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

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Abstract
Parkinson’s disease 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, few studies have assessed these biological frameworks in large patient samples across disease stages. Analysing the largest imaging cohort in Parkinson’s disease to date (n = 3096 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 Parkinson’s disease to be associated with advancing disease stage, longer time since diagnosis and poorer global cognition. Structural brain connectivity best explained cortical atrophy patterns in Parkinson’s disease 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 Parkinson’s disease. In summary, this study demonstrates in a well-powered sample that structural brain abnormalities in Parkinson’s disease across disease stages and within individual patients are influenced by both network spread and local vulnerability.
Funding Information
  • National Institutes of Health (S10OD032285)
  • Fonds de recherche du Québec
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (2013/07559-3)
  • ENIGMA (PD R01)
  • Health Research Council of New Zealand (20/538)
  • Health Research Council of New Zealand (20/538)
  • Health Research Council of New Zealand (R01 NS115114)
  • Health Research Council of New Zealand (K23 NS075097)
  • Health Research Council of New Zealand (P50 AG047366)
  • Marsden Fund New Zealand (UOC2105)
  • Neurological Foundation of New Zealand (2232 PRG)
  • Research and Education Trust Pacific Radiology
  • Parkinson's UK
  • NIHR Sheffield Biomedical Research Centre
  • University of Oxford
  • Cure Parkinson's Trust
  • Lab10X
  • National Institute for Health and Care Research
  • Michael J. Fox Foundation for Parkinson's Research
  • European Platform for Neurodegenerative Disorders (H2020)
  • GE Healthcare
  • Progressive Supranuclear Palsy Association (RF1NS136995)
  • NIHR Oxford Biomedical Research Centre
  • Wellcome Trust (203139/Z/16/Z)
  • Wellcome Trust (203139/A/16/Z)

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