Diffusion and Molecular Changes in Acute and Chronic Subcortical Stroke

197 Pages·2013·3.88 MB·English

In vivo imaging of microstructural and
molecular neuroplasticity of fibre tracts
in human subcortical stroke

Barbara (Basia) Anna Radlinska
Integrated Program in Neuroscience
Department of Neurology and Neurosurgery
McGill University, Montreal (QC), Canada

June 2013

A thesis submitted to McGill University in partial fulfilment of the degree of
Doctor of Philosophy

© Basia Radlinska, 2013

i
To
Ewa, Emilka, Filip and James

ii
The problem of neurology is to understand man himself

La neurologie cherche à comprendre l’homme lui-même

Wilder Penfield

iii
List of figures .................................................................................................... vii
List of tables ..................................................................................................... viii
Acknowledgments .............................................................................................. ix
Contributions of authors ..................................................................................... x
Personal contributions ........................................................................................ xi
Other publications ............................................................................................. xii
List of abbreviations and symbols .................................................................... xv
Abstract ........................................................................................................... xvii
Résumé ............................................................................................................. xix
Original contributions ..................................................................................... xxii
1. Chapter one: Introduction ................................................................................ 1
General introduction ........................................................................................... 2
Background ......................................................................................................... 5
Ischaemic stroke .............................................................................................. 5
Post-stroke neuroplasticity .............................................................................. 6
The motor system ............................................................................................ 9
Anisotropy in the human brain...................................................................... 11
Diffusion imaging in stroke .......................................................................... 15
Diffusion Tensor Imaging (DTI)................................................................... 17
Positron Emission Tomography (PET) ......................................................... 23
Stroke imaging with PET .............................................................................. 24
Molecular markers of post-stroke neuroinflammation.................................. 25
Fibre tracts and neuroinflammation .............................................................. 27
Goals ................................................................................................................. 29
Overall significance .......................................................................................... 31
2. Chapter two: Experiment 1 ............................................................................ 32
Goals ................................................................................................................. 33
Abstract ............................................................................................................. 34
Introduction ....................................................................................................... 35
Methods ............................................................................................................. 36
Patients .......................................................................................................... 36
Behavioural testing ....................................................................................... 37
Data acquisition ............................................................................................ 38
Data analysis ................................................................................................. 38
Results ............................................................................................................... 40
Behavioural data ........................................................................................... 42
Whole Tract Volume ratios (rTV ) and Fractional Anisotropy ratios (rFA )
PT PT
....................................................................................................................... 43
Tract portions within PT-group..................................................................... 44
Correlation analyses ...................................................................................... 45
iv
Discussion ......................................................................................................... 46
Conclusions ....................................................................................................... 50
Post-publication correspondence ...................................................................... 51
Relationship between experiment 1 and experiment 2 ..................................... 55
3. Chapter three: Experiment 2 .......................................................................... 56
Goals ................................................................................................................. 57
Abstract ............................................................................................................. 58
Introduction ....................................................................................................... 60
Methods ............................................................................................................. 62
Patients .......................................................................................................... 62
Behavioural testing ....................................................................................... 62
Magnetic Resonance Imaging (MRI) ............................................................ 64
Positron Emission Tomography (PET) ......................................................... 64
Results ............................................................................................................... 68
11C-[R]-PK11195 binding in the infarct ....................................................... 68
NonPT-group: Comparing stroke patients vs. TIA ....................................... 69
PT-group vs. NonPT-group .......................................................................... 69
Correlation between 11C-[R]-PK11195 binding and clinical parameters ..... 71
Discussion ......................................................................................................... 72
Suitability of 11C-[R]-PK11195 and PET to detect AMG ............................ 72
11C-[R]-PK11195 PET in ischaemic stroke .................................................. 73
Remote AMG: Beneficial or detrimental? .................................................... 75
In vivo imaging of AMG ............................................................................... 76
Conclusions ....................................................................................................... 77
Relationship between experiment 2 and experiment 3 ..................................... 78
4. Chapter four: Experiment 3 ........................................................................... 79
Goals ................................................................................................................. 80
Abstract ............................................................................................................. 81
Introduction ....................................................................................................... 83
Methods ............................................................................................................. 85
Patients .......................................................................................................... 85
Behavioural testing ....................................................................................... 85
Magnetic Resonance Imaging (MRI) ............................................................ 88
Positron Emission Tomography (PET) ......................................................... 89
Results ............................................................................................................... 92
Regional 11C-[R]-PK11195 uptake ............................................................... 92
PT damage and correlation with 11C-[R]-PK11195 uptake .......................... 95
Correlation between initial parameters and clinical outcome ....................... 98
Discussion ......................................................................................................... 99
Does 11C-[R]-PK11195 measure microglia activity following stroke? ........ 99
v
Activated microglia (AMG) in the infarct .................................................. 101
Remote activated microglia (AMG) ........................................................... 102
Relation to fibre tract damage ..................................................................... 103
Activated microglia (AMG) and clinical outcome ..................................... 105
Conclusions ..................................................................................................... 106
5. Chapter five: Experiment 4 .......................................................................... 107
Goals ............................................................................................................... 108
Abstract ........................................................................................................... 109
Introduction ..................................................................................................... 111
Methods ........................................................................................................... 115
Clinical measures of stroke severity ........................................................... 116
Magnetic Resonance Imaging (MRI) .......................................................... 120
Diffusion Tensor Imaging (DTI)................................................................. 120
Diffusion dataset alignment ........................................................................ 121
Fibre tracking of Callosal Motor Fibres (CMF) ......................................... 122
Fibre tracking of Callosal Occipital Fibres (COF)...................................... 123
Fibre tracking of the Pyramidal tract (PT) .................................................. 125
Statistical analyses ...................................................................................... 125
Results ............................................................................................................. 126
Callosal Motor Fibres (CMF) and Callosal Occipital Fibres (COF) .......... 126
Pyramidal tract (PT) fibres .......................................................................... 130
Clinical parameters ..................................................................................... 131
Discussion ....................................................................................................... 132
Limitations .................................................................................................. 133
Mechanisms for change in CMF microstructure......................................... 135
Conclusions ..................................................................................................... 137
Supplementary material .................................................................................. 138
The ratio approach ...................................................................................... 138
Fractional Anisotropy (FA) versus Mean Diffusivity (MD) ....................... 140
6. Chapter six: Overall Significance ................................................................ 143
Overall discussion ........................................................................................... 144
Fibre tracking and evaluating the stroke-affected pyramidal tract ............. 145
Wallerian degeneration of stroke-affected tracts ........................................ 146
Prediction of clinical outcome .................................................................... 149
Overall conclusions ......................................................................................... 153
References ........................................................................................................... 154

vi
List of figures

Figure 1.1 The motor system ................................................................................ 10
Figure 1.2 Cellular elements contributing to diffusion anisotropy ....................... 12
Figure 1.3 Wallerian degeneration (WD) in mouse model of stroke .................... 13
Figure 1.4 Calculation of a DWI from signal intensities in three orthogonal planes
....................................................................................................................... 15
Figure 1.5 Time course of DW signal hyperintensity following ischaemic stroke16
Figure 1.6 Diffusion tensor ellipsoid .................................................................... 18
Figure 1.7 Displaying diffusion tensor data .......................................................... 19
Figure 1.8 Fibre tracking using the diffusion tensor model .................................. 20
Figure 1.9 Deterministic fibre tracking of the PT in two stroke patients .............. 22
Figure 1.10 The ischaemic penumbra ................................................................... 24
Figure 1.11 Activated Microglia (AMG) following experimental lesion in the rat
brain ............................................................................................................... 27
Figure 2.1 Fibre tracking of the PT ....................................................................... 41
Figure 2.2 Whole tract rFA and rTV across groups ........................................ 43
PT PT
Figure 2.3 rFA and rTV Retrograde and Anterograde to the Infarct .............. 44
PT PT
Figure 2.4 Correlation between rFA , rTV and clinical scores ........................ 45
PT PT
Figure 3.1 Placement of VOIs along the PT ......................................................... 66
Figure 3.2 Uptake ratio TACs in the infarct and oval centre ................................ 67
Figure 3.3 Uptake ratios in the infarct across groups ........................................... 68
Figure 3.4 Uptake ratios along the PT across groups ........................................... 70
Figure 3.5 Coronal views of uptake ratios along the PT across groups ................ 71
Figure 4.1 Placement of VOIs along the PT ......................................................... 90
Figure 4.2 Uptake ratios in the infarct across groups over time ........................... 92
Figure 4.3 Uptake ratios along the PT across groups ........................................... 94
Figure 4.4 Correlation between tracer uptake ratios (UR) and rFA along the PT
PT
....................................................................................................................... 96
Figure 4.5 Activated microglia (AMG) and fractional anisotropy (FA) along the
pyramidal tract (PT) ....................................................................................... 97
Figure 5.1 Fibre tracking of the CMF and COF ................................................. 124
Figure 5.2 Midsagittal view of CMF and COF in PT-group patients ................. 127
Figure 5.3 rFA and rFA across groups .................................................... 129
CMF COF
Figure 5.4 rFA and rFA over time ...................................................... 131
PT-above CMF
Figure 5.5 Supplementary: Raw MD and MD ratios across groups over time ... 142

vii
List of tables

Table 2.1 Patient demographics and clinical scores ............................................. 42
Table 3.1 Patient demographics and clinical scores ............................................. 63
Table 4.1 Patient demographics and clinical scores ............................................. 87
Table 5.1 Patient demographics .......................................................................... 118
Table 5.2 Patient clinical scores .......................................................................... 119
Table 5.3 Supplementary: Raw FA of CMF and COF across groups ................ 139
Table 5.4 Supplementary: Raw Mean Diffusivity (MD) of CMF and COF across
groups .......................................................................................................... 141

viii
Acknowledgments

For his intellectual and moral support throughout my graduate studies, I sincerely
thank my supervisor, Dr. Alexander Thiel. Many thanks also to my colleagues
from the laboratories at the SMBD Jewish General Hospital and the Brain
Imaging Centre, in particular Caroline Paquette, Michael Sidel, Sarah Grant,
Sasan Ghinani, Peter Zepper, Thomas Funck, Sharon Shapiro and Ilana Leppert. I
would also like to thank Catherine Forbes and the Stroke team of the SMBD
Jewish General Hospital, as well as the excellent technical teams at the Cyclotron
and Magnetic Resonance Imaging Units of the McConnell Brain Imaging Centre,
including Andre Cormier, Ron Lopez, David Costa and Louise Marcotte. All the
patients who participated in this research have my utmost gratitude for their
willingness to undergo multiple MRI and PET scanning sessions and clinical
assessments. Thank you also to the Integrated Program in Neuroscience (IPN)
team at McGill University. The biggest thanks go to my closest friends and family
for their loving support and inspiration through this, and all of my endeavours.
My graduate research studies were supported financially by a “Focus on Stroke”
award from the Canadian Stroke Foundation.

ix
Contributions of authors

All manuscripts presented in this thesis are the result of a close collaboration
between my PhD supervisor, Dr Alexander Thiel, and myself. We jointly
designed the experiments, acquired the data, processed the images, conducted
statistical analyses and wrote the manuscripts. The following list summarises the
contributions of other co-authors, in alphabetical order:

 Yasmin Blunck. Assisted in image processing and algorithm optimisation
during experiment 4.
 Sasan Ghinani. Assisted in data acquisition and pre-processing during
experiments 1 & 2
 Dean Jolly. Provided supervision of isotope production during experiment
2.
 Ilana Leppert. Assisted in image processing for algorithm optimisation and
data interpretation during experiments 1& 4.
 Paul Lyon. Assisted in data acquisition and analysis during experiment 2.
 Jeffrey Minuk. Assisted in patient recruitment and clinical assessment
during experiments 1, 2, 3 & 4.
 Caroline Paquette. Assisted in data acquisition, analysis and interpretation
during experiment 3.
 G. Bruce Pike. Provided access to diffusion processing pipelines and
specialist advice, as well as assistance with data interpretation during
experiments 1& 4.
 Ralf Schirrmacher. Provided supervision of PET scanning during
experiments 2 & 3.
 Michael Sidel. Assisted in clinical assessment and data acquisition during
experiment 3.
 Jean-Paul Soucy. Provided supervision of PET scanning during
experiments 2 & 3.
x