Supervisor View Full Details 2nd

• neuroscience and mental health

• Medicine

• Neurology

Dr. Fleming leads the Systems Biochemistry Group, an interdiscipinary research group of mathematical, computational and experimental biologists. The fundamental interest is to develop scalable mathematical and numerical analysis techniques that increase the predictive fidelity of biomolecular network models, by incorporating physico-chemical constraints, motivated by optimality principles. Their applied interest is in the aetiopathogenesis and amelioration of Parkinson’s disease. Model predictions are used for optimal experimental design and compared with quantitative experimental data, including that obtained from their microfluidic cell cultures of dopaminergic neurons, derived from normal and Parkinsonian human subjects using stem cell biology techniques.

Certain neuronal populations are selectively vulnerable to alpha-synuclein pathology in Parkinson's Disease, yet the reasons for this selectivity are unclear. Pathology affects neuronal populations that are anatomically connected although the contribution of neuronal connectivity remains to be quantitatively explored. Previously, we simulated the contribution of the connectome alone to the spread of arbitrary aggregates using a computational model of temporal spread within an abstract representation of the mamailian mesoscale connectome (https://doi.org/10.1101/567222). These simulations were compared with the neuron-to-neuron spread of alpha-synuclein that has been observed in vivo. We find that neuronal connectivity appears to be compatible with the spreading pattern of alpha-synuclein pathology however, it may be per se insufficient to determine the anatomical pattern of protein spreading observed in experimental animals, suggesting a role of selective vulnerability of neuronal pathways to alpha-synuclein diffusion, accumulation and pathology. We seek to build upon this computational model by integrating it with manually curated clinico-pathological associations for the various motor and non-motor symptoms observed in Parkinson's disease and thereby simulate the natural history of Parkinson's disease clinical signs as pathology spreads through the brain, starting from different initial conditions. Furthermore, we seek to fit the natural history of clinical signs within a cohort of longitudinally observed patients to attempt to stratify PD patients based on the underlying spread of brain pathology that could explain the order of development of clinical signs. Ultimately, we aim to develop a specialist movement disorders clinic in Galway, focused on translational clinical research in Parkinson's disease, in collaboration with Dr Timothy Counihan, Consultant Neurologist, Galway University Hospital.