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.

The Pain in Dystonia Scale (PIDS) is a self-administered instrument to assess pain in dystonia, validated in cervical dystonia (CD). To translate and culturally adapt the PIDS into Italian following a standardized forward-backward procedure and to validate the resulting Italian version (I-PIDS) in patients with idiopathic adult-onset CD as part of a multicenter effort aimed at evaluating its clinimetric properties across dystonia subtypes. I-PIDS was completed by 64 Italian patients with cervical dystonia from 16 centers, three months or more after their last botulinum toxin treatment. Standard clinimetric analyses were performed. Acceptability was optimal, with no missing data. Score distributions met expected criteria, with mean-median differences <10

Background: Progressive Supranuclear Palsy (PSP) is a rare, heterogeneous neurodegenerative disease for which no treatment is currently available. In the context of clinical trials, the representativeness of the included patients is crucial for the generalizability of the results. Herein, we present results from a multicenter perspective study to identify the most restrictive criteria for patient selection and to assess the representativeness of eligible patients. Methods: we enrolled 221 PSP patients diagnosed according to the MDS clinical criteria. All patients were screened with a set of inclusion and exclusion criteria based on previous and ongoing clinical trials in PSP and underwent motor and cognitive evaluation with the Montreal Cognitive Assessment battery and the PSP rating scale, respectively. Then, clinical features of eligible and non-eligible patients were compared at baseline and after 15,93 +/- 8,77 months follow up. Results: Eligible (28 patients, 12,6 %) patients were younger, showed shorter disease duration and lower severity but similar distribution of PSP phenotype and disease progression rates compared to non-eligible patients. The most restrictive non-modifiable criteria were independent gait, disease duration and cognitive status. Willingness to undergo lumbar puncture and treatment stability for previous 60 days represented potentially modifiable criteria. Conclusion: Overall, PSP eligible for clinical trials are representative of the general PSP population. While motor and cognitive impairment represent the most important non-modifiable barriers to enter a clinical trial, other criteria as willingness to undergo lumbar puncture and treatment stability are potentially modifiable. Specific strategies are discussed to increase the number of eligible patients working on potentially modifiable criteria.

Cervical Dystonia (CD) is now recognized to encompass a constellation of non-motor symptoms, including sensory, cognitive, and psychiatric manifestations, which significantly affect patients’ quality of life. Cerebellar dysfunction may affect cognitive and affective processing in CD, mirroring cognitive and affective patterns observed in Cerebellar Cognitive and Affective Syndrome (CCAS). To investigate impairments in cerebellar-dependent cognitive and affective domains in CD patients using the Cerebellar Cognitive and Affective Syndrome scale (CCAS-S), and to analyze the potential relationship between cognitive deficits and clinical features of CD. The CCAS-S was administered to twenty CD patients and twenty controls (HC) matched for age, gender, level of education, and MMSE score. For CD patients, disease severity and disability were evaluated using the Toronto Western Spasmodic Torticollis Rating Scales (TWSTRS), while tremor was assessed through the Fahn-Tolosa‐Marin Clinical Rating Scale for Tremor (FTM). CD exhibited a significantly lower total CCAS-S score, and a higher number of failed items compared to HC, with marked deficits in specific sub-items such as fluency, delayed verbal recall, similarities, and affective domain. The total number of failed tests revealed high predictive ability (AUC = 0.90), with no significant correlations between disease duration, clinical outcomes, and CCAS-S performance. The CCAS-S is a sensitive screening tool in differentiating cognitive performance in CD and HC, showing a critical cerebellar involvement in the cognitive and affective symptoms of dystonia.

BACKGROUND:Postural instability and gait difficulties are key symptoms of Parkinson's disease (PD), elevating the risk of falls substantially. Falls afflict 35% to 90% of PD patients, representing a major challenge in managing the condition. Accurate prediction of fall risk and identification of contributing factors are essential for timely interventions. OBJECTIVES:Our objective was to develop and validate a machine learning (ML) algorithm across multiple centers in Italy to accurately forecast fall risk and identify related factors using routinely collected clinical data. METHODS:Patient data from two Italian centers (N = 251) were divided into a training cohort (N = 164) for ML model development and a validation cohort (N = 87). External validation was conducted on a subset of PPMI study patients (N = 65). We compared the performance of logistic regression (LR) and Support Vector Classifier (SVC) models trained on clinical data. The Shapley Additive exPlanations (SHAP) method was employed to examine the predictive power of individual variables. RESULTS:In the training set, SVC outperformed LR slightly (AUC: LR = 0.779 ± 0.054, SVC = 0.792 ± 0.056). However, LR demonstrated better prediction accuracy in both internal (AUC: LR = 0.753, SVC = 0.733) and external validation cohorts (AUC: LR = 0.714, SVC = 0.676). SHAP analysis on the LR model revealed associations between fall risk and both motor and non-motor variables. CONCLUSIONS:ML-based models effectively estimate fall risk across different clinical centers, enabling tailored interventions to enhance PD patients' quality of life. Challenges persist in predicting falls in US-based patients due to demographic and healthcare system differences.

BACKGROUND:Cerebellar dysfunction disrupts memory-based temporal predictions (TPs), whereas basal ganglia dysfunction affects rhythm-based TPs. Investigating TPs in cervical dystonia (CD) may help to delineate the contributions of subcortical circuits to CD pathophysiology. OBJECTIVE:The aim of this study was to explore TP ability in patients with CD compared with healthy control subjects (HCs) and to examine the relationship between TPs and clinical features of CD. METHODS:Twenty patients with CD and 20 HCs completed a TP task. Reaction times (RTs) were measured during TPs under three conditions: rhythmic and single-interval (predictable target onset) and random (unpredictable target onset). RT benefit scores were calculated by subtracting RTs in the random condition from those in predictive conditions. RESULTS:Our exploratory analysis showed that patients with CD had lower benefit scores than HCs in the single-interval task. In CD, benefit scores in the single-interval task were negatively correlated with Toronto Western Spasmodic Torticollis Rating Scales severity. CONCLUSIONS:Patients with CD exhibited selective impairments in interval-based predictions, suggesting cerebellar involvement in dystonia's pathophysiology. © 2025 International Parkinson and Movement Disorder Society.

BACKGROUND:Evidence suggests that female gender represents a risk factor for the development of motor/nonmotor fluctuations and dyskinesia in Parkinson's disease (PD). So far, no prospective study has analyzed this aspect in relation to the introduction of levodopa treatment. OBJECTIVE:This prospective multicenter study aims to assess the development of motor/nonmotor fluctuations and dyskinesia based on gender over a 2-year observation period in PD patients starting levodopa. METHODS:Two hundred and eighty-nine PD patients requiring levodopa at baseline were enrolled at 17 Movement Disorders Centers and followed for 2 years. Gender differences in the development of fluctuations, defined as a score ≥2 in the 19-item Wearing-Off Questionnaire, and dyskinesia, defined by Movement Disorders Society Unified Parkinson's Disease Rating Scale Part IV (MDS-UPDRS-IV) score >0 on item 4.1 were assessed. Baseline predictors of such complications were evaluated by stepwise multivariate logistic regression analysis. RESULTS:Two hundred and sixteen patients (139 men, 77 women) completed the follow-up (M24). By M24, 53,2% of men and 64.9% of women had fluctuations (P = 0.048), whereas 5% of men and 14.3% of women developed dyskinesia (P = 0.0185). Multivariate analysis showed that female gender significantly predicted wearing-off (Odds ratio [OR] = 1.930; P = 0.0333), whereas older age was a significant protective factor (for 5-year increase: OR = 0.712; P < 0.0001). Multivariate analysis showed that gender (OR = 3.405; P = 0.0228) and MDS-UPDRS Part III score (for a 5-unit increase: OR = 1.281; P = 0.0239) were significant predictors of dyskinesia at M24. CONCLUSIONS:Female gender was the strongest predictor of fluctuations and dyskinesia after 2-year intake of levodopa. This finding could have important implications for the development of gender-oriented therapeutic recommendations in early PD.

A few earlier observations and recent controlled studies pointed to the possible contribution of thyroid diseases in idiopathic adult-onset dystonia (IAOD). The aim of this study was to investigate the association between thyroid status and clinical characteristics of IAOD, focusing on dystonia localization, spread, and associated features such as tremors and sensory tricks. Patients were identified from those included in the Italian Dystonia Registry, a multicentre dataset of patients with adult-onset dystonia. The study population included 1518 IAOD patients. Patients with hypothyroidism and hyperthyroidism were compared with those without any thyroid disease. In the 1518 IAOD patients, 167 patients (11%; 95% CI 9.5-12.6%) were diagnosed with hypothyroidism and 42 (2.8%; 95% CI 1.99-3.74) with hyperthyroidism. The three groups were comparable in age at dystonia onset, but there were more women than men in the groups with thyroid disease. Analysing the anatomical distribution of dystonia, more patients with blepharospasm were present in the hyperthyroidism group, but the difference did not reach statistical significance after the Bonferroni correction. The remaining dystonia-affected body sites were similarly distributed in the three groups, as did dystonia-associated features and spread. Our findings provided novel information indicating that the high rate of thyroid diseases is not specific for any specific dystonia subpopulation and does not appear to influence the natural history of the disease.

BACKGROUND:The burden of Parkinson Disease (PD) represents a key public health issue and it is essential to develop innovative and cost-effective approaches to promote sustainable diagnostic and therapeutic interventions. In this perspective the adoption of a P3 (predictive, preventive and personalized) medicine approach seems to be pivotal. The NeuroArtP3 (NET-2018-12366666) is a four-year multi-site project co-funded by the Italian Ministry of Health, bringing together clinical and computational centers operating in the field of neurology, including PD. OBJECTIVE:The core objectives of the project are: i) to harmonize the collection of data across the participating centers, ii) to structure standardized disease-specific datasets and iii) to advance knowledge on disease's trajectories through machine learning analysis. METHODS:The 4-years study combines two consecutive research components: i) a multi-center retrospective observational phase; ii) a multi-center prospective observational phase. The retrospective phase aims at collecting data of the patients admitted at the participating clinical centers. Whereas the prospective phase aims at collecting the same variables of the retrospective study in newly diagnosed patients who will be enrolled at the same centers. RESULTS:The participating clinical centers are the Provincial Health Services (APSS) of Trento (Italy) as the center responsible for the PD study and the IRCCS San Martino Hospital of Genoa (Italy) as the promoter center of the NeuroartP3 project. The computational centers responsible for data analysis are the Bruno Kessler Foundation of Trento (Italy) with TrentinoSalute4.0 -Competence Center for Digital Health of the Province of Trento (Italy) and the LISCOMPlab University of Genoa (Italy). CONCLUSIONS:The work behind this observational study protocol shows how it is possible and viable to systematize data collection procedures in order to feed research and to advance the implementation of a P3 approach into the clinical practice through the use of AI models.

Valence (positive and negative) and content (embodied vs non-embodied) characteristics of visual stimuli have been shown to influence motor readiness, as tested with response time paradigms. Both embodiment and emotional processing are affected in Parkinson's disease (PD) due to basal ganglia dysfunction. Here we aimed to investigate, using a two-choice response time paradigm, motor readiness when processing embodied (emotional body language [EBL] and emotional facial expressions [FACS]) vs non-embodied (emotional scenes [IAPS]) stimuli with neutral, happy, and fearful content. We enrolled twenty-five patients with early-stage PD and twenty-five age matched healthy participants. Motor response during emotional processing was assessed by measuring response times (RTs) in a home-based, forced two-choice discrimination task where participants were asked to discriminate the emotional stimulus from the neutral one. Rating of valence and arousal was also performed. A clinical and neuropsychological evaluation was performed on PD patients. Results showed that RTs for PD patients were longer for all conditions compared to HC and that RTs were generally longer in both groups for EBL compared to FACS and IAPS, with the sole exception retrieved for PD, where in discriminating fearful stimuli, RTs for EBL were longer compared to FACS but not to IAPS. Furthermore, in PD only, when discriminating fearful respect to neutral stimuli, RTs were shorter when discriminating FACS compared to IAPS. This study shows that PD patients were faster in discriminating fearful embodied stimuli, allowing us to speculate on mechanisms involving an alternative, compensatory, emotional motor pathway for PD patients undergoing fear processing.

BACKGROUND:Given that patients with Parkinson's Disease (PD) and Freezing of Gait (FoG) may lack the cognitive resources necessary to activate the motor imagery (MI) process, investigating how to boost MI vividness and accuracy could be a valuable therapeutic strategy in MI Practice (MIP). OBJECTIVE:We aim to evaluate the priming effect of visual, or auditory, or attentional stimuli in enhancing MI ability by using quantitative data on gait and turning performance. METHODS:Nineteen PD participants with FoG underwent four one-week sessions of MIP, with pre and post clinical assessments. Each session included MI alone or one of three booster MI tasks (Attentional, Action observation, or Auditory) before imagining and executing walking straight and performing a 180° turn. Gait and turning performances were evaluated using six inertial sensors before and after each session. RESULTS:Our findings showed that both MI and boosted MI induced similar improvement in gait (speed and stride length) and 180° (step number and velocity) and 360° turning (velocity, angle) parameters compared to baseline. When differences among "booster" tasks were analyzed, results showed that Auditory and Attentional boosted MI were superior to MI alone in some gait and turning parameters. At the end of the 4 sessions, MI ability measured by means of Kinesthetic and Visual Imagery Questionnaire and Gait Imagery Questionnaire and FoG symptoms were also improved. CONCLUSION:Our preliminary results suggest that boosting MI is a feasible strategy for enhancing MI ability and addressing FoG symptoms. Auditory and Attentional conditions appear to enhance the priming effect of MI on gait and turning performance more effectively.

BACKGROUND:Family history of Parkinson's disease (PD) is a common finding in PD patients. However, a few studies have systematically examined this aspect. OBJECTIVES:We investigated the family history of PD patients, comparing demographic and clinical features between familial PD (fPD) and sporadic PD (sPD). METHODS:A cross-sectional study enrolling 2035 PD patients was conducted in 28 Italian centers. Clinical data and family history up to the third degree of kinship were collected. RESULTS:Family history of PD was determined in 21.9% of patients. fPD patients had earlier age at onset than sporadic patients. No relevant differences in the prevalence of motor and nonmotor symptoms were detected. Family history of mood disorders resulted more prevalently in the fPD group. CONCLUSIONS:fPD was found to recur more frequently than previously reported. Family history collection beyond the core family is essential to discover disease clusters and identify novel risk factors for PD.

BackgroundTremor disorders remain as clinical diagnoses and the rate of misdiagnosis between the commonest non-parkinsonian tremors is relatively high.ObjectivesTo compare the clinical features of Essential Tremor without other features (pure ET), ET plus soft dystonic signs (ET + DS), and tremor combined with dystonia (TwD).MethodsWe compared the clinical features of patients with pure ET, ET + DS, and TwD enrolled in The ITAlian tremor Network (TITAN). Linear regression models were performed to determine factors associated with health status and quality of life.ResultsThree-hundred-eighty-three patients were included. Sex distribution was significantly different between the groups with males being more represented in pure ET and females in TwD. The initial site of tremor was different between the groups with about 40% of TwD having head tremor and ET + DS unilateral upper limb tremor at onset. This pattern mirrored the distribution of overt dystonia and soft dystonic signs at examination. Sensory trick, task-specificity, and position-dependence were more common, but not exclusive, to TwD. Pure ET patients showed the lowest degree of alcohol responsiveness and ET + DS the highest. Midline tremor was more commonly encountered and more severe in TwD than in the other groups. Regression analyses demonstrated that tremor severity, sex, age, and to a lesser degree the variable "group", independently predicted health status and quality of life, suggesting the existence of other determinants beyond tremor.ConclusionsPure ET and TwD manifest with a phenotypic overlap, which calls for the identification of diagnostic biomarkers. ET + DS shared features with both syndromes, suggesting intra-group heterogeneity.

Neuropsychiatric symptoms, such as apathy, disinhibition and irritability, are common in Progressive Supranuclear Palsy (PSP). The Frontal Behaviour Inventory (FBI) is a useful instrument for the evaluation of behavioural disorders in neurodegenerative diseases. The main goal of the present study was to explore the psychometric properties of the FBI in PSP. FBI was administered to the PSP-NET cohort including Italian patients diagnosed according to the Movement Disorder Society criteria. Patients underwent a clinical interview, a motor evaluation, extensive cognitive and behavioural testing. Two hundred and eight subjects were included in this study. The internal consistency was high (Cronbach’s alpha = 0.868) and no improvement of this value was noted upon removal of any item. FBI showed also good acceptability, reliability and validity. The standard error of measurement (SEM) value for FBI total score was 0.169 [SEM = SD √ (1 – Cronbach’s alpha)]. Factor analysis indicated a five-factor structure: Apathy, Behavioural disorders, Impulsivity, Motor and speech frontal behaviour and Executive disorders that explained the 54.92

Walking encompasses a complex interplay of neuromuscular coordination and cognitive processes. Disruptions in gait can impact personal independence and quality of life, especially among the elderly and neurodegenerative patients. While traditional biomechanical analyses and neuroimaging techniques have contributed to understanding gait control, they often lack the temporal resolution needed for rapid neural dynamics. This study employs a mobile brain/body imaging (MoBI) platform with high-density electroencephalography (hd-EEG) to explore event-related desynchronization and synchronization (ERD/ERS) during overground walking. Simultaneous to hdEEG, we recorded gait spatiotemporal parameters. Participants were asked to walk under usual walking and dual-task walking conditions. For data analysis, we extracted ERD/ERS in α, β, and γ bands from 17 selected regions of interest encompassing not only the sensorimotor cerebral network but also the cognitive and affective networks. A correlation analysis was performed between gait parameters and ERD/ERS intensities in different networks in the different phases of gait. Results showed that ERD/ERS modulations across gait phases in the α and β bands extended beyond the sensorimotor network, over the cognitive and limbic networks, and were more prominent in all networks during dual tasks with respect to usual walking. Correlation analyses showed that a stronger α ERS in the initial double-support phases correlates with shorter step length, emphasizing the role of attention in motor control. Additionally, β ERD/ERS in affective and cognitive networks during dual-task walking correlated with dual-task gait performance, suggesting compensatory mechanisms in complex tasks. This study advances our understanding of neural dynamics during overground walking, emphasizing the multidimensional nature of gait control involving cognitive and affective networks.

As the global population ages, neurodegenerative diseases like Alzheimer (AD) and Parkinson (PD) are increasing, necessitating better remote monitoring methods. Here we explore quantitative analysis of handwriting skills as a tool for predicting cognitive impairment and thus, monitoring the degeneration of the disease. A novel probabilistic model using bump functions was developed to analyze handwriting's spatial organization, capturing their complexity and variability. The key findings are that AD subjects tend to organize the same dictated text into more rows than PD, and the rows' average tilt and height are predictive of cognitive functions. This approach offers a non-invasive, accessible, and effective solution for monitoring of neurodegenerative diseases.

Background Several earlier studies showed a female predominance in idiopathic adult-onset dystonia (IAOD) affecting the craniocervical area and a male preponderance in limb dystonia. However, sex-related differences may result from bias inherent to study design. Moreover, information is lacking on whether sex-related differences exist in expressing other dystonia-associated features and dystonia spread.Objective To provide accurate information on the relationship between sex differences, motor phenomenology, dystonia-associated features and the natural history of IAOD.Methods Data of 1701 patients with IAOD from the Italian Dystonia Registry were analysed.Results Women predominated over men in blepharospasm, oromandibular, laryngeal and cervical dystonia; the sex ratio was reversed in task-specific upper limb dystonia; and no clear sex difference emerged in non-task-specific upper limb dystonia and lower limb dystonia. This pattern was present at disease onset and the last examination. Women and men did not significantly differ for several dystonia-associated features and tendency to spread. In women and men, the absolute number of individuals who developed dystonia tended to increase from 20 to 60 years and then declined. However, when we stratified by site of dystonia onset, different patterns of female-to-male ratio over time could be observed in the various forms of dystonia.Conclusions Our findings provide novel evidence on sex as a key mediator of IAOD phenotype at disease onset. Age-related sexual dimorphism may result from the varying exposures to specific age-related and sex-related environmental risk factors interacting in a complex manner with biological factors such as hormonal sex factors.

INTRODUCTION:We recently demonstrated specific spectral signatures associated with updating of memory information, working memory (WM) maintenance and readout, with relatively high spatial resolution by means of high-density electroencephalography (hdEEG). WM is impaired already in early symptomatic HD (early-HD) and in pre-manifest HD (pre-HD). The aim of this study was to test whether hdEEG coupled to source localization allows for the identification of neuronal oscillations in specific frequency bands in 16 pre-HD and early-HD during different phases of a WM task. METHODS:We examined modulation of neural oscillations by event-related synchronization and desynchronization (ERS/ERD) of θ, β, gamma low, γLOW and γHIGH EEG bands in a-priori selected large fronto-parietal network, including the insula and the cerebellum. RESULTS:We found: (i) Reduced θ oscillations in HD with respect to controls in almost all the areas of the WM network during the update and readout phases; (ii) Modulation of β oscillations, which increased during the maintenance phase of the WM task in both groups; (iii) correlation of γHIGH oscillations during WM task with disease burden score in HD patients. CONCLUSIONS:Our data show reduced phase-specific modulation of oscillations in pre-HD and early-HD, even in the presence of preserved dynamic of modulation. Particularly, reduced synchronization in the θ band in the areas of the WM network, consistent with abnormal long-range coordination of neuronal activity within this network, was found in update and readout phases in HD groups.

Chorea, cognitive decline, and psychiatric symptoms are shared by Huntington's disease (HD) and similar conditions called HD phenocopies. We describe the first case reported in Italy of Huntington disease-like 2 (HDL2), clinically and radiologically indistinguishable from HD, showing the importance of considering African ancestry in the diagnostic process.