Immunotherapy reduces vascular amyloid-beta in PDAPP mice.
Sally Schroeter,Karen Khan,Robin Barbour,Minhtam Doan,Ming Chen,Terry Guido,Gill Davinder,Guriqbal S. Basi,Dale Schenk,Peter Seubert,Dora Games +10 more
TLDR
The results suggest that passive immunization can reduce VAβ levels, and modulating antibody dose can significantly mitigate the incidence of microhemorrhage while still preventing or reducing VAβ.Abstract:
In addition to parenchymal amyloid-beta (Abeta) plaques, Alzheimer's disease (AD) is characterized by Abeta in the cerebral vasculature [cerebral amyloid angiopathy (CAA)] in the majority of patients. Recent studies investigating vascular Abeta (VAbeta) in amyloid precursor protein transgenic mice have suggested that passive immunization with anti-Abeta antibodies may clear parenchymal amyloid but increase VAbeta and the incidence of microhemorrhage. However, the influences of antibody specificity and exposure levels on VAbeta and microhemorrhage rates have not been well established, nor has any clear causal relationship been identified. This report examines the effects of chronic, passive immunization on VAbeta and microhemorrhage in PDAPP mice by comparing antibodies with different Abeta epitopes (3D6, Abeta(1-5); 266, Abeta(16-23)) and performing a 3D6 dose-response study. VAbeta and microhemorrhage were assessed using concomitant Abeta immunohistochemistry and hemosiderin detection. 3D6 prevented or cleared VAbeta in a dose-dependent manner, whereas 266 was without effect. Essentially complete absence of VAbeta was observed at the highest 3D6 dose, whereas altered morphology suggestive of ongoing clearance was seen at lower doses. The incidence of microhemorrhage was increased in the high-dose 3D6 group and limited to focal, perivascular sites. These colocalized with Abeta deposits having altered morphology and apparent clearance in the lower-dose 3D6 group. Our results suggest that passive immunization can reduce VAbeta levels, and modulating antibody dose can significantly mitigate the incidence of microhemorrhage while still preventing or reducing VAbeta. These observations raise the possibility that Abeta immunotherapy can potentially slow or halt the course of CAA development in AD that is implicated in vascular dysfunction.read more
Citations
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Guidelines for the Management of Spontaneous Intracerebral Hemorrhage. A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association
J. Claude Hemphill,Steven M. Greenberg,Craig S. Anderson,Kyra J. Becker,Bernard R. Bendok,Mary Cushman,Gordon L. Fung,Joshua N. Goldstein,R. Loch Macdonald,Pamela H. Mitchell,Phillip A. Scott,Magdy Selim,Daniel Woo +12 more
TL;DR: In this article, the authors present current and comprehensive recommendations for the diagnosis and treatment of acute spontaneous intracerebral hemorrhage, including diagnosis, hemostasis, blood pressure management, inpatient and nursing management, preventing medical comorbidities, surgical treatment, outcome prediction, rehabilitation, prevention of recurrence and future considerations.
Journal ArticleDOI
Guidelines for the Management of Spontaneous Intracerebral Hemorrhage
Lewis B. Morgenstern,J. Claude Hemphill,Craig S. Anderson,Kyra J. Becker,Joseph P. Broderick,E. Sander Connolly,Steven M. Greenberg,James N. Huang,R. Loch Macdonald,Steven R. Messé,Pamela H. Mitchell,Magdy Selim,Rafael J. Tamargo +12 more
TL;DR: In this article, the authors present current and comprehensive recommendations for the diagnosis and treatment of spontaneous intracerebral hemorrhage, and a formal literature search is performed to identify the cause of the hemorrhage.
Journal ArticleDOI
C-11-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study
Juha O. Rinne,David J. Brooks,Martin N. Rossor,Nick C. Fox,Roger Bullock,William E. Klunk,Chester A. Mathis,Kaj Blennow,Jerome Barakos,A Okello,Sofia Rodriguez Martinez de Liano,Enchi Liu,Martin Koller,Gregg Keith M,Dale Schenk,Ronald Black,Michael Grundman +16 more
TL;DR: Treatment with bapineuzumab for 78 weeks reduced cortical (11)C-PiB retention compared with both baseline and placebo and seems to be useful in assessing the effects of potential Alzheimer's disease treatments on cortical fibrillar amyloid-beta load in vivo.
Journal ArticleDOI
A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease.
Stephen Salloway,Reisa A. Sperling,Sid Gilman,Nick C. Fox,Kaj Blennow,Murray A. Raskind,Marwan N. Sabbagh,Lawrence S. Honig,Rachelle S. Doody,C H van Dyck,Ruth A. Mulnard,Jerome Barakos,K.M. Gregg,E. Liu,I. Lieberburg,Dale Schenk,Ronald Black,Michael Grundman +17 more
TL;DR: Primary efficacy outcomes in this phase 2 trial were not significant, and potential treatment differences in the exploratory analyses support further investigation of bapineuzumab in phase 3 with special attention to APOE ε4 carrier status.
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Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer's Association Research Roundtable Workgroup.
Reisa A. Sperling,Reisa A. Sperling,Clifford R. Jack,Sandra E. Black,Matthew P. Frosch,Steven M. Greenberg,Bradley T. Hyman,Philip Scheltens,Maria C. Carrillo,William Thies,Martin M. Bednar,Ronald Black,H. Robert Brashear,Michael Grundman,Eric Siemers,Howard Feldman,Howard Feldman,Rachel Schindler +17 more
TL;DR: In response to concerns raised by the Food and Drug Administration, the Alzheimer's Association Research Roundtable convened a working group to review the publicly available trial data, attempts at developing animalmodels, and theliterature ontologyonthenatural historyandpathologyofrelated conditions.
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