title: Amyloid-PET predicts inhibition of de novo plaque formation upon chronic γ-secretase modulator treatment.
abstract: In a positron-emission tomography (PET) study with the β-amyloid (Aβ) tracer [(18)F]-florbetaben, we previously showed that Aβ deposition in transgenic mice expressing Swedish mutant APP (APP-Swe) mice can be tracked in vivo. γ-Secretase modulators (GSMs) are promising therapeutic agents by reducing generation of the aggregation prone Aβ42 species without blocking general γ-secretase activity. We now aimed to investigate the effects of a novel GSM [8-(4-Fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine (RO5506284) displaying high potency in vitro and in vivo on amyloid plaque burden and used longitudinal Aβ-microPET to trace individual animals. Female transgenic (TG) APP-Swe mice aged 12 months (m) were assigned to vehicle (TG-VEH, n=12) and treatment groups (TG-GSM, n=12), which received daily RO5506284 (30 mg kg(-1)) treatment for 6 months. A total of 131 Aβ-PET recordings were acquired at baseline (12 months), follow-up 1 (16 months) and follow-up 2 (18 months, termination scan), whereupon histological and biochemical analyses of Aβ were performed. We analyzed the PET data as VOI-based cortical standard-uptake-value ratios (SUVR), using cerebellum as reference region. Individual plaque load assessed by PET remained nearly constant in the TG-GSM group during 6 months of RO5506284 treatment, whereas it increased progressively in the TG-VEH group. Baseline SUVR in TG-GSM mice correlated with Δ%-SUVR, indicating individual response prediction. Insoluble Aβ42 was reduced by 56% in the TG-GSM versus the TG-VEH group relative to the individual baseline plaque load estimates. Furthermore, plaque size histograms showed differing distribution between groups of TG mice, with fewer small plaques in TG-GSM animals. Taken together, in the first Aβ-PET study monitoring prolonged treatment with a potent GSM in an AD mouse model, we found clear attenuation of de novo amyloidogenesis. Moreover, longitudinal PET allows non-invasive assessment of individual plaque-load kinetics, thereby accommodating inter-animal variations.
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Brendel
authors.affiliation: DZNE-German Center for Neurodegenerative Diseases, Munich, Germany.|Laboratory of Neurodegeneration, International Institute of Molecular and Cell Biology, Warsaw, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Jaworska
authors.affiliation: DZNE-German Center for Neurodegenerative Diseases, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Herms
authors.affiliation: Biomedical Center (BMC), Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Trambauer
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Rötzer
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: F-J
authors.initials: FJ
authors.lastname: Gildehaus
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Carlsen
authors.affiliation: Department of Psychiatry, University of Oslo, Oslo, Norway.
authors.forename: P
authors.initials: P
authors.lastname: Cumming
authors.affiliation: Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Bylund
authors.affiliation: Roche Pharma Research and Early Development, Small Molecule Research, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Luebbers
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Bartenstein
authors.affiliation: DZNE-German Center for Neurodegenerative Diseases, Munich, Germany.|Biomedical Center (BMC), Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Steiner
authors.affiliation: DZNE-German Center for Neurodegenerative Diseases, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.|Biomedical Center (BMC), Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Haass
authors.affiliation: Roche Pharma Research and Early Development, Neuroscience Discovery, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: K
authors.initials: K
authors.lastname: Baumann
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Rominger
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D016022:Case-Control Studies; D016657:Cerebral Amyloid Angiopathy / Q000628:therapy; D004195:Disease Models, Animal; D005260:Female; D008137:Longitudinal Studies; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods; D013267:Stilbenes / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D016564:Amyloid beta-Protein Precursor; D000814:Aniline Compounds; D013267:Stilbenes; D053829:Amyloid Precursor Protein Secretases; C527756:4-(N-methylamino)-4'-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)stilbene