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Longitudinal decrease in blood oxygenation level dependent response in cerebral amyloid angiopathy.

ABSTRACT: Lower blood oxygenation level dependent (BOLD) signal changes in response to a visual stimulus in functional magnetic resonance imaging (fMRI) have been observed in cross-sectional studies of cerebral amyloid angiopathy (CAA), and are presumed to reflect impaired vascular reactivity. We used fMRI to detect a longitudinal change in BOLD responses to a visual stimulus in CAA, and to determine any correlations between these changes and other established biomarkers of CAA progression. Data were acquired from 22 patients diagnosed with probable CAA (using the Boston Criteria) and 16 healthy controls at baseline and one year. BOLD data were generated from the 200 most active voxels of the primary visual cortex during the fMRI visual stimulus (passively viewing an alternating checkerboard pattern). In general, BOLD amplitudes were lower at one year compared to baseline in patients with CAA (p = 0.01) but were unchanged in controls (p = 0.18). The longitudinal difference in BOLD amplitudes was significantly lower in CAA compared to controls (p < 0.001). White matter hyperintensity (WMH) volumes and number of cerebral microbleeds, both presumed to reflect CAA-mediated vascular injury, increased over time in CAA (p = 0.007 and p = 0.001, respectively). Longitudinal increases in WMH (rs = 0.04, p = 0.86) or cerebral microbleeds (rs = -0.18, p = 0.45) were not associated with the longitudinal decrease in BOLD amplitudes.

SUBMITTER: Switzer AR

PROVIDER: S-EPMC4827726 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Longitudinal decrease in blood oxygenation level dependent response in cerebral amyloid angiopathy.

Switzer Aaron R AR McCreary Cheryl C Batool Saima S Stafford Randall B RB Frayne Richard R Goodyear Bradley G BG Smith Eric E EE

NeuroImage. Clinical 20160303

Lower blood oxygenation level dependent (BOLD) signal changes in response to a visual stimulus in functional magnetic resonance imaging (fMRI) have been observed in cross-sectional studies of cerebral amyloid angiopathy (CAA), and are presumed to reflect impaired vascular reactivity. We used fMRI to detect a longitudinal change in BOLD responses to a visual stimulus in CAA, and to determine any correlations between these changes and other established biomarkers of CAA progression. Data were acqu ...[more]

PMID: 27104140

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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.

Project description:Background and Purpose- Cerebral amyloid angiopathy (CAA) is a common small vessel disease that independently effects cognition in older individuals. The pathophysiology of CAA and CAA-related bleeding remains poorly understood. In this postmortem study, we explored whether blood-brain barrier leakage is associated with CAA and microvascular lesions. Methods- Eleven CAA cases (median [IQR] age=69 years [65-79 years], 8 males) and 7 cases without neurological disease or brain lesions (median [IQR] age=77 years [68-92 years], 4 males) were analyzed. Cortical sections were sampled from each lobe, and IgG and fibrin extravasation (markers of blood-brain barrier leakage) were assessed with immunohistochemistry. We hypothesized that IgG and fibrin extravasation would be increased in CAA cases compared with controls, that this would be more pronounced in parietooccipital brain regions compared with frontotemporal brain regions in parallel with the posterior predilection of CAA, and would be associated with CAA severity and number of cerebral microbleeds and cerebral microinfarcts counted on ex vivo magnetic resonance imaging of the intact brain hemisphere. Results- Our results demonstrated increased IgG positivity in the frontotemporal ( P=0.044) and parietooccipital ( P=0.001) cortex in CAA cases compared with controls. Within CAA cases, both fibrin and IgG positivity were increased in parietooccipital brain regions compared with frontotemporal brain regions ( P=0.005 and P=0.006, respectively). The percentage of positive vessels for fibrin and IgG was associated with the percentage of amyloid-β-positive vessels (Spearman ρ=0.71, P=0.015 and Spearman ρ=0.73, P=0.011, respectively). Moreover, the percentage of fibrin and IgG-positive vessels, but not amyloid-β-positive vessels, was associated with the number of cerebral microbleeds on magnetic resonance imaging (Spearman ρ=0.77, P=0.005 and Spearman ρ=0.70, P=0.017, respectively). Finally, we observed fibrin deposition in walls of vessels involved in cerebral microbleeds. Conclusions- Our results raise the possibility that blood-brain barrier leakage may be a contributory mechanism for CAA-related brain injury.

Project description:Cerebral amyloid angiopathy (CAA) is a small vessel disease characterized by amyloid β (Aβ) peptide deposition within the walls of medium to small-caliber blood vessels, cerebral microhemorrhage, and blood-brain barrier (BBB) leakage. It is commonly associated with late-stage Alzheimer's disease. BBB dysfunction is indicated as a pathological substrate for CAA progression with hyperpermeability, enhancing the extravasation of plasma components and inducing neuroinflammation, further worsening BBB injury and contributing to cognitive decline. Although significant effort has been made in defining the gene mutations and risk factors involved in microvascular alterations with vascular dementia and Alzheimer's disease, the intra- and intercellular pathogenic mechanisms responsible for vascular hyperpermeability are still largely unknown. The present study aimed to elucidate the transcriptional profile of the cerebral microvessels (BBB) in a murine model with CAA vasculopathy to define potential causes and underlying mechanisms of BBB injury. A comprehensive RNA sequencing analysis was performed of CAA vasculopathy in Tg-SwDI mice at 6 and 18 months in comparison to age-matched wildtype controls to examine how age and amyloid accumulation impact the transcriptional signature of the BBB. Results indicate that Aβ has a critical role in triggering brain endothelial cell and BBB dysfunction in CAA vasculopathy, causing an intense proinflammatory response, impairing oxidative metabolism, altering the coagulation status of brain endothelial cells, and remodeling barrier properties. The proinflammatory response includes both adaptive and innate immunity, with pronounced induction of genes that regulate macrophage/microglial activation and chemokines/adhesion molecules that support T and B cell transmigration. Age has an important impact on the effects of Aβ, increasing the BBB injury in CAA vasculopathy. However, early inflammation, particularly microglia/macrophage activation and the mediators of B lymphocytes' activities are underlying processes of BBB hyperpermeability and cerebral microbleeds in the early stage of CAA vasculopathy. These findings reveal a specific profile of the CAA-associated BBB injury that leads to a full progression of CAA.

Project description:Cerebral amyloid angiopathy is a small vessel disease associated with cortical microbleeds and lobar intracerebral haemorrhage due to amyloid-β deposition in the walls of leptomeningeal and cortical arterioles. The mechanisms of cerebral amyloid angiopathy-related haemorrhage remain largely unknown. Recent work has demonstrated that ruptured blood vessels have limited (or no) amyloid-β at the site of bleeding and evidence of local vascular remodelling. We hypothesized that blood-brain barrier leakage and perivascular inflammation may be involved in this remodelling process. This study examined cortical arterioles at various stages of cerebral amyloid angiopathy-related vascular pathology (without evidence of microhaemorrhage) in autopsy tissue from seven cases with definite cerebral amyloid angiopathy. We included temporo-occipital sections with microbleeds guided by ex vivo MRI from two cases with severe cerebral amyloid angiopathy and systematically sampled occipital sections from five consecutive cases with varying cerebral amyloid angiopathy severity. Haematoxylin and eosin stains and immunohistochemistry against amyloid-β, fibrin(ogen), smooth muscle actin, reactive astrocytes (glial fibrillary acidic protein) and activated microglia (cluster of differentiation 68) were performed. Arterioles were graded using a previously proposed scale of individual vessel cerebral amyloid angiopathy severity, and a blinded assessment for blood-brain barrier leakage, smooth muscle actin and perivascular inflammation was performed. Blood-brain barrier leakage and smooth muscle actin loss were observed in significantly more vessels with mild amyloid-β deposition (Grade 1 vessels; P = 0.044 and P = 0.012, respectively) as compared to vessels with no amyloid-β (Grade 0), and blood-brain barrier leakage was observed in 100% of vessels with evidence of vessel remodelling (Grades 3 and 4). Perivascular inflammation in the form of reactive astrocytes and activated microglia was observed predominantly surrounding arterioles at later stages of vessel pathology (Grades 2-4) and consistently around vessels with the same morphological features as ruptured vessel segments (Grade 4). These findings suggest a role for blood-brain barrier leakage and perivascular inflammation leading to arteriolar remodelling and haemorrhage in cerebral amyloid angiopathy, with early blood-brain barrier leakage as a potential trigger for subsequent perivascular inflammation.

Project description:Alzheimer's disease (AD) is characterised by pathologic cerebrovascular remodelling. Whether this occurs already before disease onset, as may be indicated by early Braak tau-related cerebral hypoperfusion and blood-brain barrier (BBB) impairment found in previous studies, remains unknown. Therefore, we systematically quantified Braak tau stage- and cerebral amyloid angiopathy (CAA)-dependent alterations in the alpha-smooth muscle actin (α-SMA), collagen, and elastin content of leptomeningeal arterioles, small arteries, and medium-sized arteries surrounding the gyrus frontalis medialis (GFM) and hippocampus (HIPP), including the sulci, of 17 clinically and pathologically diagnosed AD subjects (Braak stage IV-VI) and 28 non-demented control subjects (Braak stage I-IV). GFM and HIPP paraffin sections were stained for general collagen and elastin with the Verhoeff-van Gieson stain; α-SMA and CAA/amyloid β (Aβ) were detected using immunohistochemistry. Significant arterial elastin degradation was observed from Braak stage III onward and correlated with Braak tau pathology (ρ = 0.909, 95% CI 0.370 to 0.990, p < 0.05). This was accompanied by an increase in neutrophil elastase expression by α-SMA-positive cells in the vessel wall. Small and medium-sized arteries exhibited significant CAA-independent α-SMA loss starting between Braak stage I and II-III, along with accumulation of phosphorylated paired helical filament (PHF) tau in the perivascular space of intraparenchymal vessels. α-SMA remained at the decreased level throughout the later Braak stages. In contrast, arterioles exhibited significant α-SMA loss only at Braak stage V and VI/in AD subjects, which was CAA-dependent/correlated with CAA burden (ρ = -0.422, 95% CI -0.557 to -0.265, p < 0.0001). Collagen content was only significantly changed in small arteries. Our data indicate that vessel wall remodelling of leptomeningeal arteries is an early-onset, Braak tau pathology-dependent process unrelated to CAA and AD, which potentially may contribute to downstream CAA-dependent microvascular pathology in AD.

Dataset Information

Longitudinal decrease in blood oxygenation level dependent response in cerebral amyloid angiopathy.

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Longitudinal decrease in blood oxygenation level dependent response in cerebral amyloid angiopathy.

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