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

ABSTRACT 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 123 I‐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 Aβ 1‐42 , 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 Aβ 1–42 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.