title: Longitudinal noninvasive magnetic resonance imaging of brain microhemorrhages in BACE inhibitor-treated APP transgenic mice.
abstract: Currently, several immunotherapies and BACE (Beta Site APP Cleaving Enzyme) inhibitor approaches are being tested in the clinic for the treatment of Alzheimer's disease. A crucial mechanism-related safety concern is the exacerbation of microhemorrhages, which are already present in the majority of Alzheimer patients. To investigate potential safety liabilities of long-term BACE inhibitor therapy, we used aged amyloid precursor protein (APP) transgenic mice (APP23), which robustly develop cerebral amyloid angiopathy. T2*-weighted magnetic resonance imaging (MRI), a translational method applicable in preclinical and clinical studies, was used for the detection of microhemorrhages throughout the entire brain, with subsequent histological validation. Three-dimensional reconstruction based on in vivo MRI and serial Perls' stained sections demonstrated a one-to-one matching of the lesions thus allowing for their histopathological characterization. MRI detected small Perls' positive areas with a high spatial resolution. Our data demonstrate that volumetric assessment by noninvasive MRI is well suited to monitor cerebral microhemorrhages in vivo. Furthermore, 3 months treatment of aged APP23 with the potent BACE-inhibitor NB-360 did not exacerbate microhemorrhages in contrast to Aβ-antibody β1. These results substantiate the safe use of BACE inhibitors regarding microhemorrhages in long-term clinical studies for the treatment of Alzheimer's disease.
authors.affiliation: Musculoskeletal Diseases Department, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Nicolau
authors.initials: N
authors.lastname: Beckmann
authors.affiliation: Preclinical Safety Department, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Arno
authors.initials: A
authors.lastname: Doelemeyer
authors.affiliation: Neuroscience Department, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zurbruegg
authors.affiliation: Preclinical Safety Department, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Karine
authors.initials: K
authors.lastname: Bigot
authors.affiliation: Preclinical Safety Department, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Diethilde
authors.initials: D
authors.lastname: Theil
authors.affiliation: Preclinical Safety Department, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Frieauff
authors.affiliation: Preclinical Safety Department, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Carine
authors.initials: C
authors.lastname: Kolly
authors.affiliation: Preclinical Safety Department, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Pierre
authors.initials: P
authors.lastname: Moulin
authors.affiliation: Drug Metabolism and Pharmacokinetics Department, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Neddermann
authors.affiliation: Preclinical Safety Department, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Robert
authors.initials: R
authors.lastname: Kreutzer
authors.affiliation: Neuroscience Department, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Perrot
authors.affiliation: Neuroscience Department, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Irena
authors.initials: I
authors.lastname: Brzak
authors.affiliation: Neuroscience Department, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Laura H
authors.initials: LH
authors.lastname: Jacobson
authors.affiliation: Neuroscience Department, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Staufenbiel
authors.affiliation: Neuroscience Department, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Ulf
authors.initials: U
authors.lastname: Neumann
authors.affiliation: Neuroscience Department, Novartis Institutes for BioMedical Research, Basel, Switzerland. Electronic address: derya.shimshek@novartis.com.
authors.forename: Derya R
authors.initials: DR
authors.lastname: Shimshek
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging*; D002543:Cerebral Hemorrhage / Q000000981:diagnostic imaging*; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods*; D018450:Disease Progression; D005260:Female; D021621:Imaging, Three-Dimensional; D008822:Mice, Transgenic; D010848:Picolinic Acids / Q000008:administration & dosage / Q000009:adverse effects*; D013843:Thiazines / Q000008:administration & dosage / Q000009:adverse effects*; D013997:Time Factors
chemical_list: C000605932:NB-360; D010848:Picolinic Acids; D013843:Thiazines
keywords: APP23; Alzheimer's disease (AD); BACE; Cerebral amyloid angiopathy (CAA); Inhibitor; Magnetic resonance imaging (MRI); Microbleeding; Microhemorrhage