A Pragmatic Approach for Brain‐First and Body‐First Classification in Parkinson's Disease: Insights from the Personalized Parkinson Project

BACKGROUND: The brain-first versus body-first framework in Parkinson's disease (PD) proposes distinct origins of α-synuclein pathology, resulting in discrete progression patterns. Although this pathophysiological distinction implies different clinical trajectories, feasible criteria to classify subjects in large cohorts are currently lacking. OBJECTIVES: The goal was to develop a pragmatic approach for classifying brain-first and body-first PD clinical subtypes in a large early-PD cohort. METHODS: We, therefore, explored a pragmatic approach to separating these subtypes based on motor asymmetry, rapid eye movement sleep behavior disorder, and orthostatic hypotension, applied in a large cohort of persons with early PD (disease duration <5 years). RESULTS: Individuals classified as probable brain-first were more often tremor-dominant and showed a trend toward less constipation, after adjusting for disease duration, age and sex. CONCLUSIONS: This framework enables subtyping in many existing cohorts, potentially advancing our understanding of PD pathophysiology and facilitating targeted therapies. Validation against gold-standard measures is recommended to refine these criteria further.