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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The brains of individuals with Down's syndrome in their 40's and 50's begin to develop changes that are otherwise seen only in patients with Alzheimer disease. Neurons develop neurofibrillary tangles, flame-shaped alterations composed mainly of condensed cytoskeletal proteins. Another protein, beta/A4 amyloid, is deposited in large amounts in the form of senile plaques and, around blood vessels, amyloid angiopathy. With increasing age, Down syndrome individuals accumulate more and more of these changes. Different parts of the brain are affected to varying degrees by these two alterations. Surprisingly, the pattern of accumulation of neurofibrillary tangles and senile plaques is characteristic, and follows a predictable pattern. We have characterized this pattern in the hippocampal formation in a group of Down individuals, ages 13-71. Certain specific neurons such as those in layer II of entorhinal cortex and the CA1/subiculum field of the hippocampus are exquisitely vulnerable to tangle formation, and are the first neurons to be affected. Perhaps 20-30 years pass as the disease process evolves from mild to severe pathological changes. One hypothesis for why Down individuals would be predisposed to developing Alzheimer pathology is the observation that the gene that encodes the precursor of the amyloid protein is located on chromosome 21. An extra copy of this gene, such as occurs in Down syndrome, may lead to "overproduction" of amyloid, and ultimately to its accumulation as senile plaques. Experiments to test this hypothesis are now underway.
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PMID:Down syndrome and Alzheimer disease. 140 40

Clinical, radiological, and immunohistochemical findings in brain biopsy specimens from six patients with cerebral amyloid angiopathy-associated intracerebral hemorrhage were reviewed. Acute clinical presentations included headache, nausea and vomiting, loss of consciousness, and focal neurological deficits such as hemiplegia and blindness. Transient ischemic attacks experienced by one patient and referable to one hemisphere did not indicate impending hemorrhage in that region. Computed tomographic scans revealed acute, irregular, superficial, lobar hemorrhage with occasional ring enhancement. Immunohistochemical studies were performed on biopsy specimens using primary antibodies against portions of the Alzheimer A4 (beta-) peptide or gamma-trace peptide (the vascular amyloid protein in patients with hereditary cerebral hemorrhage with amyloidosis-Icelandic type). In all patients, anti-A4 and anti-gamma-trace labeled cerebral microvessels. Immunoreactive senile plaques were few compared with the numbers of stained microvessels. Reactive astrocytes in some patients were labeled by both antiserum samples, suggesting uptake or production of these proteins by the astrocytes. This study demonstrates the heterogeneous clinical and radiological features of cerebral amyloid angiopathy-related brain hemorrhage and the value of anti-A4 and anti-gamma-trace immunohistochemical study of biopsy material from patients with suspected cerebral amyloid angiopathy-related intraparenchymal bleeding.
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PMID:Cerebral hemorrhage with biopsy-proved amyloid angiopathy. 172 64

At the cellular level, Alzheimer's disease (AD) must be the result of neuronal dysfunction and degeneration leading to a reduction in synaptic density. Filamentous deposits of amyloid, which define the disease at the molecular level, occur within perikarya, axons, dendrites, and terminals of neurons as neurofibrillary tangles (NFT), in the extracellular neuropil as amyloid plaques (APC), and around blood vessels as amyloid congophilic angiopathy (ACA). These fibrillar amyloid protein aggregates are also found in the brain of all individuals with Down's syndrome after the age of 30 years. The amyloid deposits apparently occur in the terminal zones of neurons that develop NFT. It is suggested that amyloid deposition is of fundamental significance in AD and that a thorough understanding of amyloid formation will eventually lead to successful therapeutic intervention in AD. As elucidation of the reasons behind amyloid deposition must shed some light on the pathogenesis of AD, we review the current state of knowledge on the nature of the AD amyloid protein, its origin, and its formation. Although there is yet no agreement about the chemical nature of the amyloid protein of NFT, the major constituent of both APC and ACA has been shown to be a 4.5-kD amyloid protein originally termed "beta-protein" or "amyloid A4" which we now denote as "beta A4." Amyloid beta A4 protein is proteolytically derived from a transmembrane protein termed amyloid precursor protein (APP) which is encoded by a widely expressed gene on chromosome 21. Our present results are consistent with the possibility that amyloid formation requires membrane damage or APP molecules that are not or are incorrectly integrated into membranes. To allow the generation of the C-terminus of beta A4, one proteolytic cleavage step has to occur in the sequence that normally forms the transmembrane domain of the APP proteins. This cleavage is crucial for amyloid formation because we could show that the ability of synthetic beta A4 to form amyloid depositions is mainly based on hydrophobic parts of the sequence that have to interact with each other and build up large aggregates under physiologic conditions. Membrane association of APP is expected to interfere with this cleavage and the process of aggregation.
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PMID:Mechanisms of amyloid deposition in Alzheimer's disease. 177 29

To clarify the pathogenesis of cerebrovascular amyloid deposits, histological and immunocytochemical studies were performed on the central nervous system (CNS) in ten cases with type I familial amyloid polyneuropathy (FAP). They commonly suffered from peripheral somatic and autonomic nerve disorders without any CNS dysfunctions. However, all cases showed CNS amyloid deposits, mainly on the leptomeningeal vessels and pia-arachnoid membranes, with arteries and arterioles in the subarachnoidal space being the predominant site of cerebral amyloid accumulation. Using immunocytochemical staining methods with antibodies to amyloid beta-protein, human cystatin C and transthyretin (prealbumin), all of these amyloid deposits were specifically immunolabeled by the anti-human transthyretin antibody. However, there was no transthyretin-related amyloid deposits in the brain parenchyma. It is concluded that CNS transthyretin-immunoreactive amyloid deposition with cerebral amyloid angiopathy (CAA) is a common pathological finding in this disease. Moreover, the patients with type I FAP are known to have an amyloid protein precursor (a variant of transthyretin) in serum. This transthyretin type of CAA, therefore, seems to be an example of cerebrovascular amyloid deposits derived from a serum precursor.
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PMID:Transthyretin-type cerebral amyloid angiopathy in type I familial amyloid polyneuropathy. 185 83

Tissue plasminogen activator (t-PA) has been approved as thrombolytic therapy for the treatment of acute myocardial infarction, but this agent can cause serious bleeding complications including intracerebral hemorrhages. Mechanisms underlying the development of these hemorrhages have not been clarified. We report a patient who developed two intracerebral hemorrhages shortly after receiving t-PA for the treatment of an acute myocardial infarction, and who was found to have cerebral amyloid angiopathy at autopsy. Staining of cortical sections with Congo red and an antibody directed against beta amyloid protein (A4 peptide) disclosed specific involvement of most of the subarachnoid and superficial cortical vessels in the region of the two hemorrhages. Based on the findings in this patient and in 6 additional patients reported recently, it is likely that cerebral amyloid angiopathy plays a pathogenic role in some intracerebral hemorrhages associated with the administration of t-PA. The cautious use of t-PA with heparin in patients who are elderly or demented may be advisable.
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PMID:Intracerebral hemorrhage related to cerebral amyloid angiopathy and t-PA treatment. 191 Feb 76

An amyloid protein that precipitates in the cerebral vessel walls of Dutch patients with hereditary cerebral hemorrhage with amyloidosis is similar to the amyloid protein in vessel walls and senile plaques in brains of patients with Alzheimer's disease, Down syndrome, and sporadic cerebral amyloid angiopathy. Cloning and sequencing of the two exons that encode the amyloid protein from two patients with this amyloidosis revealed a cytosine-to-guanine transversion, a mutation that caused a single amino acid substitution (glutamine instead of glutamic acid) at position 22 of the amyloid protein. The mutation may account for the deposition of this amyloid protein in the cerebral vessel walls of these patients, leading to cerebral hemorrhages and premature death.
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PMID:Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. 211 84

Amyloid fibrils deposited in cerebral vessel walls in Dutch patients with hereditary cerebral hemorrhage with amyloidosis (HCHWA-D) are formed by polymerization of a 39-residue peptide similar to the beta-protein of Alzheimer's disease, Down syndrome, sporadic cerebral amyloid angiopathy and normal aging. Sequence analysis of genomic DNA in HCHWA-D patients demonstrated a point mutation, cytosine for guanine at position 1852 of the precursor beta-protein gene, which causes a single amino acid substitution (glutamine for glutamic acid) corresponding to position 22 of the amyloid protein. The normal allele was also present in these patients. To examine the expression of normal and variant beta-protein alleles in HCHWA-D we analyzed all the tryptic peptides obtained from several amyloid fractions from leptomeningeal vascular walls. Amino acid sequence of two peptides (T3a and T3b) with identical amino acid composition revealed that T3a had glutamine and T3b had glutamic acid at position 22. Thus both the normal and variant Alzheimer's beta-protein alleles are expressed in vascular amyloid in HCHWA-D and may be detected by tryptic peptide mapping. Moreover, we have developed a diagnostic assay for high risk populations and prenatal evaluation that is based on the existence of the mutation.
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PMID:Expression of a normal and variant Alzheimer's beta-protein gene in amyloid of hereditary cerebral hemorrhage, Dutch type: DNA and protein diagnostic assays. 219 78

Using immunohistochemical staining methods with antibodies to amyloid beta protein and human cystatin C, we examined cerebrovascular amyloid protein in the brains from 46 cases with cerebral amyloid angiopathy (seven with Alzheimer's disease, one with Down's syndrome, 18 with intracranial hemorrhage, 10 with cerebral infarction, and 10 elderly patients without any neurologic disorder). All cerebrovascular amyloid deposits in these 46 cases were consistently immunoreactive to anti-beta protein antibody. However, in nine cases some vascular walls with strong beta protein immunoreactivity also reacted less intensely with the anti-cystatin C antiserum. Of these nine cases, seven showed relatively heavy cerebrovascular amyloid deposition, and all seven had suffered a fatal subcortical hemorrhage presumably caused by cerebral amyloid angiopathy. Previous limited studies have suggested that the amyloid protein seen in elderly individuals with cerebral amyloid angiopathy is composed of beta protein. However, subcortical hemorrhage rarely occurs in such individuals. Our study shows that aged patients with different brain disorders commonly suffer from beta protein-type cerebral amyloid angiopathy, and we also suggest that the severity of beta protein-type cerebrovascular amyloid deposition is a fundamental factor in cerebral amyloid angiopathy-induced brain hemorrhage in the elderly. The nature of the cystatin C-immunoreactive substance in some of these vascular lesions is uncertain, but it might conceivably play an additional important role in the pathogenesis of brain hemorrhage in these cases.
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PMID:Immunohistochemical characterization of cerebrovascular amyloid in 46 autopsied cases using antibodies to beta protein and cystatin C. 221 20

Two types of familial cerebral amyloid angiopathy or hereditary cerebral hemorrhage with amyloidosis (HCHWA) have been described: the Icelandic type (HCHWA-I), and the Dutch type (HCHWA-D). Both are autosomal-dominant forms of amyloidosis restricted to the small vasculature of the brain and clinically characterized by recurrent strokes leading to an early death. In spite of their clinico-pathological similarities, the amyloid fibrils are structurally different. In the case of HCHWA-I, the amyloid protein is a degradation product of Cystatin C variant (gamma trace), a normal serum protein and an inhibitor of cysteine proteases. The amyloid protein is the expression of a genetic aberration, since it has been demonstrated that a point mutation occurred in the Cystatin C gene. On the other hand the amyloid protein in HCHWA-D type has very recently been shown to be related to Alzheimer's disease (AD) and Down's syndrome (DS) beta-protein. However, the complete sequence of HCHWA-D beta-protein obtained from leptomeninges was three residues shorter (39 instead of 42) than that reported for the insoluble plaque amyloid of AD. The distinct enzymatic cleavage at the carboxyl end of the beta protein is consistent with the concept that the amyloid fibrils derive from a larger precursor by specific and partial degradation. The difference may reflect a particular type of proteolysis that occurs in the vessel wall and not in the brain parenchyma.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Systemic and cerebral amyloidosis. 266 46

The nature of senile plaques (SP) in 27 cases of diffuse Lewy body disease (LBD) was investigated using immunocytochemistry and antibodies to beta amyloid protein synthetic peptides (BetaSP), ubiquitin (UBQ), paired helical filaments (PHF; Ab39) and a 68-kDa protein in Alzheimer brains (Alz50). Lewy bodies were present in widespread areas of the neocortex of all cases and were more easily detected with ubiquitin immunocytochemistry than with conventional stains. All cases had neocortical SP, but only six cases had neocortical neurofibrillary tangles (NFT). SP were very numerous in most cases and were usually "pale", "diffuse" or "very primitive" plaques with thioflavin S fluorescent microscopy. SP in diffuse LBD were immunostained with BetaSP. Several cases had extensive amyloid angiopathy that was also immunoreactive with BetaSP. SP in diffuse LBD were characterized by amyloid deposits with few or no neuritic elements that could be detected with thioflavin S, Bielschowsky's stain or double staining with BetaSP and Bodian's silver stain. They differed from plaques in Alzheimer's disease by lack of PHF-type neurites that could be stained with Ab39. In diffuse LBD, SP contained PHF-type neurites only in areas coexistent with NFT. Some SP had round, granular neurites that were immunoreactive with UBQ, but weakly argyrophilic with Bodian's stain and nonfluorescent with thioflavin S. Diffuse LBD lacked significant neuritic change in the neuropil that could be detected with UBQ, Ab39 and Alz50. The latter finding is a characteristic feature that distinguishes Alzheimer's disease from diffuse LBD.
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PMID:Diffuse Lewy body disease: light and electron microscopic immunocytochemistry of senile plaques. 268 63


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