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Investigating the association between hepcidin and brain amyloid-β burden in cognitively normal elderly individuals

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thesis
posted on 28.03.2022, 20:55 authored by Maryam Mohammadi
Introduction: Metal dyshomeostasis is one of the predominant pathways in the pathogenesis of Alzheimer's disease (AD). Hepcidin is a protein synthesised in the liver, and it is known to play a key role in iron regulation. Hepcidin level alteration has been previously observed in the brain and blood samples of patients with AD, however, it has not been investigated yet in preclinical AD, i.e. prior to cognitive impairment. Objective: Investigate the association of serum hepcidin with neocortical amyloid load (NAL). Also, investigate its association with AD risk factors, cognitive performance and other iron related proteins. Methods: Serum hepcidin concentration was measured by using the enzyme-linked immunosorbent assay in participants from the Kerr Anglican Retirement Village Initiative in Ageing Health cohort. Participants were aged 65-90 years and they were cognitively normal based on the neuropsychological tests. Subjects were categorised into the high NAL (n=35) and low NAL (n=65) groups via positron emission tomography (PET) scans using a standard uptake value ratio cutoff = 1.35. Results: Serum hepcidin levels were significantly higher in participants with high NAL compared to those with low NAL. Moreover, a significant positive association was observed between the serum hepcidin and NAL. To evaluate the potential of hepcidin in distinguishing the low NAL and high NAL groups, receiver operating characteristic (ROC) curves were generated using the logistic regression. The area under the curve slightly increased from 0.78 in the 'base model' to 0.81 in the 'base+hepcidin' model. Conclusion: Current findings show that increased serum hepcidin is an early event in AD pathogenesis. Therefore, hepcidin can be considered as a potential biomarker within a diagnostic panel of markers for AD, and could be helpful in the process of identifying therapeutic targets for AD.

History

Table of Contents

1.1. Alzheimer's disease -- 1.2. Neuropathological hallmarks of AD -- 1.2.1. Amyloid plaques -- 1.2.2. Neurofibrillary tangles -- 1.2.3. Cerebral amyloid angiopathy --1.3. Types of AD -- 1.4. Genetic and non-genetic risk factors --1.4.1. Apolipoprotein E allele -- 1.4.2. Age --1.4.3. Type 2 diabetes -- 1.4.4. Hypertension -- 1.5. Modifiable lifestyle factors -- 1.6. Alzheimer's disease biomarkers -- 1.6.1. CSF biomarkers -- 1.6.2. Imaging biomarkers -- 1.6.2.1. Structural magnetic resonance imaging (MRI) -- 1.6.2.2. Functional MRI -- 1.6.2.3. Positron emission tomography (PET) -- 1.6.3. Blood biomarkers -- 1.7. Treatment strategies -- 1.7.1. Anti-amyloid strategies -- 1.7.1.1. Targeting Aβ production -- 1.7.1.2. Aβ aggregation inhibitors -- 1.7.1.3. Targeting Aβ clearance -- 1.7.2. Targeting Neurofibrillary tangles -- 1.7.2.1. Tau phosphorylation inhibitors -- 1.7.2.2. Enhancing tau degradation -- 1.8. Clinical and preclinical stages of AD -- 1.9. Oxidative stress and metal dyshomeostasis in AD -- 1.10. The role of iron in healthy individuals -- 1.10.1. Peripheral iron uptake -- 1.10.2. Brain iron uptake -- 1.11. Iron dysregulation and its role in AD pathogenesis -- 1.12. Ferritin and its alteration in AD -- 1.13. Hepcidin and its biological function - 1.14. The role of hepcidin alteration in AD -- 1.15. Hypothesis and aims -- 1.15.1. Aims -- 1.15.2. Hypothesis -- Chapter 2 Materials and methods -- Chapter 3 Results -- Chapter 4 Discussion.

Notes

Bibliography: pages 51-61 Theoretical thesis.

Awarding Institution

Macquarie University

Degree Type

Thesis MRes

Degree

MRes, Macquarie University, Faculty of Medicine and Health sciences, Department of Biomedical Sciences

Department, Centre or School

Department of Biomedical Sciences

Year of Award

2018

Principal Supervisor

Ralph Martins

Rights

Copyright Maryam Mohammadi 2018. Copyright disclaimer: http://mq.edu.au/library/copyright

Language

English

Extent

1 online resource (xiii, 61 pages) illustrations

Former Identifiers

mq:71082 http://hdl.handle.net/1959.14/1270677