SUBCORTICAL HYPERINTENSITIES IN ALZHEIMER'S - T-Space

202 Pages·2012·3.71 MB·English

SUBCORTICAL HYPERINTENSITIES IN
ALZHEIMER’S DISEASE AND THE ELDERLY:
An MRI-based study examining
signs of cerebrovascular disease and dementia.

by

Joel Ramirez

A thesis submitted in conformity with the requirements for the degree of
Doctor of Philosophy
Graduate Department of Institute of Medical Science
University of Toronto

© Copyright Joel Ramirez 2012
Subcortical hyperintensities in Alzheimer’s Disease and the
elderly: An MRI-based study examining signs of
cerebrovascular disease and dementia.

Joel Ramirez, Doctor of Philosophy, 2012.
Institute of Medical Science, University of Toronto

Abstract
Subcortical hyperintensities (SH) are believed to be observable signs of
cerebrovascular disease, indicating some form of subcortical vasculopathy. Also
commonly referred to as leukoariosis, these hyperintense signals on proton density, T2-
weighted and fluid attenuated inversion recovery magnetic resonance images, are
commonly observed phenomena in Alzheimer’s disease patients and elderly persons.
Several SH sub-types with differential brain-behavior associations have been proposed
in the scientific literature: periventricular, deep white, cystic fluid filled lacunar-like
infarcts and perivascular Virchow-Robin spaces. This study will present Lesion Explorer
(LE): a comprehensive tri-feature MRI-based processing pipeline that effectively and
reliably quantifies SH sub-types in the context of additional brain tissues volumetrics in
a regionalized manner. The LE pipeline was validated using a scan-rescan procedure.
Finally, the LE pipeline was applied in a cross-sectional study of Alzheimer’s disease
patients and normal elderly controls. Brain-behavior relationships were demonstrated
with regional SH volumes and executive functioning, speed of mental processing, and
verbal memory.

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Acknowledgments
I would like to thank first and foremost, my family: Mr. Romeo I. Ramirez, Mrs. Zenaida
Lamson Ramirez, Myra Rozel Ramirez-Pham, Caitlin Joan Watson; and my extended
family: KyZr, cheech and KiNg.

I am also grateful for the kindness, hope and support from my PhD supervisor and
mentor, Dr. Sandra E. Black. I would also like to acknowledge the intellectual and
academic support from Dr. Barry Fowler, Dr. Joseé Rivest, Dr. Timothy E. Moore, Dr.
Anne Russon, Dr. Anthony Feinstein, Dr. Greg Stanisz, Dr. Nancy Lobaugh, Dr. Brian
Levine, Dr. Tiffany Chow, Dr. Rick Swartz, and Dr. Fuqiang Gao. Additionally, this
thesis would not be possible without collaboration and work provided by Conrad Rockel,
Christopher Scott, Gregory Szilagyi, Dr. Naama Levy-Cooperman, and especially Erin
Gibson.

Finally, this work would not be possible without the financial support provided by the LC
Campbell Cognitive Neurology Unit, Alzheimer Society Canada, Heart & Stroke
Foundation Centre for Stroke Recovery, and the Canadian Institutes of Health
Research: Institute of Neurosciences, Mental Health and Addictions.

Contributions
I would like to gratefully acknowledge the contributions of the LC Campbell Cognitive
Neurology Research Unit at Sunnybrook Health Sciences Centre to this project.
Neuropsychological testing, participant booking, patient assessment, and diagnosis
were provided by the neuropsychology team of the LC Campbell Cognitive Neurology
Research Unit and Heart & Stroke Foundation Centre for Stroke Recovery at
Sunnybrook. MRI was acquired through the Sunnybrook Research Institute and
Sunnybrook Health Sciences Centre. Programming support was provided by the LC
Campbell Cognitive Neurology Research Unit imaging team. Finally, I would like to
thank the many participants from the community who volunteered their time and effort to
contribute to this project as part of the Sunnybrook Study on Aging and Dementia.

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Table of Contents

Abstract ............................................................................................................................ii
Acknowledgments ........................................................................................................... iii
Contributions ................................................................................................................... iii
List of Tables ................................................................................................................. viii
List of Figures ..................................................................................................................ix
List of Abbreviations ........................................................................................................ x
Chapter 1: Thesis Introduction ........................................................................................ 1
1.1 Dementia ............................................................................................................... 2
1.1.1 Prevalence ...................................................................................................... 2
1.1.2 Consensus-based characterization & practice parameter ............................... 4
1.1.3 Clinical assessment of dementia ..................................................................... 7
1.1.4 Cognitive assessment ..................................................................................... 8
1.1.5 Neuropsychiatric assessment ......................................................................... 9
1.1.6 Laboratory testing ......................................................................................... 10
1.1.7 Neuroimaging ................................................................................................ 11
1.2 Alzheimer’s disease ............................................................................................. 11
1.2.1 Introduction ................................................................................................... 11
1.2.2 Neuropathology ............................................................................................. 12
1.2.3 Biomarkers & neuroimaging .......................................................................... 13
1.3 Cerebrovascular disease ..................................................................................... 16
1.3.1 Introduction ................................................................................................... 16
1.3.2 Cerebral small vessel disease ....................................................................... 16
1.3.3 Arteriolosclerosis ........................................................................................... 17
1.3.4 Cerebral amyloid angiopathy ......................................................................... 18
1.3.5 Venous collagenosis ..................................................................................... 19
1.3.6 Cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL) ........................................................................... 20
1.4 Alzheimer’s disease and cerebrovascular disease .............................................. 21
1.5 History of subcortical hyperintensities .................................................................. 23
1.5.1 Binswanger & Alzheimer ............................................................................... 23
1.5.2 Neuroimaging ................................................................................................ 24
1.5.3 Subcortical hyperintensities: leukoariosis ...................................................... 25
1.6 Subcortical hyperintensities ................................................................................. 25
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1.6.1 Aging white matter ........................................................................................ 25
1.6.2 Clinical relevance .......................................................................................... 27
1.6.3 Pathological correlates of subcortical hyperintensities .................................. 28
1.7 MRI-derived volumetrics ...................................................................................... 30
1.7.1 Basic tissue segmentation............................................................................. 31
1.7.2 Subcortical hyperintensities: appearance on MRI ......................................... 33
1.8 Quantification of subcortical hyperintensities ....................................................... 34
1.8.1 Rating scales ................................................................................................. 34
1.8.2 Machine learning ........................................................................................... 36
1.8.3 Intensity cut-offs points ................................................................................. 37
1.8.4 Template based ............................................................................................ 37
1.8.5 Fluid-attenuated inversion recovery (FLAIR) imaging ................................... 39
1.9 Subcortical hyperintensity sub-classifications ...................................................... 40
1.9.1 Deep white and periventricular ...................................................................... 40
1.9.2 Lacunes and dilated Virchow-Robin perivascular spaces ............................. 42
1.9.3 Microinfarcts .................................................................................................. 45
1.10 Summary of literature ........................................................................................ 47
1.11 Thesis Outline and Hypotheses ......................................................................... 49
1.11.1 Purpose ....................................................................................................... 49
1.11.2 Chapter 2: Lesion Explorer design & hypotheses ....................................... 49
1.11.3 Chapter 3: Scan-rescan design & hypotheses ............................................ 50
1.11.4 Chapter 4: Scan-rescan design & hypotheses ............................................ 51
1.11.5 Chapter 5: Discussion & future directions ................................................... 52
Chapter 2: Lesion Explorer ............................................................................................ 54
2.1 Introduction .......................................................................................................... 55
2.2 Materials and methods ........................................................................................ 60
2.2.1 Subjects ........................................................................................................ 60
2.2.2 MRI acquisition .............................................................................................. 61
2.2.3 Age-Related White Matter Changes (ARWMC) ............................................ 62
2.2.4 MRI Processing ............................................................................................. 62
2.2.5 Component 1 - Brain-Sizer ............................................................................... 63
2.2.6 Component 2 - Semi-Automated Brain Region Extraction (SABRE) ................ 67
2.2.7 Component 3 - Lesion Explorer: Subcortical Hyperintensity Segmentation ...... 69
2.2.7.1 Periventricular and deep white segmentation ............................................. 72
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2.2.7.2 Lacunar and non-lacunar ........................................................................... 73
2.2.8 Final Output ...................................................................................................... 74
2.2.9 Statistical analyses ........................................................................................... 75
2.3 Results ................................................................................................................. 76
2.3.1 Whole brain results ....................................................................................... 76
2.3.2 Regional Results ........................................................................................... 77
2.4 Discussion ........................................................................................................... 80
Chapter 3: Scan-Rescan ............................................................................................... 86
3.1 Introduction .......................................................................................................... 87
3.2 Materials and methods ........................................................................................ 90
3.2.1 Subjects ........................................................................................................ 90
3.2.2 MRI acquisition .............................................................................................. 91
3.2.3 MRI Processing ............................................................................................. 92
3.2.4 Statistics ........................................................................................................ 94
3.3 Results ................................................................................................................. 94
3.4 Discussion ........................................................................................................... 96
Chapter 4: Cross-Sectional ........................................................................................... 98
4.1 Introduction .......................................................................................................... 99
4.2 Materials and methods ...................................................................................... 100
4.2.1 Subjects ...................................................................................................... 100
4.2.2 Neuropsychological Tests ........................................................................... 101
4.2.3 MRI acquisition protocols ............................................................................ 101
4.2.4 MRI processing ........................................................................................... 102
4.2.5 Statistical analyses ...................................................................................... 103
4.3 Results ............................................................................................................... 104
4.3.1 Volumetrics ................................................................................................. 104
4.3.2 Subcortical hyperintensities and executive function: Models A&B .............. 106
4.3.3 Subcortical hyperintensities and speed of mental processing: Model C ...... 106
4.3.4 Subcortical hyperintensities and verbal learning and memory: Models D&E
............................................................................................................................. 107
4.4 Discussion ......................................................................................................... 108
Chapter 5: Limitations & Future Directions .................................................................. 114
5.1 Limitations ......................................................................................................... 115
5.2 Diffusion Tensor Imaging (DTI) .......................................................................... 116
5.3 Tract-based Spatial Statistics (TBSS) ................................................................ 125
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5.4 Anisotropy Surrounding and Within Hyperintensities ......................................... 126
5.5 Ventricular enlargement ..................................................................................... 128
5.6 Sex Differences ................................................................................................. 135
5.7 Cortical thickness ............................................................................................... 139
5.8 Cerebrovascular reactivity (CVR) ...................................................................... 140
5.9 Future Directions Summary ............................................................................... 142
Chapter 6: Thesis Discussion ...................................................................................... 145
6.1 General Summary .............................................................................................. 146
6.2 Subcortical hyperintensities ............................................................................... 147
6.3 Subcortical hyperintensities & Cognition: Clinical Importance? ......................... 148
6.4 Periventricular vs. Deep White: Relevance? ...................................................... 149
6.5 Whole Brain vs. Strategic: Does Location Matter?............................................. 153
6.6 Lacunes: Consensus? ....................................................................................... 155
6.7 Thesis Relevance .............................................................................................. 156

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List of Tables
Table 2.1: Demographics and Whole Brain Raw Volume Lesion Data….. 61
Table 2.2: Reliability Tests Summary……………………………………….. 77
Table 2.3: Regional inter-class correlation coefficients (ICC)…………….. 78
Table 2.4: Example of the volumetric profile obtained from pipeline…….. 79
Table 3.1: A summary of each participant’s age, sex, and interscan
interval (ISI)……………………………………………………….. 91
Table 3.2: Regional ICCs……………………………………………………… 94
Table 3.3: Individual whole brain volume (mm3) differences and ICCs….. 95
Table 4.1: Sample characteristics with between group comparisons
and volumetric differences……………………………………….. 105
Table 4.2: Summary of regression model results………………………….. 107
Table 5.1: Summary of demographics and vCSF changes comparing AD
and NC……………………………………………………………… 133
Table 5.2: Ventricular volume change comparing ApoE є4 positive vs. є4
negative patients with AD………………………………………… 134
Table 5.3 Age and education demographics by sex………………………. 137

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List of Figures
Figure 1.1: Frontotemporal dementia vs. Alzheimer’s disease……………….. 6
Figure 1.2: Microbleeds on MRI………………………………………………….. 18
Figure 1.3: CADASIL……………………………………………………………… 21
Figure 1.4: Clasmatodendrosis…………………………………………………... 29
Figure 1.5: Intensity histograms of young normal, elderly normal and AD….. 32
Figure 1.6: Leukoariosis on MRI…………………………………………………. 34
Figure 1.7: Decreased sensitivity of FLAIR in thalamic region………………. 40
Figure 1.8: Periventricular and deep white hyperintensities…………………. 41
Figure 1.9: Virchow-Robin space and lacunar infarct………………………… 44
Figure 2.1: Lesion Explorer-SABRE Image processing……………………… . 64
Figure 2.2: A comparison of skull stripped T1 images ………………………. 66
Figure 2.3: Brain-Sizer GUI……………………………………………………… 67
Figure 2.4: SABRE GUI………………………………………………………..... 68
Figure 2.5: Virchow-Robin perivascular spaces………………………………. 72
Figure 2.6: 3D Volume renders of pvSH and dwSH………..………………… 73
Figure 2.7: Combined tri-feature segmentation……………………………….. 74
Figure 3.1: Different Coregistration Methodologies…………………………… 93
Figure 5.1: Lesion Explorer and DTI…….……………………………………… 122
Figure 5.2: FA-BDS Scatterplot………….……………………………………… 123
Figure 5.3: Lesion Voxel Cluster Analysis……………………………………… 127
Figure 5.4: 3D Volume render of ventricular CSF……………………………… 132

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List of Abbreviations
Abbreviations
3D = Three- dimensional
Aβ42 = amyloid β
1-42
AD = Alzheimer’s Disease
ADC = apparent diffusion coefficient
ADNI = Alzheimer’s Disease Neuroimaging Initiative
AIR5 = Automated Image Registration v.5.2
ApoE = apolipoprotein E
ARWMC = Age-Related White Matter Changes
ASL = arterial spin labelling
BET = Brain Extraction Tool
BOLD = blood oxygen level dependent
BPF = Brain parenchymal fraction
cc = cubic centimeters
CADASIL = Cerebral autosomal dominant arteriopathy with subcortical infarcts
and leukoencephalopathy
CHIPS = Cholinergic HyperIntensities Scale
CP = choroid plexus
CSF = cerebrospinal fluid
CT = Computed tomography
CVD = Cerebrovascular disease
DLB = Dementia with Lewy Bodies
DSM = Diagnostic and Statistical Manual of Mental Disorders
dwSH = deep subcortical hyperintensities
FCM = fuzzy C-Means
FDG = fluorodeoxyglucose
FLAIR = fluid-attenuated inversion recovery
fMRI = functional magnetic resonance imaging
FMRIB = Oxford Centre for Functional Magnetic Resonance Imaging of the
Brain
FSL = FMRIB Software Library
FTD = frontotemporal dementia
GM = gray matter
HfB = head-from-brain
ICC = intra-class correlation coefficient of reliability
ITK = Insight ToolKit
kNN = k-nearest neighbour algorithm
LabVol = Lesion Explorer segmentation
LE = Lesion Explorer
MoCA = Montreal Cognitive Assessment tool
MMSE = Mini-Mental State Examination
MRI = magnetic resonance imaging
NAWM = normal appearing white matter
NC = normal control
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