Reduced vascular amyloid burden at microhemorrhage sites in cerebral amyloid angiopathy.
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ABSTRACT:
SUBMITTER: van Veluw SJ
PROVIDER: S-EPMC5325834 | biostudies-literature | 2017 Mar
REPOSITORIES: biostudies-literature
Publications
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]
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Project description:The pathophysiology of microhemorrhages in the context of cerebral amyloid angiopathy (CAA) remains poorly understood. Here we used in vivo two-photon microscopy in aged APP/PS1 mice with mild-to-moderate CAA to assess the formation of microhemorrhages and their spatial relationship with vascular Aβ depositions in the surrounding microvascular network. Mice with chronic cranial windows were intravenously injected with fluorescent dextran to visualize the vessels and a fluorescently labeled anti-fibrin antibody to visualize microhemorrhages. Focal vessel irradiations resulted in extravascular fibrin-positive clots at individual rupture sites that remained visible for weeks. Spontaneous extravascular fibrin-positive clots were more often observed in 19-month-old transgenic APP/PS1 mice compared to their wild-type littermate controls (p = 0.039), after heparin administration. In the transgenic mice, these spontaneous leakage sites frequently occurred at arteriolar segments without CAA at bifurcations or vessel bends. These findings suggest that the presence of vascular Aβ per se does not directly predispose vessels to leak, but that complex flow dynamics within CAA-affected vascular networks likely play a role. Our in vivo approach for the detection of individual spontaneous leakage sites may be used in longitudinal studies aimed to assess structural and functional alterations at the single-vessel level leading up to microhemorrhage formation.
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Project description:Cerebral amyloid angiopathy (CAA) is characterized by deposition of amyloid β peptide (Aβ) within walls of cerebral arteries and is an important cause of intracerebral hemorrhage, ischemic stroke, and cognitive dysfunction in elderly patients with and without Alzheimer's Disease (AD). NADPH oxidase-derived oxidative stress plays a key role in soluble Aβ-induced vessel dysfunction, but the mechanisms by which insoluble Aβ in the form of CAA causes cerebrovascular (CV) dysfunction are not clear. Here, we demonstrate evidence that reactive oxygen species (ROS) and, in particular, NADPH oxidase-derived ROS are a key mediator of CAA-induced CV deficits. First, the NADPH oxidase inhibitor, apocynin, and the nonspecific ROS scavenger, tempol, are shown to reduce oxidative stress and improve CV reactivity in aged Tg2576 mice. Second, the observed improvement in CV function is attributed both to a reduction in CAA formation and a decrease in CAA-induced vasomotor impairment. Third, anti-ROS therapy attenuates CAA-related microhemorrhage. A potential mechanism by which ROS contribute to CAA pathogenesis is also identified because apocynin substantially reduces expression levels of ApoE-a factor known to promote CAA formation. In total, these data indicate that ROS are a key contributor to CAA formation, CAA-induced vessel dysfunction, and CAA-related microhemorrhage. Thus, ROS and, in particular, NADPH oxidase-derived ROS are a promising therapeutic target for patients with CAA and AD.
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Project description:ObjectiveCerebral amyloid angiopathy (CAA) is a common age-related small vessel disease (SVD). Patients without intracerebral hemorrhage (ICH) typically present with transient focal neurologic episodes (TFNEs) or cognitive symptoms. We sought to determine if SVD lesion burden differed between patients with CAA first presenting with TFNEs vs cognitive symptoms.MethodsA total of 647 patients presenting either to a stroke department (n = 205) or an outpatient memory clinic (n = 442) were screened for eligibility. Patients meeting modified Boston criteria for probable CAA were included and markers of SVD were quantified, including cerebral microbleeds (CMBs), perivascular spaces, cortical superficial siderosis (cSS), and white matter hyperintensities (WMHs). Patients were classified according to presentation symptoms (TFNEs vs cognitive). Total CAA-SVD burden was assessed using a validated summary score. Individual neuroimaging markers and total SVD burden were compared between groups using univariable and multivariable models.ResultsThere were 261 patients with probable CAA included. After adjustment for confounders, patients first seen for TFNEs (n = 97) demonstrated a higher prevalence of cSS (p < 0.0001), higher WMH volumes (p = 0.03), and a trend toward higher CMB counts (p = 0.09). The total SVD summary score was higher in patients seen for TFNEs (adjusted odds ratio per additional score point 1.46, 95% confidence interval 1.16-1.84, p = 0.013).ConclusionsPatients with probable CAA without ICH first evaluated for TFNEs bear a higher burden of structural MRI SVD-related damage compared to those first seen for cognitive symptoms. This study sheds light on neuroimaging profile differences across clinical phenotypes of patients with CAA without ICH.
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Project description:In addition to its role in hemorrhagic stroke, advanced cerebral amyloid angiopathy (CAA) is also associated with ischemic lesions and vascular cognitive impairment. We used functional magnetic resonance imaging (MRI) techniques to identify CAA-associated vascular dysfunction.Functional MRI was performed on 25 nondemented subjects with probable CAA (mean ± standard deviation age, 70.2 ± 7.8 years) and 12 healthy elderly controls (age, 75.3 ± 6.2 years). Parameters measured were reactivity to visual stimulation (quantified as blood oxygen level-dependent [BOLD] response amplitude, time to peak response, and time to return to baseline after stimulus cessation) and resting absolute cerebral blood flow in the visually activated region (measured by arterial spin labeling).CAA subjects demonstrated reduced response amplitude (percentage change in BOLD signal, 0.65 ± 0.28 vs 0.89 ± 0.14; p < 0.01), prolonged time to peak (11.1 ± 5.1 vs 6.4 ± 1.8 seconds; p < 0.001), and prolonged time to baseline (16.5 ± 6.7 vs 11.6 ± 3.1 seconds; p < 0.001) relative to controls. These differences were independent of age, sex, and hypertension in multivariable analysis and were also present in secondary analyses excluding nonresponsive voxels or voxels containing chronic blood products. Within the CAA group, longer time to peak correlated with overall volume of white matter T2 hyperintensity (Pearson correlation, 0.53; p = 0.007). Absolute resting blood flow in visual cortex, in contrast, was essentially identical between the groups (44.0 ± 12.6 vs 45.0 ± 10.0 ml/100 g/min, p = 0.8).Functional MRI identifies robust differences in both amplitude and timing of the response to visual stimulation in advanced CAA. These findings point to potentially powerful approaches for identifying the mechanistic links between vascular amyloid deposits, vascular dysfunction, and CAA-related brain injury.
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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 β-protein (Aβ)-type CAA is most commonly found in older individuals and in patients with Alzheimer's disease (AD). Cerebrovascular Aβ 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 Aβ40 for CAA and anti-Aβ 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 Aβ 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.
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Project description:Cerebral amyloid angiopathy (CAA) is typified by the cerebrovascular deposition of amyloid. The mechanisms underlying the contribution of CAA to neurodegeneration are not currently understood. Although CAA is highly associated with the accumulation of β-amyloid (Aβ), other amyloids are known to associate with the vasculature. Alzheimer's disease (AD) is characterized by parenchymal Aβ deposition and intracellular accumulation of tau as neurofibrillary tangles (NFTs), affecting synapses directly, leading to behavioral and physical impairment. CAA increases with age and is present in 70%-97% of individuals with AD. Studies have overwhelmingly focused on the connection between parenchymal amyloid accumulation and synaptotoxicity; thus, the contribution of vascular amyloid is mostly understudied. Here, synaptic alterations induced by vascular amyloid accumulation and their behavioral consequences were characterized using a mouse model of Familial Danish dementia (FDD), a neurodegenerative disease characterized by the accumulation of Danish amyloid (ADan) in the vasculature. The mouse model (Tg-FDD) displays a hyperactive phenotype that potentially arises from impairment in the GABAergic synapses, as determined by electrophysiological analysis. We demonstrated that the disruption of GABAergic synapse organization causes this impairment and provided evidence that GABAergic synapses are impaired in patients with CAA pathology. Understanding the mechanism that CAA contributes to synaptic dysfunction in AD-related dementias is of critical importance for developing future therapeutic interventions.
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| S-EPMC10548599 | biostudies-literature
Project description:Background: Cerebral amyloid angiopathy (CAA) is a devastating condition common in patients with Alzheimer's disease but also observed in the general population. Vascular oxidative stress and neurovascular dysfunction have been implicated in CAA but the cellular source of reactive oxygen species (ROS) and related signaling mechanisms remain unclear. We tested the hypothesis that brain border-associated macrophages (BAM), yolk sac-derived myeloid cells closely apposed to parenchymal and leptomeningeal blood vessels, are the source of radicals through the Aβ-binding innate immunity receptor CD36, leading to neurovascular dysfunction, CAA, and cognitive impairment. Methods: Tg2576 mice and WT littermates were transplanted with CD36 -/- or CD36 +/+ bone marrow at 12-month of age and tested at 15 months. This approach enables the repopulation of perivascular and leptomeningeal compartments with CD36 -/- BAM. Neurovascular function was tested in anesthetized mice equipped with a cranial window in which cerebral blood flow was monitored by laser-Doppler flowmetry. Amyloid pathology and cognitive function were also examined. Results: The increase in blood flow evoked by whisker stimulation (functional hyperemia) or by endothelial and smooth muscle vasoactivity was markedly attenuated in WT®Tg2576 chimeras but was fully restored in CD36 -/- ®Tg2576 chimeras, in which BAM ROS production was suppressed. CAA-associated Aβ 1-40 , but not Aβ 1-42 , was reduced in CD36 -/- ®Tg2576 chimeras. Similarly, CAA, but not parenchymal plaques, was reduced in CD36 -/- ®Tg2576 chimeras. These beneficial vascular effects were associated with cognitive improvement. Finally, CD36 -/- mice were able to more efficiently clear exogenous Aβ 1-40 injected into the neocortex or the striatum. Conclusions: CD36 deletion in BAM suppresses ROS production and rescues the neurovascular dysfunction and damage induced by Aβ. CD36 deletion in BAM also reduced brain Aβ 1-40 and ameliorated CAA without affecting parenchyma plaques. Lack of CD36 enhanced the vascular clearance of exogenous Aβ. Restoration of neurovascular function and attenuation of CAA resulted in a near complete rescue of cognitive function. Collectively, these data implicate CNS BAM in the pathogenesis of CAA and raise the possibility that targeting BAM CD36 is beneficial in CAA and other conditions associated with vascular Aβ deposition and damage.
| S-EPMC10168479 | biostudies-literature
Project description:Cerebral amyloid angiopathy (CAA) is a degenerative vasculopathy that is classically associated with lobar intracerebral or sulcal hemorrhage. Its prevalence is estimated at 30% in the seventh decade and 50% in the eighth and ninth decades. In this review, we summarize the risks linked to CAA with respect to the treatment and prevention of stroke.This review is based on pertinent publications retrieved by a selective search employing the terms "amyloid cerebral angiopathy," "stroke," "intra - cerebral bleeding," and "acute stroke therapy."Among patients given systemic lytic treatment for stroke, those who have microhemorrhages tend to have a higher risk of treatment-associated brain hemorrhage. In a meta-analysis, 70% of patients who sustained a hemorrhage after thrombolytic therapy were found to have CAA, compared to only 22% in a control population. Patients with cerebral hemorrhages have microhemorrhages more commonly than patients with transient ischemic attacks (TIA) or infarcts. This was observed among persons under treatment with vitamin K antagonists (odds ratio, 2.7) or platelet aggregation inhibitors (odds ratio, 1.7). Moreover, the apolipoprotein E2 allele is associated with a higher incidence of intracerebral hemorrhage (ICH) under oral anticoagulation. Strict treatment of arterial hypertension can lower the risk of ICH in persons with probable CAA by 77%. On the other hand, the use of statins after a lobar ICH increases the risk for a clinically manifest recurrent hemorrhage from 14% to 22%.In patients with CAA, arterial hypertension should be tightly controlled. On the other hand, caution should be exercised in prescribing oral anticoagulants or platelet aggregation inhibitors for patients with CAA, or statins for patients who have already sustained a lobar ICH.
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