Roles of Polymorphonuclear Neutrophils in Ischemic Brain Injury and Post-Ischemic Brain Remodeling

Following ischemic stroke, polymorphonuclear neutrophils (PMNs) are rapidly recruited to the ischemic brain tissue and exacerbate stroke injury by release of reactive oxygen species (ROS), proteases and proinflammatory cytokines. PMNs may aggravate post-ischemic microvascular injury by obstruction of brain capillaries, contributing to reperfusion deficits in the stroke recovery phase. Thus, experimental studies which specifically depleted PMNs by delivery of anti-Ly6G antibodies or inhibited PMN brain entry, e.g., by CXC chemokine receptor 2 (CXCR2) or very late antigen-4 (VLA-4) blockade in the acute stroke phase consistently reduced neurological deficits and infarct volume. Although elevated PMN responses in peripheral blood are similarly predictive for large infarcts and poor stroke outcome in human stroke patients, randomized controlled clinical studies targeting PMN brain infiltration did not improve stroke outcome or even worsened outcome due to serious complications. More recent studies showed that PMNs have decisive roles in post-ischemic angiogenesis and brain remodeling, most likely by promoting extracellular matrix degradation, thereby amplifying recovery processes in the ischemic brain. In this minireview, recent findings regarding the roles of PMNs in ischemic brain injury and post-ischemic brain remodeling are summarized.

Subclinical thyroid dysfunction and autoantibodies in acute ischemic and hemorrhagic stroke patients: relation to long term stroke outcome

Background Data regarding the relation between both subclinical thyroid dysfunction, thyroid autoantibodies and clinical outcomes in stroke patients are limited. This study aimed to evaluate subclinical thyroid dysfunction and thyroid autoantibodies production in acute stroke patients and their relation to long term stroke outcome. We recruited 138 patients who were subjected to thorough general, neurological examination and brain imaging. Blood samples were collected for measurement of levels of serum thyroid function [free tri-iodothyronine (FT3), free thyroxin (FT4), thyroid stimulating hormone (TSH)], thyroid autoantibodies within 48 h after hospital admission. FT4 and TSH after 1 year were done. The stroke severity was assessed at admission by the National Institutes of Health Stroke Scale (NIHSS). The stroke outcome was assessed at 3 months and after 1 year by the modified Rankin Scale (mRS). We divided the patients into two groups according to thyroid autoantibodies (positive and negative groups). Results Subclinical hyperthyroidism was found in 23% of patients, and subclinical hypothyroidism in 10% of patients. Euthyroidism was detected in 67% of patients. 34% patients had positive thyroid autoantibody. Positive thyroid autoantibodies were commonly found in those with subclinical hyperthyroidism (28%), followed by subclinical hypothyroidism (21%) and euthyroidism (14%). 73% and 59% of stroke patients had poor outcomes (mRS was > 2) at 3 months and 1 year respectively with no significant difference between ischemic and hemorrhagic stroke patients. In the positive group final TSH level, NIHSS score at admission, and disability at 1 year were significantly higher compared with the negative group. Poor outcome was significantly associated with higher NIHSS score at admission, positive thyroid autoantibodies, subclinical hyperthyroidism, and atrial fibrillation. Conclusions Subclinical thyroid dysfunction could be found in stroke patients with positive thyroid autoantibodies. Subclinical hyperthyroidism and thyroid autoantibodies were associated with a poor outcome at 1 year in first-ever acute stroke patients especially in those presented with atrial fibrillation and higher NIHSS score at admission.

Prediction of unfavorable outcome in ischemic stroke patients with chronic kidney disease

Patients with chronic kidney disease (CKD) have significantly poorer functional outcomes and greater mortality after suffering a stroke. The present study aimed to identify the prognostic factors of an unfavorable outcome of the ischemic stroke in patients with CKD. Methods and subjects. The current study was designed retrospectively and performed with data of patients who were hospitalized due to ischemic stroke to the neurological department. A complex clinical and neuroimaging investigation was carried out in 65 patients (30 men and 35 women) aged 53 to 81 years (mean age – (67.7 ± 5.9) years) with acute stroke and CKD. Patients underwent all the necessary ancillary investigations according to guidelines. According to the clinical outcome on the 21-st day by the modified Rankin scale (mRS) all patients were divided into two groups: 1-st –favorable stroke outcome (mRS=0-3) – 34 (52.3%), 2-nd – unfavorable stroke outcome – (mRS=4-6) – 31 (47.7%). Results. During comparing the basic characteristics of both groups, it was revealed that patients with unfavorable functional outcomes were almost twice as likely to have diabetes mellitus (51.6% vs. 26.5%, p<0.037) and atrial fibrillation (41.9% vs. 17.6%, p<0.032). In age-and sex-adjusted multifactor logistic regression it was found that ischemic stroke unfavorable outcome is associated with diabetes mellitus (OR – 2.5, CI: 1.6-8.3; p=0.014), atrial fibrillation – 2.7, CI: 0.7-9.6; p=0.043), dialysis therapy (OR – 3.4, CI: 2.3-8.1; p=0.007), GFR <42 ml/min/1.73 m2 (OR – 2.7, CI: 2.1-7.8; p=0.003). Conclusions. Determining prognostic factors of unfavorable course of the ischemic stroke in patients with CKD allows to optimize the management of such patients in the acute period of ischemic stroke and improve the prognosis.

Genetic Predisposition to Mosaic Chromosomal Loss Is Associated With Functional Outcome After Ischemic Stroke

Background and ObjectivesTo test the hypothesis that a predisposition to acquired genetic alterations is associated with ischemic stroke outcome by investigating the association between a polygenic risk score (PRS) for mosaic loss of chromosome Y (mLOY) and outcome in a large international data set.MethodsWe used data from the genome-wide association study performed within the Genetics of Ischemic Stroke Functional Outcome network, which included 6,165 patients (3,497 men and 2,668 women) with acute ischemic stroke of mainly European ancestry. We assessed a weighted PRS for mLOY and examined possible associations with the modified Rankin Scale (mRS) score 3 months poststroke in logistic regression models. We investigated the whole study sample as well as men and women separately.ResultsIncreasing PRS for mLOY was associated with poor functional outcome (mRS score >2) with an odds ratio (OR) of 1.11 (95% confidence interval [CI] 1.03–1.19) per 1 SD increase in the PRS after adjustment for age, sex, ancestry, stroke severity (NIH Stroke Scale), smoking, and diabetes mellitus. In sex-stratified analyses, we found a statistically significant association in women (adjusted OR 1.20, 95% CI 1.08–1.33). In men, the association was in the same direction (adjusted OR 1.04, 95% CI 0.95–1.14), and we observed no significant genotype-sex interaction.DiscussionIn this exploratory study, we found associations between genetic variants predisposing to mLOY and stroke outcome. The significant association in women suggests underlying mechanisms related to genomic instability that operate in both sexes. These findings need replication and mechanistic exploration.

Unusually High Prevalence of Stroke and Cerebral Vasculopathy in Hemoglobin SC Disease: A Retrospective Single Institution Study

<b><i>Introduction:</i></b> Unlike homozygous hemoglobin SS (HbSS) disease, stroke is a rare complication in hemoglobin SC (HbSC) disease. However, recent studies have demonstrated a high prevalence of silent stroke in HbSC disease. The factors associated with stroke and cerebral vasculopathy in the HbSC population are unknown. <b><i>Methods:</i></b> We conducted a retrospective study of all patients with sickle cell disease treated at the University of Missouri, Columbia, over an 18-year period (2000–2018). The goal of the study was to characterize the silent, overt stroke, and cerebral vasculopathy in HbSC patients and compare them to patients with HbSS and HbS/β thalassemia1 (thal) in this cohort. We also analyzed the laboratory and clinical factors associated with stroke and cerebral vasculopathy in the HbSC population. <b><i>Results:</i></b> Of the 34 HbSC individuals, we found that the overall prevalence of stroke and cerebral vasculopathy was 17.7%. Only females had evidence of stroke or cerebral vasculopathy in our HbSC cohort (33.3%, <i>p</i> = 0.019). Time-averaged means of maximum velocities were lower in the HbSC group than the HbSS group and did not correlate with stroke outcome. Among HbSC individuals, those with stroke and cerebral vasculopathy had a marginally higher serum creatinine than those without these complications (0.77 mg/dL vs. 0.88 mg/dL, <i>p</i> = 0.08). Stroke outcome was associated with recurrent vaso-occlusive pain crises (Rec VOCs) (75 vs. 25%, <i>p</i> = 0.003) in HbSC patients. The predominant cerebrovascular lesions in HbSC included microhemorrhages and leukoencephalopathy. <b><i>Conclusion:</i></b> There is a distinct subset of individuals with HbSC who developed overt, silent stroke, and cerebral vasculopathy. A female predominance and association with Rec VOCs were identified in our cohort; however, larger clinical trials are needed to identify and confirm specific clinical and laboratory markers associated with stroke and vasculopathy in HbSC disease.

Paradoxical role of hepatocyte growth factor in ischemic stroke: stroke risk/stroke recovery

Background Hepatocyte growth factor (HGF) has an obvious pathological role in atherosclerosis and plaque instability leading to an acute ischemic stroke; however, its beneficial role in stroke recovery is still restricted to experimental studies. The aim of the current study was to investigate the association between HGF and carotid atherosclerosis and evaluate its value as a prognostic marker of ischemic stroke and its role in stroke recovery. Results This case–control study was done on 100 patients with first time anterior circulation ischemic stroke, subjected to clinical and laboratory evaluation of atherosclerosis risk factors. Brain imaging, cardiac work-up and ultrasonographic assessment of carotid atherosclerosis (using intimal medial thickness and plaque score) were all done. Clinical evaluation of initial stroke severity, using National Institutes of Health Stroke Scale (NIHSS), and stroke outcome after 3 m, using Modified Rankin Scale (MRS), was performed. Measurement of HGF serum concentration was done to all stroke patients within 24 h of stroke onset and compared to results of 100 matched healthy subjects aged more than 50 years. HGF was significantly higher in stroke patients than healthy controls and in atherothrombotic than cardioembolic stroke group and its level was significantly correlated with atherosclerosis risk factors, degree of carotid atherosclerosis and better stroke outcome; however, it was not significantly correlated with initial stroke severity. Conclusion HGF is strongly associated with carotid atherosclerosis and other atherosclerosis risk factors and subsequent atherothrombotic stroke. Also, it can be used as a good prognostic marker in atherothrombotic stroke suggesting its role in stroke recovery but more studies are needed to explore this beneficial role as well as its therapeutic potentials in ischemic stroke patients.