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. 2025 Apr 9;272(5):325.
doi: 10.1007/s00415-025-13050-y.

The natural history of body-first versus brain-first Parkinson's disease subtypes

Vittorio Velucci  1 , Angelo Fabio Gigante  2 , Giovanni Iliceto  3 , Roberta Pellicciari  4 , Barbara Vitucci  4 , Sarah Idrissi  4 , Marcello Mario Mascia  5 , Antonella Muroni  5 , Tommaso Ercoli  6 , Paolo Solla  6 , Giovanni Defazio  4   7
Affiliations

The natural history of body-first versus brain-first Parkinson's disease subtypes

Vittorio Velucci et al. J Neurol. .

Abstract

Background: Several lines of evidence support the hypothesis of brain-first and body-first Parkinson's disease (PD) subtypes, characterized by distinct origins of α-synuclein pathology. However, data on premotor non-motor burden and motor progression in these subtypes remain inconsistent.

Objective: To analyze the natural history of body-first versus brain-first PD subtypes.

Methods: Data from 400 PD patients enrolled at a single Italian center were analyzed. All patients underwent a standardized retrospective baseline assessment of premotor and motor symptoms at onset and were prospectively followed. Premotor REM sleep behavior disorder (RBD), considered a prodromal phenotype of the body-first subtype, was used to divide patients into two groups: 81 patients with probable premotor RBD (PDpreRBD+) and 319 patients without (PDpreRBD-).

Results: At motor onset, PDpreRBD+ patients were older than PDpreRBD- patients, exhibited less tremor, and more frequently presented with bilateral motor symptoms. PDpreRBD+ patients also reported a greater burden of premotor symptoms, including hyposmia, cognitive impairment, pain, constipation, and other dysautonomic symptoms. Over the follow-up period, PDpreRBD+ patients progressed more rapidly to Hoehn and Yahr stage 3, even after adjusting for sex, years of schooling, age at motor onset, and initial motor phenotype.

Conclusions: Our results align with the hypothesis of brain-first and body-first PD subtypes, providing novel insights into their different premotor non-motor burden and motor progression trajectories.

Keywords: Body-first; Brain-first; Motor progression; Parkinson’s disease subtypes; Premotor symptoms; REM sleep behavior disorder (RBD).

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Conflict of interest statement

Declarations. Conflict of interest: The authors have no competing interests to declare that are relevant to the content of this article. Ethical approval: This study was conducted in accordance with the principles of the Declaration of Helsinki. Ethical approval was waived by the local ethical review board because all procedures performed were part of routine clinical care. Consent to participate: Informed consent was obtained from all individual participants included in the study.

Figures

Fig. 1
Fig. 1
Kaplan–Meier plots of survival to Hoehn and Yahr stage 3 in patients with and without premotor RBD (PDpreRBD+ and PDpreRBD−, respectively)
Fig. 2
Fig. 2
The natural history of body-first versus brain-first Parkinson’s disease subtypes
See this image and copyright information in PMC

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