Abstract
BACKGROUND: Previous research revealed differences in cerebellar white matter integrity by disease stages, indicating a compensatory role in Parkinson's disease (PD). However, the temporal evolution of cerebellar white matter microstructure in patients with PD (PwPD) remains unclear. OBJECTIVE: To unravel temporal evolution of cerebellar white matter and its dopaminergic correlates in PD. METHODS: We recruited 124 PwPD from the PPMI study. The participants were divided into two subsets: Subset 1 (n = 41) had three MRI scans (baseline, 2 years, and 4 years), and Subset 2 (n = 106) had at least two MRI scans at baseline, 1 year, and/or 2 years. Free water-corrected diffusion metrics were used to measure the microstructural integrity in cerebellar peduncles (CP), the main white matter tracts connecting to and from the cerebellum. The ACAPULCO processing pipeline was used to assess cerebellar lobules volumes. Linear mixed-effect models were used to study longitudinal changes. We also examined the relationships between microstructural integrity in CP, striatal dopamine transporter specific binding ratio (SBR), and clinical symptoms. RESULTS: Microstructural changes in CP showed a non-linear pattern in PwPD. Free water-corrected fractional anisotropy (FAt) increased in the first two years but declined from 2 to 4 years, while free water-corrected mean diffusivity exhibited the opposite trend. The initial increased FAt in CP correlated with cerebellar regional volume atrophy, striatal dopaminergic SBR decline, and worsening clinical symptoms, but this correlation varied across disease stages. CONCLUSIONS: Our findings suggest a non-linear evolution of microstructural integrity in CP throughout the course of PD, indicating the adaptive structural reorganization of the cerebellum simultaneously with progressive striatal dopaminergic degeneration in PD.