Functional MRI studies of memory, attention and treatment response in prodromal Alzheimer's ...

398 Pages·2011·10.15 MB·English

Functional MRI Studies of Memory, Attention and
Treatment Response in
Prodromal Alzheimer’s Disease.

Thomas M. Dannhauser, MBChB, MRCPsych.
Department of Mental Health Sciences
University College London

Supervisors:
Dr Zuzana Walker
Dr Sukhwinder S. Shergill

Thesis submitted for the degree of Doctor of Philosophy (Ph.D)
at University College London

January 2011
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“Physically speaking, we humans are rather
unimpressive specimens, as organisms go….We have come to
dominate the earth only by grace of one rather important
specialization – the brain”
- Isaac Asimov

“Recent studies like those of Pearson in England, Mach
in Germany, and Henri Poincaré in France, agree rather with
Hume than with Kant: all science, even the most rigorous
mathematics, is relative in its truth. Science itself is not worried
about the matter; a high degree of probability contents it.”
- Will Durant

I, Thomas M Dannhauser, 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.
Previously published materials have been reproduced with permission from the
copyright holders and where information has been derived from other sources, it has
been appropriately indicated.
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Abstract
BACKGROUND: Alzheimer's disease (AD) is characterised by initial episodic
amnesia followed by deficits in divided attention. Amnestic mild cognitive
impairment (AMCI), considered prodromal for AD, is characterised by isolated
amnesia but attentional deficits have also been observed. Amnesia in AD is
ascribed to medial temporal lobe pathology; however, attention deficits are likely
due to lesions in other areas that demonstrate early AD neuropathology e.g.
prefrontal cortex and basal forebrain cholinergic system. These lesions could
contribute to episodic amnesia and causes attention deficits in prodromal AD.
Acetylcholinesterase inhibitor drugs are used as treatment in AD and their effects
on memory and attention remain to be determined in AMCI.
METHODS: Functional magnetic resonance imaging (fMRI) was used to study
divided and selective attention, and verbal episodic memory in AMCI (n=20) by
comparison to controls (n=10). AMCI were followed to identify those that
progressed to AD. A controlled treatment trial was conducted to study the effects
of the acetylcholinesterase inhibitor rivastigmine.
RESULTS: The AMCI sample had a high rate of progression to AD (n=12).
AMCI demonstrated slower reaction times and altered cortical activation during
divided attention. Reaction times correlated inversely with default mode network
activation. Cortical activation was altered during selective attention. Verbal
amnesia was associated with semantic deficits that correlated with altered cortical
activation. Rivastigmine improved reaction times on divided attention but did not
affect memory.
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CONCLUSIONS: Divided attention is impaired and selective attention processing
altered in prodromal AD. Verbal amnesia appears partly related to executive failure.
Furthermore, correlations between memory and attention deficits suggest that
executive failure contributes to deficits across cognitive domains in prodromal AD.
Activation changes in prodromal AD during memory and attention processing suggest
impaired regulation and failure of cortical resources. Rivastigmine improves divided
attention via enhanced cortical processing but it does not benefit verbal episodic
memory.

Key words: Alzheimer’s disease, amnestic mild cognitive impairment, episodic
memory, divided attention, prefrontal cortex, executive functioning, rivastigmine,
fMRI.
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Contents
ABSTRACT.............................................................................................................3
CONTENTS.............................................................................................................5
LIST OF FIGURES...............................................................................................12
LIST OF TABLES.................................................................................................14
ABBREVIATIONS................................................................................................18
ORIGINAL PAPERS............................................................................................21
CONFERENCE PROCEEDINGS........................................................................22
ACKNOWLEDGMENTS.....................................................................................23
1. INTRODUCTION.............................................................................................25
1.1 ALZHEIMER’S DEMENTIA ................................................................................26
1.1.1 Epidemiology and Clinical Characterisation...........................................26
1.1.2 Aetiology and Neuropathology................................................................28
1.1.3 Identifying Preclinical and Prodromal AD..............................................33
1.2 AMNESTIC MILD COGNITIVE IMPAIRMENT.......................................................41
1.2.1 Clinical Characterisation and Epidemiology...........................................41
1.2.2 AD Neuropathology in AMCI..................................................................43
1.2.3 AMCI Represents Prodromal AD............................................................46
1.3 AMCI, AD AND AGEING................................................................................53
1.3.1 Defining Normal, Ageing and Disease.....................................................54
1.3.2 The Aetiology of Ageing and AD.............................................................54
1.3.3 Age-related Cognitive Decline.................................................................56
1.4 EPISODIC MEMORY.........................................................................................66
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1.4.1 Theoretical Background..........................................................................67
1.4.2 Episodic Memory Network...................................................................68
1.4.3 The Neuropsychology of Episodic Memory..............................................72
1.4.4 Neuropsychological Findings in AMCI....................................................75
1.4.6 Functional Anatomy of Episodic Memory Encoding in AMCI..................76
1.5 ATTENTION....................................................................................................82
1.5.1 Theoretical Background..........................................................................82
1.5.2 Neuropsychological findings of attention in AMCI..................................84
1.5.3 Functional anatomy of divided attention..................................................86
1.5.4 The functional anatomy of divided attention in AMCI..............................89
1.6 THE REGULATION OF MEMORY AND ATTENTION: THE CENTRAL EXECUTIVE,
PREFRONTAL CORTEX, BASAL FOREBRAIN CHOLINERGIC SYSTEM AND BRAINSTEM
LOCUS COERULEUS..............................................................................................93
1.6.1 Memory - Attention Interaction...............................................................93
1.6.2 Central Executive Function.....................................................................95
1.6.3 The Prefrontal Cortex.............................................................................96
1.6.4 The Role of the BFCS in attention and memory.......................................99
1.6.5 The Role of the Brainstem Locus Coeruleus in Attention and Memory...104
1.7 ACETYLCHOLINE AND ACETYLCHOLINESTERASE INHIBITOR TREATMENT.......108
1.7.1 The Role of Acetylcholine in Memory and Attention.............................. 109
1.7.2 Acetylcholinesterase..............................................................................111
1.7.3 Acetylcholinesterase Inhibitors and Rivastigmine..................................111
1.7.4 ACEI Treatment Effects on Verbal Episodic Memory in Health, AMCI and
AD.................................................................................................................112
1.7.5 ACEI Treatment Effects on Attention in Health, AMCI and AD.............114
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1.7.6 The Current Status of ACEI Treatment in AD and MCI.........................118
2. RATIONALE AND AIMS OF THE THESIS................................................120
2.1 OVERALL AIMS ............................................................................................ 120
2.2 DIVIDED ATTENTION....................................................................................121
2.3 VISUAL AND AUDITORY SELECTIVE ATTENTION............................................123
2.4 VERBAL EPISODIC MEMORY.........................................................................123
2.5 ACEI TREATMENT EFFECTS ON ATTENTION AND EPISODIC MEMORY IN AMCI.
.......................................................................................................................... 125
3. METHODS......................................................................................................128
3.1 ETHICAL CONSIDERATIONS...........................................................................128
3.2 STUDY DESIGN............................................................................................. 131
3.3 PARTICIPANT RECRUITMENT.........................................................................132
3.4 AMCI PATIENTS.......................................................................................... 132
3.5 CONTROLS....................................................................................................135
3.6 NEUROPSYCHOLOGICAL MEASURES.............................................................. 135
3.7 BEHAVIOURAL MEASURES............................................................................138
3.7.1 Statistical Methods for Behavioural Data Analyses............................... 139
3.8 FUNCTIONAL MAGNETIC RESONANCE IMAGING.............................................140
3.8.1 Biophysics............................................................................................. 141
3.8.2 Imaging Sessions................................................................................... 142
3.8.3 Image Acquisition................................................................................. 143
3.8.4 Data Analysis........................................................................................144
3.8.5 Stimuli Presentation..............................................................................155
3.9 OVERVIEW OF COGNITIVE PARADIGMS........................................................... 155
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3.9.1 Divided Attention Paradigm..................................................................155
3.9.2 Visual and Auditory Selective Attention Paradigm................................ 163
3.9.3 Verbal Episodic Encoding Paradigm.....................................................164
3.9.4 Verbal Episodic Memory Recognition Paradigm...................................168
3.9.5 Post Hoc Analyses................................................................................. 177
4. RESULTS........................................................................................................179
4.1 PARTICIPANTS DEMOGRAPHICS.....................................................................179
4.2 NEUROCOGNITIVE RESULTS..........................................................................181
4.3 OVERVIEW OF SCANNING SESSIONS............................................................... 183
4.4 DIVIDED ATTENTION TASK PILOT DATA........................................................184
4.5 DIVIDED ATTENTION AT BASELINE................................................................ 184
4.5.1 Behavioural Results..............................................................................185
4.5.2 Functional Results................................................................................. 186
4.6 VISUAL AND AUDITORY SELECTIVE ATTENTION AT BASELINE.......................193
4.6.1 Functional Results Visual Selective Attention........................................194
4.6.2 Functional Results Auditory Selective Attention....................................198
4.7 VERBAL EPISODIC ENCODING AT BASELINE................................................... 202
4.7.1 Behavioural Results..............................................................................202
4.7.2 Functional Results................................................................................. 202
4.8 RECOGNITION AT BASELINE..........................................................................209
4.8.1 Behavioural Results..............................................................................210
4.8.2 Functional Results................................................................................. 212
4.9 RIVASTIGMINE TREATMENT EFFECTS ON DIVIDED ATTENTION IN AMCI........222
4.9.1 Rivastigmine Dosage and Tolerability................................................... 222
4.9.2 Neurocognitive and Behavioural Results...............................................222
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4.9.3 Functional Results................................................................................. 226
4.9.4 Post-hoc Analyses................................................................................. 231
4.10 RIVASTIGMINE TREATMENT EFFECTS ON VISUAL AND AUDITORY SELECTIVE
ATTENTION........................................................................................................233
4.10.1 Functional Results...............................................................................233
4.11 RIVASTIGMINE TREATMENT EFFECTS ON VERBAL ENCODING AND RECOGNITION
.......................................................................................................................... 246
4.11.1 Behavioural Results............................................................................246
4.11.2 Functional Results...............................................................................247
5. DISCUSSION..................................................................................................249
5.1 PARTICIPANT DEMOGRAPHICS.......................................................................250
5.2 NEUROCOGNITIVE FINDINGS.........................................................................253
5.3 DIAGNOSTIC STABILITY AND DISEASE PROGRESSION.....................................253
5.4 OVERVIEW OF SCANNING SESSIONS............................................................... 253
5.5 PILOTING THE DIVIDED ATTENTION TASK.....................................................254
5.6 DIVIDED ATTENTION IN AMCI AT BASELINE................................................. 255
5.6.1 Behavioural Findings............................................................................255
5.6.2 Functional Findings..............................................................................265
5.7 VISUAL AND AUDITORY SELECTIVE ATTENTION IN AMCI AT BASELINE........280
5.7.1 Functional Findings - Visual Selective Attention...................................280
5.7.2 Functional Findings - Auditory Selective Attention................................ 288
5.8 VERBAL EPISODIC ENCODING AT BASELINE................................................... 292
5.8.1 Behavioural Findings............................................................................293
5.8.2 Functional Findings..............................................................................297
5.9 RECOGNITION AT BASELINE..........................................................................307
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5.9.1 Behavioural Findings............................................................................308
5.9.2 Functional Findings..............................................................................308
5.10 RIVASTIGMINE TREATMENT EFFECTS ON DIVIDED ATTENTION IN AMCI......314
5.10.1 Rivastigmine Dosage and Tolerability................................................. 314
5.10.2 Demographics and Neurocognitive Results .........................................315
5.10.3 Behavioural Findings..........................................................................316
5.10.4 Functional Findings............................................................................317
5.11 RIVASTIGMINE TREATMENT EFFECTS ON VISUAL AND AUDITORY SELECTIVE
ATTENTION........................................................................................................321
5.11.1 Behavioural Findings..........................................................................322
5.11.2 Visual selective attention.....................................................................322
5.11.3 Auditory selective attention.................................................................323
5.12 RIVASTIGMINE TREATMENT EFFECTS ON VERBAL EPISODIC MEMORY.........326
6. CONCLUSIONS AND FUTURE DIRECTIONS..........................................328
6.1 AMCI AS PRODROMAL AD...........................................................................329
6.1.1 AMCI....................................................................................................329
6.1.2 Ageing...................................................................................................331
6.2 ATTENTION IN PRODROMAL AD....................................................................333
6.2.1 Visual selective attention.......................................................................333
6.2.2 Auditory selective attention...................................................................334
6.2.3 Visual-auditory divided attention.......................................................... 336
6.3 VERBAL EPISODIC MEMORY IN PRODROMAL AD............................................339
6.4 ACEI TREATMENT IN PRODROMAL AD.........................................................343
6.4.1 Visual and auditory selective attention.................................................. 343
6.4.2 Divided attention................................................................................... 344