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.

BACKGROUND:Socio-occupational functioning in patients with Parkinson's disease (PD) treated with subthalamic nucleus deep brain stimulation (STN-DBS) is not fully captured by standard motor and quality-of-life scales. OBJECTIVES:To characterize patient-reported socio-occupational functioning after STN-DBS and explore associated clinical and demographic factors. METHODS:Thirty-four PD patients were assessed 9-18 months postoperatively using a semi-structured interview covering socio-occupational domains. A composite mean score (Q_mean) was computed as a descriptive index, with clinical associations explored using univariate screening and multivariate linear regression. RESULTS:The Q_mean score following STN-DBS was 7.66 ± 0.86 (range 6.00-9.57). In exploratory multivariate analysis, female sex (n = 7) was associated with higher functioning (P = 0.003), whereas GBA variants (n = 5) with lower functioning (P = 0.007). DISCUSSION:Perceived socio-occupational functioning was overall satisfactory at postoperative assessment, with limited association with conventional motor/neuropsychiatric measures, and greater association with individual factors such as sex and genetic background. These exploratory findings support inclusion of socio-occupational perspectives in DBS outcome evaluation.

Parkinson’s disease (PD) affects approximately 1

Motor fluctuations represent a major challenge in Parkinson’s disease (PD) management. To address them, ADD-ON therapies with monoamine oxidase type B (MAO-B) and catechol-O-methyl transferase (COMT) inhibitors are used to enhance and prolong dopaminergic effects of levodopa, thereby improving motor fluctuations. Despite widespread use, real-life comparative data remain limited. We performed a retrospective, longitudinal study including PD patients referred to two Italian tertiary movement disorder centers. Patients with motor fluctuations requiring ADD-ON therapy (selegiline [SL], rasagiline [RS], safinamide [SF], or opicapone [OP]) and ≥ 12 months of follow-up were included. The primary outcome was treatment stability, defined as months without significant therapy modifications or ADD-ON discontinuation. Secondary outcomes included levodopa dosage changes, initiation of other antiparkinsonian therapies, and ADD-ON discontinuation rates. Cox regression models and Kaplan–Meier survival analyses evaluated the influence of ADD-ON type and clinical-demographic variables on treatment stability. We analyzed 169 patients (SL = 20; RS = 26; SF = 78; OP = 45). Groups differed in age at ADD-ON initiation (p = 0.020; RS > OP), disease duration (p = 0.002; OP > RS and SF), and baseline levodopa equivalent daily dose (p = 0.003; SF and OP > RS). No significant differences in treatment stability were found between groups (p = 0.29). SF group showed higher levodopa increases (p = 0.02) and initiation of new therapies (p = 0.02). ADD-ON discontinuation occurred in 23.1

Background/Objectives: Non-motor symptoms (NMS) are highly prevalent in advanced Parkinson’s disease (PD) and substantially affect quality of life. Continuous infusion therapies are established treatment options for motor fluctuations not controlled by oral medication, but their effects on NMS remain incompletely characterized. We aimed to evaluate the effects of continuous infusion therapies on NMS in advanced PD. Methods: A systematic review was conducted according to PRISMA guidelines. PubMed, Embase, and Cochrane were searched for English-language original studies published between January 2005 and 1 March 2026. Eligible studies included patients with PD treated with levodopa–carbidopa intestinal gel (LCIG), continuous subcutaneous apomorphine infusion (CSAI), subcutaneous levodopa formulations, or levodopa–entacapone–carbidopa intestinal gel (LECIG) and reported quantitative NMS outcomes. Due to methodological heterogeneity, results were synthesized qualitatively. Results: Fifty-four studies were included. Most evaluated LCIG (n = 38), followed by CSAI (n = 14), subcutaneous levodopa formulations (n = 6), and LECIG (n = 2). Overall, 4157 patients were assessed at baseline and 2919 at follow-up. Global non-motor burden improved in 33/45 (73.3%) baseline-to-follow-up comparisons. NMSS total score decreased from 84.4 ± 35.2 to 54.9 ± 17.6. The most consistent benefits were observed for sleep/fatigue and gastrointestinal symptoms. Sleep/fatigue outcomes improved in 26/31 (83.9%) baseline-to-follow-up comparisons. Cognitive outcomes were mostly stable, while cardiovascular, urinary, sexual, and mood-specific outcomes showed less consistent benefit. Conclusions: Continuous infusion therapies may be associated with reduced global non-motor burden in advanced PD, particularly sleep/fatigue and gastrointestinal symptoms. Evidence is strongest for LCIG, while data for CSAI, LECIG, and subcutaneous levodopa formulations remain limited.

Levodopa-induced dyskinesia (LID) is a major source of disability in advanced Parkinson’s disease (PD), whose impact on gait and balance across medication states still remains unclear. We aimed to compare gait and balance performance between comparable dyskinetic (Dysk-matched) and non-dyskinetic (No-Dysk) PD patients in OFF and ON state, and to explore neural correlates using structural and resting-state functional MRI (rs-fMRI). PD patients were consecutively enrolled among candidates for device-aided therapies. Gait and balance were assessed using validated wearable inertial sensors during a 2-minute walk test, a 3-meters Timed-Up-and-Go (TUG), and a sway test, providing spatiotemporal gait parameters, variability, asymmetry, and postural sway metrics. Groups were compared using propensity score matching (PSM) for age, sex, disease duration, motor severity and axial disability. A subgroup underwent exploratory investigation with structural and rs-fMRI collected in ON state. After PSM (22 pairs), Dysk-matched group showed slower gait speed (p = 0.007), shorter stride length (p = 0.006), longer double support (p = 0.047), and prolonged TUG (p = 0.049) in the OFF state. Dysk-matched patients showed increased sway from OFF to ON (p = 0.030). Neuroimaging (10 Dysk-matched, 9 No-Dysk) revealed increased functional connectivity in sensorimotor regions and reduced SMA connectivity within a cerebellar network in Dysk-matched patients, without structural difference. Overall, the association of LID with impaired gait and postural control even in the OFF state is consistent with the hypothesis of broader motor network dysfunction beyond overt involuntary movements.

BACKGROUND:Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the accumulation of misfolded alpha-synuclein (α-Syn) and the subsequent loss of dopaminergic neurons. Identifying reliable and non-invasive biomarkers is crucial for accelerating early diagnosis and monitoring disease progression. To this aim, we longitudinally investigated α-Syn in salivary extracellular vesicles (SEVs) in PD patients and the correlation with clinical outcomes. METHODS:SEVs were isolated from PD patients and healthy controls (HCs) saliva using differential ultracentrifugation followed by morphological and molecular characterization. The levels of both total (α-SynTot) and oligomeric (α-SynOlig) α-Syn were quantified by ELISA. RESULTS:We found a significant increase in both α-SynTot and α-SynOlig in PD-derived SEVs compared to HCs, and receiver operating characteristic analysis revealed that α-SynOlig displayed higher sensitivity (65%) for discriminating PD from HCs compared to α-SynTot (59%). Moreover, α-SynOlig levels correlated negatively with Mini-Mental State Examination scores and were higher in patients with motor fluctuations. Finally, we found that α-SynOlig levels did not change after one-year follow-up in patients when also the clinical parameters remained unaltered. CONCLUSIONS:These results establish for the first time that SEVs-associated α-SynOlig is a promising, sensitive and non-invasive biomarker for PD diagnosis and clinical correlation studies, bearing higher sensitivity than α-SynTot. Moreover, α-SynOlig levels closely followed the clinical outcomes in PD patients. Finally, these findings strengthen the rationale for the further exploration of SEVs to disclose still unavailable accessible biomarkers for multiple neurological diseases.

BACKGROUND:Female sex increases the risk of levodopa-induced dyskinesias in Parkinson's disease (PD). While levodopa-sparing effects of monoamine oxidase-B inhibitors (iMAO-B) are established, sex differences in response to safinamide remain unexplored. OBJECTIVES:To evaluate sex differences in longitudinal (9 ± 3 months) changes in levodopa dose and total levodopa-equivalent daily dose (LEDD) with safinamide 100 mg. METHODS:We included 259 PD patients treated with safinamide 100 mg (cases, n = 130) or never exposed to iMAO-B (controls, n = 129). The primary outcome was the sex × treatment interaction on the change in levodopa daily dose adjusted for body weight. RESULTS:Safinamide 100 mg improved UPDRS-III scores and reduced OFF-time independently of sex. A significant sex × treatment interaction emerged for change in weight-adjusted levodopa dose and total LEDD, with greater reduction in women (p = 0.025 and 0.045, respectively). CONCLUSIONS:Safinamide 100 mg provides a larger levodopa-sparing effect in women, supporting sex-specific optimization of dopaminergic therapy in PD management.

Background Adaptive deep brain stimulation (aDBS) is becoming a real therapeutic option for patients candidate to DBS, and implantable devices are now commercially available. Here we present the results of a blinded randomized cross-over pilot trial aimed at comparing aDBS with conventional DBS (cDBS). Methods Fifteen patients were implanted with the AlphaDBS device (Newronika SpA, Milan, Italy, [NCT04681534][1]). In 11 patients, the device replaced a previous Medtronic Activa PC at battery depletion, while the others were four first-time implant patients. Patients underwent two study phases, a short-term follow up (ST-FUP) in the hospital in which the patient received aDBS and cDBS for one day each (in random order), and a 1-month long-term follow-up phase (LT-FUP), with the patient at home treated for two weeks in each DBS mode. The primary endpoint was safety, measured as the occurrence of stimulation-related adverse events. Secondary outcomes regarded effectiveness measured through the UPDRS-III and the UDysRS scales used in clinical setting, and a 3-day diary used for home assessment to estimate good on time (GOT, ON time without troublesome dyskinesia). At the end of the study period, patients blindly decided their preferred stimulation mode and whether or not to keep the investigational device thus entering an open label extension phase. Findings No aDBS-related adverse events were reported. The AlphaDBS device reliably recorded deep brain signals and applied a linear algorithm that changed the stimulation current every minute based on the average local field potential amplitude calculated in a patient-specific beta frequency range. In the ST-FUP, aDBS improved patients as much as cDBS, with lower UDysRS scores. In the LT-FUP, considering intra-patient individual difference, aDBS provided greater benefit than cDBS in 80% of patients. The same percentage of patients preferred and continued with aDBS to date. Interpretation These results suggest that aDBS is safe and effective and can be applied in a large population of parkinsonian patients who are candidate for DBS. aDBS improves more than cDBS the majority of patients and it is also subjectively preferred by them in the long term. Further research is needed to better understand the profile of the best responders and the scheduling of aDBS. ### Competing Interest Statement SM, AP, LR, ML, FC, SB, FT, GF are founders and shareholders of Newronika SpA. II, E.M. is member of the scientific advisory board of Newronika SpA, J.V. is member of the scientific advisory board of Newronika SpA and works as a consultant to Boston Scientific and Medtronic, and has received honoraria for lectures from Boston Scientific and Medtronic as well as research grants from Boston Scientific and Medtronic, A.M.L. is member of the scientific advisory board of Newronika SpA, has served as a consultant for Boston Scientific, Medtronic, Aleva, and Abbott and is a co-founder of Functional Neuromodulation. ### Clinical Trial [NCT04681534][1] ### Clinical Protocols ### Funding Statement The study was sponsored by Newronika SpA ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Bioethics Committee at National Oncology Institute of Maria Skłodowska-Curie, National Research Institute in Warsaw; Comitato Etico Milano Area 2; Comitato Etico IRCCS Istituto Neurologico C. Besta; Comitato Etico interaziendale AOUC Citta della Salute e della Scienza, AO Ordine Mauriziano di Torino, ASL Citta di Torino gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04681534&atom=%2Fmedrxiv%2Fearly%2F2025%2F02%2F24%2F2025.02.20.25322374.atom

The clinical characteristics of dystonia occurring in association with sporadic neurodegenerative parkinsonism have not been systematically explored or compared with those of idiopathic adult-onset dystonia. This study aims to compare demographic and clinical features, including the distribution of dystonia at onset, dystonia-associated features, and the propensity for spread between patients with combined dystonia-parkinsonism and those with idiopathic adult-onset dystonia. Patients were selected from the Italian Dystonia Registry. The study cohort included 130 patients with combined dystonia-parkinsonism and 355 age- and sex-matched patients with isolated adult-onset idiopathic dystonia. The comparison between combined dystonia-parkinsonism and idiopathic dystonia revealed differences in the distribution of dystonia across body regions, with non-task-specific upper limb dystonia, lower limb dystonia, and trunk dystonia occurring more frequently in patients with combined dystonia-parkinsonism. Additionally, this group exhibited a lower frequency of head tremor, eye symptoms associated with blepharospasm, and sensory tricks, alongside a comparable frequency of neck pain related to cervical dystonia and a family history of dystonia or tremor. The clinical presentation of dystonia differs between combined dystonia-parkinsonism and idiopathic dystonia, especially in terms of the body regions affected. These differences underscore the necessity for additional research and suggest underlying pathophysiological disparities between etiological categories that could significantly influence future diagnostics and therapeutic approaches.

Background Freezing of gait (FoG) is a debilitating symptom of Parkinson's disease (PD) with limited response to dopaminergic medication and subthalamic deep brain stimulation (STN-DBS). Substantia nigra pars reticulata (SNr) stimulation could improve FoG. Objective To analyze the effect of combined STN-SNr stimulation at different frequencies on FoG. Methods We performed a double-blind, cross-over, randomized pilot trial involving STN-DBS treated PD patients with FoG. Participants received: high-frequency (HF) STN-DBS (S), combined HF-STN and SNr stimulation (C1), and combined HF-STN and low-frequency (LF) SNr stimulation (C2), for one month each. The primary endpoint was the score change in the New-Freezing-of-Gait-Questionnaire (NFOG-Q). Secondary analyses were performed on motor complications, axial symptoms, daily living activities, psychiatric symptoms, sleep, and patient preference. Results Fifteen patients received at least one combined stimulation. No significant difference in NFOG-Q scores was found between S, C1, and C2; one-third of patients showed a clinically significant improvement (≥8 points) with combined stimulations. Motor complications improved significantly with C1 and C2 (C1-S: 3.6 ± 3.8 vs. 4.9 ± 3.8, p = 0.046; C2-S: 2.7 ± 3.1 vs. 4.9 ± 3.8, p = 0.005). 80% of patients preferred the combined STN-SNr stimulation while blinded. All adverse events were manageable. Conclusions Our study did not prove a statistically significant improvement in NFOG-Q with STN-SNr stimulation; however, one-third of patients experienced a clinically meaningful FoG improvement, and the majority preferred to maintain STN-SNr stimulation. STN-SNr stimulation was both safe and effective in addressing motor complications and improving sleep quality, highlighting the importance of further exploration into the effects of combined STN-SNr stimulation.

BACKGROUND:Continuous subcutaneous infusion of foslevodopa/foscarbidopa (CSFLI) and intrajejunal levodopa-carbidopa intestinal gel (LCIG) are established options for advanced Parkinson's disease (PD). Real-world data on early titration and management are limited. OBJECTIVES:To compare clinical course, safety, and practical implications of titration with CSFLI versus LCIG. METHODS:In this retrospective study across nine Italian centers using uniform titration protocols, we analyzed 103 patients treated with CSFLI and 129 with LCIG. Clinical outcomes, levodopa equivalent daily dose (LEDD), follow-up needs, and adverse events were evaluated over 3 months. RESULTS:Both therapies improved motor symptoms and quality of life. CSFLI required more frequent follow-up visits and larger LEDD increases to reach optimization, with common but generally mild local reactions. LCIG showed fewer titration demands, with occasional peristomal issues. CONCLUSIONS:While equally effective, CSFLI requires closer supervision during early management. Recognizing these practical differences can guide therapy selection and service planning in advanced PD.

BACKGROUND:High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves Parkinson's disease (PD) motor symptoms but may deteriorate verbal fluency (VF). Theta stimulation showed potential cognitive benefits associated with motor worsening. OBJECTIVES:This randomized, double-blind, crossover study evaluated the efficacy and safety of combined theta-gamma frequency stimulation on VF in PD patients with STN-DBS. METHODS:Patients were randomized 1:1 for standard or theta-gamma stimulation. VF, motor, and non-motor symptoms were assessed at baseline, 1 h, and 1 month after each period. Data were analyzed using a linear mixed-effects model. RESULTS:Twelve patients completed the study. Non-episodic (P = 0.038) and episodic VF (P = 0.030) improved after 1 month of theta-gamma stimulation, while phonemic and switching fluency were unchanged. Motor and non-motor outcomes were unaffected by the stimulation, with mild adverse events. CONCLUSION:Combined theta-gamma stimulation may enhance VF in PD patients with STN-DBS without worsening motor symptoms or safety concerns. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background The factors contributing to a poor response to subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD) are not yet fully understood. Accordingly, predicting the outcome might be challenging particularly in those who display an optimal response to the Levodopa challenge test. Objective To determine which factors may contribute to poor outcome of STN-DBS in PD. Methods We performed a retrospective analysis of consecutive PD patients treated with STN-DBS. Motor and non-motor variables were retrieved before surgery and at 1-year follow-up. Patients were divided into poor and good DBS responders by a cut-off value of less than 20% improvement of UPDRS-II in the OFF-medication ON-stimulation condition at 1 year. Results Thirty-two (26.2%) of 122 patients were categorised as poor responders. Before surgery, poor responders had significantly less impairment in activity of daily living and less severe motor severity. Response to levodopa challenge test was similar between poor and good responders. Significant worsening of axial symptoms at 1-year follow-up in the off-medication off-stimulation condition was found in poor responders. On multivariable linear regression analysis, only the relative change of activity of daily living by dopaminergic medications before surgery predicted its improvement by neurostimulation at 1-year follow-up. Conclusions Candidates for surgery with less impairment in activities of daily living may have less favourable outcomes after STN-DBS, despite an optimal response during the pre-operative Levodopa challenge. The worsening of axial symptoms due to disease progression might contribute to poorer outcomes, underscoring the need for better identification of these symptoms before surgery.

Parkinson’s disease (PD) is characterized by a combination of motor and non-motor symptoms, which can fluctuate over time. Recognition of nonmotor fluctuations (NMF) as a distinct and relevant feature of PD is recent, and their impact on patients' health-related quality of life (HRQoL) and on caregivers' burden remains underexplored. This study aimed to evaluate the effect of NMF on patients’ HRQoL and caregiver burden, and to compare it with the impact of motor complications (MC). Patients and caregivers were consecutively recruited from five Italian Movement Disorder centers. Assessments included the Non-Motor Fluctuation Assessment, the MDS-sponsored Unified PD Rating Scale, the Mini-Mental State Examination, the 39-item Parkinson’s Disease Questionnaire (PDQ-39), and the Zarit Burden Interview (ZBI). Linear regression analyses examined associations between total NMF and MC scores with PDQ-39 and ZBI. Logistic regression estimated the odds of moderate-severe caregiver burden based on NMF. 149 patients and 135 caregivers were included. Higher NMF scores were associated with worse HRQoL (PDQ-39: Beta = 0.318; p < 0.001), and correlated with most PDQ-39 domains, excluding stigma. MC also correlated with PDQ-39-(Beta = 0.338; p < 0.001), particularly in domains such as mobility, ADLs, communication, and bodily discomfort. Both NMF and MC scores were associated with caregiver burden (ZBI: Beta = 0.374 and 0.437, respectively; p < 0.001). Each additional NMF point increased the odds of caregiver burden by 11.6

BACKGROUND:Cervical dystonia (CD) may affect not only head posture but also gait and balance. The relationship between quantitative gait abnormalities and perceived disability, the contribution of head tremor (HT) and the impact of botulinum toxin (BoNT) on these disturbances remain unclear. METHODS:We analyzed gait and balance in twenty-one CD patients (nine with HT) and twenty-two healthy controls (HC) by wearable sensors. Validated scales for CD severity, pain and quality of life (Tsui; TWSTRS-2; CDQ24; CDIP58) were used and CD patients re-evaluated one month after BoNT. Functional impact of gait impairment was assessed by multivariate analyses. RESULTS:Compared with HC, CD patients showed reduced gait speed, cadence, and stride length, longer double-support time, greater stride-length variability (SLV), and increased postural sway (all p < 0.05). SLV was the only gait parameter associated with the CDIP58-Walking subscale (p = 0.003) and remained an independent predictor after age, sex, CD-duration and CD-severity adjustment (p = 0.035). Patients with HT had greater sway than those without tremor after adjusting for disease severity (p = 0.038). All gait and balance parameters were similar after BoNT, except for reduced gait asymmetry. In the HT subgroup, sway improved significantly (p = 0.011). CONCLUSIONS:This study confirms subtle gait and balance abnormalities in CD, with SLV emerging as a potential biomarker of functional impairment. HT appears to exacerbate balance dysfunction, while BoNT may partly improve sway in this subgroup. These findings suggest that sensor-based gait analysis may complement clinical evaluation and guide management in CD.

BACKGROUND AND OBJECTIVES:Deep brain stimulation (DBS) is an established treatment for Parkinson disease (PD). In patients carrying GBA1 variants (GBA-PD), concerns persist that DBS may accelerate cognitive decline. This study investigated the potential additive effects of GBA1 genotype and DBS on long-term motor and nonmotor outcomes. METHODS:This multicenter retrospective, controlled, Italian study included 3 groups: DBS-treated PD patients either carrying or noncarrying GBA1 variants (DBS-nonGBA-PD and DBS-GBA-PD) and GBA-PD patients who fulfilled DBS criteria but eventually were not operated. As secondary aims, we assessed the clinical outcomes of DBS-GBA-PD stratified by GBA1 variant classes and by different DBS targets. Cognitive, motor, and other nonmotor features were collected at baseline and after 1, 3 and, when available, 5 years. Between-group comparisons used χ2 and Kruskal-Wallis tests with Bonferroni correction. Longitudinal changes were analyzed with linear mixed-effects models. Subgroup analyses were performed by GBA1 variant class and DBS target. RESULTS:A total of 615 participants were included: 430 DBS-nonGBA-PD (age 57.4 ± 7.7 years, 32% female), 109 DBS-GBA-PD (age 53.5 ± 8.4 years, 38% female), and 76 nonDBS-GBA-PD (age 57.7 ± 8.1 years, 37% female). At baseline, groups were largely matched for clinical features. Longitudinally, both DBS groups showed marked motor improvement (dyskinesias, on-off phenomenon, and wearing-off, all p vs T0 < 0.001), a benefit which was absent in nonDBS-GBA-PD. At 5 years, dementia occurred more frequently in DBS-GBA-PD and nonDBS-GBA-PD compared with DBS-nonGBA-PD (25.5% vs 36.8% vs 10.8%, p < 0.001). Hallucinations and urinary problems increased in both GBA-PD groups than nonGBA-PD (p-between <0.001 and 0.02, respectively), regardless of DBS. No relevant differences emerged on stratification for variant classes or DBS targets, up to 3 years postsurgery. DISCUSSION:Despite its retrospective design, this study supports DBS as a valid therapeutic option for GBA-PD, providing prolonged benefits on motor symptoms and quality of life. The accelerated cognitive decline observed in GBA-PD, compared with non-mutated participants, was similarly present in both operated and non-operated groups, suggesting it is driven by the genotype rather than DBS itself. CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that DBS does not worsen cognitive function in patients with GBA1-associated PD.

BACKGROUND:The outcome of levodopa/carbidopa intestinal gel (LCIG) in Parkinson's disease carriers of GBA1 mutations (GBA-PD) remains uncertain. OBJECTIVE:To evaluate the safety and efficacy of LCIG in a large PD cohort, focusing on GBA1 variants. METHODS:This multicenter, retrospective, longitudinal "real-world" study included consecutive patients with advanced PD treated with LCIG at 31 Italian centers; data were collected at baseline, 1-, 5-year, and last-available follow-up. RESULTS:Data from 512 PD patients (59% male, mean age and disease duration at LCIG initiation 67.0 ± 8.0 and 12.9 ± 5.0 years, respectively) were analyzed. GBA1 genotyping was available for 306 patients (60%), of whom 40 (13%) had GBA1 mutations or risk variants. Mean follow-up on LCIG was 3.9 ± 2.9 years; 5-year follow-up data were available for 159 subjects. At baseline, GBA-PD had a younger age, shorter PD duration, worse cognition, and more hallucinations than noncarriers. At 1- and 5-year follow-up, LCIG improved motor and non-motor symptoms, OFF-time, and dyskinesias in the entire population. In GBA-PD, MDS-UPDRS parts I, II, and III scores did not change, while part IV score improved significantly less than in noncarriers; cognition and orthostatic hypotension symptoms worsened more rapidly. Multivariate analysis of predictors for adverse events and LCIG discontinuation found no significant contribution from GBA1 mutation status. CONCLUSIONS:GBA1 status does not increase the risk of adverse events or LCIG discontinuation. LCIG is a safe option for advanced GBA-PD, even in patients with cognitive impairment at baseline. However, GBA-PD experiences lower efficacy on motor disability and complications and faster cognitive decline than noncarriers.