Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Over 30% of normal elderly people have cerebral amyloid angiopathy (CAA). Possession of APOE epsilon4 is associated with increased prevalence and severity of CAA in Alzheimer's disease (AD) and in cerebral haemorrhage. We examined CAA in relation to APOE genotype in brains from 152 people aged 60-102 years, without AD or cerebral haemorrhage. Prevalence of CAA increased with age (p = 0.003). CAA was not associated with APOE genotype. The frequency of epsilon4 showed a significant negative association with age (p = 0.016). Age at death was significantly lower in those with than without epsilon4 (p = 0.028). Possession of epsilon4 does not by itself confer an increased risk of CAA but may be associated with reduced longevity even in the absence of AD or cerebral haemorrhage.
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PMID:APOE and cerebral amyloid angiopathy in the elderly. 1296 Jul 80

Polymorphisms in the APOE promoter, ACE1 and CYP46 genes have all been reported to be associated with Alzheimer's disease (AD). We studied the relationship of these polymorphisms to the presence of AD in 86 neuropathologically confirmed cases of AD and 58 controls. In addition, we assessed the effects of these polymorphisms on the accumulation of beta-amyloid (Abeta) in the cerebral parenchyma and vasculature. No association was observed between any of the polymorphisms and the presence of AD, the parenchymal Abeta load or the severity of cerebral amyloid angiopathy (CAA). Here we report that polymorphisms within the APOE promoter, ACE1 and CYP46 gene are not risk factors for AD and are not associated with parenchymal or vascular accumulation of Abeta.
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PMID:APOE promoter, ACE1 and CYP46 polymorphisms and beta-amyloid in Alzheimer's disease. 1510 38

The epsilon4 allele of apolipoprotein E APOE is a risk factor for Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA), and the epsilon2 allele is associated with a decreased risk for AD. There is strong evidence to suggest that a major, if not the main, mechanism underlying the link between apoE and both AD and CAA is related to the ability of apoE to interact with the amyloid-beta (Abeta) peptide and influence its clearance, aggregation, and conformation. In addition to a number of in vitro studies supporting this concept, in vivo studies with amyloid precursor protein (APP) transgenic mice indicate that apoE and a related molecule, clusterin (also called apolipoprotein J), have profound effects on the onset of Abeta deposition, as well as the local toxicity associated with Abeta deposits both in the brain parenchyma and in cerebral blood vessels. Taken together, these studies suggest that altering the expression of apoE and clusterin in the brain or the interactions between these molecules and Abeta would alter AD pathogenesis and provide new therapeutic avenues for prevention or treatment of CAA and AD.
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PMID:In vivo effects of ApoE and clusterin on amyloid-beta metabolism and neuropathology. 1518 Dec 53

Alzheimer's disease (AD) is characterized by the aggregation and deposition of the normally soluble amyloid-beta (Abeta) peptide in the extracellular spaces of the brain as parenchymal plaques and in the walls of cerebral vessels as cerebral amyloid angiopathy (CAA). CAA is a common cause of brain hemorrhage and is found in most patients with AD. As in AD, the epsilon4 allele of the apolipoprotein E (apoE) gene (APOE) is a risk factor for CAA. To determine the effect of human apoE on CAA in vivo, we bred human APOE3 and APOE4 "knock-in" mice to a transgenic mouse model (Tg2576) that develops amyloid plaques as well as CAA. The expression of both human apoE isoforms resulted in a delay in Abeta deposition of several months relative to murine apoE. Tg2576 mice expressing the more fibrillogenic murine apoE develop parenchymal amyloid plaques and CAA by 9 months of age. At 15 months of age, the expression of human apoE4 led to substantial CAA with very few parenchymal plaques, whereas the expression of human apoE3 resulted in almost no CAA or parenchymal plaques. Additionally, young apoE4-expressing mice had an elevated ratio of Abeta 40:42 in brain extracellular pools and a lower 40:42 ratio in CSF, suggesting that apoE4 results in altered clearance and transport of Abeta species within different brain compartments. These findings demonstrate that, once Abeta fibrillogenesis occurs, apoE4 favors the formation of CAA over parenchymal plaques and suggest that molecules or treatments that increase the ratio of Abeta 40:42 may favor the formation of CAA versus parenchymal plaques.
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PMID:Human apolipoprotein E4 alters the amyloid-beta 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model. 1577 40

The reduced antioxidant defense in apolipoprotein E epsilon4/epsilon4 carriers may contribute to beta-amyloidosis. Previously we found that Fe(2+)-induced oxidative stress caused greater protein oxidation in epsilon4/epsilon4 than in epsilon3/epsilon3 human brain vascular smooth muscle cells. Moreover, Fe(2+) induced lysosomal accumulation of endogenous Abeta and APOE in cultured cells, and Abeta deposition in vascular tunica media in organotypic cultures of brain vessels. Here we demonstrated that Fe(2+) enhanced an uptake of exogenous Abeta 1-40 and its deposition together with APOE in lysosomes in myocytes. Abeta deposits were associated with lipid-peroxidation and protein ubiquitination, and were more abundant and stable in epsilon4/epsilon4 than in epsilon3/epsilon3 cells. In organotypic cultures of brain vessels Fe(2+) induced deposition of non-fibrillar and fibrillar Abeta 1-40 in vascular tunica media. We hypothesize that locally increased concentrations of iron induce accumulation of exogenous and endogenous Abeta in SMCs, triggering beta-amyloid angiopathy. The greater susceptibility of epsilon4 carriers to Fe(2+) ions may result in an increased risk of beta-amyloidosis.
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PMID:Induction of vascular amyloidosis-beta by oxidative stress depends on APOE genotype. 1599 87

Over 90% of patients with Alzheimer's disease (AD) develop cerebral amyloid angiopathy (CAA). Severe dyshoric CAA, in which amyloid extends into the surrounding brain parenchyma, may be associated with adjacent clustering of tau-immunopositive neurites but the relationship of CAA to neurofibrillary pathology has not been systematically investigated. In the present study this relationship was examined in sections of frontal, temporal and parietal cortex from 25 AD patients with moderate to severe CAA and 26 with mild or absent CAA. We measured immunolabelling of abnormally phosphorylated tau adjacent to A beta-laden and non-A beta-laden arteries and arterioles, and in cortex away from arteries and arterioles. We also analysed the possible influence of APOE genotype on these measurements. There were no significant differences between the lobes in measurements of tau labelling, either around blood vessels or elsewhere in the cortex. However, tau labelling around A beta-laden arteries and arterioles significantly exceeded that around non-A beta-laden blood vessels (P<0.001) and this, in turn was greater than the labelling of cortex away from blood vessels (P<0.001). There was no association between APOE epsilon 4 and the immunolabelling density for tau, whether around amyloid- or non-amyloid-laden arteries and arterioles, or in the cerebral cortex away from these. We propose that both CAA and peri-vascular accumulation of hyperphosphorylated tau may be a consequence of elevated levels of soluble A beta around cortical arteries and arterioles.
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PMID:Relationship of neurofibrillary pathology to cerebral amyloid angiopathy in Alzheimer's disease. 1600 25

Cognitive decline is a central component of the dementia process. Population-based prospective studies have confirmed the existence of age-related cognitive decline, although its conceptual basis and nosological status remain controversial. Healthy old people show decline with aging in global cognition and memory function in particular. Preclinical and clinical dementia patients exhibit deficits across multiple cognitive domains, with the largest and most consistent deficits in memory function. Cerebrovascluar disease may lead to cognitive decline and promote the clinical expression of dementia directly or by interaction with APOE epsilon4. Early treatment and prevention of cerebrovascular disease may be the major measures for preventing and postponing the progression of the vascular disease related cognitive decline.
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PMID:Epidemiology of cerebrovascular disease related cognitive decline. 1619 Dec 25

Abnormalities of cerebral white matter are present in a majority of patients with Alzheimer's disease (AD) and probably contribute to motor dysfunction and cognitive impairment. The white matter abnormalities are usually attributed to degenerative vascular disease and cerebral amyloid angiopathy (CAA) but the evidence is scanty or inconclusive. In the present study we examined sections of frontal lobe from 125 autopsy-confirmed cases of AD and assessed the relationship of degenerative large and small vessel disease, CAA, parenchymal Abeta load and APOE genotype, to several objective measures of white matter damage: extent of immunolabelling for glial fibrillary acidic protein (GFAP), axonal accumulation of amyloid precursor protein (APP), axon density in superficial and deep white matter, and intensity of staining for myelin. We found no association between atherosclerosis, arteriolosclerosis, CAA or APOE genotype and white matter damage. However, labelling of white matter for GFAP correlated strongly with the parenchymal Abeta load (P = 0.0003) and with APP accumulation (P = 0.008). Our findings suggest that severity of frontal white matter damage in AD is closely related to parenchymal Abeta load and that in most cases the contribution of degenerative vascular disease, CAA and APOE is relatively minor.
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PMID:Contributors to white matter damage in the frontal lobe in Alzheimer's disease. 1628 11

For the best understanding of aging, we must consider a genetic pool in which genes with negative effects (deleterious genes that shorten the life span) interact with genes with positive effects (helpful genes that promote longevity) in a constant epistatic relationship that results in a modulation of the final expression under particular environmental influences. Examples of deleterious genes affecting aging (predisposition to early-life pathology and disease) are those that confer risk for developing vascular disease in the heart, brain, or peripheral vessels (APOE, ACE, MTFHR, and mutation at factor II and factor V genes), a gene associated with sporadic late-onset Alzheimer's disease (APOE E4), a polymorphism (COLIA1 Sp1) associated with an increased fracture risk, and several genetic polymorphisms involved in hormonal metabolism that affect adverse reactions to estrogen replacement in postmenopausal women. In summary, the process of aging can be regarded as a multifactorial trait that results from an interaction between stochastic events and sets of epistatic alleles that have pleiotropic age-dependent effects. Lacking those alleles that predispose to disease and having the longevity-enabling genes (those beneficial genetic variants that confer disease resistance) are probably both important to such a remarkable survival advantage.
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PMID:Genetic contribution to aging: deleterious and helpful genes define life expectancy. 1639 87

Thinning and discontinuities within the vascular basement membrane (VBM) are associated with leakage of the plasma protein prothrombin across the blood-brain barrier (BBB) in Alzheimer's disease (AD). Prothrombin immunohistochemistry and ELISA assays were performed on prefrontal cortex. In severe AD, prothrombin was localized within the wall and neuropil surrounding microvessels. Factor VIII staining in severe AD patients indicated that prothrombin leakage was associated with shrinkage of endothelial cells. ELISA revealed elevated prothrombin levels in prefrontal cortex AD cases that increased with the Braak stage (Control=1.39, I-II=1.76, III-IV=2.28, and V-VI=3.11 ng prothrombin/mg total protein). Comparing these four groups, there was a significant difference between control and Braak V-VI (p=0.0095) and also between Braak stages I-II and V-VI (p=0.0048). There was no significant difference in mean prothrombin levels when cases with versus without cerebral amyloid angiopathy (CAA) were compared (p-value=0.3627). When comparing AD patients by APOE genotype (ApoE3,3=2.00, ApoE3,4=2.49, and ApoE4,4=2.96 ng prothrombin/mg total protein) an analysis of variance indicated a difference between genotypes at the 10% significance level (p=0.0705). Tukey's test indicated a difference between the 3,3 and 4,4 groups (p=0.0607). These studies provide evidence that in advanced AD (Braak stage V-VI), plasma proteins like prothrombin can be found within the microvessel wall and surrounding neuropil, and that leakage of the blood-brain barrier may be more common in patients with at least one APOE4 allele.
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PMID:Microvascular injury and blood-brain barrier leakage in Alzheimer's disease. 1678 34


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