BACKGROUND:Neuroimaging evidence suggests that the pathological alterations associated with blepharospasm (BSP) are not confined to a single brain region but involve large-scale brain networks. However, the higher-order interactions among connections within these networks remain poorly understood. This study proposes to use an edge-centric analytical approach combined with motif analysis to characterize abnormalities in information flow and functional integration in BSP brain networks. METHODS:Resting-state fMRI data were collected from 102 patients with BSP and 160 healthy controls (HCs). An edge-centric analytical framework was constructed and integrated with triadic motif analysis to characterize higher-order interaction patterns among connections within brain networks. RESULTS:In BSP patients, normalized entropy in the precuneus and network-level entropy in the cognitive control and default mode networks were significantly increased, with precuneus entropy positively correlated with symptom severity. BSP patients also showed stronger community similarity between the left caudate and supplementary motor area (SMA). Motif analysis revealed that, when the left caudate was the reference node, closed-loop motifs were over-expressed and negatively correlated with disease duration, whereas forked motifs were under-expressed. When the SMA was the second reference node, both closed-loop and forked motifs were over-expressed, with forked motifs positively correlated with disease duration, while L-shaped motifs were under-expressed. CONCLUSIONS:This study is the first to use edge functional connectivity combined with motif analysis to reveal abnormal higher-order interactions within the caudate-SMA-motor control circuit in patients with BSP, and it provides new perspectives for targeted circuit-based neuromodulation interventions.
Background The present study aimed to evaluate changes in hopelessness, psychological well-being, and quality of life following subthalamic nucleus deep brain stimulation (STN-DBS) in patients with Parkinson’s disease (PD). In addition, a secondary exploratory aim was to assess the role of anxiety and depression as predictors of psychological and quality-of-life outcomes after STN-DBS. Methods This prospective pre-post study enrolled 70 patients with PD, of whom 64 underwent STN-DBS and were analyzed. The Beck Hopelessness Scale, Ryff’s Psychological Well-Being Scale, Short Form-36 Health Survey, and motor (UPDRS-III) and medication-related (LEDD) data were assessed 30 days before STN-DBS (T0) and one year after STN-DBS (T1). In addition, the Beck Depression Inventory-II and State-Trait Anxiety Inventory-Form Y were administered at T0. Results After STN-DBS, hopelessness increased in the feelings about the future subscale, and psychological well-being decreased in the autonomy and personal growth subscales. In contrast, quality of life improved in the physical and mental components and in the physical role, general health, and vitality subscales. Moreover, UPDRS-III and LEDD scores decreased. Changes in LEDD showed a concurrent association with the quality-of-life vitality subscale after STN-DBS, while anxiety and depression did not emerge as significant predictors. Conclusions The findings suggest that although several quality-of-life dimensions in PD patients improve after STN-DBS, hopelessness related to future feelings and psychological well-being related to autonomy and personal growth worsen. A multidisciplinary approach that integrates neurological and psychological dimensions is essential for identifying, monitoring, and supporting patients who experience adverse psychological changes following STN-DBS.
OBJECTIVE:Scans Without Evidence of Dopaminergic Deficit (SWEDD) refers to individuals with Parkinsonian symptoms but no presynaptic dopaminergic deficit on dopamine transporter (DAT) imaging. Given its likely heterogeneity, we used a multimodal imaging approach to compare SWEDD with Parkinson's disease (PD) and healthy controls (HCs). METHODS:Twenty participants with Parkinsonian symptoms (15 PD, 5 SWEDD) and 10 HCs underwent PET imaging with 18F-FE-PE2I (DAT) and 11C-UCB-J (SV2A), along with structural MRI. Binding potential (BPND) was quantified in striatal and midbrain regions. SWEDD classification was based on putamen DAT binding >80% of age-matched HCs. An exploratory sub-analysis compared SWEDD with early PD (disease duration <4 years). RESULTS:SWEDD showed higher putaminal DAT binding than PD (Z = 2.41, p = 0.01) but no difference from HCs (Z = 1.24, p = 0.21), indicating preserved nigrostriatal integrity. Unexpectedly, SWEDD had lower ventral striatum DAT binding versus HCs (Z = -2.79, p < 0.01). SV2A binding in the substantia nigra was higher in SWEDD than PD (Z = 2.33, p = 0.01), with no difference from HCs (Z = 0.49, p = 0.61), suggesting preserved synaptic density. Structural MRI showed no volumetric differences across groups. Clinically, SWEDD had lower MDS-UPDRS II, III, and total scores than PD, with similar MDS-UPDRS I scores. CONCLUSION:SWEDD demonstrated preserved dopaminergic and synaptic integrity compared with PD, without structural differences. Multimodal imaging may help characterize biological heterogeneity within SWEDD, though larger studies are needed.
Hyperkinetic movement disorders force neurologists to ask: what movement are we seeing, and what does it mean? Developed from the Mark Hallett Plenary, this mini-review argues that digital technologies are best understood as tools for operationalised phenomenology: translating bedside descriptors into reproducible, clinically interpretable measures. From Charcot's visual documentation to Hallett's clinical neurophysiology, technology has long extended, rather than replaced, clinical observation. Wearables, smartphones, video/computer vision, EMG/EEG-EMG, and artificial intelligence now quantify selected features of tremor, chorea, dystonia, tics, myoclonus, dyskinesia, and functional hyperkinesia across clinic and real-world settings. We consider how these tools may clarify phenotype, capture fluctuation, guide treatment, support trials, and expose measurement pitfalls in mixed or context-dependent disorders. Their value depends on validation, interpretability, workflow integration, and patient relevance. Particular emphasis is placed on preserving clinical reasoning within the diagnostic funnel throughout care pathways. Machines may win at measurement; clinicians must ensure that measurement becomes meaning.
BACKGROUND:Parkinsonism is a motor syndrome traditionally considered sporadic, but genetic factors are increasingly recognized. While next-generation sequencing (NGS) has identified pathogenic variants in Parkinson's disease (PD) and related disorders, data from admixed populations like Brazilians remain limited. This study aimed to evaluate the utility of whole-exome sequencing (WES) in identifying pathogenic variants in Brazilian patients with early-onset parkinsonism or a family history of the condition. METHODS:Patients from the Federal University of Paraná's movement disorders clinic were recruited between December 2019 and July 2023. Inclusion criteria included parkinsonism, symptom onset before 45 years, and/or family history. WES was performed, with variant pathogenicity assessed using ACMG criteria. Clinical data included MDS-UPDRS-III and MoCA scores. RESULTS:Of 52 patients evaluated, 44 met PD criteria (pathogenic variants in 20.45%), while 8 had syndromic parkinsonism (pathogenic variants in 50%). The most commonly implicated genes were GBA and LYST, followed by LRRK2, PRKN, and NPC1. A novel C19Orf12 variant (c.362T > G, p.Leu121Arg) was identified in juvenile parkinsonism. Additionally, a LYST variant (c.9320G > A, p.Arg3107His), associated with Chédiak-Higashi syndrome but without classic hematological features, was reported. CONCLUSION:WES proved valuable in detecting rare pathogenic variants in Brazilian patients, uncovering atypical phenotypes and expanding the spectrum of genetic findings. These results highlight the need for broader genetic studies in admixed populations to refine diagnostics and better characterize such unique cohorts.
Subacute sclerosing panencephalitis (SSPE) is a progressive neurological complication of measles infection and movement disorders are commonly seen in this condition. We describe an 11-year-old boy with SSPE, with mixed movement phenomenology, including dystonia, slow as well as brief myoclonus, repetitive behaviours, and peculiar periodic vocalizations, which followed the slow myoclonic jerks, and discuss possible mechanisms.
PURPOSE:Parkinson's disease is one of the most common neurodegenerative disorders worldwide. We describe the first Australian family with the p.G51D glycine aspartate mutation in the alpha synuclein (SNCA) gene causing early onset Parkinson's disease and dementia. METHODS:The proband was referred to our Artemis Project - a community study of young onset dementia. The proband had an extrapyramidal syndrome with onset at age 38 and at 41 developed cognitive difficulties, which progressed to dementia and was shown to have extensive Lewy body pathology and the p.G51D SNCA gene mutation. His sister developed an extrapyramidal syndrome at age 51, cognitive decline at age 56 and remains alive with clinical diagnosis of Lewy body disease with the same mutation, as does her sister with onset at age 28 with Parkinsonism, who has recently developed dementia. The sister with older onset has a son, aged 27, with the mutation and subtle thumb tremor. The proband's neuropathological examination revealed Lewy body pathology in the substantia nigra and locus coeruleus with extensive Lewy bodies disseminated in the neocortex, brainstem, basal forebrain and limbic regions. Marked oro-lingual-cranial-cervical dystonia and anxiety complicated the natural history of the two sisters with the recent development of psychosis in one. CONCLUSION:This report expands the recognised phenotypic spectrum associated with the p.G51D SNCA mutation by documenting variable age-dependent expression, prominent cognitive decline, diffuse neocortical Lewy body pathology, and additional neuropsychiatric and dystonic manifestations. These findings contribute further evidence of the marked clinicopathological heterogeneity associated with pathogenic SNCA mutations.
BACKGROUND:Wilson's disease (WD) is a treatable disorder of copper metabolism in which early diagnosis remains challenging, particularly during the asymptomatic pediatric phase, limiting the feasibility of population-level screening strategies. OBJECTIVES:To assess the feasibility of salivary copper as a screening biomarker for pediatric WD and establish preliminary reference values in asymptomatic children. METHODS:In this cross-sectional pilot study, healthy children aged 5-15 years were recruited from pediatric outpatient clinics at a tertiary academic center. Salivary copper concentrations were quantified by ICP-MS, and percentile-based reference values were estimated. Associations with age and sex were assessed using multivariable linear regression with log10-transformed copper values. An exploratory post-hoc analysis integrating pediatric controls with patients with confirmed WD was performed using receiver operating characteristic (ROC) curve analysis. RESULTS:A total of 114 children were included. Salivary copper concentrations showed a right-skewed distribution, with a median of 12.19 μg/L (IQR: 8.67-19.73 μg/L). The preliminary upper reference threshold was 30.73 μg/L after exclusion of extreme outliers. Salivary copper levels were not significantly associated with age or sex. In exploratory ROC analysis, salivary copper showed promising discriminative performance for WD (AUC 0.822, 95% CI 0.701-0.942). The Youden-derived cutoff (14.94 μg/L) showed higher sensitivity and moderate specificity, whereas higher thresholds demonstrated high specificity but lower sensitivity. CONCLUSIONS:Salivary copper measurement is a feasible, non-invasive biomarker with potential application in pediatric WD screening. These findings support a dual-threshold strategy for screening and confirmatory assessment, although larger multicenter validation studies are required.
Delayed gastric emptying is a well-recognized non-motor feature of Parkinson's disease (PD) and a critical determinant of levodopa pharmacokinetics. Glucagon-like peptide-1 (GLP-1) receptor agonists are increasingly prescribed for metabolic disorders and weight loss and are under investigation as potential disease-modifying therapies in PD. However, GLP-1 signaling exerts a potent inhibitory effect on gastric motility. This creates a mechanistic convergence whereby PD-related gastrointestinal dysfunction and GLP-1-mediated gastric slowing may synergistically impair transmission of levodopa and other dopaminergic drugs to the gut and thereby limit its efficacy. Here, we synthesize current evidence on the shared neuro-gastroenterological pathways linking PD and GLP-1 signaling, and we propose a conceptual "double-hit" model of delayed gastric emptying. We further examine the implications of this interaction for levodopa pharmacokinetics and motor fluctuations, highlighting a clinically relevant trade-off between the potential benefits of GLP-1 receptor agonists and their immediate negative impact on dopaminergic therapy.
BACKGROUND:Helicobacter pylori (H. pylori) infection has been associated with impaired levodopa absorption and worse motor symptoms in Parkinson's disease (PD). However, the relationships among H. pylori infection, eradication history, levodopa pharmacokinetics, and motor severity remain unclear. METHODS:We retrospectively analyzed 40 patients with PD who underwent standardized levodopa/carbidopa pharmacokinetic testing. Participants were classified as HP-positive, never infected, or prior eradication. Plasma levodopa and carbidopa concentrations were measured serially after administration of 100 mg levodopa and 10 mg carbidopa. Pharmacokinetic parameters, including maximum plasma concentration (Cmax), time to Cmax (Tmax), and area under the concentration-time curve (AUC), were compared among groups. Motor severity was assessed using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III. RESULTS:No significant differences were observed among the three groups in levodopa or carbidopa pharmacokinetic parameters, including levodopa AUC (p = 0.956). In contrast, MDS-UPDRS Part III scores differed significantly among groups (p = 0.038). Post hoc analysis demonstrated lower motor scores in the prior eradication group than in the HP-positive group (adjusted p = 0.032). Multivariable analysis confirmed an independent association between prior eradication status and lower MDS-UPDRS Part III scores (β = -14.57, p = 0.005). No significant correlation was observed between levodopa AUC and motor severity. CONCLUSIONS:H. pylori eradication status was associated with lower motor severity despite similar levodopa and carbidopa pharmacokinetics. These findings suggest that mechanisms beyond acute levodopa absorption may contribute to the relationship between H. pylori and motor symptoms in PD.
BACKGROUND:Gait disorders are a major cause of disability in Parkinson's disease (PD). Trans-spinal magnetic stimulation (TsMS) shows therapeutic potential, and treadmill training (TT) is widely used; however, their combined effects are unclear. OBJECTIVES:To investigate whether intermittent theta burst TsMS (iTB-TsMS) modulates TT effects on gait, freezing of gait (FoG), motor symptoms, and quality of life. METHODS:In this randomized, double-blind, controlled, multicenter trial, individuals with PD and gait disturbances were recruited from three Brazilian centers (June 2023-January 2025). Participants received 10 iTB-TsMS or sham sessions plus TT over 2 weeks. Primary outcome was change in fast gait speed (FGS); secondary outcomes included MDS-UPDRS II-III, comfortable gait speed, TUG with/without dual task, Mini-BESTest, 2MWT, FoG-Q, FoG-Score, 360° Turn Test, PDQ-39, FES-I, and falls/near-falls, assessed at baseline (T0) and 3 (T3), 15 (T15), 30 (T30), and 90 (T90) days post-intervention. RESULTS:Seventy participants were included in the modified intention-to-treat analysis. Groups differed in FGS change at T3 (AMD 0.13 m/s; 95% CI 0.05-0.21; p = 0.001; f2 = 0.06), not sustained thereafter. Between-group differences in FoG severity were observed in FoG-Q at T15 (AMD -1.46; 95% CI -2.93 to 0.00; p = 0.050), T30 (AMD -2.30; 95% CI -3.77 to -0.83; p = 0.002), and T90 (AMD -1.75; 95% CI -3.22 to -0.29; p = 0.019), with small-to-moderate effect (f2 = 0.08), and in FoG-Score at T3 (cOR 0.21; 95% CI 0.05 to 0.97; p = 0.046). At T3, MDS-UPDRS II (AMD -2.10; 95% CI -4.17 to -0.03; p = 0.047; f2 = 0.02) and near-falls (cOR 0.36; 95% CI 0.18 to 0.72; p = 0.004) differed between groups, whereas PDQ-39 mobility improved at T30 (AMD -7.38; 95% CI -13.5 to -1.28; p = 0.018; f2 = 0.02). After correction for multiple comparisons, only FGS (T3) and FoG-Q (T30) remained significant. DISCUSSION:Among individuals with PD and gait disturbances, adding iTB-TsMS to TT did not produce sustained benefits over TT alone. After correction for multiple comparisons, significant effects remained for FGS at T3 and FoG severity at T30, whereas other outcomes were exploratory. The protocol was safe and well tolerated. Findings are hypothesis-generating. TRIAL REGISTRATION:ClinicalTrials.gov (NCT05938673).
Gastrointestinal dysfunction represents a pervasive and disabling group of non-motor symptoms that often go unrecognized and untreated in Parkinson's Disease(PD). These symptoms can affect levodopa responsiveness, quality of life, and nutritional status. Because gastrointestinal symptoms may be highly stigmatizing or embarrassing, some patients-particularly those from certain cultural backgrounds and genders-may feel uncomfortable raising these concerns or answering sensitive questions in the presence of family members or caregivers during clinic visits. To address this gap, a brief, discrete questionnaire was developed to facilitate proactive and practical screening andto operationalize the consensus recommendations for the management of GI dysfunction in PD established by the Parkinson Study Group. The questionnaire can be completed by patients before their visit or administered privately by nursing staff or physicians, thereby promoting recognition of GI symptoms and improving the quality of care for individuals with PD.
