Imaging the accumulation and suppression of tau pathology using multiparametric MRI

Holly E. Holmes, Niall Colgan, Ozama Ismail, Da Ma, Nick M. Powell, James M. O'Callaghan, Ian F. Harrison, Ross A. Johnson, Tracey K. Murray, Zeshan Ahmed, Morton Heggenes, Alice Fisher, M.J. Cardoso, Marc Modat, Simon Walker-Samuel, Elizabeth M.C. Fisher, Sebastien Ourselin, Michael J. O'Neill, Jack A. Wells, Emily C. Collins, Mark F. Lythgoe

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.