Objective:

To evaluate whether isotropic diffusion (ISO), a diffusion MRI-derived metric from generalized q-sampling imaging (GQI), can stratify biologically distinct subtypes of Parkinson’s disease (PD) using a data-driven clustering approach, and to assess whether these subtypes differ in motor progression.

Background:

PD is clinically heterogeneous, and biologically grounded subtyping may improve prognostic accuracy and guide therapeutic strategies. ISO quantifies extracellular water, with elevated levels linked to neurodegeneration. Whether ISO-based subtyping can delineate biologically distinct PD subgroups with distinct clinical trajectories remains unknown.

Design/Methods:

We applied an unsupervised, data-driven hierarchical clustering approach to baseline ISO values from 12 subcortical regions central to PD pathology in 156 de novo patients from the Parkinson’s Progression Markers Initiative. Subtypes were compared on baseline motor severity (MDS-UPDRS-III total and subdomains: bradykinesia, rigidity, tremor, postural instability/gait difficulty) and on longitudinal changes in ISO and motor outcomes over 4 years using mixed-effects models.

Results:

Two subtypes emerged: Subtype 1 (n=62) with lower baseline ISO and Subtype 2 (n=94) with higher ISO across all regions. At baseline, Subtype 2 showed greater rigidity (p=0.004) and bradykinesia (p=0.01), with no differences in tremor or postural instability/gait difficulty. Longitudinally, Subtype 1 exhibited progressive ISO increases across regions (p<0.001), while Subtype 2 remained stable at elevated levels. Despite these divergent imaging trajectories, both subtypes progressed at similar rates, with no differences in longitudinal motor trajectories.

Conclusions:

Clustering of ISO values from GQI identified distinct PD subgroups with divergent imaging trajectories, but these did not correspond to differences in motor progression. ISO may capture extracellular heterogeneity in PD, although its prognostic value remains uncertain. Larger cohorts and longer follow-up are needed to clarify its clinical utility for stratification in care and trials.