Objective: We aimed to analyze the real-world use of COMT inhibitors associated with levodopa in patients with Parkinson’s disease (PD) who present early fluctuations and to explore whether early COMT inhibition optimizes treatment outcomes. Methods: REONPARK is an ongoing 2-year prospective observational study. We included patients diagnosed with PD who presented signs of end-of-dose motor fluctuations for <2 years and started COMT inhibitors according to clinical practice. Outcomes included the clinician and patient global impression of change (CGI-C, PGI-C), the Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), the Parkinson’s Disease Questionnaire-8 (PDQ-8), Non-Motor Symptoms Scale (NMSS), 19-Symptom Wearing-off Questionnaire (WOQ-19), and safety. We present a pre-planned interim analysis (cut-off date 3 July 2023) of patients who completed the first 3 months of follow-up. Results: Seventy patients were analyzed (mean levodopa dose at inclusion 484.8 mg; duration of motor fluctuations 0.6 years). In all cases, COMT inhibition was initiated with opicapone, and 81% maintained a stable levodopa dose at 3 months. After 3 months of treatment with opicapone, 73.5% and 62.8% of patients improved on CGI-C and PGI-C, respectively. MDS-UPDRS scores improved significantly with a mean change from baseline of −3.3 ± 7.7 (p < 0.001) for Part III and −1.3 ± 1.7 (p < 0.001) for Part IV. The mean OFF time decreased from 3.7 ± 2.6 h at baseline to 2.2 ± 2.3 h, and 20.6% of patients no longer experienced OFF periods. Patients experiencing no impact of fluctuations increased from 10% to 45.6%. Conclusions: In PD patients with early fluctuations, three months of opicapone reduced the OFF time and improved functional outcomes, suggesting potential benefits in the early stages.

Background: CVT‐301 (Inbrija) has demonstrated its effectiveness in treating OFF periods in people with Parkinson's disease (PwP). However, its effect on non‐motor symptoms (NMS) and quality of life has not been researched yet. Our aim was to analyze the change observed in health‐related quality of life (HRQoL) and, as a secondary exploratory analysis, NMS associated with OFF episodes in PwP treated with CVT‐301. Methods: INLEVO‐LIFE PD (an open‐label study of the effect of INhaled LEVOdopa on quality of LIFE and non‐motor symptoms in Parkinson's Disease) is a prospective open‐label study conducted in five centers in Spain. The change from baseline (V0) to the end of the observational period (12 ± 2 weeks) (V12w) in the 39‐item Parkinson's Disease Quality of Life Questionnaire (PDQ‐39) total score was the primary efficacy measure. Results: Forty PD patients (age 62.3 ± 9.2 years; 55% males) were included between March/2024 and November/2025. At 12 weeks, 34 patients were using CVT‐301 and completed the follow‐up (85%). The PDQ39 total score decreased from 43.6 ± 24.2 at V0 to 31.4 ± 20.6 at V12w ( p < 0.0001). A significant decrease was observed in the mean score of 4 domains of the PDQ39. NMS burden was reduced at v12w from the OFF state to 30, 60, and 90 min after using CVT‐301 ( p < 0.0001). Mean daily OFF time decreased by 1.6 ± 1.9 h ( p < 0.0001). Adverse events related to CVT‐301 were reported in 35% of the patients. Conclusion: HRQoL and NMS associated with OFF episodes improved in PwP after 12 weeks using CVT‐301.

We report a 49-year-old patient suffering from spastic paraplegia with a novel heterozygous mutation and analyzed the levels of heat shock proteins (hsp)-27, dopamine (DA), and its metabolites in their cerebrospinal fluid (CSF). The hsp27 protein concentration in the patient’s CSF was assayed by an ELISA kit, while DA levels and its metabolites in the CSF, 3,4-dihydroxyphenylacetic acid (DOPAC), Cys-DA, and Cys-DOPA were measured by HPLC. Whole exome sequencing demonstrated SPG-11 c.1951C>T and novel SYNJ1 c.2614G>T mutations, both heterozygous recessive. The patient’s DA and DOPAC levels in their CSF were significantly decreased (53.0 ± 6.92 and 473.3 ± 72.19, p < 0.05, respectively) while no differences were found in their Cys-DA. Nonetheless, Cys-DA/DOPAC ratio (0.213 ± 0.024, p < 0.05) and hsp27 levels (1073.0 ± 136.4, p < 0.05) were significantly higher. To the best of our knowledge, the c.2614G>T SYNJ1 mutation has not been previously reported. Our patient does not produce fully functional spatacsin and synaptojanin-1 proteins. In this line, our results showed decreased DA and DOPAC levels in the patient’s CSF, indicating loss of DAergic neurons. Many factors have been described as being responsible for the increased cys-DA/DOPAC ratio, such as MAO inhibition and decreased antioxidant activity in DAergic neurons which would increase catecholquinones and consequently cysteinyl-catechols. In conclusion, haploinsufficiency of spatacsin and synaptojanin-1 proteins might be the underlying cause of neurodegeneration produced by protein trafficking defects, DA vesicle trafficking/recycling processes, autophagy dysfunction, and cell death leading to hsp27 upregulation as a cellular mechanism of protection and/or to balance impaired protein trafficking.

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 (NMS) 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 27 participants with early improvement in both outcomes, median benefit retained at 90 min was 61.9% for motor symptoms versus 100% for NMS (p = 0.0015). 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.

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Objective: To evaluate the sustained real-world effectiveness and safety of catechol-O-methyltransferase (COMT) inhibitors added to levodopa in patients with Parkinson’s disease (PD) presenting early motor fluctuations. Methods: REONPARK is an ongoing, multicenter, prospective observational study conducted in Spain. Adult patients with PD and end-of-dose motor fluctuations for <2 years initiating a COMT inhibitor were included. Outcomes assessed at 3, 6, and 12 months included Clinician and Patient Global Impression of Change (CGI-C, PGI-C), Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), Wearing-off Questionnaire (WOQ-19), Non-Motor Symptoms Scale (NMSS), Parkinson’s Disease Questionnaire-8 (PDQ-8), and safety. This article presents the 3-, 6-, and 12-month planned interim analysis of the study. Results: A total of 143 patients were included (99.3% treated with opicapone), of whom 138, 131, and 89 patients completed the 3, 6, and 12 months of follow-up, respectively. Levodopa doses remained stable in most patients (73% at 12 months). Significant and sustained improvements were observed in MDS-UPDRS Parts III and IV scores, as well as the total MDS-UPDRS score over 12 months, with greater likelihood of Part IV improvement in patients receiving <4.5 mg/kg/day of levodopa. OFF time decreased by 1.6–2.0 h from baseline. ON-time quality was maintained over time with 97.7% of patients reporting no or minimal functional impact from dyskinesia, while 47.7% of patients had no impact from motor fluctuations and 36.4% of patients no longer experienced OFF periods at 12 months. PDQ-8 scores remained stable and no overall benefit on total non-motor symptoms burden was demonstrated, despite improvements in selected domains among patients with a higher baseline non-motor symptoms burden. WOQ-19 scores improved significantly. Conclusions: In PD patients with early motor fluctuations, opicapone initiation was associated with sustained improvements in motor outcomes and reduced OFF time, and maintained the ON-time quality over 12 months, with stable levodopa dosing.