GRECOS Project (Genotyping Recurrence Risk of Stroke): The Use of Genetics to Predict the Vascular Recurrence After Stroke.

BACKGROUND AND PURPOSE: Vascular recurrence occurs in 11% of patients during the first year after ischemic stroke (IS) or transient ischemic attack. Clinical scores do not predict the whole vascular recurrence risk; therefore, we aimed to find genetic variants associated with recurrence that might improve the clinical predictive models in IS. METHODS: We analyzed 256 polymorphisms from 115 candidate genes in 3 patient cohorts comprising 4482 IS or transient ischemic attack patients. The discovery cohort was prospectively recruited and included 1494 patients, 6.2% of them developed a new IS during the first year of follow-up. Replication analysis was performed in 2988 patients using SNPlex or HumanOmni1-Quad technology. We generated a predictive model using Cox regression (GRECOS score [Genotyping Reurrence Risk of Stroke]) and generated risk groups using a classification tree method. RESULTS: The analyses revealed that rs1800801 in the MGP gene (hazard ratio, 1.33; P=9×10-03), a gene related to artery calcification, was associated with new IS during the first year of follow-up. This polymorphism was replicated in a Spanish cohort (n=1.305); however, it was not significantly associated in a North American cohort (n=1.683). The GRECOS score predicted new IS (P=3.2×10-09) and could classify patients, from low risk of stroke recurrence (1.9%) to high risk (12.6%). Moreover, the addition of genetic risk factors to the GRECOS score improves the prediction compared with previous Stroke Prognosis Instrument-II score (P=0.03). CONCLUSIONS: The use of genetics could be useful to estimate vascular recurrence risk after IS. Genetic variability in the MGP gene was associated with vascular recurrence in the Spanish population.

Variaciones en el perfil clínico y pronóstico de las hemorragias intracerebrales no traumáticas (1986-2004) / Trends in risk factors, clinical characteristics and prognosis in primary intracerebral haemorrhage (1986-2004)

Fundamento y objetivo: Analizar las variaciones de los factores de riesgo y el perfil clínico de las hemorragias intracerebrales no traumáticas (HIC) entre 1986 y 2004 a partir del registro de ictus del Hospital del Sagrat Cor, y comparar los datos de las HIC con los de los infartos cerebrales. Pacientes y método: Estudio hospitalario de 380 pacientes consecutivos con HIC y 2.082 pacientes con infarto cerebral. Se efectúa un análisis comparativo de las tendencias y variaciones clínicas observadas entre los períodos 1986-1992, 1993-1998 y 1999-2004. Resultados: La edad se incrementó significativamente (p < 0,001) durante los 3 períodos de estudio y se observó un aumento significativo en la frecuencia de fibrilación auricular, enfermedad pulmonar obstructiva crónica (EPOC) y de topografía cerebral lobular. El uso de la resonancia magnética (RM) cerebral también aumentó de forma significativa a través del período de estudio. En comparación con los infartos cerebrales, en las HIC fue más frecuente la mortalidad hospitalaria (28,2 frente al 12%) y menos habituales la presencia de un síndrome lacunar (9,5 frente al 31,4%) y la ausencia de sintomatología neurológica al alta hospitalaria (6,1 frente al 18,3%). Conclusiones: Se observan variaciones clínicas significativas durante dicho período de tiempo de 19 años, con un incremento en la edad de presentación, en la frecuencia de fibrilación auricular y EPOC y en el uso de la RM cerebral. La HIC constituye un subtipo de ictus grave con una mayor mortalidad precoz y una menor frecuencia de ausencia de sintomatología al alta hospitalaria en comparación con los infartos cerebrales (AU)

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 patient's 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 (AU)

[Trends in risk factors, clinical characteristics and prognosis in primary intracerebral haemorrhage (1986-2004)]. / 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 patient's 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.

Cognitive profile in patients with a first-ever lacunar infarct with and without silent lacunes: a comparative study.

BACKGROUND: The detection of early neuropsychological abnormalities as precursors of cognitive decline of vascular origin in patients with lacunar stroke is a subject of increasing interest. The objective of this study was to assess whether there were differences in the performance of a battery of neuropsychological tests in first-ever lacunar stroke patients with and without associated silent multiple lacunar infarctions found incidentally on the brain magnetic resonance imaging (MRI) scan. METHODS: A total of 72 consecutive patients with first-ever lacunar infarction were studied 1 month after stroke. All patients underwent a comprehensive neuropsychological evaluation, which included the California Verbal Learning Test (CVLT), Phonetic Verbal Fluency Test (PMR), Semantic Verbal Fluency Test (category "animals"), Digit Span Forward and Backward from the Wechsler Adult Intelligence Scale (WAIS-III), and Mini-Mental State Examination (MMSE). RESULTS: A total of 38 patients (52.7%) had silent multiple lacunar infarcts, with corona radiata as the most frequent topography (P < 0.023). White matter hyperintensities (leukoaraiosis) were observed in 81.1% of patients with silent multiple lacunar infarcts and in 50% with a single lacunar infarction (P < 0.007). Patients in both groups showed similar scores in the MMSE, but those with associated silent lacunar infarctions showed a poorer performance in the semantic fluency test (P < 0.008) and in short delayed verbal memory (P < 0.001). In both cases, however, leukoaraiosis was not statistically significant in multivariate linear regression models adjusted by confounding covariates. In these models, multiple silent lacunar infarctions and education were independent predictors of poor performance in the semantic fluency test and in short delayed verbal memory. CONCLUSIONS: The presence of silent multiple lacunar infarctions documented on brain MRI scans in patients with first-ever lacunar stroke was associated with mild neuropsychological abnormalities, particularly in the performance of executive functions (semantic fluency) and short delayed verbal memory. According to these findings, in the initial stages of small vessel disease, mild neuropsychological abnormalities appear to be related to lacunes rather than to leukoaraiosis or perivascular hyperintensities of vascular cause.

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.

Therapeutic applications of hyaluronan.

Hyaluronan (HA), a multifunctional, high molecular weight glycosaminoglycan, is a component of the majority of extracellular matrices. HA is synthesised in a unique manner by a family of hyaluronan synthases, degraded by hyaluronidases and exerts a biological effect by binding to families of cellular receptors, the hyaladhedrins. Receptor binding activates signal pathways in endothelial cells leading to proliferation, migration and differentiation collectively termed angiogenesis. HA and associated enzymes are implicated in the aetiology of cardiovascular disease and cancer and manipulation of HA expression offers a therapeutic target. HA microspheres have been developed as drug delivery agents to deliver HA to sites of disease and also in diagnosis. In this review we discuss some of the recent therapeutic applications of hyaluronan in tissue repair, as a drug delivery system and the synthesis, application and delivery of hyaluronan nanoparticles to target drugs to sites of disease.

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.

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

BACKGROUND: Formation 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. RESULTS: Here, 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 microg/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). CONCLUSION: This 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.

Voxel-based morphometry to detect brain atrophy in progressive mild cognitive impairment.

Recent research has shown an increased rate of conversion to dementia in subjects with mild cognitive impairment (MCI) compared to controls. However, there are no specific methods to predict who will later develop dementia. In the present study, 22 controls and 56 MCI subjects were followed on average for 37 months (max. 60 months) and studied with magnetic resonance imaging (MRI) at baseline to assess changes in brain structure associated to later progression to dementia. Voxel-based morphometry (VBM) was used to investigate gray matter atrophy. During the follow-up, 13 subjects progressed to dementia. At baseline, no differences were detected in age or education between the control and MCI subjects, but they differed by several neuropsychological tests. The stable and progressive MCI subjects differed only by CDR sum of boxes scores and delayed verbal recall, which were also significant predictors of conversion to dementia. At the baseline imaging, the MCI subjects showed reduced gray matter density in medial temporal, temporoparietal as well as in frontal cortical areas compared to controls. Interestingly, the progressive MCI subjects showed atrophy in the left temporoparietal and posterior cingulate cortices and in the precuneus bilaterally, and a trend for hippocampal atrophy when compared to the stable MCI subjects. We conclude that widespread cortical atrophy is present already two and a half years before a clinical diagnosis of dementia can be set.

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.

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. BACKGROUND: The relationship between topography of infarction and the incidence of headache as well as the influence of headache on neurological outcome in patients with lacunar stroke are still unclear. METHODS: In a cohort of 387 patients with neuroimaging-proven acute lacunar infarction collected from a prospective hospital-based stroke registry over a 12-year period, 43 patients (11.1%) presented with headache within a 72-hour interval of stroke onset. RESULTS: Headache was more common in deep brain gray matter or brainstem lacunar infarction than in supratentorial white matter lacunar infarction (14.9% vs 8%, P < .033), but lacunar infarctions in the supratentorial white matter had less frequently absence of limitation at discharge (15.1% vs 25.1%, P < .013). In deep brain gray matter or brainstem lacunar infarction, early neurological recovery decreased from 26.2% to 19.2% when headache was present at stroke onset. In the multivariate analysis, dysarthria-clumsy hand and absence of headache in deep brain gray matter or brainstem lacunar infarction were independent predictors of favorable outcome. CONCLUSIONS: In patients with lacunar infarction, headache at stroke onset was more common in deep brain gray matter or brainstem topographies than in supratentorial white matter lesions. In deep brain gray matter or brainstem lacunar infarctions, early neurological recovery was less likely when headache was present.