Marta Grau-Olivares

C-reactive protein exerts angiogenic effects on vascular endothelial cells and modulates associated signalling pathways and gene expression

BackgroundFormation of haemorrhagic neovessels in the intima of developing atherosclerotic plaques is thought to significantly contribute to plaque instability resulting in thrombosis. C-reactive protein (CRP) is an acute phase reactant whose expression in the vascular wall, in particular, in reactive plaque regions, and circulating levels increase in patients at high risk of cardiovascular events. Although CRP is known to induce a pro-inflammatory phenotype in endothelial cells (EC) a direct role on modulation of angiogenesis has not been established.ResultsHere, we show that CRP is a powerful inducer of angiogenesis in bovine aortic EC (BAEC) and human coronary artery EC (HCAEC). CRP, at concentrations corresponding to moderate/high risk (1–5 μg/ml), induced a significant increase in proliferation, migration and tube-like structure formation in vitro and stimulated blood vessel formation in the chick chorioallantoic membrane assay (CAM). CRP treated with detoxi-gel columns retained such effects. Western blotting showed that CRP increased activation of early response kinase-1/2 (ERK1/2), a key protein involved in EC mitogenesis. Furthermore, using TaqMan Low-density Arrays we identified key pro-angiogenic genes induced by CRP among them were vascular endothelial cell growth factor receptor-2 (VEGFR2/KDR), platelet-derived growth factor (PDGF-BB), notch family transcription factors (Notch1 and Notch3), cysteine-rich angiogenic inducer 61 (CYR61/CCN1) and inhibitor of DNA binding/differentiation-1 (ID1).ConclusionThis data suggests a role for CRP in direct stimulation of angiogenesis and therefore may be a mediator of neovessel formation in the intima of vulnerable plaques.

Neuropsychological abnormalities associated with lacunar infarction

The objective of this study was to assess neuropsychological abnormalities in 40 patients with lacunar infarction. Topography of infarction, presence of isolated or multiple silent infarcts and white matter hyperintensities were correlated with results of neuropsychological tests and subtypes of lacunar infarction. Patients were studied within 1 month after stroke. A total of 21 patients were males and the mean age was 70.7 years; 30% had a single infarction (mean number of infarctions was 3.4). Twelve patients had pure motor hemiparesis, 9 pure sensory stroke, 8 dysarthria-clumsy hand/ataxic hemiparesis, 8 atypical lacunar syndrome, and 3 sensorimotor stroke. The mean score of the Mini-Mental State Examination was 28.4. Mild cognitive impairment of subcortical vascular features occurred in 23 patients and isolated executive disturbances in 4. Neuropsychological results showed that patients with atypical lacunar syndrome followed by pure motor hemiparesis showed significantly more cognitive executive disturbances. Patients with dysarthria-clumsy hand/ataxic hemiparesis accounted for the best scores in some tests of visuoconstructive function and visual memory. In summary, mild neuropsychological disturbances (57.5%) are not infrequent in acute lacunar infarcts especially in patients with atypical lacunar syndrome and pure motor hemiparesis. Neuropsychological impairment should be considered as common clinical feature in acute lacunar infarction.

Mild Cognitive Impairment after Lacunar Infarction: Voxel-Based Morphometry and Neuropsychological Assessment

Background: The aim of the present study was to investigate whether there were differences in neuroradiological features, including white-matter lesions and gray-matter volumes, between patients with lacunar infarction with and without mild cognitive impairment of the vascular type (MCI-V). Methods: A total of 40 patients with lacunar infarction were studied within 1 month after stroke. Results: MCI-V was found in 22 patients, who in comparison with patients without cognitive impairment were significantly older and had fewer years of formal education. MRI subcortical hyperintensities especially in the basal ganglia (putamen and thalamus) were significantly more frequent in the MCI-V group. In the voxel-based morphometric study, patients with MCI-V showed more atrophy bilaterally in the middle temporal gyrus, right and left frontal and posterior bilateral occipitoparietal regions including the posterior cingulate as well as in the cerebellum. A region of interest analysis restricted to the parahippocampi and hippocampi showed further reduced bilateral parahippocampal gyrus and right hippocampus volume reductions in this group of patients. Finally, the amount of white-matter lesions among MCI-V showed negative correlations with gray-matter volume in frontal and temporal areas as well as with the thalamus and mesencephalon. Conclusions: The present findings provide support for an anatomical substrate of the MCI entity in patients with lacunar infarction. Both gray- and white-matter changes seem to contribute to the cognitive impairment of such patients.

Mild cognitive impairment in stroke patients with ischemic cerebral small-vessel disease: a forerunner of vascular dementia?

Ischemic cerebral small-vessel disease accounts for a third of acute cerebral ischemic events and contributes to the development of cognitive decline and dementia. Cerebral small-vessel disease can be visualized on MRI studies as lacunar infarcts, white matter lesions and cerebral microbleeds. In general, the short-term prognosis of ischemic cerebral small-vessel disease compared with other stroke subtypes is more favorable, with almost negligible early mortality, absence of neuropsychological impairment and excellent neurological recovery. However, it has been shown recently that the proportion of dementia caused by small-vessel disease ranges from 36 to 67%. On the other hand, patients with a first-ever lacunar infarction present with cognitive impairment (mainly executive dysfunction) in more than half of cases and more than 55% of patients fulfil the criteria of mild cognitive impairment of the vascular type. Moreover, patients with small-vessel disease have an increase in the mid- and long-term risk of death, stroke recurrence and dementia. Neuropsychological abnormalities in small-vessel disease occurred more frequently than previously recognized. Ischemic cerebral small-vessel disease should be regarded as a potentially severe condition prodrome of subcortical vascular dementia rather than a relatively benign disorder.

Progressive Gray Matter Atrophy in Lacunar Patients with Vascular Mild Cognitive Impairment

Background and Method: We investigated the progression of cognitive and cerebral changes in 30 patients with a first-ever lacunar infarct (LI): 15 with vascular mild cognitive impairment (MCI-V) and 15 without cognitive impairment. All cases were followed up 18 ± 6 months after the stroke and underwent neurological, neuropsychological and MRI assessments at baseline and longitudinally. Results: Differences in the changes in cognitive function over time were observed between the 2 groups, with the MCI-V patients showing slight memory improvements and frontal-lobe-related test impairments from baseline to follow-up evaluations. At baseline, the 2 groups presented similar white matter hyperintensity (WMH) ratings and whole brain gray matter (GM) volumes, and at the follow-up evaluations, both groups had increased WMH lesions and decreased GM volumes; no statistical differences between groups were found. In contrast, a voxel-based morphometry analysis revealed that only MCI-V patients presented clear regional GM volume losses between the first and the second evaluations in cortical (frontal and temporal) and subcortical (pons, cerebellum and caudate) regions. Conclusion: Frontal lobe dysfunction and regional cortical and subcortical GM atrophy best differentiate the clinical course of LI patients with and without cognitive impairment.

New VEGF antagonists as possible therapeutic agents in vascular disease

Background: In this review we provide the reader with an analysis of the importance of VEGF in modulating the angiogenic process in vascular diseases. Objectives: We have described the key role of VEGF in the development of the major angiogenic diseases including ocular retinopathies, solid tumour growth and atherosclerotic plaque development. Methods: Following a brief description of the disease, a detailed literature review of the mechanisms through which VEGF induces promotion of neovascularisation and current anti-VEGF therapies is provided for the reader. Results/conclusions: Current and future potential clinical therapies are discussed in particular concerning our thoughts on future directives involving adenoviral-mediated gene targeting, nanotechnology and combinational therapies.

Clinical Implications of Headache in Lacunar Stroke: Relevance of Site of Infarct

Objective.—To assess whether the infarction topography influenced upon the incidence of headache and the likelihood of neurological recovery in lacunar infarction.

B-cell translocation gene 2 is over-expressed in peri-infarct neurons after ischaemic stroke.

Objectives: Recovery from stroke is dependent on the survival of neurons in the dynamic peri-infarcted region. Although several markers of neuronal injury and apoptotic cell death have been described, administration of neuroprotective drugs directed at specific molecules has had limited success. A complete understanding of deregulated genes associated with neuronal death would be beneficial. Our previous microarray studies identified increased expression of a novel protein, the B-cell translocation gene 2 (BTG2), in infarcted regions. Methods: We have used immunohistochemistry and Western blotting to examine the expression and localization of BTG2 in stroked brain tissue and immunofluorescent staining of human fetal brain neurons to determine if oxygen-glucose deprivation affected its expression. Results: We show that BTG2 is strongly expressed in peri-infarcted and infarcted regions of brain tissue, localizing in neuronal nuclei and cytoplasm, whilst being absent or very weakly expressed in normal looking contralateral tissue. Exposure of human fetal brain neurons to oxygen-glucose deprivation also induced BTG2 expression in the cytoplasm and perinuclear regions of cells staining positive for propidium iodide (a marker of nuclear damage). Conclusions: BTG2 may be a modulator of cell survival and differentiation and could help to protect against cell death by inhibition of necrosis and/or apoptotic signalling pathways.

Higher severity of frontal periventricular white matter and basal ganglia hyperintensities in first-ever lacunar stroke with multiple silent lacunes

Background and purpose:  We investigated whether patients with a lacunar infarct (LI) syndrome exhibiting unique LI or multiple LI on magnetic resonance imaging (MRI) examinations differed in terms of topography and severity of white matter hyperintensities (WMH) ratings.

Variaciones en el perfil clínico y pronóstico de las hemorragias intracerebrales no traumáticas (1986-2004)

BACKGROUND AND OBJECTIVES Cardiovascular risk factors, clinical features and early outcome of first-ever primary intracerebral haemorrhage (PIH) from 1986 to 2004 using the Sagrat Cor Hospital of Barcelona Stroke Registry were assessed, and compared with data from patients with first-ever ischemic stroke. PATIENTS AND METHODS The study population consisted of 380 patients with PIH and 2,082 patients with ischemic stroke. Secular trends for the periods 1986-1992, 1993-1998 and 1999-2004 were analyzed. RESULTS Age increased significantly (P<.001) throughout the 3 study periods and there was a significant increase in the percentage of patients with atrial fibrillation, chronic obstructive pulmonary disease (COPD) and lobar topography. The use of brain magnetic resonance imaging (MRI) also increased significantly throughout the study periods. In comparison with ischemic stroke in-hospital death was more frequent (28,2 vs. 12%) and lacunar syndrome (9,5 vs. 31,4%) and symptom-free patients at discharge were less frequent in the intracerebral haemorrhage group (6,1 vs. 18,3%). CONCLUSIONS Significant changes over a 19-year period included an increase in the patients age, frequency of COPD and atrial fibrillation and use of MRI imaging studies. PIH is a severe subtype of stroke with a higher risk of early death and lower asymptomatic frequency at discharge than ischemic cerebral infarct.