UMLS:C0038454 - FACTA Search

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Query: UMLS:C0038454 (stroke)
147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism linking the APOE4 gene with increased susceptibility for Alzheimer's disease (AD) and poorer outcomes following closed head injury and stroke is unknown. One potential link is activation of the innate immune system in the CNS. Our previously published data demonstrated that apolipoprotein E regulates production of nitric oxide, a critical cytoactive factor released by immune active macrophages. To determine if immune regulation is different in the presence of apolipoprotein E4 compared to apolipoprotein E3, we have measured NO production by peritoneal and CNS macrophages (microglia) cultured from transgenic mice that only express the human apoE4 or apoE3 protein isoform. Significantly more NO was produced in APOE4 mice compared to APOE3 transgenic mice that only express human apoE3 protein. Similarly, monocyte derived macrophages from humans carrying APOE4 gene alleles also produce significantly greater NO than those individuals with APOE3. The mechanism for this isoform-specific difference in NO production is not known and multiple sites in the NO production pathway may be affected. Expression of inducible nitric oxide synthase (iNOS) mRNA and protein are not significantly different between the APOE3 and APOE4 mice, suggesting that induction of iNOS is not a primary cause of the increased NO production in APOE4 animals. One alternative regulatory mechanism that demonstrates isoform specificity is arginine transport, which is greater in microglia from APOE4 transgenic mice compared to microglia from APOE3 mice. Increased transport is consistent with an increased production of NO and may reflect a direct or indirect effect of the APOE genotype on microglial arginine uptake and microglial activation in general. Overall, greater NO production in APOE4 carriers where characteristically high levels of oxidative/nitrosative stress are found in diseases such as AD provides a mechanism that potentially explains the genetic association between APOE4 and human diseases.
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PMID:APOE and the regulation of microglial nitric oxide production: a link between genetic risk and oxidative stress. 1239 81

We aimed to assess whether the effectiveness of statins in the prevention of myocardial infarction, stroke and total mortality is influenced by apolipoprotein E (apoE) genotype in an elderly population. We used data from the Rotterdam Study, a prospective population-based cohort study in the Netherlands which started in 1990 and included 7983 subjects aged 55 years and older. Subjects who were treated with cholesterol lowering drugs at baseline or with a serum total cholesterol > or = 6.5 mmol/l at baseline were included. We compared the incidence of myocardial infarction, stroke and total mortality in subjects who received > or = 2 years of statin treatment with that in subjects who had been treated for less than 2 years, and in untreated subjects, using a Cox proportional hazard model with cumulative statin use defined as time-dependent covariates. The adjusted relative risk of all-cause mortality was 0.79 [95% confidence interval (CI) 0.51-1.22] and of myocardial infarction and stroke 0.50 (95% CI 0.28-0.91) for subjects treated with statins for > or = 2 years compared to untreated subjects. The adjusted relative risks for subjects with the epsilon4 allele were 0.91 (95% CI 0.45-1.84) for all-cause mortality and 0.63 (95% CI 0.23-1.78) for myocardial infarction and stroke. In subjects without the epsilon4 allele, adjusted relative risks were 0.71 (95% CI 0.41-1.24) for all-cause mortality and 0.46 (95% CI 0.22-0.95) for myocardial infarction and stroke. We found a protective effect of statins on the risk of myocardial infarction and stroke that was independent of apoE genotype. The protective effect of statins on total mortality was not statistically significant, but did not seem to differ between subjects with different apoE genotypes.
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PMID:The effectiveness of hydroxy-methylglutaryl coenzyme A reductase inhibitors (statins) in the elderly is not influenced by apolipoprotein E genotype. 1243 25

Diffusion- and perfusion-weighted magnetic resonance imaging (MRI) was used to study the putative effects of apolipoprotein E (ApoE) polymorphism in stroke. Thirty-one patients with acute stroke, comparative for age and gender were scanned, nine of whom were ApoE allele epsilon 4 carriers. Initially, less than 24 hours from the onset of stroke, the epsilon 4 carriers had significantly smaller volumes of hypoperfusion on relative cerebral blood volume map (P = 0.001), and smaller infarct volumes (P = 0.008) compared with the noncarriers. By day 8, this difference in the infarct volumes had disappeared, suggesting relatively enhanced infarct growth. On average, the total infarct volume increased 145% of the initial infarct volume in the epsilon 4 carriers, and 84% in the noncarriers. There were strong correlations between the imaging findings and clinical status initially and with the outcome 3 months after the stroke in the epsilon 4 noncarriers, but, with a single exception at acute phase, a lack thereof in the epsilon 4 carriers. These patterns were virtually similar in a subgroup of patients with middle cerebral artery stroke. These data support the hypothesis of increased general vulnerability of the brain in the epsilon 4 carriers. Thus, the effects of ApoE polymorphism should be accounted for when interpreting diffusion- and perfusion-weighted MRI studies, particularly if predicting lesion growth.
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PMID:Apolipoprotein E polymorphism and acute ischemic stroke: a diffusion- and perfusion-weighted magnetic resonance imaging study. 1243 91

This case-control study was designed to identify risk factors for cryptogenic brain infarction. We assessed the frequency of prothrombotic states, homocysteine, lipoprotein (a) [Lp(a)] and other lipids and the apolipoprotein E phenotype together with conventional risk factors in 46 patients (19 women and 27 men) with cryptogenic brain infarction aged from 15 to 60 years and in 104 community-based controls. Multivariate odds ratios (ORs) for risk factors and 95% CIs were calculated by logistic regression. Hypertension (OR 4.5; 95% CI, 1.5-13.2; P = 0.006), current smoking (OR 2.9; 95% CI, 1.2-6.8; P = 0.012), low HDL cholesterol (HDL-C) (OR 5.4; 95% CI, 1.1-25.5; P = 0.035) and high clotting factor VIII activity (OR 3.6; 95% CI, 1.1-12.2; P = 0.041) were variables associated with cryptogenic brain infarction. These risk factors were not equally frequent in women and men. Low HDL-C and high factor VIII activity in the women, and hypertension, current smoking and a low level of plasma folate in the men were risk factors for cryptogenic stroke. Several of the observed risk factors for cryptogenic brain infarction were lifestyle-associated, which emphasizes the role of health education in addition to pharmacological treatment in the prevention of stroke.
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PMID:Risk factors for cryptogenic ischaemic stroke. 1245 78

We report a sporadic case of unusual cerebral amyloid angiopathy (CAA) with prominent capillary involvement. A 67-year-old doctor developed gait disturbance, resting tremor and rigidity. He was diagnosed to have Parkinson's disease, for which the treatment with levodopa was effective. Four years later he began to exhibit progressive cognitive decline and behavioral abnormalities consisting of hallucination and agitation. Subsequently, his condition steadily worsened and became bedridden with severe dementia, and he died eight years after the disease onset. During the clinical course, there had been no episode of stroke. Postmortem examinations revealed the typical pathology of Parkinson's disease with frequent cortical Lewy bodies in the amygdala. The most striking pathological feature of this patient was widespread CAA where prominent beta-amyloid (A beta) deposition was observed in the capillaries of the neocortex, most pronouncedly in the occipital lobe, as well as leptomeningeal and cerebral medium-sized and small vessels. Further, perivascular plaques were found in half of the amyloid-laden capillaries. Tau-positive dystrophic neurites were only sparsely detectable within a few perivascular plaques. Despite the severe A beta pathology, there was no microaneurysmal dilatation, fibrinoid necrosis or vascular occlusion. There was only one small ischemic lesion in the brain. The cerebral white matter was unremarkable. Senile plaques of neuritic type and neurofibrillary tangles were mostly limited to the hippocampal regions and, to a lesser degree, in the amygdaloid nucleus, which did not meet the neuropathological criteria of Alzheimer's disease. On the gene analyses, his apolipoprotein E (ApoE) genotyping was verified to be heterozygous epsilon 3/epsilon 4, and no mutation was seen in exons 16 and 17 of the amyloid precursor protein gene. Severe A beta capillary angiopathy as seen in our patient is exceptional in sporadic CAA. Further, A beta angiopathy of this patient was notable in the absence of an associated cerebrovascular disease despite prominent A beta deposition in the vessel walls. Regarding the development of his severe dementia, the limbic pathology of Lewy body disease might be one of the potential causes, but A beta angiopathy appears more likely because of its severity. We speculate that widespread A beta deposition disregulates the blood-brain barrier of the capillaries leading to a disturbance of the microcirculation throughout the cerebral cortex without obvious ischemic disintegration of the neuropil. We should take into consideration that A beta angiopathy can present as progressive dementia without cerebrovascular disease.
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PMID:[Sporadic cerebral amyloid angiopathy presenting with dementia and prominent capillary beta-amyloid deposition: a case report]. 1260 81

The clinical significance of the apolipoprotein E genotype in patients with hypertension has been a subject of debate. We enrolled 94 patients with hypertension and 102 healthy controls in this study and determined their plasma levels of triglyceride, total cholesterol, high- and low-density lipoprotein-cholesterol, apolipoprotein AI, and apolipoprotein B. The apolipoprotein E genotypes were identified by polymerase chain reaction, restriction fragment length polymorphism, and polyacrylamide gel electrophoresis. Apolipoprotein E3/4 genotype and set membership, vertical bar on horizontal stroke 4 allele frequencies in the hypertensive group were higher than in controls. In hypertensive patients with apolipoprotein E3/4 and E4/4 genotypes, systolic blood pressure was significantly higher than in those with apolipoprotein E2/3 or E3/3 genotypes. Meanwhile, the plasma levels of total cholesterol, low-density lipoprotein-cholesterol, and apolipoprotein B were higher in hypertensive patients with the.4 allele than the set membership, vertical bar on horizontal stroke 2 or set membership, vertical bar on horizontal stroke 3 allele. The echographic measurements of carotid artery intimal-medial thickness showed increasing values from set membership, vertical bar on horizontal stroke 2 to set membership, vertical bar on horizontal stroke 4 allele carriers in the hypertensive group. Analysis of variance showed that the carotid intimal-medial thickness was significantly greater in hypertensive patients with set membership, vertical bar on horizontal stroke 4 alleles compared with set membership, vertical bar on horizontal stroke 2 or set membership, vertical bar on horizontal stroke 3 alleles. Our data show an association between apolipoprotein E genotype and hypertension and support the hypothesis that the apolipoprotein set membership, vertical bar on horizontal stroke 4 allele is a susceptibility locus for systolic hypertension and carotid artery atherosclerosis.
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PMID:Association of apolipoprotein E gene polymorphism with essential hypertension and its complications. 1262 8

There is evidence that indicates the involvement of environmental and genetic factors in the pathogenesis of post-stroke dementia (PSD). In the present work, we examined different polygenic influences on the risk of PSD in a series of stroke patients. We studied 150 consecutive patients evaluated 3 months after suffering acute strokes. All patients were evaluated with a prospective standard protocol and genotyped for vascular disease-associated polymorphisms in the genes coding for apolipoprotein E (including apoE coding and apoE promoter polymorphisms), angiotensin-converting enzyme (ACE) and alpha-1-antichymotrypsin (ACT). Thirty-two cases (21.3%) resulted in dementia 3 months after the stroke. In patients with PSD, the frequency of apoE epsilon 4 (0.08), ACE-D (0.64), ACT-A (0.62) alleles and apoE gene promoter polymorphisms (-491/A, 0.88; -427/C, 0.02) was similar to that of patients without PSD (apoE epsilon 4: 0.10, p=0.79; ACE-D: 0.56, p=0.36; ACT-A: 0.51, p=0.21; -491/A: 0.86, p=1.00; -427/C: 0.08, p=0.29). Our data indicate that PSD is not associated with the genetic risk factors of vascular dementia (VD) that were studied, and that additional factors may contribute to the pathogenesis of PSD.
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PMID:Apolipoprotein E, angiotensin-converting enzyme and alpha-1-antichymotrypsin genotypes are not associated with post-stroke dementia. 1273 93

The treatment of ischemic strokes is limited to the prevention of cerebrovascular risk factors and to the modulation of the coagulation cascade during the acute phase. A new therapeutic strategy could be to preventively protect the brain against noxious biological reactions induced by cerebral ischemia such as oxidative stress and inflammation to minimize their neurological consequences. Here, we show that a peroxisome proliferator-activated receptor (PPAR-alpha) activator, fenofibrate, protects against cerebral injury by anti-oxidant and anti-inflammatory mechanisms. A 14 d preventive treatment with fenofibrate reduces susceptibility to stroke in apolipoprotein E-deficient mice as well as decreases cerebral infarct volume in C57BL/6 wild-type mice. The neuroprotective effect of fenofibrate is completely absent in PPAR-alpha-deficient mice, suggesting that PPAR-alpha activation is involved as a mechanism of the protection against cerebral injury. Furthermore, this neuroprotective effect appears independently of any improvement in plasma lipids or glycemia and is associated with (1) an improvement in middle cerebral artery sensitivity to endothelium-dependent relaxation unrelated to an increase in nitric oxide synthase (NOS) type III expression, (2) a decrease in cerebral oxidative stress depending on the increase in numerous antioxidant enzyme activities, and (3) the prevention of ischemia-induced expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in cerebral vessels without any change in NOS II expression. These data demonstrate that PPAR-alpha could be a new pharmacological target to preventively reduce the deleterious neurological consequences of stroke in mice and suggest that PPAR-alpha activators could preventively decrease the severity of stroke in humans.
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PMID:Peroxisome proliferator-activated receptor-alpha activation as a mechanism of preventive neuroprotection induced by chronic fenofibrate treatment. 1286 11

Cerebral amyloid angiopathy (CAA) is a feature of ageing and Alzheimer's disease (AD); it is also associated with intracerebral hemorrhage and stroke. Here, the pathogenesis of CAA and its effects on the brain are reviewed and the possible effects of CAA on therapies for Alzheimer's disease are evaluated. Tracer experiments in animals and observations on human brains suggest that peptides such as A beta are eliminated along the peri-arterial interstitial fluid drainage pathways that are effectively the lymphatics of the brain. In CAA, A beta becomes entrapped in drainage pathways in the walls of cerebral arteries, reflecting a failure of elimination of A beta from the ageing brain. One consequence of failure in clearance of A beta is accumulation of soluble and insoluble A beta associated with cognitive decline in AD. Replacement of vascular smooth muscle cells by A beta occurs in severe CAA with weakening of artery walls and increased risk of vessel rupture and intracerebral hemorrhage. Risk factors for CAA include mutations of the amyloid precursor protein (APP) gene and possession of the epsilon 4 allele of apolipoprotein E. There is also evidence that cerebrovascular disease may be a factor in the failure of elimination of A beta along perivascular pathways in sporadic AD; this would link ageing in cerebral arteries with the pathogenesis of Alzheimer's disease. If therapeutic agents, including anti-A beta antibodies, are to be used to eliminate A beta in the treatment of Alzheimer's disease, the effects of CAA on the treatment and the effects of the treatment on the CAA need to be considered.
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PMID:Cerebral amyloid angiopathy: pathogenesis and effects on the ageing and Alzheimer brain. 1450 15

The expression of apolipoprotein E (apoE) after ischemic brain damage has been associated with plasticity involved in promoting functional recovery. We therefore examined the expression and distribution of apoE in rats that received intraparenchymal grafts of the conditionally immortal stem cell line MHP36 either ipsilateral or contralateral to the lesion or intraventricular grafts 4 months after transplantation. ApoE immunoreactivity was highly expressed in the striatum, somatosensory cortex, and thalamus of the lesioned hemisphere in all rats subjected to middle cerebral artery occlusion. Only in rats with intraparenchymal grafts, apoE was significantly upregulated in the contralateral hemisphere, whereas levels and distribution in rats with intraventricular grafts resembled those of ischemic controls. In ischemic rats, apoE was seen in both astrocytes and neurons on the lesioned side, and in grafted rats, apoE was present in host and transplanted neurons and astrocytes. Previously we have shown that intraparenchymal grafts reduced sensorimotor asymmetry, whereas intraventricular grafts improved cognitive dysfunction, with transplanted cells being widely distributed in cortex, striatum, and corpus callosum on both sides of the brain in all grafted groups. Thus, stem cells grafted in the parenchyma are not only capable of limited expression of apoE in the host brain but also trigger a robust increase on the side contralateral to stroke damage where this does not normally occur. Findings that parenchymal, but not ventricular, grafts facilitated sensorimotor recovery suggests that apoE might contribute to plastic changes in relevant pathways, possibly on both sides of the brain. In contrast, no evidence was found for an association between apoE and recovery of cognitive function in rats with intraventricular grafts.
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PMID:Transplantation of neural stem cells modulates apolipoprotein E expression in a rat model of stroke. 1455 73

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