Bridging the gap: biophysical models of human frontotemporal lobar degeneration (360G-Wellcome-220258_Z_20_Z)

To treat and prevent dementia in patients, it is essential to understand how microscopic changes in the human brain cause complex cognitive and behavioural disorders. My program addresses this critical gap in translational research, to facilitate clinical application of basic science discoveries. I have three goals, set in the context of frontotemproal dementia and progressive supranuclear palsy. First, I will develop quantitative biophysical models of human brain function that capture key cellular and pharmacological pathologies in vivo, with regional, laminar and synaptic specificity. These models of degenerating neuronal circuits are informed by individual measures of synaptic density (PET imaging with a SV2a ligand), GABA and glutamate (ultrahigh-field MR spectroscopy). They are optimised in vivo by inversion to magnetoencephalography, and tested post-mortem against neuropathology. This synergy of multi-modal imaging, together with Bayesian model comparison of Dynamic Casual Models, means one can drill down to the best mechanistic model of the human cognitive disorder. Second, I will show how harmful effects of dementia like apathy can be explained in terms of changes in synaptic density and loss of precision in hierarchical brain networks. Third, I will I demonstrate the readiness of my approach for experimental medicine, through longitudinal designs and pharmacological interventions.