Neurogenetic Traits Conferring Vulnerability to Cortical Progression of Parkinson's Disease

Background: The genetic traits that underlie vulnerability to neuronal damage across specific brain circuits in Parkinson’s disease (PD) remain to be elucidated. In this study, we characterized the brain topological intersection between propagating connectivity networks in healthy controls (HC) and PD participants and gene expression patterns across the human cortex – such as the SNCA gene (encoding alpha-synuclein protein, a hallmark of PD pathology). Methods: To characterize the functional scaffolding of connections emanating from PD-related pathology epicenters in the brainstem, we first performed Stepwise Functional Connectivity (SFC) analysis using intrinsic connectivity as revealed by neuroimaging. We then leveraged the Allen Human Brain Atlas (AHBA) to examine the spatial intersection of the observed SFC patterns with genetic transcription profiles. Findings: A rich set of genes were transcriptionally associated to PD-related biologic processes, including dopamine secretion, neuropeptide transmission, and axonal and synaptic assemblies, for which the gene SNCA played a central role. As hypothesized, we further confirmed that brain connectivity originated from PD-related pathology epicenters in the brainstem largely recapitulated the anatomical distribution of alpha-synuclein histopathology in postmortem data. Finally, we discovered that the gene set most related to cortical propagation patterns of PD-related pathology was primarily involved in microtubule cellular components. Interpretation: This study sheds light on exciting new avenues for enhancing detection of PD neuronal vulnerability via an evaluation of in vivo connectivity trajectories across the human brain and successful integration of neuroimaging-genetic strategies. Funding Statement: This research was supported by grants from the National Institutes of Health (NIH; R01AG061811, and R01AG061445 to J.S.), the Ministry of Education, Science, and Technological Development of the Republic of Serbia (grant number 175090), the Italian Ministry of Health (grant number RF-2018-12366746) and Carlos III Institute of Health (PI11/02109) Spain, the Basque Government through the BERC 2018-2021 program and by the Spanish State Research Agency through BCBL Severo Ochoa excellence accreditation SEV-2015-0490 and the Spanish Ministry of Economy and Competitiveness (RYC-2017- 21845 and PID2019-105520GB-100 to C.C-G.). Declaration of Interests: S.B. reports no disclosures. F.A. is Section Editor of NeuroImage: Clinical; has received speaker honoraria from Philips, Novartis and Biogen Idec; and receives or has received research supports from the Italian Ministry of Health, AriSLA (Fondazione Italiana di Ricerca per la SLA), and the European Research Council. I.D. reports no disclosures. E.B. reports no disclosures. F.d. O.U. reports no disclosures. M.D-A. report honoraria for lectures, travel, and accommodation to attend scientific meetings from Alter, Bial, Merk, Novartis, Sanofi Genzyme, UCB, and Zambon. C.C-G. reports no disclosures. M.R-O. reports honoraria for lectures, travel and accommodation to attend scientific meetings from Boston Scientific and Bial. T. Stojkovic has received speaker honoraria from Actavis and Alzheimer's Association International Research Grant. V.S. Kostic has received speaker honoraria from Actavis and Solveo. M. Filippi is Editor-in-Chief of the Journal of Neurology; received compensation for consulting services and/or speaking activities from Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). J. Sepulcre reports no disclosures. Ethics Approval Statement: Both studies were approved by the local ethics committees at University of Belgrade and Gipuzkoa Clinical Research Ethics Committee respectively and written informed consent to participate in the study was obtained from all participants.