Search Results (25)

Background: Aneurysmal subarachnoid hemorrhage (aSAH) is a disease associated with high mortality, caused by the rupture of a cerebral aneurysm. Decision-support scoring systems used for managing unruptured aneurysms (UIAs) include only radiological parameters related to the size and configuration of the aneurysm, without incorporating blood-based markers. Our aim is to identify a serum marker that shows a correlation with aneurysm size in patients with ruptured aneurysms. Methods: Arterial blood samples were collected from patients who experienced aSAH within 24 h of the ictus, and serum desmosine levels were determined using ELISA. The morphological parameters of the aneurysms were assessed during 3D DSA. A favorable outcome was defined as a 3-month mRS score of 0–3. Results: This study included 135 aSAH patients and 25 controls. (i) The desmosine level in serum collected within 24 h after aneurysm rupture in patients with aSAH was significantly higher compared to the serum level in the control group (aSAH: 0.737 ng/mL [IQR: 0.401–1.214], vs. control: 0.365 ng/mL [IQR: 0.251–0.531], p < 0.001); (ii) examining the size of ruptured aneurysms, patients with aneurysms larger than 7 mm had significantly higher serum desmosine levels than those with aneurysms smaller than 7 mm; (iii) in the group with aneurysms smaller than 7 mm, serum desmosine levels correlated with the aneurysm neck width and the size ratio. Conclusions: Serum desmosine shows a strong correlation with the size of ruptured aneurysms in aSAH patients. Full article

Neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases are among the leading causes of physical and cognitive disability across the globe. Fifty million people worldwide suffer these diseases, and that number is expected to rise as the population ages. Ictus is another pathology that also courses with neurodegeneration and is a leading cause of mortality and long-term disability in developed countries. Schizophrenia is not as common as other mental disorders, affecting approximately 24 million people worldwide. All these disorders have in common that still there is not an effective pharmacological treatment to cure them. The N-methyl-D-aspartate (NMDA) receptor (NMDAR) has attracted attention as a potential therapeutic target due to its important role in learning and memory and also due to its implication in excitotoxicity processes. Some drugs targeting NMDARs are already being used to treat symptoms of disorders affecting the central nervous system (CNS). Here, we aim to review the implications of NMDAR in these CNS pathologies, its role as a potential therapeutic target, and the future perspectives for developing new treatments focused on these receptors. Full article

Despite extensive research on aneurysm treatment and neurocritical care, aneurysmal subarachnoid hemorrhage (SAH) is still a life-threatening disease, often leaving survivors with lasting neurological and cognitive impairments. Early brain injury (EBI) and delayed cerebral ischemia (DCI) are the main contributors to brain damage, with neuroinflammation being a critical shared pathophysiological process. While numerous inflammatory markers and their temporal profiles in cerebrospinal fluid (CSF) have already been identified, comparisons with age- and sex-matched controls are limited. This study analyzed CSF from 17 SAH patients requiring an external ventricular drain (EVD) due to symptomatic hydrocephalus, sampled on days 4 and 10 post-ictus. An age- and sex-matched control group included 17 cerebrovascularly healthy patients requiring lumbar drains during aortic surgery. Chemokines and cytokines were quantified using immunoassays. Significantly elevated markers in SAH patients across both time points included MCP-1, CXCL-13, Eotaxin-1, CXCL-10, IL-8, and MIF. MIP-1α and MIP-1β showed significant differences at particular time points, indicating a distinct temporal profile for each parameter. These findings highlight neuroinflammation’s key role in intracranial and systemic pathophysiology following SAH, emphasizing its complexity and individual variability. Knowing demographic factors impact the specific manifestations of pathophysiological processes, the comparison with an age- and sex-matched control group is meaningful. Full article

Aneurysmal subarachnoid hemorrhage (aSAH) is a serious condition complicated by delayed cerebral ischemia (DCI), where inflammation plays a key role. Although altered gut permeability is noted in other conditions, its significance in aSAH remains unclear. Fatty acid-binding protein (FABP-I), lipopolysaccharide-binding protein (LBP), and soluble CD-14 (sCD-14) are established markers of barrier dysfunction. This study investigates gut permeability marker changes in early and late aSAH phases. The study included 177 aSAH patients and 100 controls. Serum samples were collected on days 1 (D1) and 9 (D9) after ictus. FABP-I, LBP, and sCD-14 levels were measured via ELISA, and clinical data were recorded. Outcomes were assessed using the 90-day modified Rankin scale (mRS 0–3 = favorable outcome). Serum FABP-I was significantly lower in aSAH patients (p < 0.05), while LBP and sCD-14 were higher (p < 0.001) compared to controls. FABP-I did not differ between outcome groups, but LBP and sCD-14 were significantly elevated in unfavorable outcomes (p < 0.001). These markers differed in patients without in-hospital infection, with higher levels noted in DCI patients during the later phase (p < 0.05). In aSAH patients without infection, differences in LBP and sCD-14 levels between outcome groups suggest potential endotoxin release from microbial systems, contributing to neuroinflammation and influencing outcomes. Full article

Despite recent advances in treatment options, stroke remains a highly prevalent and devastating condition with significant socioeconomic impact. Recanalization therapies, including intravenous thrombolysis and endovascular treatments, have revolutionized stroke management and prognosis, providing a promising framework for exploring new therapeutic strategies. Endothelial dysfunction plays a critical role in the pathophysiology, progression, and prognosis of stroke. This review aims to synthesize the current evidence regarding the involvement of the nitric oxide (NO)/endothelium pathway in ischemic stroke, with a particular focus on aging, response to recanalization therapies, and therapeutic approaches. While significant progress has been made in recent years in understanding the relationship between endothelial dysfunction and stroke, many uncertainties persist, and although treatments targeting this pathway are promising, they have yet to demonstrate clear clinical benefits. Full article

NADPH oxidases (NOXs) have been described as critical players in vascular remodeling, a mechanism modulated by matrix metalloproteinases. In this study, we describe for the first time the upregulation of MMP-10 through the activation of NOX5 in endothelial cells. In a chronic NOX5 overexpression model in human endothelial cells, MMP-10 production was measured at different levels: extracellular secretion, gene expression (mRNA and protein levels), and promoter activity. Effects on cell migration were quantified using wound healing assays. NOX5 overexpression increased MMP-10 production, favoring cell migration. In fact, NOX5 and MMP-10 silencing prevented this promigratory effect. We showed that NOX5-mediated MMP-10 upregulation involves the redox-sensitive JNK/AP-1 signaling pathway. All these NOX5-dependent effects were enhanced by angiotensin II (Ang II). Interestingly, MMP-10 protein levels were found to be increased in the hearts of NOX5-expressing mice. In conclusion, we described that NOX5-generated ROS may modulate the MMP-10 expression in endothelial cells, which leads to endothelial cell migration and may play a key role in vascular remodeling. Full article

Background: Intravenous thrombolysis is one of the most effective therapies for the treatment of acute ischemic stroke (AIS), with urokinase offering a cost-effective alternative to newer agents like alteplase and tenecteplase, especially in resource-limited settings. Methods: This review provides a comprehensive overview of the application of intravenous thrombolysis with urokinase for AIS in the clinical practice of stroke management, including the efficacy, safety, and cost-effectiveness of urokinase compared to other thrombolytic agents. Results: Urokinase, a first-generation thrombolytic drug, is a non-specific plasminogen activator that offers a cost-effective alternative. It has been used in clinical practice for over two decades to improve neurological outcomes in patients with AIS if administered within 6 h of ictus. Numerous studies have indicated that urokinase remains a viable option for patients who cannot access alteplase or tenecteplase because of economic constraints, time window limitations, availability, or other reasons. Conclusions: In low- and middle-income countries, urokinase is a cost-effective alternative thrombolytic drug. High-level evidence-based medical research is therefore urgently needed to confirm that urokinase is not inferior to new-generation thrombolytic drugs, and to assess whether it may even be superior in some patient populations. Full article

ApTOLL, a TLR4 modulator aptamer, has demonstrated cerebroprotective effects in a permanent ischemic stroke mouse model, as well as safety and efficacy in early phase clinical trials. We carried out reverse translation research according to STAIR recommendations to further characterize the effects and mechanisms of ApTOLL after transient ischemic stroke in rats and to better inform the design of pivotal clinical trials. Adult male rats subjected to transient middle cerebral artery occlusion were treated either with ApTOLL or the vehicle intravenously at different doses and time-points. ApTOLL was compared with TAK-242 (a TLR4 inhibitor). Female rats were also studied. After neurofunctional evaluation, brains were removed for infarct/edema volume, hemorrhagic transformation, and histologic determinations. Peripheral leukocyte populations were assessed via flow cytometry. ApTOLL showed U-shaped dose-dependent cerebroprotective effects. The maximum effective dose (0.45 mg/kg) was cerebroprotective when given both before reperfusion and up to 12 h after reperfusion and reduced the hemorrhagic risk. Similar effects occurred in female rats. Both research and clinical ApTOLL batches induced slightly superior cerebroprotection when compared with TAK-242. Finally, ApTOLL modulated circulating leukocyte levels, reached the brain ischemic tissue to bind resident and infiltrated cell types, and reduced the neutrophil density. These results show the cerebroprotective effects of ApTOLL in ischemic stroke by reducing the infarct/edema volume, neurofunctional impairment, and hemorrhagic risk, as well as the peripheral and local immune response. They provide information about ApTOLL dose effects and its therapeutic time window and target population, as well as its mode of action, which should be considered in the design of pivotal clinical trials. Full article

Objective: There is a relationship between the incidence of spontaneous intracerebral haemorrhage (ICH) and age. The incidence increases with age. This study aims to facilitate the decision-making process in the treatment of ICH. It therefore investigated the outcome after ICH and decompressive craniectomy (DC) in older adults (>65 years of age). Methods: Retrospective, multicentre, descriptive observational study including only consecutive patients who received DC as the consequence of ICH. Additive evacuation of ICH was performed after the individual decision of the neurosurgeon. Besides demographic data, clinical outcomes both at discharge and 12 months after surgery were evaluated according to the Glasgow Outcome Scale (GOS). Patients were divided into age groups of ≤65 and >65 years and cohorts with favourable outcome (GOS IV–V) and unfavourable outcome (GOS I to III). Results: 56 patients were treated. Mean age was 53.3 (SD: 16.13) years. There were 41 (73.2%) patients aged ≤65 years and 15 (26.8%) patients aged >65 years. During hospital stay, 10 (24.4%) patients in the group of younger (≤65 years) and 5 (33.3%) in the group of older patients (>65 years) died. Mean time between ictus and surgery was 44.4 (SD: 70.79) hours for younger and 27.9 (SD: 41.71) hours for older patients. A disturbance of the pupillary function on admission occurred in 21 (51.2%) younger and 2 (13.3%) older patients (p = 0.014). Mean arterial pressure was 99.9 (SD: 17.00) mmHg for younger and 112.9 (21.80) mmHg in older patients. After 12 months, there was no significant difference in outcome between younger patients (≤65 years) and older patients (>65 years) after ICH and DC (p = 0.243). Nevertheless, in the group of younger patients (≤65 years), 9% had a very good and 15% had a good outcome. There was no good recovery in the group of older patients (>65 years). Conclusion: Patients >65 years of age treated with microsurgical haematoma evacuation and DC after ICH are likely to have a poor outcome. Furthermore, in the long term, only a few older adults have a good functional outcome with independence in daily life activities. Full article

Accurate etiologic diagnosis provides an appropriate secondary prevention and better prognosis in ischemic stroke (IS) patients; still, 45% of IS are cryptogenic, urging us to enhance diagnostic precision. We have studied the transcriptomic content of plasma extracellular vesicles (EVs) (n = 21) to identify potential biomarkers of IS etiologies. The proteins encoded by the selected genes were measured in the sera of IS patients (n = 114) and in hypertensive patients with (n = 78) and without atrial fibrillation (AF) (n = 20). IGFBP-2, the most promising candidate, was studied using immunohistochemistry in the IS thrombi (n = 23) and atrium of AF patients (n = 13). In vitro, the IGFBP-2 blockade was analyzed using thromboelastometry and endothelial cell cultures. We identified 745 differentially expressed genes among EVs of cardioembolic, atherothrombotic, and ESUS groups. From these, IGFBP-2 (cutoff > 247.6 ng/mL) emerged as a potential circulating biomarker of embolic IS [OR = 8.70 (1.84–41.13) p = 0.003], which was increased in patients with AF vs. controls (p < 0.001) and was augmented in cardioembolic vs. atherothrombotic thrombi (p < 0.01). Ex vivo, the blockage of IGFBP-2 reduced clot firmness (p < 0.01) and lysis time (p < 0.001) and in vitro, diminished endothelial permeability (p < 0.05) and transmigration (p = 0.06). IGFBP-2 could be a biomarker of embolic IS and a new therapeutic target involved in clot formation and endothelial dysfunction. Full article

In this study, the plausible role of trimethylamine N-oxide (TMAO), a microbiota metabolite, was investigated as a link between peripheral inflammation and the inflammation of the central nervous system using different cell lines. TMAO treatment favored the differentiation of adipocytes from preadipocytes (3T3-L1 cell line). In macrophages (RAW 264.7 cell line), which infiltrate adipose tissue in obesity, TMAO increased the expression of pro-inflammatory cytokines. The treatment with 200 μM of TMAO seemed to disrupt the blood–brain barrier as it induced a significant decrease in the expression of occludin in hCMECs. TMAO also increased the expression of pro-inflammatory cytokines in primary neuronal cultures, induced a pro-inflammatory state in primary microglial cultures, and promoted phagocytosis. Data obtained from this project suggest that microbial dysbiosis and increased TMAO secretion could be a key link between peripheral and central inflammation. Thus, TMAO-decreasing compounds may be a promising therapeutic strategy for neurodegenerative diseases. Full article

Introduction: Strokes continue to be considered public health problems due to the great social and health impact they entail. They are the second cause of death in the world, with a high incidence and prevalence. They are time-dependent diseases, and more than 80% of cases could be avoidable with greater management of risk factors. Objective: to analyze the factors that influence prehospital time in a stroke code. Assess the population’s knowledge of stroke symptoms and teach them how to act when a case is suspected. Document the continued training of health professionals for the early identification of patients with a suspected stroke. Demonstrate the importance of calling EMS as the first contact to reduce delays in prehospital time in a stroke. Methodology: A bibliographic review was carried out focusing on articles published between December 2014 and August 2023. The following databases were consulted: Pubmed (Medline), Dialnet, Google Scholar, Web of Science (WOS), Scielo, Scopus, and ScienceDirect. Results: After applying the article selection criteria and evaluating the quality of the methodology, a total of 18 articles were obtained. The results affirm that the importance of achieving a reduction in prehospital time is based mainly on knowledge of the symptoms and the use of new technologies. Conclusions: The evidence supports that the prehospital time of action in the stroke code is affected by numerous factors. These factors are determining factors in the time of action to achieve good effectiveness in the treatment of the pathology. Full article

The concept of early brain injury (EBI) is based on the assumption of a global reduction in brain perfusion following aneurysmal subarachnoid hemorrhage (aSAH). However, the heterogeneity of computed tomography perfusion (CTP) imaging in EBI has not yet been investigated. In contrast, increased mean transit time (MTT) heterogeneity, a possible marker of microvascular perfusion heterogeneity, in the delayed cerebral ischemia (DCI) phase has recently been associated with a poor neurological outcome after aSAH. Therefore, in this study, we investigated whether the heterogeneity of early CTP imaging in the EBI phase is an independent predictor of the neurological outcome after aSAH. We retrospectively analyzed the heterogeneity of the MTT using the coefficient of variation (cvMTT) in early CTP scans (within 24 h after ictus) of 124 aSAH patients. Both linear and logistic regression were used to model the mRS outcome, which were treated as numerical and dichotomized values, respectively. Linear regression was used to investigate the linear dependency between the variables. No significant difference in cvMTT between the patients with and those without EVD could be observed (p = 0.69). We found no correlation between cvMTT in early CTP imaging and initial modified Fisher (p = 0.07) and WFNS grades (p = 0.23). The cvMTT in early perfusion imaging did not correlate significantly with the 6-month mRS for the entire study population (p = 0.15) or for any of the subgroups (without EVD: p = 0.21; with EVD: p = 0.3). In conclusion, microvascular perfusion heterogeneity, assessed by the heterogeneity of MTT in early CTP imaging, does not appear to be an independent predictor of the neurological outcome 6 months after aSAH. Full article

The prognosis for patients with aneurysmal subarachnoid hemorrhage (aSAH) is heavily influenced by the development of delayed cerebral ischemia (DCI), but the adequate and effective therapy of DCI to this day has not been resolved. Multiplex serum biomarker studies may help to understand the pathophysiological processes underlying DCI. Samples were collected from patients with aSAH at two time points: (1) 24 h (Day 1) and (2) 5–7 days after ictus. Serum concentrations of eotaxin, FGF-2, FLT-3L, CX3CL1, Il-1b, IL-4, IP-10, MCP3, and MIP-1b were determined using a customized MILLIPLEX Human Cytokine/Chemokine/Growth Factor Panel A multiplex assay. The functional outcome was defined by the modified Rankin scale (favorable: 0–2, unfavorable: 3–6) measured on the 30th day after aSAH. One-hundred and twelve patients with aSAH were included in this study. The median level of CX3CL1 and MCP-3 measured on Days 5–7 were significantly higher in patients with DCI compared with those without DCI (CX3CL1: with DCI: 110.5 pg/mL, IQR: 82–201 vs. without DCI: 82.6, 58–119, p = 0.036; and MCP-3: with DCI: 22 pg/mL (0–32) vs. without DCI: 0 (0–11), p < 0.001). IP-10, MCP-3, and MIP-1b also showed significant associations with the functional outcome after aSAH. MCP-3 and CX3CL1 may play a role in the pathophysiology of DCI. Full article

Background: Intrasaccular flow disruptors (IFD) have been introduced in the treatment of intracranial aneurysms (IAs) to overcome the low aneurysm occlusion rate and the high recanalization rate of the coiling technique. Among them, the Contour Neurovascular System (CNS) and the Neqstent (NQS) were designed to reconstruct the aneurysmal neck and both can be used as assisting coiling devices. We aimed to report our preliminary experience with the flow disruptor-assisted coiling (IFD-AC) technique. Methods: We performed a retrospective analysis of prospectively collected data of all patients with IAs treated with the IFD-AC. Results: Between February 2021 and April 2022, we treated 15 IAs with the IFD-AC: 10 ruptured and 5 unruptured. The IFD-AC was successfully performed in 13 cases, with a post-operative RROC 1 in 12 cases (92.3%) and RROC 2 in 1 case (7.7%). There was one ischemic event (6.7%) and no hemorrhagic complications. Twelve patients underwent a mid-term radiologic follow-up: Ten IAs (83.4%) presented an adequate occlusion, while 2 (16.7%) had a recurrence. Conclusions: The IFD-AC, both with the CNS and the NQS, seems a safe technique with promising efficacy profile. The IFD-AC has proved to be safe without antiplatelet therapy in ruptured cases. Further studies are needed to confirm our preliminary results. Full article