Beckmann, Nicolau, Doelemeyer, Arno, Zurbruegg, Stefan, Bigot, Karine, Theil, Diethilde, Frieauff, Wilfried, Kolly, Carine, Neddermann, Daniel, Kreutzer, Robert, Perrot, Ludovic, Brzak, Irena, Jacobson, Laura, Staufenbiel, Matthias, Neumann, Ulf and Shimshek, Derya (2016) Longitudinal noninvasive magnetic resonance imaging of brain microhemorrhages in BACE inhibitor-treated APP transgenic mice. Neurobiology of Aging, 45. pp. 50-60. ISSN 01974580

Abstract

Currently, several immunotherapy- and BACE inhibitor-based approaches are being tested in the clinic for the treatment of Alzheimer`s disease. A crucial mechanistically related safety concern in case of a fast removal of brain blood vessel-associated amyloid-beta is the exacerbation of microhemorrhages which is already present in the majority of Alzheimer patients. To investigate potential safety liabilities for long-term Bace inhibitor therapies we used aged APP23 mice, an Alzheimer disease model, which robustly develops cerebral amyloid angiopathy (CAA). MRI, a translational tool easily applied in clinical studies, was used for the detection of the very sparse events of microhemorrhages throughout the entire brain, with a subsequent histological validation. 3D reconstruction of in vivo MRI and serial Perls` stained sections allowed a one-to-one matching of lesions and their histopathological characterization. MRI detected small Perls`s positive areas with sufficient extent along the z-axis. Our data demonstrates that volumetric assessment by non-invasive MRI is sensitive and specific to monitor cerebral microhemorrhages in vivo and that Bace inhibitor NB-360 in contrast to β1 antibody treatment of aged APP23 for three months did not exacerbate microhemorrhages.

Item Type:	Article
Date Deposited:	15 Jun 2016 23:45
Last Modified:	15 Jun 2016 23:45
URI:	https://oak.novartis.com/id/eprint/26300