Development of magnetic resonance imaging techniques for mouse models of Alzheimer's Disease

195 Pages·2015·5.26 MB·English

Development of magnetic
resonance imaging techniques
for mouse models of
Alzheimer’s Disease

James Martin O’Callaghan

Ph.D. Thesis
Submitted for the degree of Doctor of Philosophy,
University College London,
October 2015

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Declaration

I, James Martin O’Callaghan confirm that the work presented in this thesis is my own.
Where information has been derived from other sources, I confirm that this has been
indicated in the thesis. This work is based on research that I carried out at the Centre for
Advanced Biomedical Imaging, University College London, UK, between September 2011
and September 2015.

James O’Callaghan

Publications arising from this thesis

Is Your System Calibrated? MRI Gradient System Calibration for Pre-Clinical, High-
Resolution Imaging.
PLoS ONE 2014; 9(5):e96568.
J O’Callaghan, J Wells, S Richardson, H Holmes, Y Yu, S Walker-Samuel, B Siow, MF Lythgoe.

In-Vivo Imaging of Tau pathology using Multi-Parametric Quantitative MRI
NeuroImage, 2015, 111(0): 369-378
J Wells*, J O'Callaghan* , H Holmes, N Powell, R Johnston , B Siow, F Torrealdea , O Ismail, S
Walker-Samuel, X Golay, M Rega , S Richardson, M Modat, M Cardoso, S Ourselin, A
Schwarz, Z Ahmed, T Murray, M O'Neill, E Collins, N Colgan, M F Lythgoe
*Joint first authors
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Acknowledgements

I would like to extend my deepest gratitude to all those who have guided and supported
me over the last four years. Firstly, I am thankful to Professor Mark Lythgoe for taking me
on as a Ph. D. student. He has provided endless words of encouragement, inspiration and
also cappuccinos when I needed them most and has inspired me with his drive and
dedication to science. In the Centre for Advanced Biomedical Imaging he has created a
truly unique environment of learning and collaboration.
For the practical and theoretical understanding of MRI physics I have gained, I am indebted
to Dr. Jack Wells. Not only did he spend a disproportionate amount of his days and
evenings teaching me the workings of the 9.4T scanner and the pulse programming
environment, he always did it with a smile on his face. His guidance and words of wisdom
have been hugely helpful in many aspects of my work. Jack has played a key role in my
progress both academically and at table tennis, and I am hopeful that our paths will cross in
both endeavours in the future.
I am grateful to Dr. Bernard Siow for his insight, advice and knowledge on all things physics.
The close proximity of his desk to mine meant that it was a little too easy interrupt what he
was doing and fire questions his way, yet he was always willing to share his infectious
excitement for science and encourage me to pursue new directions in my work.
I would like to thank my collaborators at Eli Lilly & Co. Ltd. for providing mouse models and
performing histology. I am also grateful to all members of CABI and in particular I’d like to
thank Holly Holmes for performing perfuse fixations (of which there were many); Nick
Powell for helping with image registration; Dr. Karin Shmueli for her expertise in magnetic
susceptibility; and Dr. Rajiv Ramasawmy for organising regular football games.
I’d also like to extend a huge thank you to all my family members. My parents Mary and
Patrick O’Callaghan have always offered unwavering support and have given my wife and I
so much help in settling in the UK after moving from the USA. I am also very grateful to my
American parents-in-law Deb and Ken Grass for their encouragement – and also for being
so understanding of our transatlantic move. When he was born last year, my son Thomas
O’Callaghan transformed my life immeasurably for the better and he has been a source of
joy even during the difficult final stages of writing this thesis. Finally, and most importantly
by far, I would like to acknowledge the exceptional role of my wife, without whom this
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work would never have come to pass. Her love, inspiration, support, and self sacrifice have
made it possible to get to this point and I therefore dedicate this thesis to her, Tiffany
O’Callaghan, the love of my life.

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Abstract
Due to increasing life expectancy in western societies, a rise in the prevalence of
Alzheimer’s Disease (AD) is expected to have adverse social and economic consequences.
The success of emerging treatments for AD relies heavily on the ability to test their efficacy.
Sensitive biomarkers are required that provide information specific to the therapeutic
targets. Through manipulation of the genome, transgenic mice have been bred to exhibit
particular pathological features of AD in isolation. Magnetic Resonance Imaging (MRI) of
these mouse models can be used to observe phenotypic abnormalities in-vivo in a
controlled environment. As summarised in the introductory chapter, the aim of this work
was to develop MRI techniques for inclusion in multi-parametric protocols to characterise
AD models in-vivo.
Structural MRI has become an increasingly popular tool in the measurement of atrophy of
brain tissue over time and requires both accuracy and stability of the imaging system. In
chapter 3, a protocol for the calibration of system gradients for high resolution, pre-clinical
MRI is described. A structural phantom has been designed and 3D printed for use in a 9.4T
small bore MRI and micro CT system. Post processing software is used to monitor gradient
stability and provide corrections for scaling errors and non-linearity.
Diffusion Tensor Imaging (DTI) and Quantitative Susceptibility Mapping (QSM) are MRI
techniques that have shown sensitivity to changes in white matter regions of the brain.
QSM may also provide a non invasive method for measurement of increased iron
concentration in grey matter tissue observed in AD. Chapters 4 and 5 evaluate the utility of
these measurements as imaging biomarkers in a mouse model that exhibits tau pathology
associated with AD. Discrepancies between transgenic and wild-type groups were
identified for both MRI techniques indicating the potential benefit of their inclusion in a
multi-parametric in-vivo protocol.
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Contents
Abstract .................................................................................................................................... 5
Contents ................................................................................................................................... 6
Figures .................................................................................................................................... 10
Tables ..................................................................................................................................... 12
Abbreviations ......................................................................................................................... 13
1 Alzheimer’s Disease ................................................................................................... 15
1.1 A brief history ..................................................................................................... 15
1.2 Biomarkers ......................................................................................................... 18
1.3 Mouse models of disease................................................................................... 21
1.4 Pre-clinical imaging biomarkers ......................................................................... 23
1.5 Summary and thesis aims .................................................................................. 25
2 Magnetic resonance imaging theory and methodology ............................................ 27
2.1 Chapter summary ............................................................................................... 27
2.2 NMR signal generation ....................................................................................... 27
2.3 Echo formation ................................................................................................... 34
2.4 Relaxometry ....................................................................................................... 36
2.5 Spatial encoding ................................................................................................. 38
2.6 Echo Planar Imaging ........................................................................................... 42
2.6.1 Single and multi-shot acquisitions ............................................................. 42
2.6.2 Artifacts ...................................................................................................... 44
2.6.3 Nyquist ghost reduction ............................................................................. 47
2.7 Diffusion MRI ..................................................................................................... 48
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2.7.1 Diffusion weighting of the MR signal ......................................................... 48
2.7.2 Diffusion Tensor Imaging ........................................................................... 51
2.8 Quantitative Susceptibility Mapping .................................................................. 54
2.8.1 Magnetic susceptibility .............................................................................. 54
2.8.2 Magnetic susceptibility from the phase of the MR signal ......................... 54
2.8.3 Phase unwrapping ...................................................................................... 56
2.8.4 Removal of background field contributions ............................................... 57
2.9 References ......................................................................................................... 59
3 Development of a gradient calibration protocol for pre-clinical imaging at high
resolution ........................................................................................................................... 60
3.1 Overview ............................................................................................................ 60
3.2 Background ........................................................................................................ 60
3.3 Gradient calibration protocol description ......................................................... 62
3.4 Methods ............................................................................................................. 64
3.4.1 3D Grid phantom........................................................................................ 64
3.4.2 CT and MRI imaging ................................................................................... 65
3.4.3 System Calibration ..................................................................................... 67
3.4.4 Longitudinal assessment of calibration accuracy ...................................... 68
3.4.5 Scaling measurements for correction of Total Brain Volume estimates ... 68
3.4.6 Post-Processing Correction ........................................................................ 69
3.5 Results ................................................................................................................ 70
3.5.1 Phantom stability measurements .............................................................. 70
3.5.2 System Calibration ..................................................................................... 70
3.5.3 Post-Processing Correction ........................................................................ 73
3.5.4 MRI sequence comparison ......................................................................... 74
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3.5.5 Scaling of Total Brain Volume estimates ................................................... 75
3.6 Discussion ........................................................................................................... 76
3.7 Conclusions ........................................................................................................ 79
4 A Diffusion Tensor Imaging protocol for in-vivo multi-parametric MRI .................... 80
4.1 Overview ............................................................................................................ 80
4.2 Background ........................................................................................................ 80
4.2.1 White matter pathology in AD ................................................................... 80
4.2.2 DTI of white matter disease ....................................................................... 82
4.2.3 Potential of DTI as a disease biomarker ..................................................... 84
4.2.4 DTI in mouse models .................................................................................. 85
4.3 Development of a time-efficient DTI protocol ................................................... 86
4.3.1 Introduction and aims ................................................................................ 86
4.3.2 Methods ..................................................................................................... 88
4.3.3 Results ........................................................................................................ 95
4.3.4 Discussion ................................................................................................. 101
4.4 Diffusion Tensor Imaging in a mouse model of Tau Pathology ....................... 103
4.4.1 Introduction ............................................................................................. 103
4.4.2 Materials and Methods ............................................................................ 104
4.4.3 Results ...................................................................................................... 106
4.4.4 Discussion ................................................................................................. 113
4.5 Conclusions ...................................................................................................... 116
5 Quantitative Susceptibility Mapping in the rTg4510 mouse model ........................ 117
5.1 Overview .......................................................................................................... 117
5.2 Background ...................................................................................................... 118
5.2.1 Introduction ............................................................................................. 118
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5.2.2 Role of Iron in Neurodegenerative disease ............................................. 118
5.2.3 Iron measurement in-vivo using MRI ....................................................... 119
5.2.4 Motivation and aims ................................................................................ 123
5.3 An ex vivo pilot study of contrast enhanced QSM in the rTg4510 .................. 124
5.3.1 Introduction ............................................................................................. 124
5.3.2 Methods ................................................................................................... 125
5.3.3 Results ...................................................................................................... 128
5.3.4 Discussion ................................................................................................. 132
5.4 Development of gradient echo acquisitions for QSM in the mouse ................ 134
5.4.1 Introduction ............................................................................................. 134
5.4.2 Methods ................................................................................................... 136
5.4.3 Results ...................................................................................................... 140
5.4.4 Discussion ................................................................................................. 144
5.5 In-vivo and Ex vivo QSM in the rTg4510 .......................................................... 146
5.5.1 Introduction ............................................................................................. 146
5.5.2 Methods ................................................................................................... 147
5.5.3 Results ...................................................................................................... 152
5.5.4 Discussion ................................................................................................. 167
5.6 Conclusions ...................................................................................................... 171
6 Thesis summary, discussion, and conclusions ......................................................... 172

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Figures
Figure 1. Alzheimer’s disease historical images ................................................................ 15
Figure 2. Spin angular momentum ................................................................................... 28
Figure 3. Spin energy states .............................................................................................. 31
Figure 4. Rotation of the net magnetic vector .................................................................. 32
Figure 5. Free Induction Decay ......................................................................................... 34
Figure 6. Echo formation ................................................................................................... 35
Figure 7. T2* measurement .............................................................................................. 37
Figure 8. 2D Gradient Echo pulse sequence ..................................................................... 39
Figure 9. K-space ............................................................................................................... 41
Figure 10. Single shot EPI ................................................................................................ 43
Figure 11. Multi shot EPI ................................................................................................. 44
Figure 12. Echo misalignment ......................................................................................... 47
Figure 13. Pulsed gradient spin echo pulse sequence .................................................... 49
Figure 14. The diffusion tensor ellipsoid ......................................................................... 52
Figure 15. Phase aliasing ................................................................................................. 57
Figure 16. Gradient calibration protocol flowchart ........................................................ 63
Figure 17. 3D grid phantom design ........................................................................... 65
Figure 18. CT and MRI images of phantom ..................................................................... 66
Figure 19. Gradient scaling values before and after system calibration ........................ 72
Figure 20. Displacement fields generated from post-processing correction ................. 74
Figure 21. Sequence Comparison ................................................................................... 75
Figure 22. Scaling factor adjustments of TBV estimates ................................................. 76
Figure 23. Anatomy of the human brain ......................................................................... 81
Figure 24. Images of mouse head holder ....................................................................... 89
Figure 25. Respiratory gating for EPI sequence .............................................................. 90
Figure 26. Slice positioning for DW SE-EPI protocol ....................................................... 94
Figure 27. ROIs for study comparison ............................................................................. 95
Figure 28. Dodecane diffusion weighted difference images .......................................... 96
Figure 29. Effect of reference scan on EPI images .......................................................... 97
Figure 30. Multi-shot EPI with RF fat saturation ............................................................. 97
Figure 31. Respiratory motion artifacts in EPI images .................................................... 98
Figure 32. DW SE-EPI in-vivo images............................................................................... 99
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