Investigating hypotheses of neurodegeneration by learning dynamical systems of protein propagation in the brain

•A framework for spatio–temporal modeling of protein dynamics over brain networks from short term imaging data is proposed (GPPM–DS).•GPPM–DS enables the investigation of bio–mechanical hypotheses governing disease progression via Bayesian model comparison.•GPPM–DS provides new insights on the mechanisms of amyloid deposition in Alzheimer’s disease, indicating the ”Accumulation–Clearance–Propagation” model as the best suited dynamical system for interpretation of amyloid dynamics.•GPPM–DS achieves accurate predictions of individual protein deposition in unseen data and provides plausible simulations of protein propagation. We introduce a theoretical framework for estimating, comparing and interpreting mechanistic hypotheses on long term protein propagation across brain networks in neurodegenerative disorders (ND). The model is expressed within a Bayesian non-parametric regression setting, where mechanisms of protein dynamics are inferred by means of gradient matching on dynamical systems (DS). The Bayesian formalism, combined with stochastic variational inference, naturally allows for model comparison via assessment of model evidence, while providing uncertainty quantification of causal relationship underlying protein progressions. When applied to in–vivo AV45-PET brain imaging data measuring topographic amyloid deposition in Alzheimer’s disease (AD), our model identified the mechanisms of accumulation, clearance and propagation as the best suited DS for bio-mechanical description of amyloid dynamics in AD, enabling realistic and accurate personalized simulation of amyloidosis.