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

Andrew Vo¹, Christina Tremblay², Shady Rahayel², Sarah Al-Bachari^{3

4}, Henk W Berendse^{5

6}, Joanna K Bright⁷, Fernando Cendes⁸, Emile d'Angremont^{6

9}, John C Dalrymple-Alford^{10

11}, Ines Debove¹², Michiel F Dirkx^{13

14}, Jason Druzgal¹⁵, Gaëtan Garraux^{16

17}, Rick C Helmich^{13

14}, Michele T Hu¹⁸, Neda Jahanshad¹⁹, Martin E Johansson^{13

14}, Johannes C Klein²⁰, Max A Laansma^{6

9}, Corey T McMillan²¹, Tracy R Melzer^{10

11

22

23}, Bratislav Misic¹, Philip Mosley²⁴, Conor Owens-Walton¹⁹, Laura M Parkes^{25

26}, Clelia Pellicano²⁷, Fabrizio Piras²⁷, Kathleen L Poston²⁸, Mario Rango²⁹, Christian Rummel³⁰, Petra Schwingenschuh³¹, Melanie Suette³¹, Paul M Thompson¹⁹, Duygu Tosun³², Chih-Chien Tsai³³, Tim D van Balkom^{6

9

34}, Odile A van den Heuvel^{6

9

34}, Ysbrand D van der Werf^{6

9}, Eva M van Heese^{6

9}, Chris Vriend^{9

34

35}, Jiun-Jie Wang³⁶, Roland Wiest³⁰, Clarissa L Yasuda^{8

37}, Alain Dagher¹

Affiliations

¹ Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal H3A 2B4, Canada.
² Centre for Advanced Research in Sleep Medicine, Hôpital du Sacré-Cœur de Montréal, Montreal H4J 1C5, Canada.
³ Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4AT, UK.
⁴ Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK.
⁵ Department of Neurology, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands.
⁶ Amsterdam Neuroscience, Neurodegeneration, 1081 HV Amsterdam, The Netherlands.
⁷ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.
⁸ Department of Neurology, University of Campinas-UNICAMP, Campinas 13083-888, Brazil.
⁹ Department of Anatomy and Neurosciences, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands.
¹⁰ Te Kura Mahi ā-Hirikapo | School of Psychology, Speech and Hearing, University of Canterbury, 8041 Christchurch, New Zealand.
¹¹ New Zealand Brain Research Institute, 8011 Christchurch, New Zealand.
¹² Department of Neurology, Inselspital, University Hospital Bern, University of Bern, CH-3010 Bern, Switzerland.
¹³ Department of Neurology and Center of Expertise for Parkinson & Movement Disorders, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GC Nijmegen, The Netherlands.
¹⁴ Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6525 EN Nijmegen, The Netherlands.
¹⁵ Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA 22903, USA.
¹⁶ MoVeRe group, GIGA-CRC in vivo imaging, University of Liège, 4000 Liège, Belgium.
¹⁷ Department of Neurology, CHU Liège, 4000 Liège, Belgium.
¹⁸ Division of Clinical Neurology, Department of Clinical Neurosciences, Oxford Parkinson's Disease Centre, Nuffield, University of Oxford, Oxford OX3 9DU, UK.
¹⁹ Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA 90033, USA.
²⁰ Division of Clinical Neurology, Department of Clinical Neurosciences; Oxford Centre for Integrative Neuroimaging, Oxford Parkinson's Disease Centre, Nuffield, University of Oxford, Oxford OX3 9DU, UK.
²¹ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
²² Department of Medicine, University of Otago, 8011 Christchurch, New Zealand.
²³ Pacific Radiology Canterbury, 8031 Christchurch, New Zealand.
²⁴ QIMR Berghofer Medical Research Institute, Queensland 4006, Australia.
²⁵ Division of Psychology, Communication and Human Neuroscience, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK.
²⁶ Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance & University of Manchester, Manchester M6 8HD, UK.
²⁷ Laboratory of Neuropsychiatry, IRCCS Santa Lucia Foundation, 00179 Rome, Italy.
²⁸ Department of Neurology & Neurological Sciences, Movement Disorders, Stanford University, Palo Alto, CA 94304, USA.
²⁹ Excellence Interdepartmental Center for Advanced MR Techniques and Department of Neurosciences, Neurology Unit, Parkinson's Disease Center, Fondazione Cà Granda, IRCCS, Ospedale Policlinico, University of Milan, 20122 Milan, Italy.
³⁰ Support Center for Advanced Neuroimaging (SCAN), University Institute of Diagnostic and Interventional Neuroradiology, University Hospital Bern, CH-3010 Bern, Switzerland.
³¹ Department of Neurology, Medical University of Graz, 8036 Graz, Austria.
³² Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA 94143, USA.
³³ Healthy Ageing Research Center, Chang Gung University, Taoyuan City 33302, Taiwan.
³⁴ Department of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands.
³⁵ Amsterdam Neuroscience, Brain Imaging, 1081 HV Amsterdam, The Netherlands.
³⁶ Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan City 33302, Taiwan.
³⁷ Brazilian Institute of Neuroscience and Neurotechnology, Campinas 13083-888, Brazil.

PMID: 41237265
DOI: 10.1093/brain/awaf432

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

Andrew Vo et al. Brain. 2025.

. 2025 Nov 14:awaf432.

doi: 10.1093/brain/awaf432. Online ahead of print.

Authors

Affiliations

¹ Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal H3A 2B4, Canada.
² Centre for Advanced Research in Sleep Medicine, Hôpital du Sacré-Cœur de Montréal, Montreal H4J 1C5, Canada.
³ Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4AT, UK.
⁴ Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK.
⁵ Department of Neurology, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands.
⁶ Amsterdam Neuroscience, Neurodegeneration, 1081 HV Amsterdam, The Netherlands.
⁷ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.
⁸ Department of Neurology, University of Campinas-UNICAMP, Campinas 13083-888, Brazil.
⁹ Department of Anatomy and Neurosciences, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands.
¹⁰ Te Kura Mahi ā-Hirikapo | School of Psychology, Speech and Hearing, University of Canterbury, 8041 Christchurch, New Zealand.
¹¹ New Zealand Brain Research Institute, 8011 Christchurch, New Zealand.
¹² Department of Neurology, Inselspital, University Hospital Bern, University of Bern, CH-3010 Bern, Switzerland.
¹³ Department of Neurology and Center of Expertise for Parkinson & Movement Disorders, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GC Nijmegen, The Netherlands.
¹⁴ Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6525 EN Nijmegen, The Netherlands.
¹⁵ Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA 22903, USA.
¹⁶ MoVeRe group, GIGA-CRC in vivo imaging, University of Liège, 4000 Liège, Belgium.
¹⁷ Department of Neurology, CHU Liège, 4000 Liège, Belgium.
¹⁸ Division of Clinical Neurology, Department of Clinical Neurosciences, Oxford Parkinson's Disease Centre, Nuffield, University of Oxford, Oxford OX3 9DU, UK.
¹⁹ Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA 90033, USA.
²⁰ Division of Clinical Neurology, Department of Clinical Neurosciences; Oxford Centre for Integrative Neuroimaging, Oxford Parkinson's Disease Centre, Nuffield, University of Oxford, Oxford OX3 9DU, UK.
²¹ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
²² Department of Medicine, University of Otago, 8011 Christchurch, New Zealand.
²³ Pacific Radiology Canterbury, 8031 Christchurch, New Zealand.
²⁴ QIMR Berghofer Medical Research Institute, Queensland 4006, Australia.
²⁵ Division of Psychology, Communication and Human Neuroscience, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK.
²⁶ Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance & University of Manchester, Manchester M6 8HD, UK.
²⁷ Laboratory of Neuropsychiatry, IRCCS Santa Lucia Foundation, 00179 Rome, Italy.
²⁸ Department of Neurology & Neurological Sciences, Movement Disorders, Stanford University, Palo Alto, CA 94304, USA.
²⁹ Excellence Interdepartmental Center for Advanced MR Techniques and Department of Neurosciences, Neurology Unit, Parkinson's Disease Center, Fondazione Cà Granda, IRCCS, Ospedale Policlinico, University of Milan, 20122 Milan, Italy.
³⁰ Support Center for Advanced Neuroimaging (SCAN), University Institute of Diagnostic and Interventional Neuroradiology, University Hospital Bern, CH-3010 Bern, Switzerland.
³¹ Department of Neurology, Medical University of Graz, 8036 Graz, Austria.
³² Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA 94143, USA.
³³ Healthy Ageing Research Center, Chang Gung University, Taoyuan City 33302, Taiwan.
³⁴ Department of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands.
³⁵ Amsterdam Neuroscience, Brain Imaging, 1081 HV Amsterdam, The Netherlands.
³⁶ Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan City 33302, Taiwan.
³⁷ Brazilian Institute of Neuroscience and Neurotechnology, Campinas 13083-888, Brazil.

PMID: 41237265
DOI: 10.1093/brain/awaf432

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.

Keywords: Parkinson’s disease; connectivity; imaging transcriptomics; neurodegeneration; structural MRI.

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Update of

Convergent large-scale network and local vulnerabilities underlie brain atrophy across Parkinson's disease stages: a worldwide ENIGMA study.
Vo A, Tremblay C, Rahayel S, Al-Bachari S, Berendse HW, Bright JK, Cendes F, d'Angremont E, Dalrymple-Alford JC, Debove I, Dirkx MF, Druzgal J, Garraux G, Helmich RC, Hu M, Jahanshad N, Johansson ME, Klein JC, Laansma MA, McMillan CT, Melzer TR, Misic B, Mosley P, Owens-Walton C, Parkes LM, Pellicano C, Piras F, Poston KL, Rango M, Rummel C, Schwingenschuh P, Suette M, Thompson PM, Tosun D, Tsai CC, van Balkom TD, van den Heuvel OA, van der Werf YD, van Heese EM, Vriend C, Wang JJ, Wiest R, Yasuda C, Dagher A; ENIGMA-Parkinson’s Study. Vo A, et al. medRxiv [Preprint]. 2025 May 29:2025.05.25.25326586. doi: 10.1101/2025.05.25.25326586. medRxiv. 2025. Update in: Brain. 2025 Nov 14:awaf432. doi: 10.1093/brain/awaf432. PMID: 40492073 Free PMC article. Updated. Preprint.

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

Affiliations

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

Authors

Affiliations

Abstract

Update of

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