Background Motor asymmetry is a characteristic feature of Parkinson’s disease (PD); however, its definition and long-term evolution and clinical implications remain unclear. Objectives Assess the trajectory of motor asymmetry at 3 and 5 years post-STN-DBS, as well as its impact on axial symptoms and quality of life (QoL). Methods Utilizing data from the PREDISTIM cohort, which includes over 500 patients and is representative of a large advanced PD population, we analyzed motor asymmetry (defined as the difference between right and left appendicular motor scores) at 1, 3, and 5 years following STN-DBS. Absolute and normalized (normalization based on global motor severity) asymmetry were quantified using MDS-UPDRS III scores in the Stim ON/Med ON state. Axial symptoms and QoL were assessed using the axial subscore and PDQ-39, respectively. Statistical analyses included mediation models to explore the interplay between asymmetry, motor severity, and clinical outcomes. Results Normalized motor asymmetry decreased over time, despite an increase in absolute asymmetry and overall motor severity. Higher normalized asymmetry was associated with lower axial scores and better QoL. Mediation analyses confirmed that the relationship between motor asymmetry, axial scores, and QoL was largely associated with overall motor severity. Conclusions These findings suggest that a higher normalized motor asymmetry in advanced PD stage reflects an appendicular phenotype, which is associated with better QoL. Its reduction over time corresponds to increased axial involvement.

Freezing of gait (FOG) in Parkinson's disease (PD) involves impaired integration of posture and locomotion with altered body-segment coordination. We measured coordination using gait kinematics during walking in 16 PD patients with FOG, preoperatively with and without dopaminergic medication (OFF/ON-DOPA), and postoperatively with and without subthalamic deep brain stimulation (OFF/ON-DBS). Body-segment coordination was modeled from acceleration-based intersegmental correlations across trunk, pelvis, and limbs. We tested whether coordination metrics predict individual postoperative FOG severity using LASSO regression with nested cross-validation, including preoperative demographics, clinical scores, gait and coordination metrics. Preoperatively, DOPA decreased trunk-pelvis-upper-limb coordination but increased crossed upper-lower-limbs coupling; while STN-DBS selectively increased inter-upper-limb coordination, with DOPA- and STN-DBS-induced changes being correlated. Whole-body coordination predicted individual postoperative FOG severity, with the most important couplings being the trunk-pelvis and pelvis-lower-limb. Body-segment coordination captures clinically relevant gait metrics in PD, highlighting coordination as a potential biomarker for patient stratification and treatment response. ### Competing Interest Statement M Romanato, AC Costa, A Jannou, A Zhou, S Cherif, M Yeche, C Wyart, and B Lau declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ML Welter received fees from Boston Scientific and Abbott for scientific meetings outside of this work. C Karachi received fees from Boston Scientific and Medtronic for scientific board and meetings, outside of this work. Boston Scientific (United States), N°ISRNMB0015 Fondation de France, N° 00121421 Richard Mille Foundation

Background Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) is a well-established treatment for motor fluctuations (MF) in Parkinson’s disease (PD), but its impact on non-motor fluctuations (NMF) remains unclear. As NMFs are frequent, disabling, and affect quality of life, understanding their response to DBS is critical. Objectives To assess the presence of NMF after STN-DBS, identify preoperative factors of improvement, and compare NMF responses to DBS and levodopa. Methods This project is an ancillary study of the French multicenter PREDISTIM cohort. We used the validated Non-Motor Fluctuation Severity Scale (NMF2S) to evaluate NMFs one year after STN-DBS and before surgery when data were available. Evaluations were performed under standardized conditions (OFF-Dopa/OFF-Stim vs. OFF-Dopa/ON-Stim). Results We included 284 PD patients assessed one year after STN-DBS using the NMF2S scale. Preoperative data were available for 153 patients. Evaluations were performed under standardized stimulation conditions (OFF-Dopa/OFF-Stim vs. OFF-Dopa/ON-Stim).STN-DBS led to a 41.1% reduction in NMF severity, with anxiety, concentration difficulties, and pain showing the most improvement. However, DBS effects were less pronounced than those of levodopa, especially for psychiatric symptoms. NMF improvement did not correlate with motor improvement. Among all preoperative variables, only the levodopa response in the cognitive domain was associated with post-DBS NMF benefit. Conclusions STN-DBS significantly improves NMFs, although to a lesser extent than levodopa. The dissociation between motor and non-motor responses underscores the need for specific markers to predict NMF outcomes. These findings support the integration of NMF assessment into DBS indications and patient selection.

Background:Levodopa equivalent dopaminergic dose (LEDD) reduction after subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease varies widely. Identifying predictors may guide patient selection and programming. Our objectives were to identify predictors of LEDD reduction and to test whether motor improvement mediates this association. Methods:Data from 144 patients treated by STN-DBS were analysed. Predictors of LEDD reduction were selected using the Boruta algorithm, a machine-learning method comparing variable importance to randomised features and then tested in a structural equation model for direct and motor-mediated effects. Results:Mean LEDD reduction was 41.7% (±38.2%) and motor improvement was 48.6% (±26.7%) at 1 year. Among the four predictors identified by Boruta, lower baseline LEDD (β=0.39, p=0.001), greater axial impairment (β=-0.25, p=0.003) and higher total volume of tissue activated (β=-0.17, p=0.031) were directly associated with lower LEDD reduction, independent of motor improvement. Sensorimotor STN overlap was not directly linked to LEDD reduction but was positively associated with motor improvement (β=0.34, p=0.001), which showed a trend-level effect on LEDD reduction (β=0.16, p=0.065). The total effect of sensorimotor STN overlap on LEDD reduction was not significant. Discussion:Dopaminergic dose reduction after STN-DBS is constrained by preoperative axial symptoms and stimulation spread, independently of motor improvement, while sensorimotor STN overlap improves motor symptoms but not dose reduction. Integrating motor phenotype with anatomical guidance may enhance medication management post DBS.

BACKGROUND:Pain is a frequent and heterogeneous non-motor symptom of Parkinson's disease (PD). Identifying its various underlying mechanisms remains challenging, while such mechanisms are likely to drive proper therapeutic management. Among the various PD-related pain subtypes, primary Parkinsonian pain (PPP) is particularly difficult to identify and differentiate from musculoskeletal pain, due to the absence of positive diagnostic criteria. OBJECTIVES:The aim is to develop and validate the "Primary Parkinsonian Pain Diagnostic Questionnaire" (3PDQ), a self-reported tool for identifying PPP in PD. METHODS:The 3PDQ was developed through literature review and expert consensus, and refined based on patient feedback. In this multicentric study, 227 PD patients with chronic pain were recruited from 11 French Parkinson's Expert Centers; 179 were analyzed after cases were excluded where two independent expert raters made discordant types of pain diagnoses. Psychometric validation followed COSMIN standards, assessing acceptability, internal consistency, reproducibility, and diagnostic accuracy versus expert diagnosis. RESULTS:PPP was diagnosed in 36.3% of patients, whereas musculoskeletal pain was the most frequent pain subtype (42.5%). The final 11-item 3PDQ showed good acceptability (96.5% computable data), satisfactory internal consistency (Kuder-Richardson = 0.71), and excellent test-retest reliability (Lin's concordance = 0.82). The questionnaire demonstrated good discrimination between PPP and musculoskeletal pain (AUC = 0.82), with sensitivity = 82%, specificity = 74%, and a negative predictive value = 82%. CONCLUSIONS:The 3PDQ is the first validated self-reported tool for diagnosing PPP in PD. It provides a reliable, clinically feasible tool to facilitate pain phenotyping and supports the development of mechanism-based treatment strategies. © 2026 International Parkinson and Movement Disorder Society.

BACKGROUND:As Parkinson's disease progresses, patients require second-line treatments such as subthalamic stimulation, the benefits of which may be diminished by the onset of non-dopaminergic axial motor and cognitive disorders. This study aimed to identify blood biomarkers of ferroptosis for predicting the progression of Parkinson's disease at the stage of L-DOPA-related complications. METHODS:We analyzed 598 blood samples from patients with PD enrolled in the French multicentric PREDISTIM study. Neurofilament light chain, 4-hydroxy-2-nonenal, glutathione peroxidase activity, ferritin, alpha-synuclein and selenium levels were determined by electrochemiluminescence, ELISA or inductively coupled plasma mass spectrometry. We assessed three single-nucleotide polymorphisms in ACSL4 and GPX4 genes, two key players in ferroptosis. Overall clinical outcomes were evaluated at baseline and one-year post-surgery. RESULTS:At baseline, UPDRS III-Worst OFF was positively correlated with log-4-HNE (p = 0.007). PDQ-39 was negatively correlated with log-ferritin concentration (p = 2.38*10-4), selenium concentration (p = 0.033) and the rs7887981 in the ACSL4 gene (p = 0.033). Milder cognitive problems were correlated with the rs139736475 in ACSL4 (p = 0.028). One-year post-surgery, change in UPDRS III-Worst OFF was inversely correlated with log-4-HNE levels (p = 0.002).This association remained significant after multivariate analysis and correction for multiple testing. CONCLUSIONS:Our results strongly support an association between 4-HNE levels and the progression of motor disability in advanced PD. They also provide multiple lines of evidence favoring a role for ferroptosis in PD progression. Subject to further validation, they could therefore be used to select and stratify patients for future clinical trials. TRIAL REGISTRATION:Cohort registered with ClinicalTrials.gov: NCT02360683, on January 2015.

BACKGROUND:Levodopa is the gold-standard therapy for motor symptoms in Parkinson's disease (PD). However, individual responses vary substantially among patients, and the biological mechanisms underlying this heterogeneity remain incompletely understood. OBJECTIVE:This study aimed to investigate the neural substrates associated with variability in levodopa responsiveness using multimodal magnetic resonance imaging (MRI). METHODS:Data were retrieved for this ancillary study from the PREDISTIM cohort, that aims to define predictors for deep brain stimulation outcomes. Patients were stratified through a data-driven clustering approach according to their dopa responsiveness and disease duration. MRI analyses included T1-weighted imaging and multi-echo fast gradient-echo sequences. Structural and iron-sensitive MRI measures were compared across clusters within key regions. RESULTS:A three-phenotype response pattern previously reported in the Parkinson's Progression Markers Initiative dataset was identified, extending beyond the conventional binary classification of good (C3) and poor responders (C1). An intermediate phenotype (C2) showed preserved pharmacological responsiveness despite longer disease duration. Structural MRI revealed significant putaminal atrophy in this cluster. In contrast, patients in cluster C1 exhibited reduced grey matter in the temporo-parietal operculum and inferior frontal cortex as well as an increased iron deposition in the substantia nigra and globus pallidus internus. CONCLUSION:These findings, that should be validated in other populations, suggest that variability in levodopa responsiveness reflects distinct neurobiological substrates rather than a simple continuum of disease severity. Integrating markers of structural degeneration and iron-related microenvironmental changes within basal ganglia-cortical circuits may improve phenotypic stratification and support the development of precision therapeutic strategies in PD.

INTRODUCTION:Patients with Parkinson's Disease (PD) vary markedly in terms of non-motor symptoms (NMS) as the disease progresses. To improve PD management and clinical-trial assessment, we aimed to determine NMS endotypes in a cohort of patients with advanced PD. METHODS:We conducted an ancillary cluster analysis of the 2013-2018 cohort (n = 722) of PREDISTIM. In this French multicenter interventional cohort, consecutive candidates for subthalamic deep brain stimulation undergo thorough assessment of motor symptoms (MS) and NMS at the inclusion visit. The NMS data are based on the MDS-UPDRS, Montreal Cognitive Assessment (MoCA), and several psychiatric scales: Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HAM-D), and Lille Apathy Rating Scale (LARS). Cluster analysis with 17 NMS was conducted to identify groups with homogenous NMS profiles. RESULTS:Three distinct NMS clusters were identified. The largest had mild MS. The smallest had moderate MS and the most severe NMS, including cognitive and psychiatric dysfunction. The middle-large group had moderate MS and NMS but was distinguished by having the worst sleeping problems. The clusters did not differ in onset age or patient age and may be underpinned by disparate patterns of anatomical brain damage. CONCLUSION:The mainly-motor (Cluster 1), mainly non-motor (Cluster 3), and intermediate (Cluster 2) NMS endophenotypes must be replicated in an independent cohort but may help stratify patients for management (pharmacological, deep-brain stimulation, and non-pharmacological treatments) and inclusion and assessment in clinical trials.

CONTEXT:After observing increased sudden death risk associated with domperidone use, the European Medicines Agency (EMA) imposed usage restrictions in 2014, limiting age (≤60 years), daily dose (≤30 mg/day), and duration (≤7 days). Nausea commonly occurs as an adverse effect of dopaminergic drugs in Parkinson's disease (PD) patients, with few alternative anti-emetic options. This study aimed to assess domperidone prescription patterns in French PD patients. METHODS:In this multicenter study, all consecutive PD patients from participating expert centers, hospitals, and private neurologists were included. We documented demographics, clinical data, comorbidities, domperidone use (indication, dose, and duration), and concurrent medications (related to PD or not). Domperidone misuse was assessed based on EMA guidelines. RESULTS:Between January and October 2021, 1579 patients from 16 centers (12 French PD expert centers, two general hospitals, and two private practice neurologists) were included. Among them, 109 (7%) received domperidone: 32 (29%) for nausea during apomorphine infusion, 71 (65%) for nausea during other dopaminergic therapies, and three (3%) for orthostatic hypotension. Domperidone misuse was found in 103 patients (95%): treatment duration >7 days (84%), age >60 years (79%), contraindicated drug interactions (6%), and contraindications due to cardiac comorbidity (5%). Only one patient exceeded the recommended dose (30 mg/day). CONCLUSION:Domperidone is still prescribed in France for PD patients with dopaminergic-induced nausea, mostly disregarding EMA guidelines due to patient age (>60 years) and prolonged treatment (>7 days). Our study underscores the unmet need for managing gastrointestinal symptoms in PD, highlighting the inadequacy of EMA guidelines in this population.

BACKGROUND:There are currently no consensus guidelines on how to progressively optimize treatment when initiating continuous subcutaneous apomorphine infusion (CSAI) in patients with Parkinson's disease (PwPD). AIMS:To provide practical guidelines on CSAI initiation in PwPD with motor fluctuations, with a focus on the target dose of apomorphine over time and subsequent adjustment of oral treatment according to the patient's characteristics. METHODS:A panel of French neurologists with extensive experience in treating patients with advanced Parkinson's disease used a modified Delphi approach to generate a knowledge synthesis on CSAI initiation according to patient characteristics. RESULTS:We identified five profiles based on patient characteristics. The target dose of apomorphine over time and the subsequent adjustment of oral therapy were highly dependent on these profiles. The CSAI flow rate varied from a maximum of 3 mg/h for older or more sensitive patients to 6-10 mg/h for younger patients experiencing early fluctuations. In most cases, the preferred approach was to reduce both levodopa and dopamine agonists when increasing CSAI. For optimum efficacy, the total target dose of levodopa equivalent (calculated as the sum of the oral dose and the apomorphine dose) should be greater than or equal to the pre-initiation dose after initiation of CSAI, regardless of patient characteristics. CONCLUSION:We provide patient-tailored recommendations with precise indications for the adjustment of apomorphine, oral therapy and levodopa equivalent dose over time during CSAI initiation, based on distinct patient profiles.

The recreational nitrous oxide (N2O) use is increasingly recognized as a cause of serious neurological disorders, particularly among young individuals. This retrospective multicenter study aimed to describe the clinical, biological, and electrophysiological features of 41 patients with neurological impairments linked to recreational N2O use. Most patients presented myeloneuropathy and motor-dominant, length-dependent, axonal neuropathy involving the lower limbs. Notably, two distinct electroclinical patterns emerged from nerve conduction studies and electromyography: a predominant sensorimotor axonal neuropathy (78.4% of cases) and a pure motor neuropathy (13.5%), both primarily involving the lower limbs. Despite normal serum B12 levels in most cases, elevated homocysteine and methylmalonic acid levels confirmed a functional vitamin B12 deficiency. These findings highlight the characteristic electrophysiological profiles associated with recreational N2O use and underscore the importance of early detection and targeted management to prevent long-term disability.

OBJECTIVE:Investigate the efficacy of immediate-release (IR) amantadine in reducing the risk of peak-dose dyskinesia in early Parkinson's disease (PD) as add-on to levodopa. BACKGROUND:While the use of amantadine to manage dyskinesia in PD is well supported by controlled clinical trials, data on its efficacy in patients without motor complications remain limited. METHODS:This 22-month, multicenter, randomized, placebo-controlled trial (NCT01538329) enrolled early PD patients on stable levodopa (≥150 mg/day for ≤1 year) without motor complications. The study included three double-blind phases: an 18-month treatment phase with adjunct amantadine-IR (200 mg/day) or placebo (Period 1), a 3-month delayed-start phase where all participants received amantadine-IR (Period 2), and a 1-month washout with placebo (Period 3). The primary outcome was dyskinesia incidence at month 18; secondary outcomes included dyskinesia rates at the end of Periods 2 and 3 to assess potential long-lasting mechanisms of the drug. Exploratory outcomes investigated the potential effects of amantadine-IR on motor and non-motor symptoms and quality of life. RESULTS:A total of 207 patients were randomized to amantadine-IR (N = 99) or placebo (N = 108). Significantly fewer patients in the amantadine-IR group developed dyskinesia versus placebo during Period 1 (11% vs. 22%, P = 0.025), while the mean daily dose of levodopa (95% CI) increased by 70 (21-119) mg less (P = 0.005). The proportion of patients with dyskinesia was less in the amantadine-IR group versus placebo at the end of Periods 2 and 3, but the difference was not statistically significant (12% vs. 20%, P = 0.13 and 16% vs. 22%, P = 0.23, respectively). Mild but significant positive effects on freezing of gait, fatigue, and quality of life were observed during Period 1. The safety profile of amantadine-IR was in line with previous reports. CONCLUSIONS:Adjunctive amantadine-IR in early PD halved dyskinesia incidence over 18 months. Long-lasting mechanisms could not be demonstrated and merit further investigation. Exploratory positive findings on the potential benefit of amantadine-IR on symptoms like freezing of gait and fatigue also call for further investigation. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background Parkinson's disease (PD) patients on dopaminergic drugs may experience non-motor fluctuations (NMFs) which are often heterogeneous and respond variably to treatments. Objective We evaluated if personality was associated to NMFs and could modulate the NMFs responsiveness to dopaminergic medication and deep brain stimulation of the sub-thalamic nucleus (STN-DBS). Methods From the PREDISTIM cohort, personality dimensions of 235 PD patients were assessed by the Temperament and Character Inventory (TCI) before STN-DBS (V0). NMFs were evaluated using the NMFs Severity Scale at V0 and one year after STN-DBS (V1). Linear regression models were performed between TCI dimensions and NMFs at V0; and logistic regression models were done between TCI dimensions and 1) groups of dopa-sensitive patients (responders to ON medication at V0) versus non-dopa-sensitive ones, and 2) responders versus non-responders to STN-DBS at V1. Odds ratios (OR) were also calculated. Results Significant associations were found between two TCI personality dimensions (“Harm Avoidance” and “Self-Directedness”) and severity of NMFs in OFF medication at V0: PD patients with higher Harm Avoidance and lower Self-Directedness scores having more NMFs. TCI personality dimensions were not associated with the dopa-sensitivity while Novelty Seeking was significantly associated with the STN-DBS-responder group for the psychiatric (OR = 1.09 [1.02–1.17]) and for the dysautonomic NMFs (OR = 1.11 [1.04–1.18]). Conclusions Certain personality dimensions (Harm Avoidance and Self-Directedness) are associated with NMFs severity at baseline, and PD patients with high Novelty Seeking seem to be better candidates for NMFs improvement after STN-DBS.

The impact of subthalamic deep-brain stimulation (STN-DBS) on motor asymmetry and its influence on both motor and non-motor outcomes remain unclear. The present study aims at assessing the role of STN-DBS on motor asymmetry and how its modulation translates into benefits in motor function, activities of daily living (ADLs) and quality of life (QoL). Postoperative motor asymmetry has been assessed on the multicentric, prospective Predictive Factors and Subthalamic Stimulation in Parkinson’s Disease cohort. Asymmetry was evaluated at both baseline (pre-DBS) and 1 year after STN-DBS. A patient was considered asymmetric when the right-to-left MDS-UPDRS part III difference was ≥ 5. In parallel, analyses have been carried out using the absolute right-to-left difference. The proportion of asymmetric patients at baseline was compared to that in the post-surgery evaluation across different medication/stimulation conditions. 537 PD patients have been included. The proportion of asymmetric patients was significantly reduced after both STN-DBS and medication administration (asymmetric patients: 50

To assess amantadine use and associated factors in the patients with Parkinson’s disease (PD). Immediate-release amantadine is approved for the treatment of PD and is largely used in clinical practice to treat “levodopa-induced dyskinesia (LIDs). Its use varies according to countries and PD stages. The prospective NS-Park cohort collects features of PD patients followed by 26 French PD Expert Centres. Variables used for the analyses included demographics, motor and non-motor PD symptoms and motor complications [motor fluctuations (MFs), LIDs)], antiparkinsonian pharmacological classes and levodopa equivalent daily dose (LEDD). We evaluated: (i) prevalence of amantadine use and compared clinical features of amantadine users vs. non-users (cross-sectional analysis); (ii) factors associated with amantadine initiation (longitudinal analysis); (iii) amantadine effect on LIDs, MFs, apathy, impulse control disorders and freezing of gait (Fog) (longitudinal analysis). Amantadine use prevalence was 12.6

BACKGROUND:Among the different types of pain related to Parkinson's disease (PD), parkinsonian central pain (PCP) is the most disabling. OBJECTIVES:We investigated the analgesic efficacy of two therapeutic strategies (opioid with oxycodone- prolonged-release (PR) and higher dose of levodopa/benserazide) compared with placebo in patients with PCP. METHODS:OXYDOPA was a randomized, double-blind, double-dummy, placebo-controlled, multicenter parallel-group trial run at 15 centers within the French NS-Park network. PD patients with PCP (≥30 on the Visual Analogue Scale [VAS]) were randomly assigned to receive oxycodone-PR (up to 40 mg/day), levodopa/benserazide (up to 200 mg/day) or matching placebo three times a day (tid) for 8 weeks at a stable dose, in add-on to their current dopaminergic therapy. The primary endpoint was the change in average pain intensity over the previous week rated on VAS from baseline to week-10 based on modified intention-to-treat analyses. RESULTS:Between May 2016 and August 2020, 66 patients were randomized to oxycodone-PR (n = 23), levodopa/benserazide (n = 20) or placebo (n = 23). The mean change in pain intensity was -17 ± 18.5 on oxycodone-PR, -8.3 ± 11.1 on levodopa/benserazide, and -14.3 ± 18.9 in the placebo groups. The absolute difference versus placebo was -1.54 (97.5% confidence interval [CI], -17.0 to 13.90; P = 0.8) on oxycodone-PR and +7.79 (97.5% CI, -4.99 to 20.58; P = 0.2) on levodopa/benserazide. Similar proportions of patients in each group experienced all-cause adverse events. Those leading to study discontinuation were most frequently observed with oxycodone-PR (39%) than levodopa/benserazide (5%) or placebo (15%). CONCLUSIONS:The present trial failed to demonstrate the superiority of oxycodone-PR or a higher dose of levodopa in patients with PCP, while oxycodone-PR was poorly tolerated. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.