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Sterol Biomarker Discovery In Neurodegenerative Diseases / MANUELA PACCIARINI

Swansea University Author: MANUELA PACCIARINI

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DOI (Published version): 10.23889/SUthesis.65375

Abstract

Neurodegenerative diseases (ND) are age-related heterogeneous disorders leading to uncontrollable neuroneal cell death. Nowadays, there is no cure or specific diagnostic biomarkers for ND. However, much evidence links disrupted brain cholesterol metabolism with the development of Alzheimer’s (AD) an...

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Published: Swansea, Wales, UK 2023
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
Supervisor: Wang, Yuqin. and Griffiths, William J.
URI: https://cronfa.swan.ac.uk/Record/cronfa65375
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spelling v2 65375 2023-12-22 Sterol Biomarker Discovery In Neurodegenerative Diseases 38b74c14e1d6b745fd5e6eeceaff06b3 MANUELA PACCIARINI MANUELA PACCIARINI true false 2023-12-22 Neurodegenerative diseases (ND) are age-related heterogeneous disorders leading to uncontrollable neuroneal cell death. Nowadays, there is no cure or specific diagnostic biomarkers for ND. However, much evidence links disrupted brain cholesterol metabolism with the development of Alzheimer’s (AD) and Parkinson’s (PD) diseases, the two most common ND. Cholesterol is the most abundant sterol lipid in the human brain, the main component of myelin and a modulator of many neuroneal pivotal pathways. Several attempts have been made to understand the role and the entity of the sterol variations over PD and AD, highlighting modifications in the plasma and CSF content of the main brain cholesterol metabolite (24S)-hydroxycholesterol, (24S)-HC, and cholesterol itself but no conclusive results are yet reported. This thesis has been designed to study the plasma and CSF cholesterol and cholesterol metabolite variations in AD and PD, evaluating the ability of the discriminating sterols to be putative biomarkers. Our findings report a complete sterolome profile for AD CSF and PD plasma/CSF, identifying up to 21 different sterols. The results show an increase in the plasma levels of (24S)-HC and of 7α-hydroxy-3-ketone-cholestenoic acids in PD patients with respect to healthy controls. A decrease in plasma cholesterol is also observed in the PD group. However, (24S)-HC is the only sterol to also discriminate between males and females affected by PD and to demonstrate a diagnostic ability to predict PD. CSF and plasma sterols have also been screened in progressive PD, resulting in no significant variation, making them unsuitable prognostic biomarkers. In AD CSF, a positive correlation between the level of extracerebral 26-hydroxycholesterol, (24S)-HC and disease severity is reported. In conclusion, the results reported in this thesis support the use of cholesterol metabolites as diagnostic biomarkers for ND. However, validation studies on different cohorts of patients are needed. E-Thesis Swansea, Wales, UK Mass Spectrometry, Sterols, Sterolomics, Lipids, Oxysterols, Sterols, Orbitrap, iDX, SPE 6 12 2023 2023-12-06 10.23889/SUthesis.65375 COLLEGE NANME COLLEGE CODE Swansea University Wang, Yuqin. and Griffiths, William J. Doctoral Ph.D SURES SURES 2023-12-22T11:50:02.0974985 2023-12-22T11:23:49.9471500 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science MANUELA PACCIARINI 1 65375__29318__2949fc9c77d54ad391fa5ef1a0d5fa19.pdf 2023_Pacciarini_M.final.65375.pdf 2023-12-22T11:35:32.9031361 Output 14893274 application/pdf E-Thesis – open access true Copyright: The Author, Manuela Pacciarini, 2023. Distributed under the terms of a Creative Commons Attribution 4.0 International License (CC BY 4.0). true eng https://creativecommons.org/licenses/by/4.0/
title Sterol Biomarker Discovery In Neurodegenerative Diseases
spellingShingle Sterol Biomarker Discovery In Neurodegenerative Diseases
MANUELA PACCIARINI
title_short Sterol Biomarker Discovery In Neurodegenerative Diseases
title_full Sterol Biomarker Discovery In Neurodegenerative Diseases
title_fullStr Sterol Biomarker Discovery In Neurodegenerative Diseases
title_full_unstemmed Sterol Biomarker Discovery In Neurodegenerative Diseases
title_sort Sterol Biomarker Discovery In Neurodegenerative Diseases
author_id_str_mv 38b74c14e1d6b745fd5e6eeceaff06b3
author_id_fullname_str_mv 38b74c14e1d6b745fd5e6eeceaff06b3_***_MANUELA PACCIARINI
author MANUELA PACCIARINI
author2 MANUELA PACCIARINI
format E-Thesis
publishDate 2023
institution Swansea University
doi_str_mv 10.23889/SUthesis.65375
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 1
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description Neurodegenerative diseases (ND) are age-related heterogeneous disorders leading to uncontrollable neuroneal cell death. Nowadays, there is no cure or specific diagnostic biomarkers for ND. However, much evidence links disrupted brain cholesterol metabolism with the development of Alzheimer’s (AD) and Parkinson’s (PD) diseases, the two most common ND. Cholesterol is the most abundant sterol lipid in the human brain, the main component of myelin and a modulator of many neuroneal pivotal pathways. Several attempts have been made to understand the role and the entity of the sterol variations over PD and AD, highlighting modifications in the plasma and CSF content of the main brain cholesterol metabolite (24S)-hydroxycholesterol, (24S)-HC, and cholesterol itself but no conclusive results are yet reported. This thesis has been designed to study the plasma and CSF cholesterol and cholesterol metabolite variations in AD and PD, evaluating the ability of the discriminating sterols to be putative biomarkers. Our findings report a complete sterolome profile for AD CSF and PD plasma/CSF, identifying up to 21 different sterols. The results show an increase in the plasma levels of (24S)-HC and of 7α-hydroxy-3-ketone-cholestenoic acids in PD patients with respect to healthy controls. A decrease in plasma cholesterol is also observed in the PD group. However, (24S)-HC is the only sterol to also discriminate between males and females affected by PD and to demonstrate a diagnostic ability to predict PD. CSF and plasma sterols have also been screened in progressive PD, resulting in no significant variation, making them unsuitable prognostic biomarkers. In AD CSF, a positive correlation between the level of extracerebral 26-hydroxycholesterol, (24S)-HC and disease severity is reported. In conclusion, the results reported in this thesis support the use of cholesterol metabolites as diagnostic biomarkers for ND. However, validation studies on different cohorts of patients are needed.
published_date 2023-12-06T11:50:03Z
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