Imaging the brain in children taking metformin to improve cognitive outcome following treatment

Supervisors: Professor Chris Clark, Dr Christine Dahl (Great Ormond Street Hospital), Dr Patrick Hales, Professor Donald Mabbott (University of Toronto)

Imaging the brain in children taking metformin to improve cognitive outcome following treatment for medulloblastoma

Background:
Recent therapeutic advances have led to increased survival in paediatric cancer.  This progress has not come without problems: powerful therapies used to treat cancer have harmful long-term effects on the health and well-being of paediatric cancer survivors, specifically resulting in physical, neurological and psychological problems. This PhD project builds on a phase 3 study to examine the effects of metformin in children with medulloblastoma to reduce cognitive deficits post-treament to be conducted in 7 paediatric hospitals in North America the UK and Australia with comprehensive Hematology/Oncology programs – including neuro-oncology expertise and with advanced neuroimaging capabilities.  The PhD will focus on the analysis and exploration of different diffusion MRI models to better understand changes to brain microstructure.

Aims/Objectives:
Primary:

• To examine the effectiveness of 16 weeks of treatment with metformin versus 16 weeks of placebo for promoting white matter growth within the corpus callosum as measured by multi-shell diffusion MRI.

Exploratory:

• To examine the effectiveness of 16 weeks of treatment with metformin versus 16 weeks of placebo for promoting white matter growth within global white matter as measured by multi-shell diffusion MRI. 
• To examine the effectiveness of 16 weeks of treatment with metformin versus 16 weeks of placebo for increasing hippocampal volume as measured by MRI.

Methods:
The models to be investigated and tested include NODDI (Zhang et al), SMT (Kaden et al) and SANDI (Polombo et al) as well as tractography of specific anatomical pathways of the brain from which these model parameters can be obtained. Part of the assessment of these models will be correlations between diffusion parameters and collected neurocognitive data. This will reveal the neuroanatomical underpinnings of the beneficial effects of metformin on the brain in children treated for medulloblastoma.

Timeline:
Year 1: Examination of different diffusion model fitting routines. Modelling of diffusion in brain tissue by simulation. Examine various brain degeneration scenarios. Collection of data in patients in the metformin trial.
Year 2: Interim correlation of diffusion MRI data with cognitive data. Assessment of reproducibility of different diffusion models. 6 month placement in Dr Mabbott’s lab – application of chosen optimal diffusion models to all data obtained internationally. Correlation of optimal diffusion models with cognitive data.
Year 3: Completion of patient study and completion of data analyses. Writing up of thesis.

Collaboration with University of Toronto:
6 month placement in Dr Mabbott’s lab at SickKids in year 2. Dr Mabbott and his team are leading the international trial. The student will have the opportunity to learn and develop their understanding of the Diffusion Kurtosis model during their 6 month placement in Toronto and will be able to compare this with the models tested and developed at UCL. Part of the assessment of these models will be correlations between diffusion parameters and collected neurocognitive data. This will reveal the neuroanatomical underpinnings of the beneficial effects of metformin on the brain in children treated for medulloblastoma.

References:
1. Ayoub, R, Ruddy, R, Cox, E, Oyefiade, A, Derkach, D, Laughlin, S, Ades-aron, B, Shirzadi, Z, Fieremans, E, MacIntosh, B, de Medeiros, CB, Skocic, J, Bouffet, E, Miller, F, Morshead, C, Mabbott, DJ. Assessment of cognitive and neural recovery in survivors of paediatric brain tumours in a pilot clinical trial using Metformin. Nature Medicine, In press.
2.  Zhang H et al. NODDI: practical in vivo neurite orientation dispersion and density imaging of the human brain. Neuroimage. 2012 Jul 16;61(4):1000-16.
3.  Kaden E et al. Quantitative mapping of the per-axon diffusion coefficients in brain white matter. Magn Reson Med. 2016 Apr;75(4):1752-63.
4.  Palombo M et al. SANDI: a compartment-based model for non-invasive apparent soma and neurite imaging by diffusion MRI Neuroimage 2020 (in press).