Specific Cerebellar Structural Alterations in Parkinson Disease Associated With Disease Staging

Rebecca Kerestes, PhD

A recently published analysis of the ENIGMA study showed evidence of regionally specific alterations in anterior and posterior cerebellar lobe volume in Parkinson disease (PD) associated with different clinical stages of the disease. All told, results suggested that changes in cerebellar volume were temporally ordered, with larger anterior “motor” lobe regions earlier in the course of the disease, and smaller posterior “non-motor” lobes in later stages.

Led by Rebecca Kerestes, PhD, a research fellow at the University of Monash, the multisite analysis included 2847 adults with PD and 1212 age- and sex-matched controls from the global ENIGMA-PD working group. Linear mixed models were used to compare total and regional cerebellar volume between the 2 groups at each Hoehn and Yahr (HY) disease stage. Relationships between total and regional cerebellar volume and time since diagnosis, and motor symptom severity were assessed.

The HY ranged from 1-5, with HY1 considered “unilateral involvement only usually with minimal or no functional disability,” and HY5 defined as “confinement to bed or wheelchair unless aided.” Coming into the study, there was no significant between-group differences in total (gray and white) cerebellar volume (P >.05). Regions of interest (ROI) analyses, however, revealed significantly lower gray matter volume in patients with PD in 3 cerebellar lobules with small effect sizes (d_min = –0.11; d_max = –0.15; all P <.05 false discovery rate [FDR]).

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The matching procedure selected 689 controls to match the 345 HY1 participants, 1018 controls to match the 1018 HY2 participants, 557 controls to match the 281 HY3 participants, and 164 controls to match the 82 HY4-5 participants. A side-by-side comparison of HY stages showed significantly larger bilateral left and right lobule V in the HY1 group vs HY4-5 group (PFDR <.05). In contrast, the lobule VIIB was significantly smaller in the HY4-5 group bilaterally compared with HY1 and HY2 groups (all PFDR <.05). Notably, the right VIIB lobule was also significantly smaller in the HY3 group compared with the HY1 group (P <.05). Lobule VIIB, which showed the largest differences across stages, is a “non-motor” region of the cerebellar cortex and is preferentially connected to prefrontal and posterior parietal regions of the cerebral cortex.

"Our findings align with an ongoing neurodegenerative process in the posterior lobe; each HY increment replicates the pattern of lower volume in bilateral VIIB from the previous stage, denoted by larger group differences and further substantiated by statistically significant differences between disease stage," the study authors wrote. "Notably, our findings were associated with the clinical state (disease stage), but not with time since diagnosis (disease duration). It remains unclear whether this cerebellar degeneration results from primary disease-related pathology or, if it is a secondary consequence of cortical and basal ganglia degeneration and associated progressive loss of functional capacity."

Of the cohort, 2297 people with PD had time since diagnosis scores available for analysis and 1189 had MDS-Unified Parkinson’s Disease Rating Scale (UPDRS)-3 scores obtained in the OFF state. Results showed no significant association between time since diagnosis and total or regional cerebellar volume, as well as no association between overall motor symptom severity and total or regional cerebellar volume. Of note, a trend negative relationship between motor symptom severity and total cerebellar volume was observed (PFDR = .06). In HY1 (n = 148), there was a significant positive correlation between left limb rigidity (P = .02) and right limb rigidity (P = .03) and right lobule V volume.

Among patients with PD who had Montreal Cognitive Assessment (MoCA) and MDS-UPDRS-3 data available (n = 1252), a significant positive association was observed between total cerebellar volume and MoCA score, independent of time since diagnosis (PFDR = .002). Within this group, significantly lower total cerebellar volume (d = –.17; 95% CI, –0.02 to –0.30; P = .01) was observed in cognitively impaired patients vs those who were cognitively normal.

REFERENCE
1. Kerestes R, Laansma MA, Owens-Walton C, et al. Cerebellar volume and disease staging in Parkinson’s disease: an ENIGMA study. Mov Disord. Published online November 14, 2023. doi:10.1002/mds.29611