Drug-resistant rest tremor is associated with slower disease progression in Parkinson’s disease

Rest tremor in Parkinson’s disease (PD) shows heterogeneous responsiveness to dopaminergic therapy. Drug-resistant rest tremor reflects mechanisms distinct from striatal dopamine depletion. We examined whether patients with drug-resistant rest tremor had a unique disease progression pattern. Using data from the Parkinson’s Progression Markers Initiative, we studied 229 PD patients with rest tremor and 268 without rest tremor. Patients with rest tremor were classified by estimated drug responsiveness after adjustment for confounders. Linear mixed-effects models were used to compare longitudinal progression between groups, and mediation analyses to explore whether differences in disease progression were attributed to striatal DAT availability. PD patients with drug-resistant rest tremor exhibited milder motor and non-motor symptoms at baseline, and worsened more slowly in the MDS-UPDRS III non-tremor score than those with drug-responsive rest tremor (estimated difference in annual change: β = –1.54, p = 0.014) and those without rest tremor ( β = –1.06, p = 0.016). These differences were not mediated by either baseline striatal DAT availability or its longitudinal changes.