Cerebellar contributions to cognitive deterioration in Parkinson's disease: Insights from multi-omics and longitudinal data

Increasing evidence suggests that pathological damage in Parkinson's disease (PD) involves the cerebellum, thus resulting in structural and functional alterations. However, whether these alterations predict the progression of cognitive impairment in PD remains unclear. We recruited 30 healthy controls and 72 PD patients across different cognitive states with available plasma biomarker data. We used voxel-based morphometry to identify cerebellar atrophy and subsequently performed seed-based whole-brain voxel-wise Granger causality analysis (GCA) on these regions to map cerebello-cerebral effective connectivity. Cerebellar compensatory capacity thresholds were determined through restricted cubic splines and threshold effect analysis. We applied these thresholds to stratify patients in two independent cohorts from the Parkinson's Progression Markers Initiative ( n = 106) and an in-house dataset ( n = 87); moreover, we conducted Kaplan-Meier survival curve analyses to predict longitudinal cognitive decline risk. Our study revealed cerebellar atrophy in the left Crus I, right Crus II, and right lobule VI. Cross-sectionally, we identified a dynamic functional connectivity alteration pattern and critical threshold with significant differences in phosphorylated tau 217, glial fibrillary acidic protein, and neurofilament light chain. Subsequently, findings from two longitudinal cohorts further revealed that patients exceeding this threshold exhibited a significantly increased risk of cognitive decline over time. Our study indicates that the effective connectivity threshold from Crus I to the inferior frontal gyrus may predict short-term cognitive decline. These findings highlight the role of the cerebellum in PD-related cognitive decline and may provide important insights for early intervention strategies. • Posterior lobe-predominant atrophy presented in PD patients with dementia. • Cerebellum-to-frontal cortex and intra-cerebellum output dynamically covaried with cognitive status during the pre-dementia stage and was lost at the dementia stage. • Plasma levels of GFAP, NfL and p-Tau 217 were elevated during the dementia stage. • GC connectivity threshold from Crus I to Frontal_Inf may predict short-term cognitive decline.