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.

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.

Adaptive deep brain stimulation (aDBS) represents an important evolution in the treatment of Parkinson's disease (PD), building on conventional DBS (cDBS) by adjusting stimulation in response to real-time physiological signals. By enabling dynamic targeting of disease-related neural activity, aDBS offers the potential for more precise modulation of motor symptoms. Additional anticipated advantages include reduced stimulation-related side effects and improved energy efficiency, supporting long-term device performance. Although clinical uptake is still at an early stage, growing experience has highlighted both opportunities and areas requiring further refinement. Key challenges include inter-individual variability in biomarker expression, diversity in programming approaches, and ongoing debate regarding optimal thresholds and response latencies. The clinical significance of short-term local field potential (LFP) recordings continues to be actively investigated, particularly in the context of signal artifacts, physiological variability, and current hardware limitations. Beyond technical considerations, factors such as patient selection, ethical frameworks, and cost-effectiveness remain important determinants of broader implementation. Continued progress will depend on the development of robust and flexible control strategies that incorporate multimodal biomarkers, including wearable-derived motor metrics and patient-reported outcomes, to support personalized therapy. With an expanding evidence base and recent regulatory approvals, aDBS is increasingly transitioning from an experimental concept to a viable clinical tool. Future efforts should prioritize the translation of research paradigms into scalable clinical workflows that effectively balance automation with individualized patient care. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of 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.

Background Functional neurological disorders (FND) represent a significant public health challenge due to their prevalence and impact on quality of life. Functional movement disorders (FMD) and functional gait disorders (FGD) represent a large part of the broad phenotype spectrum of FND. Objective This study aimed to describe the clinical profiles and associated characteristics of FMD and FGD, with particular attention to age-related symptoms. Methods A retrospective review of medical records with standardized collection of data of FND and FMD patients from three Neurological Referral Centers was conducted from 2016 to 2024. Data collected included demographic information and clinical outcomes. Results Sixty-eight patients were included with a female predominance (75.53 %). Thirty-seven had FMD (mean age 47.19 ± 18.66 years), 14 had FGD (63.0 ± 11.50), and 17 had both (49.53 ± 20.90 years). FGD were more frequent in older patients compared with FMD patients (p = 0.0046) and with patients with the mixed phenotype (p = 0.043). Tremors were the most common FMD subtype (70.3 %), while astasia-abasia was the predominant FGD phenotype (57.1 %). Fifty-three percent of patients were lost to follow-up, 20.6 % improved, and 26.5 % remained stable. Lack of physical and psychological rehabilitation was predominant in lost-to-follow-up subjects. Conclusion FND age of onset was significantly associated with phenotype, with older patients being more affected by FGD. This association may be partially influenced by societal perceptions of aging and mobility.

Beta bursts are increasingly being studied as biomarkers of Parkinson's disease (PD) symptoms and therapeutic response. While most prior work has focused on time-frequency burst features such as duration or amplitude, recent evidence suggests that the temporal waveform of individual bursts carries additional functional significance. Here, we investigated whether distinct beta burst waveform motifs in the subthalamic nucleus (STN) and sensorimotor cortex are modulated by levodopa and whether these modulations relate to cortico-subcortical connectivity and clinical improvement. We analyzed resting-state activity from 11 PD patients recorded from deep contacts in the STN and EEG electrodes over the motor cortex, both before and after levodopa administration. Using a novel adaptive burst detection algorithm, we extracted individual beta bursts and characterized their waveform variability using principal component analysis. While levodopa had inconsistent effects on conventional time-frequency burst features, it selectively modulated the rate of specific burst waveform motifs in the sensorimotor cortex, consistently across patients. Furthermore, we found that levodopa increased functional connectivity between the STN and cortex specifically during bursts with certain waveform motifs, and these connectivity changes predicted individual clinical improvement. Our findings suggest that beta bursts are not uniform events but comprise a set of functionally distinct motifs whose rates and network involvement are modulated by dopaminergic therapy. This waveform-based approach refines our understanding of pathological beta activity in PD and offers novel targets for personalized, adaptive neuromodulation strategies. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by Agence Nationale de la Recherche (ANR-18-CE37-0018) SENCE and Ecole Centrale Méditerranée. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of Comité de Protection des Personnes (CPP) Sud Méditerranée I gave ethical approval for this work. The registration number is RCB: 2009-A00913-54. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Due to the sensitive clinical nature of the data, it cannot be made publicly available. The code used in this study is available at:https://github.com/danclab/beta\_bursts\_ldopa

Parkinson's disease (PD) is a neurodegenerative disease characterized by severe motor symptoms, transiently alleviated by medication (e.g. levodopa), and widespread brain activity alterations that remain poorly understood at a large scale level. To address this issue, we used resting-state STN-DBS and motor EEG data from 11 PD patients before and after levodopa treatment. Neuronal avalanches, i.e., brief, widespread bursts of activities, were detected and compared across the two conditions. Interestingly, we noted shorter and smaller avalanches in the OFF-condition and fewer, longer, and larger avalanches in the ON-condition. We then computed the avalanche transition matrices to track the contact-wise patterns of avalanche spread. We found a significantly higher probability of avalanche spread within and between the STN and motor cortex in the ON-condition. Furthermore, increased propagation of avalanches correlated with clinical improvement. Our study identifies potential biomarkers for electrophysiological changes in PD through cross-modality assessment of aperiodic activities.

OBJECTIVE:The objective of this study was to characterize changes in candidate biomarkers in early multiple system atrophy (MSA) and identify baseline predictors of faster progression. METHODS:This 1-year, multicenter, prospective study assessed clinical, neuroimaging (3T-magnetic resonance imaging [MRI], dopamine transporter single-photon emission computed tomography [DaT-SPECT]), and neurofilament light chain (NfL) changes in patients with early MSA (< 5 years from symptom onset) and healthy controls (HCs). Clinical and biomarker changes from baseline to 6 months (M6) and 12 months (M12) were analyzed. Survival status was collected at 24 months. Mixed linear regression analyzed repeated measures, whereas univariate regression identified biomarkers linked to progression. Sample size simulations were conducted for future trials. RESULTS:Forty-one patients with MSA and 20 HCs were included in this study. The Unified Multiple System Atrophy Rating Scale (UMSARS)-I + II scores worsened (mean percent change from baseline was 19.8% at M6; 95% confidence interval [CI] = 13.3 to 26.4% and 31.1% 95% CI = 24.9 to 37.2% at M12). Patients with MSA showed increased cerebellar white matter and pons atrophy (M6 = -5.9 to -2.8% and M12 = -9 to -4.9%) and decreased striatal specific binding ratio (SBR; M6 = -15.8 to -7.9% and M12 = -24 to -10.4%). Patients with multiple system atrophy parkinsonian (MSA-P) exhibited greater striatal SBR reduction, whereas patients with multiple system atrophy cerebellar (MSA-C) had greater cerebellar and pons atrophy, evident at M6. Baseline brainstem and pons volume predicted clinical worsening at M6, whereas SBR predicted worsening at M12. Higher plasma NfL levels correlated with early dropout (14% at M12), worse UMSARS scores, lower SBR, and increased mortality risk within 24 months. INTERPRETATION:Neuroimaging changes occur within 6 months in early MSA. High plasma NfL levels are linked to increased mortality and dropout risk. Longitudinal biomarker assessments provide valuable insights into disease progression. ANN NEUROL 2026;99:96-113.

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.

This study investigates the influence of the pharmacological nigrostriatal dopaminergic stimulation on the entire brain by analyzing EEG and deep electrodes, placed near the subthalamic nuclei, from 10 Parkinsonian patients before (OFF) and after (ON) L-Dopa administration. We characterize large-scale brain dynamics as the spatio-temporal spreading of aperiodic bursts. We then simulate the effects of L-Dopa utilizing a novel neural-mass model that includes the local dopamine concentration. Whole-brain dynamics are simulated for different dopaminergic tones, generating predictions for the expected dynamics, to be compared with empirical EEG and deep electrode data. To this end, we invert the model and infer the most likely dopaminergic tone from empirical data, correctly identifying a higher Dopaminergic tone in the ON-state, and a lower dopaminergic tone in the OFF-state, for each patient. In conclusion, we successfully infer the dopaminergic tone by integrating anatomical and functional knowledge into physiological predictions, using solid ground truth to validate our findings.

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