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)

To better understand the characteristics of amyloid deposition in the choroid plexus, we examined autopsied brain by routine histology, immunohistochemistry, and electron microscopy in three group of patients: primary systemic amyloidosis (n = 7), cerebral amyloid angiopathy (CAA, n = 6), and controls (n = 3). Three of the CAA patients had Alzheimer's disease. Congophilic, birefringent amyloid deposits of the choroid plexus were seen in six of the seven cases of systemic light chain amyloidosis. Immunohistochemistry revealed that the deposited amyloids had reactivity for immunoglobulin light chain and amyloid P component. Accumulation of macrophages labeled with monoclonal antibodies against CD 68 and major histocompatibility complex class II antigens were observed around the massive amyloid deposits. The presence of approximately 10 nm amyloid fibrils along the epithelial basement membrane as well as in the vascular walls was ascertained by electron microscopy. In CAA, Congo red-positive amyloid deposits were consistently present in meningeal blood vessels and were often found in senile plaques of the cerebral parenchyma; congophilic amyloid deposits were absent in the choroid plexus. Choroid plexus epithelial cells exhibited immunostaining for beta amyloid precursor protein (APP) with N-terminal- and C-terminal-specific antibodies; in particular, consistent staining was obtained for the latter antibody. Immunoreactivity for amyloid beta protein (A beta) with monoclonal antibodies (6E10, 4G8) was often found in choroid plexus epithelial cells. These findings suggest that amyloid deposition of the choroid plexus depends on the major component protein in amyloidosis, and that the choroid plexus may produce APP and A beta protein although A beta amyloidosis is not evident in the choroid plexus.
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PMID:Human choroid plexus is an uniquely involved area of the brain in amyloidosis: a histochemical, immunohistochemical and ultrastructural study. 917 87

beta-amyloid toxicity is central to the pathology of Alzheimer's disease. Recent evidence implicates vascular dysfunction as a contributing factor to the dementia of Alzheimer type. Using intravital microscopy we demonstrate that in vivo administration of beta-amyloid produces extensive vascular disruption including endothelial and smooth muscle damage, adhesion and migration of leukocytes across arteries and venules. Amyloid angiopathy with vascular damage and inflammatory changes are hallmarks in the brains of Alzheimer disease victims. The vascular actions of beta-amyloid are distinct from the neurotoxic properties of the peptide and were prevented by the free radical scavenging enzyme superoxide dismutase. Oxygen radical mediated vascular dysfunction may induce ischemic and inflammatory responses leading to neurodegeneration as seen in Alzheimer's disease.
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PMID:In vivo vascular damage, leukocyte activation and inflammatory response induced by beta-amyloid. 926 37

Current evidence is not inconsistent with the suggestion that cerebrovascular functions decline during normal aging with pronounced effects in both sporadic and familial Alzheimer's disease (AD). The primary causes of these changes remain unknown. It is possible that amyloid beta (A beta) protein is involved in the degeneration of both the larger penetrating vessels as well as the cerebral capillaries that represent the blood-brain barrier (BBB). A beta-induced endothelial changes could also alter muscular tone, resulting not only in increased expression of vascular amyloid precursor protein (APP) and production of A beta, but also in oxidative injury. We used immunochemical methods to examine the status of the perfusing cerebral vessels and the microvascular endothelium in relation to deposition of A beta in AD and non-AD aging control subjects. Double-immunostaining with antibodies to vascular markers revealed marked loss of smooth muscle in larger vessels and absence or attenuation of the endothelium in capillary profiles that still appeared to retain their basement membranes. These vascular changes were predominantly restricted to neocortical regions abundant in A beta deposits. Quantitative studies showed that the microvascular abnormalities were correlated to A beta deposition rather than neurofibrillary tangles or neuronal numbers. Our studies suggest that A beta, irrespective of its origin within vascular myocytes or brain parenchyma, is responsible not only for cerebral amyloid angiopathy, but also for the degeneration of the cerebral microvasculature, which may profoundly affect brain perfusion and BBB functions.
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PMID:Cerebrovascular degeneration is related to amyloid-beta protein deposition in Alzheimer's disease. 932 98

To further investigate the process of amyloid beta-protein (Abeta) deposition, we determined, using sensitive enzyme immunoassays, the levels of Abeta40 and Abeta42 (Abetas) in the soluble and insoluble fractions of the leptomeninges (containing arachnoid mater and leptomeningeal vessels) and cerebral cortices from elderly control subjects showing various stages of Abeta deposition and from patients affected by Alzheimer's disease (AD). In both locations, insoluble Abeta levels were higher by orders of magnitude than soluble Abeta levels. Soluble Abeta levels in cortices were much lower than those in leptomeninges. In insoluble Abeta in the cortex, Abeta42 was by far the predominant species, and Abeta42 in AD cortices was characterized by the highest degree of modifications in the amino terminus. In contrast, this Abeta42 predominance was not observed in insoluble Abeta in the leptomeninges, which were found to be able to accumulate Abetas to an extent similar to that in the cortex, on a weight basis. The levels of insoluble Abeta in the leptomeninges or cortex generally correlated with the degree of cerebral amyloid angiopathy or the abundance of senile plaque, respectively. However, the presence of plaque-free cortical samples showing significant levels of insoluble Abeta42 suggests that biochemically detectable Abeta accumulation precedes immunocytochemically detectable Abeta deposition in the cortex.
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PMID:Amyloid beta-protein deposition in the leptomeninges and cerebral cortex. 940 83

The beta-amyloid (A beta 1-40) peptide has previously been shown to enhance phenylephrine contraction of aortic rings in vitro. We have employed a novel observation, that A beta peptides enhance endothelin-1 (ET-1) contraction, to examine the relationship between vasoactivity and potential amyloidogenicity of A beta peptides, the role played by free radicals and calcium in the vasoactive mechanism, and the requirement of an intact endothelial layer for enhancement of vasoactivity. Rings of rat aortae were constricted with ET-1 before and after addition of amyloid peptide and/or other compounds, and a comparison was made between post- and pre-treatment contractions. In this system, vessel constriction is consistently dramatically enhanced by A beta 1-40, is enhanced less so by A beta 1-42, and is not enhanced by A beta 25-35. The endothelium is not required for A beta vasoactivity, and calcium channel blockers have a greater effect than antioxidants in blocking enhancement of vasoconstriction by A beta peptides. In contrast to A beta-induced cytotoxicity, A beta-induced vasoactivity is immediate, occurs in response to low doses of freshly solubilized peptide, and appears to be inversely related to the amyloidogenic potential of the A beta peptides. We conclude that the mechanism of A beta vasoactivity is distinct from that of A beta cytotoxicity. Although free radicals appear to modulate the vasoactive effects, the lack of requirement for endothelium suggests that loss of the free radical balance (between NO and O2-) may be a secondary influence on A beta enhancement of vasoconstriction. These effects of A beta on isolated vessels, and reported effects of A beta in cells of the vasculature, suggest that A beta-induced disruption of vascular tone may be a factor in the pathogenesis of cerebral amyloid angiopathy and Alzheimer's disease. Although the mechanism of enhanced vasoconstriction is unknown, it is reasonable to propose that in vivo contact of A beta peptides with small cerebral vessels may increase their tendency to constrict and oppose their tendency to relax. The subclinical ischemia resulting from this would be expected to up-regulate beta APP production in and around the vasculature with further increase in A beta formation and deposition. The disruptive and degenerative effects of such a cycle would lead to the complete destruction of cerebral vessels and consequently neuronal degeneration in the affected areas.
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PMID:Characteristics of the in vitro vasoactivity of beta-amyloid peptides. 951 24

Intracranial vasculitis, or primary angiitis of the central nervous system (PACNS), is an uncommon, often fatal disorder that frequently responds to aggressive immunosuppressive therapy. Magnetic resonance imaging (MRI), cerebral angiography, and brain biopsy are diagnostic modalities that vary in invasiveness and diagnostic accuracy. The purpose of this study was to determine whether certain clinical or radiologic features were predictive of a diagnostic biopsy. Thirty consecutive patients undergoing brain biopsy to "rule out vasculitis" were studied. Nine patients demonstrated granulomatous or lymphocytic vasculitis, 1 had lymphocytic vasculitis and encephalitis secondary to arbovirus infection, 5 had thickened vessels consistent with hypertensive changes, 5 had amyloid angiopathy and/or changes of Alzheimer disease, 5 demonstrated no pathologic abnormalities, and 1 each had acute infarct, vascular malformation, aneurysm, acellular fibrinoid necrosis, and demyelination. The spectrum of MRI and angiographic changes associated with PACNS were nonspecific, overlapping extensively with changes of chronic hypertension and amyloid deposition. The predictive values of brain biopsy (90-100%) were significantly higher than those of angiography (37-50%) or MRI (43-72%). In this study, morbidity associated with aggressive immunosuppression was significantly greater than that associated with cerebral angiography or brain biopsy. Thus, wedge biopsy of cortical and leptomeningeal tissues is central to the multi-disciplinary approach to a patient with clinical suspicion of PACNS.
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PMID:Diagnosis of intracranial vasculitis: a multi-disciplinary approach. 960 Jan 95

Extracellular deposition of amyloid beta protein (A beta) as senile plaques and cerebral amyloid angiopathy (CAA) is one of the essential pathological characteristics of Alzheimer's disease (AD). Several A beta species with different carboxyl termini, including A beta 42 (43) and A beta 40 ending at residue 42 (43) and 40, respectively, have been identified in CAA and in senile plaque cores. Because A beta 42 (43), the major component of diffuse plaque which is the earliest pathological change in AD brains, forms insoluble amyloid fibrils more rapidly than does A beta 40, it has been hypothesized that A beta 42 (43) plays a role in amyloid seeding and A beta 40, in the elongation of amyloid fibrils on a seed of A beta 42 (43). We used enzyme-linked immunosorbent assay (ELISA) with site-specific monoclonal antibodies to differentiate A beta 42 (43) from A beta 40. First, we measured the amounts of different A beta species in plasma from patients with sporadic probable AD, age-matched patients with neurologic diseases but without dementia, and age-matched normal controls. Concentrations of A beta 1-40 and A beta 1-42 (43) in plasma did not differ significantly among the three groups. Second, CSF levels of A beta species (CSF-A beta) with different carboxy termini, i.e., A beta X-40 and A beta X-42 (43) as well as A beta 1-40 and A beta 1-42 (43), were measured in patients with AD and in age-matched controls without dementia using ELISA. Levels of both CSF-A beta X-42 (43) and A beta 1-42 (43) were significantly lower in the patients with AD that in the controls, but neither the levels of CSF-A beta X-40 nor those of CSF-A beta 1-40 differed between the two groups, which suggest that increased adsorption of A beta 42 (43) to A beta deposition in AD brains, decreased secretion of A beta 42 (43) in CSF, or increased clearance of A beta 42 (43) from CSF might explain the low levels of A beta 42 (43) in the CSF of patients with AD. Third, we measured the concentrations of various A beta species post-mortem in the cerebral cortex of patients with PS-1 mutations and beta amyloid precursor protein (APP) 717 mutation linked to familial AD or Down syndrome. The results indicate that one effect of PS-1 mutations, APP717 mutation and Down syndrome is to cause dramatic and accelerated accumulation of A beta 42 (43) in the brain as compared with sporadic AD. In particular, the increases in A beta 1-42 (43) showed a crude inverse correlation with the age of onset in each subtype of AD. Thus, quantitative studies differentiating A beta 42 (43) from A beta 40 have established the fundamental importance of A beta 42 (43) in AD.
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PMID:[Characterization of amyloid beta protein species in the plasma, cerebrospinal fluid and brains of patients with Alzheimer's disease]. 964 8

Alzheimer's disease (AD) can be diagnosed with a considerable degree of accuracy. In some centers, clinical diagnosis predicts the autopsy diagnosis with 90% certainty in series reported from academic centers. The characteristic histopathologic changes at autopsy include neurofibrillary tangles, neuritic plaques, neuronal loss, and amyloid angiopathy. Mutations on chromosomes 21, 14, and 1 cause familial AD. Risk factors for AD include advanced age, lower intelligence, small head size, and history of head trauma; female gender may confer additional risks. Susceptibility genes do not cause the disease by themselves but, in combination with other genes or epigenetic factors, modulate the age of onset and increase the probability of developing AD. Among several putative susceptibility genes (on chromosomes 19, 12, and 6), the role of apolipoprotein E (ApoE) on chromosome 19 has been repeatedly confirmed. Protective factors include ApoE-2 genotype, history of estrogen replacement therapy in postmenopausal women, higher educational level, and history of use of nonsteroidal anti-inflammatory agents. The most proximal brain events associated with the clinical expression of dementia are progressive neuronal dysfunction and loss of neurons in specific regions of the brain. Although the cascade of antecedent events leading to the final common path of neurodegeneration must be determined in greater detail, the accumulation of stable amyloid is increasingly widely accepted as a central pathogenetic event. All mutations known to cause AD increase the production of beta-amyloid peptide. This protein is derived from amyloid precursor protein and, when aggregated in a beta-pleated sheet configuration, is neurotoxic and forms the core of neuritic plaques. Nerve cell loss in selected nuclei leads to neurochemical deficiencies, and the combination of neuronal loss and neurotransmitter deficits leads to the appearance of the dementia syndrome. The destructive aspects include neurochemical deficits that disrupt cell-to-cell communications, abnormal synthesis and accumulation of cytoskeletal proteins (e.g., tau), loss of synapses, pruning of dendrites, damage through oxidative metabolism, and cell death. The concepts of cognitive reserve and symptom thresholds may explain the effects of education, intelligence, and brain size on the occurrence and timing of AD symptoms. Advances in understanding the pathogenetic cascade of events that characterize AD provide a framework for early detection and therapeutic interventions, including transmitter replacement therapies, antioxidants, anti-inflammatory agents, estrogens, nerve growth factor, and drugs that prevent amyloid formation in the brain.
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PMID:Alzheimer's disease: etiologies, pathophysiology, cognitive reserve, and treatment opportunities. 967 58

Extracellular fluid in the central nervous system (CNS) is composed of cerebrospinal fluid (CSF), derived from the choroid plexus, and of interstitial fluid (ISF) in gray and white matter. Investigation of CSF plays a significant role in diagnosis and management of neurological disease and pathologies involving the CSF have important effects on the CNS itself. Hydrocephalus has many causes; clinical effects are due to a mixture of obstruction to CSF flow and damage to periventricular white matter with CSF edema, axonal loss and gliosis. Meningitis and subarachnoid hemorrhage are mainly confined to the subarachnoid space emphasising how this compartment is separated from the CNS by the pia mater and glia limitans; brain damage results from thrombosis of leptomeningeal vessels and infarction of CNS tissue. ISF from white matter appears to drain mainly to CSF, but ISF from gray matter drains along periarterial pathways in CNS and meninges, to lymph nodes in experimental animals, and probably in humans. Beta-amyloid in Alzheimer disease and prion proteins accumulate in the extracellular spaces of gray matter and in periarterial ISF drainage pathways as cerebral amyloid angiopathy, emphasising the role of periarterial drainage for the elimination of high molecular weight substances from the brain, possibly to regional lymph nodes. Lymphatic drainage of ISF drainage plays a major role in B- and T-lymphocyte mediated immune reactions in the CNS in animals. By analogy with experimental autoimmune encephalomyelitis, lymphatic drainage of brain antigens in ISF from the human CNS may play a key role in the pathogenesis of Multiple Sclerosis.
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PMID:Pathology of cerebrospinal fluid and interstitial fluid of the CNS: significance for Alzheimer disease, prion disorders and multiple sclerosis. 978 39

Alzheimer's disease (AD) is a neurodegenerative disorder that is the most common cause of dementia in the elderly. It is a clinical-pathologic entity characterized by progressive dementia associated with the neuropathologic hallmarks of Abeta amyloid plaques, neurofibrillary tangles (NFTs), neuronal loss, and amyloid angiopathy. Three "causative" AD genes (i.e., genes in which a mutation is sufficient to result in clinical AD) for early-onset familial Alzheimer's disease (FAD) and one "susceptibility" gene that affects risk and age of onset of AD in familial and sporadic late-onset AD have been identified. The three causative genes are the amyloid precursor protein (APP gene) on chromosome 21, the presenilin-1 gene on chromosome 14, and the presenilin-2 gene on chromosome 1. The susceptibility gene is the apolipoprotein E (APOE) gene on chromosome 19. Investigations of the normal and aberrant function of these genes will provide insights into the mechanisms underlying AD and will suggest new strategies for therapeutic intervention.
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PMID:Recent advances in the genetics of Alzheimer's disease. 987 25


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