Connectome architecture, gene expression and functional co-activation shape the propagation of misfolded proteins in neurodegenerative disease

It is becoming increasingly clear that brain network organization shapes the course and expression of neurodegenerative diseases. Parkinson’s disease (PD) is marked by progressive spread of atrophy from the midbrain to subcortical structures and eventually, to the cerebral cortex. Recent discoveries suggest that the neurodegenerative process involves the misfolding of endogenous proteins (α-synuclein) and prion-like spread of these pathogenic proteins via axonal projections. However, the mechanisms that translate local “synucleinopathy” to large-scale network dysfunction and atrophy remain unknown. Here we use an agent-based epidemic spreading model to integrate structural connectivity, functional connectivity and gene expression, and to predict sequential volume loss due to neurodegeneration. We demonstrate three key findings. First, the dynamic model replicates the spatial distribution of empirical atrophy identified in an independent dataset of PD patients. Second, the model implicates the substantia nigra as the disease epicenter, consistent with previous literature. Third, we reveal a significant role for both connectome topology and spatial embedding (geometry) in shaping the distribution of atrophy. Gene expression and functional co-activation further amplify the course set by connectome architecture. Altogether, these results support the notion that the progression of neurodegenerative disease is a multifactorial process that depends on both cell-to-cell spreading of misfolded proteins and local regional vulnerability. The model proves powerful in modelling neurodegeneration and provides insights into developing preventative procedures.