Cerebral amyloid angiopathy--a disease or age-related condition.
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Cerebral amyloid angiopathy is characterized by deposition of amyloid in the walls of leptomeninged and cerebral blood vessels. Its most common form, sporadic CAA that results from deposition of beta-amyloid peptide, which is the subject of this short review, is present in virtually all cases of Alzheimer disease and is also common among non-demented subjects where its prevalence increases with age. Stroke due to massive cerebral lobar hemorrhage is the main clinical presentation of CAA, but transient neurologic symptoms due to microhemorrhages may also occur. CAA is also a risk factor for cerebral infarction and there is increasing evidence that CAA contributes to cognitive impairment in the elderly, usually in association with white matter abnormalities on imaging. Although the definitive diagnosis of CAA is neuropathologic, reliable diagnosis can be reached clinically, based on the occurrence of strictly lobar hemorrhages, particularly in the cortico-subcortical area when using gradient-echo or T2*-weighted magnetic resonance imaging. Experimental studies have shown that the origin of the vascular amyloid is neuronal, and that age-related degenerative changes in the vessel walls prevent its clearance from the brain along perivascular spaces and promote Abeta aggregation and CAA formation. The entrapped Abeta aggregates are toxic to various vascular wall components, including smooth muscle cells, pericytes and endothelial cells, leading to their eventual destruction and predisposition of the vessel wall to rupture and hemorrhage. However, more research is necessary to decipher the mechanism of CAA formation and its relation to cognitive decline in the elderly. (+info)
Cognitive impact of subcortical vascular and Alzheimer's disease pathology.
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OBJECTIVE: To assess the interactions among three types of pathology (ie, cerebrovascular disease, hippocampal sclerosis [HS], and Alzheimer's disease [AD]), cognitive status, and apolipoprotein E genotype. METHODS: We report clinicopathological correlations from 79 autopsy cases derived from a prospective longitudinal study of subcortical ischemic vascular disease and AD. RESULTS: Thirty percent of the cases had significant cerebrovascular parenchymal pathology scores (CVDPS), 54% had significant AD pathology, and 18% had HS. In an ordinal logistic regression analysis that included interaction terms to assess the effects of each pathological variable when the other variables are interpolated to zero, each of the three pathology variables contributed independently to cognitive status: Braak and Braak stage odds ratio (OR) = 2.84 (95% confidence interval, 1.81-4.45), HS score OR = 2.43 (95% confidence interval, 1.01-5.85), and CVDPS OR = 1.02 (95% confidence interval, 1.00-1.04). Only Braak and Braak stage contributed to a global neuropsychological measure of cognitive impairment. Apolipoprotein E4 genotype was associated with Braak and Braak stage (OR, 1.31 [95% confidence interval, 1.03-1.68]), but not CVDPS or HS scores. INTERPRETATION: In this convenience sample enriched for subcortical ischemic vascular disease, HS was a common unsuspected neuropathological finding. Apolipoprotein E4 genotype was associated with cerebral amyloid angiopathy, but not HS or arteriosclerosis. When Braak and Braak stage was interpolated to zero, both CVDPS and HS contributed to cognitive impairment. However, advancing stages of AD pathology overwhelmed the effects of CVDPS and HS, to become the major determinant of dementia. (+info)
Imaging cerebral amyloid angiopathy with susceptibility-weighted imaging.
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Gradient-echo (GE) imaging is recognized as a means to detect hemorrhagic changes in cerebral amyloid angiopathy (CAA). However, almost 25% of patients with CAA do not show microhemorrhages on T2* GE imaging. We applied a new imaging method, susceptibility weighted imaging (SWI), to evaluate the presence of microhemorrhages. In a suspected case of CAA, where cognitive effects are also present, we show that SWI is much more sensitive in detecting microhemorrhages than conventional methods. (+info)
Antibody-mediated clearance of amyloid-beta peptide from cerebral amyloid angiopathy revealed by quantitative in vivo imaging.
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Cerebral amyloid angiopathy (CAA) is the accumulation of amyloid-beta peptide (Abeta) in the vessel wall of arteries in the brain. Because CAA is commonly associated with Alzheimer's disease (AD), characterized by parenchymal deposition of the same peptide in the form of senile plaques, there is considerable interest in the relationship of the two deposits in generating human disease. The study of CAA is of particular importance for immunotherapeutic approaches to AD, because reports of anti-Abeta immunotherapy in mice and humans have suggested that, whereas CAA appeared resistant to clearance, its response to this treatment promoted potential adverse effects, including meningoencephalitis. We used multiphoton microscopy and longitudinal imaging to monitor CAA in a mouse model of amyloid deposition to evaluate the effects of anti-Abeta passive immunotherapy. We found detectable clearance of CAA deposits within 1 week after a single administration of antibody directly to the brain, an effect that was short-lived. Chronic administration of antibody over 2 weeks led to more robust clearance without evidence of hemorrhage or other destructive changes. We found that the progressive clearance of Abeta from vessels follows distinct kinetics from what has been previously reported for clearance of plaques (parenchymal deposits of Abeta). This quantitative in vivo imaging approach directly demonstrates that CAA in a transgenic mouse model can be cleared with an optimized immunotherapy. (+info)
Early-onset subicular microvascular amyloid and neuroinflammation correlate with behavioral deficits in vasculotropic mutant amyloid beta-protein precursor transgenic mice.
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Cerebral microvascular amyloid beta protein (Abeta) deposition and associated neuroinflammation are increasingly recognized as an important component leading to cognitive impairment in Alzheimer's disease and related cerebral amyloid angiopathy (CAA) disorders. Transgenic mice expressing the vasculotropic Dutch/Iowa (E693Q/D694N) mutant human Abeta precursor protein in brain (Tg-SwDI) accumulate abundant cerebral microvascular fibrillar amyloid deposits exhibiting robust neuroinflammation. In the present study, we sought to determine if the unique amyloid pathology of Tg-SwDI mice was associated with deficits in behavioral performance. Behavioral performance tests that assessed a variety of psychological functions, including overall activity, motor ability, balance and strength, anxiety, impulsivity, and learning were conducted on homozygous Tg-SwDI mice and similarly aged wild-type C57Bl/6 mice. Our results indicate that Tg-SwDI mice were impaired in the performance of the Barnes maze learning and memory task at 3, 9, and 12 months of age. While more widespread cerebral microvascular Abeta pathology was evident in older animals, the evaluation of the Abeta pathology in the 3 months old transgenic animals revealed specific accumulation of microvascular amyloid and markedly elevated numbers of reactive astrocytes and activated microglia restricted to the subiculum. These findings indicate that early-onset accumulation of subicular microvascular amyloid and accompanying neuroinflammation correlates with impaired performance in the learning and memory task in Tg-SwDI mice. (+info)
Minocycline reduces microglial activation and improves behavioral deficits in a transgenic model of cerebral microvascular amyloid.
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Cerebral microvascular amyloid beta protein (Abeta) deposition and associated neuroinflammation is increasingly recognized as an important component leading to cognitive impairment in Alzheimer's disease and related cerebral amyloid angiopathy disorders. Transgenic mice expressing the vasculotropic Dutch/Iowa (E693Q/D694N) mutant human Abeta precursor protein in brain (Tg-SwDI) accumulate abundant cerebral microvascular fibrillar amyloid deposits and exhibit robust neuroinflammation. In the present study, we investigated the effect of the anti-inflammatory drug minocycline on Abeta accumulation, neuroinflammation, and behavioral deficits in Tg-SwDI mice. Twelve-month-old mice were treated with saline or minocycline by intraperitoneal injection every other day for a total of 4 weeks. During the final week of treatment, the mice were tested for impaired learning and memory. Brains were then harvested for biochemical and immunohistochemical analysis. Minocycline treatment did not alter the cerebral deposition of Abeta or the restriction of fibrillar amyloid to the cerebral microvasculature. Similarly, minocycline-treated Tg-SwDI mice exhibited no change in the levels of total Abeta, the ratios of Abeta40 and Abeta42, or the amounts of soluble, insoluble, or oligomeric Abeta compared with the saline-treated control Tg-SwDI mice. In contrast, the numbers of activated microglia and levels of interleukin-6 were significantly reduced in minocycline-treated Tg-SwDI mice compared with saline-treated Tg-SwDI mice. In addition, there was a significant improvement in behavioral performance of the minocycline-treated Tg-SwDI mice. These finding suggest that anti-inflammatory treatment targeted for cerebral microvascular amyloid-induced microglial activation can improve cognitive deficits without altering the accumulation and distribution of Abeta. (+info)
AD brain pathology: vascular origins? Results from the HAAS autopsy study.
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An increasing number of studies suggest a vascular contribution to Alzheimer's disease (AD). One major question these findings raise is whether vascular disease enhances the formation of AD-like lesions, or whether vascular disease just adds to clinical severity. We examined this question in a fully characterized autopsy sample based on the Honolulu Asia Aging Study. We found that AD markers of neurodegeneration (amyloid plaques, cerebral amyloid angiopathy and neurofibrillary tangles) were no more prevalent in those with neuropathologically defined vascular lesions compared to those without lesions. Our study suggests the burden of vascular and AD type lesions are independent of each other, and are consistent with an additive effect of the two types of lesions on cognitive impairment. (+info)
Pathological study on cerebral amyloid angiopathy.
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The cerebral amyloid angiopathy (CAA) was pathologically confirmed in 26 cases in which there were 20 cerebral hemorrhages, 2 subarachnoid hemorrhages, 3 cerebral infarctions, and 1 subdural hematoma. The CAA mainly involved the media and extima of small and medium-sized arteries as well as the capillaries of the brain tissue. Half of all cases in our series had the CAA associated vasculopathies (CAA-AV), including microaneurysms, "double barreling", onion skin-like intima, fibrinoid necrosis, clusters of arterioles and perivascular lymphocytic infiltrations. The CAA was often accompanied with the senile plaques and neurofibrillary tangles. (+info)