Patient-specific multi-modal modeling uncovers neurotransmitter receptor involvement in motor and non-motor axes of Parkinson's disease

Abstract

Multi-systemic neurodegeneration in Parkinson's disease (PD) is increasingly acknowledged, involving several neurotransmitter systems beyond the classical dopaminergic circuit and resulting in heterogeneous motor and non-motor symptoms. Nevertheless, the mechanistic basis of neuropathological and symptomatic heterogeneity remains unclear. Here, we use patient-specific generative brain modeling to identify neurotransmitter receptor-mediated mechanisms involved in PD progression. Combining receptor maps with longitudinal neuroimaging (PPMI data), we detect a diverse set of receptors influencing gray matter atrophy, microstructural degeneration, and dendrite loss in PD. Importantly, identified receptor mechanisms correlate with symptomatic variability along two distinct axes, representing motor/psychomotor symptoms with large GABAergic contributions, and cholinergically-driven visuospatial dysfunction. Furthermore, we map cortical and subcortical regions where receptors exert significant influence on neurodegeneration. Our work constitutes the first personalized causal model linking the progression of multi-factorial brain reorganization in PD across spatial scales, including molecular systems, accumulation of neuropathology in macroscopic brain regions, and clinical phenotypes.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This research was undertaken thanks in part to funding from: the Parkinson's Canada graduate training award to AFK, the Canada First Research Excellence Fund, awarded to McGill University for the Healthy Brains for Healthy Lives Initiative, the Canada Research Chair tier-2, Fonds de la recherche en sant&eacute du Qu&eacutebec (FRQS) Junior 1 Scholarship, Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant, and Weston Brain Institute awards to YIM, the Brain Canada Foundation and Health Canada support to the McConnell Brain Imaging Center at the Montreal Neurological Institute, and the European Union's Horizon 2020 Framework Programme for Research and Innovation under the Specific Grant Agreements 785907 (Human Brain Project SGA2) and 945539 (Human Brain Project SGA3) awarded to NPG and KZ. Multimodal imaging and clinical data collection and sharing for this project was funded by PPMI. A public-private partnership, PPMI is funded by the Michael J. Fox Foundation for Parkinson's Research and funding partners, including AbbVie, Allergan, Amathus Therapeutics, Avid Radiopharmaceuticals, Biogen, BioLegend, Bristol Myers Squibb, Celgene, Denali Therapeutics, GE Healthcare, Genentech, GlaxoSmithKline plc., Golub Capital, Handl Therapeutics, Insitro, Janssen Neuroscience, Eli Lilly and Company, Lundbeck, Merck Sharp & Dohme Corp., Meso Scale Discovery, Neurocrine Biosciences, Pfizer Inc., Piramal Group, Prevail Therapeutics, Roche, Sanofi Genzyme, Servier Laboratories, Takeda Pharmaceutical Company Limited, Teva Pharmaceutical Industries Ltd., UCB, Verily Life Sciences, and Voyager Therapeutics Inc.

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 used only publically-available datasets from the PPMI database (neuroimaging and cognitive evaluations; https://www.ppmi-info.org/), the HCP database (tractography template for connectivity estimation; http://www.humanconnectomeproject.org/), and receptor autoradiography data published in [Zilles and Palomero-Gallagher, 2017].

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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

The three datasets used in this study are available from the PPMI database (neuroimaging and cognitive evaluations; https://www.ppmi-info.org/), the HCP database (tractography template for connectivity estimation; http://www.humanconnectomeproject.org/), and receptor autoradiography data published in [Zilles and Palomero-Gallagher, 2017].

https://www.ppmi-info.org/

http://www.humanconnectomeproject.org/

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