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 (PD(preRBD+)) and 319 patients without (PD(preRBD-)). RESULTS: At motor onset, PD(preRBD+) patients were older than PD(preRBD-) patients, exhibited less tremor, and more frequently presented with bilateral motor symptoms. PD(preRBD+) patients also reported a greater burden of premotor symptoms, including hyposmia, cognitive impairment, pain, constipation, and other dysautonomic symptoms. Over the follow-up period, PD(preRBD+) 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.