Effects of Physical Activity and Cognitive Stimulation on Cognitive Functioning, Alzheimer‟s

373 Pages·2013·4.43 MB·English

Effects of Physical Activity and Cognitive Stimulation on
Cognitive Functioning, Alzheimer‟s Disease Related
Blood Biomarkers and Brain Glucose Metabolism in
Older Adults

Dr Tejal Madhukar Shah
MD(Ayu.)

Supervisors: Professor Ralph Martins
Dr. Giuseppe Verdile
Dr. Mathew Samuel

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

School of Psychiatry and Clinical Neurosciences
December 2012

Abstract

Alzheimer‟s disease (AD) is a progressive and neurodegenerative condition caused by
nerve cell death resulting in atrophy of the brain. It is the commonest cause of dementia.
The more prevalent type of AD is late onset AD (LOAD) and is believed to commence
many years prior to the clinical diagnosis of AD. With no effective pharmacological
interventions at present, non-pharmacological interventions such as lifestyle
modifications are currently being investigated to prevent and/or delay the onset of AD.
Evidence from observational and interventional studies show benefits of physical
activity (PA) or staying mentally active at enhancing cognition and reducing the risk of
cognitive decline. Very few studies have investigated whether a combination of these
activities can further improve cognitive functioning and none has assessed the effects of
physical activity together with computerised brain training software in cognition
togather with AD related blood biomarkers and neuroimaging markers.

In this pilot study (referred to as the physical exercise and cognitive stimulation study-
PEACS), 223 cognitively healthy community dwelling older adults were allocated into
one of the following four groups of physical activity (PA), cognitive stimulation (CS), a
combination of both and a no contact control group. The PA protocol included 3 days of
walking and 2 days of resistance training exercises for 16 weeks. Participants
undergoing the CS protocol, were either administered the insight program (visual
stimulation) or the brain fitness program (BFP-auditory stimulation) (Posit Science,
USA) (5 days/week, for 1 hour) for the first 8 weeks, and then the software programs
were swapped for the last 8 weeks. Assessments included a neuropsychological battery
and blood biomarkers at baseline, 8 weeks and at 16 weeks post intervention. A subset
of participants underwent DXA scans to assess body fat content and FDG-PET to assess
brain glucose metabolism were performed at week 16 of the study. A follow-up analysis
on cognitive performance post-intervention was undertaken at week 52 of the study.

The findings presented in this thesis showed that compared to the control (non-training
group), the combination of physical activity and computerised brain training only,
increased Long-term delayed recall (LTDR) scores, indicating improvements in verbal
memory. No significant improvements were observed for other cognitive domains. The
improvement in verbal memory was maintained on follow up after completion of the
training, suggesting long lasting effects on this particular cognitive domain. Further
I
analysis revealed that auditory followed by visual stimulation had a greater impact on
verbal memory than visual followed by auditory stimulation.

Reductions in levels of plasma homoscysteine, insulin levels and body fat content and
increased plasma Aβ were evident only in the physical activity group. Compared to
1-40
the control group, the combination of physical activity and cognitive stimulation
significantly increased FDG regional count in the left primary sensorimotor cortex (p=
0.039) and trends towards increases (p=0.051) were observed in the frontal cortex. The
increase in glucose metabolism within these regions was correlated with increased
LTDR scores (verbal episodic memory).

Overall the results indicate that compared to the non-training/contact control group, a
combination of physical activity and cognitive stimulation results in improvements in
verbal memory and this is associated with increases in brain glucose metabolism. The
results presented in this thesis contribute to the body of knowledge that leads to a better
understanding and development of physical activity and cognitive training as protective
factors against cognitive decline and AD. It also provides pilot information that is useful
for the design of future intervention trials utilising physical activity or cognitive
training.

II
Table of Contents
Abstract ......................................................................................................................... I
Table of Contents………………………………………………………………………III
Dedication ............................................................................................................... VIII
Acknowledgement ...................................................................................................... IX
Statement of Candidature ............................................................................................ XI
List of Figures ............................................................................................................ XII
List of Tables ............................................................................................................ XV
List of Abbreviations .............................................................................................. XVII

Chapter 1
Literature Review
The Role of Physical Activity and Cognitive Stimulation in Healthy Brain Aging
1.1 Background ......................................................................................................... 1
1.1.1 Introduction .............................................................................................. 1
1.2 Literature Review ................................................................................................ 3
1.2.1 History ..................................................................................................... 3
1.2.2 Statistics ................................................................................................... 3
1.2.3 Clinical Features ....................................................................................... 6
1.2.4 Diagnosis ................................................................................................. 6
1.2.5 Cerebrospinal Fluid (CSF) – tau and Aβ ................................................... 7
1.2.6 Neuroimaging........................................................................................... 8
1.3 Neuropathological Hallmarks............................................................................. 10
1.3.1 Morphological Changes .......................................................................... 10
1.3.2 Microscopic Changes ............................................................................. 11
1.4 The Amyloid Cascade Hypothesis...................................................................... 12
1.5 Etiology ............................................................................................................. 17
1.5.1 Other Genetic Risk Factors ..................................................................... 20
1.6 Treatment .......................................................................................................... 20
1.7 Aging and Cognition .......................................................................................... 21
1.8 Cognitive Reserve and Brain Plasticity .............................................................. 23
1.9 Cognition and Neurochemicals in Aging ............................................................ 25
1.10 Interventions Influencing Cognition ................................................................... 25
1.10.1 Physical Activity .................................................................................... 25
1.10.2 Benefits of PA on Cognition ................................................................... 26
1.10.3 Benefits of Physical Activity in Dementia and AD ................................. 27
1.10.4 PA as a Preventive Factor - Observational Findings ................................ 28
1.10.5 Resistance Exercise and Cognition in the Elderly ................................... 30
1.10.6 Reduction of Body Fat and Cholesterol .................................................. 30
1.10.7 Body Mass Index .................................................................................... 31
1.10.8 Genetic Interactions: PA and ApolipoproteinE 4 ................................... 31
1.11 Cognitive Stimulation ........................................................................................ 32
1.11.1 Brain Training Products .......................................................................... 35
1.11.2 Benefits of Cognitive Stimulation ........................................................... 36
1.11.3 Cognitive Stimulation, Dementia and AD ............................................... 37
1.11.4 Synergistic Benefits of PA and Cognitive Stimulation ............................ 38
1.12 Possible Mechanisms of Action for the Protective Effect of PA and/or CS ......... 39
1.12.1 Physical Activity Exercise Promotes Angiogenesis ................................. 39
1.12.2 Physical Activity Promotes Neurogenesis ............................................... 40
1.12.3 Cognitive Training Promotes Synaptogenesis ......................................... 40
1.12.4 Enriched Environment Increases Neural Plasticity/Brain Plasticity ......... 40
III
1.12.5 Physical Activity Increases Spine Density .............................................. 41
1.12.6 Physical Activity and Brain Training Activates Growth Factors .............. 41
1.12.7 Physical Activity Increases levels of Neurotransmitters .......................... 41
1.12.8 Physical Activity Regulates Brain Volume ............................................. 42
1.12.9 Physical Activity Offers Neuroprotection ............................................... 42
1.12.10 Mental Activities Promotes Cognitive Reserve ....................................... 42
1.12.11 Physical Activity and Oxidative Stress.................................................... 43
1.12.12 Physical Activity Promotes the Clearance of Aβ ..................................... 44
1.13 Prospects for the Prevention of AD .................................................................... 44
1.14 Summary ........................................................................................................... 45
1.15 Hypotheses ........................................................................................................ 47
1.16 Aims ……………………………………………………………………………..47
Chapter 2
Methods
2.1 Introduction ....................................................................................................... 50
2.2 Subjects ............................................................................................................. 50
2.3 Eligibility, Inclusion and Exclusion Criteria ....................................................... 51
2.3.1 Eligibility ................................................................................................... 51
2.3.2 Inclusion Criteria ........................................................................................ 52
2.3.3 Exclusion Criteria ............................................................................................ 52
2.3.4 Adherence Criteria ........................................................................................... 52
2.3.5 Research Design .............................................................................................. 53
2.3.5.1 Baseline .................................................................................................. 54
2.3.5.2. Intervention period ................................................................................. 54
2.3.5.3. Follow-up Study Time Points ................................................................. 55
2.3.5.4. Recruitment of Participants ..................................................................... 57
2.3.5.5. Assessments Completed ......................................................................... 59
2.3.5.6. Adherence .............................................................................................. 60
2.4 Group 1: Physical Activity (PA) ........................................................................... 61
2.4.1 Protocol ........................................................................................................... 62
2.4.1.1 Ankle weight ........................................................................................... 62
2.4.1.2 Gymstick ................................................................................................. 63
2.4.1.3 Upper Body ............................................................................................. 63
2.4.1.3.1 Chest press ............................................................................................ 63
2.4.1.3.2 Seated Row ........................................................................................... 63
2.4.1.3.3 Biceps Curls.......................................................................................... 64
2.4.1.4 Lower Body ............................................................................................. 64
2.4.1.4.1 Leg Press (Chair Rise) .......................................................................... 64
2.4.1.4.2 Leg Extension ....................................................................................... 64
2.4.1.4.3 Leg Curls .............................................................................................. 65
2.5 Group 2: Cognitive Stimulation (CS)..................................................................... 65
2.5.1 Brain Fitness Program ................................................................................ 66
2.5.2 Insight Program .......................................................................................... 69
2.6 Group 3: Physical Activity + Cognitive Stimulation ............................................. 72
2.7 Group 4: Control Group ........................................................................................ 72
2.8 Monitoring and Motivation.................................................................................... 72
2.9. Assessment Criteria .............................................................................................. 73
2.9.1 Neuropsychological Tests and Questionnaires .................................................. 73
2.9.2 Blood Fractionation Procedure and DNA Extraction ........................................ 76
2.9.2.1. Blood Chemistry ..................................................................................... 76
2.9.2.2 Plasma Aβ ............................................................................................... 77
2.9.2.3 Plasma BDNF .......................................................................................... 78
IV
2.9.2.4 APOE Genotyping ................................................................................... 79
2.9.3 Dual Energy X-Ray Absorptiometry (DXA Scan) ............................................ 80
2.9.3.1 DXA SCAN Procedure at HPH: .............................................................. 80
2.9.3.2 DXA Scan Procedure at Vario Health Institute, ECU, Joondalup, WA ..... 81
2.9.4 FDG PET scan ................................................................................................. 81
2.9.4.1 FDG PET Procedure at Oceanic Medical Imaging, HPH, WA ................. 81
2.9.4.2 FDG PET Procedure at SCGH ................................................................. 81
2.9.4.3 FDG PET Analysis .................................................................................. 81
2.9.5 Physical Function Testing ................................................................................ 82
2.9.5.3 Borg Scale ............................................................................................... 85
2.9.5.4 Pedometers .............................................................................................. 85
2.9 Dropouts ............................................................................................................. 86
2.10 Adverse Events ................................................................................................... 86
2.11 Statistical Analysis .............................................................................................. 86
Chapter 3
Baseline Demographics and Characteristics
3.1. Introduction ......................................................................................................... 89
3.2. Methods ............................................................................................................... 89
3.3. Baseline Demographics ........................................................................................ 90
3.4. Clinical Characteristics......................................................................................... 92
3.5. Physiological and Lifestyle Factors ...................................................................... 93
3.6. Cognitive Profile .................................................................................................. 96
3.7. Blood Biomarkers ................................................................................................ 98
3.8. Body Composition and Body Fat (DXA Scan) ..................................................... 99
3.9. Significant Group Differences and Their Baseline Overall Associations with the
Outcome Variables ................................................................................................... 100
3.10. Summary .......................................................................................................... 106
Chapter Four
Combined Physical Activity and Cognitive Stimulation Improves Verbal Episodic
Memory
4.1 Introduction ........................................................................................................ 109
4.2 Aims and Objectives ........................................................................................... 111
4.3 Methods .............................................................................................................. 112
4.3.1 Study Approach ............................................................................................. 112
4.3.2 Data analysis .................................................................................................. 113
4.4 Results ................................................................................................................ 114
4.4.2. Verbal Memory ............................................................................................. 115
4.4.3 Executive Functions ....................................................................................... 118
4.4.4. Processing Speed .......................................................................................... 122
4.4.5. Attention / working memory ......................................................................... 124
4.4.6. Visual Memory ............................................................................................. 127
4.4.7. Self-Report Questionnaires ........................................................................... 130
4.4.7.1 Memory Functioning Questionnaire ....................................................... 130
4.4.7.2 Short Form – 36 Questionnaire .............................................................. 131
4.4.7.3 Hospital Anxiety and Depression Scale.................................................. 131
4.4.8. Physical Fitness Assessments ........................................................................ 138
4.5 Summary............................................................................................................. 140
4.6 Discussion ........................................................................................................... 142
4.6.1Effects of combined physical activity and cognitive stimulation on cognition
(Combined Group): ................................................................................................... 143
4.6.2 Effects of physical activity on cognition (PA group):........................................ 147
4.6.3 Effects of Cognitive Stimulation (CS group) on Cognitive Functions:....... 152
V
4.6.4 Control Group and Cognition ........................................................................... 161
4.6.5 Effects of the Interventions on Self Report Questionnaires: ............................. 163
Chapter Five
Effects of Physical Activity, Cognitive Stimulation or a Combination of Both in
Alzheimer's disease Related Blood Biomarkers and Body Fat
5.1. Introduction ........................................................................................................ 167
5.2. Aims and Objectives .......................................................................................... 170
5.3. Methods ............................................................................................................. 170
5.4. Data Analysis ..................................................................................................... 171
5.5. Results ............................................................................................................... 172
5.5.1 Plasma Homocysteine .................................................................................... 173
5.5.2 Serum Cortisol ............................................................................................... 174
5.5.3 Serum Insulin ................................................................................................. 175
5.5.4 Lipid Profile ................................................................................................... 175
5.5.5 Plasma Aβ ................................................................................................. 178
1-40
5.5.6 Plasma BDNF ................................................................................................ 179
5.5.7 Body fat content ............................................................................................. 179
5.6. Summary ............................................................................................................ 182
5.7 Discussion ........................................................................................................... 182
5.7.1 Physical Activity reduces plasma homocysteine levels. .................................... 182
5.7.2 Physical activity modestly reduced serum insulin levels. .................................. 184
5.7.3 Physical activity increased levels of plasma A . .......................................... 185
1-40
5.7.4 Physical activity and / or cognitive stimulation did not alter levels of serum
cortisol. ..................................................................................................................... 186
5.7.5 PA and / or CS did not alter levels of plasma BDNF. ..................................... 188
5.7.6 No changes in lipid profile but reductions in body fat following 16 weeks of
physical activity: ....................................................................................................... 191
Chapter Six
The Effects of Visual Followed by Auditory Training and Vice Versa With and
Without Physical Activity on Cognitive Functioning, Plasma BDNF and Serum
Cortisol Levels
6.1 Introduction ......................................................................................................... 196
6.2 Aims ................................................................................................................... 197
6.3 Methods .............................................................................................................. 197
6.4 Statistical Analysis .............................................................................................. 200
6.5 Results ................................................................................................................ 201
6.5.1: Effects of cross training (visual followed by auditory or auditory followed by
visual) in combination with / without physical activity on cognitive domains. ........... 201
6.5.1.1: A combination of physical activity and auditory followed by visual cognitive
stimulation improves long term delayed recall (verbal memory). ............................... 201
6.5.1.2: Physical activity or both combinations of cognitive stimulation improves
executive functioning in non-APOEε4 carriers. ......................................................... 205
6.5.1.3: A combination of physical activity and cognitive stimulation does not improve
processing speed. ...................................................................................................... 209
6.5.1.4: A combination of physical activity and cognitive stimulation does not improve
attention/working memory. ....................................................................................... 211
6.5.1.5: Visual cognitive stimulation improves visual memory. ................................. 213
6.5.2: Cognitive stimulation (visual followed by auditory or auditory followed by
visual) in combination with physical activity does not alter blood levels of BDNF or
cortisol. ..................................................................................................................... 216
6.6 Summary ............................................................................................................. 217
6.7 Discussion ........................................................................................................... 218
VI