Small vessel disease and biomarkers of endothelial dysfunction after ischaemic stroke

Abstract Introduction: Although pathogenesis of small vessel disease is poorly understood, increasing evidence suggests that endothelial dysfunction may have a relevant role in development and progression of small vessel disease. In this crosssectional study, we investigated the associations between imaging signs of small vessel disease and blood biomarkers of endothelial dysfunction at two different time points in a population of ischaemic stroke patients. Patients and methods: In stroke patients treated with intravenous thrombolysis, we analysed blood levels of von Willebrand factor, intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and vascular endothelial growth factor. Three reviewers independently assessed small vessel disease features using computed tomography. At baseline and 90 days after the index stroke, we tested the associations between single and combined small vessel disease features and levels of blood biomarkers using linear regression analysis adjusting for age, sex, hypertension, diabetes, smoke. Results: A total of 263 patients were available for the analysis. Mean age (SD) was 69 (13) years, 154 (59%) patients were male.We did not find any relation between small vessel disease and endothelial dysfunction at baseline. At 90 days, leukoaraiosis was independently associated with intercellular adhesionmolecule-1 (b¼0.21; p¼0.016) and vascular cell adhesionmolecule- 1 (b¼0.22; p¼0.009), and lacunes were associated with vascular endothelial growth factor levels (b¼0.21; p¼0.009) whereas global small vessel disease burden was associated with vascular endothelial growth factor (b¼0.26; p¼0.006). Discussion: Leukoaraiosis and lacunes were associated with endothelial dysfunction, which could play a key role in pathogenesis of small vessel disease

Unbalanced metalloproteinase-9 and tissue inhibitors of metalloproteinases ratios predict hemorrhagic transformation of lesion in ischemic stroke patients treated with thrombolysis: Results from the MAGIC study

Background Experimentally, metalloproteinases (MMPs) play a detrimental role related to severity of ischemic brain lesions. Both MMPs activity and function in tissues reflect the balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs). We aimed to evaluate the role of MMPs/TIMPs balance in the setting of rtPA treated stroke patients Methods Blood was taken before and 24-hours after rtPA from 327 patients (mean age 68 years, median NIHSS 11) with acute ischemic stroke. Delta median values of each MMP/TIMP ratio [(post rtPA MMP/TIMP-baseline MMP/TIMP)/(baseline MMP/TIMP)] were analyzed related to symptomatic intracranial hemorrhage (sICH) according to NINDS criteria, relevant hemorrhagic transformation (HT) defined as hemorrhagic infarction type 2 or any parenchimal hemorrhage, stroke subtypes (according to Oxfordshire Community Stroke Project) and 3-month death. The net effect of each MMP/TIMP ratio was estimated by a logistic regression model including major clinical determinants of outcomes Results Adjusting for major clinical determinants, only increase in MMP9/TIMP1 and MMP9/TIMP2 ratios remained significantly associated with sICH (odds ratio [95% confidence interval], 1.67 [1.17 – 2.38], p = 0.005; 1.74 [1.21 – 2.49], p=0.003 respectively). Only relative increase in MMP9/TIMP1 ratio proved significantly associated with relevant HT (odds ratio [95% confidence interval], 1.74 [1.17 – 2.57], p=0.006) with a trend towards significance for MMP9/TIMP2 ratio (p=0.007).Discussion Our data add substantial clinical evidence about the role of MMPs/TIMPs balance in rtPA treated stroke patients. These results may serve to generate hypotheses on MMPs inhibitors to be administered together with rtPA in order to counteract its deleterious effect

Evidence of the association of BIN1 and PICALM with the AD risk in contrasting European populations

Recent genome-wide association studies have identified five loci (BIN1, CLU, CR1, EXOC3L2 and PICALM) as genetic determinants of Alzheimer’s disease (AD). We attempted to confirm the association between these genes and the AD risk in three contrasting European populations (from Finland, Italy and Spain). Since CLU and CR1 had already been analyzed in these populations, we restricted our investigation to BIN1, EXO2CL3 and PICALM. In a total of 2,816 AD cases and 2,706 controls, we unambiguously replicated the association of rs744373 (for BIN1) and rs541458 (for PICALM) polymorphisms with the AD risk (OR=1.26, 95% CI [1.15-1.38], p=2.9x10-7, and OR=0.80, 95% CI [0.74-0.88], p=4.6x10-7, respectively). In a meta-analysis, rs597668 (EXOC3L2) was also associated with the AD risk, albeit to a lesser extent (OR=1.19, 95% CI [1.06-1.32], p=2.0x10-3). However, this signal did not appear to be independent of APOE. In conclusion, we confirmed that BIN1 and PICALM are genetic determinants of AD, whereas the potential involvement of EXOC3L2 requires further investigation

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10−5. We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10−17; including ADGC data, meta P = 5.0 × 10−21) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10−14; including ADGC data, meta P = 1.2 × 10−16) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10−4; including ADGC data, meta P = 8.6 × 10−9), CD33 (GERAD+, P = 2.2 × 10−4; including ADGC data, meta P = 1.6 × 10−9) and EPHA1 (GERAD+, P = 3.4 × 10−4; including ADGC data, meta P = 6.0 × 10−10)

Fostering the Aesthetic Pleasure: The Effect of Verbal Description on Aesthetic Appreciation of Ambiguous and Unambiguous Artworks

Background: Aesthetic experience begins through an intentional shift from automatic visual perceptual processing to an aesthetic state of mind that is evidently directed towards sensory experience. In the present study, we investigated whether portrait descriptions affect the aesthetic pleasure of both ambiguous (i.e., Arcimboldo’s portraits) and unambiguous portraits (i.e., Renaissance portraits). Method: A total sample of 86 participants were recruited and completed both a baseline and a retest session. In the retest session, we implemented a sample audio description for each portrait. The portraits were described by three types of treatment, namely global, local, and historical descriptions. Results: During the retest session, aesthetic pleasure was higher than the baseline. Both the local and the historical treatments improved the aesthetic appreciation of ambiguous portraits; instead, the global and the historical treatment improved aesthetic appreciation of Renaissance portraits during the retest session. Additionally, we found that the response times were slower in the retest session. Conclusion: taken together, these findings suggest that aesthetic preference was affected by the description of an artwork, likely due to a better knowledge of the painting, which prompts a more accurate (and slower) reading of the artwork

Translational Stroke Research Review: Using the Mouse to Model Human Futile Recanalization and Reperfusion Injury in Ischemic Brain Tissue

The approach to reperfusion therapies in stroke patients is rapidly evolving, but there is still no explanation why a substantial proportion of patients have a poor clinical prognosis despite successful flow restoration. This issue of futile recanalization is explained here by three clinical cases, which, despite complete recanalization, have very different outcomes. Preclinical research is particularly suited to characterize the highly dynamic changes in acute ischemic stroke and identify potential treatment targets useful for clinical translation. This review surveys the efforts taken so far to achieve mouse models capable of investigating the neurovascular underpinnings of futile recanalization. We highlight the translational potential of targeting tissue reperfusion in fully recanalized mouse models and of investigating the underlying pathophysiological mechanisms from subcellular to tissue scale. We suggest that stroke preclinical research should increasingly drive forward a continuous and circular dialogue with clinical research. When the preclinical and the clinical stroke research are consistent, translational success will follow

Blood markers of inflammation and endothelial dysfunction in cardioembolic stroke: systematic review and meta-analysis

<p><b>Context:</b> Various processes including inflammation and endothelial dysfunction have been implicated in the pathogenesis of cardioembolic (CE) strokes.</p> <p><b>Objective:</b> To review the evidence and investigate the association between immune-inflammatory biomarkers and CE strokes versus other stroke subtypes.</p> <p><b>Methods:</b> We systematically reviewed the literature (sources: MEDLINE, web-based register <a href="http://stroke-biomarkers.com" target="_blank">http://stroke-biomarkers.com</a>, reference lists) with quality assessment and meta-analysis of selected articles.</p> <p><b>Results:</b> The most consistent association was found between C-reactive protein (CRP) and CE strokes when compared to other stroke subtypes (standardized mean difference 0.223 (0.116, 0.343); <i>p</i> < 0.001)</p> <p><b>Conclusions:</b> Our findings confirm a possible association between selected inflammatory biomarkers and CE stroke.</p

Relevance of Prehospital Stroke Code Activation for Acute Treatment Measures in Stroke Care: A Review

Background: The use of emergency services with prehospital stroke assessment and early notification to the treatment hospital (stroke code) is a crucial determinant of delay time for acute stroke treatment. We reviewed and summarized the literature on prehospital stroke code system implementation. Methods: Two databases were explored (last update June 20, 2011) with 3 key words (stroke code, stroke prehospital management and stroke prehospital services). Inclusion criteria were: randomized and quasirandomized controlled trials, cohort and case-control studies, and hospital-and emergency-based registers, with no year or language restrictions. We examined the reference lists of all included articles. All potentially relevant reports and abstracts were transcribed into a specifically designed data abstraction form. Results: Only 19 of the 680 studies which were initially retrieved, published from 1999 to 2011, fulfilled our inclusion criteria. One clinical trial was identified. Large differences in stroke code procedures and study designs within and across countries prohibited the pooling of the data. Most studies were carried out in urban areas. Assuming the rate of tissue-plasminogen activator treatment as the performance measure, most studies report a significant increase in the rate of treatment (increase between 3.2 and 16%) with only 1 study not reporting any increase. Conclusions: Despite its limitations, this review suggests that the use of prehospital stroke code is an important intervention to improve the accessibility of the benefits of thrombolysis, especially when implemented together with educational campaigns to optimize the awareness and behavior of patients and bystanders. Copyright (C) 2012 S. Karger AG, Base

Analysis of Metabolite and Lipid Association Networks Reveals Molecular Mechanisms Associated with 3-Month Mortality and Poor Functional Outcomes in Patients with Acute Ischemic Stroke after Thrombolytic Treatment with Recombinant Tissue Plasminogen Activator

Here, we present an integrated multivariate, univariate, network reconstruction and differential analysis of metabolite-metabolite and metabolite-lipid association networks built from an array of 18 serum metabolites and 110 lipids identified and quantified through nuclear magnetic resonance spectroscopy in a cohort of 248 patients, of which 22 died and 82 developed a poor functional outcome within 3 months from acute ischemic stroke (AIS) treated with intravenous recombinant tissue plasminogen activator. We explored differences in metabolite and lipid connectivity of patients who did not develop a poor outcome and who survived the ischemic stroke from the related opposite conditions. We report statistically significant differences in the connectivity patterns of both low- and high-molecular-weight metabolites, implying underlying variations in the metabolic pathway involving leucine, glycine, glutamine, tyrosine, phenylalanine, citric, lactic, and acetic acids, ketone bodies, and different lipids, thus characterizing patients' outcomes. Our results evidence the promising and powerful role of the metabolite-metabolite and metabolite-lipid association networks in investigating molecular mechanisms underlying AIS patient's outcome