The Relationship Between Physical Activity, Cognition and Alzheimer's Disease-Related Blood ...

340 Pages·2013·2.36 MB·English

The Relationship Between Physical Activity, Cognition
and Alzheimer’s Disease-Related Blood and Brain
Biomarkers

Belinda Michelle Brown
B.Sc

Supervisors: Professor Ralph Martins
Dr Jeremiah Peiffer
Dr Veer Gupta

This thesis is presented for the degree of Doctor of Philosophy at
The University of Western Australia

School of Psychiatry and Clinical Neurosciences
January 2013

Abstract
Abstract
Alzheimer’s disease (AD) is the most common form of dementia, and is characterised
by a gradual decline in cognitive function, changes in personality, and an eventual loss
of normal bodily functions, eventually leading to death. Currently, there is no effective
treatment for AD, with pharmaceutical therapies only providing partial temporary relief
of symptoms for some people affected by this devastating disease. Drugs that target the
underlying cause of the disease have all failed, as the critical regions of the brain
involved with memory and learning are too severely damaged. Thus, attention is now
being directed at prevention approaches to fighting AD.

A large body of research has linked lifestyle factors with the onset and development of
Alzheimer’s disease (AD) and its associated neuropathology. In particular, previous
studies have recognised that physically active individuals have a reduced risk of
dementia and AD, compared with their sedentary counterparts. Nevertheless, the effect
of physical activity on biological factors associated with AD has been predominantly
restricted to animal research, and thus these findings require confirmation in human
cohorts.

The present thesis has aimed to further the understanding of the association between
physical activity and AD risk, by evaluating factors that have been previously linked
with AD development. More specifically, the relationship between habitual physical
activity levels (three measures of physical activity used; self-report total physical
activity, actigraphy total volume and actigraphy peak counts) and measures of cognition
and biomarkers of AD (from both blood and brain) have been investigated in a cohort of
cognitively healthy individuals.
Abstract

The cohort in this project is derived from the larger (n = 1112) Australian Imaging,
Biomarkers, and Lifestyle (AIBL) study cohort. Only cognitively healthy individuals
(as determined by a panel of expert clinicians) from the AIBL study were selected for
inclusion and comprised the group of 564 (mean age 69.9 ± 6.9, 57% female)
participants. A sub-group of study participants (n = 124) underwent neuroimaging. Each
individual filled out an International Physical Activity Questionnaire, donated a fasted
blood sample and underwent comprehensive neuropsychological battery. A sub-set
underwent activity monitoring, using actigraphy (n = 217). The n for each analysis
varied due to missing data for some variables, thus each chapter will provide details of
available data. The first three chapters detail cross-sectional analyses of physical
activity and:
 Cognitive function (Chapter 3)
 AD-related blood biomarkers (Chapter 4)
 AD-related neuroimaging biomarkers (Chapter 5)
The findings from these chapters were then re-evaluated in longitudinal analyses
(follow-up period 18 months or 36 months; Chapter 6) in an attempt to validate the
cross-sectional findings.

The findings obtained in this research indicated a link between intensity of physical
activity (quantified by actigraphy) and better cognitive functioning. Furthermore,
physical activity was associated with biological markers of AD. Using multiple linear
regression analysis (covarying for age, gender, Apolipoprotein (APOE) ε4 allele
carriage – and years of education, where appropriate), self-reported physical activity
was associated with larger hippocampal volume, and lower levels of plasma Aβ
1-42/1-40
and brain amyloid (measured by [11C] Pittsburgh compound B positron emission
Abstract

tomography). Carriage of the APOE ε4 allele appears to play a role in modulating the
relationship between physical activity and AD risk. Non-carriers of the APOE ε4 allele
received the greatest benefit from physical activity in terms of reduced plasma Aβ
1-42/1-
ratio. Conversely, carriers of the APOE ε4 allele reporting the lowest levels of
40
physical activity had the highest PiB SUVR, compared with the more physically active
APOE ε4 carriers (who had levels of PiB SUVR similar to non-carriers of the APOE ε4
allele).

Based on the evidence presented here, combined with previous literature, physical
activity is involved in the prevention or delay of AD; however, it is clear that the link is
complex. The exact mechanism as to how physical activity can modulate the disease
course requires further investigation. Furthermore, for physical activity to be used
clinically as a preventative measure for dementia and AD, prospective clinical trials
need to be undertaken.
Table of contents

Table of Contents
Abstract ........................................................................................................................... III 
Table of Contents ............................................................................................................ VI 
Acknowledgements ......................................................................................................... XI 
Statement of Candidature ............................................................................................. XIII 
List of Figures .............................................................................................................. XIV 
List of Tables ............................................................................................................... XVI 
Abbreviations ................................................................................................................ XX 
Publications ................................................................................................................. XXII 
Conference Proceedings .............................................................................................. XXII 

-Chapter One-
Introduction
1.1.  Alzheimer’s disease ............................................................................................... 1 
1.1.1.  Microscopic Alzheimer’s disease neuropathology ......................................... 2 
1.1.2.  Neuroimaging in Alzheimer’s disease ............................................................ 6 
1.1.3.  Genetic risks factors for Alzheimer’s disease .............................................. 10 
1.1.4.  Biochemical markers associated with Alzheimer’s disease ......................... 11 
1.1.5.  Cardiovascular disease and Alzheimer’s disease ......................................... 23 
1.2.  Physical activity ................................................................................................... 26 
1.2.1.  Can physical activity/exercise enhance cognitive function and protect
against dementia? ............................................................................................................ 27 
1.2.2.  Influence of physical activity on Alzheimer’s disease associated biomarker
levels and brain processes ............................................................................................... 43 
1.2.3.  The effect of the Apolipoprotein E ε4 allele................................................. 51 
1.2.4.  Summary ....................................................................................................... 54 
1.3.  Hypotheses ........................................................................................................... 54 
1.3.1.  Chapter 3. Physical activity and cognitive function ..................................... 54 
1.3.2.  Chapter 4. Physical activity and blood biomarkers of AD ........................... 55 
1.3.3.  Chapter 5. Physical activity and neuroimaging biomarkers of AD .............. 56 
1.3.4.  Chapter 6. Physical activity, cognitive function, and blood and
neuroimaging biomarkers: A longitudinal study ............................................................ 56 

-Chapter Two-
Methods
2.1. Introduction .............................................................................................................. 61 
2.2. Ethics ........................................................................................................................ 61 
VI
Table of contents

2.3. Study population ...................................................................................................... 61 
2.4. Eligibility screening and exclusion criteria .............................................................. 62 
2.5. Study visit ................................................................................................................ 63 
2.6. Measures, materials and instruments ....................................................................... 64 
2.7. Physical activity assessment .................................................................................... 64 
2.7.1.  International Physical Activity Questionnaire (IPAQ) ................................. 64 
2.7.2.  Actigraphy .................................................................................................... 65 
2.7.3.  Timing of physical activity assessments ....................................................... 66 
2.7.4.  Normality analysis ........................................................................................ 67 
2.7.5.  Justification of physical activity group sizes ................................................ 67 
2.8. Neuropsychological assessment ............................................................................... 71 
2.8.1.  Mini Mental State Examination (MMSE) .................................................... 71 
2.8.2.  Digit Span ..................................................................................................... 71 
2.8.3.  Logical memory ............................................................................................ 72 
2.8.4.  California Verbal Learning Test Version 2 (CVLT-II) ................................ 74 
2.8.5.  Rey Complex Figure Test (RCFT) ............................................................... 74 
2.8.6.  Controlled Oral Word Association Task (COWAT) .................................... 75 
2.8.7.  Digit Symbol Coding .................................................................................... 75 
2.8.8.  The Stroop Test ............................................................................................. 75 
2.9. Classification of participants .................................................................................... 76 
2.10. Blood biomarker analysis ....................................................................................... 76 
2.10.1.  Blood collection ............................................................................................ 76 
2.10.2.  Fractionating plasma from whole blood ....................................................... 77 
2.10.3.  DNA extraction and Apolipoprotein E (APOE) genotyping ........................ 77 
2.10.4.  Lipid, insulin and hormone analysis ............................................................. 78 
2.10.5.  Plasma beta-amyloid assessment .................................................................. 79 
2.10.6.  Plasma Apolipoprotein E assessment ........................................................... 80 
2.10.7.  Plasma brain-derived neurotrophic factor assessment .................................. 81 
2.10.8.  Plasma cortisol assessment ........................................................................... 82 
2.10.9.  Rules Based Medicine analysis and biomarker panel ................................... 82 
2.11. Neuroimaging biomarker analysis ......................................................................... 84 
2.11.1.  Image acquisition .......................................................................................... 84 
2.11.2.  Image processing .......................................................................................... 85 
2.12. Demographics, medical history and medication use .............................................. 87 
2.13. Blood pressure and body mass index ..................................................................... 88 
2.14. Statistical Analysis ................................................................................................. 88 

VII
Table of contents

-Chapter Three-
Physical activity and cognitive function
3.1.  Introduction .......................................................................................................... 93 
3.2.  Materials and Methods ......................................................................................... 95 
3.2.1.  Participants ................................................................................................... 95 
3.2.2.  Procedures .................................................................................................... 95 
3.2.3.  Physical activity assessments ....................................................................... 97 
3.2.4.  Cognitive assessments .................................................................................. 98 
3.2.5.  Statistical analysis ....................................................................................... 100 
3.3.  Results ................................................................................................................ 102 
3.3.1.  Descriptive statistics for the self-report IPAQ cohort ................................ 102 
3.3.2.  Descriptive statistics of the actigraphy subset ............................................ 106 
3.3.3.  Actigraphy measures and self-report IPAQ measure ................................. 110 
3.3.4.  Self-reported physical activity (IPAQ) and cognitive function .................. 111 
3.3.5.  Actigraphy measured total activity and cognitive function ........................ 113 
3.3.6.  Actigraphy measured physical activity intensity and cognitive function ... 115 
3.3.7.  Role of gender ............................................................................................ 124 
3.4.  Discussion ......................................................................................................... 125 

-Chapter Four-
Physical activity and AD-related blood biomarkers
4.1. Introduction ............................................................................................................ 135 
4.2. Methods .................................................................................................................. 138 
4.2.1.  Participants ................................................................................................. 138 
4.2.2.  Blood collection and biomarker analysis .................................................... 140 
4.2.3.  Statistical analysis ....................................................................................... 143 
4.3. Results .................................................................................................................... 145 
4.3.1.  Descriptive statistics ................................................................................... 145 
4.3.2.  Correlations between blood biomarkers and age ........................................ 152 
4.3.3.  Self-report physical activity and blood biomarkers associated with AD ... 154 
4.3.4.  Actigraphy measured physical activity and AD blood biomarkers ............ 160 
4.3.5.  Associations between physical activity levels and the AD blood biomarker
panel (Doecke et al., 2012) ........................................................................................... 169 
4.3.6.  Potential mediators of the relationship between physical activity levels and
plasma Aβ ratios ................................................................................................. 172 
1-42/1-40
4.4. Discussion .............................................................................................................. 174 
4.4.1.  Physical activity and beta-amyloid ............................................................. 174 
4.4.2.  Physical activity and cardiovascular disease risk ....................................... 177 
VIII
Table of contents

4.4.3.  Physical activity and brain-derived neurotrophic factor ............................. 179 
4.4.4.  Physical activity and cortisol ...................................................................... 180 
4.4.5.  Physical activity and reproductive hormones ............................................. 181 
4.4.6.  Physical activity and AD biomarker panel ................................................. 183 
4.4.7.  Limitations .................................................................................................. 184 
4.4.8.  Conclusion .................................................................................................. 184 

-Chapter Five-
Physical activity and AD-related neuroimaging biomarkers
5.1. Introduction ............................................................................................................ 189 
5.2. Methods .................................................................................................................. 192 
5.2.1. Participants ................................................................................................. 192 
5.2.2. Procedures ................................................................................................... 192 
5.2.3. Image acquisition and analysis ................................................................... 194 
5.2.4. Statistical Analysis ...................................................................................... 194 
5.3. Results .................................................................................................................... 196 
5.3.1. Demographic and medical characteristics .................................................. 196 
5.3.2. Differences in neuroimaging between APOE ε4+ and APOE ε4- ............ 198 
5.3.3. Associations between self-reported physical activity (continuous variable)
and brain region volume measurements ........................................................................ 200 
5.3.4. Associations between self-reported physical activity (tertiles) and brain
region volume measurements ........................................................................................ 202 
5.3.5. Associations between physical activity level (as a continuous variable) and
brain A amyloid load, as measured by regional [11C] PiB uptake .............................. 204 
5.3.6. Difference in brain A amyloid load across self-report IPAQ tertiles. ...... 206 
5.4. Discussion .............................................................................................................. 210 
5.4.1. Physical activity and volumetric measures of brain structures ................... 210 
5.4.2. Physical activity and beta-amyloid deposition ........................................... 213 
5.4.3. Limitations .................................................................................................. 216 
5.4.4. Summary ..................................................................................................... 217 

-Chapter Six-
Longitudinal Analysis
6.1.  Introduction ........................................................................................................ 221 
6.2.  Methods .............................................................................................................. 223 
6.2.1.  Design ......................................................................................................... 223 
6.2.2.  Classification changes ................................................................................ 224 
6.2.3.  Statistical analysis ....................................................................................... 224 
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Table of contents

6.3.  Results ............................................................................................................... 226 
6.3.1.  Descriptive statistics ............................................................................... 226 
6.3.2.  Physical activity and conversion from HC to MCI or AD ...................... 228 
6.3.3.  Changes in cognition, brain volume and blood biomarkers over time ... 230 
6.3.4.  Change in physical activity tertiles from baseline to follow-up ............. 234 
6.3.5.  Physical activity and cognitive functioning ............................................ 236 
6.3.6.  Baseline IPAQ self-report physical activity levels and blood biomarkers at
the 18 or 36 month follow-up ....................................................................................... 243 
6.3.7.  Baseline actigraphy peak counts and blood biomarker levels ................. 245 
6.3.8.  Baseline actigraphy total counts and blood biomarker levels.................. 247 
6.3.9.  Baseline IPAQ self-reported physical activity and PiB PET SUVR at 36
month follow-up ............................................................................................................ 249 
6.3.10.  Baseline IPAQ self-report physical activity levels with volumetric brain
measured at 36-month follow-up .................................................................................. 252 
6.4.  Discussion ......................................................................................................... 254 

-Chapter Seven-
General Discussion
7.1.  Introduction ........................................................................................................ 265 
7.2.  Physical activity and cognitive functioning: intensity versus total volume of
physical activity ............................................................................................................ 265 
7.3.  Physical activity and risk of metabolic syndrome and cardiovascular disease:
how does this alter AD risk? ......................................................................................... 267 
7.4.  Physical activity and AD pathology................................................................... 270 
7.5.  The effect of the Apolipoprotein E ε4 allele ...................................................... 273 
7.6.  Limitations ......................................................................................................... 274 
7.7.  Future directions ................................................................................................ 276 
7.8.  Physical activity in people with AD: Future directions ..................................... 277 
7.9.  Conclusions ........................................................................................................ 278 

-References-..................................................................................................................273

-Appendix-....................................................................................................................295
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