Search Results (24)

Ischemic stroke accounts for approximately 80–85% of all stroke cases and triggers a complex cascade of metabolic, immunological, and neurodegenerative processes. Among the key mediators involved, TNF-α occupies a central position due to its distinctly dual and phase-dependent actions. Importantly, the biological effects of TNF-α are not static but evolve dynamically over time following ischemic insult. During the acute phase of ischemia, a rapid increase in TNF-α levels, primarily originating from activated microglia, leads to the predominant activation of the TNFR1 receptor. This results in enhanced apoptosis and necroptosis, disruption of the blood–brain barrier, increased leukocyte recruitment, and the progression of secondary neuronal injury. In later phases, the role of TNF-α shifts, with signaling through TNFR2 becoming more prominent, thereby supporting reparative mechanisms, including neurogenesis, angiogenesis, and synaptic remodeling. The dual nature of TNF-α means that both its excessive activation and complete inhibition may produce detrimental effects. Notably, the therapeutic relevance of TNF-α critically depends on the timing of intervention relative to stroke onset. A comprehensive analysis of current evidence underscores the central, temporally and contextually dependent role of TNF-α in the pathophysiology of ischemic stroke. It also indicates that future therapeutic strategies should aim to selectively suppress the harmful TNFR1-mediated signaling while preserving or enhancing TNFR2-dependent neuroprotective pathways. Such time-sensitive and receptor-selective modulation holds promise for limiting acute ischemic injury and promoting endogenous repair processes, representing a compelling direction for the development of next-generation neuroprotective therapies. Full article

Dementia blood biomarkers are becoming increasingly important. Various factors, such as ischemic lesions and inflammation, can influence the pathomechanism of dementia. We aimed to evaluate the effects of past stroke lesions on blood biomarkers (BMs). Following approval from the institutional ethics committee, patients who were admitted to the memory clinic and were consented to written documents were enrolled (n = 111, average [standard deviation] age: 74.5 [9.1] years-old). Brain magnetic resonance imaging, cognitive function, and neuropsychological symptoms were analyzed. The amyloid-β 42 (Aβ42)/Aβ40 ratio, phosphorylated tau181 (p-tau181), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and Aβ42/p-tau181 ratio were assessed as plasma BMs. The patients were diagnosed with Alzheimer’s disease (n = 45), mild cognitive impairment (n = 56), depression (n = 8), and subjective cognitive impairment (n = 4). Bivariate analysis exhibited that all measured BM indicators were significantly associated with cognitive decline in patients without past stroke lesions. Whereas the patients with stroke lesions presented a significant association only between GFAP and cognitive decline (p = 0.0011). Multiple regression analysis showed that NfL significantly correlated with cognitive decline only in patients without stroke lesions (r = 0.4988, p = 0.0003) and with delusion only in those with stroke lesions (r = 0.5492, p = 0.0121). Past stroke lesions should be addressed in the assessment of the correlation between blood biomarkers and cognitive decline in dementia patients. Full article

Background/Objectives: An embolic stroke of undetermined source (ESUS) is a subtype of ischemic stroke characterized by a non-lacunar infarct in the absence of a clearly identifiable embolic source, despite comprehensive diagnostic evaluation. While ESUS patients are typically younger, have fewer cardiovascular comorbidities, and experience milder strokes than those with cardioembolic strokes (CEs), their functional recovery remains underexplored. Methods: We retrospectively analyzed data from 374 ischemic stroke patients (n = 94 ESUS, n = 280 CE) admitted to the Department of Neurology, University of Pécs, between February 2023 and September 2024. Functional recovery was assessed using the modified Rankin Scale (mRS). Propensity score matching (PSM) was performed to balance the baseline characteristics, and the mRS-shift was compared between groups. Independent predictors of mRS-shift were identified using Huber regression and extreme gradient boosting (XGBoost). Results: The ESUS patients were significantly younger (60.7 ± 13.8 years vs. 75.1 ± 11.3 years, p < 0.001), had lower pre-morbid modified Rankin Scale (pre-mRS) scores (0.34 ± 0.91 vs. 0.81 ± 1.23, p < 0.001), were less likely to have hypertension (75.5% vs. 86.1%, p = 0.027) and diabetes (23.4% vs. 36.8%, p = 0.024), and presented with milder strokes (National Institutes of Health Stroke Scale [NIHSS] score at admission: 5.4 ± 4.5 vs. 8.1 ± 6.3, p < 0.001, and 72 h post-stroke: 3.0 ± 4.4 vs. 6.5 ± 6.3, p < 0.001) compared to the CE patients. After adjusting for baseline differences, the ESUS patients demonstrated significantly greater functional recovery than the CE patients (adjusted mRS-shift: 1.84 ± 1.14 vs. 2.53 ± 1.69, p = 0.022). Age, pre-mRS score, and NIHSS score at 72 h post-stroke were the strongest predictors of mRS-shift, with an older age, a higher pre-mRS score, and a greater stroke severity significantly decreasing the odds of recovery. Conclusions: The ESUS patients showed superior functional recovery compared to the CE patients, even after accounting for baseline differences. These findings highlight the need for further research into the pathomechanisms underlying ESUSs and the development of optimal treatment strategies to improve patient outcomes. Full article

People of all ages can contract pneumonia, and it can cause mild to severe disease and even death. In addition to being a major cause of death for elderly people and those with prior medical conditions such as diabetes, it isthe world’s biggest infectious cause of death for children. Diabetes mellitus is a metabolic condition with a high glucose level and is a leading cause of lower limb amputation, heart attacks, strokes, blindness, and renal failure. Hyperglycemia is known to impair neutrophil activity, damage antioxidant status, and weaken the humoral immune system. Therefore, diabetic patients are more susceptible to pneumonia than people without diabetes and linked fatalities. The absence of quick, precise, simple, and affordable ways to identify the etiologic agents of community-acquired pneumonia has made diagnostic studies’ usefulness contentious. Improvements in biological markers and molecular testing techniques have significantly increased the ability to diagnose pneumonia and other related respiratory infections. Identifying the risk factors for developing severe pneumonia and early testing in diabetic patients might lead to a significant decrease in the mortality of diabetic patients with pneumonia. In this regard, various risk factors, traditional testing techniques, and pathomechanisms are discussed in this review. Further, biomarkers and next-generation sequencing are briefly summarized. Finding biomarkers with the ability to distinguish between bacterial and viral pneumonia could be crucial because identifying the precise pathogen would stop the unnecessary use of antibiotics and effectively save the patient’s life. Full article

Migraine and stroke are neurological disorders with significant global prevalence and impact. Recent advances in migraine therapy have focused on the calcitonin gene-related peptide (CGRP) pathway. This review examines the shared pathomechanisms between migraine and stroke, with emphasis on the role of CGRP. We analyze the current literature on CGRP’s functions in cerebrovascular regulation, edema formation, neuroinflammation, and neuroprotection. CGRP acts as a potent vasodilator and plays a crucial role in trigeminovascular activation during migraine attacks. In stroke, CGRP has demonstrated neuroprotective effects by improving collateral circulation and reducing ischemia-reperfusion injury. Concerns have been raised about the potential impact of CGRP inhibitors on stroke risk and outcomes. Studies in animals suggest that CGRP receptor antagonists may worsen cerebral ischemia by impairing collateral flow. We discuss the implications of these findings for the use of CGRP-targeting therapies in migraine patients, especially those at increased risk of stroke. Additionally, we explore the complex interplay between CGRP, endothelial function, and platelet activity in both conditions. This review highlights the need for further research to elucidate the long-term cerebrovascular safety of CGRP pathway inhibitors and to identify potential subgroups of migraine patients who may be at higher risk of adverse cerebrovascular events with these novel therapies. Full article

Accidental arterial embolization of hyaluronic acid (HA) fillers can lead to severe complications, including skin ischemia, blindness, and stroke. Currently, the intra-arterial dispersal and fragmentation behavior of HA gels is unknown but critical to our understanding of the pathomechanism of these injuries. This work introduces the Pulsatile Unit for the Laboratory Simulation of Arterio-embolic Restrictions (PULSAR) and evaluates the intravascular behavior of different HA gels. The fragmentation and dispersal behaviors of four HA gels with distinct rheological properties were evaluated via high-resolution videography and ImageJ particle size and morphology analysis. The gels’ elastic modulus (G′), loss modulus (G″), tan(δ), and HA concentration were subsequently correlated with their intra-arterial behaviors. This study effectively confirms the extensive fragmentation of HA gels upon arterial inoculation, with particle sizes ranging from <50 µm to >1 mm. Gel particle size and morphology correlated most significantly with tan(δ). Conversely, arterial flow rates did not significantly influence gel fragmentation behavior, though the probability of proximal, macrovascular obstruction was affected. Overall, this study validates the PULSAR model for simulation of arterial dynamics and the testing of intravascular filler kinematics. The findings demonstrate the ability of gels to microfragment and disseminate distally, as well as induce partial proximal occlusion depending on gel rheology and arterial flow parameters. Full article

Homoarginine is associated with cardio- and cerebrovascular morbidity and mortality. However, the underlying pathomechanisms remain elusive. Here, we evaluated the association of homoarginine with adverse events (i.e., death, stroke, and myocardial infarction) and carotid intima-media thickness (cIMT) in stroke patients. In the prospective bioMARKers in STROKE (MARK-STROKE) cohort, patients with acute ischemic stroke or transient ischemic attack (TIA) were enrolled. Plasma homoarginine concentrations were analyzed and associated with clinical phenotypes in cross-sectional (374 patients) and prospective (273 patients) analyses. Adjustments for possible confounders were evaluated. A two-fold increase in homoarginine was inversely associated with the National Institutes of Health Stroke Scale (NIHSS) score at admission, cIMT, and prevalent atrial fibrillation (mean factor −0.68 [95% confidence interval (CI): −1.30, −0.07], −0.14 [95% CI: −0.22, −0.05]; and odds ratio 0.57 [95% CI: 0.33, 0.96], respectively). During the follow-up (median 284 [25th, 75th percentile: 198, 431] days), individuals with homoarginine levels in the highest tertile had fewer incident events compared with patients in the lowest homoarginine tertile independent of traditional risk factors (hazard ratio 0.22 [95% CI: 0.08, 0.63]). A lower prevalence of atrial fibrillation and a reduced cIMT pinpointed potential underlying pathomechanisms. Full article

This review discusses the evolving topic of atrial cardiomyopathy concerning valvular heart disease. The pathogenesis of atrial cardiomyopathy involves multiple factors, such as valvular disease leading to atrial structural and functional remodeling due to pressure and volume overload. Atrial enlargement and dysfunction can trigger atrial tachyarrhythmia. The complex interaction between valvular disease and atrial cardiomyopathy creates a vicious cycle of aggravating atrial enlargement, dysfunction, and valvular disease severity. Furthermore, atrial remodeling and arrhythmia can predispose to atrial thrombus formation and stroke. The underlying pathomechanism of atrial myopathy involves molecular, cellular, and subcellular alterations resulting in chronic inflammation, atrial fibrosis, and electrophysiological changes. Atrial dysfunction has emerged as an essential determinant of outcomes in valvular disease and heart failure. Despite its predictive value, the detection of atrial fibrosis and dysfunction is challenging and is not included in the clinical routine. Transthoracic echocardiography and cardiac magnetic resonance imaging are the main diagnostic tools for atrial cardiomyopathy. Recently published data have revealed that both left atrial volumes and functional parameters are independent predictors of cardiovascular events in valvular disease. The integration of atrial function assessment in clinical practice might help in early cardiovascular risk estimation, promoting early therapeutic intervention in valvular disease. Full article

Hypertrophic cardiomyopathy (HCM) is a genetic disease with heterogeneous clinical presentation and prognosis. Within the broad phenotypic expression of HCM, there is a subgroup of patients with a left ventricular (LV) apical aneurysm, which has an estimated prevalence between 2% and 5%. LV apical aneurysm is characterized by an area of apical dyskinesis or akinesis, often associated with regional scarring. To date, the most accepted pathomechanism of this complication is, in absence of coronary artery disease, the high systolic intra-aneurysmal pressure, which, combined with impaired diastolic perfusion from lower stroke volume, results in supply–demand ischemia and myocardial injury. Apical aneurysm is increasingly recognized as a poor prognostic marker; however, the efficacy of prophylactic anticoagulation and/or intracardiac cardioverted defibrillator (ICD) in improving morbidity and mortality is not yet clearly demonstrated. This review aims to elucidate the mechanism, diagnosis and clinical implication of LV aneurysm in patients with HCM. Full article

Ischaemic stroke is characterized by a sudden loss of blood circulation to an area of the brain, resulting in a corresponding loss of neurologic function. As a result of this process, neurons in the ischaemic core are deprived of oxygen and trophic substances and are consequently destroyed. Tissue damage in brain ischaemia results from a complex pathophysiological cascade comprising various distinct pathological events. Ischaemia leads to brain damage by stimulating many processes, such as excitotoxicity, oxidative stress, inflammation, acidotoxicity, and apoptosis. Nevertheless, less attention has been given to biophysical factors, including the organization of the cytoskeleton and the mechanical properties of cells. Therefore, in the present study, we sought to evaluate whether the oxygen-glucose deprivation (OGD) procedure, which is a commonly accepted experimental model of ischaemia, could affect cytoskeleton organization and the paracrine immune response. The abovementioned aspects were examined ex vivo in organotypic hippocampal cultures (OHCs) subjected to the OGD procedure. We measured cell death/viability, nitric oxide (NO) release, and hypoxia-inducible factor 1α (HIF-1α) levels. Next, the impact of the OGD procedure on cytoskeletal organization was evaluated using combined confocal fluorescence microscopy (CFM) and atomic force microscopy (AFM). Concurrently, to find whether there is a correlation between biophysical properties and the immune response, we examined the impact of OGD on the levels of crucial ischaemia cytokines (IL-1β, IL-6, IL-18, TNF-α, IL-10, IL-4) and chemokines (CCL3, CCL5, CXCL10) in OHCs and calculated Pearsons’ and Spearman’s rank correlation coefficients. The results of the current study demonstrated that the OGD procedure intensified cell death and nitric oxide release and led to the potentiation of HIF-1α release in OHCs. Moreover, we presented significant disturbances in the organization of the cytoskeleton (actin fibers, microtubular network) and cytoskeleton-associated protein 2 (MAP-2), which is a neuronal marker. Simultaneously, our study provided new evidence that the OGD procedure leads to the stiffening of OHCs and a malfunction in immune homeostasis. A negative linear correlation between tissue stiffness and branched IBA1 positive cells after the OGD procedure suggests the pro-inflammatory polarization of microglia. Moreover, the negative correlation of pro- and positive anti-inflammatory factors with actin fibers density indicates an opposing effect of the immune mediators on the rearrangement of cytoskeleton induced by OGD procedure in OHCs. Our study constitutes a basis for further research and provides a rationale for integrating biomechanical and biochemical methods in studying the pathomechanism of stroke-related brain damage. Furthermore, presented data pointed out the interesting direction of proof-of-concept studies, in which follow-up may establish new targets for brain ischemia therapy. Full article

Diabetes mellitus, a well-established risk factor for stroke, is related to higher mortality and poorer outcomes following the stroke event. Advanced glycation end products(AGEs), their receptors RAGEs, other ligands, and several other processes contribute to the cerebrovascular pathomechanism interaction in the diabetes–ischemic stroke combination. Critical reappraisal of molecular targets and therapeutic agents to mitigate them is required to identify key elements for therapeutic interventions that may improve patient outcomes. This scoping review maps evidence on the key roles of AGEs, RAGEs, other ligands such as Leukotriene B4 (LTB4), High-mobility group box 1 (HMGB1) nuclear protein, brain–kidney–muscle crosstalk, alternate pathomechanisms in neurodegeneration, and cognitive decline related to diabetic ischemic stroke. RAGE, HMGB1, nitric oxide, and polyamine mechanisms are important therapeutic targets, inflicting common consequences of neuroinflammation and oxidative stress. Experimental findings on a number of existing–emerging therapeutic agents and natural compounds against key targets are promising. The lack of large clinical trials with adequate follow-up periods is a gap that requires addressing to validate the emerging therapeutic agents. Five therapeutic components, which include agents to mitigate the AGE–RAGE axis, improved biomarkers for risk stratification, better renal dysfunction management, adjunctive anti-inflammatory–antioxidant therapies, and innovative neuromuscular stimulation for rehabilitation, are identified. A comprehensive therapeutic strategy that features all the identified components is needed for outcome improvement in diabetic stroke patients. Full article

Ischemic stroke is one of the major causes of death and permanent disability worldwide. The only efficient treatment to date is anticoagulant therapy and thrombectomy, which enable restitution of blood flow to ischemic tissues. Numerous promising neuroprotectants have failed in clinical trials. Given the complex pathomechanism of stroke, a multitarget pharmacotherapy seems a more rational approach in stroke prevention and treatment than drugs acting on single molecular targets. Recently, vitamin D3 has emerged as a potential treatment adjunct for ischemic stroke, as it interferes with the key prosurvival pathways and shows neuroprotective, anti-inflammatory, regenerative and anti-aging properties in both neuronal and vascular tissue. Moreover, the stimulatory effect of vitamin D3 on brain-derived neurotrophic factor (BDNF) signaling and neuroplasticity may play a role not only in the recovery of neurological functions, but also in ameliorating post-stroke depression and anxiety. This narrative review presents advances in research on the biochemical mechanisms of stroke-related brain damage, and the genomic and non-genomic effects of vitamin D3 which may interfere with diverse cell death signaling pathways. Next, we discuss the results of in vitro and in vivo experimental studies on the neuroprotective potential of 1alpha,25-dihydroxyvitamin D3 (calcitriol) in brain ischemia models. Finally, the outcomes of clinical trials on vitamin D3 efficiency in ischemic stroke patients are briefly reviewed. Despite the mixed results of the clinical trials, it appears that vitamin D3 still holds promise in preventing or ameliorating neurological and psychiatric consequences of ischemic stroke and certainly deserves further study. Full article

Stroke-like episodes (SLEs) are significant clinical manifestations of metabolic disorders affecting the central nervous system. Morphological equivalents presented in neuroimaging procedures are described as stroke-like lesions (SLLs). It is crucial to distinguish SLEs from cerebral infarction or intracerebral hemorrhage, mainly due to the variety in management. Another significant issue to underline is the meaning of the main pathogenetic hypotheses in the development of SLEs. The diagnostic process is based on the patient’s medical history, physical and neurological examination, neuroimaging techniques and laboratory and genetic testing. Implementation of treatment is generally symptomatic and includes L-arginine supplementation and adequate antiepileptic management. The main aim of the current review was to summarize the basic and actual knowledge about the occurrence of SLEs in various inherited neurometabolic disorders, discuss the possible pathomechanism of their development, underline the role of neuroimaging in the detection of SLLs and identification of the electroencephalographic patterns as well as histological abnormalities in inherited disorders of metabolism. Full article

Post-stroke cognitive impairment is one of the most common complications in stroke survivors. Concomitant vascular risk factors, including aging, diabetes mellitus, hypertension, dyslipidemia, or underlying pathologic conditions, such as chronic cerebral hypoperfusion, white matter hyperintensities, or Alzheimer’s disease pathology, can predispose patients to develop post-stroke dementia (PSD). Given the various clinical conditions associated with PSD, a single animal model for PSD is not possible. Animal models of PSD that consider these diverse clinical situations have not been well-studied. In this literature review, diverse rodent models that simulate the various clinical conditions of PSD have been evaluated. Heterogeneous rodent models of PSD are classified into the following categories: surgical technique, special structure, and comorbid condition. The characteristics of individual models and their clinical significance are discussed in detail. Diverse rodent models mimicking the specific pathomechanisms of PSD could provide effective animal platforms for future studies investigating the characteristics and pathophysiology of PSD. Full article

Stroke in patients with COVID-19 has received increasing attention throughout the global COVID-19 pandemic, perhaps due to the substantial disability and mortality that can result when the two conditions co-occur. We reviewed the existing literature and found that the proposed pathomechanism underlying COVID-19-associated ischemic stroke is broadly divided into the following three categories: vasculitis, endothelialitis, and endothelial dysfunction; hypercoagulable state; and cardioembolism secondary to cardiac dysfunction. There has been substantial debate as to whether there is a causal link between stroke and COVID-19. However, the distinct phenotype of COVID-19-associated strokes, with multivessel territory infarcts, higher proportion of large vessel occlusions, and cryptogenic stroke mechanism, that emerged in pooled analytic comparisons with non-COVID-19 strokes is compelling. Further, in this article, we review the various treatment approaches that have emerged as they relate to the proposed pathomechanisms. Finally, we briefly cover the logistical challenges, such as delays in treatment, faced by providers and health systems; the innovative approaches utilized, including the role of tele-stroke; and the future directions in COVID-19-associated stroke research and healthcare delivery. Full article