Associations of the neutrophil to lymphocyte ratio with intracranial artery stenosis and ischemic stroke.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) has emerged as an inflammatory marker. However, the associations of NLR with intracranial artery stenosis (ICAS) and ischemic stroke remain unclear. This study aimed to examine the associations of NLR with ICAS and ischemic stroke among a large and high-risk population. METHODS: Participants with records of clinical characteristics were prospectively recruited from the Neurology Department and Health & Physical Examination Center of Qingdao Municipal Hospital. Logistic regression analysis was used to examine the associations of NLR with ICAS and ischemic stroke. Moreover, we also conducted parametric mediation analysis to estimate the effect of NLR on the risk of ischemic stroke mediated through ICAS. RESULTS: A total of 2989 participants were enrolled in this study. After adjusting for covariates, NLR (OR = 1.125, 95%CI 1.070-1.183) and ICAS (OR = 1.638, 95%CI 1.364-1.967) were significantly associated with ischemic stroke. Compared with the first quartile NLR, the second, third and fourth quartiles NLR were independent risk predictors for ischemic stroke (P for trend < 0.001); the third and fourth quartiles were independent predictors for ICAS (P for trend < 0.001). The mediation analysis showed that ICAS partially mediated the association between NLR and ischemic stroke, accounting for 14.4% of the total effect (P < 0.001). CONCLUSIONS: NLR was significantly associated with ICAS and ischemic stroke. Besides, ICAS partially mediated the association between NLR and ischemic stroke.

PM2.5 exposure induces systemic inflammation and oxidative stress in an intracranial atherosclerosis rat model.

OBJECTIVES: Exposure to airborne particle (PM2.5 ) is a risk factor for intracranial atherosclerosis (ICA). Because of the established role of systemic inflammation and oxidative stress by PM2.5 , we determined whether these processes account for PM2.5 -mediated ICA, and also whether omega-3 fatty acid (O3FA) dietary supplementation could attenuate them. METHODS: Adult Sprague-Dawley rats were exposed to filtered air (FA) or PM2.5 and fed either a normal chow diet (NCD) or a high-cholesterol diet (HCD), administered with or without O3FA (5 mg/kg/day by gavage) for 12 weeks. The lumen and thickness of the middle cerebral artery (MCA) were assessed. Serum tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin-1ß (IL-1ß), and interferon gamma (IFN-γ) were detected by ELISA. Reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD) activity, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activity, mRNA levels of Nrf2, HO-1, NQO-1, and protein level of NOX subunit gp91 were quantified to determine the oxidative profile of brain vessels. RESULTS: PM2.5 increased (P < .05) ICA, especially in the HCD group; elevated serum TNF-α, IL-6, IL-1ß, and IFN-γ; increased cerebrovascular ROS, MDA, NOX activity, and gp91 protein levels; and decreased cerebrovascular SOD activity. Nrf2, HO-1, and NQO-1 mRNA levels were upregulated (P < .05) by PM2.5 exposure, especially in the HCD group. O3FA attenuated (P < .05) PM2.5 -induced systemic inflammation, vascular oxidative injury, and ICA. CONCLUSIONS: PM2.5 exposure induced systemic inflammation, cerebrovascular oxidative injury, and ICA in rats with HCD. O3FA prevented ICA development, and may therefore exert a protective effect against the atherogenic potential of PM2.5 .

Anti-inflammatory approaches to ischaemic stroke prevention.

Stroke is a major cause of neurological morbidity and mortality. Atherosclerosis is a major contributor to first and recurrent stroke. A growing evidence base indicates that inflammation is a key process in the pathogenesis of atherosclerosis, leading to thromboembolic events. In this review, we summarise the evidence linking inflammation to stroke risk and discuss clinical trials addressing the 'inflammation hypothesis' in coronary disease and stroke. Trial registration number CONVINCE trial ClinicalTrials.gov number; NCT 02898610; Pre-results.

Association between inflammatory biomarkers and progression of intracranial large artery stenosis after ischemic stroke.

BACKGROUND: Proinflammatory state has been implicated as a pathogenetic mechanism in the progression of intracranial large artery atherosclerosis (ILA). High levels of inflammatory biomarkers in healthy populations and in patients with acute stroke or acute coronary syndrome are known to be associated with subsequent stroke events. This study investigated the relationship between circulating biomarkers measured early after stroke onset and future ILA progression. METHODS: In 48 patients with acute ischemic stroke, high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), IL-18, tumor necrosis factor-α, matrix metalloproteinase (MMP)-2 and MMP-9 were measured within 48 hours after onset. Baseline severity and ILA progression were assessed by serial magnetic resonance angiography (MRA). The median follow-up period for MRA was 3.1 years. Hazard ratio (HR) was calculated using the Cox proportional hazard model adjusted for traditional risk factors, and accuracy of predicted ILA progression was analyzed by receiver operating characteristic (ROC) curve analysis. RESULTS: ILA progression was observed in 6 of 48 patients (12.5%). After adjusting for age, sex, and presence of hypertension, baseline ILA severity score (HR 2.814; 95% confidence interval [CI] 1.172-6.754) and IL-6 (HR 1.215; 95% CI 1.002-1.473) were significantly associated with ILA progression. Area under the ROC curve (AUC) for prediction of ILA progression by traditional risks, baseline ILA severity score and IL-6, was 0.647. When IL-6 was removed from this model, AUC remained at 0.631. CONCLUSIONS: In addition to traditional risk factors and baseline radiologic findings, circulating levels of IL-6 measured soon after stroke onset are associated with future ILA progression.

Inflammaging and neurodegenerative diseases: Role of NLRP3 inflammasome activation in brain atherosclerotic vascular disease.

The activation of the NLRP3 inflammasome-IL-1ß pathway has been clearly shown to be involved in the pathophysiology of cardiovascular diseases, but its role in cerebral atherosclerotic vascular disease has not been fully clarified. Here we provide an overview on the current knowledge about the relevance of the activation of this mechanism in the onset of acute brain atherosclerotic vascular disease and the subsequent tissue damage. Some variants of NLRP3-related genes seem to reduce the susceptibility to acute ischaemic stroke in selected cohorts, although no clear evidence exists either supporting or excluding any role of this pathway in its pathophysiology. Interestingly, robust experimental and clinical data support a major role of the activation of the NLRP3 inflammasome-IL-1ß pathway in the post-event inflammatory cascade which leads to neurodegeneration. This evidence highlights a potential dual role of these molecules in brain pre- and post-ischaemic events, supporting the need for further studies, including clinical trials evaluating the modulation of this pathway for stroke prevention and post-stroke treatment.

Systemic infection, inflammation and acute ischemic stroke.

Extensive evidence implicates inflammation in multiple phases of stroke etiology and pathology. In particular, there is growing awareness that inflammatory events outside the brain have an important impact on stroke susceptibility and outcome. Numerous conditions, including infection and chronic non-infectious diseases, that are established risk factors for stroke are associated with an elevated systemic inflammatory profile. Recent clinical and pre-clinical studies support the concept that the systemic inflammatory status prior to and at the time of stroke is a key determinant of acute outcome and long-term prognosis. Here, we provide an overview of the impact of systemic inflammation on stroke susceptibility and outcome. We discuss potential mechanisms underlying the impact on ischemic brain injury and highlight the implications for stroke prevention, therapy and modeling.

The role of high-sensitivity C-reactive protein in asymptomatic intra- and extracranial large artery diseases.

BACKGROUND: It remains unclear whether high-sensitivity CRP (hs-CRP) is predictive of atherosclerosis in the intracranial artery. The aim of this study is to assess the role of hs-CRP in asymptomatic intracranial artery occlusive diseases. METHODS: Of the 3,366 apparently healthy subjects who received a brain checkup, 138 with > or =25% intracranial artery stenosis on magnetic resonance angiography, 267 with > or =25% extracranial carotid artery stenosis on B-mode ultrasonography and 435 without intracranial artery or extracranial carotid artery stenosis (age-matched controls) were selected for this study. RESULTS: The mean CRP concentration in the subjects with intracranial artery stenosis was not significantly different from that in the control subjects, and the differences of mean CRP concentrations among the subgroups with 25-49, 50-74 and 75% or greater stenosis in the intracranial artery were not significant. The odds ratios of hs-CRP for extracranial carotid artery stenosis tended to increase with increasing CRP concentrations, but those of hs-CRP for intracranial artery stenosis showed no significant difference. CONCLUSION: The degree of atherogenic inflammation in asymptomatic intracranial artery stenosis may be less than that in extracranial carotid artery stenosis.

The autonomic nervous system and ischemic stroke: a reciprocal interdependence.

Signs and symptoms of autonomic nervous system (ANS) dysfunction are frequently reported after ischemic or haemorrhagic stroke and in many cases they exhibit peculiar patterns in relationship with the site and the extension of brain lesion. However if an ANS disorder can cause or predispose to a stroke is far from being correctly known. Evidences in favor of a pathogenetic mechanism of an ANS dysfunction are reported for myocardial infarction and such data are likely to be appropriate also for atherothrombotic type of ischemic stroke. On the other hand, it is well known that many risk factors for this pathology are strongly correlated with an altered functioning of ANS so that a reciprocal interdependence between ANS and stroke can be hypothesized. This review points to evidence the possible relationship existing between these two conditions and suggests a quite different diagnostic and therapeutic approach to both on the basis of their pathogenetic mechanisms.

Inflammation, C-reactive protein, and atherothrombosis.

Atherothrombosis of the coronary and cerebral vessels is understood to be a disorder of inflammation and innate immunity, as well as a disorder of lipid accumulation. From a vascular biology perspective, the processes of cellular adhesion, monocyte and macrophage attachment, and transmigration of immune cells across the endothelium are crucial steps in early atherogenesis and in the later stages of mature plaque rupture, particularly the transition of unstable plaque at the time of acute thrombosis. There is abundant clinical evidence demonstrating that many biomarkers of inflammation are elevated years in advance of first ever myocardial infarction (MI) or thrombotic stroke and that these same biomarkers are highly predictive of recurrent MI, recurrent stroke, diabetes, and cardiovascular death. In daily practice, the inflammatory biomarker in widest use is high-sensitivity C-reactive protein (hsCRP); when interpreted within the context of usual risk factors, levels of hsCRP <1, 1 to 3, and >3 mg/l denote lower, average, and higher relative risk for future vascular events. Risk-prediction models that incorporate hsCRP, such as the Reynolds Risk Score, have been developed that improve risk classification and the accuracy for global risk prediction, particularly for those deemed at "intermediate risk" by usual algorithms, such as the Framingham Risk Score. With regard to cerebral vessels, increased biomarkers of inflammation, including hsCRP, have been associated with increased stroke risk as well as an increased rate of atherosclerosis progression in the carotid vessels. Although the proportion of variation in hsCRP explained by genetic factors may be as large as 20% to 40%, diet, exercise, and smoking cessation remain critical tools for risk reduction and CRP reduction. Statin therapy reduces hsCRP in a largely low-density lipoprotein (LDL)-independent manner, and the "anti-inflammatory" properties of these agents have been suggested as a potential mechanism beyond LDL reduction for the efficacy of these agents. The ongoing multinational Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial of 17,802 initially healthy men and women with low levels of LDL cholesterol but increased levels of hsCRP will help to define whether vascular protection can be achieved with statin therapy, even in the absence of hyperlipidemia. Targeted anti-inflammatory therapies are being developed that may provide a direct method of translating the biology of inflammation into new clinical treatments across multiple vascular beds. This article summarizes data supporting a role for inflammation in cardiovascular disease and offers the possibility that other disorders characterized by inflammation, such as periodontal disease, may have an indirect role by influencing the risk, manifestation, and progression of vascular events.

Treatment of Susac's syndrome.

Susac's syndrome (SS) is an immune-mediated endotheliopathy that affects the microvasculature of the brain, retina, and inner ear. SS responds well to immunosuppressive therapies when treatment is prompt, aggressive, and sustained. Striking similarities exist between SS and dermatomyositis (DM), regarding immunopathogenesis, natural history, and treatment needs. We apply lessons learned from study of DM to SS, and offer our current treatment protocol for SS. Since these treatment guidelines are based mainly on anecdotal evidence, they represent only preliminary recommendations.

Hyperhomocysteinemia relates to the subtype of antiphospholipid antibodies in non-SLE patients.

Abnormal increases of antiphospholipid antibody and plasma homocysteine levels are recently emerging as nonlipidic risk factors for cerebral atherogenesis and thrombosis. Both antiphospholipid antibody and homocysteine share many similar bioeffects in hemostasis, but their interaction is still inconsistent. In this study, we examined the relation between the plasma homocysteine level and lupus anticoagulant, anticardiolipin antibody, and anti-beta2-glycoprotein I antibody in patients with noncardiac cerebral ischemia. Systemic lupus erythrematosus patients were excluded. The results showed a higher frequency of moderate hyperhomocysteinemia in patients with an abnormal increase of lupus anticoagulant only. Neither the serum folate and cobalamin levels nor methylenetetrahydrofolate reductase allele mutation contributes to this result. Accordingly, homocysteine interacts with lupus anticoagulant to promote cerebral atherosclerosis and ischemia. The role of vasculopathic or prothrombotic autoantibody generation in response to specific pathological change such as hyperhomocysteinemia warrants further investigation.

Omega-3 fatty acid supplement prevents development of intracranial atherosclerosis.

OBJECTIVES: Intracranial atherosclerotic stenosis (ICAS) is one of the most common causes of stroke worldwide and, in particular, has been implicated as a leading cause of recurrent ischemic stroke. We adapted a rat model of atherosclerosis to study brain intracranial atherosclerosis, and further investigated the effect of omega-3 fatty acids (O3FA) in attenuating development of ICAS. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were divided into control normal-cholesterol or high-cholesterol diet groups with or without O3FA for up to 6weeks. During the first 2weeks, NG-nitro-l-arginine methyl ester (l-NAME, 3mg/mL) was added to the drinking water of the high-cholesterol groups. The rats received supplementation with O3FA (5mg/kg/day) by gavages. Blood lipids including low density lipoprotein (LDL), cholesterol (CHO), triglycerides (TG) and high density lipoprotein (HDL) were measured at 3 and 6weeks. The lumen of middle cerebral artery (MCA) and the thickness of the vessel wall were assessed. Inflammatory molecular markers were assessed by Western blot. RESULTS: A high-cholesterol diet exhibited a significant increase in the classic blood markers (LDL, CHO, and TG) for atherosclerosis, as well as a decrease in HDL. These markers were found to be progressively more severe with time. Lumen stenosis and intimal thickening were increased in MCA. O3FA showed attenuation of blood lipids with an absence of morphological changes. O3FA significantly reduced the inflammatory marker CD68 in MCA and prevented monocyte chemotactic protein (MCP-1) and interferon-γ (IFN-γ) expression in the brain. O3FA similarly decreased inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6), markers affiliated with monocyte activity in atherosclerosis. Furthermore, O3FA significantly inhibited the expression of vascular cell adhesion molecule-1 (VCAM-1), a marker for endothelial activation. Lastly, O3FA increased ATP-binding cassette transporter A1 (ABCA1) protein expression via silent information regulator 1 (SIRT1) activation, thus increasing cholesterol efflux from macrophages to HDL. CONCLUSIONS: Long-term O3FA dietary supplementation prevents the development of intracranial atherosclerosis. This O3FA effect appears to be mediated by its prevention of macrophage infiltration into the vessel wall, therefore reducing inflammation and intimal thickening. While similar effects in humans need to be determined, O3FA dietary supplement shows promising results in the prevention of ICAS.

Studies on the occurrence of circulating immune complexes in vascular diseases.

The presence of circulating immune complexes was studied in 347 samples of serum from 212 patients with various vascular diseases. Two quantitative methods (complement-consumption assay and C1q-solubility test) were used for the measurement of the concentration of the complexes. Immune complexes were detected in each group of patients tested (coronary arteriosclerosis, myocardial infarction, cerebral artery sclerosis, arteriosclerosis obliterans, phlebothrombosis, pulmonary infarction). A high proportion of positivity was recorded in myocardial infarction (in 43 patients out of the 94 tested) and in arteriosclerosis obliterans (7 out of 11 cases). The possible pathogenic role of the circulating immune complexes is discussed.

Antibodies to the atherosclerotic plaque components beta2-glycoprotein I and heat-shock proteins as risk factors for acute cerebral ischemia.

One third of cases of cerebral ischemia have no clear etiology. A humoral response to the atherosclerotic plaques components beta2-glycoprotein l (beta2-gpl) and heat-shock proteins (Hsp) might be involved in the pathogenesis of stroke. This case-control study includes a complete profile of anti-beta2-gpl antibodies and testing of IgG antibodies to the 60/65 kilodaltons (kDa) Hsp in stroke patients. Ninety-three patients with acute ischemic stroke and 93 controls were evaluated for age, sex, race, hypertension, smoking, previous cardiopathy, diabetes mellitus, hypercholesterolemia and previous history of cerebral ischemia. lgG/lgM/lgA anticardiolipin (aCL) and anti-beta2-gpl antibodies, as well as lgG antibodies to human 60 kDa Hsp and to Mycobacterium bovis 65 kDa Hsp, were detected by immunoassay. Adjusted odds ratios (OR) were calculated by logistic regression. The adjusted OR for IgA anti-beta2-gpl antibodies was 4.6 (90%Cl 1.5 to 14.3; p = 0.025). The non-adjusted OR for IgG antibodies to Hsp 60 was 26.1. The adjusted OR for IgG antibodies to Hsp 65 was 3.2 (90%Cl 1.2 to 8.3; p = 0.044). The adjusted OR for lgG to any Hsp (60 or 65) was 4.8 (90%Cl 1.9 to 12.1; p = 0.006). This study demonstrates that elevated IgA anti-beta2-gpl and lgG anti-Hsp 60/65 antibodies are associated with increased risk of ischemic stroke. The association occurred independently of other risk factors. This humoral response might link autoimmunity, thrombophilia and atherosclerosis in stroke patients.

[The presence of anti-Chlamydia pneumoniae antibodies in peripheral vascular and neurological disorders]. / Presencia de anticuerpos anti-Chlamydia pneumoniae en procesos vasculares periféricos y neurológicos.

OBJECTIVES: To make a retrospective analysis of the synthesis of antibodies to the MOMPS and LPS antigens of Chlamydia pneumoniae in patients with occlusive disease of the peripheral arteries (ODPA) and multiple sclerosis (MS). PATIENTS AND METHODS: We studied 190 samples of plasma from patients included in the following groups: group 1:66 samples from 66 patients with ODPA; group 2:74 samples from 31 patients with MS (20 remittent-relapsing and 11 secondarily progressive), followed over time; and group 3:50 samples from persons acting as controls. In all cases determinations were made using ELISA, of the IgG anti-MOMP and the IgG and IgA anti-LPS. Comparison of the continuous variables was made using the Mann-Whitney U Test. Discrete variables were analysed using the exact bilateral Fisher Test. The Wilcoxon Test over ranges was used to compare the evolution of antibodies in the patients with MS. RESULTS: The percentage of positive results in groups 1 to 3 for anti-LPS IgG were: 24.6%, 18.9% and 20.8%, respectively, with no differences between patients and controls; nor were there any differences with IgA (29%, 29.7% and 25%, respectively). However differences were seen in the anti-MOMP IgG between patients and controls (group 1:80.3%, group 2:37.8% and group 3: 33.3%). In patients with MS the results of the evolution of the antibodies did not reflect a uniform tendency of the levels of the different antibodies. CONCLUSION: A higher level of IgG anti-MOMP was seen in ODPA and MS, although this did not occur with anti-LPS or IgA.

[Clinico-immunologic parallels in atherosclerotic discirculatory encephalopathy]. / Kliniko-immunologicheskie paralleli pri ateroskleroticheskoi distsirkuliatornoi éntsefalopatii.

For disclosing the character of the immunological reactivity disturbances in atherosclerotic discirculatory encephalopathy the humoral and tissue immunity was examined in 160 patients. Signs of an increase of the hypersensitivity (both immediate and delayed) to local antigens were revealed, these signs correlating with the stage of the encephalopathy development. The changes discovered may be of a diagnostic and prognostic value in chronic forms of vascular encephalopathies.

[Quantitative characteristics of the state of the T- and B-systems of immunity in the peripheral blood of patients with cerebrovascular disorders]. / Kolichestvennaia kharakteristika sostoianiia T- i B-sistem immuniteta v perifericheskoi krovi u bol'nykh s tserebrovaskuliarnymi narusheniiami.

A clinical-immunologic study of 133 patients was carried out to elucidate the status of the T- and B-immune systems in atherosclerotic dyscirculatory encephalopathy (ADE) in the acute period of cerebral infarction and hemorrhagic stroke. A similar pattern of elevation in humoral and tissue immunity, with quantitative fluctuations in the intensity of individual parameters in various dyscirculatory disorders, was found. The changes indicate that cerebral stroke develops in the body already sensitized in the prestroke period and its development involves the central and peripheric links of the immune system.

[Immunologic reactions to tissue antigens in patients with different stages of cerebral atherosclerosis]. / Immunologicheskie reaktsii k tkanevym antigenam u bol'nykh s razlichnymi stadiiami tserebral'nog ateroskleroza

The results of the conducted studies testify to the existence of a certain correlation between the stage of the pathological process and immunological reactions to brain antigens and vessels in patients with cerebral atherosclerosis. In the I and II stages of cerebral atherosclerosis there is a certain predominance of seropositive reactions to brain beta-lipoproteids. In transient disorders of brain circulation there were prevalent reactions to water soluble proteins of the vascular tissue. In patients with residual symptoms of ischemic strokes the most frequent findings were seropositive reactions to brain proteins and beta-lipoproteids.

[Functional activity of natural killers and lymphocyte antibody-dependent cytotoxicity in patients with acute disorders of the cerebral circulation]. / Funktsional'naia aktivnost' estestvennykh killerov i antitelozavisimaia tsitoksichnost' limfotsitov u bol'nykh s ostrymi narusheniiami mozgovogo krovoobrashcheniia.

Dynamic examination of 47 patients over the first three weeks after the development of ischemic stroke (IS) has revealed a significant decrease in the natural killer activity (NKA) and antibody-dependent cellular cytotoxicity (ADCC). A decrease in the NK activity in IS patients appears to be related to dyslipoproteinemia, which has been confirmed by the detection of a reverse correlation between the values of the NKA and the atherogenicity coefficient, while suppression of ADCC in the same patients is explained by the suppressive influence of the prostaglandin system, which has been investigated in vitro. The elucidation in IS patients of immunopathological phenomena related to impairments of the effector component of immunity and of activities of NK- and K-cells justifies the inclusion of immunocorrecting drugs into the comprehensive therapy of IS.

[Autoimmune factors in cerebral circulatory disorders associated with hypertension and atherosclerosis of the cerebral vessels]. / Autoimmunnye faktory u bol'nykh s narusheniiami mozgovogo krovoobrashcheniia pri gipertonicheskoi bolezni i ateroskleroze sosudov golovnogo mozga

In 160 patients with disorders of brain circulation in cerebral atherosclerosis, 68 normals and 38 patients with different neurological diseases (a control group), a special study was undertaken to study the antibrain antibodies with the aid of a complement fixation test (CFT), and a test of complement utilization (CUT). Positive results in the CFT and CUT were seen in patients with ischemic strokes and transient disorders of brain circulation. The formation of antibodies to brain tissues depends upon their type, duration of the disease and is more characteristic of the rehabilitation period. In studying autoimmune processes in patients with disordered brain circulation previous diseases should be taken into consideration (brain trauma, epilepsy, strokes). The existence of antibrain antibodies correlates with the intensity of the process.