1/21. Novel presenilin-1 mutation with widespread cortical amyloid deposition but limited cerebral amyloid angiopathy.OBJECTIVE: To clarify the phenotypic heterogeneity in deposition of amyloid beta (Abeta) in the parenchyma and in cerebral vessels of the brains of the patients having presenilin-1 (PS1) mutations. Mutations in PS1 induce increased production of Abeta42(43), resulting in an enhanced overall deposition of Abeta protein within the cerebral cortex. methods: sequence analysis of the PS1 gene of dna from patients with early onset Alzheimer's disease, and immunostaining of brain tissues by end specific monoclonal antibodies against Abeta. RESULTS: sequence analysis disclosed a novel mutation (N405S) in the PS1 gene in a Japanese patient with early-onset Alzheimer's disease. Postmortem examination of one patient with N405S showed limited cerebral amyloid angiopathy, whereas postmortem examination of another Japanese patient with Alzheimer's disease with the E184D mutation disclosed severe cerebral amyloid angiopathy. The brains of both patients showed widespread neuritic plaques, neurofibrillary tangles, and neuronal loss. Immunostaining showed that Abeta42 was predominant over Abeta40 in neuritic plaques in both patients, whereas Abeta40 was found to be predominant over Abeta42 in cerebral amyloid angiopathy in the patient with E184D. However, most cortical vessels of the patient with N405S were not reactive with either of the antibodies. CONCLUSION: The N405S mutation of PS1 is a major determinant of cortical Abeta deposition but not cerebral amyloid angiopathy in Alzheimer's disease.- - - - - - - - - - ranking = 1keywords = vessel (Clic here for more details about this article) |
2/21. Cerebrovascular pathology in Alzheimer's disease and leukoaraiosis.A high percentage of patients with Alzheimer's disease (AD) show evidence of white matter degeneration known as leukoaraiosis (LA), which is due to chronic ischemia. We found that the periventricular veins tend to become occluded by multiple layers of collagen in the vessel walls in the elderly. This collagen deposition is particularly excessive in LA lesions. Therefore, it is present in the brains of many AD patients, along with other ischemia-causing cerebrovascular pathology. We found evidence that there is severe loss of oligodendrocytes in LA, due to extensive apoptosis. No evidence of inflammation was found in the LA lesions. In thick celloidin sections of AD brain, we have obtained detailed 3D views of small (early) deposits of amyloid (stained with beta-amyloid antibody) around capillaries (stained with collagen IV antibody).- - - - - - - - - - ranking = 0.5keywords = vessel (Clic here for more details about this article) |
3/21. Vascular and metabolic reserve in Alzheimer's disease.Vascular and metabolic reserve were analyzed in probable Alzheimer's disease (AD) and vascular dementia (VaD). Cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral metabolic rate of oxygen (CMRO(2)), and oxygen extraction fraction (OEF) were measured quantitatively with positron emission tomography (PET). Vascular reactivity (VR) was also calculated by comparing the CBF during 5% CO(2) inhalation with the CBF during normal breathing. Vascular transit time (VTT) that was calculated as a ratio of CBV/CBF and VR reflect vasodilating capacity of the small resistance vessels, whereas OEF designates metabolic (oxygen-extraction) reserve in threatening brain ischemia. Significant increase in OEF was seen in the parieto-temporal cortex and both VTT and VR were preserved in AD patients. By constrast, there was no significant increase in OEF whereas VTT was prolonged and VR was markedly depressed in VaD patients. The increase of OEF and preserved VTT and VR seen in AD patients indicate the possible participation of vascular factors in the pathogenesis of AD perhaps at the capillary level.- - - - - - - - - - ranking = 0.5keywords = vessel (Clic here for more details about this article) |
4/21. Senile dementia associated with amyloid beta protein angiopathy and tau perivascular pathology but not neuritic plaques in patients homozygous for the APOE-epsilon4 allele.Amyloid beta protein deposition in cortical and leptomeningeal vessels, causing the most common type of cerebral amyloid angiopathy, is found in sporadic and familial Alzheimer's disease (AD) and is the principal feature in the hereditary cerebral hemorrhage with amyloidosis, Dutch type. The presence of the Apolipopriotein E (APOE)-epsilon4 allele has been implicated as a risk factor for AD and the development of cerebral amyloid angiopathy in AD. We report clinical, pathological and biochemical studies on two APOE-epsilon4 homozygous subjects, who had senile dementia and whose main neuropathological feature was a severe and diffuse amyloid angiopathy associated with perivascular tau neurofibrillary pathology. Amyloid beta protein and ApoE immunoreactivity were observed in leptomeningeal vessels as well as in medium-sized and small vessels and capillaries in the parenchyma of the neocortex, hippocampus, thalamus, cerebellum, midbrain, pons, and medulla. The predominant peptide form of amyloid beta protein was that terminating at residue Val40, as determined by immunohistochemistry, amino acid sequence and mass spectrometry analysis. A crown of tau-immunopositive cell processes was consistently present around blood vessels. dna sequence analysis of the Amyloid Precursor Protein gene and presenilin-1 (PS-1) gene revealed no mutations. In these APOE-epsilon4 homozygous patients, the pathological process differed from that typically seen in AD in that they showed a heavy burden of perivascular tau-immunopositive cell processes associated with severe amyloid beta protein angiopathy, neurofibrillary tangles, some cortical lewy bodies and an absence of neuritic plaques. These cases emphasize the concept that tau deposits may be pathogenetically related to amyloid beta protein deposition.- - - - - - - - - - ranking = 2keywords = vessel (Clic here for more details about this article) |
5/21. Amyloid angiopathy and variability in amyloid beta deposition is determined by mutation position in presenilin-1-linked Alzheimer's disease.The presenilins (PSs) are components of large molecular complexes that contain beta-catenin and function as gamma-secretase. We report here a striking correlation between amyloid angiopathy and the location of mutation in PS-1 linked Alzheimer's disease. The amount of amyloid beta protein, Abeta(42(43)), but not Abeta(40,) deposited in the frontal cortex of the brain is increased in 54 cases of early-onset familial Alzheimer's disease, encompassing 25 mutations in the presenilin-1 (PS-1) gene, compared to sporadic Alzheimer's disease. The amount of Abeta(40) in PS-1 Alzheimer's disease varied according to the copy number of epsilon4 alleles of the Apolipoprotein E gene. Although the amounts of Abeta(40) and Abeta(42(43)) deposited did not correlate with the genetic location of the mutation in a strict linear sense, the histological profile did so vary. Cases with mutations between codon 1 and 200 showed, in frontal cortex, many diffuse plaques, few cored plaques, and mild or moderate amyloid angiopathy. Cases with mutations occurring after codon 200 also showed many diffuse plaques, but the number and size of cored plaques were increased (even when epsilon4 allele was not present) and these were often clustered around blood vessels severely affected by amyloid angiopathy. Similarly, diverging histological profiles, mainly according to the degree of amyloid angiopathy, were seen in the cerebellum. Mutations in the PS-1 gene may therefore alter the topology of the PS-1 protein so as to favor Abeta formation and deposition, generally, but also to facilitate amyloid angiopathy particularly in cases in which the mutation lies beyond codon 200. Finally we report that the amount of Abeta(42(43)) deposited in the brain correlated with the amount of this produced in culture by cells bearing the equivalent mutations.- - - - - - - - - - ranking = 0.5keywords = vessel (Clic here for more details about this article) |
6/21. The effects of AbetaPP mutations and APOE polymorphisms on cerebral amyloid angiopathy.Analysis of causative mutations and genetic risk factors aid in the understanding of important processes of cerebral amyloid angiopathy (CAA) in humans. We identified a mutation at a novel site of the beta-amyloid precursor protein (AbetaPP) gene associated with familial CAA; this mutation causes an aspartate to asparagine substitution at position 23 of the Abeta peptide. Neuropathological analysis of a 68-year-old man with this mutation showed dramatic Abeta deposition in blood vessels, diffiuse parenchymal Abeta deposits, dystrophic neurites and neurofibrillary tangles. The Abeta deposition showed complete co-localization of Abeta40 and Abeta42, compared to the predominant Abeta42 deposition seen in AD. We hypothesize that the loss of an acidic residue at position 23 of Abeta might be important in the process of Abeta aggregation on smooth muscle cells on the cerebrovasculature. We also analyzed how the apolipoprotein E (APOE) gene might influence aggregation of Abeta by examining the physical association of apoE domains with Abeta via immunohistochemistry. We found that the lipid-binding domain of apoE was more strongly associated with Abeta than the receptor-binding domain, and that 40% of all Abeta deposits had no apoE bound to them. We suggest that the initial deposition of Abeta occurs in the absence of apoE, and that the process of Abeta deposit growth or stabilization is apoE-dependent.- - - - - - - - - - ranking = 0.5keywords = vessel (Clic here for more details about this article) |
7/21. cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease due to a novel presenilin 1 mutation.The dense-cored plaques are considered the pathogenic type of amyloid deposition in Alzheimer's disease brains because of their predominant association with dystrophic neurites. Nevertheless, in > 90% of cases of Alzheimer's disease amyloid is also deposited in cerebral blood vessel walls (congophilic amyloid angiopathy; CAA) but its role in Alzheimer's disease pathogenesis remains enigmatic. Here, we report a family (family GB) in which early-onset Alzheimer's disease was caused by a novel presenilin 1 mutation (L282V). This was unusually severe CAA reminiscent of the Flemish amyloid precursor protein (A692G) mutation we reported previously, which causes Alzheimer's disease and/or cerebral haemorrhages. In family GB, however, the disease presented as typical progressive Alzheimer's disease in the absence of strokes or stroke-like episodes. Similarly, neuroimaging studies and neuropathological examination favoured a degenerative over a vascular dementia. Interestingly, an immunohistochemical study revealed that, similar to causing dense-cored amyloid plaques, CAA also appeared capable of instigating a strong local dystrophic and inflammatory reaction. This was suggested by the observed neuronal loss, the presence of tau- and ubiquitin-positive neurites, micro- and astrogliosis, and complement activation. Together, these data suggest that, like the dense-cored neuritic plaques, CAA might represent a pathogenic lesion that contributes significantly to the progressive neurodegeneration that occurs in Alzheimer's disease.- - - - - - - - - - ranking = 0.5keywords = vessel (Clic here for more details about this article) |
8/21. presenilin-1 mutation (E280G), spastic paraparesis, and cranial MRI white-matter abnormalities.The authors report unusual presentations of members of an Irish family with familial AD due to an E280G mutation in exon 8 of presenilin-1. One had spastic paraparesis and white matter abnormalities on cranial MRI. A sibling had an internuclear ophthalmoplegia, spastic-ataxic quadriparesis, and "cotton-wool plaques" with amyloid angiopathy on brain biopsy. Another affected sibling also had MRI white matter abnormalities. The MRI findings may reflect an ischemic leukoencephalopathy due to amyloid angiopathy affecting meningocortical vessels.- - - - - - - - - - ranking = 0.5keywords = vessel (Clic here for more details about this article) |
9/21. Mini-infarct encephalopathy associated with uncommon microvessel convolute formation presenting with presenile dementia.A female patient started to suffer from transient ischemic attacks when she was 47 years of age, followed by increasing predominantly left-side spastic tetraparesis, generalized seizures and progressive dementia over a period of 11 years. She died when she was 58 years of age. On gross examination the brain showed enlarged ventricles and arteriosclerotic changes of large extracerebral vessels of the circulus arteriosus. Microscopic examination of the atrophic brain showed innumerable incomplete microinfarcts in the white and gray matter throughout all parts of the brain. In the white matter these lesions were characterized by small foci of demyelination and loss of oligodendrocytes while occasionally some scavenger cells were seen. axons seemed to be unaffected or displayed irregular axonal regeneratory growth. Any inflammatory reaction failed. In the cerebral cortex and subcortical nuclei the lesions showed loss of neurons and decrease in synaptophysin expression. Intracerebral arteries showed fibrosis or fibrohyalinosis of the entire intracerebral small-vessel network. In addition, numerous uncommon clusters of angioma-like telangiectatic vessels were observed. Medium-sized ischemic infarcts were found in the right putamen and adjacent internal capsule region, left-side dorsolateral brain stem and cerebellar hemisphere as well as a left-side pyramidal tract degeneration. Contralateral pseudohypertrophy of the inferior olivary nucleus was seen. The clinical and the neuropathologic observations made in this patient are compatible with small vessel disease characterized by a multicentric special and not yet described type of incomplete mini-infarcts in cerebral cortex and white matter accompanied by some larger ischemic infarcts of the common type in brain stem and cerebellum.- - - - - - - - - - ranking = 4keywords = vessel (Clic here for more details about this article) |
10/21. Involvement of immature endothelial cells in vascular alterations in Alzheimer's disease.The aim of the present study was to investigate ultrastructural features of cerebral capillaries and the pattern of new vessel formation in a patient with Alzheimer's disease (AD). Recent neuropathological studies have demonstrated that patients with AD have cerebrovascular pathology. Using electron microscopy, we showed that alterations of the capillaries are a common finding both in vascular disease and in AD, suggesting that vascular factors may also play a role in the pathogenesis of AD. We also found regionally increased capillary density, and in many sections immature endothelial cells lying on the preexisting endothelium were present in the lumen of capillaries. These cells might thus contribute to the pathological pattern of capillaries. The cytoplasm of immature endothelial cells in the patient with AD was characterized by accumulation of amyloid fibrils. We suggest that immature endothelial cells may be an important source of circulation-derived amyloid in the brain.- - - - - - - - - - ranking = 0.5keywords = vessel (Clic here for more details about this article) |
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