Background/Objectives: Driving abilities require the synchronized activity of cerebral networks associated with sensorimotor integration, motricity, and executive functions. Drivers with Parkinson’s disease (DwP) have impaired driving ability, but little is known about the impact of “wearing-off” and therapies in addition to L-DOPA on driving capacities. This study aimed to (i) compare driving performance between DwP during different motor states and healthy controls and (ii) assess the impact of add-on therapies on driving abilities. Methods: DwP (n = 26) were enrolled as individuals experiencing wearing-off symptoms and treated (within 6 months before the enrollment) with add-on therapies to L-DOPA, including MAO inhibitors for DwP-A (n = 12) or opicapone for DwP-B (n = 14). Age- and sex-matched controls (CON, n = 12) were also enrolled. DwP received two driving assessments in a driving simulator during their “best-on” time and during their wearing-off time on different days. An anamnestic driving questionnaire was collected with the assistance of partners. A Virtual Driving Rating Scale (VDRS) was calculated, as well as learning curves (LCs) for driving items calculated in minutes. Results: DwP reported worse driving performance than CON at the driving questionnaire. In line with this, DwP showed worse VDRS (p < 0.01) and LC (p = 0.021) than CON. Lower VDRS was associated with wearing-off (p < 0.01), but DwP-B had better driving performance while in their “best-on” time (p = 0.037) and more items improving with LCs (7 vs. 3) than DwP-A. Conclusions: DwP demonstrated impaired driving compared to controls. Wearing-off symptoms can also affect driving ability, but therapies (opicapone more so than MAO inhibitors) may play a role in preserving specific driving skills, possibly through maintaining learning abilities.

Autonomic dysfunction is a key non-motor feature of Parkinson’s disease (PD) and may influence motor performance, particularly gait. While heart rate variability (HRV) has been associated with freezing of gait, its relationship with broader gait parameters remains unclear. The objective was to investigate correlations between resting-state HRV time-domain measures and spatiotemporal gait parameters during comfortable and fast walking in patients with idiopathic PD. Twenty-eight PD patients (mean age 68 ± 9 years) were evaluated at Campus Bio-Medico University Hospital. HRV was recorded at rest using the e-Sense pule™ portable sensor, including the Baevsky’s Stress Index a measure increasing with sympathetic burden. Gait parameters were assessed via the 10 m Timed Up and Go (TUG) test using the Mon4t™ smartphone app at comfortable and fast pace. Clinical data included UPDRS III, MoCA, and disease characteristics. Gait metrics significantly changed between walking conditions. HRV parameters clustered separately from gait metrics but intersected with significant correlations. Higher Stress Index values, reflecting sympathetic dominance, were associated with poorer gait performance, including prolonged transition times, shorter steps, and increased variability (p < 0.001, r = 0.57–0.61). MoCA scores inversely correlated with the Stress Index (r = −0.52, p = 0.004), linking cognitive and autonomic status. UPDRS III and MoCA were related to TUG metrics but not HRV. Time-domain HRV measures, particularly the Stress Index, are significantly associated with spatiotemporal gait features in PD, independent of gait speed. These findings suggest that impaired autonomic regulation contributes to functional mobility deficits in PD and supports the role of HRV as a biomarker in motor assessment.