Network Diffusion Modeling Explains Longitudinal Tau PET Data

Abstract

Alzheimer's disease is associated with the cerebral accumulation of neurofibrillary tangles of hyperphosphorylated tau protein. The progressive occurrence of tau aggregates in different brain regions is closely related to neurodegeneration and cognitive impairment. However, our current understanding of tau propagation relies almost exclusively on postmortem histopathology, and the precise propagation dynamics of misfolded tau in the living brain remain poorly understood. Here we combine longitudinal positron emission tomography and dynamic network modeling to test the hypothesis that misfolded tau propagates preferably along neuronal connections. We follow 46 subjects for three or four annual positron emission tomography scans and compare their pathological tau profiles 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 pathological tau. Across all subjects, the mean protein production rate was 0.21 ± 0.15 and the intracellular diffusion coefficient was 0.34 ± 0.43. Our network diffusion model can serve as a tool to detect non-clinical symptoms at an earlier stage and make informed predictions about the timeline of neurodegeneration on an individual personalized basis.