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The Multiphysics of Neurodegeneration

Ellen Kuhl, Stanford University

Neurodegeneration will undoubtedly become a major challenge in medicine and public health because of demographic changes worldwide. More than 45 million people are living with dementia today and this number is expected to triple by 2050. Recent studies have reinforced the hypothesis that the prion paradigm, the templated growth and spreading of misfolded proteins, could help explain the progression of a variety of neurodegenerative disorders. However, our current understanding of prion-like growth and spreading is rather empirical and the precise propagation dynamics of misfolded protein within the living brain remain poorly understood. Here we show that a physics-based reaction-diffusion model can explain the growth and spreading of misfolded protein in a variety of neurodegenerative disorders. We integrate the classical Fisher-Kolmogorov equation for population dynamics into a brain network model, which we represent through a connectivity-weighted Laplacian graph created from 418 human brain images. To test the hypothesis that misfolded proteins propagate preferably along neuronal connections, we follow 46 subjects for three years and compare their positron emission tomography scans against brain network models of intracellular and extracellular spreading. For each subject, we identify a personalized set of model parameters that characterizes the individual progression of misfolded tau protein. We show that intracellular spreading along neuronal connections explains the propagation dynamics of Alzheimer's disease better than extracellular spreading. Our results suggest that misfolded proteins in neurodegenerative disorders grow and spread according to a universal law that follows the basic physical principles of nonlinear reaction and anisotropic diffusion. A more quantitative understanding of the timeline of neurodegeneration could help detect non-clinical symptoms at an earlier stage and make informed predictions about the timeline of neurodegeneration on an individual personalized basis.