Cerebrovascular function in presymptomatic and symptomatic individuals with hereditary cerebral amyloid angiopathy: a case-control study

AbstractObjectiveTo study blood anti-Aβ antibodies in the context of spontaneous inflammatory or hemorrhagic CAA manifestations, which are similar to complications occurring after monoclonal anti-Aβ antibody immunotherapies.MethodsIn this case-control study, serum anti-Aβ antibody isotype, concentration, avidity, and reactivity toward soluble or fibrillary Aβ1-40 and Aβ1-42 isoforms were assessed using an ELISA-based multiplex analysis. Anti-Aβ serologic patterns were defined in CAA and CAA subgroups using multivariable logistic regression analyses.ResultsFourty-one healthy aged controls and 64 CAA patients were recruited: 46 with hemorrhagic features (CAA-he) and 18 with CAA-related inflammation (CAA-ri). As compared to controls, the most striking features of CAA-related serological profiles were the following: i) both CAA-he and CAA-ri patients displayed lower binding diversity of anti-soluble Aβ1-40 IgM; ii) CAA-he patients displayed higher anti-soluble Aβ1-40 / fibrillary Aβ1-42 IgG4 concentrations ratio and higher anti-soluble Aβ1-42 IgG4 and IgA avidity; iii) CAA-ri patients displayed higher binding diversity of anti-soluble Aβ1-40 IgG3 and higher anti-fibrillary/soluble Aβ1-42 IgG4 dilution curve steepness ratio.ConclusionThis proof-of-concept study revealed anti-Aβ antibody variations in CAA patients, some of which were associated to CAA clinical phenotypes, unveiling pathophysiological insights regarding CAA-hemorrhagic and inflammatory related events.

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Clinical features distinguish cerebral amyloid angiopathy-associated convexity subarachnoid haemorrhage from suspected TIA

Journal of Neurology ◽

10.1007/s00415-019-09558-9 ◽

2019 ◽

Vol 267 (1) ◽

pp. 133-137 ◽

Cited By ~ 2

Author(s):

Joel Elliot Dane Stanton ◽

Arvind Chandratheva ◽

Duncan Wilson ◽

Isabel Charlotte Hostettler ◽

Saiful Islam ◽

...

Keyword(s):

Subarachnoid Haemorrhage ◽

Clinical Features ◽

Cerebral Amyloid Angiopathy ◽

Amyloid Angiopathy ◽

Retrospective Case ◽

Presenting Symptoms ◽

Clinical Databases ◽

Cerebral Amyloid ◽

And Gender ◽

Control Study

Abstract Objective To identity clinical features that distinguish between cerebral amyloid angiopathy (CAA)-associated convexity subarachnoid haemorrhage (cSAH) and suspected TIA. Methods We undertook a single-centre, retrospective case–control study. We identified cases [patients with cSAH presenting with transient focal neurological episodes (TFNE)] from radiological and clinical databases of patients assessed at the National Hospital for Neurology and Neurosurgery and UCLH Comprehensive Stroke Service. We identified age- and gender-matched controls at a 1:4 ratio from a database of consecutive suspected TIA clinic attendances at UCLH. We compared presenting symptoms and vascular risk factors between cases and controls. Results We included 19 patients with cSAH-associated TFNE and 76 matched controls with suspected TIA. Migratory (spreading) symptoms (32% vs. 3%, OR 17.3; p = 0.001), sensory disturbance (47% vs. 14%, OR 5.3; p = 0.003,) and recurrent stereotyped events (47% vs. 19%, OR 3.7; p = 0.02,) occurred more frequently in patients with cSAH compared to controls. Hypercholesterolaemia was less common in patients with cSAH (16% vs 53%, OR 0.17; p = 0.008). Conclusion Simple clinical features could help distinguish cSAH-associated TFNE from suspected TIA, with relevance for investigation and management, including the use of antithrombotic drugs.

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Cerebral Beta Amyloid Angiopathy Is a Risk Factor for Cerebral Ischemic Infarction. A Case Control Study in Human Brain Biopsies

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/59.9.768 ◽

2000 ◽

Vol 59 (9) ◽

pp. 768-773 ◽

Cited By ~ 80

Author(s):

Diego Cadavid ◽

Hernando Mena ◽

Kelly Koeller ◽

Robert A. Frommelt

Keyword(s):

Risk Factor ◽

Human Brain ◽

Case Control Study ◽

Beta Amyloid ◽

Case Control ◽

Amyloid Angiopathy ◽

Ischemic Infarction ◽

Cerebral Ischemic ◽

Control Study

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APOE immunotherapy reduces cerebral amyloid angiopathy and amyloid plaques while improving cerebrovascular function

Science Translational Medicine ◽

10.1126/scitranslmed.abd7522 ◽

2021 ◽

Vol 13 (581) ◽

pp. eabd7522 ◽

Cited By ~ 3

Author(s):

Monica Xiong ◽

Hong Jiang ◽

Javier Remolina Serrano ◽

Ernesto R. Gonzales ◽

Chao Wang ◽

...

Keyword(s):

Cerebral Amyloid Angiopathy ◽

Late Onset ◽

Amyloid Β ◽

Amyloid Angiopathy ◽

Therapeutic Effects ◽

Amyloid Pathology ◽

Human Apoe ◽

Cerebrovascular Function ◽

Cerebral Amyloid

The ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD) and greatly influences the development of amyloid-β (Aβ) pathology. Our current study investigated the potential therapeutic effects of the anti-human APOE antibody HAE-4, which selectively recognizes human APOE that is co-deposited with Aβ in cerebral amyloid angiopathy (CAA) and parenchymal amyloid pathology. In addition, we tested whether HAE-4 provoked brain hemorrhages, a component of amyloid-related imaging abnormalities (ARIA). ARIA is an adverse effect secondary to treatment with anti–Aβ antibodies that can occur in blood vessels with CAA. We used 5XFAD mice expressing human APOE4+/+ (5XE4) that have prominent CAA and parenchymal plaque pathology to assess the efficacy of HAE-4 compared to an Aβ antibody that removes parenchymal Aβ but increases ARIA in humans. In chronically treated 5XE4 mice, HAE-4 reduced Aβ deposition including CAA compared to a control antibody, whereas the anti–Aβ antibody had no effect on CAA. Furthermore, the anti–Aβ antibody exacerbated microhemorrhage severity, which highly correlated with reactive astrocytes surrounding CAA. In contrast, HAE-4 did not stimulate microhemorrhages and instead rescued CAA-induced cerebrovascular dysfunction in leptomeningeal arteries in vivo. HAE-4 not only reduced amyloid but also dampened reactive microglial, astrocytic, and proinflammatory-associated genes in the cortex. These results suggest that targeting APOE in the core of both CAA and plaques could ameliorate amyloid pathology while protecting cerebrovascular integrity and function.

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