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            <funder>This research was funded in part by the European Research Council (ERC) under grant agreement No. 678304, the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 826421 (TVB-Cloud), Agence Nationale de la Recherche (ANR) under grant agreements ANR-10-IAIHU-06 (IHU ICM), ANR-11-INBS-0006, ANR-19-P3IA-0001 (PRAIRIE Institute), ANR-19-JPW2-000 (JPND E-DADS), ANR-21-JPW2-0005-05 (JPND CONTROL-PD); association France Parkinson (PRECISE-PD project), the Fondation d’Entreprise EDF, Biogen Inc., Fondation Thérèse and René Planiol, Fondation Saint Michel. The work received unrestricted support for Research on Parkinson’s disease from Energipole (M. Mallart), M. Villain and the Société Française de MédecineEsthétique (M. Legrand).</funder>
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                <title level="j">Movement Disorders</title>
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              <p>Abstract Background Clinical presentation and progression dynamics are variable in patients with Parkinson's disease (PD). Disease course mapping is an innovative disease modelling technique that summarizes the range of possible disease trajectories and estimates dimensions related to onset, sequence, and speed of progression of disease markers. Objective To propose a disease course map for PD and investigate progression profiles in patients with or without rapid eye movement sleep behavioral disorders (RBD). Methods Data of 919 PD patients and 88 isolated RBD patients from three independent longitudinal cohorts were analyzed (follow‐up duration = 5.1; 95% confidence interval, 1.1–8.1] years). Disease course map was estimated by using eight clinical markers (motor and non‐motor symptoms) and four imaging markers (dopaminergic denervation). Results PD course map showed that the first changes occurred in the contralateral putamen 13 years before diagnosis, followed by changes in motor symptoms, dysautonomia, sleep—all before diagnosis—and finally cognitive decline at the time of diagnosis. The model showed earlier disease onset, earlier non‐motor and later motor symptoms, more rapid progression of cognitive decline in PD patients with RBD than PD patients without RBD. This pattern was even more pronounced in patients with isolated RBD with early changes in sleep, followed by cognition and non‐motor symptoms and later changes in motor symptoms. Conclusions Our findings are consistent with the presence of distinct patterns of progression between patients with and without RBD. Understanding heterogeneity of PD progression is key to decipher the underlying pathophysiology and select homogeneous subgroups of patients for precision medicine. © 2023 International Parkinson and Movement Disorder Society.</p>
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