BackgroundFunctional Motor Disorders (FMDs) represent a diagnostic and therapeutic challenge in pediatric neurology, particularly among adolescents. Their clinical presentation is common but often nonspecific, leading to frequent misdiagnoses and diagnostic delays. We aimed to characterize FMDs in adolescents and to examine the frequency of isolated and combined phenotypes and their associations with demographic and clinical variables.MethodsIn this observational study, data were obtained from the Italian Registry of FMDs, including patients with a clinically definite diagnosis of FMD consecutively enrolled at 25 Italian tertiary movement disorders centers.ResultsAmong 847 patients, 93 (10.9%) had adolescent-onset FMDs. Motor phenotypes did not differ significantly between adolescent- and adult-onset FMDs, with the exception of parkinsonism, which was observed only in the latter. Compared with adult-onset FMDs, adolescent-onset FMDs were associated with a longer disease duration, a higher number of medical consultations before diagnosis, and a higher frequency of functional seizures and infections, but with lower rates of insomnia, fatigue, and antipsychotic use. In multivariable analysis, adolescent-onset FMDs remained independently associated with a greater number of medical consultations (adjusted OR 1.07; 95% CI 1.02-1.13), the presence of functional seizures (adjusted OR 2.06; 95% CI 1.09-3.8), and with lower occurrence of insomnia (adjusted OR 0.49; 95% CI 0.27-0.92) and fatigue (adjusted OR 0.51; 95% CI 0.30-0.86). Pain was more likely to be associated with the combined FMDs phenotype.ConclusionsAdolescent-onset FMDs are common and are associated with several non-motor symptoms in tertiary movement disorders centers. Early and accurate diagnosis may help to reduce unnecessary investigations and inappropriate treatments.

BACKGROUND:GBA1 mutation is the most significant genetic risk factor for Parkinson's disease (PD). It encodes glucocerebrosidase (GCase), whose dysfunction - seen in Gaucher disease - leads to the accumulation of glucosylceramide and its derivate glucosylsphingosine (GlcSph). However, it remains unclear whether GCase and GlcSph are relevant in PD patients carrying no or monoallelic GBA1 variants, and what their clinical impact might be. OBJECTIVE:Investigating the relationships between GBA1 mutations, GCase, GlcSph, and clinical features in a large PD cohort. METHODS:We performed a cross-sectional study of PD patients screened for GBA1 mutations, GCase activity, and GlcSph via dried blood spot tests. Patients were classified as heterozygous mutation carriers (GBA1-PD) or non-carriers (nonGBA1-PD). Collected data included motor and non-motor parameters. Molecular and clinical differences were compared between GBA1-PD and nonGBA1-PD. Distinctive clinical features were further investigated through multivariate models to test their correlations with biochemical data. RESULTS:The cohort included 611 subjects (225 GBA1-PD, 386 nonGBA1-PD). GBA1-PD presented earlier onset, lower cognitive scores, higher incidence of mood disturbances and more advanced stage. Motor assessment revealed a higher frequency and severity of dyskinesias, independently from disease duration and LEDD. GlcSph levels showed an independent correlation with dyskinesia severity and time at onset in GBA1-PD patients, which was independent of sex, LEDD, UPDRS-III, disease duration and GBA1 mutation class. CONCLUSIONS:This study reveals an association between GlcSph and dyskinesias in GBA1-PD, that should prompt further investigation to assess the GlcSph role as a possible biomarker and target to tackle dyskinesias in GBA1-PD.

Introduction The state of mild cognitive impairment related to Parkinson's disease (PD-MCI) is unstable. However, the mechanisms underlying reversion to normal cognition in patients with early PD-MCI are still not fully understood. Objectives To investigate whether reversion to normal cognition in PD-MCI is associated with the architecture of brain structural covariance networks (SCNs). Methods Graph-theoretical analyses of SCNs were conducted using MRI-derived cortical thickness and subcortical volume measures from 119 drug-naïve PD patients and 51 healthy controls (HCs) at baseline. Among patients, 16 reverted from PD-MCI to normal cognition (Reverters) at the 1-year follow-up, 39 showed persistent PD-MCI (Non-Reverters), and 64 remained cognitively normal (PD-CN). Hub identification and global (efficiency, path length, clustering, small-worldness) and regional (clustering, efficiency) measures of SCNs were compared across groups. Results Higher educational level and better cognitive performance were associated with reversion to normal cognition at the 1-year follow-up. At baseline MRI assessment, 15 hubs were identified in HCs and PD-CN, 8 in Reverters, and 5 in Non-Reverters. Reverters exhibited higher global efficiency than the other groups. Non-Reverters showed higher regional efficiency and clustering than PD-CN and HCs in the precentral regions. Conclusions The loss of brain regions as network hubs within SCNs reflects cognitive impairment in early PD, suggesting a close link between the organization of brain SCNs and clinical outcomes. Cognitive resilience appears to be associated with a distinct SCN architecture at the earliest PD stages. These findings may contribute to understanding of the mechanisms underlying PD-MCI reversion and inform future treatments.

Non-motor symptoms (NMSs) are highly prevalent in Parkinson’s disease (PD) and affect patients’ quality of life. Data on gender differences in NMSs are largely cross-sectional and derived from chronically treated populations. Longitudinal evidence in early, levodopa-naïve PD patients remains limited. This study aims to longitudinally investigate gender differences in a wide range of NMSs in early-stage levodopa-naïve PD patients during the first 2 years following levodopa initiation. This multicenter, prospective study enrolled 216 levodopa-naïve PD patients (139 men, 77 women) from 17 Italian movement disorder centers. Patients were evaluated at baseline and after 24 months (24 M) using validated scales. Baseline gender differences were explored using group comparisons. Gender effects at 24 M were examined using ANCOVA models adjusted for baseline values and levodopa dose at follow-up. At baseline, women showed greater cardiovascular and thermoregulatory autonomic dysfunction, higher anxiety, pain, fatigue, and worse quality of life, whereas men exhibited greater sexual dysfunction, daytime sleepiness, and better attentional performance. At the 24 M, gender differences persisted only for anxiety, pain, mobility, and emotional well-being, while additional significant differences emerged, including hypersexuality, visuo- spatial domain, and orthostatic-hypotension. Women exhibited greater symptom severity than men across all aforementioned variables, with the exception of hypersexuality. Gender significantly influences the expression and early evolution of NMSs in PD, independently of levodopa exposure. Gender-specific NMSs profiles are already evident in the first two years of treatment. These findings highlight the importance of integrating gender considerations into early assessment and personalized management of NMSs in PD.

Parkinson’s disease (PD) affects approximately 1

This study aimed to develop and evaluate a spatiotemporal deep-neural-network (stDNN) using resting-state fMRI (rs-fMRI) data to identify brain biomarkers associated with isolated REM sleep behavior disorder (iRBD) and Parkinson’s disease (PD) and to differentiate these conditions from controls. The final sample included 771 subjects, comprising 423 patients with PD, 144 with iRBD, and 204 healthy controls. stDNN model was applied to mean timeseries extracted for each subject from rs-fMRI data. By integrating spatio-temporal features, the network classified subjects based on distinct neural patterns. Model generalizability was assessed using subject-wise k-fold cross-validation. Explainable artificial intelligence (XAI) methods were applied. stDNN achieved balanced accuracy rates of 71.0% in distinguishing controls from PD and up to 71.9% in middle-stage PD cases. It also demonstrated over 80% accuracy in differentiating healthy controls from iRBD. XAI analysis highlighted the involvement of fronto-parietal and temporal regions, including the dorsolateral prefrontal cortex, and anterior temporal gyri, in distinguishing controls from PD. In the comparison with iRBD, key contributing areas included the bilateral superior and medial frontal gyri, dorsolateral prefrontal cortex, parietal and occipital regions (lingual gyri and cuneus). This study demonstrates the potential of stDNN to differentiate between iRBD, PD, and controls using rs-fMRI data.

BACKGROUND AND OBJECTIVES:Substitution therapy with oral levodopa is the primary treatment of Parkinson's disease (PD). However, long-term levodopa use is associated with fluctuations in response and dyskinesia. These complications severely affect the patient quality of life. Fluctuation management in long-standing PD is poorly documented. The Parkinson's Disease Fluctuations treatment Pathway (PD-FPA) study was an Italian multicenter, observational study designed to describe how fluctuations are treated in patients with advanced disease. PATIENTS AND METHODS:Between July 2018 and December 2020, ten centres enrolled consecutive patients aged ≥18 years who had been diagnosed with PD 10-15 years before enrollment and had been experiencing fluctuations for at least 2 years before enrollment. Data on patient characteristics, PD stage, fluctuations, and treatments were collected at enrollment (T0) and prospectively at 6 months (T1) and 12 months (T2). Data were also collected retrospectively, at 1 and 2 years before T0. RESULTS:At T0, patients (n = 296, 60.1% male, mean age 68 years) had Hoehn and Yahr disease stage 2-3 and 47% had comorbidities (29.8% cardiovascular disease). PD stage and other PD assessment scores were overall stable during the entire 3-year observation period. Over 3 years, the use of dopamine agonists progressively decreased (51% of patients at T2), the use of monoamine oxidase-B inhibitors was stable (63%), while the use of catechol-O-methyltransferase inhibitors progressively increased (42%). Safinamide and opicapone showed the biggest increase in use over the 3-year observation period. Treatment changes were mostly prompted by fluctuations and were reported in about 50% of patients at T0 and 30% at T1 and T2. CONCLUSION:Maintenance of stable disease in patients with long-standing PD and fluctuations is feasible with non-invasive treatments. Accurate treatment adjustments and individualized strategies with new-generation add-on drugs may be of key importance.

Cognitive evolution in people with multiple sclerosis (pwMS) may follow different trajectories. This study investigated long-term cognitive evolution in pwMS while controlling for methodological factors and psychological variables, to refine neuropsychological monitoring. A cohort of pwMS (n = 148) underwent neuropsychological evaluations at three time points: baseline (BL), re-baseline (RBL; 1 year later), and long-term follow-up (LTFU; 6 years after BL). Annualized cognitive change scores were analyzed to compare changes during BL-RBL interval with those in RB-LTFU. Participants were classified over time as cognitively preserved (CP) or cognitively impaired (CI) and McNemar’s test evaluated classification changes. Sensitivity analysis was conducted in a subgroup of recently diagnosed pwMS (n = 91). Reliable Change Indices (RCI) at the 95

INTRODUCTION AND AIMS:The European Academy of Neurology (EAN) joined the Horizon Europe EBRAINS 2.0 research consortium to co-develop recommendations for prospective acquisition and integration of clinical and research core multi-scale human datasets for connectome analysis in stroke, Parkinson's disease (PD), and glioma (GBM). METHODS:Using an online Delphi survey method, expert consensus was sought on 28 statements for each of the following protocols in stroke, PD and GBM: clinical core/research brain MRI, minimum/extended clinical outcomes, minimum/extended cognition assessments, case report forms (CRF). The level of agreement for each statement was predefined as ≥ 80%. 536 experts from four EAN Scientific Panels (SP) (SP Neuro-oncology [n = 70], SP Movement Disorders [n = 206], SP Neuroimaging [n = 112], SP Stroke [n = 148]) were invited to participate in this Delphi process. RESULTS:Two Delphi voting rounds were conducted to reach the predefined level of agreement (≥ 80%; range: 80.49%-100%) for all items to establish consensus on protocol recommendations for stroke, PD and GBM. Cumulative response rate from SP experts was 25% (n = 135 from 30 European countries) for the first, and 32% (n = 173 from 35 European countries) for the second Delphi voting round. DISCUSSION:These consented protocols provide a pragmatic framework for harmonizing multi-scale data acquisition for connectome analyses in stroke, PD, and GBM. Further, these protocols allow future modular extensions for other datasets, e.g., neurophysiological data or non-imaging biomarkers, and serve as a role model for brain network analyses in other neurological disorders.

BACKGROUND:Parkinson's disease (PD) is the second most common neurodegenerative disease. It imposes substantial and growing burden on patients, families, and caregivers and reduces quality of life. The disability and care needs associated with PD carry economic ramifications. OBJECTIVE:The objective of the study was to estimate the socioeconomic costs of PD across 47 European countries in 2019. METHODS:Estimation is based on four steps: (1) determination of prevalence, (2) systematic review of costs, (3) data preparation and imputation, and (4) expert validation. Prevalence data were obtained from the Global Burden of Disease 2021 study (reference year: 2019). Direct, indirect, and informal care costs were analyzed. For countries lacking primary data, an imputation method was employed on the basis of gross national income categories and country-specific economic indicators. RESULTS:Fourteen cost-of-illness studies met the inclusion criteria, with all but one being conducted in high-income countries and no eligible data being available for lower-middle-income countries, which precluded cost estimation for these regions. The estimated total costs are €22.8 billion (2019, purchasing power parities [PPP]-adjusted), of which €17.3 billion (76%) are direct costs, €1 billion (5%) are indirect costs, and €4.4 billion (19%) are informal care costs. The mean cost per patient was €14,278 (median: €8393). CONCLUSIONS:The increasing economic burden of PD reflects its increasing prevalence, posing significant challenges for health care systems. Our findings emphasize the need for disease-modifying therapies and preventive strategies. Considerable knowledge gaps remain in the cost-of-illness literature, particularly in lower-middle-income regions. The results provide evidence to inform political and health economic decision-making. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background: Current treatments for myasthenia gravis (MG), while improving outcomes, are often associated with adverse effects, and a proportion of patients remain refractory to standard therapies. Eculizumab, a humanized monoclonal antibody targeting complement protein C5, is approved for refractory anti-acetylcholine receptor antibody-positive generalized MG (AChR-Ab+ gMG). Aim of the present study is to explore the rapidity of onset of eculizumab efficacy in a single-center cohort of MG patients. Methods: This retrospective, observational, single-center study evaluated the real-world effectiveness and rapidity of response to eculizumab in patients with AChR-Ab+ gMG. Patients received eculizumab according to the approved regimen and were assessed at baseline (T0), 5 weeks (T1), and 3 months (T2) using the Myasthenia Gravis Activities of Daily Living (MG-ADL) score, Quantitative Myasthenia Gravis (QMG) score, and Myasthenia Gravis Foundation of America (MGFA) classification. Results: Eight patients were eligible for the study with a mean age of 73.1 years. A rapid clinical improvement was observed after treatment initiation. Mean MG-ADL scores decreased from 8.38 at T0 to 2.13 at T1 (p < 0.001; Cohen’s d = 2.075), while QMG scores declined from 13.75 to 5.63 (p = 0.001; Cohen’s d = 1.824). Improvements were maintained at T2. Mean percentage reductions from T0 to T1 were 73.5% for MG-ADL and 60.6% for QMG. Eculizumab was well tolerated. Conclusions: These real-world findings confirm a rapid and clinically meaningful response to eculizumab in elderly patients with refractory gMG. These findings highlight its potential role in achieving early symptom control and reducing disease burden in this clinically vulnerable population.

A sex-specific pattern within the dopaminergic pathways may underlie the clinical divergences between male and female patients with Parkinson’s disease (PD) over the disease course. One hundred forty-seven drug-naive PD patients and 38 controls were enrolled. Anatomical and rs-fMRI images were acquired at baseline. Clinical assessments were performed at baseline and (yearly) at follow-ups for 4 years. Using connectivity-based parcellation, we obtained three ROIs for the sensorimotor, limbic, and cognitive striatal functional subregions, which were used as seeds for functional connectivity (FC) analyses. Baseline and longitudinal clinical data at 4 years were correlated with baseline imaging findings. Female PD showed reduced sensorimotor FC with the superior frontal gyrus compared with male PD patients, while no significant sex-related effects emerged for limbic or cognitive striatal seeds. Compared with controls, PD males and females showed both increased and decreased FC involving the three striatal subregions and frontal, insula, hippocampus, and cingulate areas, while voxel-based morphometry revealed no significant sex-related structural differences. Baseline FC changes in limbic and cognitive striatal circuits were associated with slower motor and cognitive progression over 4 years. Although not supported by formal interaction effects, this pattern may underlie sex-specific vulnerability, possibly reflecting different plasticity responses shaped by biological sex.

The “Neuroimaging and Pathology Biomarkers in Parkinson’s Disease” course held on 12–13 September 2025 in Milan, Italy, convened an international faculty to review state-of-the-art biomarkers spanning neurotransmitter dysfunction, protein pathology and clinical translation. Here, we synthesize the four themed sessions and highlights convergent messages for diagnosis, stratification and trial design. The first session focused on neuroimaging markers of neurotransmitter dysfunction, highlighting how positron emission tomography (PET), single photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI) provided complementary insights into dopaminergic, noradrenergic, cholinergic and serotonergic dysfunction. The second session addressed in vivo imaging of protein pathology, presenting recent advances in PET ligands targeting α-synuclein, progress in four-repeat tau imaging for progressive supranuclear palsy and corticobasal syndromes, and the prognostic relevance of amyloid imaging in the context of mixed pathologies. Imaging of neuroinflammation captures inflammatory processes in vivo and helps study pathophysiological effects. The third session bridged pathology and disease mechanisms, covering the biology of α-synuclein and emerging therapeutic strategies, the clinical potential of seed amplification assays and skin biopsy, the impact of co-pathologies on disease expression, and the “brain-first” versus “body-first” model of pathological spread. Finally, the fourth session addressed disease progression and clinical translation, focusing on imaging predictors of phenoconversion from prodromal to clinically overt stages of synucleinopathies, concepts of neural reserve and compensation, imaging correlates of cognitive impairment, and MRI approaches for atypical parkinsonism. Biomarker-informed pharmacological, infusion-based, and surgical strategies, including network-guided and adaptive deep brain stimulation, were discussed as examples of how multimodal biomarkers may inform personalized management. Across all sessions, the need for harmonization, longitudinal validation, and pathology-confirmed outcome measures was consistently emphasized as essential for advancing biomarker qualification in multicentre research and clinical practice.

Age at onset is a key determinant of disease course in the general Parkinson’s disease (PD) population, but its influence among GBA-PD remains undetermined. This study investigates whether age at onset affects cognitive decline in GBA-PD patients and compares symptoms between GBA-PD and nonGBA-PD groups, stratified by age of onset. In this multicentric cross-sectional study, PD patients were stratified into early onset (< 50 years), intermediate onset (50–60 years), and late onset (> 60 years). Demographic–clinical data and scores of the Movement Disorder Society—Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), Montreal Cognitive Assessment (MoCA), Scales for Outcomes in Parkinson’s Disease—Autonomic Dysfunction (SCOPA-AUT), and Beck Depression Inventory (BDI-II) were compared using ANCOVA. The effects of age of onset, GBA1 status, and their interaction were investigated. External validation on cognition was performed using data from the PPMI cohort. We analyzed 80 GBA-PD and 236 nonGBA-PD patients. Among GBA-PD, late-onset patients exhibited worse axial scores (p = 0.037), while early-onset had more severe motor complications (p = 0.007) and dysautonomia (p = 0.012). Age of onset and GBA1 status did not influence MoCA scores. Conversely, GBA1 status independently affected MDS-UPDRS parts I and II (p < 0.001 and p = 0.019, respectively) and BDI-II scores (p = 0.002). Analysis on the external dataset (PPMI) showed late-onset PD had lower MoCA scores (p < 0.001) and confirmed GBA1 status did not influence cognition. In the first decade of PD, cognitive decline is mainly age and duration dependent, irrespective of GBA1 genotype. Early onset does not increase cognitive risk in GBA-PD, supporting its relevance for counseling and treatment planning.

BACKGROUND:Cognitive impairment (CI) is a common and disabling feature of multiple sclerosis (MS), closely linked to brain neurodegeneration (e.g., brain atrophy). Optical coherence tomography (OCT) may offer a rapid and cost-effective method to evaluate neurodegeneration and its relationship with CI in MS. OBJECTIVE:To explore the relationship between cognitive performance, retinal layer thickness, and brain volumetric measures in people with MS (pwMS), focusing on the relative contribution of individual retinal layers. METHODS:In this cross-sectional study, 100 pwMS underwent: neurological and neuropsychological evaluation; brain 3T-MRI scan to compute brain volumes; spectral-domain OCT to assess peripapillary retinal nerve fiber layer (pRNFL), macular ganglion cell layer (GCL), inner plexiform layer (IPL), and combined ganglion cell-inner plexiform layer (GCIPL) thickness. Correlation, t-tests, and regression analyses were performed to explore the abovementioned associations. RESULTS:Thinner retinal layers were associated with reduced brain volumes and lower cognitive performance. Among OCT-derived measures, GCL thickness showed the strongest association with both global cognitive Z-scores and domain-specific Z-scores for processing speed and executive functions. GCL also emerged as the only retinal predictor in regression models of cognitive outcomes. Classifying pwMS based on cognitive performance, cognitive impaired pwMS showed significantly lower GCL and pRNFL thickness compared to cognitive preserved pwMS. CONCLUSION:OCT-derived metrics of retinal damage linked to brain atrophy and CI in pwMS. Among retinal layers, GCL thickness is associated with both domain-specific and global cognitive performance and may potentially outperform GCIPL as an OCT-based marker of neurodegeneration, although findings should be interpreted with caution.

GBA1 variants increase neuropsychiatric vulnerability in Parkinson’s disease (PD). In a multicenter cohort of 234 PD patients (78 GBA-PD, 156 nonGBA-PD), we investigated how GBA1 genotype and sex relate to depression. REM sleep behavior disorder was associated with depression in GBA-PD, while sex, cognition, and motor complications were predictors in nonGBA-PD. Depressive symptoms were more severe and progressed faster in GBA-PD, supporting specific monitoring of this genetic subgroup.

BACKGROUND:Although treatment goals in migraine prevention have moved beyond the benchmark of a 50% reduction in monthly attacks, residual disease burden is still evaluated based on residual headache frequency. However, migraine-related symptoms can persist despite headache freedom, leading to so-called unclear days that may meaningfully contribute to interictal burden. METHODS:In this prospective, real-world study, patients with chronic or high-frequency episodic migraine treated with CGRP-monoclonal antibodies (CGRP-mAbs) were followed for six months. Interictal burden was assessed using the Migraine Interictal Burden Scale (MIBS-4) alongside the monthly unclear and crystal clear days. Patients achieving optimal (< 4 monthly attacks) or modest (4-6 monthly attacks) migraine control were stratified according to the presence of "residual interictal burden" (MIBS-4 ≥ 3). RESULTS:Two hundred patients were included. CGRP-mAbs treatment was associated with a reduction in MIBS-4 scores and an increase in crystal clear days (p < 0.001). Despite optimal or modest migraine control, 45.1% of patients at month 3 and 27.2% at month 6 continued to exhibit a substantial "residual interictal burden". Patients with "residual interictal burden" showed significantly more unclear days and fewer crystal clear days compared with those without residual interictal migraine burden, while no differences were observed in residual headache days, concomitant preventive treatments, or cephalalgiophobia. DISCUSSION:Even when migraine attacks are adequately controlled, residual interictal burden may remain and seems to be predominantly associated with unclear days rather than with residual attacks. Assessing crystal clear and unclear days provides a complementary, patient-centered perspective on treatment response and interictal recovery in migraine.

IntroductionAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving widespread network disruption beyond the motor cortex. Deep gray matter (DGM) nuclei, crucial for motor and cognitive integration, remain underexplored in vivo. This study applied neurite orientation dispersion and density imaging (NODDI) to evaluate DGM microstructure and its relationship with clinical disability in ALS.MethodsDiffusion-weighted MRI data were acquired from 23 ALS patients and 24 age- and sex-matched healthy controls. Orientation dispersion index (ODI), neurite density index (NDI), and free water fraction (FWF) were extracted from the bilateral thalamus, caudate, putamen, pallidum, hippocampus, and amygdala using the Destrieux atlas. Group comparisons and partial correlations were adjusted for age, sex, and disease duration.ResultsNo significant group differences in DGM volumes or NODDI-derived metrics survived correction for multiple comparisons. Within the ALS group, several nominal (uncorrected) associations were observed between DGM microstructural metrics and ALSFRS-R subscores. Reduced respiratory subscores were associated with higher ODI in the left thalamus (ρ = 0.57, p = 0.0047, uncorrected). Fine-motor subscores showed nominal positive associations with ODI in the left (ρ = 0.48, p = 0.021, uncorrected) and right amygdala (ρ = 0.51, p = 0.012, uncorrected). Gross motor subscores were nominally associated with NDI in the right thalamus (ρ = 0.58, p = 0.004, uncorrected), left thalamus (ρ = 0.42, p = 0.047, uncorrected), left caudate (ρ = 0.52, p = 0.011, uncorrected), and right caudate (ρ = 0.57, p = 0.033, uncorrected). None of these associations survived false discovery rate correction and should therefore be interpreted as exploratory.DiscussionThese findings suggest subtle and predominantly exploratory associations between DGM microstructural properties and clinical measures in ALS. NODDI derived metrics, particularly ODI and NDI, may provide sensitive indices of subcortical microstructural variation, warranting further investigation in larger cohorts.

Non-motor symptoms affect over 90% of people with Parkinson's disease at all stages, with pain and fatigue being among the most prevalent yet often neglected in clinical practice. Despite their significant impact, these symptoms are frequently underdiagnosed and inadequately treated, adding substantial burden to patients' lives. The lack of a clear definition and classification of these symptoms has led neurologists to underestimate their presence among people with Parkinson's disease and limited the ability to address them with mechanism-based care and effective treatments. Managing these symptoms is challenging because of the lack of robust, specifically designed, randomized-controlled trials on effective treatments. This review delves into the current understanding of diagnosing, assessing, and treating pain and fatigue in Parkinson's disease, highlighting critical knowledge gaps and suggesting future research directions. The framework emphasizes improving classification methods, deepening our understanding of the underlying pathophysiology, evaluating treatment impacts on pain and fatigue, and leveraging longitudinal data collection through consensus-based methodology. By addressing these critical areas, we strive to enhance the management of these debilitating non-motor symptoms and ultimately improve patients' quality of life.