Imaging trace metals in neurodegenerative disorders. Healthcare technologies: Analytical Science

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