Comparison of In Vivo and Ex Vivo MRI for the Detection of Structural Abnormalities in a Mouse Model of Tauopathy
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 morphometr...
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| Published in | Frontiers in neuroinformatics Vol. 11; p. 20 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
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Frontiers Research Foundation
31.03.2017
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| Abstract | 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. |
|---|---|
| AbstractList | With increasingly large numbers of mouse models of human disease dedicated to MRI studies, compromises between
in vivo
and
ex vivo
MRI must be fully understood in order to inform the choice of imaging methodology. We investigate the application of high resolution
in vivo
and
ex vivo
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
in vivo
and
ex vivo
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,
ex vivo
imaging enabled the detection of more regions of morphological brain changes. The disadvantages of
ex vivo
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
in vivo
and
ex vivo
MRI underlines the importance of appropriate study design, given the trade-off between these two imaging approaches. We support the utility of
in vivo
MRI for morphological phenotyping of mouse models of disease; however, for subtler phenotypes,
ex vivo
offers enhanced sensitivity to discrete morphological changes. With increasingly large numbers of mouse models of human disease dedicated to MRI studies, compromises between in vivo and ex vivo MRI must be fully understood in order to inform the choice of imaging methodology. We investigate the application of high resolution in vivo and ex vivo 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 in vivo and ex vivo 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, ex vivo imaging enabled the detection of more regions of morphological brain changes. The disadvantages of ex vivo 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 in vivo and ex vivo MRI underlines the importance of appropriate study design, given the trade-off between these two imaging approaches. We support the utility of in vivo MRI for morphological phenotyping of mouse models of disease; however, for subtler phenotypes, ex vivo offers enhanced sensitivity to discrete morphological changes. With increasingly large numbers of mouse models of human disease dedicated to MRI studies, compromises between in vivo and ex vivo MRI must be fully understood in order to inform the choice of imaging methodology. We investigate the application of high resolution in vivo and ex vivo 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 in vivo and ex vivo 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, ex vivo imaging enabled the detection of more regions of morphological brain changes. The disadvantages of ex vivo 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 in vivo and ex vivo MRI underlines the importance of appropriate study design, given the trade-off between these two imaging approaches. We support the utility of in vivo MRI for morphological phenotyping of mouse models of disease; however, for subtler phenotypes, ex vivo offers enhanced sensitivity to discrete morphological changes.With increasingly large numbers of mouse models of human disease dedicated to MRI studies, compromises between in vivo and ex vivo MRI must be fully understood in order to inform the choice of imaging methodology. We investigate the application of high resolution in vivo and ex vivo 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 in vivo and ex vivo 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, ex vivo imaging enabled the detection of more regions of morphological brain changes. The disadvantages of ex vivo 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 in vivo and ex vivo MRI underlines the importance of appropriate study design, given the trade-off between these two imaging approaches. We support the utility of in vivo MRI for morphological phenotyping of mouse models of disease; however, for subtler phenotypes, ex vivo offers enhanced sensitivity to discrete morphological changes. 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. |
| Author | Holmes, Holly E. Johnson, Ross A. Ourselin, Sébastien Fisher, Elizabeth M. C. Wells, Jack A. O'Callaghan, James M. Colgan, Niall Powell, Nick M. Modat, Marc Collins, Emily C. Lythgoe, Mark F. Ma, Da O'Neill, Michael J. Murray, Tracey K. Heggenes, Morten Cardoso, M. Jorge Ismail, Ozama Fisher, Alice Harrison, Ian F. Ahmed, Zeshan |
| AuthorAffiliation | 5 Department of Neurodegenerative Disease, Institute of Neurology, University College London London, UK 2 Centre for Medical Image Computing, University College London London, UK 1 Division of Medicine, UCL Centre for Advanced Biomedical Imaging, University College London London, UK 4 Molecular Pathology, Eli Lilly & Co. Ltd Windlesham, UK 3 Tailored Therapeutics, Eli Lilly and Company, Lilly Corporate Center Indianapolis, IN, USA |
| AuthorAffiliation_xml | – name: 2 Centre for Medical Image Computing, University College London London, UK – name: 1 Division of Medicine, UCL Centre for Advanced Biomedical Imaging, University College London London, UK – name: 4 Molecular Pathology, Eli Lilly & Co. Ltd Windlesham, UK – name: 3 Tailored Therapeutics, Eli Lilly and Company, Lilly Corporate Center Indianapolis, IN, USA – name: 5 Department of Neurodegenerative Disease, Institute of Neurology, University College London London, UK |
| Author_xml | – sequence: 1 givenname: Holly E. surname: Holmes fullname: Holmes, Holly E. – sequence: 2 givenname: Nick M. surname: Powell fullname: Powell, Nick M. – sequence: 3 givenname: Da surname: Ma fullname: Ma, Da – sequence: 4 givenname: Ozama surname: Ismail fullname: Ismail, Ozama – sequence: 5 givenname: Ian F. surname: Harrison fullname: Harrison, Ian F. – sequence: 6 givenname: Jack A. surname: Wells fullname: Wells, Jack A. – sequence: 7 givenname: Niall surname: Colgan fullname: Colgan, Niall – sequence: 8 givenname: James M. surname: O'Callaghan fullname: O'Callaghan, James M. – sequence: 9 givenname: Ross A. surname: Johnson fullname: Johnson, Ross A. – sequence: 10 givenname: Tracey K. surname: Murray fullname: Murray, Tracey K. – sequence: 11 givenname: Zeshan surname: Ahmed fullname: Ahmed, Zeshan – sequence: 12 givenname: Morten surname: Heggenes fullname: Heggenes, Morten – sequence: 13 givenname: Alice surname: Fisher fullname: Fisher, Alice – sequence: 14 givenname: M. Jorge surname: Cardoso fullname: Cardoso, M. Jorge – sequence: 15 givenname: Marc surname: Modat fullname: Modat, Marc – sequence: 16 givenname: Michael J. surname: O'Neill fullname: O'Neill, Michael J. – sequence: 17 givenname: Emily C. surname: Collins fullname: Collins, Emily C. – sequence: 18 givenname: Elizabeth M. C. surname: Fisher fullname: Fisher, Elizabeth M. C. – sequence: 19 givenname: Sébastien surname: Ourselin fullname: Ourselin, Sébastien – sequence: 20 givenname: Mark F. surname: Lythgoe fullname: Lythgoe, Mark F. |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/28408879$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | 2017. This work is licensed under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. Copyright © 2017 Holmes, Powell, Ma, Ismail, Harrison, Wells, Colgan, O'Callaghan, Johnson, Murray, Ahmed, Heggenes, Fisher, Cardoso, Modat, O'Neill, Collins, Fisher, Ourselin and Lythgoe. 2017 Holmes, Powell, Ma, Ismail, Harrison, Wells, Colgan, O'Callaghan, Johnson, Murray, Ahmed, Heggenes, Fisher, Cardoso, Modat, O'Neill, Collins, Fisher, Ourselin and Lythgoe |
| Copyright_xml | – notice: 2017. This work is licensed under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. – notice: Copyright © 2017 Holmes, Powell, Ma, Ismail, Harrison, Wells, Colgan, O'Callaghan, Johnson, Murray, Ahmed, Heggenes, Fisher, Cardoso, Modat, O'Neill, Collins, Fisher, Ourselin and Lythgoe. 2017 Holmes, Powell, Ma, Ismail, Harrison, Wells, Colgan, O'Callaghan, Johnson, Murray, Ahmed, Heggenes, Fisher, Cardoso, Modat, O'Neill, Collins, Fisher, Ourselin and Lythgoe |
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| Keywords | mouse models tensor-based morphometry in vivo imaging tauopathy MRI imaging neurodegeneration phenotyping preclinical imaging |
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| Snippet | 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... With increasingly large numbers of mouse models of human disease dedicated to MRI studies, compromises between in vivo and ex vivo MRI must be fully understood... With increasingly large numbers of mouse models of human disease dedicated to MRI studies, compromises between in vivo and ex vivo MRI must be fully understood... |
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| SubjectTerms | 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 |
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| Title | Comparison of In Vivo and Ex Vivo MRI for the Detection of Structural Abnormalities in a Mouse Model of Tauopathy |
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