María Cerdán Sánchez

Background/Objectives: OFF episodes in Parkinson’s disease (PD) include motor and non-motor manifestations, but their resolution after on-demand therapy may not be synchronous. We examined within-patient temporal dynamics of motor and non-motor responses after inhaled levodopa. Methods: This post hoc analysis used data from the prospective, multicenter, open-label INLEVO-LIFE PD study. At week 12, UPDRS-III and 10 OFF-related non-motor symptoms (NMSs) were assessed in OFF and 30, 60, and 90 min after inhaled levodopa. The principal post hoc outcome was the proportion of maximum early (30–60 min) benefit retained at 90 min for motor versus non-motor outcomes. Individual trajectories were also examined descriptively. Results: Thirty-four participants had complete serial assessments. Mean UPDRS-III scores were 25.91, 11.21, 12.00, and 16.00 at OFF, 30, 60, and 90 min, respectively (p < 0.0001); corresponding NMSS-OFF/ON total scores were 6.65, 2.09, 1.91, and 2.71 (p < 0.0001). Among 28 participants with early improvement in both outcomes, median benefit retained at 90 min was 67.1% for motor symptoms versus 100% for NMSs (p = 0.0011). Motor and non-motor improvement magnitudes were not significantly correlated at any time point. Individual trajectories showed marked interindividual heterogeneity in the timing and persistence of motor and non-motor responses. Conclusions: Motor and non-motor OFF manifestations improved rapidly after inhaled levodopa but showed partially dissociated temporal trajectories, challenging the assumption that OFF resolution is necessarily synchronous across symptom dimensions. Greater relative persistence of non-motor benefit at 90 min is hypothesis-generating and requires confirmation using validated NMF instruments and controlled designs.