RESUMO
BACKGROUND AND PURPOSE: The Coronary Artery Disease Genome-Wide Replication and Meta-Analysis Study (CARDIoGRAM) reported 25 single-nucleotide polymorphisms (SNPs) on 15 chromosomes to be associated with coronary artery disease (CAD) risk. Because common vascular risk factors are shared between CAD and ischaemic stroke (IS), these SNPs may also be related to IS overall or one or more of its pathogenetic subtypes. METHODS: We performed a candidate gene study comprising 3986 patients with IS and 2459 control subjects. The 25 CAD-associated SNPs reported by CARDIoGRAM were examined by allelic association analysis including logistic regression. Weighted and unweighted genetic risk scores (GRSs) were also compiled and likewise analysed against IS. We furthermore considered the IS main subtypes large-vessel disease (LVD), small-vessel disease and cardioembolic stroke [according to Trial of Org 10172 in Acute Stroke Treatment (TOAST)] separately. RESULTS: SNP rs4977574 on chromosome 9p21.3 was associated with overall IS [odds ratio (OR) = 1.12; 95% confidence interval (CI): 1.04-1.20; P = 0.002] as well as LVD (OR = 1.36; 95% CI: 1.13-1.64; P = 0.001). No other SNP was significantly associated with IS or any of its main subtypes. Analogously, the GRSs did not show any noticeable effect. CONCLUSIONS: Besides the previously reported association with SNPs on chromosome 9p21, this study did not detect any significant association between IS and CAD-susceptible genetic variants. Also, GRSs compiled from these variants did not predict IS or any pathogenetic IS subtype, despite a total sample size of 6445 participants.
Assuntos
Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença da Artéria Coronariana/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto JovemRESUMO
Expression of p75 neurotrophin receptor and survival of medium-sized spiny projection neurons and cholinergic interneurons in the rat striatum were studied using immunocytochemistry at different times after transient, unilateral middle cerebral artery occlusion. Thirty minutes of middle cerebral artery occlusion caused a major loss of projection neurons, identified by their immunoreactivity to dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein with a molecular weight of 32,000, in the lateral part of the striatum, as observed at 48 h following the insult with no further change at one week. In contrast, no reduction of the number of choline acetyltransferase-positive, cholinergic interneurons, which also expressed TrkA, was detected at either time-point. At 48 h following middle cerebral artery occlusion, expression of p75 neurotrophin receptor was observed in striatal cells which, by the use of double-label immunostaining, were identified as the cholinergic interneurons. No p75 neurotrophin receptor immunoreactivity remained in cholinergic cells after one week of reperfusion. Based on current hypotheses regarding the function of the p75 neurotrophin receptor, the transient expression of this receptor in striatal cholinergic interneurons might contribute to their high resistance to ischemic neuronal death. However, the expression of p75 neurotrophin receptor could also be a first step in a pathway leading to apoptosis, which is inhibited after the present insult due to concomitant activation of TrkA.
Assuntos
Isquemia Encefálica/metabolismo , Neostriado/metabolismo , Neurônios/metabolismo , Sistema Nervoso Parassimpático/metabolismo , Fosfoproteínas , Receptores de Fator de Crescimento Neural/biossíntese , Animais , Pressão Sanguínea/fisiologia , Artérias Cerebrais/fisiologia , Colina O-Acetiltransferase/biossíntese , Fosfoproteína 32 Regulada por cAMP e Dopamina , Imuno-Histoquímica , Interneurônios/metabolismo , Masculino , Neostriado/citologia , Proteínas do Tecido Nervoso/biossíntese , Sistema Nervoso Parassimpático/citologia , Proteínas Proto-Oncogênicas/biossíntese , Ratos , Ratos Wistar , Receptores Proteína Tirosina Quinases/biossíntese , Receptor de Fator de Crescimento Neural , Receptor trkA , Ácido gama-Aminobutírico/fisiologiaRESUMO
SUMMARY: Reduction of the cerebral perfusion pressure caused by vessel occlusion or stenosis is a cause of neurological symptoms and border-zone infarctions. The aim of this article is to describe perfusion patterns in hemodynamic stroke, to give a practical approach for the assessment of colour encoded CT- and MR-perfusion maps and to demonstrate the clinical use of comprehensive imaging in the workup of patients with hemodynamic stroke. Five patients with different duration cause and degree of hemodynamic stroke were selected. The patients shared the typical presentation with fluctuating and transient symptoms. All were examined by MR or CT angiography and MR or CT perfusion in the symptomatic phase. All patients were examined with diffusion weighted imaging. All five cases showed the altered perfusion patterns of hemodynamic insufficiency with a slight or marked increase in CBV in the supply area of the affected vessel and only slightly reduced or maintained CBF. The perfusion disturbances were most easily detected on the MTT maps. Border-zone infarctions were seen in all cases. The typical pattern for hemodynamic insufficiency is characterized by increased CBV, normal or decreased CBF and prolonged MTT in the affected areas. The increased CBV is the hallmark of stressed autoregulation. Reading the color-encoded perfusion maps enables a quick and robust assessment of the cerebral perfusion and its characteristic patterns. Internal border-zone infarctions can be regarded as a marker for hemodynamic insufficiency. Finding of the typical rosary-like pattern of DWI lesions should call for further work up.
RESUMO
The survival of different neuron types and the expression of the p75 neurotrophin receptor (p75(NTR)) after focal cerebral ischemia were studied in the mouse striatum using immunocytochemical and histochemical techniques and stereological procedures. As assessed at 1 week after 30 min of middle cerebral artery occlusion, the order of vulnerability was projection neurons > parvalbumin-expressing interneurons > nitric oxide synthase-containing interneurons > cholinergic interneurons. Within the ischemic lesion, projection neurons were almost completely lost whereas cholinergic interneurons were spared. Calretinin-immunoreactive interneurons also seemed resistant to the insult. Expression of p75(NTR) was induced in cholinergic interneurons within the lesioned area, raising the possibility of a protective action. However, the number of cholinergic interneurons was unaffected in p75(NTR) knockout mice subjected to the same ischemic insult. These quantitative data demonstrate that striatal neurons in the mouse are differentially susceptible to ischemic damage and argue against a significant role of p75(NTR) for the high resistance of cholinergic interneurons.
Assuntos
Corpo Estriado/metabolismo , Ataque Isquêmico Transitório/genética , Neurônios/metabolismo , Receptores de Fator de Crescimento Neural/genética , Acidente Vascular Cerebral/genética , Regulação para Cima , Animais , Calbindina 2 , Corpo Estriado/patologia , Lateralidade Funcional , Regulação da Expressão Gênica , Humanos , Interneurônios/metabolismo , Interneurônios/patologia , Ataque Isquêmico Transitório/metabolismo , Ataque Isquêmico Transitório/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Artéria Cerebral Média , Neurônios/patologia , Óxido Nítrico Sintase/metabolismo , Parvalbuminas/análise , Receptor de Fator de Crescimento Neural , Receptores de Fator de Crescimento Neural/deficiência , Receptores de Fator de Crescimento Neural/fisiologia , Proteína G de Ligação ao Cálcio S100/análise , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologiaRESUMO
Cellular localization and tissue levels of BDNF protein were studied using immunocytochemistry and enzyme immunoassay, respectively, in the cortex and striatum at different reperfusion times (0-24 h) after 2 h of unilateral middle cerebral artery occlusion (MCAO) in rats. The distribution of neuronal injury was analyzed in NeuN-, cresyl violet-, and Fluoro-Jade-stained sections. At 2 h postischemia, but not at later time points, there was a several-fold increase of the number of BDNF-immunoreactive (-ir) cells in the ipsilateral cingulate and frontal cortices outside the damaged area. Animals with cortical injury showed loss of BDNF-ir fibers in the striatum at 2-24 h, whereas rats with cell damage confined to the striatum exhibited no such change. At 2-16 h, strongly BDNF-ir fibers were observed along the myelinated fascicles medially in the striatum, in the anterior commissure, and in the corpus callosum ipsilateral to the MCAO. BDNF protein levels were increased (by 133-213%) at 2 h in the cingulate and frontal cortices and decreased (by 40%) at 24 h in the striatum. These findings show that the increased expression of BDNF mRNA in cortical neurons previously demonstrated after transient focal ischemia is accompanied by elevated levels of BDNF protein. The rapid decline of BDNF protein levels suggests a pronounced release or anterograde axonal transport in the postischemic phase. The reduction of BDNF protein in the striatum of animals with cortical damage provides further evidence for anterograde transport, which is also supported by the accumulation of BDNF protein in several preterminal fiber systems. The changes of BDNF protein after focal ischemia could play a role for survival and plasticity of cortical and striatal neurons.
Assuntos
Transporte Axonal/fisiologia , Isquemia Encefálica/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Córtex Cerebral/metabolismo , Corpo Estriado/metabolismo , Animais , Arteriopatias Oclusivas/metabolismo , Glicemia , Pressão Sanguínea , Fator Neurotrófico Derivado do Encéfalo/análise , Dióxido de Carbono/sangue , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/citologia , Corpo Estriado/irrigação sanguínea , Corpo Estriado/citologia , Lobo Frontal/irrigação sanguínea , Lobo Frontal/citologia , Lobo Frontal/metabolismo , Giro do Cíngulo/irrigação sanguínea , Giro do Cíngulo/citologia , Giro do Cíngulo/metabolismo , Concentração de Íons de Hidrogênio , Técnicas Imunoenzimáticas , Masculino , Neurônios Aferentes/química , Neurônios Aferentes/metabolismo , Oxigênio/sangue , Lobo Parietal/irrigação sanguínea , Lobo Parietal/citologia , Lobo Parietal/metabolismo , Ratos , Ratos WistarRESUMO
The objective of the present study was to explore whether grafted immortalized neural stem cells, genetically modified to secrete nerve growth factor (NGF), can ameliorate neuronal death in the adult rat striatum following transient middle cerebral artery occlusion (MCAO). One week after cell implantation in the striatum, animals were subjected to 30 min of MCAO. Striatal damage was evaluated at the cellular level after 48 h of recirculation using immunocytochemical and stereological techniques. The ischaemic insult caused an extensive degeneration of projection neurons, immunoreactive for dopamine- and adenosine 3': 5'-monophosphate-regulated phosphoprotein with a molecular weight of 32 kilodaltons (DARPP-32). 3H-Thymidine autoradiography demonstrated surviving grafted cells in the lesioned striatum in all transplanted rats. The loss of striatal projection neurons was significantly reduced (by an average of 45%) in animals with NGF-secreting grafts, whereas control cells, not producing NGF, had no effect. The neuroprotective action of NGF-secreting grafts was also observed when the total number of striatal neurons immunopositive for the neuronal marker NeuN was quantified, as well as in cresyl violet-stained sections. The present findings indicate that administration of NGF by ex vivo gene transfer and grafting of neural stem cells can ameliorate death of striatal projection neurons caused by transient focal ischaemia.