Parkinson’s disease is a progressive neurodegenerative disorder characterized by accumulation of abnormal isoforms of alpha-synuclein. Alpha-synuclein is proposed to act as a prion in Parkinson’s disease: In its misfolded pathologic state, it favors the misfolding of normal alpha-synuclein molecules, spreads trans-neuronally, and causes neuronal damage as it accumulates. This theory remains controversial. We have previously developed a Susceptible-Infected-Removed (SIR) computational model that simulates the templating, propagation, and toxicity of alpha-synuclein molecules in the brain. In this study, we test this model with longitudinal MRI collected over 4 years from the Parkinson’s Progression Markers Initiative (1,068 T1 MRI scans, 790 Parkinson’s disease scans, and 278 matched control scans). We find that brain deformation progresses in subcortical and cortical regions. The SIR model recapitulates the spatiotemporal distribution of brain atrophy observed in Parkinson’s disease. We show that connectome topology and geometry significantly contribute to model fit. We also show that the spatial expression of two genes implicated in alpha-synuclein synthesis and clearance, SNCA and GBA , also influences the atrophy pattern. We conclude that the progression of atrophy in Parkinson’s disease is consistent with the prion-like hypothesis and that the SIR model is a promising tool to investigate multifactorial neurodegenerative diseases over time. Author Summary It has been suggested that neurodegenerative diseases are caused by abnormal generation, propagation, and accumulation of neurotoxic protein isoforms. In the case of Parkinson’s disease, the culprit is alpha-synuclein, which has been shown in animal models to exhibit prion-like properties. We devised a Susceptible-Infected-Removed agent-based model of synucleinopathy, in which we simulate the fates of normal and misfolded alpha-synuclein molecules moving along a brain network. We show that the progression of brain atrophy in Parkinson’s disease over the first 2 years following diagnosis can be simulated by our model. We conclude that the pattern of brain atrophy in Parkinson’s disease is shaped by a combination of the connectome and regional expression of genes that control the clearance and synthesis of alpha-synuclein. Our work supports the prion-like model of neurodegeneration in Parkinson’s disease.

The brain is a complex network of interconnected and interacting neuronal populations. Global efforts to understand the emergence of behavior and the effect of perturbations depend on accurate reconstruction of white matter pathways, both in humans and in model organisms. An emerging animal model for next-generation applied neuroscience is the common marmoset ( Callithrix jacchus ). A recent open respository of retrograde and anterograde tract tracing presents an opportunity to systematically study the network architecture of the marmoset brain (Marmoset Brain Architecture Project; http://www.marmosetbrain.org ). Here we comprehensively chart the topological organization of the mesoscale marmoset cortico-cortical connectome. The network possesses multiple nonrandom attributes that promote a balance between segregation and integration, including near-minimal path length, multiscale community structure, a connective core, a unique motif composition, and multiple cavities. Altogether, these structural attributes suggest a link between network architecture and function. Our findings are consistent with previous reports across a range of species, scales, and reconstruction technologies, suggesting a small set of organizational principles universal across phylogeny. Collectively, these results provide a foundation for future anatomical, functional, and behavioral studies in this model organism. Author Summary Emerging research points to network connectivity as a fundamental feature of brains, influencing interregional signaling, cognition, and behavior. Global efforts are under way to map, image, and trace cellular connection patterns in humans and in a variety of model organisms. The common marmoset is increasingly becoming the most used nonhuman primate model for neuroimaging, genomics, and behavioral research. Here we provide a comprehensive characterization of the marmoset brain connectome using a recently published cortico-cortical tract tracing atlas. We find evidence of nonrandom organization across multiple scales, including near-minimal path length, multiscale community structure, densely interconnected hubs, a unique motif fingerprint, and the existence of topological cavities. Collectively, these features suggest that the network is configured to support the coexistence of segregation and integration of information.