Mitochondrial dysfunction underlies cortical atrophy in prodromal synucleinopathies

Isolated rapid eye movement sleep behavior disorder (iRBD) is a prodromal synucleinopathy characterized by several changes including brain atrophy. The mechanisms underlying atrophy in iRBD are poorly understood. Here, we performed imaging transcriptomics and comprehensive spatial mapping in a multicentric cohort of 171 polysomnography-confirmed iRBD patients and 238 controls with T1-weighted MRI to investigate the gene expression patterns and the specific neurotransmitter, functional, cytoarchitectonic, and cognitive brain systems associated with cortical thinning in iRBD. We found that genes involved in mitochondrial function and macroautophagy were the strongest contributors to the thinning occurring in iRBD. Moreover, we demonstrated that thinning was constrained by the brain’s connectome and that it mapped onto specific networks involved in motor and planning functions. In contrast with thickness, changes in cortical surface area related to distinct gene and spatial mapping patterns. This study demonstrates that the development of atrophy in synucleinopathies is constrained by specific genes and networks. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The work performed in Paris was funded by grants from the Programme d'investissements d'avenir (ANR-10-IAIHU-06), the Paris Institute of Neurosciences-IHU (IAIHU-06), the Agence Nationale de la Recherche (ANR-11-INBS-0006), Electricite de France (Fondation d'Entreprise EDF), Biogen Inc., the Fondation Therese et Rene Planiol, the Fonds Saint-Michel; by unrestricted support for research on Parkinson's disease from Energipole (M. Mallart) and Societe Francaise de Medecine Esthetique (M. Legrand); and by a grant from the Institut de France to Isabelle Arnulf (for the Alice Study). The work performed in Montreal was supported by the Canadian Institutes of Health Research, the Fonds de recherche du Quebec-Sante, and the W. Garfield Weston Foundation. Jean-Francois Gagnon holds a Canada Research Chair in Cognitive Decline in Pathological Aging and reports grants from the Fonds de recherche du Quebec-Sante, the Canadian Institutes of Health Research, the W. Garfield Weston Foundation, the Michael J. Fox Foundation for Parkinson's Research, and the National Institutes of Health. Ronald B. Postuma reports grants and personal fees from the Fonds de recherche du Quebec-Sante, the Canadian Institutes of Health Research, the Parkinson Society of Canada, the W. Garfield Weston Foundation, the Michael J. Fox Foundation for Parkinson's Research, the R. Howard Webster Foundation, and the National Institutes of Health. Ziv Gan-Or reports funding from the Michael J. Fox Foundation, Canadian Consortium for Neurodegeneration in Aging, Fonds de recherche du Quebec-Sante, and Healthy Brains, Healthy lives initiative. Ziv Gan-Or is supported by the Fonds de recherche du Quebec-Sante Chercheur-Boursier award and is a William Dawson Scholar. This work was also funded by awards from the Canadian Institutes of Health Research Foundation Scheme and the Healthy Brain, Healthy Lives initiative to Alain Dagher. The work performed in Sydney was supported by a Dementia Team Grant from the National Health and Medical Research Council (1095127). Simon Lewis is supported by a Leadership Fellowship from the National Health and Medical Research Council (1195830). Elie Matar reports funding from the National Health and Medical Research Council (2008565). Kaylena Ehgoetz Martens reports funding from Parkinson Canada, Parkinson's Movement Disorder Foundation, University of Waterloo International Research Partnership grant, and Natural Science and Engineering Research Council of Canada. The work performed in Aarhus was supported by funding from the Lundbeck Foundation, Parkinsonforeningen (The Danish Parkinson Association), and the Jascha Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study uses regional values of cortical thickness and surface area that were previously made publicly available (). All participants were part of research protocols approved by local ethics committees, and the current project was approved by the Research Ethics Board of the McGill University Health Centre. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The regional cortical thickness and surface area values are available at . Codes used for performing the genetic and connectivity analyses are available publicly from the cited references.