Vessels Sing Their ARIAs: The Role of Vascular Amyloid in the Age of Aducanumab

Stroke ◽  
2021 ◽  
Author(s):  
Lukas Sveikata ◽  
Andreas Charidimou ◽  
Anand Viswanathan
Keyword(s):  
Clinical Trials ◽  
Alzheimer Disease ◽  
Cerebral Amyloid Angiopathy ◽  
Amyloid Β ◽  
High Rate ◽  
Amyloid Angiopathy ◽  
Cerebrovascular Pathology ◽  
Cerebral Amyloid

We review the implications of the recently approved aducanumab amyloid-β immunotherapy for treating Alzheimer disease with comorbid cerebral amyloid angiopathy. In clinical trials, amyloid-β immunotherapy has been associated with a high rate of amyloid-related imaging abnormalities, potentially driven by coexisting cerebral amyloid angiopathy. Therefore, immunotherapy’s efficacy in patients may be modified by coexisting cerebrovascular pathology. We discuss the contributions of cerebral amyloid angiopathy on the development of amyloid-related imaging abnormalities and propose strategies to identify cerebral amyloid angiopathy in patients considered for immunotherapy.

scholarly journals Early-Onset Cerebral Amyloid Angiopathy and Alzheimer Disease Related to an APP Locus Triplication

2021 ◽  
Vol 7 (5) ◽  
pp. e609 ◽  
Author(s):  
Lou Grangeon ◽  
Kévin Cassinari ◽  
Stéphane Rousseau ◽  
Bernard Croisile ◽  
Maïté Formaglio ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Cerebral Amyloid Angiopathy ◽  
Early Onset ◽  
Brain Mri ◽  
Amyloid Β ◽  
Fold Increase ◽  
Comparative Genomic ◽  
Amyloid Angiopathy ◽  
Mrna Levels ◽  
Cerebral Amyloid

Background and ObjectiveTo report a triplication of the amyloid-β precursor protein (APP) locus along with relative messenger RNA (mRNA) expression in a family with autosomal dominant early-onset cerebral amyloid angiopathy (CAA) and Alzheimer disease (AD).MethodsFour copies of the APP gene were identified by quantitative multiplex PCR of short fluorescent fragments, fluorescent in situ hybridization (FISH), and array comparative genomic hybridization. APP mRNA levels were assessed using reverse-transcription–digital droplet PCR in the proband's whole blood and compared with 10 controls and 9 APP duplication carriers.ResultsBeginning at age 39 years, the proband developed severe episodic memory deficits with a CSF biomarker profile typical of AD and multiple lobar microbleeds in the posterior regions on brain MRI. His father had seizures and recurrent cerebral hemorrhage since the age of 37 years. His cerebral biopsy showed abundant perivascular amyloid deposits, leading to a diagnosis of CAA. In the proband, we identified 4 copies of a 506-kb region located on chromosome 21q21.3 and encompassing the whole APP gene without any other gene. FISH suggested that the genotype of the proband was 3 copies/1 copy corresponding to an APP locus triplication, which was consistent with the presence of 2 APP copies in the healthy mother and with the paternal medical history. Analysis of the APP mRNA level showed a 2-fold increase in the proband and a 1.8 fold increase in APP duplication carriers compared with controls.DiscussionIncreased copy number of APP is sufficient to cause AD and CAA, with likely earlier onset in case of triplication compared with duplication.

Abstract 211: The Role of Vascular Amyloid β in the Formation of Microhemorrhages in Cerebral Amyloid Angiopathy

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Susanne J van Veluw ◽  
Andreas Charidimou ◽  
Anand Viswanathan ◽  
Matthew Frosch ◽  
Brian Bacskai ◽  
...  
Keyword(s):  
Cerebral Amyloid Angiopathy ◽  
Amyloid Β ◽  
Direct Consequence ◽  
Transgenic Animals ◽  
Diagnostic Feature ◽  
Amyloid Angiopathy ◽  
Wild Type ◽  
Cerebral Amyloid

Introduction: Cerebral microhemorrhages are a key diagnostic feature of advanced cerebral amyloid angiopathy (CAA), but the underlying mechanisms remain poorly understood. We investigate the role of vascular Amyloid β (Aβ) in the formation of microhemorrhages in CAA, examining both human tissue and mouse models. Methods: First, we examined the histopathology of microhemorrhages, targeted with post-mortem MRI in humans. Brain slabs from nine cases with moderate/severe CAA were subjected to 7 T MRI. Samples were taken from representative MRI-observed microhemorrhages. On the corresponding histopathological sections we assessed the presence of Aβ in the walls of involved vessels, as well as number of Aβ-positive cortical vessels in areas (<2 mm) surrounding the rupture site. Second, to evaluate microhemorrhage formation in real-time in 3D, we performed in vivo two-photon microscopy in aged APP/PS1 mice with advanced CAA. Mice with previously installed cranial windows were injected with fluorescently labeled anti-fibrin, dextran, and methoxy-XO4 to study clot formation (i.e. microhemorrhages) and their spatial localization in relation to Aβ-positive vessels. Results: Human data: in 7/19 microhemorrhages the involved vessels were preserved. Only one of these vessels was positive for Aβ. Moreover, the density of Aβ-positive cortical vessels was lower close to the site of microhemorrhage (~1 positive vessel/mm 2 ), compared to control areas (~2 positive vessels/mm 2 ). Mouse data: we studied six transgenic ~21 month old APP/PS1 mice and two age-matched wild-type littermates. Mean number of in vivo observed microhemorrhages did not differ between groups (Tg: 1.3 / WT: 1), but the transgenic mice tended to have bigger microhemorrhages (mean size 4706 μm 3 ) than their wild-type controls (2505 μm 3 ). Interestingly, in the transgenic animals only one microhemorrhage was found in close proximity to vascular Aβ deposits. Conclusions: These findings question the widely held assumption that microhemorrhages in CAA are a direct consequence of Aβ deposition in the walls of responsible vessels. Our observations suggest that microhemorrhage formation may not be a direct consequence of more severe CAA locally, but may occur preferentially in areas of relatively low CAA.

Down syndrome, Alzheimer disease, and cerebral amyloid angiopathy: The complex triangle of brain amyloidosis

2019 ◽  
Vol 79 (7) ◽  
pp. 716-737 ◽  
Author(s):  
María Carmona‐Iragui ◽  
Laura Videla ◽  
Alberto Lleó ◽  
Juan Fortea
Keyword(s):  
Down Syndrome ◽  
Alzheimer Disease ◽  
Cerebral Amyloid Angiopathy ◽  
Amyloid Angiopathy ◽  
Cerebral Amyloid

scholarly journals Cerebral amyloid angiopathy severity is linked to dilation of juxtacortical perivascular spaces

2015 ◽  
Vol 36 (3) ◽  
pp. 576-580 ◽  
Author(s):  
Susanne J van Veluw ◽  
Geert Jan Biessels ◽  
Willem H Bouvy ◽  
Wim GM Spliet ◽  
Jaco JM Zwanenburg ◽  
...  
Keyword(s):  
Cerebral Amyloid Angiopathy ◽  
Small Vessel Disease ◽  
Amyloid Β ◽  
Amyloid Angiopathy ◽  
Perivascular Spaces ◽  
Resonance Imaging ◽  
Centrum Semiovale ◽  
Tissue Sections ◽  
Cortical Areas ◽  
Cerebral Amyloid

Perivascular spaces are an emerging marker of small vessel disease. Perivascular spaces in the centrum semiovale have been associated with cerebral amyloid angiopathy. However, a direct topographical relationship between dilated perivascular spaces and cerebral amyloid angiopathy severity has not been established. We examined this association using post-mortem magnetic resonance imaging in five cases with evidence of cerebral amyloid angiopathy pathology. Juxtacortical perivascular spaces dilation was evaluated on T2 images and related to cerebral amyloid angiopathy severity in overlying cortical areas on 34 tissue sections stained for Amyloid β. Degree of perivascular spaces dilation was significantly associated with cerebral amyloid angiopathy severity (odds ratio = 3.3, 95% confidence interval 1.3–7.9, p = 0.011). Thus, dilated juxtacortical perivascular spaces are a promising neuroimaging marker of cerebral amyloid angiopathy severity.

scholarly journals Characteristics of Aquaporin Expression Surrounding Senile Plaques and Cerebral Amyloid Angiopathy in Alzheimer Disease

2012 ◽  
Vol 71 (8) ◽  
pp. 750-759 ◽  
Author(s):  
Akihiko Hoshi ◽  
Teiji Yamamoto ◽  
Keiko Shimizu ◽  
Yoshikazu Ugawa ◽  
Masatoyo Nishizawa ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Cerebral Amyloid Angiopathy ◽  
Senile Plaques ◽  
Amyloid Angiopathy ◽  
Cerebral Amyloid

P2-168: Screening for Serum Biomarkers for Cerebral Amyloid Angiopathy and Alzheimer Disease: Results from a Discovery Assay of 65 Cytokines

2016 ◽  
Vol 12 ◽  
pp. P680-P680
Author(s):  
Janka Hegedus ◽  
Ana Alvarez-Veronesi ◽  
Angela Zwiers ◽  
Anna Charlton ◽  
Ramnik Sekhon ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Cerebral Amyloid Angiopathy ◽  
Serum Biomarkers ◽  
Amyloid Angiopathy ◽  
Cerebral Amyloid

scholarly journals Evidence of amyloid-β cerebral amyloid angiopathy transmission through neurosurgery

2018 ◽  
Vol 135 (5) ◽  
pp. 671-679 ◽  
Author(s):  
Zane Jaunmuktane ◽  
Annelies Quaegebeur ◽  
Ricardo Taipa ◽  
Miguel Viana-Baptista ◽  
Raquel Barbosa ◽  
...  
Keyword(s):  
Cerebral Amyloid Angiopathy ◽  
Amyloid Β ◽  
Amyloid Angiopathy ◽  
Cerebral Amyloid

scholarly journals Cerebrovascular reactivity in cerebral amyloid angiopathy, Alzheimer disease, and mild cognitive impairment

Neurology ◽  
2020 ◽  
Vol 95 (10) ◽  
pp. e1333-e1340 ◽  
Author(s):  
Aaron R. Switzer ◽  
Ikreet Cheema ◽  
Cheryl R. McCreary ◽  
Angela Zwiers ◽  
Anna Charlton ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Alzheimer Disease ◽  
Cerebral Amyloid Angiopathy ◽  
Response Amplitude ◽  
Cerebrovascular Reactivity ◽  
White Matter Hyperintensity ◽  
Amyloid Angiopathy ◽  
Bold Response ◽  
Cerebral Amyloid

ObjectiveTo assess cerebrovascular reactivity in response to a visual task in participants with cerebral amyloid angiopathy (CAA), Alzheimer disease (AD), and mild cognitive impairment (MCI) using fMRI.MethodsThis prospective cohort study included 40 patients with CAA, 22 with AD, 27 with MCI, and 25 healthy controls. Each participant underwent a visual fMRI task using a contrast-reversing checkerboard stimulus. Visual evoked potentials (VEPs) were used to compare visual cortex neuronal activity in 83 participants. General linear models using least-squares means, adjusted for multiple comparisons with the Tukey test, were used to estimate mean blood oxygen level–dependent (BOLD) signal change during the task and VEP differences between groups.ResultsAfter adjustment for age and hypertension, estimated mean BOLD response amplitude was as follows: CAA 1.88% (95% confidence interval [CI] 1.60%–2.15%), AD 2.26% (1.91%–2.61%), MCI 2.15% (1.84%–2.46%), and control 2.65% (2.29%–3.00%). Only patients with CAA differed from controls (p = 0.01). In the subset with VEPs, group was not associated with prolonged latencies or lower amplitudes. Lower BOLD amplitude response was associated with higher white matter hyperintensity (WMH) volumes in CAA (for each 0.1% lower BOLD response amplitude, the WMH volume was 9.2% higher, 95% CI 6.0%–12.4%) but not other groups (p = 0.002 for interaction) when controlling for age and hypertension.ConclusionsMean visual BOLD response amplitude was lowest in participants with CAA compared to controls, without differences in VEP latencies and amplitudes. This suggests that the impaired visual BOLD response is due to reduced vascular reactivity in CAA. In contrast to participants with CAA, the visual BOLD response amplitude did not differ between those with AD or MCI and controls.

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