Comparison of In Vivo and Ex Vivo MRI for the Detection of Structural Abnormalities in a Mouse Model of Tauopathy

• Published in: Frontiers in neuroinformatics Vol. 11; p. 20
• Main Authors: Holmes, Holly E., Powell, Nick M., Ma, Da, Ismail, Ozama, Harrison, Ian F., Wells, Jack A., Colgan, Niall, O'Callaghan, James M., Johnson, Ross A., Murray, Tracey K., Ahmed, Zeshan, Heggenes, Morten, Fisher, Alice, Cardoso, M. Jorge, Modat, Marc, O'Neill, Michael J., Collins, Emily C., Fisher, Elizabeth M. C., Ourselin, Sébastien, Lythgoe, Mark F.
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 31.03.2017; Frontiers Media S.A
• Subjects: Alzheimer's disease; Animal models; Atrophy; Automation; Autopsy; Brain; Cerebellum; Doxycycline; Genes; Genomes; Immunohistochemistry; Magnetic resonance imaging; Morphology; Morphometry; Neurodegenerative diseases; Neuroimaging; Neuroscience; NMR; Nuclear magnetic resonance; Olfactory bulb; Pathology; Phenotypes; Phenotyping; Rodents; Studies; Tau protein; Transgenic animals; University colleges; United Kingdom > UK; United States > US; mouse models; tensor-based morphometry; in vivo imaging; tauopathy; MRI imaging; neurodegeneration; phenotyping; preclinical imaging
• ISSN: 1662-5196; 1662-5196
• DOI: 10.3389/fninf.2017.00020

With increasingly large numbers of mouse models of human disease dedicated to MRI studies, compromises between and MRI must be fully understood in order to inform the choice of imaging methodology. We investigate the application of high resolution and MRI, in combination with tensor-based morphometry (TBM), to uncover morphological differences in the rTg4510 mouse model of tauopathy. The rTg4510 mouse also offers a novel paradigm by which the overexpression of mutant tau can be regulated by the administration of doxycycline, providing us with a platform on which to investigate more subtle alterations in morphology with morphometry. Both and MRI allowed the detection of widespread bilateral patterns of atrophy in the rTg4510 mouse brain relative to wild-type controls. Regions of volume loss aligned with neuronal loss and pathological tau accumulation demonstrated by immunohistochemistry. When we sought to investigate more subtle structural alterations in the rTg4510 mice relative to a subset of doxycycline-treated rTg4510 mice, imaging enabled the detection of more regions of morphological brain changes. The disadvantages of MRI may however mitigate this increase in sensitivity: we observed a 10% global shrinkage in brain volume of the post-mortem tissues due to formalin fixation, which was most notable in the cerebellum and olfactory bulbs. However, many central brain regions were not adversely affected by the fixation protocol, perhaps due to our "in-skull" preparation. The disparity between our TBM findings from and MRI underlines the importance of appropriate study design, given the trade-off between these two imaging approaches. We support the utility of MRI for morphological phenotyping of mouse models of disease; however, for subtler phenotypes, offers enhanced sensitivity to discrete morphological changes.