Pathologic Substrates of Structural Brain Network Resilience and Topology in Parkinson Disease Decedents

Background and ObjectivesIn Parkinson disease (PD), alpha-synuclein spreading through connected brain regions leads to neuronal loss and brain network disruptions. With diffusion-weighted imaging (DWI), it is possible to capture conventional measures of brain network organization and more advanced measures of brain network resilience. We aimed to investigate which neuropathologic processes contribute to regional network topologic changes and brain network resilience in PD.MethodsUsing a combined postmortem MRI and histopathology approach, PD and control brain donors with available postmortem in situ 3D T1-weighted MRI, DWI, and brain tissue were selected from the Netherlands Brain Bank and Normal Aging Brain Collection Amsterdam. Probabilistic tractography was performed, and conventional network topologic measures of regional eigenvector centrality and clustering coefficient, and brain network resilience (change in global efficiency upon regional node failure) were calculated. PSer129 alpha-synuclein, phosphorylated-tau, beta-amyloid, neurofilament light-chain immunoreactivity, and synaptophysin density were quantified in 8 cortical regions. Group differences and correlations were assessed with rank-based nonparametric tests, with age, sex, and postmortem delay as covariates.ResultsNineteen clinically defined and pathology-confirmed PD (7 F/12 M, 81 +/- 7 years) and 15 control (8 F/7 M, 73 +/- 9 years) donors were included. With regional conventional measures, we found lower eigenvector centrality only in the parahippocampal gyrus in PD (d = -1.08, 95% CI 0.003-0.010, p = 0.021), which did not associate with underlying pathology. No differences were found in regional clustering coefficient. With the more advanced measure of brain network resilience, we found that the PD brain network was less resilient to node failure of the dorsal anterior insula compared with the control brain network (d = -1.00, 95% CI 0.0012-0.0015, p = 0.018). This change was not directly driven by neuropathologic processes within the dorsal anterior insula or in connected regions but was associated with higher Braak alpha-synuclein staging (rs = -0.40, p = 0.036).DiscussionAlthough our cohort might suffer from selection bias, our results highlight that regional network disturbances are more complex to interpret than previously believed. Regional neuropathologic processes did not drive regional topologic changes, but a global increase in alpha-synuclein pathology had a widespread effect on brain network reorganization in PD.