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Reduced vascular amyloid burden at microhemorrhage sites in cerebral amyloid angiopathy.

ABSTRACT: Microhemorrhages are strongly associated with advanced cerebral amyloid angiopathy (CAA). Although it has been frequently proposed that the deposition of A? in the walls of cortical vessels directly causes microhemorrhages, this has not been studied in great detail, mainly because the ruptured vessels are often missed on routine histopathologic examination. Here, we examined histopathological data from studies targeting microhemorrhages with high-resolution ex vivo 7 T MRI in nine cases with moderate-to-severe CAA, and assessed the presence of A? in the walls of involved vessels. We also assessed the density of A? positive cortical vessels in areas surrounding microhemorrhages compared to control areas. In seven out of 19 microhemorrhages, the presumed involved vessel could be identified on the histopathological section. Only one of these vessels was positive for A? at the site of rupture. Moreover, the density of A? positive cortical vessels was lower (1.0 per mm2) within a range of 315 µm surrounding the microhemorrhage, compared to control areas (2.0 per mm2; p < 0.05). These findings question the widely held assumption that the deposition of A? in the walls of cortical vessels directly causes microhemorrhages.

SUBMITTER: van Veluw SJ

PROVIDER: S-EPMC5325834 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Reduced vascular amyloid burden at microhemorrhage sites in cerebral amyloid angiopathy.

van Veluw Susanne J SJ Kuijf Hugo J HJ Charidimou Andreas A Viswanathan Anand A Biessels Geert Jan GJ Rozemuller Annemieke J M AJ Frosch Matthew P MP Greenberg Steven M SM

Acta neuropathologica 20161022 3

Microhemorrhages are strongly associated with advanced cerebral amyloid angiopathy (CAA). Although it has been frequently proposed that the deposition of Aβ in the walls of cortical vessels directly causes microhemorrhages, this has not been studied in great detail, mainly because the ruptured vessels are often missed on routine histopathologic examination. Here, we examined histopathological data from studies targeting microhemorrhages with high-resolution ex vivo 7 T MRI in nine cases with mod ...[more]

PMID: 27771772

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Project description:Cerebral amyloid angiopathy (CAA) involves cerebrovascular amyloid deposition and is classified into several types according to the amyloid protein involved. Of these, sporadic amyloid ?-protein (A?)-type CAA is most commonly found in older individuals and in patients with Alzheimer's disease (AD). Cerebrovascular A? deposits accompany functional and pathological changes in cerebral blood vessels (CAA-associated vasculopathies). CAA-associated vasculopathies lead to development of hemorrhagic lesions [lobar intracerebral macrohemorrhage, cortical microhemorrhage, and cortical superficial siderosis (cSS)/focal convexity subarachnoid hemorrhage (SAH)], ischemic lesions (cortical infarction and ischemic changes of the white matter), and encephalopathies that include subacute leukoencephalopathy caused by CAA-associated inflammation/angiitis. Thus, CAA is related to dementia, stroke, and encephalopathies. Recent advances in diagnostic procedures, particularly neuroimaging, have enabled us to establish a clinical diagnosis of CAA without brain biopsies. Sensitive magnetic resonance imaging (MRI) methods, such as gradient-echo T2(*) imaging and susceptibility-weighted imaging, are useful for detecting cortical microhemorrhages and cSS. Amyloid imaging with amyloid-binding positron emission tomography (PET) ligands, such as Pittsburgh Compound B, can detect CAA, although they cannot discriminate vascular from parenchymal amyloid deposits. In addition, cerebrospinal fluid markers may be useful, including levels of A?40 for CAA and anti-A? antibody for CAA-related inflammation. Moreover, cSS is closely associated with transient focal neurological episodes (TFNE). CAA-related inflammation/angiitis shares pathophysiology with amyloid-related imaging abnormalities (ARIA) induced by A? immunotherapies in AD patients. This article reviews CAA and CAA-related disorders with respect to their epidemiology, pathology, pathophysiology, clinical features, biomarkers, diagnosis, treatment, risk factors, and future perspectives.

Project description:Cerebral amyloid angiopathy (CAA) induces various forms of cerebral infarcts and hemorrhages from vascular amyloid-? accumulation, resulting in acceleration of cognitive impairment, which is currently untreatable. Soluble amyloid-? protein likely impairs cerebrovascular integrity as well as cognitive function in early stage Alzheimer's disease. Taxifolin, a flavonol with strong anti-oxidative and anti-glycation activities, has been reported to disassemble amyloid-? in vitro but the in vivo relevance remains unknown. Here, we investigated whether taxifolin has therapeutic potential in attenuating CAA, hypothesizing that inhibiting amyloid-? assembly may facilitate its clearance through several elimination pathways. Vehicle- or taxifolin-treated Tg-SwDI mice (commonly used to model CAA) were used in this investigation. Cognitive and cerebrovascular function, as well as the solubility and oligomerization of brain amyloid-? proteins, were investigated. Spatial reference memory was assessed by water maze test. Cerebral blood flow was measured with laser speckle flowmetry and cerebrovascular reactivity evaluated by monitoring cerebral blood flow changes in response to hypercapnia. Significantly reduced cerebrovascular pan-amyloid-? and amyloid-?1-40 accumulation was found in taxifolin-treated Tg-SwDI mice compared to vehicle-treated counterparts (n?=?5). Spatial reference memory was severely impaired in vehicle-treated Tg-SwDI mice but normalized after taxifolin treatment, with scoring similar to wild type mice (n?=?10-17). Furthermore, taxifolin completely restored decreased cerebral blood flow and cerebrovascular reactivity in Tg-SwDI mice (n?=?4-6). An in vitro thioflavin-T assay showed taxifolin treatment resulted in efficient inhibition of amyloid-?1-40 assembly. In addition, a filter trap assay and ELISA showed Tg-SwDI mouse brain homogenates exhibited significantly reduced levels of amyloid-? oligomers in vivo after taxifolin treatment (n?=?4-5), suggesting the effects of taxifolin on CAA are attributable to the inhibition of amyloid-? oligomer formation. In conclusion, taxifolin prevents amyloid-? oligomer assembly and fully sustains cognitive and cerebrovascular function in a CAA model mice. Taxifolin thus appears a promising therapeutic approach for CAA.

Dataset Information

Reduced vascular amyloid burden at microhemorrhage sites in cerebral amyloid angiopathy.

Publications

Reduced vascular amyloid burden at microhemorrhage sites in cerebral amyloid angiopathy.

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