Clinical progression and genetic pathways in body-first and brain-first Parkinson’s disease

Abstract

Parkinson’s disease (PD) is a heterogeneous disorder with distinct phenotypes that may emerge years before motor diagnosis. We investigated the proposed “body-first” and “brain-first” PD phenotypes across prodromal and clinical stages using longitudinal clinical, imaging, and genetic data from 2,030 participants in the Parkinson Progression Marker Initiative followed for up to 12 years. Body-first cases showed greater baseline motor impairment, anxiety, and depression, as well as faster longitudinal motor and attentional decline compared to brain-first cases. These phenotypes were stable over time, predicted conversion to clinical PD, and were independently identified using unsupervised deep learning approaches. Imaging analyses revealed phenotype-specific patterns in the locus coeruleus, striatum, and glymphatic system consistent with bottom-up versus top-down pathological progression. Genetic analyses further identified phenotype-associated variants, including TRIM40 and IP6K2. Our findings support biologically distinct PD subtypes with implications for precision medicine