Stroke Mechanism Research Articles

Four phases of a force transient emerge from a binary mechanical system.

Accurate models of muscle contraction are important for understanding both muscle performance and the therapeutics that enhance physiological function. However, models are only accurate and meaningful if they are consistent with physical laws. A single muscle fiber contains billions of randomly fluctuating atoms that on the spatial scale of a muscle fiber generate unidirectional force and power output. This thermal system is formally constrained by the laws of thermodynamics, and a recently developed thermodynamic model of muscle force generation provides qualitative descriptions of the muscle force-velocity relationship, muscle force generation, muscle force transients, and the thermodynamic work loop of muscle with a thermodynamic (not molecular) power stroke mechanism. To demonstrate the accuracy of this model requires that its outputs be quantitatively compared with experimentally observed muscle function. Here I show that a two-state thermodynamic model accurately describes the experimentally observed four-phase force transient response to both mechanical and chemical perturbations. This is the simplest possible model of one of the most complex characteristic signatures of muscle mechanics.

The influence of the prolactin/vasoinhibin axis on post-stroke lesion volume, astrogliosis, and survival.

Ischemic stroke is a significant global health issue, ranking fifth among all causes of death and a leading cause of serious long-term disability. Ischemic stroke leads to severe outcomes, including permanent brain damage and neuronal dysfunction. Therefore, decreasing and preventing neuronal injuries caused by stroke has been the focus of therapeutic research. In recent years, many studies have shown that fluctuations in hormonal levels influence the prognosis of ischemic stroke. Thus, it is relevant to understand the role of hormones in the pathophysiological mechanisms of ischemic stroke for preventing and treating this health issue. Here, we investigate the contribution of the prolactin/vasoinhibin axis, an endocrine system regulating blood vessel growth, immune processes, and neuronal survival, to the pathophysiology of ischemic stroke. Male mice with brain overexpression of prolactin or vasoinhibin by adeno-associated virus (AAV) intracerebroventricular injection or lacking the prolactin receptor (Prlr-/-) were exposed to transient middle cerebral artery occlusion (tMCAO) for 45 min followed by 48 h of reperfusion. Overexpression of vasoinhibin or the absence of the prolactin receptor led to an increased lesion volume and decreased survival rates in mice following tMCAO, whereas overexpression of prolactin had no effect. In addition, astrocytic distribution in the penumbra was altered, glial fibrillary acidic protein and S100b mRNA expressions were reduced, and interleukin-6 mRNA expression increased in the ischemic hemisphere of mice overexpressing vasoinhibin. Of note, prolactin receptor-null mice (Prlr-/-) showed a marked increase in serum vasoinhibin levels. Furthermore, vasoinhibin decreased astrocyte numbers in mixed hippocampal neuron-glia cultures. These observations suggest that increased vasoinhibin levels may hinder astrocytes' protective reactivity. Overall, this study suggests the involvement of the prolactin/vasoinhibin axis in the pathophysiology of ischemic stroke-induced brain injury and provides insights into the impact of its dysregulation on astrocyte reactivity and lesion size. Understanding these mechanisms could help develop therapeutic interventions in ischemic stroke and other related neurological disorders.

Stroke Risk After Mitral Valve Interventions: A Systematic Review and Network Meta-Analysis

Previous research indicates varying stroke rates after mitral valve (MV) interventions. This study aimed to compare post-procedural stroke risks following transcatheter and surgical MV interventions. Electronic databases were searched from inception to February 2024 for studies comparing stroke rates after mitral transcatheter edge-to-edge repair (mTEER), surgical MV repair/replacement, or guideline-directed medical therapy (GDMT). Primary endpoints were all-time and early (<30 days) stroke. Secondary outcomes included new-onset atrial fibrillation and 1-year all-cause mortality. A frequentist network meta-analysis was employed to compare outcomes. The network meta-analysis included 18 studies (3 randomized clinical trials and 15 observational), with 51,703 patients. mTEER was associated with a decreased risk of all-time (odds ratio [OR] 0.61, 95% CI 0.41-0.89) and early stroke (OR 0.41, 95% CI 0.33-0.51) compared with surgery, and a similar risk of all-time (OR 1.54, 95% CI 0.76-3.12) and early stroke (OR 2.12, 95% CI 0.53-8.47) compared with GDMT. Conversely, surgery was associated with an increased risk of all-time (OR 2.55, 95% CI 1.17-5.57) and early stroke (OR 5.15, 95% CI 1.27-20.84) compared with GDMT. There were no statistically significant differences in the risk of new-onset atrial fibrillation (OR 0.38, 95% CI 0.11-1.31) and 1-year all-cause mortality (OR 1.43, 95% CI 0.91-2.24) between mTEER vs. surgery. In conclusion, mTEER was associated with a lower risk of stroke and similar risks of new-onset atrial fibrillation and 1-year mortality compared with surgical MV interventions. Further studies are needed to understand the mechanisms of stroke and to determine strategies to reduce stroke risk following MV interventions.

European Stroke Organisation (ESO) Guidelines on the diagnosis and management of patent foramen ovale (PFO) after stroke.

Patent foramen ovale (PFO) is frequently identified in young patients with cryptogenic ischaemic stroke. Potential stroke mechanisms include paradoxical embolism from a venous clot which traverses the PFO, in situ clot formation within the PFO, and atrial arrhythmias due to electrical signalling disruption. The purpose of this guideline is to provide recommendations for diagnosing, treating, and long-term managing patients with ischaemic stroke and PFO. Conversely, Transient Ischaemic Attack (TIA) was not considered an index event in this context because only one RCT involved TIA patients. However, this subgroup analysis showed no significant differences between TIA and stroke outcomes. The working group identified questions and outcomes, graded evidence, and developed recommendations following the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach and the European Stroke Organisation (ESO) standard operating procedure for guideline development. This document underwent peer-review by independent experts and members of the ESO Guideline Board and Executive Committee. The working group acknowledges the current evidentiary gap in delineating an unequivocal diagnostic algorithm for the detection of PFO. Although transoesophageal echocardiography is conventionally held as the most accurate diagnostic tool for PFO identification, its status as the 'gold standard' remains unsubstantiated by rigorously validated evidence. We found high-quality evidence to recommend PFO closure plus antiplatelet therapy in selected patients aged 18-60 years in whom no other evident cause of stroke is found but a PFO (i.e. PFO-associated stroke). The PASCAL classification system can be used to select such candidates for PFO closure. Patients with both a large right-to-left shunt and an atrial septal aneurysm benefit most from PFO closure. There is insufficient evidence to make an evidence-based recommendation on PFO closure in patients older than 60 and younger than 18 years. We found low quality evidence to suggest against PFO closure in patients with unlikely PFO-related stroke according to the PASCAL classification, except in specific scenarios (Expert Consensus). We suggest against long-term anticoagulation in patients with PFO-associated stroke unless anticoagulation is indicated for other medical reasons. Regarding the long-term AF monitoring after PFO closure, the working group concluded that there remains significant uncertainty regarding the risks and benefits associated with the use of long-term cardiac monitoring, such as implantable loop recorders. This document provides additional guidance, in the form of evidence-based recommendations or expert consensus statements, on diagnostic methods for PFO detection, and medical management after PFO closure.

HMGB1: A New Target for Ischemic Stroke and Hemorrhagic Transformation.

Stroke in China is distinguished by its high rates of morbidity, recurrence, disability, and mortality. The ultra-early administration of rtPA is essential for restoring perfusion in acute ischemic stroke, though it concurrently elevates the risk of hemorrhagic transformation. High-mobility group box 1 (HMGB1) emerges as a pivotal player in neuroinflammation after brain ischemia and ischemia-reperfusion. Released passively by necrotic cells and actively secreted, including direct secretion of HMGB1 into the extracellular space and packaging of HMGB1 into intracellular vesicles by immune cells, glial cells, platelets, and endothelial cells, HMGB1 represents a prototypical damage-associated molecular pattern (DAMP). It is intricately involved in the pathogenesis of atherosclerosis, thromboembolism, and detrimental inflammation during the early phases of ischemic stroke. Moreover, HMGB1 significantly contributes to neurovascular remodeling and functional recovery in later stages. Significantly, HMGB1 mediates hemorrhagic transformation by facilitating neuroinflammation, directly compromising the integrity of the blood-brain barrier, and enhancing MMP9 secretion through its interaction with rtPA. As a systemic inflammatory factor, HMGB1 is also implicated in post-stroke depression and an elevated risk of stroke-associated pneumonia. The role of HMGB1 extends to influencing the pathogenesis of ischemia by polarizing various subtypes of immune and glial cells. This includes mediating excitotoxicity due to excitatory amino acids, autophagy, MMP9 release, NET formation, and autocrine trophic pathways. Given its multifaceted role, HMGB1 is recognized as a crucial therapeutic target and prognostic marker for ischemic stroke and hemorrhagic transformation. In this review, we summarize the structure and redox properties, secretion and pathways, regulation of immune cell activity, the role of pathophysiological mechanisms in stroke, and hemorrhage transformation for HMGB1, which will pave the way for developing new neuroprotective drugs, reduction of post-stroke neuroinflammation, and expansion of thrombolysis time window.

Head Injury and Risk of Incident Ischemic Stroke in Community-Dwelling Adults.

While stroke is a recognized short-term sequela of traumatic brain injury, evidence about long-term ischemic stroke risk after traumatic brain injury remains limited. The Atherosclerosis Risk in Communities Study is an ongoing prospective cohort comprised of US community-dwelling adults enrolled in 1987 to 1989 followed through 2019. Head injury was defined using self-report and hospital-based diagnostic codes and was analyzed as a time-varying exposure. Incident ischemic stroke events were physician-adjudicated. We used Cox regression adjusted for sociodemographic and cardiovascular risk factors to estimate the hazard of ischemic stroke as a function of head injury. Secondary analyses explored the number and severity of head injuries; the mechanism and severity of incident ischemic stroke; and heterogeneity within subgroups defined by race, sex, and age. Our analysis included 12 813 participants with no prior head injury or stroke. The median follow-up age was 27.1 years (25th-75th percentile=21.1-30.5). Participants were of median age 54 years (25th-75th percentile=49-59) at baseline; 57.7% were female and 27.8% were Black. There were 2158 (16.8%) participants with at least 1 head injury and 1141 (8.9%) participants with an incident ischemic stroke during follow-up. For those with head injuries, the median age to ischemic stroke was 7.5 years (25th-75th percentile=2.2-14.0). In adjusted models, head injury was associated with an increased hazard of incident ischemic stroke (hazard ratio [HR], 1.34 [95% CI, 1.12-1.60]). We observed evidence of dose-response for the number of head injuries (1: HR, 1.16 [95% CI, 0.97-1.40]; ≥2: HR, 1.94 [95% CI, 1.39-2.71]) but not for injury severity. We observed evidence of stronger associations between head injury and more severe stroke (National Institutes of Health Stroke Scale score ≤5: HR, 1.31 [95% CI, 1.04-1.64]; National Institutes of Health Stroke Scale score 6-10: HR, 1.64 [95% CI, 1.06-2.52]; National Institutes of Health Stroke Scale score ≥11: HR, 1.80 [95% CI, 1.18-2.76]). Results were similar across stroke mechanism and within strata of race, sex, and age. In this community-based cohort, head injury was associated with subsequent ischemic stroke. These results suggest the importance of public health interventions aimed at preventing head injuries and primary stroke prevention among individuals with prior traumatic brain injuries.

Exploring the potential molecular intersection of stroke and major depression disorder

Stroke and major depression disorder are common neurological diseases, and a large number of clinical studies have shown that there is a close relationship between the two diseases, but whether the two diseases are linked at the genetic level needs to be further explored. The purpose of this study was to explore the comorbidity mechanism of stroke and major depression by using bioinformatics technology and animal experiments. From the GEO database, we gathered transcriptome data of stroke and depression mice (GSE104036, GSE131712, GSE81672, and GSE146845) and identified comorbid gene set through edgR and WGCNA analyses. Further analysis revealed that these genes were enriched in pathways associated with cell death. Programmed cell death gene sets (PCDGs) are generated from genes related to apoptosis, necroptosis, pyroptosis and autophagy. The intersection of PCDGs and comorbid gene set resulted in two hub genes, Mlkl and Nlrp3. Single-cell sequencing analysis indicated that Mlkl and Nlrp3 are mainly influential on endothelial cells and microglia, suggesting that the impairment of these two cell types may be a factor in the relationship between stroke and major depression. This was experimentally confirmed by RT–PCR and immunofluorescence staining. Our research revealed that two specific genes, namely, Mlkl and Nlrp3, play crucial roles in the complex mechanism that links stroke and major depression. Additionally, we have predicted six possible therapeutic agents and the outcomes of docking simulations of target proteins and drug molecules.

Vasculopathy Leading to Stroke in Adult Onset Still’s Disorder

Abstract Background Rheumatological disorders may predispose patients to hypercoagulability and/or vasculopathy increasing stroke risk. Adult-Onset Still’s Disease (AOSD) is not usually associated with either, with only two reported cases in the literature to have had strokes. We present a case of AOSD with acute stroke manifesting as lateral medullary syndrome. We hypothesize that vasculopathy and thrombocytosis may have contributed to stroke occurrence. We further explore the possible underlying pathomechanism in this patient population. Case Presentation A 35-year-old woman with AOSD on methotrexate, tocilizumab and daily prednisone presented with vertigo and numbness involving her right face and left arm. She was found to have an ischemic stroke in the lateral medulla with vertebral artery thrombotic changes. No recent trauma. Investigation of other underlying stroke etiologies was unyielding with negative lupus anticoagulants, ANCAs and normal ESR and CRP. Discussion &amp; Conclusion Our case marks the third report of stroke occurrence in AOSD in the literature. While our patient had no elevated inflammatory markers, she still developed stroke due to ongoing endothelial inflammation and thrombotic changes in the vertebral artery. The presence of vascular involvement leading to stroke may provide initial insight into the nature of this event. Further research should thus be done to investigate the exact mechanism of stroke and vasculopathy in AOSD patients.

Percutaneous Patent Foramen Ovale Closure: Stroke and Beyond.

Over 750,000 individuals suffer from stroke annually in the United States, with 87% of these strokes being ischemic in nature. Roughly 40% of ischemic strokes occur in individuals 60 years of age or under. A quarter of all ischemic strokes have no identifiable cause despite extensive workup and are deemed cryptogenic in nature. Patent Foramen Ovales (PFO) has been postulated in stroke causation by either paradoxical embolization or platelet activation in the tunnel of the defect. The incidence of PFO is reported to be 15-25% in the general population but rises to 40% in patients with cryptogenic stroke. While the initial trials evaluating PFO closures were non-revealing, subsequent long-term follow-ups, as well as recent trials evaluating PFO closures in cryptogenic stroke patients 60 years of age or under, demonstrated the superiority of percutaneous closure compared to medical therapy alone, leading to FDA approval of PFO closure devices. In this review, we review the diagnosis of PFO, postulated stroke mechanisms, literature supporting PFO closure, patient selection for percutaneous closure, procedural considerations, and associated procedural complications.

Organoids Modeling Stroke in a Petri Dish.

Stroke is a common neurological disorder, the second leading cause of death, and the third leading cause of disability. Unfortunately, the only approved drug for it is tissue plasminogen, but the therapeutic window is limited. In this context, preclinical studies are relevant to better dissect the underlying mechanisms of stroke and for the drug screening of potential therapies. Brain organoids could be relevant in this setting. They are derived from pluripotent stem cells or isolated organ progenitors that differentiate to form an organ-like tissue, exhibiting multiple cell types that self-organize to form a structure not unlike the organ in vivo. Brain organoids mimic many key features of early human brain development at molecular, cellular, structural, and functional levels and have emerged as novel model systems that can be used to investigate human brain diseases including stroke. Brain organoids are a promising and powerful tool for ischemic stroke studies; however, there are a few concerns that need to be addressed, including the lack of vascularization and the many cell types that are typically present in the human brain. The aim of this review is to discuss the potential of brain organoids as a novel model system for studying ischemic stroke, highlighting both the advantages and disadvantages in the use of this technology.

Risk of Stroke Among HIV Patients: A Systematic Review and Meta-analysis of Global Studies and Associated Comorbidities.

Despite advancements in the management of HIV infection, the factors contributing to stroke development among HIV-positive individuals remain unclear. This systematic review and meta-analysis aim to identify and evaluate the relative risk factors associated with stroke susceptibility in the HIV population. A comprehensive search was conducted in PubMed, Scopus, and Web of Science databases to identify studies investigating the risk of stroke development in HIV patients and assessing the role of different risk factors, including hypertension, diabetes, dyslipidemia, smoking, sex, and race. The quality assessment of case-control studies was conducted using the Newcastle-Ottawa Scale, whereas cohort studies were assessed using the National Institute of Health tool. Meta-analyses were performed using a random-effects model to determine pooled hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs). A total of 18 observational studies involving 116,184 HIV-positive and 3,184,245 HIV-negative patients were included. HIV-positive patients exhibited a significantly higher risk of stroke compared with HIV-negative patients [OR (95% CI): 1.31 (1.20 to 1.44)]. Subgroup analyses revealed increased risks for both ischemic stroke [OR (95% CI): 1.32 (1.19 to 1.46)] and hemorrhagic stroke [OR (95% CI): 1.31 (1.09 to 1.56)]. Pooled adjusted HRs showed a significant association between stroke and HIV positivity (HR: 1.37, 95% CI: 1.22 to 1.54). Among HIV-positive patients with stroke, hypertension [OR (95% CI): 3.5 (1.42 to 8.65)], diabetes [OR (95% CI): 5 (2.12 to 11.95)], hyperlipidemia, smoking, male gender, and black race were associated with an increased risk. Our study revealed a significant increased risk of stroke development among people with HIV. A multitude of factors, encompassing sociodemographic characteristics, racial background, underlying health conditions, and personal behaviors, significantly elevate the risk of stroke in individuals living with HIV. The use of observational studies introduces inherent limitations, and further investigations are necessary to explore the underlying mechanisms of stroke in people with HIV for potential treatment strategies. HIV patients face a higher risk of stroke development, either ischemic and hemorrhagic strokes. Hypertension, diabetes, hyperlipidemia, smoking, male gender, and black race were identified as significant risk factors. Early identification and management of these risk factors are crucial in reducing stroke incidence among patients living with HIV.

Clinical Differences between Radiographic and Physical Horizontal Gaze Deviation: Utility of Using the Two in Patients with Ischemic Stroke.

Radiographic horizontal gaze deviation (RHGD) has been identified as a useful finding on computed tomography (CT) that indicates the affected side in supratentorial ischemic stroke; however, it remains unclear whether RHGD is essentially the same phenomenon as physical horizontal gaze deviation (PHGD). To resolve the issue, this study was conducted. Retrospective analyses were performed for 671 patients with ischemic stroke and 142 controls who were hospitalized and underwent head CT. First, clinical findings were examined to find differences between RHGD-positive and RHGD-negative patients. Second, patients were classified by their stroke mechanisms and/or affected vascular territories. For each subgroup, RHGD was compared with PHGD in frequency. Third, the proportions for patients divided by positivity for PHGD and RHGD were calculated in the subgroups. Patients with RHGD had PHGD more often than those without. In all stroke subgroups, RHGD was more frequent than PHGD. The frequency difference was prominent in small-artery occlusion (SAO) and posterior inferior cerebellar artery (PICA) stroke. In SAO of the basilar artery pontine perforator, RHGD was positive in 25% and largely contralesionally-directed. In PICA stroke, lesions in the vestibulocerebellum were associated with contralesional RHGD. Moreover, lesions in the lateral medulla also caused RHGD, which was mainly directed to the ipsilesional side. PHGD-positive stroke without RHGD was infrequent, whereas RHGD-positive stroke without PHGD was commonly observed (PICA stroke, 45.9%; other subgroups, 21.1%-27.5%). RHGD had different characteristics from PHGD; therefore, assessments of both PHGD and RHGD may lead to more accurate diagnoses.

Molecular Mechanisms of Ischemic Stroke: A Review Integrating Clinical Imaging and Therapeutic Perspectives.

Ischemic stroke poses a significant global health challenge, necessitating ongoing exploration of its pathophysiology and treatment strategies. This comprehensive review integrates various aspects of ischemic stroke research, emphasizing crucial mechanisms, therapeutic approaches, and the role of clinical imaging in disease management. It discusses the multifaceted role of Netrin-1, highlighting its potential in promoting neurovascular repair and mitigating post-stroke neurological decline. It also examines the impact of blood-brain barrier permeability on stroke outcomes and explores alternative therapeutic targets such as statins and sphingosine-1-phosphate signaling. Neurocardiology investigations underscore the contribution of cardiac factors to post-stroke mortality, emphasizing the importance of understanding the brain-heart axis for targeted interventions. Additionally, the review advocates for early reperfusion and neuroprotective agents to counter-time-dependent excitotoxicity and inflammation, aiming to preserve tissue viability. Advanced imaging techniques, including DWI, PI, and MR angiography, are discussed for their role in evaluating ischemic penumbra evolution and guiding therapeutic decisions. By integrating molecular insights with imaging modalities, this interdisciplinary approach enhances our understanding of ischemic stroke and offers promising avenues for future research and clinical interventions to improve patient outcomes.

The case for neuregulin-1 as a clinical treatment for stroke.

Ischemic stroke is the leading cause of serious long-term disability and the 5th leading cause of death in the United States. Revascularization of the occluded cerebral artery, either by thrombolysis or endovascular thrombectomy, is the only effective, clinically-approved stroke therapy. Several potentially neuroprotective agents, including glutamate antagonists, anti-inflammatory compounds and free radical scavenging agents were shown to be effective neuroprotectants in preclinical animal models of brain ischemia. However, these compounds did not demonstrate efficacy in clinical trials with human patients following stroke. Proposed reasons for the translational failure include an insufficient understanding on the cellular and molecular pathophysiology of ischemic stroke, lack of alignment between preclinical and clinical studies and inappropriate design of clinical trials based on the preclinical findings. Therefore, novel neuroprotective treatments must be developed based on a clearer understanding of the complex spatiotemporal mechanisms of ischemic stroke and with proper clinical trial design based on the preclinical findings from specific animal models of stroke. We and others have demonstrated the clinical potential for neuregulin-1 (NRG-1) in preclinical stroke studies. NRG-1 significantly reduced ischemia-induced neuronal death, neuroinflammation and oxidative stress in rodent stroke models with a therapeutic window of >13 h. Clinically, NRG-1 was shown to be safe in human patients and improved cardiac function in multisite phase II studies for heart failure. This review summarizes previous stroke clinical candidates and provides evidence that NRG-1 represents a novel, safe, neuroprotective strategy that has potential therapeutic value in treating individuals after acute ischemic stroke.

Update on the Acute Management of Ischemic Stroke

Acute ischaemic stroke is a major public health priority and will become increasingly relevant to neurologists of the future. The cornerstone of effective stroke care continues to be timely reperfusion treatment. This requires early recognition of symptoms by the public and first responders, triage to an appropriate stroke centre and efficient assessment and investigation by the attending stroke team. The aim of treatment is to achieve recanalisation and reperfusion of the ischaemic penumbra with intravenous thrombolysis and/or endovascular thrombectomy in appropriately selected patients. All patients should be admitted directly to an acute stroke unit for close monitoring for early neurological deterioration and prevention of secondary complications. Prompt investigation of the mechanism of stroke allows patients to start appropriate secondary preventative treatment. Future objectives include improving accessibility to endovascular thrombectomy, using advanced imaging to extend therapeutic windows and developing neuroprotective agents to prevent secondary neuronal damage. Bangladesh Crit Care J March 2024; 12 (1): 41-49

MRI in the Evaluation of Cryptogenic Stroke and Embolic Stroke of Undetermined Source.

Cryptogenic stroke refers to a stroke of undetermined etiology. It accounts for approximately one-fifth of ischemic strokes and has a higher prevalence in younger patients. Embolic stroke of undetermined source (ESUS) refers to a subgroup of patients with nonlacunar cryptogenic strokes in whom embolism is the suspected stroke mechanism. Under the classifications of cryptogenic stroke or ESUS, there is wide heterogeneity in possible stroke mechanisms. In the absence of a confirmed stroke etiology, there is no established treatment for secondary prevention of stroke in patients experiencing cryptogenic stroke or ESUS, despite several clinical trials, leaving physicians with a clinical dilemma. Both conventional and advanced MRI techniques are available in clinical practice to identify differentiating features and stroke patterns and to determine or infer the underlying etiologic cause, such as atherosclerotic plaques and cardiogenic or paradoxical embolism due to occult pelvic venous thrombi. The aim of this review is to highlight the diagnostic utility of various MRI techniques in patients with cryptogenic stroke or ESUS. Future trends in technological advancement for promoting the adoption of MRI in such a special clinical application are also discussed.

COVID 19- Biochemical and Other Mechanisms associated with Neuropathy and Stroke.

The Coronavirus (SARS-C0V-2) caused COVID 19 disease, commencing from China in December 2019 and soon in 2020 its neurological manifestations were noted. The viral spike (S) protein binding with host cell receptor angiotensin-converting enzyme 2 (ACE2) with assistance of membrane fusion protease (TMPRSS) caused viral entry in host cells. We searched 47 articles using PubMed from January 2021 to January 2023. The initial pooling of virus in nasal mucosa was followed by spread to respiratory and other tissues. This review highlights the neuropathy and stroke mechanisms. The role of receptors, enzymes, proteins and genes in neuropathological mechanisms are highlighted. Vascular endothelial effects, choroid plexus and Blood Brain Barrier disruptions were noted. The epigenetic neuropathological mechanisms need to be explored further to help in designing new therapeutic modalities. The post vaccination neurological manifestations as well as the post COVID effects both need further attention to promptly diagnose and start timely treatment.

Characteristics of Atherosclerotic Plaques and Stroke Mechanism in Patients with Border-Zone Infarcts: A High-resolution Magnetic Resonance Imaging Study

BackgroundRelatively little is known about the plaque characteristics of border-zone infarcts and how they differ between cortical border-zone (CBZ) and internal border-zone (IBZ) infarcts. MethodsWe conducted a prospective observational cohort study of patients of intracranial atherosclerotic disease who underwent high-resolution magnetic resonance imaging (HR-MRI) examination. Individuals with border-zone infarcts in the middle cerebral artery (MCA) territory, detected by diffusion-weighted imaging, were enrolled. Plaque morphological and compositional parameters of both IBZ and CBZ groups were compared. Independent predictors were identified using a binary logistic regression model, and the sensitivity and specificity of the model were assessed using a receiver operating characteristic curve. Kaplan-Meier survival analysis further explored differences in stroke recurrence between BZ patients with mono or dual antiplatelet therapy. ResultsWe reviewed 101 symptomatic patients with border-zone infarcts (BZ) within the MCA territory in the study. Out of the patients meeting the imaging eligibility criteria, we detected 34 cases with isolated IBZ, 23 cases with isolated CBZ, and 6 cases with both IBZ and CBZ infarcts. Those with IBZ infarcts had a higher plaque burden than those without (p<0.001), and those with CBZ infarcts exhibited a complicated plaque less frequently than those without (37.9% vs 67.6%, p=0.018). In those with isolated IBZ or CBZ infarcts, plaque burden was independently associated with isolated IBZ infarcts (odd ratio=1.08; 95% CI, 1.02-1.15; p=0.023). During the median follow-up period of 37 (27, 50) months, 13.8% of patients receiving early dual antiplatelet treatment and 30.4% of those on single antiplatelet therapy experienced stroke recurrence (p=0.182). ConclusionsIntracranial atherosclerotic plaque morphology and composition differ between patients with IBZ and those with CBZ infarcts. Higher plaque burden is more associated with IBZ infarcts.

Unraveling the molecular interplay of ferroptosis and immune regulation in stroke pathogenesis: A comprehensive bioinformatics analysis

Neurological disorders, particularly stroke, pose significant public health challenges, prompting a comprehensive investigation into the intricate interplay between ferroptosis and immune responses. This study aims to uncover the molecular mechanisms of stroke, emphasizing the connection between ferroptosis and immune regulation. Objectives include identifying differentially expressed genes in stroke patients, assessing immune cell subtype activation, employing advanced predictive modeling to pinpoint key candidate genes such as STMN1 and ATG16L1, exploring associations with immune cell subtypes, and revealing critical pathways, such as matrix degradation and inflammatory responses, activated in stroke through Gene Set Variation Analysis (GSVA). A comprehensive approach was adopted, involving differential gene expression analysis, functional enrichment analysis, weighted gene co-expression network analysis, Lasso regularization, random forest models, and the CIBERSORT (https://cibersortx.stanford.edu) algorithm, to assess immune cell subtypes. The study pinpointed genes with significant expression differences in stroke patients, highlighting the activation of Th17 cells and the NF-κ B signaling pathway. Key candidate genes, including STMN1 and ATG16L1, were identified using advanced predictive modeling. The relative abundance of immune cell subtypes, particularly natural killer cells (NK cells) and T cell subgroups, was associated with stroke through CIBERSORT. GSVA uncovered the activation of critical biological pathways such as matrix degradation and inflammatory responses. The analysis pinpointed STMN1 and ATG16L1 as robust predictors, emphasizing their potential as therapeutic targets. Th17 cells and the NF-κ B signaling pathway emerged as pivotal contributors to stroke pathogenesis. Notably, NK cells and specific T cell subgroups demonstrated significant associations with stroke. GSVA further illuminated the activation of key pathways, providing deeper insights into the biological processes underlying stroke. This study sheds light on crucial genes and pathways implicated in stroke, emphasizing the roles of ferroptosis and immune cell subtypes. The identified genes and pathways offer promising avenues for targeted therapeutic interventions in stroke, with a broader implication for advancing neurological disorder treatments through innovative perspectives on ferroptosis and immune regulation.

Using machine learning to identify proteomic and metabolomic signatures of stroke in atrial fibrillation

Atrial fibrillation (AF) is a common cardiac arrhythmia, with stroke being its most detrimental comorbidity. The exact mechanism of AF related stroke (AFS) still needs to be explored. In this study, we integrated proteomics and metabolomics platform to explore disordered plasma proteins and metabolites between AF patients and AFS patients. There were 22 up-regulated and 31 down-regulated differentially expressed proteins (DEPs) in AFS plasma samples. Moreover, 63 up-regulated and 51 down-regulated differentially expressed metabolites (DEMs) were discovered in AFS plasma samples. We integrated proteomics and metabolomics based on the topological interactions of DEPs and DEMs, which yielded revealed several related pathways such as arachidonic acid metabolism, serotonergic synapse, purine metabolism, tyrosine metabolism and steroid hormone biosynthesis. We then performed a machine learning model to identify potential biomarkers of stroke in AF. Finally, we selected 6 proteins and 6 metabolites as candidate biomarkers for predicting stroke in AF by random forest, the area under the curve being 0.976. In conclusion, this study provides new perspectives for understanding the progressive mechanisms of AF related stroke and discovering innovative biomarkers for determining the prognosis of stroke in AF.