8.7 years) cross-sectionaly. Among these participants, 603 underwent longitudinal analysis, with an average follow-up time of 5.59 years (range: 4.34-7.20 years). Serum NfL was positively associated with baseline lacunes (OR = 1.40, 95% CI: 1.12-1.75) and WMHV (P < 0.001). GFAP was positively associated with WMHV (P = 0.016), while the association disappeared when including NfL simultaneously in the model. CMBs, PVS, and BPF were not associated with the biomarkers. Logitudinally, baseline NfL was significantly higher among participants with incident lacunes (OR: 1.44, 95% CI: 1.07-1.92); however, this association was attenuated and lost statistical significance after further adjustment for baseline lacune. Increased serum NfL appears to be indicative of lacunes and also the progression of lacunes among middle-to-old-age population. The association between serum NfL and CSVD image markers was less pronounced in the middle-to-old-age population than in the elderly, while GFAP did not prove to be a valuable CSVD biomarker. KEY POINTS: The association between serum NfL and CSVD was less pronounced in the middle-to-old-age population than in the elderly. Serum NfL was positively associated with lacunes (OR = 1.40, 95% CI: 1.12-1.75) and WMHV (P < 0.001). Baseline serum NfL was associated with a 44% increased risk of incident lacunes over a 5.59-year follow-up, but was attenuated after controlling for baseline lacune. Other CVSD markers, including CMBs, PVS, and BPF, showed no association with either NfL or GFAP.

Incomplete stent apposition (ISA) of intracranial stents is recognized as a significant issue in aneurysm treatment leading to in-stent thrombosis and aneurysm recurrence. Traditional imaging techniques like DSA have limitations in accurately assessing stent apposition. This study aimed to explore the efficacy of optical coherence tomography (OCT) in the detection of ISA after stent-assisted coiling (SAC) and its impact on stent endothelialization and aneurysm healing in a porcine model. Twelve healthy minipigs with surgically established common carotid artery sidewall aneurysm were utilized and treated with SAC. DSA and OCT were used immediately post-procedure and during follow-ups at 4 and 12 weeks to assess aneurysm occlusion and stent apposition. Histopathology ultimately assessed stent endothelialization and aneurysm healing. ISA distance, measured by OCT, was analyzed using logistic regression to predict the association between ISA severity and stent endothelialization outcome. OCT detected ISA sites (n = 30) in all subjects at the aneurysm neck, stent ends, and locally in the stent, with a mean ISA distance of 639.65 ± 146.82 µm immediately after the procedure. One experimental pig developed in-stent occlusion after 4 weeks, resulting in death. OCT detected residual ISAs in 54.2% (13/24) at 4 weeks, decreasing to 16.7% (4/24) at 12 weeks in the remaining 11 subjects. DSA showed complete aneurysm occlusion in the remaining subjects at 12 weeks. An ISA distance of > 600 µm was found to be associated with significantly higher rates of poor stent endothelialization at the 12-week follow-up. OCT demonstrated higher sensitivity in detecting ISA after SAC. ISA distance > 600 µm can be a critical prognostic factor, associated with poor outcomes.

Stroke recovery is a multifaceted process influenced by various neuroprotective mechanisms that support long-term rehabilitation. Recent studies on hypoxia-induced neuroprotection have shown promising potential in enhancing stroke recovery through adaptive cellular responses. Hypoxic conditioning in techniques of passive intermittent hypoxic exposures (IHE) or intermittent hypoxic-hyperoxic exposures (IHHE), which alternates between low and normal/high oxygen levels, is emerging as a novel complementary therapy that may improve post-stroke outcomes by promoting neuroprotection, neurogenesis, and vascular remodeling. This review aims to explore the therapeutic implications of IHE/IHHE as a novel complementary therapy to mitigate post-stroke exacerbations and enhance recovery through various physiological and molecular mechanisms. A comprehensive literature search was conducted using public databases such as PubMed, Scopus, Relemed, the National Library of Medicine, and Google Scholar. The search focused on studies related to hypoxia training, neuroprotection, stroke recovery, and IHE/IHHE. The review synthesizes current findings on the pathophysiological insights and therapeutic potential of intermittent hypoxic conditioning in stroke rehabilitation. The review highlights several key areas where IHE/IHHE shows adaptive responses involving hypoxia-inducible factor (HIF) signaling, reactive oxygen species (ROS) regulation, and mitochondrial energetics, contributing to enhanced neuroprotection and tissue recovery. Angiogenesis and vascular remodeling: IHE/IHHE promotes angiogenesis and improves cerebral blood flow, facilitating vascular remodeling and improved perfusion in damaged brain areas. Neurogenesis: IHE/IHHE enhances neurogenesis, aiding in brain repair and functional recovery by promoting neuronal survival and regeneration. Cognitive and motor function: IHE/IHHE has been shown to improve cognitive performance and motor function in post-stroke patients, as well as in elderly individuals with mild cognitive impairment. Cardioprotection: IHE/IHHE reduces cardiovascular risk factors, such as hypertension and inflammation, and has been shown to enhance cardiac function in patients with ischemic heart disease. Integrative rehabilitation: Incorporating IHE/IHHE into post-stroke rehabilitation programs may enhance physical and cognitive outcomes, supporting a holistic approach to recovery. Hypoxic conditioning in modes of IHE/IHHE represents a promising complementary therapy for stroke recovery, leveraging adaptive responses to hypoxia and hyperoxia to promote neuroprotection, neurogenesis, and vascular remodeling. Further research is needed to optimize IHHE protocols, understand their long-term effects, and integrate them effectively into clinical practice. This review benefits physicians, molecular biologists, and neurologists and describes the potential of IHE/IHHE in enhancing stroke rehabilitation outcomes, and highlights the need for wel

Remote ischemic conditioning (RIC) is a simple, non-invasive procedure that has been shown to be safe and feasible in multiple smaller clinical trials. Recent large randomized controlled trials have yielded mixed results regarding clinical effect. Patients with severe stroke may experience greater benefit from cerebroprotective interventions, highlighting the need for adjunctive therapies to enhance endovascular therapy (EVT) outcomes. This post hoc analysis of the RESIST trial evaluates the effect of RIC in the subgroup of patients who underwent EVT. Eligible patients were adults (≥ 18 years old), independent in activities of daily living, who had prehospital stroke symptoms with a duration of less than 4 h. They were randomized to RIC or sham. The primary analysis was performed using the entire range ("shift analysis") of the modified Rankin scale (mRS) at 90 days. A total of 737 patients had acute ischemic stroke, and 134 received EVT. The median (IQR) age was 74 (62, 82) years, median NIHSS was 16 (8, 20), and 52 (39%) were female. Median (IQR) overall adherence to RIC/sham was 81% (56, 96). Intravenous thrombolysis (IVT) was initiated in 76 out of the 134 (57%) EVT-treated patients. There was no significant effect of RIC on mRS in EVT-treated patients, OR (95% CI) 1.26 (0.68-2.32). When IVT was given in addition to EVT, RIC was associated with improved functional outcome at 90 days, adjusted OR 2.46 (1.05, 5.78), p = 0.038 but not without adjunctive IVT, aOR 0.57 (0.21-1.53). The effect of RIC was present only in patients achieving complete reperfusion (mTICI 3) following EVT and IVT (54 out of 134 patients). RIC treatment in addition to IVT and EVT was associated with significantly improved functional outcome at 90 days, observed only in patients who achieved complete reperfusion. These results should only serve as hypothesis-generating for future trials. ClinicalTrials.gov:NCT03481777.

Subarachnoid hemorrhage (SAH) frequently results in early brain injury (EBI), which remains a major barrier to favorable neurological recovery. Understanding the molecular underpinnings of EBI is crucial for developing targeted therapeutics. Circular RNAs (circRNAs) have emerged as influential molecular players in various brain injury contexts. This study focuses on one such molecule, circ_0004058, examining its impact on EBI through interaction with miR-221-3p and the VE1 signaling pathway. Utilizing an established SAH rodent model, our team conducted a detailed investigation of the expression patterns and interactions involving circ_0004058. Our analyses revealed a significant post-SAH upregulation of circ_0004058, which affected miR-221-3p activity and VE1 signaling. Furthermore, functional modulation of circ_0004058 expression altered the severity of EBI, presenting evidence that it serves as a critical determinant in the injury process. The results suggest that circ_0004058 holds promise as a therapeutic target, offering new possibilities for the development of strategies to mitigate SAH-induced brain damage. Through this study, circ_0004058 is highlighted not only as a biomarker but also as a possible avenue for therapeutic modulation in SAH management.

Metabolomics reflects the body's metabolic state and holds substantial promise for identifying associated biomarkers and exploring pathological processes. This study used serum metabolomics to predict malignant brain edema (MBE) following endovascular therapy (EVT) for acute ischemic stroke (AIS) and investigate the underlying mechanisms. In this prospective observational study, we enrolled patients with anterior circulation large vessel occlusion who underwent successful recanalization post-EVT for AIS, including those with or without concomitant hemorrhagic transformation. Eligible patients were stratified into two groups according to the subsequent presence of MBE. Following propensity score matching to adjust for potential confounders, widely targeted metabolomic analysis was conducted on the serum samples. A prediction model, based on the identified differential metabolites, was then developed and validated in another independent cohort. Through widely targeted metabolomic analysis of serum samples from matched 46 patients, we identified 30 metabolites that were significantly altered between patients with and without MBE, including notable differences in acylcarnitine, lysophosphatidylcholine, riboflavin, and tyrosine. A prediction model incorporating 9 differential metabolites was constructed using 10-fold frame shift cross-validation, demonstrating prediction performance in the training set, test set, and external validation, with areas under the curve (AUC) of 0.842, 0.815, and 0.734, respectively. Dynamic change analysis based on multiple time points may suggest a potential role of diminished oxidative energy supply and sustained stress in MBE. The identified acylcarnitine and lysophosphatidylcholine might play influential roles in the pathogenesis of MBE. The prediction model derived from these differential metabolites holds promise as a noninvasive assay for the early detection of MBE and warrants additional refinement and validation.

Background: Prior clinical research demonstrated that rapid reduction in arterial carbon dioxide (PaCO₂) levels during extracorporeal membrane oxygenation (ECMO) is associated with acute brain injury (ABI), which may be due to sudden cerebral vasoconstriction and impaired cerebrovascular autoregulation (CVAR). However, the causal relationship between rapid PaCO₂ correction and its impact on ABI has not been firmly established due to the lack of high-quality evidence. We aimed to investigate whether rapid PaCO₂ correction following extracorporeal cardiopulmonary resuscitation (ECPR) causes CVAR impairment and neuronal injury in a porcine model.

Methods: In this prospective preclinical experimental study, six female pigs (mean weight: 50.75 ± 1.89 kg) were subjected to 15 min of ventricular fibrillation and were then supported by ECMO. The return of spontaneous circulation (ROSC) was attempted in animals at 20 min post-ECMO initiation. Arterial blood gas (ABG) was sampled at specific time points, while arterial blood pressure (ABP) and intracranial pressure (ICP) were continuously monitored. Sweep gas flow was set relative to each animal's ECMO flow rate: 100% in the control group, 200% in the rapid correction group, and 25% in the slow correction group. PRx was computed as the Pearson correlation coefficient between 10-s average mean arterial pressure (MAP) and ICP values using 1-min windows updated every 30 s. Experimental phases were defined for data analysis, including baseline, fibrillation, ECMO I (0-10 min after ECMO initiation), ECMO II (10-20 min), and POST-R (post-ROSC, 20-30 min). Linear mixed-effects models were used to assess group-wise differences in ΔPRx over time. Histopathological analysis was performed to quantify neuronal injury across cortical and subcortical regions. Brain tissues were harvested and histologically analyzed for neuronal injury ischemia vulnerable regions: the midbrain, cerebellum, striatum in the basal ganglia, temporal cortex, hypothalamus, and hippocampus.

Results: In the rapid group, PaCO₂ correction caused a steep drop in PaCO₂-from 60 to approximately 30 mmHg within 5 min-and was associated with impaired CVAR. Following ECMO initiation, the rapid group exhibited a significant rise in ΔPRx, indicating impaired CVAR. Group differences in ΔPRx were significant at ECMO I (F = 8.12, p = 0.001), ECMO II (F = 6.21, p = 0.003), and POST-R (F = 13.47, p < 0.001). At ECMO II, median PRx in the rapid group was 0.50 (IQR: 0.10, 0.78), significantly higher than the control (0.11, IQR: - 0.27, 0.42) and slow (0.38, IQR: - 0.06, 0.55). Histologically, the rapid correction group exhibited significantly increased ischemic neuronal injury in ischemia-prone regions: caudate (43.1% injured neurons vs. 10.6% in control, p = 0.041), putamen (66.6% vs. 23.9%, p = 0.003), temporal cortex (34.9% vs. 8.9%, p = 0.013), and hi