Objective: In this study, we characterized the brain topological intersection between propagating connectivity networks in healthy controls (HC) and Parkinson’s disease (PD) participants and gene expression patterns across the human cortex – such as the SNCA gene (encoding alpha-synuclein protein, a hallmark of PD pathology).

Background: The genetic traits that underlie vulnerability to neuronal damage across specific brain circuits in PD remain to be elucidated.

Method: 146 PD patients performed clinical-cognitive evaluations and resting-state functional MRI (rs-fMRI) at baseline. Cluster analysis using data on demographic information, motor symptoms and signs, cognitive and behavioural testing and other non-motor manifestations identified PD subtypes: 86 patients were classified as “mild” and 60 as “moderate-to-severe”. 60 controls were enrolled. To characterize the functional scaffolding of connections emanating from PD-related pathology epicenters in the brainstem, we first performed Stepwise Functional Connectivity (SFC) analysis using intrinsic connectivity as revealed by neuroimaging. We then leveraged the Allen Human Brain Atlas (AHBA) to examine the spatial intersection of the observed SFC patterns with genetic transcription profiles. A rich set of genes were transcriptionally associated to PD-related biologic processes, including dopamine secretion, neuropeptide transmission, and axonal and synaptic assemblies, for which the gene SNCA played a central role.

Results: As hypothesized, we further confirmed that brain connectivity originated from PD-related pathology epicenters in the brainstem largely recapitulated the anatomical distribution of alpha-synuclein histopathology in postmortem data. Finally, we discovered that the gene set most related to cortical propagation patterns of PD-related pathology was primarily involved in microtubule cellular components.

Conclusion: This study sheds light on exciting new avenues for enhancing detection of PD neuronal vulnerability via an evaluation of in vivo connectivity trajectories across the human brain and successful integration of neuroimaging-genetic strategies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/neurogenetic-traits-outline-vulnerability-to-cortical-disruption-in-parkinsons-disease/