Combining nanotechnology with current biomedical knowledge for the vascular imaging and treatment of atherosclerosis.

Activation of vasa vasorum (the microvessels supplying the major arteries) at specific sites in the adventitia initiates their proliferation or 'angiogenesis' concomitant with development of atherosclerotic plaques. Haemorrhagic, leaky blood vessels from unstable plaques proliferate abnormally, are of relatively large calibre but are immature neovessels poorly invested with smooth muscle cells and possess structural weaknesses which may contribute to instability of the plaque by facilitation of inflammatory cell infiltration and haemorrhagic complications. Weak neovascular beds in plaque intima as well as activated adventitial blood vessels are potential targets for molecular imaging and targeted drug therapy, however, the majority of tested, currently available imaging and therapeutic agents have been unsuccessful because of their limited capacity to reach and remain stably within the target tissue or cells in vivo. Nanoparticle technology together with magnetic resonance imaging has allowed the possibility of imaging of neovessels in coronary or carotid plaques, and infusion of nanoparticle suspensions using infusion catheters or implant-based drug delivery represents a novel and potentially much more efficient option for treatment. This review will describe the importance of angiogenesis in mediation of plaque growth and development of plaque instability and go on to investigate the possibility of future design of superparamagnetic/perfluorocarbon-derived nanoparticles for imaging of the vasculature in this disease or which could be directed to the adventitial vasa vasorum or indeed intimal microvessels and which can release active payloads directed against primary key external mitogens and intracellular signalling molecules in endothelial cells responsible for their activation with a view to inhibition of angiogenesis.

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.

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.

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. METHODS: Forty consecutive patients with a first-ever acute LI, who presented a lacunar syndrome according to Miller-Fisher's classification were recruited and were classified into a group presenting isolated LI on MRI (n = 17) or multiple LI (n = 23). RESULTS: Despite equivalent demographic, clinical and cognitive characteristics, patients with multiple LI had increased ratings of WMH in frontal, occipital and subcortical regions. No significant correlations could be evidenced between the number of LI and WMH ratings. CONCLUSIONS: Present findings provide support to previous hypothesis considering single and multiple LI MRI presentations of lacunar infarct patients as distinct entities.

Apolipoprotein E epsilon 4 allele is associated with increased atrophy in progressive mild cognitive impairment: a voxel-based morphometric study.

BACKGROUND: The apolipoprotein E (APOE) epsilon4 allele is a risk factor for Alzheimer's disease. Earlier studies have shown differences in brain structure according to the APOE epsilon4 status. OBJECTIVE: To assess possible differences in brain structure according to the APOE epsilon4 status in mild cognitive impairment (MCI) subjects in relation to conversion to dementia. METHODS: In a follow-up study of 56 MCI subjects, 13 MCI subjects progressed to dementia (PMCI) during a mean follow-up time of 31 months. Brain structure differences in both stable MCI (SMCI) and PMCI epsilon4 carriers and noncarriers in the baseline MRI scan were assessed with voxel-based morphometry. RESULTS: The SMCI epsilon4 carriers had atrophy in the amygdala and hippocampus compared to the SMCI noncarriers. The PMCI epsilon4 carriers revealed atrophy of the left inferior frontal gyrus and parietal cortex compared to the PMCI noncarriers. CONCLUSION: The rate of brain atrophy in certain brain areas may be increased in epsilon4-positive MCI subjects progressing to dementia.

Alteraciones neuropsicológicas en los infartos cerebrales de tipo lacunar / Neuropsychological dysfunction associated to lacunar stroke

Introducción: Hasta el momento se han realizado múltiples trabajos sobre los infartos lacunares (ILs), su etiología y los factores de riesgo para padecerlos, pero se han realizado muy pocos sobre las secuelas neuropsicológicas que éstos pueden comportar. Objetivo: Correlacionar la topografía de los infartos lacunares con diferentes perfiles de afectación cognitiva, relacionando la clínica neurológica con los parámetros de resonáncia magnética (RM anatómica) y los hallazgos obtenidos mediante la administración de pruebas neuropsicológicas. Material y método: Los pacientes que formaron parte del estudio fueron 20 pacientes consecutivos que ingresaron en el Servicio de Neurología del Hospital Sagrat Cor de Barcelona, presentando un síndrome lacunar según la clasificación de Miller Fisher: hemiparesia motora pura, síndrome sensitivo puro, hemiparesiaataxia, disartria-mano torpe y síndrome sensitivo-motriz. De los sujetos seleccionados se obtuvieron imágenes de RM cerebral potenciadas en T1, FLAIR y en densidad protónica (DP) para distinguir entre los infartos lacunares agudos y los existentes con anterioridad al ingreso. Posteriormente, a todos los pacientes se les realizó una exploración neuropsicológica completa. Resultados y conclusiones: Los resultados hallados son los siguientes: a) no hay ningún grupo sindrómico que se caracterice por presentar una mayor o menor representación de infartos únicos o múltiples. b) la diferencia entre la proporción de casos que presentaban o no leucoaraiosis no fue significativa para ninguno de los grupos clinicos. c) hallamos una diferencia significativa en el rendimiento en el Test de orientación de líneas de Benton, en la que los sujetos que presentaban un síndrome de Disartria-mano torpe puntuaban mejor que los que tenían un Sd.Sensitivo puro. d) el rendimiento neuropsicológico de los sujetos con un único o múltiples ILs difería en las pruebas de fluencia fonética (PMR) y semántica (animales en 1 minuto), obteniendo mejores puntuaciones los sujetos con un único IL. e) los resultados hallados no mostraron diferencias significativas en cuanto al rendimiento neuropsicológico y la presencia/ausencia de leucoaraiosis. Estos resultados indican que los infartos lacunares, clásicamente considerados desde una perspectiva neurológica «silente», se pueden asociar a una disfunción neuropsicológica significativa. En estudios posteriores se podría investigar si los pacientes que presentan una disfunción cognitiva causada por infartos lacunares, tienen un mayor riesgo de desarrollar demencia, particularmente de tipo vascularsubcortical (AU)

Introduction: A number of investigations have been developed to date, to study the causes and risk factors leading to lacunar infarcts. However only few works were addressed to investigate the neuropsychological correlates of these cerebrovascular lesions. Objective: To correlate lacunar infarct topography with distinct patterns of cognitive dysfunction relating clinic aspects with magnetic resonance parameters and neuropsychological assessment. Methods: Twenty consecutive patients from the Neurology Service at the Sagrat Cor Hospital in Barcelona were included in the study. Al patients were diagnosed as presenting a lacunar syndrome according to Miller’s and Fisher’s classification: pure motor hemiparesis, pure sensitive syndrome, ataxia-hemiparesia, disartria-clumsy hand and sensitive-motor syndrome. Structural magnetic resonance images were acquired from all cases using T1 weighted, FLAIR and proton density (PD) sequences to distinguish between acute and chronic lacunar infarcts. Finally, all patients were assessed by means of an exhaustive neuropsychological battery. Results and conclusions: The following results were obtained: a) any syndrome group is characterized by presenting increased or reduced severity of lacunar infarcts, b) similarly, clinical groups did not differ in the amount of white matter damage as reflected by the presence of leuko-araiosis. C) Significant differences were found on the Benton’s Line Orientation Test where patients with a disartriaclumsy hand syndrome exhibited better performance as compared to patients with pure sensitive syndrome. D) Significant differences were found in category and phonetic fluency tests between patients presenting with a single lacunar infarct and multiple infarct patients. E) Leuko-araiosis was not related to cognitive performance among patients. Present results indicate that lacunar infarcts, classically considered as ‘silent’ from a neurological perspective, may associate with significant neuropsychological dysfunction. Future studies should investigate whether patients exhibiting cognitive impairment caused by lacunar infarcts are at increased risk for developing dementia, particularly of a subcortical vascular type (AU)