Translational Stroke Research最新文献

Patients presenting with stroke symptoms suffer from either ischemic stroke, hemorrhagic stroke, transient ischemic attacks (TIA), or "stroke mimics," which include benign headaches, epilepsy, and vestibular disorders. As ischemic and hemorrhagic stroke patients require different medical treatments, early identification of the underlying cause of symptoms is essential for tailored and urgent medical intervention. This study investigates whether extracellular vesicles (EVs), present in peripheral blood of patients presenting with stroke symptoms, can be used to identify patients with ischemic stroke. Blood was collected from 155 patients presenting with stroke symptoms in the emergency room and analyzed for EVs by flow cytometry (ethics approval number NL72929.018.20). The primary endpoint was to compare platelet EV concentrations between patients with (n = 66) and without (n = 89) ischemic stroke. Concentrations of EVs from both activated platelets and leukocytes were lower in patients presenting with ischemic stroke compared to other patients (p = 0.038 and p = 0.015, respectively). No significant differences in other EV types were observed. In addition, ischemic stroke patients were older and had a higher diastolic blood pressure compared to patients with other diagnoses. In a multivariable analysis, leukocyte EVs and diastolic blood pressure were independent indicators of ischemic stroke. To conclude, this study demonstrates that the plasma concentration of leukocyte EVs can be useful to identify ischemic stroke patients in an emergency setting.

Prognostication after acute ischemic stroke is crucial for long-term care plans. Although hyperacute management significantly affects outcomes, prognostic factors for patients receiving delayed care remain unknown. This study aimed to evaluate predictors and develop a method for estimating long-term mortality in patients with delayed hospital arrival 24 h after stroke symptom onset. Between January 2008 and December 2014, ischemic stroke patients who were admitted to the hospital more than 24 h from symptom onset were included in the linked dataset provided by the Clinical Research Center for Stroke, linked with claims data from the Health Insurance Review and Assessment Service. A nomogram was developed to estimate long-term mortality using clinical variables, with a predictive model assessed by Harrell's C-index. A total of 14,298 patients with acute ischemic stroke (66.5 years, mean age; 58.3%, male) were randomly assigned to training (n = 10,009) and validation (n = 4289) groups. Significant predictors of long-term mortality included older age, lower BMI, higher NIHSS score, stroke etiology, comorbidities (diabetes, coronary artery disease, dialysis, cancer), fasting blood sugar, use of antithrombotics/statins, and functional status at discharge. The Stroke Measures Analysis for Prognostic Testing - Mortality24 (SMART-M24) nomogram incorporated 17 predictors and achieved a C-index of 0.80 (95% CI, 0.79-0.81) in both groups. The SMART-M24 nomogram provides a prognostic tool for estimating long-term mortality in ischemic stroke patients with delayed hospital arrival 24 h after symptom onset. This model can assist clinical decision-making and long-term care planning for patients who have not undergone hyperacute treatment.

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.