Local vulnerability and global connectivity jointly shape neurodegenerative disease propagation

Ying-Qiu Zheng, Yu Zhang, Yvonne Yau, Yashar Zeighami, Kevin Larcher, Bratislav Misic and Alain Dagher

PLOS Biology, 2019, vol. 17, issue 11, 1-27

Abstract: It is becoming increasingly clear that brain network organization shapes the course and expression of neurodegenerative diseases. Parkinson 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 and prion-like propagation of endogenous α-synuclein 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. The dynamic model replicates the spatial and temporal patterning of empirical atrophy in PD and implicates the substantia nigra as the disease epicenter. We reveal a significant role for both connectome topology and geometry in shaping the distribution of atrophy. The model also demonstrates that SNCA and GBA transcription influence α-synuclein concentration and local regional vulnerability. Functional coactivation further amplifies the course set by connectome architecture and gene expression. Altogether, these results support the theory that the progression of PD is a multifactorial process that depends on both cell-to-cell spreading of misfolded proteins and regional vulnerability.Many neurodegenerative diseases, including Parkinson's disease, may be prion illnesses characterized by propagation of abnormal proteins through the brain. An agent-based model informed by infectious disease epidemiology recapitulates the distribution of atrophy in Parkinson's disease, suggesting that connectomics and local gene expression interact to shape the spatial progression of the disease in the brain.

Date: 2019
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pbio00:3000495

DOI: 10.1371/journal.pbio.3000495

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