Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is overwhelming evidence to suggest that the neuropathology of Alzheimer disease (AD) extends beyond amyloid plaques and neurofibrillary tangles. Review of various consortium data shows that more than 30% of AD cases exhibit cerebrovascular pathology. However, certain vascular lesions such as cerebral amyloid angiopathy, microvascular degeneration, and periventricular white matter lesions are evident in almost all cases of AD. Whether these vascular lesions are coincidental or causal in the pathogenetic processes of AD remains to be defined. Although systemic vascular influences such as hypertension, coronary artery disease, and other cardiovascular disturbances may be responsible for such pathology in AD, it is equally intriguing that about one third of patients diagnosed with vascular dementia (VaD) will have AD-type pathology at autopsy. Moreover, previous studies have revealed that deficits in cholinergic indices related to the basal forebrain neurones are apparent in multi-infarct dementia. In this short review, we evaluate cerebrovascular pathology of AD in light of peripheral vascular pathophysiology implicated in the etiopathogenesis of the dementia. We also consider pathological findings in relation to genetic influences such as apolipoprotein E that may shed light on the link between AD and VaD. In view of these commonalties, it is reasonable to consider the same treatment strategies for both AD and VaD.
 ...
PMID:Overlap between pathology of Alzheimer disease and vascular dementia. 1060 90

The pathology of Alzheimer's disease (AD) is not limited to amyloid plaques and neurofibrillary tangles. Recent evidence suggests that more than 30% of AD cases exhibit cerebrovascular pathology, which involves the cellular elements that represent the blood-brain barrier. Certain vascular lesions such as microvascular degeneration affecting the cerebral endothelium, cerebral amyloid angiopathy and periventricular white matter lesions are evident in virtually all cases of AD. Furthermore, clinical studies have demonstrated blood-brain barrier dysfunction in AD patients who exhibit peripheral vascular abnormalities such as hypertension, cardiovascular disease and diabetes. Whether these vascular lesions along with perivascular denervation are coincidental or causal in the pathogenetic processes of AD remains to be defined. In this chapter, I review biochemical and morphological evidence in context with the variable but distinct cerebrovascular pathology described in AD. I also consider genetic influences such as apolipoprotein E in relation to cerebrovascular lesions that may shed light on the pathophysiology of the cerebral vasculature. The compelling vascular pathology associated with AD suggests that transient and focal breach of the blood-brain barrier occurs in late onset AD and may involve an interaction of several factors, which include perivascular mediators as well as peripheral circulation derived factors that perturb the endothelium. These vascular abnormalities are likely to worsen cognitive disability in AD.
 ...
PMID:The blood-brain barrier and cerebrovascular pathology in Alzheimer's disease. 1067 33

Following the identification of the role of the apolipoprotein E (APOE) gene polymorphism in Alzheimer's disease (AD), this gene was examined in cerebral amyloid angiopathy (CAA). As in AD, the APOE epsilon 4 allele was found to be associated with CAA. Lobar intracerebral hemorrhage is the major clinical manifestation of CAA. Initial studies on a small number of patients with CAA-related hemorrhage (CAAH) identified overrepresentation of APOE epsilon 4. However, it became clear that confounding bias from concomitant AD and the need for pathologically confirmed cases of CAAH would also have to be considered. A larger series of pathologically confirmed cases of CAAH, also assessed for AD pathology, found a surprising overrepresentation of the APOE epsilon 2 allele. Because of the association between CAA and AD, it might have been predicted that patients with CAAH would have a low, rather than a high, epsilon 2 frequency. The overrepresentation of APOE epsilon 2 was present both in patients with and without AD, whereas a high epsilon 4 frequency correlated with concomitant AD. Further studies found that overrepresentation of APOE epsilon 2 is specific for CAAH and is not found in intracranial hemorrhages due to other causes. In CAAH, APOE epsilon 2 may interact with putative risk factors for hemorrhage, including antiplatelet/anticoagulant medication, minor head trauma, and hypertension. Several microvascular abnormalities in amyloid-laden blood vessels have been assumed to antedate CAAH and increase its likelihood. APOE epsilon 2 has now been found to be associated with some of these vascular abnormalities, specifically a "double-barrel" appearance and fibrinoid necrosis. The currently favored interpretation is that APOE epsilon 4 enhances deposition of amyloid-beta protein in the walls of cerebral blood vessels, whereas epsilon 2 is a risk factor for hemorrhage from amyloid-laden blood vessels by promoting specific "CAA-associated vasculopathies."
 ...
PMID:Apolipoprotein E genotype and cerebral amyloid angiopathy-related hemorrhage. 1081 5

Amyloid-beta (A beta) deposition in cerebral vessels (cerebral amyloid angiopathy, CAA) is accompanied by degeneration of vascular cells, including pericytes and smooth muscle cells. Previous studies indicated that specific A beta protein isoforms are toxic for cultured human brain pericytes and smooth muscle cells. In particular, A beta 1-40 carrying the E22Q mutation, as in hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), is toxic. We investigated the effects of the A beta-binding protein apolipoprotein E (ApoE) on the toxicity of A beta for cultured human brain pericytes. We compared the toxicity of HCHWA-D A beta 1-40 for pericyte cultures with different ApoE genotypes, studied the accumulation of A beta and ApoE in these different cell cultures, and investigated the effects of exogenous ApoE. Pericyte cultures with an ApoE epsilon 2/epsilon 3 genotype were more resistant to HCHWA-D A beta 1-40 treatment than cultures with a epsilon 3/epsilon 3 or epsilon 3/epsilon 4 genotype. Cell death was highest in cultures homozygous for ApoE epsilon 4. The extent to which both A beta ApoE accumulated at the cell surface was parallel to the degree of toxicity. The addition of purified ApoE resulted in a decrease in cell death. These data suggest that ApoE4 may direct A beta more efficiently than other ApoE isoforms into a pathological interaction with the HBP cell surface. The results of this study are in line with the observations that inheritance of the ApoE epsilon 4 allele increases the risk of developing Alzheimer's disease, and that the ApoE epsilon 2 allele has a relatively protective effect.
 ...
PMID:Amyloid-beta-induced degeneration of human brain pericytes is dependent on the apolipoprotein E genotype. 1081 7

The epsilon4 allele of apolipoprotein E (APOE) is reported to be a genetic risk factor of atherosclerosis through hyperlipidemia and late-onset Alzheimer's dementia. A recent report showed that a genetic variant (A -491T) in the promoter region of the APOE gene increases the risk of Alzheimer's disease. In the present study, we examined whether these APOE polymorphisms were genetically involved in essential hypertension. Japanese hypertensives (n=180) with a family history of hypertension and normotensive controls (n=195, sex and age matched with hypertensives) were recruited from the outpatients of Osaka University Hospital, and an informed consent to participate in the study was obtained from each person. APOE polymorphisms were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The frequencies of the A -491 allele in hypertensives and normotensives were 0.98 and 0.97, respectively, and the TT/-491 genotype was not found in either group. No significant differences between hypertensives and normotensives were observed in allele frequencies in either APOE polymorphism; however, the mean diastolic blood pressure in normotensive subjects with AA/-491 was significantly higher than in the subjects with AT/-491 (p < 0.01). These results suggest that the presence of the APOE promoter polymorphism is not a major risk factor for hypertension but that it does have some minor effect on basal blood pressure variation.
 ...
PMID:Association of polymorphism in the promoter region of the apolipoprotein E gene with diastolic blood pressure in normotensive Japanese. 1082 Nov 38

High blood pressure is a known risk factor for multi-infarct dementia, a subtype of dementia caused by the occurrence of several strokes. However, this form of dementia is relatively uncommon and the influence of blood pressure on the risk of other subtypes of vascular dementia remains to be clarified. Furthermore, recent studies have suggested that vascular risk factors could also play a part in Alzheimer's disease. One of the aims of Perindopril Protection Against Recurrent Stroke Study (PROGRESS) is to test the hypothesis that blood pressure decreasing treatment based on perindopril would reduce the incidence of dementia among patients with cerebrovascular disease. The dementia procedures in PROGRESS involve a classical two-phase design, with an initial screening phase based mainly on the Mini-Mental State Examination - a simple, brief, and widely used screening test for dementia. The second phase involves a diagnostic assessment for dementia in individuals screened as positive according to the criteria of the American Psychiatric Association's Diagnostic and statistical manual of mental disorders (4th ed.). In this project, two other domains of the relationship between vascular risk factors and cognition are being explored in relation to PROGRESS substudies. The apolipoprotein E polymorphism, a genetic risk factor for Alzheimer's disease, is being determined in each patient, as part of the genetic substudy. This will allow study of the relationship between this polymorphism and blood pressure, and of the effect of blood pressure decreasing treatment on the risk of dementia. The magnetic resistance imaging substudy will improve understanding of the relationship between blood pressure decreasing and the occurrence of cerebral white matter lesions, which are known to be related to cognitive decline and dementia.
 ...
PMID:Blood pressure reduction and risk of dementia in patients with stroke: rationale of the dementia assessment in PROGRESS (Perindopril Protection Against Recurrent Stroke Study). PROGRESS Management Committee. 1093 86

Alzheimer's disease is a primary degenerative dementia and is not considered to be of vascular origin. Furthermore, severe cerebrovascular diseases are generally exclusionary for the clinical diagnosis. During recent years both epidemiological and neuropathological studies have suggested an association between Alzheimer's disease and several vascular risk factors, such as hypertension, inheritance of the apolipoprotein E epsilon4 allele, coronary heart disease, diabetes mellitus, ischaemic white matter lesions and generalised atherosclerosis. These findings may reflect an overdiagnosis of Alzheimer's disease in individuals with silent cerebrovascular disease or that cerebrovascular disease may affects the clinical expression of Alzheimer's disease. Further possibilities include that Alzheimer's disease may increase the risk of vascular disease or that vascular disease may stimulate the Alzheimer's disease process. Similar mechanisms may also be involved in the pathogenesis of both disorders, such as disturbances in the renin-angiotensin system, apoptosis, and psychological stress.
 ...
PMID:Vascular aspects in Alzheimer's disease. 1096 16

Seventy-one mutations of the low density lipoprotein (LDL) receptor gene were identified in 282 unrelated Italian familial hypercholesterolemia (FH) heterozygotes. By extending genotype analysis to families of the index cases, we identified 12 mutation clusters and localized them in specific areas of Italy. To evaluate the impact of these mutations on the clinical expression of FH, the clusters were separated into 2 groups: receptor-defective and receptor-negative, according to the LDL receptor defect caused by each mutation. These 2 groups were comparable in terms of the patients' age, sex distribution, body mass index, arterial hypertension, and smoking status. In receptor-negative subjects, LDL cholesterol was higher (+18%) and high density lipoprotein cholesterol lower (-5%) than the values found in receptor-defective subjects. The prevalence of tendon xanthomas and coronary artery disease (CAD) was 2-fold higher in receptor-negative subjects. In patients >30 years of age in both groups, the presence of CAD was related to age, arterial hypertension, previous smoking, and LDL cholesterol level. Independent contributors to CAD in the receptor-defective subjects were male sex, arterial hypertension, and LDL cholesterol level; in the receptor-negative subjects, the first 2 variables were strong predictors of CAD, whereas the LDL cholesterol level had a lower impact than in receptor-defective subjects. Overall, in receptor-negative subjects, the risk of CAD was 2.6-fold that of receptor-defective subjects. Wide interindividual variability in LDL cholesterol levels was found in each cluster. Apolipoprotein E genotype analysis showed a lowering effect of the epsilon2 allele and a raising effect of the epsilon4 allele on the LDL cholesterol level in both groups; however, the apolipoprotein E genotype accounted for only 4% of the variation in LDL cholesterol. Haplotype analysis showed that all families of the major clusters shared the same intragenic haplotype cosegregating with the mutation, thus suggesting the presence of common ancestors.
 ...
PMID:Clinical expression of familial hypercholesterolemia in clusters of mutations of the LDL receptor gene that cause a receptor-defective or receptor-negative phenotype. 1097 68

The present review focuses on evolving concepts in the pathogenesis and management of deep and lobar intracerebral hemorrhage subtypes, with particular focus on the relationship between lobar intracerebral hemorrhage, apolipoprotein E subtypes and cerebral amyloid angiopathy; deep intracerebral hemorrhage and the potential interaction between hypertension and low cholesterol; and new concepts in medical and surgical therapy for acute intracerebral hemorrhage.
 ...
PMID:Intracerebral hemorrhage: update. 1117 25

A reduced risk of Alzheimer's disease (AD) associated with the apolipoprotein E (APOE) epsilon4 allele is reported in populations of African origin. In order to clarify possible reasons for this, we examined the association between APOE genotype and early cognitive impairment in a community-based African Caribbean UK population aged 55-75 years. APOE genotype was available for 202 participants, 57 (28%) of whom were classified as having relative cognitive impairment on a battery of neuropsychological tests. Cognitive impairment was negatively associated with epsilon2 and positively but more weakly associated with epsilon4. Effects of both alleles increased markedly after age 70. The effect of epsilon4 was increased in combination with hypertension, diabetes or lower educational attainment, but these factors did not influence epsilon2 effects. Cholesterol and triglyceride levels partially explained effects of epsilon2, but did not account for those of epsilon4. A reduced association between epsilon4 and later AD in populations of African origin is unlikely to be explained by reduced cognitive effects or by differential mortality. However, it may be accounted for by vascular comorbidity. The different patterns of association between epsilon2 and epsilon4 alleles suggest different pathways of effect.
 ...
PMID:Apolipoprotein E genotype, vascular risk and early cognitive impairment in an African Caribbean population. 1135 Nov 36


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>