Mitochondrial function-associated genes underlie cortical atrophy in prodromal synucleinopathies
Shady Rahayel, Christina Tremblay, Andrew Vo, Bratislav Mišić, Stéphane Lehéricy, Isabelle Arnulf, Marie Vidailhet, Jean-Christophe Corvol, the ICEBERG Study Group, Marie Vidailhet, Jean‐Christophe Corvol, Isabelle Arnulf, Stéphane Lehéricy, Marie Vidailhet, Graziella Mangone, Jean‐Christophe Corvol, Isabelle Arnulf, Sara Sambin, Jonas Ihle, Caroline Weill, David Grabli, Florence Cormier‐Dequaire, Louise‐Laure Mariani, Bertrand Degos, Richard J. Levy, Fanny Pineau, Julie Socha, Eve Benchetrit, Virginie Czernecki, Marie-Alexandrine Glachant, Sophie Rivaud-Péchoux, Élodie Hainque, Isabelle Arnulf, Smaranda Leu Semenescu, Pauline Dodet, Jean‐Christophe Corvol, Graziella Mangone, Samir Bekadar, Alexis Brice, Suzanne Lesage, Fanny Mochel, Farid Ichou, Vincent Perlbarg, Benoît Colsch, Arthur Tenenhaus, Stéphane Lehéricy, Rahul Gaurav, Nadya Pyatigorskaya, Lydia Yahia‐Cherif, Romain Valabrègue, Cécile Galléa, Marie‐Odile Habert, Dijana Petrovska, Laetitia Jeancolas, Vanessa Brochard, Alizé Chalançon, Carole Dongmo-Kenfack, Christelle Laganot, Valentine Maheo, Jean‐François Gagnon, Ronald B. Postuma, Jacques Montplaisir, Simon J.G. Lewis, Elie Matar, Kaylena A. Ehgoetz Martens, Per Borghammer, Karoline Knudsen, Allan K. Hansen, Oury Monchi, Ziv Gan‐Or, Alain Dagher, for the Alzheimer’s Disease Neuroimaging Initiative
Abstract
Isolated rapid eye movement sleep behaviour disorder (iRBD) is a sleep disorder characterized by the loss of rapid eye movement sleep muscle atonia and the appearance of abnormal movements and vocalizations during rapid eye movement sleep. It is a strong marker of incipient synucleinopathy such as dementia with Lewy bodies and Parkinson's disease. Patients with iRBD already show brain changes that are reminiscent of manifest synucleinopathies including brain atrophy. However, the mechanisms underlying the development of this atrophy remain poorly understood. In this study, we performed cutting-edge imaging transcriptomics and comprehensive spatial mapping analyses in a multicentric cohort of 171 polysomnography-confirmed iRBD patients [67.7 ± 6.6 (49-87) years; 83% men] and 238 healthy controls [66.6 ± 7.9 (41-88) years; 77% men] with T1-weighted MRI to investigate the gene expression and connectivity patterns associated with changes in cortical thickness and surface area in iRBD. Partial least squares regression was performed to identify the gene expression patterns underlying cortical changes in iRBD. Gene set enrichment analysis and virtual histology were then done to assess the biological processes, cellular components, human disease gene terms, and cell types enriched in these gene expression patterns. We then used structural and functional neighbourhood analyses to assess whether the atrophy patterns in iRBD were constrained by the brain's structural and functional connectome. Moreover, we used comprehensive spatial mapping analyses to assess the specific neurotransmitter systems, functional networks, cytoarchitectonic classes, and cognitive brain systems associated with cortical changes in iRBD. All comparisons were tested against null models that preserved spatial autocorrelation between brain regions and compared to Alzheimer's disease to assess the specificity of findings to synucleinopathies. We found that genes involved in mitochondrial function and macroautophagy were the strongest contributors to the cortical thinning occurring in iRBD. Moreover, we demonstrated that cortical thinning was constrained by the brain's structural and functional connectome and that it mapped onto specific networks involved in motor and planning functions. In contrast with cortical thickness, changes in cortical surface area were related to distinct genes, namely genes involved in the inflammatory response, and to different spatial mapping patterns. The gene expression and connectivity patterns associated with iRBD were all distinct from those observed in Alzheimer's disease. In summary, this study demonstrates that the development of brain atrophy in synucleinopathies is constrained by specific genes and networks.