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

Publications

10 25 50

Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/N509796/1 01/10/2016 30/09/2021
1745807 Studentship EP/N509796/1 03/10/2016 31/03/2020 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.
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.
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.
First Year Of Impact 2018
Sector Other
Impact Types Cultural,Societal

 
Description STEM for Britain event - engaging politicians with early career researchers
Geographic Reach National 
Policy Influence Type Participation in a national consultation
 
Description Diamond Light Source beam time
Amount £0 (GBP)
Funding ID SP15230-2, SP15230-3, SP19779-1, SP20809-1, SP15854-6, SP15854-8, MG24534-1 
Organisation Diamond Light Source 
Sector Private
Country United Kingdom
Start 04/2017 
End 03/2020
 
Title neuromelanin mapping in human brain tissue 
Description Development of a new approach to specific, label-free mapping of neuromelanin in human brain tissues using synchrotron x-rays.The manuscript is currently in review. 
Type Of Material Biological samples 
Year Produced 2020 
Provided To Others? No  
Impact None yet 
 
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 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 
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 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 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/