title: Imaging the accumulation and suppression of tau pathology using multiparametric MRI.
abstract: Mouse models of Alzheimer's disease have served as valuable tools for investigating pathogenic mechanisms relating to neurodegeneration, including tau-mediated and neurofibrillary tangle pathology-a major hallmark of the disease. In this work, we have used multiparametric magnetic resonance imaging (MRI) in a longitudinal study of neurodegeneration in the rTg4510 mouse model of tauopathy, a subset of which were treated with doxycycline at different time points to suppress the tau transgene. Using this paradigm, we investigated the sensitivity of multiparametric MRI to both the accumulation and suppression of pathologic tau. Tau-related atrophy was discernible from 5.5 months within the cortex and hippocampus. We observed markedly less atrophy in the treated rTg4510 mice, which was enhanced after doxycycline intervention from 3.5 months. We also observed differences in amide proton transfer, cerebral blood flow, and diffusion tensor imaging parameters in the rTg4510 mice, which were significantly less altered after doxycycline treatment. We propose that these non-invasive MRI techniques offer insight into pathologic mechanisms underpinning Alzheimer's disease that may be important when evaluating emerging therapeutics targeting one of more of these processes.
authors.affiliation: Division of Medicine, Centre for Advanced Biomedical Imaging, University College London, London, UK. Electronic address: h.holmes.11@ucl.ac.uk.
authors.forename: Holly E
authors.initials: HE
authors.lastname: Holmes
authors.affiliation: Division of Medicine, Centre for Advanced Biomedical Imaging, University College London, London, UK.
authors.forename: Niall
authors.initials: N
authors.lastname: Colgan
authors.affiliation: Division of Medicine, Centre for Advanced Biomedical Imaging, University College London, London, UK.
authors.forename: Ozama
authors.initials: O
authors.lastname: Ismail
authors.affiliation: Division of Medicine, Centre for Advanced Biomedical Imaging, University College London, London, UK; Translational Imaging Group, Centre for Medical Image Computing, University College London, London, UK.
authors.forename: Da
authors.initials: D
authors.lastname: Ma
authors.affiliation: Division of Medicine, Centre for Advanced Biomedical Imaging, University College London, London, UK; Translational Imaging Group, Centre for Medical Image Computing, University College London, London, UK.
authors.forename: Nick M
authors.initials: NM
authors.lastname: Powell
authors.affiliation: Division of Medicine, Centre for Advanced Biomedical Imaging, University College London, London, UK.
authors.forename: James M
authors.initials: JM
authors.lastname: O'Callaghan
authors.affiliation: Division of Medicine, Centre for Advanced Biomedical Imaging, University College London, London, UK.
authors.forename: Ian F
authors.initials: IF
authors.lastname: Harrison
authors.affiliation: Tailored Therapeutics, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA.
authors.forename: Ross A
authors.initials: RA
authors.lastname: Johnson
authors.affiliation: Eli Lilly & Co. Ltd, Windlesham, Surrey, UK.
authors.forename: Tracey K
authors.initials: TK
authors.lastname: Murray
authors.affiliation: Eli Lilly & Co. Ltd, Windlesham, Surrey, UK.
authors.forename: Zeshan
authors.initials: Z
authors.lastname: Ahmed
authors.affiliation: Eli Lilly & Co. Ltd, Windlesham, Surrey, UK.
authors.forename: Morton
authors.initials: M
authors.lastname: Heggenes
authors.affiliation: Eli Lilly & Co. Ltd, Windlesham, Surrey, UK.
authors.forename: Alice
authors.initials: A
authors.lastname: Fisher
authors.affiliation: Translational Imaging Group, Centre for Medical Image Computing, University College London, London, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Cardoso
authors.affiliation: Translational Imaging Group, Centre for Medical Image Computing, University College London, London, UK.
authors.forename: Marc
authors.initials: M
authors.lastname: Modat
authors.affiliation: Division of Medicine, Centre for Advanced Biomedical Imaging, University College London, London, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Walker-Samuel
authors.affiliation: Department of Neurodegenerative Diseases, Institute of Neurology, University College London, London, UK.
authors.forename: Elizabeth M C
authors.initials: EM
authors.lastname: Fisher
authors.affiliation: Translational Imaging Group, Centre for Medical Image Computing, University College London, London, UK.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Ourselin
authors.affiliation: Eli Lilly & Co. Ltd, Windlesham, Surrey, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: O'Neill
authors.affiliation: Division of Medicine, Centre for Advanced Biomedical Imaging, University College London, London, UK.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Wells
authors.affiliation: Tailored Therapeutics, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA.
authors.forename: Emily C
authors.initials: EC
authors.lastname: Collins
authors.affiliation: Division of Medicine, Centre for Advanced Biomedical Imaging, University College London, London, UK.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Lythgoe
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D001284:Atrophy / Q000235:genetics; D002540:Cerebral Cortex / Q000473:pathology; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D005260:Female; D006624:Hippocampus / Q000473:pathology; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000473:pathology*; D024801:Tauopathies / Q000473:pathology*; D019076:Transgenes / Q000187:drug effects; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016875:tau Proteins; D004318:Doxycycline
keywords: Alzheimer's disease; Biomarker; In vivo; Longitudinal; MRI; Tauopathy