Identification of plasma lipid biomarkers in Alzheimer's disease

353 Pages·2017·7.15 MB·English

Edith Cowan University
Research Online
Theses: Doctorates and Masters Theses
2014
Identification of plasma lipid biomarkers in
Alzheimer's disease
Rhona Creegan
Edith Cowan University
Recommended Citation
Creegan, R. (2014).Identification of plasma lipid biomarkers in Alzheimer's disease. Retrieved from https://ro.ecu.edu.au/theses/1340
This Thesis is posted at Research Online.
https://ro.ecu.edu.au/theses/1340
Edith Cowan University
Research Online
Theses: Doctorates and Masters Theses
2014
Identification of plasma lipid biomarkers in
Alzheimer's disease
Rhona Creegan
Edith Cowan University
Recommended Citation
Creegan, R. (2014).Identification of plasma lipid biomarkers in Alzheimer's disease. Retrieved from http://ro.ecu.edu.au/theses/1340
This Thesis is posted at Research Online.
http://ro.ecu.edu.au/theses/1340
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USE OF THESIS

The Use of Thesis statement is not included in this version of the thesis.
Identification of Plasma Lipid Biomarkers in Alzheimer’s
Disease

Rhona Creegan
BSc
MSc Clinical Biochemistry
MSc Nutrition Medicine

Supervisors:
Professor Ralph Martins
Professor Markus Wenk
Dr Ian Martins

This thesis is presented for the degree of Doctor of Philosophy at
Edith Cowan University
Faculty of Computing and Health Sciences
School of Medical Sciences

Abstract
Abstract
Alzheimer’s disease (AD), the commonest form of dementia, is a chronic,
progressive neurodegenerative disease which manifests clinically as a slow
global decline in cognitive function, including deterioration of memory,
reasoning, abstraction, language and emotional stability, culminating in a
patient with end-stage disease, totally dependent on custodial care. With an
ageing population, there is predicted to be a marked increase in the number of
people diagnosed with AD in the coming decades, making this a significant
challenge to socio-economic policy and aged care. Currently there is no cure for
AD and while current therapies may temporarily ameliorate symptoms, death
usually occurs approximately 8 years after diagnosis. Attention is now being
directed to the discovery of biomarkers that may not only facilitate pre-
symptomatic diagnosis but provide an insight into aberrant biochemical
pathways that may reveal potential therapeutic targets. AD pathogenesis
develops over many years before clinical symptoms appear, providing the
opportunity to develop therapy that could slow or stop disease progression well
before any clinical manifestations develop.
Research and understanding of AD pathology has been driven in recent years
by advances in technologies, enabling the precise investigation of the lipidome;
the repertoire of lipid species present in cells and tissues that reflect the net
effect of gene and protein expression, which in turn are influenced by the
cellular environment. Lipidomic studies have identified abnormal lipid
metabolism as a key component of the pathological processes which lead to the
development of AD. Therefore, lipidomic studies are crucial for advancing the
understanding of AD pathology and for identifying potential therapeutic targets;
these studies may also facilitate biomarker discovery. Many studies have
reported abnormal lipid profiles in both AD plasma and brain tissue.
This thesis investigated plasma lipid species using a “shotgun” lipidomics
approach by electrospray ionisation tandem mass spectrometry (ESI/MS/MS).
Additionally, Phospholipid Transfer Protein (PLTP); a protein involved in lipid
metabolism was assayed using a commercial kit. The utility of these analytes as
potential AD biomarkers was investigated by testing plasma samples from the
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Abstract
highly characterised Australian Imaging, Biomarkers and Lifestyle (AIBL) study.
The study cohort comprised over 1000 participants at inception who were
classified as either healthy control (n=733), mild cognitive impairment (MCI,
n=125) or AD (n=204): Samples from the baseline and 18 month follow-up time
points were utilised. Plasma PLTP activity levels were measured in a subset of
the baseline samples (n=259). Lipid and PLTP measurements were analysed in
conjunction with supplementary neuroimaging and blood biomarker data
collected as part of the AIBL study.
The thesis identified significant differences in several plasma lipids between
clinical classification groups, including several ceramide, sphingomyelin (SM),
phosphatidylethanolamine (PE), phosphatidylcholine (PC) and plasmalogen
species. Additionally, a panel of lipids was identified which could distinguish AD
participants from healthy controls with a sensitivity and specificity of 80%.
Plasma PLTP activity was significantly lower in AD and MCI groups compared
to healthy controls, and levels correlated with plasma Aβ in all groups and

cerebral Aβ in the healthy controls.
The results of this thesis validate and extend previous findings reported in the
literature. The current findings provide evidence to indicate that several lipid
species and PLTP show promise as potential blood biomarkers of AD. Further
investigation using a targeted lipidomics platform and prospective longitudinal
follow-up is warranted.

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Declaration
I certify that this thesis does not, to the best of my knowledge and belief:
i. Incorporate without acknowledgement any material previously submitted
for a degree or diploma in any institution of higher education;

ii. Contain any material previously published or written by another person
except where due reference is made in the text of this thesis; or

iii. Contain any defamatory material;

Date 10-03-14

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Acknowledgements
Acknowledgements
Firstly, I would like to thank my supervisor Ralph Martins for the opportunities
and guidance you have provided me.
This research was supported by funding provided by the Cooperative Research
Centres (CRC) for mental health.
This thesis includes data from the AIBL study and involves many collaborators
from around Australia. I would like to thank all those who have made the AIBL
study possible and so kindly shared their data and expertise. Thank you also to
Dr Veer Gupta for the measurement of plasma ApoE and clusterin, Dr Steve
Pedrini and Dr Eugene Hone for the measurement of HDL subfractions, Dr Alan
Rembach for the measurement of plasma Aβ and Dr Simon Laws for the APOE
genotyping. I am very grateful for the assistance provided by Mike Morici and Dr
Andrea Wilson with the set up of the PLTP assay.
Thank you for the hard work and assistance provided by Dr Florence Lim and
her collaborators whose expertise in the field of lipidomics was invaluable, with
special thanks to Florence for the data extraction; a huge undertaking!
The statistical analysis of the data for this thesis was complex and time
consuming and I am very grateful for the expertise and time provided by Dr
James Doecke and Dr Samantha Burnham at CSIRO and was impressed by
your efficiency and patience with my demands.
I would also like to thank everybody at the ECU laboratory for their assistance
and support, with particular thanks to Rimi who was with me from the beginning
and offered so many kind words.
My sincere thanks to Dr Stephanie-Rainey Smith who was so unconditionally
giving of her time and expertise (and always with a smile!) in putting together
this thesis; it would not have happened without you. THANK YOU.
There are so many people from my non-PhD life who have supported and
encouraged me throughout this journey. Mel, you were outstanding with excel,
prism and word, but your friendship and encouragement was the best. A huge
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