Imaging trace metals in neurodegenerative disorders. Healthcare technologies: Analytical Science
Lead Research Organisation:
University of Warwick
Department Name: Sch of Engineering
Abstract
Research Areas: Healthcare technologies: Analytical Science. The project dovetails with EPSRC-funded research using a systems modeling approach to describe and predict iron metabolism in healthy and Parkinson's disease brains.
AIMS
1. To tackle a long-standing challenge in Parkinson's disease, by optimizing state-of-the-art spectral imaging to describe transition-metal-rich pathological material in Parkinson's disease brain compared with healthy brains;
2. To use experiments and computational models of Parkinson's disease to predict and test how the metal-rich material is altered by chelating drug treatment, and predict if the modifications protect against metal toxicity.
BACKGROUND
Iron is the most abundant of the transition metals in the human brain and is vital to many metabolic processes in the central nervous system (Collingwood 2014a; Crichton 2011); it is also toxic to cells if mishandled, so a sophisticated regulatory system is in place to sense and meet local iron requirements (Devos 2014; Visanji 2013). Iron dysregulation in the brain is implicated in many neurodegenerative disorders, with evidence of disease-specific accumulation in sub-compartments of the brain, and associated toxicity (Collingwood 2014a; Crichton 2011).
The regulatory system controlling iron levels in various compartments of the human brain is only partly described. Scope to use patterns of brain iron as diagnostic marker presently depends on empirical work, and is constrained by limited availability of validated post-mortem brain iron measurements. The effect of chelating drugs on iron in brain compartments is unclear, and the impact on brain iron stores takes months to become clinically detectable by MRI.
A group of iron-rich brain cells, the dopaminergic neurons, are selectively lost in Parkinson's disease. Typically 70% of these cells have died by the time a patients symptoms become apparent. In this project we propose to better understand the cell death from a systems perspective, both as an enabler of earlier detection and to better describe the materials properties of the iron-rich cell contents to create opportunities for intervention with protective drugs.
It is well-known that these vulnerable neurons are responsible for producing dopamine, but it is less well-known that the level of iron in these vulnerable cells almost doubles in Parkinson's disease (Oakley 2007), or that incorrectly regulated iron is very toxic (Crichton 2011). Many suggest that iron contributes to neurodegeneration, but the complexity of the problem and the materials science challenges involved mean the system is only partially described.
Better understanding the system makes it possible to tailor and monitor use of chelating drugs for individual needs, ensuring sufficient supply of iron for essential processes while protecting the vulnerable brain cells from iron toxicity.
SUMMARY POINTS FROM PROPOSAL
The application of synchrotron X-ray spectral imaging in this field, including the unique application to melanin imaging, is emerging in the host group and there is excellent scope for original work to refine the approach.
Application to Parkinson's disease is very timely, as the first study indicating a beneficial effect from iron chelation was published in 2014 (Devos 2014), but the impact of the drug on iron in the cells is not well understood. The proposed PhD project provides a unique analytical approach to advance understanding this area.
The project dovetails with EPSRC-funded research using a systems modeling approach to describe and predict iron metabolism in healthy and Parkinson's disease brains.
The high resolution characterization methods may be useful to a range of biomedical and materials engineering challenges, and the project presents an excellent opportunity to build specialist knowledge in the field of materials engineering, with the potential to provide healthcare benefits tackling some of the world's most widesp
AIMS
1. To tackle a long-standing challenge in Parkinson's disease, by optimizing state-of-the-art spectral imaging to describe transition-metal-rich pathological material in Parkinson's disease brain compared with healthy brains;
2. To use experiments and computational models of Parkinson's disease to predict and test how the metal-rich material is altered by chelating drug treatment, and predict if the modifications protect against metal toxicity.
BACKGROUND
Iron is the most abundant of the transition metals in the human brain and is vital to many metabolic processes in the central nervous system (Collingwood 2014a; Crichton 2011); it is also toxic to cells if mishandled, so a sophisticated regulatory system is in place to sense and meet local iron requirements (Devos 2014; Visanji 2013). Iron dysregulation in the brain is implicated in many neurodegenerative disorders, with evidence of disease-specific accumulation in sub-compartments of the brain, and associated toxicity (Collingwood 2014a; Crichton 2011).
The regulatory system controlling iron levels in various compartments of the human brain is only partly described. Scope to use patterns of brain iron as diagnostic marker presently depends on empirical work, and is constrained by limited availability of validated post-mortem brain iron measurements. The effect of chelating drugs on iron in brain compartments is unclear, and the impact on brain iron stores takes months to become clinically detectable by MRI.
A group of iron-rich brain cells, the dopaminergic neurons, are selectively lost in Parkinson's disease. Typically 70% of these cells have died by the time a patients symptoms become apparent. In this project we propose to better understand the cell death from a systems perspective, both as an enabler of earlier detection and to better describe the materials properties of the iron-rich cell contents to create opportunities for intervention with protective drugs.
It is well-known that these vulnerable neurons are responsible for producing dopamine, but it is less well-known that the level of iron in these vulnerable cells almost doubles in Parkinson's disease (Oakley 2007), or that incorrectly regulated iron is very toxic (Crichton 2011). Many suggest that iron contributes to neurodegeneration, but the complexity of the problem and the materials science challenges involved mean the system is only partially described.
Better understanding the system makes it possible to tailor and monitor use of chelating drugs for individual needs, ensuring sufficient supply of iron for essential processes while protecting the vulnerable brain cells from iron toxicity.
SUMMARY POINTS FROM PROPOSAL
The application of synchrotron X-ray spectral imaging in this field, including the unique application to melanin imaging, is emerging in the host group and there is excellent scope for original work to refine the approach.
Application to Parkinson's disease is very timely, as the first study indicating a beneficial effect from iron chelation was published in 2014 (Devos 2014), but the impact of the drug on iron in the cells is not well understood. The proposed PhD project provides a unique analytical approach to advance understanding this area.
The project dovetails with EPSRC-funded research using a systems modeling approach to describe and predict iron metabolism in healthy and Parkinson's disease brains.
The high resolution characterization methods may be useful to a range of biomedical and materials engineering challenges, and the project presents an excellent opportunity to build specialist knowledge in the field of materials engineering, with the potential to provide healthcare benefits tackling some of the world's most widesp
Publications
Lermyte F
(2019)
Metal Ion Binding to the Amyloid ß Monomer Studied by Native Top-Down FTICR Mass Spectrometry.
in Journal of the American Society for Mass Spectrometry
Lermyte F
(2020)
Metallic iron in cornflakes.
in Food & function
Lermyte F
(2019)
Emerging Approaches to Investigate the Influence of Transition Metals in the Proteinopathies.
in Cells
Jacomin AC
(2019)
Impact of Autophagy and Aging on Iron Load and Ferritin in Drosophila Brain.
in Frontiers in cell and developmental biology
Everett J
(2021)
Nanoscale chemical speciation of ß-amyloid/iron aggregates using soft X-ray spectromicroscopy
in Inorganic Chemistry Frontiers
Everett J
(2020)
Iron stored in ferritin is chemically reduced in the presence of aggregating Aß(1-42)
in Scientific Reports
Everett J
(2018)
Nanoscale Examination of Biological Tissues Using X-ray Spectromicroscopy
in Microscopy and Microanalysis
Brooks J
(2020)
Analysis of neuronal iron deposits in Parkinson's disease brain tissue by synchrotron x-ray spectromicroscopy.
in Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)
Brooks J
(2020)
Label-Free Nanoimaging of Neuromelanin in the Brain by Soft X-ray Spectromicroscopy.
in Angewandte Chemie (International ed. in English)
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
EP/N509796/1 | 30/09/2016 | 29/09/2021 | |||
1745807 | Studentship | EP/N509796/1 | 02/10/2016 | 30/03/2020 | Jake Brooks |
Description | Synchrotron x-ray microscopy is being optimised to locate regions of pathology in Alzheimer's and Parkinson's disease brain tissue with minimised chemical or physical changes to the native state of the tissue. Mapping of specific biological components associated with neurodegeneration has been advanced during this grant, posing a remarkable improvement on currently available staining or electron microscopy techniques where native chemistry is significantly altered. During this grant, the first label-free approach to mapping neuromelanin at nanoscale resolution was developed using synchrotron x-ray spectromicroscopy. This enables neuromelanin and associated metal ions, both heavily implicated in Parkinson's disease pathogenesis, to be characterised without inducing chemical or physical changes to the tissue. The work was published in Angewandte Chemie in 2020 (DOI: 10.1002/anie.202000239). Variation in iron chemical state was also discovered, associated with neuromelanin granules in the neurons most vulnerable to loss in the Parkinson's disease brain. This finding further implicates changes in metal biochemistry in disease pathogenesis, whilst also highlighting the advanced chemical sensitivity and specificity of synchrotron techniques. This work was published in the Journal of Trace Elements in Medicine and Biology in 2020 (DOI: 10.1016/j.jtemb.2020.126555). |
Exploitation Route | This work will of interest to other researchers investigating biochemical changes within the brain, particularly in cases where ex vivo tissue is used to represent the condition inside a living person. Information obtained relating to trace metal metabolism where great precautions have been taken to avoid chemical interference will be beneficial to the safe development of chelation therapies, currently being trialled as a treatment for Parkinson's disease. Findings published in Angewandte Chemie (DOI: 10.1002/anie.202000239) and the Journal of Trace Elements in Medicine and Biology (DOI: 10.1016/j.jtemb.2020.126555) are anticipated to have significant impact for non-destructive studies investigating relationships between depigmentation, metal binding and neurodegeneration in Parkinson's disease. |
Sectors | Environment Healthcare Pharmaceuticals and Medical Biotechnology |
Description | Group findings published as a research paper in the academic journal Nanoscale was the subject of a university press release in June 2018. The paper subsequently inspired a series of popular science articles in magazines such as Science Daily and R&D magazine. Media coverage has elevated the profile of this niche area within Alzheimer's research, raising awareness for the association between metal dysregulation and neurodegeneration that is not necessarily common knowledge in the public perception of Alzheimer's. Project work on label-free mapping of neuromelanin, originally published in the academic journal Angewandte Chemie, was selected to be featured in the Diamond Light Source Annual Review. I have contributed an article based on the original research paper but re-written for a non-specialist audience. The article will be published in Diamond's Annual Review magazine to showcase outputs from Diamond Light Source beamlines I08 and I14, where primary data for the study was collected. It is anticipated that this will enable the research to reach a wider community of synchrotron users and also elevate the readership of the original publication. |
Sector | Other |
Impact Types | Cultural Societal |
Description | STEM for Britain event - engaging politicians with early career researchers |
Geographic Reach | National |
Policy Influence Type | Contribution to a national consultation/review |
Description | Diamond Light Source beam time |
Amount | £0 (GBP) |
Funding ID | SP15230, SP15854, SP19779, SP20809, MG24534 |
Organisation | Diamond Light Source |
Sector | Private |
Country | United Kingdom |
Start | 03/2017 |
End | 03/2021 |
Title | Neuromelanin imaging |
Description | Identification and use of feature in soft x-ray spectrum to image neuromelanin, demonstrated in human brain tissue where the neuromelanin was identified independently of the surrounding tissue. |
Type Of Material | Technology assay or reagent |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | 1. Supported progression of researcher into funded postdoctoral position. 2. Work featured in forthcoming DLS Annual Report to showcase work at the beamline where the method was developed. |
URL | https://onlinelibrary.wiley.com/doi/full/10.1002/anie.202000239 |
Description | X-ray fluorescence mapping of metals in mouse brain |
Organisation | University of Sydney |
Department | Bosch Institute |
Country | Australia |
Sector | Academic/University |
PI Contribution | Input on sample preparation and data processing/analysis in studying the changes to metal metabolism in genetically modified mouse models. Work performed in collaboration with Prof. Liz Milward at the University of Newcastle and Dr. Dan Johnstone at the University of Sydney. |
Collaborator Contribution | Study design and data collection at the synchrotron facility. |
Impact | Multidisciplinary: genetics, biochemistry, physics, metrology |
Start Year | 2017 |
Description | X-ray fluorescence mapping of progressive supranuclear palsy brain tissue |
Organisation | University of Toronto |
Country | Canada |
Sector | Academic/University |
PI Contribution | Input on sample preparation and actively involved in the collection and analysis of synchrotron data investigating metal distributions in pathological regions of progressive supranuclear palsy human brain tissue. Work performed in collaboration with Dr Naomi Visanji and Seojin Lee at the University of Toronto. |
Collaborator Contribution | Study design, sample preparation and data collection at the synchrotron facility. |
Impact | Multidisciplinary: biochemistry, physics, metrology |
Start Year | 2021 |
Description | Alzheimer's UK conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Conference on UK research into Alzheimer's and related disorders, held in Harrogate. I presented a poster at this meeting and engaged with academics and industry professionals. The meeting provided a useful source of inspiration for future studies. |
Year(s) Of Engagement Activity | 2019 |
URL | https://ukdri.ac.uk/events/aruk-conference-2019 |
Description | Alzheimer's disease/ Parkinson's disease conference 2019 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Large international congress held in Lisbon, Portugal, on developments in research relating to neurodegeneration. The event was attended by approximately 4000 people. I presented a poster at this meeting and engaged with researchers, industry professionals, and charity representatives from around the world. A lot was learnt from this meeting regarding the wider context of the field. |
Year(s) Of Engagement Activity | 2019 |
URL | https://aat-adpd.kenes.com/ad-pd-2019-conference/ |
Description | Alzheimer's disease/ Parkinson's disease conference 2021 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Large international congress held online, on developments in research relating to neurodegeneration. I presented a poster at this meeting and listened to talks from researchers and industry professionals from around the world. This meeting helped to place my own research in context with the wider picture of neurodegeneration research. |
Year(s) Of Engagement Activity | 2021 |
URL | https://adpd.kenes.com/ |
Description | Conference on trace metals in human health and disease |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Conference on trace metals in human health and disease held in Bali, Indonesia. I gave a talk at this conference and engaged in lively discussion with numerous other researchers from around the world. Several academics showed great interest in the work presented. |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.isterh2019.com/ |
Description | Engineering outreach day |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | The activity was an outreach day run by the School of Engineering at Warwick University, intended to inform the general public of the diverse engineering disciplines currently represented within the school. The activity runs on an annual basis, attracting members of the public from all age groups. People are keen to ask questions to undergraduate/postgraduate students manning the various stands and often report that they have learnt something new as a result of attending. |
Year(s) Of Engagement Activity | 2017,2018 |
URL | https://warwick.ac.uk/study/outreach/news/engineering_day/ |
Description | Parkinson's disease UK conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Conference on UK research into Parkinson's disease and related disorders, held in online. I presented a poster at this meeting and engaged with academics and industry professionals. The meeting provided a useful source of inspiration for future studies. |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.parkinsons.org.uk/events/online-research-conference-2020 |
Description | STEM for Britain event |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Policymakers/politicians |
Results and Impact | A conference held in Westminster to engage politicians with early career researchers. Work was presented in poster format, and MPs reported increased awareness and interest in active areas of research. |
Year(s) Of Engagement Activity | 2020 |
URL | http://www.setforbritain.org.uk/index.asp |
Description | UKSR50 conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Conference celebrating 50 years of synchrotron science in the UK, held in Liverpool. The event was attended by synchrotron users from around the world to discuss the future of synchrotron-based research. I presented a poster at this meeting and gained insight into the potential of different techniques for use in our group work. |
Year(s) Of Engagement Activity | 2018 |
URL | http://www.uksr50.org/ |