Following an initial phase characterized by a good response to dopaminergic therapies, Parkinson's disease progresses toward a stage marked by motor complications-notably motor fluctuations and dyskinesias. When the optimization of oral therapy proves insufficient, the use of second-line treatments must be considered. These strategies are based on three main approaches: deep brain stimulation, continuous subcutaneous infusions (apomorphine, foslevodopa-foscarbidopa), and intra-intestinal levodopa infusions. The indication for these therapies depends on a multidisciplinary assessment that considers dopa-responsiveness, motor and cognitive status, comorbidities, and the patient's lifestyle. At least 5 doses of L-dopa, 2 hours of OFF and 1 hour of disabling dyskinesias every day constitute a simple tool to identify eligible patients in routine practice. Therapeutic choices must be individualized, balancing efficacy, tolerability, and practical constraints. General practitioners play an essential role in identifying complications, monitoring treatment, and coordinating care. Early collaborative management can significantly improve patients' quality of life.

The management of cognitive disorders associated with Parkinson's disease (PD) requires early diagnosis. Due to its advantages, including accessibility and millisecond temporal resolution, electroencephalography (EEG), has been widely investigated. However, it has so far have only enabled the detection of mild to severe stage of cognitive impairment. In this study, we explored EEG microstates analysis as a method for detecting early-stage cognitive impairment. Three groups of PD patients were included: those with normal cognition (NC), patients with slight mental slowing (Pre_MCI), and patients with mild cognitive impairment (MCI). All underwent high-density, eyes-closed, resting-state EEG recordings. Microstates parameters were derived from the signal and compared across groups. A four-states configuration (labelled A, B, C and D) was identified in all patients, explaining 82% of signal variability. The duration and time coverage of microstate A were significant greater in both the Pre_MCI and the MCI groups compared to the cognitively intact group. Moreover, time coverage of microstate D was higher in the Pre-MCI group than in the MCI group. To date, EEG microstates analysis has mainly been used to explore underlying physiological mechanisms. Our findings show that it may also yield measurable indicators suitable as biomarkers, with potential clinical applicability. The next step is to validate this approach in PD patients with subjective cognitive decline who do not yet present objective deficits in comprehensive neuropsychological assessment.

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.

INTRODUCTION:Peripheral demyelinating neuropathies impair gait and increase fall risk, particularly under cognitively demanding conditions. While gait disturbances in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and Charcot-Marie-Tooth disease type 1A (CMT1A) are well documented, their differential responses to cognitive dual-tasking remain poorly understood. METHODS:In this prospective study, 62 patients (31 CIDP, 31 CMT1A) performed 10-m barefoot walking trials under three conditions: natural walking, low dual-task (answering factual questions), and high dual-task (introspective questions about illness impact). Gait parameters, including speed, stride length, stride time, foot and heel clearance, were measured using a motion capture system. Group, condition, and interaction effects were analyzed using linear mixed-effects models. RESULTS:Both groups showed significant reductions in gait speed and stride length under dual-task conditions. Compared to CMT1A, CIDP patients exhibited more pronounced slowing and increased stride time, especially during high dual-tasking. Heel clearance decreased significantly in CIDP, with a group × condition interaction, while CMT1A patients maintained more stable gait patterns. Foot clearance at peak swing declined in both groups without intergroup differences. DISCUSSION:These results suggest that CIDP patients adopt a more cautious gait under cognitive load, reflecting reduced automatism and adaptability. In contrast, CMT1A patients appear to benefit from long-term compensatory strategies developed over the disease course. Moreover, the CIDP patients decreased their heel clearance during dual-task, increasing the fall risk. CONCLUSION:Dual-task gait analysis reveals distinct adaptations in hereditary and acquired neuropathies. Parameters such as heel clearance and stride time may serve as functional markers to guide diagnosis and rehabilitation.

BACKGROUND:Theory of Mind (ToM) Refers to the ability to infer other people's thoughts (Cognitive ToM) and emotions (Affective ToM). Myotonic Dystrophy Type 1 (DM1) Patients Showed an impairment of ToM capacities, but the underlying neural mechanisms remain poorly understood. METHODS:We included 58 adult non-congenital DM1 patients from the DMVASCOG cohort, who underwent a ToM evaluation using the Movie for the Assessment of Social Cognition and a brain MRI. Association of ToM scores with cortical thickness and gyrification was assessed using FreeSurfer software, and associations with white matter hyperintensities were assessed using SVR-LSM. Finally, we included all the significantly associated parameters in a multivariate model. RESULTS:The ToM total score and cognitive subscore were both associated with the local gyrification in the right superior parietal gyrus and with the hyperintensities in the bilateral temporopolar white matter. The ToM total score was also associated with hyperintensities in the bilateral temporo-parietal and left frontal white matter. Multivariate models based on these parameters allowed a better prediction of the ToM total score (R2 = 0.49) and cognitive subscore (R2 = 0.52) than univariate models. There was no association between ToM measures and cortical thickness, nor between brain MRI measures and affective subscore/error types. CONCLUSIONS:The ToM cognitive involvement in DM1 is associated with both the gyrification in the right superior parietal gyrus and the volume of hyperintensities in the anterior-temporal white matter, suggesting the possible joint implication of a neurodevelopmental phenomenon and disconnections arising from white matter changes.

BACKGROUND:Levodopa, dopamine agonists (DA) and monoamine oxidase inhibitors (MAOI) are all approved first-line therapies for Parkinson's disease (PD), as monotherapy or in combination. Data on their use in the early management of patients with PD in real-life are lacking. Our objective was to assess the impact of early therapeutic strategies on the development of motor and neuropsychiatric complications using a nationwide PD cohort. METHODS:NS-PARK is a cohort of patients with PD recruited between 2011 and 2021 from 26 expert centres for PD in France. We analysed the patients with less than 5-years disease duration and no motor complications at inclusion. We used interval censoring survival models to assess the associations between therapeutic strategies (levodopa monotherapy, levodopa alternative therapies or levodopa combinations) and motor fluctuations, dyskinesia, impulse control and related behaviours (ICRBs), apathy, psychosis/hallucination and daytime sleepiness. Analyses were adjusted for sex, age, disease duration, dopaminergic dose and disease severity. RESULTS:We included 1722 patients (38.4% female, median age 67.7 years). At inclusion, 41% received levodopa monotherapy, 31% received levodopa alternative therapies and 28% received levodopa combinations. Compared with levodopa monotherapy, levodopa alternative therapies were associated with a lower dyskinesia risk (hazard ratio (HR) 0.48, 95% confidence interval (CI)[0.28-0.84]), but there was no significant difference in motor fluctuations. Both levodopa alternative and combinations therapies increased ICRBs risk (HR 4.06, 95% CI [2.48-6.67]; HR 5.16, 95% CI [3.00-8.86]) and decreased apathy risk (HR 0.36, 95% CI [0.26-0.49]; HR 0.52, 95% CI [0.39-0.69]). No association was found with psychosis/hallucination or daytime sleepiness. CONCLUSIONS:In this real-life cohort, our data supported an association between levodopa alternative therapies and a lower risk of dyskinesia and apathy, but a higher risk of ICRBs compared with levodopa monotherapy. CLINICALTRIALS: GOV IDENTIFIER:NCT04888364. Registered June 2021.

BACKGROUND:Speech impairment is a recognized but unpredictable adverse effect of sub-thalamic nucleus deep brain stimulation (STN-DBS) for Parkinson's disease (PD). OBJECTIVES:To evaluate the prevalence of speech impairment 1 year after STN-DBS in PD patients and to determine the predictive factors for speech outcome following STN-DBS. METHODS:Data for 417 patients from the French national PREDISTIM study were collected preoperatively. The combined effect of medical treatment and surgery on speech was compared using specific items from dedicated clinical scales (MDS-UPDRS III.1: primary endpoint) and patient self-assessment questionnaires (items 34 and 35 of the PDQ39: secondary endpoints). For each variable, three patient groups were generated according to speech outcome at 1 year: worsening, stability, and improvement. In the second step analysis, the three groups were compared for demographic and clinical variables at baseline and STN-DBS parameters. RESULTS:There was a significant deterioration in speech of all considered items 1 year after combined STN-DBS and dopaminergic treatment. Four predictive factors for speech deterioration were detected: (i) the absence of preoperative speech impairment (p < 0.001); (ii) severity of motor activity of daily living (MDS-UPDRS II off total score) (p = 0.037); (iii) high-intensity stimulation of the left electrode (i.e., above 3.6 V) (p = 0.046); and (iv) the absence of any change in non-motor experiences of daily life (MDS-UPDRS I total score) (p = 0.048). CONCLUSIONS:Speech outcome should be carefully monitored after STN-DBS, especially in PD patients without preoperative speech impairment, with motor difficulties in daily-living activities, and with increased left electrode intensity. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT02360683.

The present study aimed to provide an overview of the experiences of couples coping with Parkinson's disease (PD), along with a synthesis of the mechanisms involved in changes within the couple's relationship in the context of PD. These mechanisms were identified using a qualitative approach: dyadic Interpretative Phenomenological Analysis. Forty-five couples separated in three groups according to disease progression, participated. Interviews were conducted separately with each partner. After individual analysis, the salient individual and dyadic phenomena were identified at the group level. Three mechanisms emerged regardless of disease stage: having divergent views on PD, being united and cohesive, avoiding discussing the disease. Other mechanisms were more specific to some stages. Even with few consequences on independence, PD can significantly impact the couple's dynamics. In most cases, strategies for adjusting to PD and/or the changes it causes in the couple's relationship lead to tension and negative emotions. Better support for both partners is needed to promote better adjustment strategies from the early stage of PD.

There is a distinct lack of consensus on the most effective treatments for neurodegeneration with brain iron accumulation. This is due to the rarity of the disease, its phenotypic variability, and the multiplicity of pathophysiological mechanisms. Our team has already proposed the use of conservative iron chelation in cases of neuroferritinopathy, with interesting results. However, no mention has yet been made of the treatment of parkinsonism-dystonia related to VAC14 gene mutations. The case reported here illustrates clinical stability after 2 years of conservative iron chelation, with an improvement in radiological images.

BACKGROUND:Postural abnormalities (PA) and motor complications (MCs, including motor fluctuations - MFs- and levodopa-induced dyskinesia - LIDs) are hallmark of Parkinson's disease (PD) progression, yet their relationship remains poorly understood. OBJECTIVE:To investigate the association between PA and MCs, motor symptoms, and non-motor symptoms (NMS) in patients with PD, and to assess whether PA influences the development of MCs over time. METHODS:Data of the prospective NS-Park cohort (27 French PD Expert Centers) were analysed. PA was defined by a score ≥2 on item 3.13 of the MDS-UPDRS-III. Associations between PA and MCs, as well as with other motor symptoms and NMS, were assessed using logistic regression models. We used interval censoring survival models to assess the associations between PA at inclusion and the incidence of MCs. Analyses were adjusted for sex, age, disease duration, dopaminergic dose, and disease severity. RESULTS:Among 13,037 included PD patients (58.7 % male, median age at diagnosis 61 years), 724 (5.6 %) presented with PA. Patients with PA had longer disease duration, higher disease severity, and higher dopaminergic treatment. PA exhibited a higher prevalence of troublesome MFs (OR: 5.96; 95 % CI: 4.25-8.32) and LIDs (OR: 2.81; 95 % CI: 1.79-4.30), while associations with milder MCs were inconsistent. However, PA was not significantly associated with the development of MCs during follow-up. CONCLUSIONS:PA are associated with more frequent severe MCs, and a higher burden of motor and NMS, making patient care particularly challenging.

Background In pediatric age, the PRKN mutation is reported as one of the most common genetic causes of Parkinson's disease. However, detailed clinical data on PRKN patients with pediatric onset are scarce. Objective To describe clinical characteristics, disease progression, and management of PRKN patients with pediatric onset. Methods PRKN patients with onset of clinical signs before the age of 18 years were included in this retrospective multicenter study. Collected data included detailed clinical characteristics, progression, and disease management. Data presentation is descriptive due to the sample size. Results Nine patients (five females) were included from five French movement disorders centers. The mean age at symptom onset was 10.78 ± 2.22 years (median, 11; range, 7–14). Dystonia was the first most common motor symptom (six patients). The mean time from symptom onset to genetic diagnosis was 13.33 ± 9.21 years (median, 11; range, 3–32). The most commonly reported non-motor symptoms were sleep disorders (seven patients), anxiety (six patients), and depression (five patients). The first treatment was L-dopa in four patients, dopamine agonist in two, carbamazepine in two, and rasagiline in one. Dyskinesia and impulse control disorders were the most common treatment-related side effects (nine and six patients, respectively). Four patients underwent deep brain stimulation surgery. The last available follow-up was at 27.22 ± 14.05 years (median, 28; range, 6–56) after the diagnosis. Conclusions This is the first study reporting detailed clinical features and long-term management of PRKN patients with pediatric onset. Prompt diagnosis and appropriate treatment strategies are important to optimize disease management.

Background High-grade diffuse gliomas in adults are common malignant primary tumors of the central nervous system. The association with Lynch syndrome (LS) is documented but remains under-researched. However, there are implications for prevention, genetic counseling, and therapeutic approaches. The objective of this study is to conduct a descriptive cohort of patients with high-grade glial tumors in the context of LS.Methods We included adult patients with glioblastoma (GBM) or grade 4 astrocytoma (WHO 2021 classification) associated with LS, diagnosed at Lille University Hospital or Valenciennes Hospital between 2014 and 2022. We retrospectively collected clinical, radiological, histopathological, molecular, and therapeutic data.Results We included 6 GBM cases with a median age of 58.7 years (IQR 32.4-63.3). Five cases had MSH2 mutations, and one had PMS2 mutation. In one case, MMR protein expression was preserved, and the RER phenotype showed low microsatellite instability. Loss of ATRX expression, overexpression of p53, and giant cells were observed in 50%, 83%, and 66% of cases, respectively. TP53 mutations were found in all cases, and PTEN mutations in 4 cases. Immunotherapy was given to two cases. The 24-month overall survival rate was 50%.Conclusions GBMs associated with LS exhibit specific histopathological and molecular biology characteristics that may guide syndrome-related research. These tumors could represent a particular subclassification, potentially leading to specific therapies such as immunotherapy. We propose with a review of case in the literature an algorithm for investigating LS upon discovering a GBM. These exploratory results need to be confirmed by a larger cohort.

INTRODUCTION:Demyelinating neuropathies, such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and Charcot-Marie-Tooth type 1A (CMT1A), significantly impair postural control. While both conditions affect sensory integration, differences in compensatory mechanisms remain poorly understood. This study aimed to explore how visual, proprioceptive, and cognitive perturbations influence postural stability in CIDP and CMT1A patients. METHODS:A single-center, prospective study was conducted with 25 CIDP and 24 CMT1A patients. Posturographic recordings were used to assess postural stability under standard conditions and during visual tracking, proprioceptive perturbation (Achilles tendon vibration), and cognitive dual-tasking (DT) (backward counting). Center of pressure parameters, including area, velocity, and body sway, were analyzed to evaluate postural control. RESULTS:CMT1A patients demonstrated improved postural stability during visual tracking tasks, suggesting better visual integration and long-term compensatory adaptations. In contrast, CIDP patients showed greater postural instability and reliance on static visual cues. Both groups experienced increased postural sway during proprioceptive and cognitive perturbations, with no significant differences between them in DT performance. CONCLUSION:The study highlights distinct postural control mechanisms in CIDP and CMT1A patients. CMT1A patients exhibit better adaptation to visual disturbances, while CIDP patients struggle with visual integration and rely more on static visual cues. This difference reflects the progressive nature of CMT1A, which may facilitate better development of compensatory strategies over time. These findings underscore the need for personalized rehabilitation approaches, focusing on visual integration for CIDP patients and reinforcing compensatory mechanisms in CMT1A patients to enhance balance and reduce fall risk.

OBJECTIVES:The aim was to evaluate the safety, tolerability, pharmacokinetics, and potential clinical efficacy of AZP2006, an oral pleiotropic drug modulating progranulin levels, in patients with progressive supranuclear palsy (PSP), a rare tauopathy. METHODS:A randomized, double-blind, placebo-controlled, parallel-group trial was conducted at three sites in France. Eligible participants (age 40-80 years, diagnosed with probable or possible PSP) were randomized to receive AZP2006 (60 mg once per day [QD] or 80/50 mg QD [80 mg for 10 days followed by 50 mg]) or placebo for 12 weeks. Assessments included safety, pharmacokinetics (plasma and whole blood), pharmacodynamics (cerebrospinal fluid and plasma biomarkers), and exploratory clinical efficacy (PSP rating scale, clinical global impression, and activities of daily living). Approximately 2 years post-trial, an open-label extension (OLE) enrolled 15 patients who received active treatment (AZP2006) for 6 months. RESULTS:Forty-one patients were screened, 36 randomized, and 34 completed the study. AZP2006 demonstrated acceptable tolerability and safety with no treatment-related serious adverse events. Pharmacokinetic analysis confirmed rapid absorption, a long half-life (60 mg: 764.3 hours; 80/50 mg: 684.7 hours), and steady-state by day 45 (60 mg) and day 28 (80/50 mg). Biomarker analyses indicated blood-brain barrier crossing, target engagement, and stabilized progranulin levels. Trends in efficacy favored slower disease progression in AZP2006 groups. The OLE demonstrated a slowed progression of the disease and revealed no notable safety concerns. CONCLUSIONS:AZP2006 was well-tolerated and demonstrated favorable trends in biomarker and clinical outcomes. These preliminary signals support further investigation to determine whether a meaningful clinical benefit can be achieved in PSP with AZP2006. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Waisman's syndrome is a rare genetic disease related to mutation in the RAB39B gene, on the X-chromosome, and characterized by intellectual disability and parkinsonism. First case is a male with hemizygous deletion, associated with severe symptoms and acanthocytosis, second case is a female with heterozygous deletion and skewed X-inactivation.

BACKGROUND AND OBJECTIVES:Idiopathic normal-pressure hydrocephalus (iNPH) remains a diagnostic challenge because of the lack of a single reliable diagnostic test. The aim of this study was to evaluate the performance of the lumbar infusion test (LIT) in the decision-making process for shunting in patients with suspected iNPH. METHODS:A total of 201 patients with suspected iNPH underwent complete clinical, radiological, and hydrodynamic evaluation, including LIT, between January 2016 and January 2024 at Lille University Hospital. Patients were categorized into unlikely, possible, or probable iNPH groups before and after LIT. The decision to shunt was made in a multidisciplinary setting. The sensitivity, specificity, and predictive values of the resistance coefficient (R out ) thresholds were analyzed. Clinical outcomes after shunting were assessed using the Larsson categorization, walking test, and Mini-Mental State Examination. RESULTS:Among 165 patients who completed an interpretable LIT for iNPH diagnosis suspicion, the mean age was 79 years. Gait disturbances were present in 98.8%, cognitive impairment in 86.6% and urinary disturbances in 58.8% of cases. The mean R out values varied significantly across the diagnostic groups ( P < .0001). The optimal threshold for R out was determined to be 12 mm Hg/mL/min, with a sensitivity of 78.1% and specificity of 74.3% (area under the curve = 0.8441, P < .0001). Among 41 patients in the possible iNPH group who underwent shunting based on LIT findings, 75.6% demonstrated clinical improvement. In the probable iNPH group, 87.1% of shunted patients showed improvement. None of the unlikely patients with iNPH with negative LIT results underwent surgery. CONCLUSION:Although LIT does not provide a definitive diagnosis of iNPH, it serves as a safe and valuable adjunct in cases of diagnostic uncertainty, aiding in early decision making and potentially improving postshunting outcomes. Its reproducibility, ease of implementation, and low morbidity make it a useful tool in the diagnosis of iNPH when combined with clinical and radiological assessments.

BACKGROUND:Impulse control disorders (ICD) are common non-motor complications in Parkinson's disease (PD), particularly in patients receiving oral dopamine agonists (DA). Continuous subcutaneous apomorphine infusion (CSAI) is a device-aided therapy for advanced PD, but its effects on ICD remain underexplored in real-world settings. OBJECTIVES:To assess the impact of CSAI initiation on ICD prevalence and severity in a large real-world PD cohort and to compare ICD evolution in CSAI-treated patients versus orally-treated controls. METHODS:We analyzed data from the national prospective observational NS-Park cohort, selecting patients with documented ICD status before and after CSAI initiation. Changes in ICD prevalence and severity based on the MDS-UPDRS sub-item 1.6 were assessed using paired statistical tests, with additional sensitivity analyses based on time-restricted sub-cohorts (considering 60-, 24- and 12-months follow-up). A matched case-control analysis and a propensity score matching were used to compare CSAI-treated patients to orally-treated PD patients. RESULTS:149 patients were included in the analysis. Before CSAI initiation, slight and mild/severe ICDs were present in 17% and 5% of the patients, respectively. After CSAI starting, ICD prevalence significantly decreased from 22% to 13%, (P = 0.003). These improvements were consistent across different time windows, despite an overall increase in DA levodopa-equivalent dose, with no associated mood worsening (up to 24-month follow-up). CSAI was associated with longitudinal ICD reduction, contrasting with the stable or worsening ICD trajectory in orally-treated controls, though trajectories were not statistically different. CONCLUSIONS:The presented findings of our real-life cohort suggest that ICD tend to improve following CSAI initiation in patients with PD, likely due to a reduction of oral DA or the effect of continuous dopaminergic stimulation provided by the pump. While this observation is clinically relevant, it should be interpreted with caution given the study's observational design and the limitations inherent to using MDS-UPDRS sub-items for ICD assessment.