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Cerebral Amyloid Angiopathy (cerebral + amyloid_angiopathy)
Selected AbstractsOligomeric A, in Alzheimer's Disease: Relationship to Plaque and Tangle Pathology, APOE Genotype and Cerebral Amyloid AngiopathyBRAIN PATHOLOGY, Issue 2 2010Zoë Van Helmond Abstract Despite accumulating evidence of a central role for oligomeric amyloid , (A,) in the pathogenesis of Alzheimer's Disease (AD), there is scant information on the relationship between the levels and distribution of oligomeric A, and those of other neurodegenerative abnormalities in AD. In the present study, we have found oligomeric A, to be associated with both diffuse and neuritic plaques (mostly co-localized with A,1,42) and with cerebrovascular deposits of A, in paraffin sections of formalin-fixed human brain tissue. The amount of oligomeric A, that was labeled in the sections correlated with total A, plaque load, but not phospho-tau load, cerebral amyloid angiopathy (CAA) severity or APOE genotype. Although soluble, oligomeric and insoluble A, levels were all significantly increased in AD brain homogenates, case-to-case variation and overlap between AD and controls were considerable. Over the age-range studied (43,98 years), the levels of soluble A,, oligomeric A,42, oligomeric A,40 and insoluble A, did not vary significantly with age. Oligomeric A,1,42 and insoluble A, levels were significantly higher in women. Overall, the level of insoluble A,, but neither oligomeric nor soluble A,, was associated with Braak stage, CAA severity and APOE,4 frequency, raising questions as to the role of soluble and oligomeric A, in the progression of AD. [source] The Role of Cystatin C in Cerebral Amyloid Angiopathy and Stroke: Cell Biology and Animal ModelsBRAIN PATHOLOGY, Issue 1 2006Efrat Levy A variant of the cysteine protease inhibitor, cystatin c, forms amyloid deposited in the cerebral vasculature of patients with hereditary cerebral hemorrhage with amyloidosis, icelandic type (hchwa-i), leading to cerebral hemorrhages early in life. however, cystatin c is also implicated in neuronal degenerative diseases in which it does not form the amyloid protein, such as alzheimer disease (ad). accumulating data suggest involvement of cystatin c in the pathogenic processes leading to amyloid deposition in cerebral vasculature and most significantly to cerebral hemorrhage in patients with cerebral amyloid angiopathy (caa). This review focuses on cell culture and animal models used to study the role of cystatin c in these processes. [source] Cerebral amyloid angiopathy: An overviewNEUROPATHOLOGY, Issue 1 2000Masahito Yamada Cerebral amyloid angiopathy (CAA) is characterized by amyloid deposition in cortical and leptomeningeal vessels. Several cerebrovascular amyloid proteins (amyloid ,-protein (A,), cystatin C (ACys), prion protein (AScr), transthyretin (ATTR), gelsolin (AGel), and ABri (or A-WD)) have been identified, leading to the classification of several types of CAA. Sporadic CAA of A, type is commonly found in elderly individuals and patients with Alzheimer's disease. Cerebral amyloid angiopathy is an important cause of cerebrovascular disorders including lobar cerebral hemorrhage, leukoencephalopathy, and small cortical hemorrhage and infarction. We review the clinicopathological and molecular aspects of CAA and discuss the pathogenesis of CAA with future perspectives. [source] Cerebrospinal fluid amyloid ,40 is decreased in cerebral amyloid angiopathy,ANNALS OF NEUROLOGY, Issue 2 2009Marcel M. Verbeek MSc Cerebral amyloid angiopathy is caused by deposition of the amyloid , protein in the cerebral vasculature. In analogy to previous observations in Alzheimer disease, we hypothesized that analysis of amyloid ,40 and ,42 proteins in the cerebrospinal fluid might serve as a molecular biomarker. We observed strongly decreased cerebrospinal fluid amyloid ,40 (p < 0.01 vs controls or Alzheimer disease) and amyloid ,42 concentrations (p < 0.001 vs controls and p < 0.05 vs Alzheimer disease) in cerebral amyloid angiopathy patients. The combination of amyloid ,42 and total tau discriminated cerebral amyloid angiopathy from controls, with an area under the receiver operator curve of 0.98. Our data are consistent with neuropathological evidence that amyloid ,40 as well as amyloid ,42 protein are selectively trapped in the cerebral vasculature from interstitial fluid drainage pathways that otherwise transport amyloid , proteins toward the cerebrospinal fluid. Ann Neurol 2009;66:245,249 [source] Dementia in hereditary cerebral hemorrhage with amyloidosis-Dutch type is associated with cerebral amyloid angiopathy but is independent of plaques and neurofibrillary tanglesANNALS OF NEUROLOGY, Issue 6 2001Remco Natté MD Cerebral amyloid angiopathy is frequently found in demented and nondemented elderly persons, but its contribution to the causation of dementia is unknown. Therefore, we investigated the relation between the amount of cerebral amyloid angiopathy and the presence of dementia in 19 patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type. The advantage of studying hereditary cerebral hemorrhage in amyloidosis-Dutch type is that patients with this disease consistently have severe cerebral amyloid angiopathy with minimal neurofibrillary pathology. The amount of cerebral amyloid angiopathy, as quantified by computerized morphometry, was strongly associated with the presence of dementia independent of neurofibrillary pathology, plaque density, or age. The number of cortical amyloid ,-laden severely stenotic vessels, vessel-within-vessel configurations, and cerebral amyloid angiopathy-associated microvasculopathies was associated with the amount of cerebral amyloid angiopathy and dementia. A semiquantitative score, based on the number of amyloid ,-laden severely stenotic vessels, completely separated demented from nondemented patients. These results suggest that extensive (more than 15 amyloid ,-laden severely stenotic vessels in five frontal cortical sections) cerebral amyloid angiopathy alone is sufficient to cause dementia in hereditary cerebral hemorrhage with amyloidosis,Dutch type. This may have implications for clinicopathological correlations in Alzheimer's disease and other dementias with cerebral amyloid angiopathy. [source] Clinical image: Cerebral amyloid angiopathyARTHRITIS & RHEUMATISM, Issue 7 2009Chien-Hsueh Tung MD No abstract is available for this article. [source] Cerebral Microinfarcts Associated with Severe Cerebral ,-Amyloid AngiopathyBRAIN PATHOLOGY, Issue 2 2010Virawudh Soontornniyomkij Abstract Cerebral amyloid angiopathy (CAA) is common in elderly individuals, especially those affected with Alzheimer's disease. Eighteen brains with severe SCAA (SCAA) were compared with 21 brains with mild CAA (MCAA) to investigate whether the presence of SCAA in the brains of demented patients was associated with a higher burden of old microinfarcts than those with MCAA. Immunohistochemistry for CD68 was employed to highlight old microinfarcts in tissue blocks from various brain regions. Old microinfarcts, manually counted by light microscopy, were present in 14 of 18 SCAA brains and in 7 of 21 MCAA brains (P = 0.01, two-tailed Fisher's exact test). The average number of old microinfarcts across geographic regions in each brain ranged from 0 to 1.95 (mean rank 24.94, sum of ranks 449) in the SCAA group, and from 0 to 0.35 (mean rank 15.76, sum of ranks 331) in the MCAA group (P = 0.008, two-tailed Mann,Whitney U-test). Frequent old microinfarcts in demented individuals with severe CAA may contribute a vascular component to the cognitive impairment in these patients. [source] Clinical features of non-hypertensive lobar intracerebral hemorrhage related to cerebral amyloid angiopathyEUROPEAN JOURNAL OF NEUROLOGY, Issue 6 2010M. Hirohata Background and purpose: The present study aims to clarify the clinical features of non-hypertensive cerebral amyloid angiopathy-related lobar intracerebral hemorrhage (CAA-L-ICH). Methods: We investigated clinical, laboratory, and neuroimaging findings in 41 patients (30, women; 11, men) with pathologically supported CAA-L-ICH from 303 non-hypertensive Japanese patients aged ,55, identified via a nationwide survey as symptomatic CAA-L-ICH. Results: The mean age of patients at onset of CAA-L-ICH was 73.2 ± 7.4 years; the number of patients increased with age. The corrected female-to-male ratio for the population was 2.2, with significant female predominance. At onset, 7.3% of patients received anti-platelet therapy. In brain imaging studies, the actual frequency of CAA-L-ICHs was higher in the frontal and parietal lobes; however, after correcting for the estimated cortical volume, the parietal lobe was found to be the most frequently affected. CAA-L-ICH recurred in 31.7% of patients during the average 35.3-month follow-up period. The mean interval between intracerebral hemorrhages (ICHs) was 11.3 months. The case fatality rate was 12.2% at 1 month and 19.5% at 12 months after initial ICH. In 97.1% of patients, neurosurgical procedures were performed without uncontrollable intraoperative or post-operative hemorrhage. Conclusions: Our study revealed the clinical features of non-hypertensive CAA-L-ICH, including its parietal predilection, which will require further study with a larger number of patients with different ethnic backgrounds. [source] Cerebral vascular accumulation of Dutch-type A,42, but not wild-type A,42, in hereditary cerebral hemorrhage with amyloidosis, Dutch typeJOURNAL OF NEUROSCIENCE RESEARCH, Issue 13 2007Kazuchika Nishitsuji Abstract Hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), is an autosomal dominant disorder caused by the Dutch mutation (E693Q) in the ,-amyloid precursor protein. This mutation produces an aberrant amyloid , (A,) species (A,E22Q) and causes severe meningocortical vascular A, deposition. We analyzed the A, composition of the vascular amyloid in the brains of HCHWA-D patients. Immunohistochemistry demonstrated that the vascular amyloid contained both A,40 and A,42, with a high A,40/A,42 ratio. In Western blotting of cerebral microvessel fractions isolated from the brains, both wild-type and Dutch-type A,40 were observed as major species. Reverse-phase HPLC-mass spectrometric analysis of the fractions revealed both wild-type and Dutch-type A,38 as the other main components of the vascular amyloid. Moreover, we detected peaks corresponding to Dutch-type A,42 but not to wild-type A,42. These results suggest a pathogenic role for the mutant A,42 in addition to the mutant A,40 in the cerebral amyloid angiopathy of HCHWA-D. © 2007 Wiley-Liss, Inc. [source] Hereditary cerebral hemorrhage with amyloidosis-Dutch typeNEUROPATHOLOGY, Issue 4 2005Marion Maat-Schieman The amyloid ,-protein (A,) E22Q mutation of the rare disorder hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) causes severe cerebral amyloid angiopathy (CAA) with hemorrhagic strokes of mid-life onset and dementia. The mutation does not affect total A, production but may alter the A,1,42:A,1,40 ratio, and affect the proteolytic degradation of A, and its transport across the blood,brain barrier. A, E22Q aggregates faster into more stable amyloid-like fibrils than wild-type A,. Non-fibrillar A,(x-42) deposits precede the appearance of fibrils and the deposition of A,(x-40) in the vascular basement membrane. CAA severity tends to increase with age but may vary greatly among patients of comparable ages. Lumenal narrowing of affected blood vessels, leukoencephalopathy, CAA-associated vasculopathies, and perivascular astrocytosis, microgliosis, and neuritic degeneration complicate the development of HCHWA-D CAA. Parenchymal A, deposition is also enhanced in the HCHWA-D brain with non-fibrillar membrane-bound A,(x-42) deposits evolving into relatively fibrillar diffuse plaques variously associated with reactive astrocytes, activated microglia, and degenerating neurites. Plaque density tends ,to ,decrease ,with ,age. ,Neurofibrillary ,degeneration is absent or limited. HCHWA-D dementia is associated with CAA severity independently of Braak stage, age, and plaque density. Particularly, microaneurysms may contribute to the development of (small) hemorrhages/infarcts and the latter to cognitive decline in affected subjects. However, the relative importance of cerebral hemorrhages/infarcts, white matter damage and/or other CAA- or A,-related factors for cognitive deterioration in HCHWA-D remains to be determined. [source] Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunologyNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 2 2008R. O. Carare Elimination of interstitial fluid and solutes plays a role in homeostasis in the brain, but the pathways are unclear. Previous work suggests that interstitial fluid drains along the walls of arteries. Aims: to define the pathways within the walls of capillaries and arteries for drainage of fluid and solutes out of the brain. Methods: Fluorescent soluble tracers, dextran (3 kDa) and ovalbumin (40 kDa), and particulate fluospheres (0.02 ,m and 1.0 ,m in diameter) were injected into the corpus striatum of mice. Brains were examined from 5 min to 7 days by immunocytochemistry and confocal microscopy. Results: soluble tracers initially spread diffusely through brain parenchyma and then drain out of the brain along basement membranes of capillaries and arteries. Some tracer is taken up by vascular smooth muscle cells and by perivascular macrophages. No perivascular drainage was observed when dextran was injected into mouse brains following cardiac arrest. Fluospheres expand perivascular spaces between vessel walls and surrounding brain, are ingested by perivascular macrophages but do not appear to leave the brain even following an inflammatory challenge with lipopolysaccharide or kainate. Conclusions: capillary and artery basement membranes act as ,lymphatics of the brain' for drainage of fluid and solutes; such drainage appears to require continued cardiac output as it ceases following cardiac arrest. This drainage pathway does not permit migration of cells from brain parenchyma to the periphery. Amyloid-, is deposited in basement membrane drainage pathways in cerebral amyloid angiopathy, and may impede elimination of amyloid-, and interstitial fluid from the brain in Alzheimer's disease. Soluble antigens, but not cells, drain from the brain by perivascular pathways. This atypical pattern of drainage may contribute to partial immune privilege of the brain and play a role in neuroimmunological diseases such as multiple sclerosis. [source] Specific association of small heat shock proteins with the pathological hallmarks of Alzheimer's disease brainsNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 2 2006M. M. M. Wilhelmus The small heat shock protein family (sHsp) comprises molecular chaperones able to interact with incorrectly folded proteins. Alzheimer's disease (AD) is characterized by pathological lesions such as senile plaques (SPs), cerebral amyloid angiopathy (CAA) and neurofibrillary tangles (NFTs), predominantly consisting of the incorrectly folded proteins amyloid-, (A,) and tau respectively. The aim of this study was to investigate the association of the chaperones Hsp20, HspB2, ,B-crystallin and Hsp27 with the pathological lesions of AD brains. For this purpose, a panel of well-characterized antibodies directed against these sHsps was used in immunohistochemistry and immunoblotting. We observed extracellular expression of Hsp20, Hsp27 and HspB2 in classic SPs, and Hsp20 expression in diffuse SPs. In addition, extracellular expression of HspB2 was observed in CAA. Both Hsp27 and ,B-crystallin were also observed in astrocytes associated with both SPs and CAA. Furthermore, none of the sHsps were observed in NFTs in AD brains. We conclude that specific sHsp species may be involved in the pathogenesis of either SPs or CAA in AD. [source] Genetic,morphologic association study: association between the low density lipoprotein-receptor related protein (LRP) and cerebral amyloid angiopathyNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 1 2005M. Christoforidis Accumulating evidence suggests that genetic factors such as apolipoprotein E (APOE), can act in different ways in the pathogenesis of cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD). The role of the low-density lipoprotein-receptor related protein (LRP), the major cerebral APOE receptor, in AD has been discussed controversially depending on data from different populations and methodological approaches. We examined the influence of LRP polymorphisms on CAA in 125 post-mortem cases genotyped for APOE and classified according to the neurofibrillary Braak and Braak staging of AD (indicating neurodegeneration grade). CAA was assessed separately for leptomeningeal (CAAlep.), noncapillary cortical (CAAcort.) and capillary cortical (CAAcap.) vessels in ,-amyloid stained sections. Our results suggest: (i) the 87 bp allele of LRP5, polymorphism (LRP5,) is an independent predictive factor for CAAcort. and CAAlep.; (ii) the C/C genotype (C allele) of the LRP exon 3 polymorphism is positively associated with, the, severity, of, CAAlep., and, CAAcort.,, implicating a younger age of CAA onset and/or faster CAA progression; (iii) as CAAcort. and CAAlep. showed different genetic associations in contrast to CAAcap., we can underscore the hypothesis that different molecular mechanisms are involved in CAA pathogenesis of noncapillary and capillary cerebral vessels. Our results lead us to postulate that the LRP5,87 bp and the LRP exon 3 C alleles of the LRP gene (or another locus that might be in linkage disequilibrium with these LRP polymorphic sites) could modify cerebrovascular LRP function or expression in noncapillary cerebral vessels, leading to an increased cerebrovascular amyloid deposition. [source] APOE,4 influences the pathological phenotype of Alzheimer's disease by favouring cerebrovascular over parenchymal accumulation of A, proteinNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 3 2003K. Chalmers The relative amounts of amyloid ,-protein (A,) in cerebral blood vessels and parenchyma vary considerably amongst patients with Alzheimer's disease (AD). Although several mechanisms have been proposed to explain this variability, the underlying genetic and environmental determinants are still unclear, as are the functional consequences. Polymorphisms in APOE, the gene for apolipoprotein E (ApoE), influence the risk of developing AD and of deposition of A, within the brain. We examined the relationship between the APOE genotype and the relative extent of accumulation of A, as plaques within the cerebral parenchyma and in cortical blood vessels in the form of cerebral amyloid angiopathy (CAA), in autopsy brain tissue from 125 AD cases and from 53 elderly, neurologically normal controls of which 19 had CAA without other neuropathological features of AD. In the AD cases, we also assessed whether the severity of CAA was related to the age of onset and duration of dementia, risk factors for atherosclerotic vascular disease, and histologically demonstrable cerebral in-farcts or foci of haemorrhage. The APOE genotype was determined by a standard polymerase chain reaction-based method. Paraffin sections of frontal, temporal and parietal lobes were immunolabelled for A, and the parenchymal A, load (total A, minus vessel-associated A,) was quantified by computer-assisted image analysis. CAA severity was scored for cortical and leptomeningeal vessels. The relevant clinical data were obtained from the database of the South West Brain Bank. In AD, we found the severity of CAA to be strongly associated with the number of ,4 alleles (P < 0.0001) but the parenchymal A, load to be independent of APOE genotype. Cases with severe CAA had a lower parenchymal A, load than had those with moderate CAA (P = 0.003). Neither the severity of CAA nor the parenchymal A, load correlated with age of onset, duration of disease or age at death, and the severity of CAA also did not correlate with the presence of cerebral infarcts or foci of haemorrhage. These findings indicate that possession of the APOE,4 allele favours vascular over parenchymal accumulation of A, in AD. This may influence the pathogenesis of neurodegeneration in ,4-associated AD. [source] Familial amyloidotic polyneuropathy (ATTR Val30Met) with widespread cerebral amyloid angiopathy and lethal cerebral hemorrhagePATHOLOGY INTERNATIONAL, Issue 6 2001Naomi Sakashita We report an autopsy case of familial amyloidotic polyneuropathy (FAP) with cerebral hemorrhage. A 38-year-old woman with a typical FAP pedigree started developing severe diarrhea and sensori-motor polyneuropathy at the age of 28 years; autonomic nervous system, heart and renal dysfunction manifested themselves in the following years. Genetic analysis revealed a single amino acid substitution at codon 30 of transthyretin (ATTR Val30Met). Ten years after her initial symptoms, the patient died of a sudden convulsive attack and respiratory failure. Autopsy revealed lethal cerebral hemorrhages and uremic lungs. Histochemical and immunohistochemical analyses revealed TTR-derived amyloid protein in every tissue examined, particularly in glomeruli and peripheral vessels. Severe meningo-cerebrovascular amyloidosis was also detected. Because uremia causes oxidative damage to the vascular system and amyloid formation is closely associated with oxidative stress, it is possible that uremic endothelial damage facilitated an unusual cerebral amyloid deposition. In typical FAP (ATTR Val30Met), cerebral amyloid angiopathy does not usually have clinical manifestations. However, cerebral amyloid angiopathy should be considered to explain FAP symptoms when some risk factors such as uremic vascular damage are accompanying features. [source] Cerebrospinal fluid amyloid ,40 is decreased in cerebral amyloid angiopathy,ANNALS OF NEUROLOGY, Issue 2 2009Marcel M. Verbeek MSc Cerebral amyloid angiopathy is caused by deposition of the amyloid , protein in the cerebral vasculature. In analogy to previous observations in Alzheimer disease, we hypothesized that analysis of amyloid ,40 and ,42 proteins in the cerebrospinal fluid might serve as a molecular biomarker. We observed strongly decreased cerebrospinal fluid amyloid ,40 (p < 0.01 vs controls or Alzheimer disease) and amyloid ,42 concentrations (p < 0.001 vs controls and p < 0.05 vs Alzheimer disease) in cerebral amyloid angiopathy patients. The combination of amyloid ,42 and total tau discriminated cerebral amyloid angiopathy from controls, with an area under the receiver operator curve of 0.98. Our data are consistent with neuropathological evidence that amyloid ,40 as well as amyloid ,42 protein are selectively trapped in the cerebral vasculature from interstitial fluid drainage pathways that otherwise transport amyloid , proteins toward the cerebrospinal fluid. Ann Neurol 2009;66:245,249 [source] Imaging of amyloid burden and distribution in cerebral amyloid angiopathyANNALS OF NEUROLOGY, Issue 3 2007Keith A. Johnson MD Objective Cerebrovascular deposition of ,-amyloid (cerebral amyloid angiopathy [CAA]) is a major cause of hemorrhagic stroke and a likely contributor to vascular cognitive impairment. We evaluated positron emission tomographic imaging with the ,-amyloid,binding compound Pittsburgh Compound B (PiB) as a potential noninvasive method for detection of CAA. We hypothesized that amyloid deposition would be observed with PiB in CAA, and based on the occipital predilection of CAA pathology and associated hemorrhages, that specific PiB retention would be disproportionately greater in occipital lobes. Methods We compared specific cortical PiB retention in 6 nondemented subjects diagnosed with probable CAA with 15 healthy control subjects and 9 patients with probable Alzheimer's disease (AD). Results All CAA and AD subjects were PiB-positive, both by distribution volume ratio measurements and by visual inspection of positron emission tomographic images. Global cortical PiB retention was significantly increased in CAA (distribution volume ratio 1.18 ± 0.06) relative to healthy control subjects (1.04 ± 0.10; p = 0.0009), but was lower in CAA than in AD subjects (1.41 ± 0.17; p = 0.002). The occipital-to-global PiB ratio, however, was significantly greater in CAA than in AD subjects (0.99 ± 0.07 vs 0.86 ± 0.05; p = 0.003). Interpretation We conclude that PiB-positron emission tomography can detect cerebrovascular ,-amyloid and may serve as a method for identifying the extent of CAA in living subjects. Ann Neurol 2007 [source] Spatial distribution of hemorrhages in cerebral amyloid angiopathyANNALS OF NEUROLOGY, Issue 1 2006Kurt A. Jellinger MD No abstract is available for this article. [source] Dementia in hereditary cerebral hemorrhage with amyloidosis-Dutch type is associated with cerebral amyloid angiopathy but is independent of plaques and neurofibrillary tanglesANNALS OF NEUROLOGY, Issue 6 2001Remco Natté MD Cerebral amyloid angiopathy is frequently found in demented and nondemented elderly persons, but its contribution to the causation of dementia is unknown. Therefore, we investigated the relation between the amount of cerebral amyloid angiopathy and the presence of dementia in 19 patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type. The advantage of studying hereditary cerebral hemorrhage in amyloidosis-Dutch type is that patients with this disease consistently have severe cerebral amyloid angiopathy with minimal neurofibrillary pathology. The amount of cerebral amyloid angiopathy, as quantified by computerized morphometry, was strongly associated with the presence of dementia independent of neurofibrillary pathology, plaque density, or age. The number of cortical amyloid ,-laden severely stenotic vessels, vessel-within-vessel configurations, and cerebral amyloid angiopathy-associated microvasculopathies was associated with the amount of cerebral amyloid angiopathy and dementia. A semiquantitative score, based on the number of amyloid ,-laden severely stenotic vessels, completely separated demented from nondemented patients. These results suggest that extensive (more than 15 amyloid ,-laden severely stenotic vessels in five frontal cortical sections) cerebral amyloid angiopathy alone is sufficient to cause dementia in hereditary cerebral hemorrhage with amyloidosis,Dutch type. This may have implications for clinicopathological correlations in Alzheimer's disease and other dementias with cerebral amyloid angiopathy. [source] Oligomeric A, in Alzheimer's Disease: Relationship to Plaque and Tangle Pathology, APOE Genotype and Cerebral Amyloid AngiopathyBRAIN PATHOLOGY, Issue 2 2010Zoë Van Helmond Abstract Despite accumulating evidence of a central role for oligomeric amyloid , (A,) in the pathogenesis of Alzheimer's Disease (AD), there is scant information on the relationship between the levels and distribution of oligomeric A, and those of other neurodegenerative abnormalities in AD. In the present study, we have found oligomeric A, to be associated with both diffuse and neuritic plaques (mostly co-localized with A,1,42) and with cerebrovascular deposits of A, in paraffin sections of formalin-fixed human brain tissue. The amount of oligomeric A, that was labeled in the sections correlated with total A, plaque load, but not phospho-tau load, cerebral amyloid angiopathy (CAA) severity or APOE genotype. Although soluble, oligomeric and insoluble A, levels were all significantly increased in AD brain homogenates, case-to-case variation and overlap between AD and controls were considerable. Over the age-range studied (43,98 years), the levels of soluble A,, oligomeric A,42, oligomeric A,40 and insoluble A, did not vary significantly with age. Oligomeric A,1,42 and insoluble A, levels were significantly higher in women. Overall, the level of insoluble A,, but neither oligomeric nor soluble A,, was associated with Braak stage, CAA severity and APOE,4 frequency, raising questions as to the role of soluble and oligomeric A, in the progression of AD. [source] SYMPOSIUM: Clearance of A, from the Brain in Alzheimer's Disease: A,-Degrading Enzymes in Alzheimer's DiseaseBRAIN PATHOLOGY, Issue 2 2008James Scott Miners Abstract In Alzheimer's disease (AD) A, accumulates because of imbalance between the production of A, and its removal from the brain. There is increasing evidence that in most sporadic forms of AD, the accumulation of A, is partly, if not in some cases solely, because of defects in its removal,mediated through a combination of diffusion along perivascular extracellular matrix, transport across vessel walls into the blood stream and enzymatic degradation. Multiple enzymes within the central nervous system (CNS) are capable of degrading A,. Most are produced by neurons or glia, but some are expressed in the cerebral vasculature, where reduced A,-degrading activity may contribute to the development of cerebral amyloid angiopathy (CAA). Neprilysin and insulin-degrading enzyme (IDE), which have been most extensively studied, are expressed both neuronally and within the vasculature. The levels of both of these enzymes are reduced in AD although the correlation with enzyme activity is still not entirely clear. Other enzymes shown capable of degrading A,in vitro or in animal studies include plasmin; endothelin-converting enzymes ECE-1 and -2; matrix metalloproteinases MMP-2, -3 and -9; and angiotensin-converting enzyme (ACE). The levels of plasmin and plasminogen activators (uPA and tPA) and ECE-2 are reported to be reduced in AD. Reductions in neprilysin, IDE and plasmin in AD have been associated with possession of APOE,4. We found no change in the level or activity of MMP-2, -3 or -9 in AD. The level and activity of ACE are increased, the level being directly related to A, plaque load. Up-regulation of some A,-degrading enzymes may initially compensate for declining activity of others, but as age, genetic factors and diseases such as hypertension and diabetes diminish the effectiveness of other A,-clearance pathways, reductions in the activity of particular A,-degrading enzymes may become critical, leading to the development of AD and CAA. [source] The Role of Cystatin C in Cerebral Amyloid Angiopathy and Stroke: Cell Biology and Animal ModelsBRAIN PATHOLOGY, Issue 1 2006Efrat Levy A variant of the cysteine protease inhibitor, cystatin c, forms amyloid deposited in the cerebral vasculature of patients with hereditary cerebral hemorrhage with amyloidosis, icelandic type (hchwa-i), leading to cerebral hemorrhages early in life. however, cystatin c is also implicated in neuronal degenerative diseases in which it does not form the amyloid protein, such as alzheimer disease (ad). accumulating data suggest involvement of cystatin c in the pathogenic processes leading to amyloid deposition in cerebral vasculature and most significantly to cerebral hemorrhage in patients with cerebral amyloid angiopathy (caa). This review focuses on cell culture and animal models used to study the role of cystatin c in these processes. [source] | ||||||||||||||||||||||