An increasing number of studies indicate that ferroptosis, a lethal pathway initiated by excessive iron-dependent lipid peroxidation, and pivotal to the survival of dopaminergic neurons and the progression of Parkinson's disease (PD), may be regulated by the lysosomal pathway. Mutation and loss of function of the lysosomal enzyme, glucocerebrosidase, induce the accumulation of glycosphingolipids and alterations in lysosome activity, which have been associated with a higher risk of developing PD. Our present study showed that transient inhibition of glucocerebrosidase activity had a positive effect on lipid peroxidation and ferroptosis. In a dopaminergic cell line (LUHMES cells), it was shown that a 10-day inhibition of glucocerebrosidase activity using conduritol-beta-epoxide (CBE) specifically impeded susceptibility to RSL3-induced ferroptosis, but not to several other inducers of cell death. CBE impaired the lysosomal pathway, modified lipid membrane composition by reducing ether-linked phospholipids in phosphatidylethanolamines, and promoted an increase in glutathione peroxidase 4 (GPX4) protein levels. This phenomenon was transient and disappeared after 20 days of glucocerebrosidase inhibition, suggesting that the cells have the capacity to return to their basal homeostasis. Most of the current compounds acting on GPX4 promote its degradation, thus information on drugs leading to GPX4 stability is key in order to protect neurons against excessive lipid peroxidation occurring in neurodegenerative diseases.

Visceral fat gain and the progressive onset of metabolic disorders precipitate stroke risk and prompt the middle-aged population to cognitive decline. Preclinical research has recently focused on total apelin, a neuroprotective peptide whose cerebral action after release in plasma by adipose tissue remains elusive. The ratio between plasma apelin and lipids is suspected to influence prognosis in patients with cardiovascular diseases. This study challenged ratios of plasma apelin to cholesterol or glucose in reflecting post-stroke recovery of mature adult mice after a 6-month high-fat diet (HFD). Mice under HFD developed overweight (+10%, p < 0.001), hyperglycemia (21%, p < 0.001) and hypercholesterolemia (+68%, p < 0.001). Plasma apelin decreased with age in all mice (F2,360 = 35.94, p < 0.001), but a 30-min middle cerebral artery occlusion (MCAO) induced a 27% drop in plasma apelin (p < 0.01) in HFD-fed mice only, as well as a higher acute mortality (29%) than in normal diet (ND)-fed mice (19%). Ten days after MCAO, apelin levels normalized in HFD-fed mice, but were still decreasing in ND-fed mice (p < 0.01). However, high pre-stroke ratios revealed an upregulation of brain apelin receptor expression in these mice, that was lost in metabolically disturbed mice displaying lower ratios. This was functionally confirmed since mice with higher pre-stroke ratios displayed significantly better locomotor and cognitive performances, as validated by ROC analysis (AUC = 0.85). This study highlights pre-stroke ratios of plasma apelin to cholesterol or glucose as potential new biomarkers of post-stroke recovery.

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.

Objectif Évaluer si une perfusion nocturne d’apomorphine, un agoniste dopaminergique, peut moduler les caractéristiques des ondes lentes du sommeil lent chez des patients parkinsoniens insomniaques. Méthodes Étude ancillaire d’un essai randomisé, multicentrique, en double aveugle et en cross-over (apomorphine nocturne vs placebo). Trente-trois participants ont bénéficié de deux polysomnographies en fin de période de traitement. Les ondes lentes, définies par une amplitude ≥10μV, ont été analysées dans les stades N2 et N3 combinés, au niveau des régions frontale et centrale. Les paramètres étudiés étaient l’amplitude, la durée, la pente et la densité (nombre d’ondes lentes/heure). Les comparaisons ont été réalisées à l’aide de modèles linéaires mixtes (effets fixes : traitement, nuit, séquence ; effet aléatoire : sujet). Des corrélations cliniques ont été explorées avec le test de Spearman. Résultats Sous apomorphine, les ondes lentes présentaient des modifications significatives de leur morphologie, avec notamment une tendance à une pente plus faible, une durée plus longue et une densité réduite, en frontal comme en central. L’amplitude apparaissait globalement diminuée, avec des variations régionales. Par ailleurs, certaines caractéristiques des ondes lentes, en particulier leur durée, étaient associées à une sévérité accrue de l’insomnie et à une perception altérée de la qualité du sommeil. Conclusion Chez les patients parkinsoniens insomniaques, l’administration nocturne d’apomorphine influence la dynamique des ondes lentes. Ces résultats suggèrent un effet spécifique de la stimulation dopaminergique sur le sommeil lent. L’association entre la durée des ondes lentes, la sévérité de l’insomnie et la qualité perçue du sommeil souligne l’importance de poursuivre ces analyses pour mieux comprendre le lien entre perception du sommeil et caractéristiques polysomnographiques.

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.

Rhythmic auditory exposure modulates subsequent speech processing, yet its effect on speech production remains poorly understood. People with Parkinson's disease (PD) or spinocerebellar ataxia (SCA) suffer from dysarthria, for which there is no treatment. Using a rhythmic priming approach, we investigated whether brief rhythmic primes modulate speech production and facilitate it in people with PD and SCA considered here as clinical models of basal ganglia dysfunction and cerebellar dysfunction, respectively. Fifty-eight native French speakers (20 controls, 24 people with PD, 14 people with SCA) read sentences following a regular prime, an irregular prime, or silence. We measured accuracy and the temporal features of speech production including speech initiation time, speech rate, and rhythmic metrics. Bayesian mixed-effects models were used for the statistical analyses of these outputs. Accuracy showed no effect of rhythmic priming. Regular primes consistently shortened speech initiation time in all populations, but the benefit of regular primes was smaller in people with PD than in controls. In People with SCA, speech rate decreased after regular primes. The impact of rhythmic priming on rhythmic metrics was limited. Together, these results indicate that perception-to-production rhythmic priming mainly affects global, rather than fine-grained, timing control of speech during speech production. They also shed light on the implications of the basal ganglia and cerebellum in the modulation of speech by rhythm. They also provide insights for speech production models, which currently lack an explicit mechanism for external rhythmic inputs. Clinically, they help inform rhythm-based speech and language therapy methods.

Parkinson's disease (PD) involves progressive loss of dopaminergic neurons in the Substantia Nigra pars compacta, with regulated cell death (RCD) pathways - ferroptosis and apoptosis - contributing to neurodegeneration. Ferroptosis, an iron-dependent form of oxidative cell death, was evaluated here in human dopaminergic neurons exposed to urban industrial ultrafine particles (UFP) from Dunkirk. Differentiated LUHMES cells were treated with 2 or 10 μg/cm2 UFP for 24 h, for comparison, cells received 5 μM MPP+, a reference PD toxin. UFP exposure caused reductions in cytosolic GPx4 and the GSH/GSSG ratio, and increased oxidative damage and electrophilic stress (4-HNE); neither TfR nor DMT1 expression nor ferritin levels changed. Mechanistically, UFP activated p53, downregulating xCT and compromising GSH synthesis, thereby driving ferroptosis-like stress. By contrast, MPP+ induced more pronounced oxidative imbalance, elevated GSSG, and activated both intrinsic (BAX, caspase-9) and extrinsic (caspase-8) apoptotic cascades. These findings constitute the first evidence that environmentally relevant UFP concentrations trigger ferroptosis-like stress features in human dopaminergic neurons. They implicate chronic UFP inhalation as a potential modifiable risk factor in PD pathogenesis.

Parkinson's disease (PD) affects physical activity, and physical activity reduces the burden of PD. Although shown in studies using inertial measurement units (IMU), it remains unclear at which position physical activity change can best be detected in this population. Within the FAIRPARK-II trial, a subgroup of 25 newly diagnosed persons with PD (pwPD) not taking disease-specific medication yet documented their physical activity and, in parallel, wore IMUs on the most affected ankle, wrist and the lower back for two weeks. Participant-reported physical activity was transformed into Metabolic Equivalents of Tasks (METs) in 15-minute intervals using The Compendium of Physical Activities; Euclidean Norm Minus One (ENMO) values were calculated and averaged over the same intervals for the IMU data. Data of at least 3 days with at least four simultaneous 15-minute epochs of both valid IMU and diary data within the time window (9.00 to 18.00) per participant was included, resulting in a total of 8,494 15-minute epochs used for this analysis. Root mean square error (RMSE) values were calculated between scaled normalized IMU-derived ENMO and normalized MET values for each of the nine IMU-MET combinations (three IMU positions × three MET intensity levels). The wrist and lower back IMU showed comparable RMSE values across all MET intensity levels, with both IMU positions showing lower RMSE values than the ankle position. Tremor affected RMSE negatively, whereby the lower back position may be slightly favorable for the assessment of physical activity in those with tremor. This prospective longitudinal dataset from a very rare cohort provides novel insights into the assessment of physical activity during the earliest clinically evident phase of Parkinson's disease without disease-specific medication, which may inform future clinical trials and observational studies.

BACKGROUND:Magnetic resonance imaging (MRI) relaxometry using R 2 * measurement is a promising non-invasive marker of brain iron-related changes in Parkinson's disease (PD). Although longitudinal susceptibility MRI studies have demonstrated progression over time, the stage-dependent dynamics of R 2 * changes across the full spectrum of PD duration remain incompletely characterized. OBJECTIVES:The goal was to assess 1-year longitudinal R 2 * changes across PD stages within a multicenter framework, compared with healthy controls (HC). METHODS:In this prospective multicenter study, 95 PD patients and 65 age- and sex-matched HC underwent 3 T MRI and clinical evaluation at baseline and 1 year. PD patients were stratified by disease duration (<5, 5-10, 10-15, >15 years). R 2 * values were extracted from basal ganglia regions, focusing primarily on the substantia nigra (SN). Motor and non-motor assessments, performed in the on-medication state, included the Movement Disorder Society-Unified Parkinson's Disease Rating Scale, Montreal Cognitive Assessment, and mood/apathy scales. RESULTS:SN R 2 * increased significantly over 1 year across PD patients (+5% within-group) and HC (+2% within-group), resulting in a +3% greater longitudinal change in PD versus HC (P < 0.001). Larger SN R 2 * changes were observed in patients with longer disease duration (r = 0.28; P = 0.006). Significant R 2 * changes were also detected in other basal ganglia regions. No significant change in motor or non-motor disability in the on-medication state was observed over 1 year. CONCLUSIONS:SN R 2 * increased over 1 year in PD across disease stages, with larger changes in more advanced patients and no evidence of an early plateau. These findings support the potential of R 2 * as a sensitive imaging marker of PD progression over short intervals. © 2026 International Parkinson and Movement Disorder Society.

Platelet-derived biotherapies are emerging as innovative approaches for complex neurological disorders requiring multimodal interventions. Platelet-derived products, including lysates, platelet concentrate supernatants, secretome, extracellular vesicles, and fractionated components, represent a scalable and clinically accessible biotechnology platform for precision neuromedicine. Platelets provide a reservoir of trophic factors, cytokines, chemokines, lipids, antioxidants, and noncoding RNAs with demonstrated neuroprotective, anti-inflammatory, and antiferroptotic effects in models of neurodegeneration, trauma, and aging. Preclinical and patient-derived omics and neuroimaging data can help characterize mechanisms of action, identify biomarkers, and refine platelet secretome preparations toward indication-specific formulations. Combined with virus inactivation and purification technologies adapted from plasma protein manufacturing, these advances position platelet-derived biotherapies as a rational and versatile path toward future acellular therapeutics for brain disorders.

La maladie de Parkinson (MP) est une maladie neurodégénérative et neuropsychiatrique progressive complexe, qui associe de très nombreux signes moteurs et non moteurs. L’évolution de la maladie peut être décomposée en plusieurs étapes : 1) la phase prodromale (évoluant parfois 10 à 15 ans avant le diagnostic), 2) la phase précoce, 3) la phase avancée. Lors de la phase avancée, trois grandes complications sont à anticiper : 1) les complications motrices liées à la L-dopa (pouvant survenir dans 50% des cas après 5 ans d’évolution), 2) les signes dits axiaux sévères (troubles de la marche, de l’équilibre, de la parole, de la déglutition) et 3) les troubles cognitifs sévères. La prévalence de la MP devrait doubler dans les 25 prochaines années. A l’heure actuelle, il n’existe pas de traitements susceptibles de ralentir sa progression. Toutefois, il existe de nombreuses stratégies thérapeutiques symptomatiques pharmacologiques et non pharmacologiques, allant de la dopathérapie substitutive orale, à des dispositifs de stimulation dopaminergique continue (type traitements dopaminergiques par dispositifs externes ou stimulation cérébrale profonde). La maladie de Parkinson demande un accompagnement multidisciplinaire et personnalisé, dans un parcours de soin impliquant le médecin généraliste, le pharmacien, le neurologue, les infirmières, les kinésithérapeutes, les orthophonistes et d’autres professionnels paramédicaux, qui par la précocité de leur intervention, peuvent limiter la perte d’autonomie et les hospitalisations futiles et dangereuses. Nous reprenons dans cet article les grands principes de la prise en charge pour que le patient et chaque acteur du parcours de santé puisse intervenir précocement pour maximiser la qualité de vie et favoriser l’autonomie des malades.

Plain language summary Continuous intracerebroventricular administration of anaerobic dopamine represents a potential new device-aided therapy option for Parkinson's disease with L-dopa-related complications. A-dopamine is administered via a telemetry-controlled subcutaneous abdominal pump connected to a catheter implanted in the ventricle, near the striatum. We present the case of one patient with A-dopamine as monotherapy. Continuous intracerebroventricular administration of anaerobic dopamine (A-dopamine) represents a potential new device-aided therapy option for Parkinson's disease in the stage of severe L-dopa-related complications. A-dopamine is administered via a telemetry-controlled subcutaneous abdominal pump connected to a catheter implanted in the ventricle, near the striatum. We previously demonstrated its value as an add-on therapy in a Phase I/II trial, which showed a 4.4-hour increase in the duration of perfect control without “off” episodes or dyskinesia, and a 6.2-hour increase in the duration of good autonomy, compared to the best oral treatment with a 60% reduction in oral L-dopa. We present here the case of one such patient who benefited from long-term administration of A-dopamine as monotherapy, as the sole treatment. A dose of 240 mg of A-dopamine during the day and 40 mg at night allowed for complete control of motor symptoms without any dyskinesia, painful dystonia, fluctuations, or mental agitation, and without any oral medication. Monotherapy with A-dopamine produced greater benefits than those of adjunctive therapy added to optimized oral treatment. It is interesting to note that A-dopamine and L-dopa had a different clinical effect, since no dyskinesia or psychic excitation was observed with A-dopamine, unlike with L-dopa.

Parkinson's disease (PD) is preceded by a prolonged prodromal phase during which subtle cognitive and behavioral alterations emerge before overt motor symptoms. Experimental models reproducing these early stages are essential for understanding disease mechanisms and identifying early biomarkers. In this study, we performed the multimodal characterization of two toxin-based rat models of prodromal PD induced by bilateral nigral injections of 6-hydroxydopamine or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Animals were assessed over 2 months using behavioral testing, functional magnetic resonance imaging (fMRI), and histologic analyses. Both models produced moderate, heterogeneous dopaminergic degeneration within the nigrostriatal pathway, consistent with prodromal stages. Motor impairments remained limited whereas robust attentional deficits were detected. fMRI revealed region-specific connectivity alterations aligned with behavioral impairments, suggesting early circuit-level dysfunction despite the absence of widespread network disruption. To address inter-individual variability, a clinically inspired staging framework was implemented based on dopaminergic lesion severity, attentional performance, and sensorimotor impairment. This phenotype-based classification stratified animals into sham, asymptomatic, early, and advanced stages independent of the toxin used. Together, these findings demonstrate that moderate bilateral dopaminergic degeneration produces early cognitive and circuit-level alterations, and highlight the value of multimodal phenotyping for studying prodromal PD and identifying early functional biomarkers.

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.

Ferroptosis, an iron-dependent form of regulated necrosis, is implicated in the pathogenesis of Parkinson's disease (PD). We studied the influence of energy stress on ferroptosis in differentiated dopaminergic neurons (LUHMES). Glucose deprivation conferred protection against ferroptosis induced by erastin or arachidonic acid plus iron by reducing lipid peroxidation. Glucose withdrawal did not protect against RSL3-induced ferroptosis, suggesting that direct GPX4 inhibition cannot be reversed by metabolic modulation. The expression of ferroptosis markers ACSL4, GPX4, xCT, and TFRc remained unaltered during glucose deprivation. Inhibition of glycolysis using 2-deoxyglucose confirmed the role of energy stress in the regulation of ferroptosis. Activation of AMP-activated protein kinase (AMPK) by AICAR protected LUHMES cells from erastin-induced ferroptosis, even in the presence of glucose. Conversely, AMPK expression inhibition by siRNA re-sensitized cells to ferroptosis under glucose-free conditions. These findings suggest that glucose metabolism and AMPK-mediated energetic stress play crucial roles in regulating ferroptosis in dopaminergic neurons, with potential implications for understanding the mechanisms of neurodegeneration in PD. These findings identify a potential bioenergetic checkpoint regulating ferroptosis susceptibility under conditions of severe energy stress.

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.