Free water imaging unravels unique patterns of longitudinal structural brain changes in Parkinson’s disease subtypes

Background: Research shows that individuals with Parkinson’s disease (PD) who have a postural instability and gait difficulties (PIGD) subtype have a faster disease progression compared to those with a tremor dominant (TD) subtype. Nevertheless, our understanding of the structural brain changes contributing to these clinical differences remains limited, primarily because many brain imaging techniques are only capable of detecting changes in the later stages of the disease. Objective: Free water (FW) has emerged as a robust progression marker in several studies, showing increased values in the posterior substantia nigra that predict symptom worsening. Here, we examined longitudinal FW changes in TD and PIGD across multiple brain regions. Methods: Participants were TD and PIGD enrolled in the Parkinson’s Progression Marker Initiative (PPMI) study who underwent diffusion MRI at baseline and 2 years later. FW changes were quantified for regions of interest (ROI) within the basal ganglia, thalamus, brainstem, and cerebellum. Results: Baseline FW in all ROIs did not differ between groups. Over 2 years, PIGD had a greater percentage increase in FW in the putamen, globus pallidus, and cerebellar lobule V. A logistic regression model incorporating percent change in motor scores and FW in these brain regions achieved 91.4% accuracy in discriminating TD and PIGD, surpassing models based solely on clinical measures (74.3%) or imaging (76.1%). Conclusion: The results further suggest the use of FW to study disease progression in PD and provide insight into the differential course of brain changes in early-stage PD subtypes.