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Background: Parkinson’s disease (PD) is a progressive neurodegenerative condition marked by brain atrophy in multiple cortical and subcortical regions. It is now known to be caused by the prion‐like propagation of misfolded alpha‐synuclein, supporting Braak’s hypothesis. The pattern of neurodegeneration is now thought to be explained by a combination of brain connectivity and local vulnerability. Method: We used MRI and clinical data from the Parkinson Progression Markers Initiative to map the progression of brain atrophy over one, two and four years and related it to brain functional and structural connectivity, cell type expression and gene ontology enrichment analyses. We use two methods to measure atoprhy: cortical thickness measures and deformation based morphometry. We will compare these results to pathology in wild‐type mice sacrificed at different time‐points after injection of alpha‐synuclein preformed fibrils. In both cases we use a spreading model inspired by infectious‐disease epidemiology to map the propagation of misfolded alpha‐synuclein. This Susceptible‐Infectious‐Recovered (SIR) model assumes that alpha‐synuclein molecules become misfolded, propagate along the connectome, and cause tissue damage when they accumulate. Result: 1) The pattern of brain atrophy in de novo PD is compatible with a propagating process with an epicenter in the substantia nigra. 2) The SIR model recapitulates the observed atrophy pattern, and supports connectivity‐based propagation. 3) In addition, the SIR model suggests that brain areas with higher alpha‐synuclein concentration appear to be more susceptible to injury but also more likely to act as disease propagators. 4) Progression over four years is also explained by connectivity. 5) Gene ontology analyses suggest that synapses are especially targeted by neurodegeneration. 6) Studies in mice, where the injection site of alpha‐synuclein preformed fibrils is determined by the investigator, also confirm the connectivity by local vulnerability model. Conclusion: Human and animal studies support the Braak hypothesis of a “toxic agent” propagating from the brainstem to the cortex, accounting for the stereotyped progression of PD manifestations. Data from gene expression studies and animal experiments confirm the important role of prion‐like alpha‐synuclein in PD pathogenesis. [ABSTRACT FROM AUTHOR]