CD4+CD28− lymphocytes and cerebral ischaemic stroke. Part II: CD4+CD28− lymphocytes and carotid artery atherosclerotic plaque characteristics

Background and purposeCD4⁺CD28^? lymphocytes can directly contribute to the instability of atherosclerotic plaque. This paper attempts to answer the question of the potential influence of the CD4⁺CD28^? lymphocyte population on the ultrasound image of atherosclerotic plaque in the common carotid artery (CCA) wall.Material and methodsThe study involved a group of 109 patients, aged 45 to 65 years, including 42 patients with first-ever ischaemic stroke, experiencing symptoms resulting from disturbances of the anterior area of cerebral circulation, arterial hypertension and/or type 2 diabetes mellitus (group 1). Group 2 consisted of 34 patients with mentioned risk factors, without ischaemic stroke. The control group comprised 33 healthy individuals. The percentage of CD4⁺CD28^? lymphocytes was assessed with flow cytometry.ResultsA significant difference in the incidence of heterogeneous plaques was noted between groups 1 and 3 (p = = 0.0023) as well as between group 2 and 3 (p = 0.0005), whereas groups 1 and 2 did not differ from each other. The proportion of CD4⁺CD28^? lymphocytes was similar in groups 1 and 2 (p = 0.97), but it differed between groups 1 and 3 (p < 0.0001) and between groups 2 and 3 (p < 0.001). A correlation was found between the proportion of CD4⁺CD28^? lymphocytes in the blood and the number of CCA atherosclerotic plaques (Rs = 0.191, p = 0.046). The proportion of CD4⁺CD28^? lymphocytes in peripheral blood did not correlate with the ultrasound types of atherosclerotic plaques. No correlation between the proportion of CD4⁺CD28^? lymphocytes and the area of atherosclerotic plaques was found.ConclusionsThe correlation between the proportion of CD4⁺CD28^? lymphocytes and the number of atherosclerotic plaques within the CCA suggests that the cells are involved in the mechanism of carotid plaque formation. There is no proof of the involvement of the above-mentioned cells in the mechanism of plaque destabilization in those arteries.     

Is the common carotid artery intima–media thickness associated with functional outcome after acute ischaemic stroke?

BACKGROUND: Common carotid artery intima-media thickness (CCA-IMT) is an independent and early marker of generalised atherosclerosis. Brain affected by atherosclerosis may be more vulnerable to an ischaemic insult. OBJECTIVE: To investigate the association between CCA-IMT and functional outcome after an acute ischaemic stroke. DESIGN: Prospective cohort analysis. METHODS: 284 consecutive patients (mean (SD) age, 68.7 (12.7) years, 126 (44%) female) with an acute ischaemic stroke had carotid ultrasonography, carried out by a single operator. Demographic data, vascular risk factors, initial stroke severity, and brain imaging findings were recorded. Outcome was assessed at seven days from stroke onset, at discharge from hospital, and at one year post-stroke. RESULTS: CCA-IMT was not significantly associated with adverse short or long term functional outcome in univariate analysis, or after adjustment in a multivariate logistic regression analysis for demographic data, initial stroke severity, conventional vascular risk factors, and the characteristics of the ischaemic lesion. Age and initial stroke severity were the only independent predictors of outcome. CONCLUSIONS: CCA-IMT was not associated with adverse functional outcome after an ischaemic stroke. Adding CCA-IMT in a prediction model for stroke outcome would probably not improve the power of the model.     

Severe ipsilateral carotid stenosis and middle cerebral artery disease in lacunar ischaemic stroke: innocent bystanders?

Objectives Lacunar infarcts are thought to be mostly due to intracranial small vessel disease. Therefore, when a stroke patient with a relevant lacunar infarct does have severe ipsilateral internal carotid artery (ICA) or middle cerebral artery (MCA) disease, it is unclear whether the arterial disease is causative or coincidental. If causative, we would expect ICA/MCA disease to be more severe on the symptomatic side than on the asymptomatic side. Therefore, our aim was to compare the severity of ipsilateral with contralateral ICA and MCA disease in patients with lacunar ischaemic stroke. Methods We studied 259 inpatients and outpatients with a recent lacunar ischaemic stroke and no other prior stroke. We used carotid Duplex ultrasound and transcranial Doppler (TCD) ultrasound to identify ICA and MCA disease, and compared our results with previously published data. Results In our study, there was no difference between the severity of ipsilateral and contralateral ICA stenosis within individuals (median difference 0 %, Wilcoxon paired data p=0.24, comparing severity of ipsilateral and contralateral stenosis). The overall prevalence of severe ipsilateral stenosis was 5 %, and the prevalence of severe contralateral stenosis was 4 % (OR 1.6, 95 % CI 0.6, 4.8). There was no difference in the prevalence of ipsilateral and contralateral MCA disease. A systematic review of the other available studies strengthened this conclusion. Conclusion Carotid stenosis in patients with a lacunar ischaemic stroke may be coincidental. Further studies are required to elucidate the causes of lacunar stroke, and to evaluate the role of carotid endarterectomy. Received: 24 February 2001, Received in revised form: 15 June 2001, Accepted: 3 July 2001     

Cerebrovascular disorders: carotid-wall intima-media thickness,stroke recurrence,and β-blocker selectivity

Journal of Neurology -     

Coexistence of external carotid artery embolus and internal carotid artery occlusion in acute ischemic stroke: An indicator of cardioembolic etiology?

ObjectivesThis study aims to evaluate whether the presence of an external carotid artery embolism accompanying internal carotid artery occlusion may contribute to identifying the etiology of internal carotid artery occlusion in the early period.Material and methodsThe presence of external carotid artery embolism was evaluated in 117 patients who were adjudicated for internal carotid artery occlusion based on digital subtraction angiography images.ResultsEmbolus in the external carotid artery was detected in 8 (6.8%) of the 117 patients with internal carotid artery occlusion (7 (87.5%) patients were found to have tandem and 1 (12.5%) patient had carotid T occlusion). In all of these patients, the thrombus was of embolic origin. Evaluation of the etiology revealed cardioembolic etiology in 4 patients and dissection in 1 patient, and the cause could not be determined in the remaining 3 patients. Patients with external carotid artery embolism accompanying an internal carotid artery occlusion had significantly higher The National Institutes of Health Stroke Scale scores at admission and significantly lower recanalization success compared to those without external carotid artery embolism (p = 0.009, p = 0.01). In the comparison of prognosis, poorer prognosis was observed in those with external carotid artery embolism, although without a statistically significant difference (p = 0.07).ConclusionsThis study observed that the etiology was mostly embolic in patients with external carotid artery embolism accompanying an internal carotid artery occlusion, most of whom were found to have tandem embolic occlusion, and cardiac origin appeared to be the prominent etiology of stroke.     

Prevalence of and risk factors associated with carotid artery stenosis: the Troms? Study.

BACKGROUND AND PURPOSE: To assess prevalence, distribution, ultrasound characteristics and determinants of carotid artery stenosis in a large, population-based study of both women and men. METHODS: A total of 6,727 persons aged 25-84 years were screened for extracranial stenosis with Duplex ultrasound of the right carotid artery. Risk factors were compared in 225 persons with stenosis and 5,514 persons without. RESULTS: The prevalence of carotid stenosis was higher in men than in women, where 3.8% (95% CI, 3.2-4.6%) had carotid stenosis, compared to 2.7% (95% CI, 2.2-3.3%) in women (p = 0.001). The prevalence gradually increased by age in both genders. Cholesterol, HDL cholesterol, fibrinogen, systolic blood pressure levels and current smoking were independently associated with carotid artery stenosis in both women and men. The presence of carotid stenosis was significantly associated with a history of cerebrovascular disease, coronary heart disease and peripheral artery disease. For each 10% increase in the degree of carotid stenosis, the risk of having had a cerebrovascular event increased by 26%. CONCLUSIONS: The prevalence of carotid stenosis in the general population, as measured by ultrasound, is low. Age, male gender, smoking, total cholesterol, HDL cholesterol (inverse), fibrinogen and systolic blood pressure are all independent predictors of carotid artery stenosis.     

MMP-9 and/or TIMP as predictors of ischaemic stroke in patients with symptomatic and asymptomatic atherosclerotic stenosis of carotid artery treated by stenting or endarterectomy – A review

We still lack an optimal tool to predict ischaemic stroke in patients with symptomatic and asymptomatic carotid stenosis (CS). It has already been shown that patients at increased risk of ischaemic stroke can be identified based on the elevated plasma levels of metalloproteinases (MMPs) and reduced activity tissue inhibitor of metalloproteinase (TIMP). There are few studies presenting the role of MMP-9 and TIMP in ischaemic stroke both in patients with symptomatic and asymptomatic CS treated with stenting or endarterectomy, however we have not found any published review summarizing the role of abovementioned markers. MEDLINE was accessed via Pub Med, and searched for published studies that analyzed MMP-9 and TIMP levels in patients with asymptomatic and symptomatic internal carotid stenosis and/or examined these parameters as potential risk markers for ischaemic stroke. A total of 13 articles documenting the outcomes of patients with symptomatic or asymptomatic carotid stenosis treated by carotid stenting or endarterectomy, were analyzed. Statistically significant differences in the levels of MMP-9 and/or TIMP in patients with symptomatic and asymptomatic CS have been reported. Also the concentrations of MMP-9 and TIMP in CS patients subjected to stenting or endarterectomy were higher than in baseline group. Moreover higher levels of MMP-9 and decreased TIMP was reported to be associated with the risk of restenosis. This systematic review shows that available evidence regarding the dynamics of MMP-9 and TIMP levels may be a predictor of cerebrovascular events in both symptomatic and asymptomatic carotid stenosis in patients treated with stenting or endarterectomy.     

Asymptomatic carotid artery stenosis: past, present and future. How to improve patient selection?

BACKGROUND: The role of carotid endarterectomy (CEA) for asymptomatic carotid artery stenosis (aCAS) remains a matter of debate. It seems that not only the degree of stenosis, but also other factors have to be taken in account to improve patient selection and increase the benefit of CEA for aCAS. METHODS AND RESULTS: The literature pertaining aCAS was reviewed in order to describe the natural history, risk of stroke and benefit of CEA for patients with aCAS in regard to several factors. CONCLUSION: The benefit of CEA for aCAS is low. Current factors influencing the indication for CEA are severity of stenosis, age, contralateral disease, stenosis progression to >80%, gender, concomitant operations and life expectancy. To improve patient selection investigations will concentrate on plaque characteristics and instability and cerebral hemodynamics and metabolism.     

CXCR4+CD45− BMMNC subpopulation is superior to unfractionated BMMNCs for protection after ischemic stroke in mice

Cell-based therapy is considered to be a promising therapeutic strategy for stroke treatment. Although unfractionated bone marrow mononuclear cells (BMMNCs) have been tried in both preclinical and clinical trials, the effective subpopulations need to be identified. In this study, we used fluorescence-activated cell sorting to harvest the CXCR4⁺CD45⁺ and CXCR4⁺CD45⁻ BMMNC subpopulations from transgenic mice that express enhanced green fluorescent protein. We then allogeneically grafted unfractionated BMMNCs or a subpopulation into mice subjected to transient middle cerebral artery occlusion (tMCAO) and compared the effects on stroke outcomes. We found that CXCR4⁺CD45⁻ BMMNCs, but not CXCR4⁺CD45⁺ BMMNCs, more effectively reduced infarction volume and neurologic deficits than did unfractionated BMMNCs. Brain tissue from the ischemic hemisphere of mice treated with CXCR4⁺CD45⁻ BMMNCs had higher levels of vascular endothelial growth factor and lower levels of TNF-α than did tissue from mice treated with unfractionated BMMNCs. In contrast, CXCR4⁺CD45⁺ BMMNCs showed an increase in TNF-α. Additionally, CXCR4⁺CD45⁺ and CXCR4⁺CD45⁻ populations exhibited more robust migration into the lesion areas and were better able to express cell-specific markers of different linages than were the unfractionated BMMNCs. Endothelial and astrocyte cell markers did not colocalize with eGFP⁺ cells in the brains of tMCAO mice that received CXCR4⁺CD45⁺ BMMNCs. In vitro, the CXCR4⁺CD45⁻ BMMNCs expressed significantly more Oct-4 and Nanog mRNA than did the unfractionated BMMNCs. However, we did not detect gene expression of these two pluripotent markers in CXCR4⁺CD45⁺ BMMNCs. Taken together, our study shows for the first time that the CXCR4⁺CD45⁻ BMMNC subpopulation is superior to unfractionated BMMNCs in ameliorating cerebral damage in a mouse model of tMCAO and could represent a new therapeutic approach for stroke treatment.     

Relationship between circulating CD4+ T lymphocytes and cognitive impairment in patients with Parkinson’s disease

IntroductionParkinson’s disease (PD) is characterized by loss of dopaminergic neurons. Neuroinflammation may represent an important factor in the pathophysiology of PD and recent findings indicate that PD patients present a pro-inflammatory peripheral profile of CD4+ T lymphocytes, which may correlate with motor disability. However, no data are currently available on the relationship between CD4+ T lymphocytes and cognitive function in PD.The aim of our study is to evaluate the relationship between cognitive profile and circulating CD4+ T lymphocyte subsets in PD patients.MethodsPD patients underwent blood withdrawal and CD4+ T lymphocyte subpopulations, including CD4+ T naïve and memory cells, Th1, Th2, Th17, Th1/17 and T regulatory (Treg) cells were evaluated by flow cytometry. Cognitive evaluation was performed using Addenbrooke Cognitive Examination (ACE-R).Results43 consecutive PD patients (31 males; age [mean ± SD]: 68.9 ± 8.4 years) were enrolled. 14/43 (32.6%) were drug naïve. Based on the ACE-R score, patients were divided in two groups using defined cutoff values. In comparison to patients with normal cognitive profile, patients with cognitive impairment had a higher number of circulating lymphocytes. Moreover, drug naïve patients with a worse cognitive outcome had a lower number of resting Treg and higher number of activated Treg. Furthermore, we found a correlation between pro-inflammatory peripheral immune phenotype and worse cognitive outcome in the ACE-R total and sub-items scores.ConclusionsIn our cohort of PD patients, cognitive impairment was associated with higher number of circulating lymphocytes, and – at least in drug naïve patients – with dysregulation of the Treg compartment. Further studies are needed to assess whether and to what extent peripheral immunity mechanistically contributes to cognitive decline in PD.     

Biological markers for anxiety disorders,OCD and PTSD – a consensus statement. Part I: Neuroimaging and genetics

Objectives: Biomarkers are defined as anatomical, biochemical or physiological traits that are specific to certain disorders or syndromes. The objective of this paper is to summarise the current knowledge of biomarkers for anxiety disorders, obsessive–compulsive disorder (OCD) and post-traumatic stress disorder (PTSD).

Methods: Findings in biomarker research were reviewed by a task force of international experts in the field, consisting of members of the World Federation of Societies for Biological Psychiatry Task Force on Biological Markers and of the European College of Neuropsychopharmacology Anxiety Disorders Research Network.

Results: The present article (Part I) summarises findings on potential biomarkers in neuroimaging studies, including structural brain morphology, functional magnetic resonance imaging and techniques for measuring metabolic changes, including positron emission tomography and others. Furthermore, this review reports on the clinical and molecular genetic findings of family, twin, linkage, association and genome-wide association studies. Part II of the review focuses on neurochemistry, neurophysiology and neurocognition.

Conclusions: Although at present, none of the putative biomarkers is sufficient and specific as a diagnostic tool, an abundance of high-quality research has accumulated that will improve our understanding of the neurobiological causes of anxiety disorders, OCD and PTSD.     

European clinical guidelines for Tourette syndrome and other tic disorders—version 2.0. Part I: assessment

In 2011 a working group of the European Society for the Study of Tourette Syndrome (ESSTS) has developed the first European assessment guidelines for Tourette syndrome (TS). Now, we present an updated version 2.0 of these European clinical guidelines for Tourette syndrome and other tic disorders, part I: assessment. Therefore, the available literature has been thoroughly screened, supplemented with national guidelines across countries and discussions among ESSTS experts. Diagnostic changes between DSM-IV and DSM-5 classifications were taken into account and new information has been added regarding differential diagnoses, with an emphasis on functional movement disorders in both children and adults. Further, recommendations regarding rating scales to evaluate tics, comorbidities, and neuropsychological status are provided. Finally, results from a recently performed survey among ESSTS members on assessment in TS are described. We acknowledge that the Yale Global Tic Severity Scale (YGTSS) is still the gold standard for assessing tics. Recommendations are provided for scales for the assessment of tics and psychiatric comorbidities in patients with TS not only in routine clinical practice, but also in the context of clinical research. Furthermore, assessments supporting the differential diagnosis process are given as well as tests to analyse cognitive abilities, emotional functions and motor skills.

     

Effect of IFN-ß therapy on the frequency and function of CD4+CD25+ regulatory T cells and Foxp3 gene expression in relapsing–remitting multiple sclerosis (RRMS): A preliminary study

Interferon-ß (IFN-ß) is an immunomodulatory drug of choice to control relapsing–remitting multiple sclerosis (RR-MS), although its function is still unclear. A reduced suppressive function of CD4⁺CD25⁺ regulatory T cells (T_reg) has been shown in RR-MS patients. In this study, to understand the effect of IFN-ß on CD4⁺CD25⁺ regulatory T cells, we analyzed the frequency and function of these cells and Foxp3 gene expression before and after treatment.We evaluated the frequency and function of CD4⁺CD25⁺Foxp3⁺ regulatory T cells by flow cytometry and co-culture inhibition test respectively and gene expression of Foxp3 by real-time PCR in a longitudinal follow-up study in 18 relapsing–remitting MS patients. Our data revealed that IFN-ß significantly improved frequency and suppressive function of T_reg cells (P < 0.05) without any significant effect on gene expression of Foxp3 after 6 months. The results of the present study indicate that IFN-ß therapy in some of patients with RR-MS may restore function of regulatory T cells and control the unchecked immune cascade activity. Larger longitudinal studies on more MS patients are required to confirm our findings.