Global network and local vulnerabilities underlie brain atrophy across Parkinson’s disease stages

Parkinson's disease (PD) is associated with extensive structural brain changes. Recent work has proposed that the spatial pattern of disease pathology is shaped by both network spread and local vulnerability. However, only few studies assessed these biological frameworks in large patient samples across disease stages. Analyzing the largest imaging cohort in PD to date (n = 3,096 patients), we investigated the roles of network architecture and local brain features by relating regional abnormality maps to normative profiles of connectivity, intrinsic networks, cytoarchitectonics, neurotransmitter receptor densities, and gene expression. We found widespread cortical and subcortical atrophy in PD to be associated with advancing disease stage, longer time since diagnosis, and poorer global cognition. Structural brain connectivity best explained cortical atrophy patterns in PD and across disease stages. These patterns were robust among individual patients. The precuneus, lateral temporal cortex, and amygdala were identified as likely network-based epicentres, with high convergence across disease stages. Individual epicentres varied significantly among patients, yet they consistently localized to the default mode and limbic networks. Furthermore, we showed that regional overexpression of genes implicated in synaptic structure and signalling conferred increased susceptibility to brain atrophy in PD. In summary, this study demonstrates in a well-powered sample that structural brain abnormalities in PD across disease stages and within individual patients are influenced by both network spread and local vulnerability.

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Journal
Brain
Published
2025-11-13
DOI
https://doi.org/10.1093/brain/awaf432
Citations
1
Primary Topic
Functional Brain Connectivity Studies
Type
article
Field-Weighted Citation Impact
1.43

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Global network and local vulnerabilities underlie brain atrophy across Parkinson’s disease stages

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Global network and local vulnerabilities underlie brain atrophy across Parkinson’s disease stages

Tim D. van Balkom, Christina Tremblay, Tracy R. Melzer, Christian Rummel, Conor Owens‐Walton, Duygu Tosun, Max A. Laansma, Ines Debove, Gaëtan Garraux, Ysbrand D. van der Werf, Chris Vriend, Neda Jahanshad, Petra Schwingenschuh, Shady Rahayel, Jiun‐Jie Wang, Rick C. G. Helmich, Andrew Vo, Henk W. Berendse, Johannes Klein, Sarah Al–Bachari, Corey T. McMillan, Fernando Cendes, Emile d’Angremont, Kathleen L. Poston, Bratislav Mišić, Alain Dagher, John C. Dalrymple‐Alford, Michiel F. Dirkx, Roland Wiest, Laura M. Parkes, Clelia Pellicano, Eva M. van Heese, Philip Mosley, Odile A. van den Heuvel, Martin E. Johansson, Clarissa Lin Yasuda, Jason Druzgal, Mario Rango, Joanna K. Bright, Chih‐Chien Tsai, Paul M. Thompson, Fabrizio Piras, Melanie Suette
article en
1 citations

Abstract

Parkinson's disease (PD) is associated with extensive structural brain changes. Recent work has proposed that the spatial pattern of disease pathology is shaped by both network spread and local vulnerability. However, only few studies assessed these biological frameworks in large patient samples across disease stages. Analyzing the largest imaging cohort in PD to date (n = 3,096 patients), we investigated the roles of network architecture and local brain features by relating regional abnormality maps to normative profiles of connectivity, intrinsic networks, cytoarchitectonics, neurotransmitter receptor densities, and gene expression. We found widespread cortical and subcortical atrophy in PD to be associated with advancing disease stage, longer time since diagnosis, and poorer global cognition. Structural brain connectivity best explained cortical atrophy patterns in PD and across disease stages. These patterns were robust among individual patients. The precuneus, lateral temporal cortex, and amygdala were identified as likely network-based epicentres, with high convergence across disease stages. Individual epicentres varied significantly among patients, yet they consistently localized to the default mode and limbic networks. Furthermore, we showed that regional overexpression of genes implicated in synaptic structure and signalling conferred increased susceptibility to brain atrophy in PD. In summary, this study demonstrates in a well-powered sample that structural brain abnormalities in PD across disease stages and within individual patients are influenced by both network spread and local vulnerability.

Brain
University of Southern California (US), University of Bern (CH), Montreal Neurological Institute and Hospital (CA), Radboud University Nijmegen (NL), University of Liège (BE), Chang Gung University (TW), University of California, San Francisco (US), Universidade Estadual de Campinas (UNICAMP) (BR), King's College London (GB), University of Canterbury (NZ), Medical University of Graz (AT), QIMR Berghofer Medical Research Institute (AU), Manchester Academic Health Science Centre (GB), University Hospital of Bern (CH), Radboud University Medical Center (NL), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), University of California System (US), University of Manchester (GB), University of Oxford (GB), Pacific Radiology (New Zealand) (NZ), New Zealand Brain Research Institute (NZ), Wellcome Centre for Integrative Neuroimaging (GB), Amsterdam Neuroscience (NL), Centre for Movement Disorders (CA), Center for Neurosciences (US), Centre Hospitalier Universitaire de Liège (BE), Hôpital du Sacré-Cœur de Montréal (CA), Brazilian Institute of Neuroscience and Neurotechnology (BR), Fondazione Santa Lucia (IT), Amsterdam University Medical Centers (NL), Istituti di Ricovero e Cura a Carattere Scientifico (IT), McGill University (CA), University of Virginia (US), Lancaster University (GB), University of Pennsylvania (US), University of Otago (NZ), Vrije Universiteit Amsterdam (NL), Stanford University (US)
Michael J. Fox Foundation for Parkinson's Research, Wellcome Trust, National Institute for Health and Care Research, Parkinson's UK, University of Oxford, Neurological Foundation of New Zealand, Fundação de Amparo à Pesquisa do Estado de São Paulo, National Institutes of Health, Horizon 2020 Framework Programme, Health Research Council of New Zealand, Marsden Fund, NIHR Oxford Biomedical Research Centre
Openalex Percentile: Top 14%
Functional Brain Connectivity Studies
1.43
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