Clustering Algorithm Reveals Dopamine-Motor Mismatch in Cognitively Preserved Parkinson's Disease

Objective: To explore the relationship between dopaminergic denervation and motor impairment in two de novo Parkinson's disease (PD) cohorts. Methods: n = 249 PD patients from Parkinson's Progression Markers Initiative (PPMI) and n = 84 from an external clinical cohort. Clustering analysis stratified dopaminergic denervation, measured with 123I-FP-CIT-SPECT, and motor impairment into mild [D and M] and severe [D+ and M+]. Differences in terms of biomarkers and clinical progression were assessed across subgroups. Causal mediation analysis evaluated the effect of co-pathology on the relationship between subgroups and cognitive decline. Results: Four subgroups were identified. Two subgroups showed concordant profiles: the severe dopaminergic and motor impairment subgroup [D+/M+] exhibited poorer memory performance, pathological Aβ1-42, as well as higher longitudinal Levodopa equivalent daily dose (LEDD) values and faster progression of motor disability; the mild dopaminergic and motor deficits [D/M] subgroup displayed a benign clinical profile and stable disease progression. Two subgroups exhibited dopaminergic and motor severity mismatch: the mild dopaminergic but severe motor impairment [D/M+] subgroup showed severe and rapidly progressive rigidity. CSF Aβ1–42 levels mediated the association between D+/M+ and cognitive decline in patients who were cognitively preserved at onset, accounting for 13% of the total effect. The external cohort supported the malignancy of D+/M+ and the presence of rigidity in D/M+. Interpretation: Concordant severe impairment reflects a malignant profile linked to Aβ-related cognitive decline, while mild concordant cases show stable progression. Mismatch subgroups display distinct clinical patterns, underscoring the value of integrating imaging and motor features for early disease stratification.