Parkinson’s disease subtypes and their association with probable rapid eye movement sleep behavior disorder severity: a brainstem tractography and machine learning investigation

Rapid Eye Movement (REM) sleep behavior disorder (RBD) affects nearly half of Parkinson’s disease (PD) patients. However, the structural heterogeneity within the brainstem, which regulates REM sleep, remains largely unexplored in PD. Our objective was to identify distinct PD subtypes based on microstructural characteristics in the brainstem and examine their associations with the severity of RBD. Data, including diffusion tensor imaging and REM sleep behavior disorder screening questionnaire (RBDSQ) responses, were obtained from 124 PD patients and 61 healthy controls through the Parkinson’s Progression Marker Initiative database. Mean Quantitative Anisotropy (QA) values, representing axonal density, were extracted from 14 brainstem tracts and input into the semi-supervised machine learning algorithm, Heterogeneity through Discriminative Analysis (HYDRA), to cluster subtypes. Applying HYDRA, we identified two distinct PD subtypes (Subtype 1: n = 66, Subtype 2: n = 58). Subtype 2 exhibited reduced QA across assessed brainstem tracts and significantly higher RBDSQ scores than Subtype 1 and healthy controls (p < 0.001). Conversely, Subtype 1, characterized by lower RBDSQ scores, exhibited increased QA, notably in the right medial longitudinal fasciculus, when compared to Subtype 2 and controls (p < 0.001). These findings suggest that heterogeneous axonal damage in brainstem circuits correlates with variations in RBD severity, providing insights into the neurobiological underpinnings of early PD.