Neural Mechanisms of Cognitive Reserve in Alzheimer's Disease

104 Pages·2017·6.91 MB·English

by  Nicolai Franzmeier

Dissertation der
Graduate School of Systemic Neurosciences der
Ludwig-Maximilians-Universität München

Neural Mechanisms of Cognitive Reserve
in Alzheimer’s Disease

submitted by
Nicolai Franzmeier
2nd of June 2017
Date of submission:
02.06.2017
Date of Defense:
29.09.2017

First Supervisor:
Prof. Dr. Michael Ewers
Second supervisor:
PD Dr. Kathrin Koch
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Abstract
Alzheimer’s disease (AD) is the most common cause of age-related dementia, where
neuropathological changes develop gradually over years before the onset of dementia
symptoms. Yet, despite the progression of AD pathology, the decline in cognitive abilities
such as episodic memory can be relatively slow. A slower decline of cognition and
delayed onset of dementia relative to the progression of neuropathology has been
associated with particular intellectual and lifestyle factors such as more years of education
and IQ. Thus education and IQ are seen as protective factors that are associated with an
increased ability to cope with brain pathology, i.e. cognitive reserve.
While numerous studies showed that education, IQ and other lifestyle factors are
associated with relatively high cognitive abilities in AD, little is known about the
underlying brain mechanisms of reserve. Most previous studies tested the association
between protective factors such as education or IQ and differences in brain structure and
function in order to identify brain mechanisms underlying reserve. Since such protective
factors are global in nature and unspecific with regard to reserve, the results were highly
variable. So far, there is a lack of knowledge of brain features that are associated with a
higher ability to maintain cognition in the face of AD pathology. The overall aim of this
dissertation was to test a priori selected functional network features that may underlie
cognitive reserve.
We focused on resting-state functional networks, and in particular the fronto-parietal
control network as correlate of cognitive reserve. Such functional networks are thought to
be composed of brain regions that are co-activated during a particular task, where the
interaction between brain regions may be critical to support cognitive function. During
task-free resting-state periods, the different and often distant brain regions of such network
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show correlated activity, i.e. functional connectivity. For the fronto-parietal control
network, and in particular its globally connected hub in the left frontal cortex (LFC),
higher resting-state connectivity has been previously shown to be associated with higher
cognitive abilities as well as higher education and IQ, i.e. protective factors associated
with reserve. Since that network and its LFC hub are relatively spared in AD, in contrast
to more posterior parietal networks, we investigated whether higher connectivity of the
fronto-parietal control network is associated with higher reserve in AD. We argued that
the fronto-parietal control network is relatively stable during the initial stages of AD and
may thus be well posited to subserve reserve in AD. In contrast, networks like the default
mode network (DMN) that cover midline brain structures including the medial frontal lobe
and the posterior cingulate may be highly vulnerable to AD pathology, given the previous
observations of altered DMN connectivity and posterior parietal FDG-PET
hypometabolism in AD.
In particular, the resting-state connectivity between the DMN and the dorsal attention
network (DAN) may be predictive of lower episodic memory in AD. Both networks
interact in a competitive (i.e. anti-correlated) way during task and resting-state, which is
critical for cognitive processes such as episodic memory.
In a first step, we tested whether the resting-state connectivity between the DMN and the
DAN (i.e. anti-correlated activity) is associated with lower episodic memory in subjects
with amnestic mild cognitive impairment (MCI), i.e. subjects at increased risk to convert
to AD dementia. Furthermore, we tested whether protective factors such as higher
education moderate the association between the DMN-DAN anti-correlation and
cognition. Here, the DMN-DAN anti-correlation was a measure of AD related
pathological change rather than a substrate of reserve.
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We could show in two independent samples of patients at risk of AD dementia that a
weaker DMN-DAN anti-correlation was associated with lower episodic memory, where
the decrements in episodic memory were however weaker in subjects with higher
education or IQ (interaction DMN-DAN x education/IQ). These results suggest that MCI
subjects with higher protective factors (education, IQ) maintain episodic memory
relatively well at a given level of AD-related brain changes.
In the second step, we sought to identify those network differences that support cognitive
reserve, i.e. that may explain the association between higher education and milder
cognitive impairment in AD. Here, we could show that greater resting-state fMRI assessed
global connectivity of the LFC, i.e. a key hub of the fronto-parietal control network, was
associated with greater education and attenuated effects of neurodegeneration (measured
by parietal FDG-PET hypometabolism) on memory in prodromal AD. Together, these
results support the idea that global connectivity of a fronto-parietal control network hub
supports cognitive reserve in AD. Based on this finding, we developed a novel resting-
state fMRI index of fronto-parietal control network connectivity as a functional imaging
marker of cognitive reserve. This marker is highly correlated with education and may thus
be used as an imaging-based index of cognitive reserve. Together, our results provide for
the first time evidence that cognitive reserve in AD is supported by higher functional
connectivity of the fronto-parietal control network, in particular its LFC hub.
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Overview
The thesis is structured in five main chapters. The introduction briefly summarizes the
clinical course of Alzheimer’s disease and highlights its’ relevance for our aging society.
In this context, we will review the concept of cognitive reserve that is associated with
attenuated effects of Alzheimer’s disease pathology on cognition and may thus help
prevent dementia. We will summarize previous research on functional brain differences as
a correlate of cognitive reserve and point out the major research gaps that motivated our
studies to investigate the functional network changes that underlie cognitive reserve.

The main body of the thesis is presented in form of three research articles that have all
been published in peer-reviewed journals from 2016 to 2017. The articles are embedded in
three separate chapters in their published format, each introduced with a short summary of
the article’s content.

The first paper aims to assess whether protective factors including years of education &
IQ moderate the impact of posterior parietal neural network failure on cognition in
patients with mild cognitive impairment who are at risk of developing early stage
Alzheimer’s disease dementia.

The second paper aims to determine which functional network differences underlie
cognitive reserve in patients with prodromal Alzheimer’s disease. Specifically, the paper
demonstrates that a functional hub region in the left frontal cortex belonging to the fronto-
parietal control network may constitute the long sought-after neural substrate of cognitive
reserve.
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The third paper translates these previous findings on the neural mechanisms of cognitive
reserve into a novel imaging-based measure that captures cognitive reserve-related
functional properties of the fronto-parietal control network and summarizes them in a
single index.

The discussion addresses how our findings may provide a general framework for future
cognitive reserve research which may foster a deeper neural understanding of its’
compensatory nature.

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Contents
1 | INTRODUCTION .............................................................................................................. 10
1.1. ALZHEIMER’S DISEASE – A CHALLENGE FOR OUR AGING SOCIETY ................................... 10
1.2. WHAT IS RESERVE? ........................................................................................................... 12
1.3. FUNCTIONAL MRI ........................................................................................................... 16
1.4. FUNCTIONAL NETWORK CHANGES IN ALZHEIMER’S DISEASE ........................................... 17
1.5. FUNCTIONAL NEUROIMAGING EVIDENCE FOR COGNITIVE RESERVE MECHANISMS IN
AGING AND ALZHEIMER’S DISEASE ................................................................................................ 19
1.6. DEFINING NOVEL CRITERIA TO TEST NEURAL MECHANISMS OF COGNITIVE RESERVE ...... 22
1.7. A FRONTO-PARIETAL CONTROL NETWORK MODEL OF COGNITIVE RESERVE .................. 23
1.8. AIMS OF THE THESIS ......................................................................................................... 26
2 | COGNITIVE RESERVE AND FUNCTIONAL NETWORK CHANGES IN MILD
COGNITIVE IMPAIRMENT ..................................................................................................... 28
2.1 SUMMARY ........................................................................................................................ 28
2.2 REFERENCE ....................................................................................................................... 29
3 | A FRONTO-PARIETAL CONTROL NETWORK HUB AS A SUBSTRATE OF COGNITIVE
RESERVE ................................................................................................................................... 43
3.1. SUMMARY ........................................................................................................................ 43
3.2. REFERENCE ....................................................................................................................... 44
4 | AN IMAGING-BASED MARKER OF COGNITIVE RESERVE ............................................ 59
4.1. SUMMARY ........................................................................................................................ 59
4.2. REFERENCE ....................................................................................................................... 60
5 | DISCUSSION AND CONCLUSION ................................................................................. 77
5.1. COGNITIVE RESERVE IN ALZHEIMER’S DISEASE .................................................................. 78
5.2. CONNECTIVITY OF FRONTO-PARIETAL CONTROL NETWORK HUBS AS A NEURAL
SUBSTRATE OF COGNITIVE RESERVE .............................................................................................. 80
5.3. LIMITATIONS .................................................................................................................... 85
5.4. OUTLOOK & CONCLUDING REMARKS ............................................................................. 86
6 | REFERENCES ...................................................................................................................... 88

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Abbreviations
AD – Alzheimer’s Disease
CSF – Cerebrospinal Fluid
DAN – Dorsal Attention Network
DMN – Default Mode Network
FDG-PET – Fluordesoxyglucose Positron Emission Tomography
LFC – Left Frontal Cortex
MCI – Mild Cognitive Impairment
MRI – Magnetic Resonance Imaging

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