Epilepsy-dyskinesia syndromes cover a broad spectrum of neurogenetic disorders defined by the co-occurrence of epileptic and movement disorder phenotypes. Advances in next-generation sequencing have demonstrated more than 100 causative genes converging on shared molecular pathways regulating neuronal excitability, synaptic transmission, and neurodevelopment. Despite their clinical relevance, movement disorders in these conditions remain underrecognized and incompletely characterized. This review integrates recent clinical and molecular evidence to delineate the landscape of genetic epilepsy-dyskinesia syndromes, highlighting key mechanisms, including ion channel dysfunction, G-protein-coupled signaling, transcriptional regulation, synaptic vesicle cycling, and autophagy pathways, that underlie combined epilepsy-movement disorder phenotypes. We synthesize current knowledge of genotype-phenotype correlations, emphasizing phenotypic pleiotropy and recurrent variant hot spots that modulate disease severity and dominant movement phenomenology. Building on this framework, we propose complementary categorical and phenomenology-based classification systems to guide diagnosis and management. Finally, we discuss therapeutic implications, ranging from conventional pharmacological approaches and deep brain stimulation to emerging gene-directed and RNA-based precision therapies. Recognizing epilepsy-dyskinesia syndromes as a unified nosological spectrum provides a foundation for mechanistic understanding, improved diagnostic accuracy, and the development of targeted interventions addressing both seizures and movement disorders. © 2026 International Parkinson and Movement Disorder Society.
Cervical dystonia (CD) is a movement disorder with a complex pathophysiology, including cerebellar abnormalities. Transcranial alternating current stimulation (tACS), a noninvasive neuromodulation technique capable of entraining brain oscillations, can transiently modulate neuronal activity and enhance resonant rhythms. The aim of this study was to explore whether cerebellar tACS delivered at specific cerebellar-resonant frequencies modifies fast voluntary neck movements in patients with CD and whether botulinum toxin (BoNT) therapy influences tACS effects. Eighteen patients with CD, predominantly exhibiting the torticollis phenotype, were included. Fast voluntary neck movements were objectively assessed using motion analysis during two experimental sessions: (1) pre-BoNT and (2) 1 month after BoNT. Cerebellar tACS was applied at theta (θ), beta (β), and gamma (γ) frequencies, along with sham stimulation, while patients performed fast neck movements. Peak angular velocity and angular amplitude of both prodystonic and antidystonic movements were measured. In the OFF-BoNT state, neck (antidystonic) movements' velocity and amplitude decreased with θ-tACS, particularly when stimulation was applied to the cerebellar hemisphere ipsilateral to the side of torticollis. BoNT ameliorated movement velocity and amplitude, but it did not change the detrimental effect of cerebellar θ oscillations on antidystonic movements. Driving cerebellar θ oscillations interferes with the execution of fast voluntary neck movements in CD, and BoNT therapy does not influence this effect. These findings support the view of dystonia as a network disorder in which the cerebellum plays a key role. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Cervical dystonia (CD) has a varied motor presentation, combining abnormal postures with complex involuntary head movements. Classification of these motor patterns remains imprecise, relying on descriptive terminology without robust definitions. To provide a kinematically-grounded description of the motor phenomenology of CD. Sixty-two patients with CD and 32 age-matched controls were recorded wearing inertial sensors. Voluntary movement was assessed during a head-turning task, including velocity, range of motion, smoothness, and trajectory. Kinematic metrics were extracted from samples of involuntary movements and cluster analysis was applied to identify different patterns. These were then compared with clinical appraisal of movement phenotype. Exploratory factor analysis was conducted to investigate the relationship between motor characteristics. Voluntary deficits included impaired velocity, range, smoothness, and symmetry, with no evidence of sequence effect. Three distinct clusters of involuntary head movement were identified: low-frequency oscillations with a sawtooth waveform consisting of alternating fast and slow phases (Cluster 1); erratic mid-frequency movements with constant changes in speed, waveform profile, and axis (Cluster 2); and high-frequency sinusoidal movements (Cluster 3). Cluster 2 was specifically associated with a 'jerky' clinical phenotype, while Cluster 3 was associated with a 'tremulous' phenotype. Factor analysis identified distinct latent components driving variation in voluntary deficits and involuntary movement. CD is characterized by a heterogeneous combination of oscillatory movements and impairments in voluntary head control. Kinematic analysis has the potential to refine disease classification and support the development of objective instrumental outcome measures for clinical assessment and research. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Deep brain stimulation (DBS) is an established and increasingly utilized therapy for childhood-onset movement disorders. However, pediatric DBS poses unique challenges that are not adequately addressed by adult-derived paradigms. To identify key gaps in the current use of DBS in childhood-onset movement disorders and to highlight emerging pediatric-specific strategies across the care pathway, including patient selection, targeting, surgical approaches, programming, and outcome assessment. This educational review represents the opinions of seven clinicians and clinical researchers with extensive experience in pediatric DBS and was informed by a focused literature review of key domains identified by the authors as current gaps in the field. Despite substantial progress, important gaps persist across multiple domains of pediatric DBS, including the lack of standardized, pediatric-specific selection frameworks, limited biomarkers to guide therapy, challenges in defining meaningful outcomes, and significant global disparities in access. Emerging approaches, including individualized and genotype-informed strategies, advances in neuromodulation technology, and international collaboration, offer potential pathways to address these limitations. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
The Movement Disorder Society (MDS) research criteria for possible prodromal multiple system atrophy (PP-MSA) have not been prospectively validated. To evaluate the diagnostic performance of the PP-MSA criteria in a longitudinal cohort of patients with pure autonomic failure (PAF) and to assess whether additional clinical features improve their predictive value. Seventy-six patients with PAF enrolled across eight centers in the Natural History Study of the Synucleinopathies were followed for ≥6 years or until phenoconversion. Participants were classified according to MDS PP-MSA criteria and followed for development of MSA, Parkinson's disease, or dementia with Lewy bodies. Diagnostic performance was assessed longitudinally. Analyses were repeated using a stricter olfactory threshold (University of Pennsylvania Smell Identification Test [UPSIT]≤28) as an exclusion criterion. Thirty-eight participants met PP-MSA criteria, of whom 12 phenoconverted to MSA within 6 years. Sensitivity was 100% at year 1 and 92% at year 6, whereas specificity ranged from 56% to 67%. Positive predictive value (PPV) ranged from 21% to 34%. Applying a stricter olfactory threshold improved specificity (90%-97%) and PPV (53%-83%), with a modest reduction in sensitivity (to 83%). Participants who phenoconverted to MSA were younger, had more severe urinary dysfunction, and greater orthostatic heart rate responses. The PP-MSA criteria demonstrate high sensitivity but limited specificity in patients with PAF. A stricter olfactory threshold improves diagnostic performance and may enhance cohort enrichment for clinical trials. © 2026 International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
KIF1A-associated neurological disorder (KAND) encompasses a broad neurodevelopmental and neurodegenerative spectrum in which motor and movement disorders are common but incompletely defined. To systematically characterize motor and movement disorder phenotypes in KAND. In this cross-sectional study, 51 individuals with likely-pathogenic or pathogenic KIF1A variants underwent standardized neurological assessment using the Spastic Paraplegia Rating Scale (SPRS), SPATAX disability scale, Gross Motor Function Classification System (GMFCS), and Modified Ashworth Scale. A history of global developmental delay was present in 96.1% and neonatal or infantile hypotonia in 62.7%. Progressive spasticity occurred in 72.5%, predominantly affecting the lower extremities and correlated with age (β = 0.45, odds ratio [OR] = 1.56, 95% confidence intervals [95% CI] 1.09-2.25, P = 0.016). Lower extremity weakness was nearly universal (88.2%) and inversely related with age (β = -0.08, OR = 0.93, 95% CI 0.86-0.99, P = 0.032). Independent walking was achieved by 62.7% at a median age of 24 months, but only 31.4% retained independent ambulation at last evaluation. Movement disorders included motor stereotypies (43.1%), ataxia (19.6%), action tremor (15.6%), and dystonia (3.9%). Cerebellar signs were present in 37.2%. The p.Glu253Lys variant was associated with the most severe phenotype. KAND encompasses a continuous spectrum of motor and movement disorders that integrates developmental and neurodegenerative features. These findings inform clinical management, genetic counseling, and the design of future clinical trials. © 2026 International Parkinson and Movement Disorder Society.
The identification of Parkinson's disease (PD) subtypes is crucial for predicting the disease course and designing personalized therapeutic strategies. The aim of the study was to characterize the heterogeneity of the spatiotemporal evolutionary patterns of striatal dopamine depletion and cerebral hypoperfusion in PD. We retrospectively enrolled 708 patients with newly diagnosed PD and 50 healthy controls who underwent dual-phase 18F-FP-CIT PET scans. We applied subtype and stage inference (SuStaIn) to delineate three PD subtypes after quantifying the dual-phase 18F-FP-CIT PET data. We compared the baseline clinical features as well as the longitudinal motor and cognitive outcomes between subtypes. Subtype 1 (n = 406) initially presented with asymmetric dopamine loss in the posterior putamen, followed by dopaminergic deficits in other striatal subregions and, later, cerebral hypoperfusion. Subtype 2 (n = 205) exhibited diffuse and symmetric striatal dopamine loss in the early stages, followed by cerebral hypoperfusion in the mid-stages. Subtype 3 (n = 89) initially showed the parieto-occipital hypoperfusion, followed by cerebral hypoperfusion in other cortical areas and striatal dopamine depletion. Subtype 2 had an older age of onset, and subtype 3 had a younger age of onset and a lower prevalence of rapid eye movement sleep behavior disorder. Time-dependent Cox regression models showed that the risk of dementia conversion within a follow-up period of 4 years was higher in subtypes 2 and 3 (hazard ratios 1.772 and 2.802, respectively) than subtype 1, after the confounding effects were adjusted. The risk of developing levodopa-induced dyskinesia and freezing of gait was comparable between subtypes. The spatiotemporal trajectories of striatal dopamine depletion and cerebral hypoperfusion on dual-phase 18F-FP-CIT PET images could serve as a potential progression marker for cognitive decline in early-stage PD. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Long-read sequencing and multi-omic analytical frameworks are increasingly being adopted in rare disease diagnostics. However, clinical workflows comprehensively integrating these methodologies remain uncommon. This study aimed to assess the potential and limitations of integrating long-read genomic, transcriptomic, and proteomic analyses to characterize complex structural variants. Two unrelated patients presenting with dystonia and comorbid neurological features underwent nanopore-based long-read DNA sequencing. In patient 1, complementary transcriptomic and proteomic analyses were performed. The workflow enabled the identification and characterization of two pathogenic complex structural variants: a homozygous AluY-mediated inversion disrupting PANK2, underlying neurodegeneration with brain iron accumulation (patient 1), and a heterozygous de novo 16p13.3 duplication-triplication event associated with an atypical dystonia-parkinsonism phenotype (patient 2). Our findings underscore the diagnostic potential of integrated long-read and multi-omic approaches for complex structural variant characterization, while illustrating persistent limitations of automated pipelines and highlighting unpredictable relationships between genomic, transcriptomic, and proteomic findings. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
This invited perspective paper celebrating the 40th anniversary of Movement Disorders demonstrates that the topic of physical activity and exercise as a treatment for Parkinson's disease did not feature before 2002 in this journal. The topic of physical activity and exercise garnered increasing recognition over the next two decades with several important papers published in Movement Disorders. As of 2026, there are four well-recognized treatments for Parkinson's disease: (1) exercise and physical activity; (2) general lifestyle modifications, including avoiding harmful environmental toxins; (3) medication; and (4) surgery and devices. The paper concludes by suggesting a variety of questions, the answers to which will improve clinicians' ability to help patients understand and implement the full Parkinson's exercise prescription. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Functional motor disorders (FMD) are disabling conditions modulated by attentional demands. Immersive virtual reality (iVR) engages multiple attentional and sensory networks, but its application in people with FMD (PwFMD) remains limited. We investigated whether iVR modulates spatiotemporal gait parameters in PwFMD differently from people with Parkinson's disease (PwPD) and healthy controls (HC). Wearable insoles tracked spatiotemporal gait parameters in the PwFMD (n = 30), the PwPD (n = 32), and HCs (n = 42) across three real-world (C1-C3) and three iVR (C4-C6) walking conditions with increasing cognitive and sensory load. Discriminative performance was evaluated using receiver operating characteristic (ROC) analysis, whereas group and condition effects were examined using repeated-measures analysis of variance (ANOVA) adjusted for age, sex, and body mass index (BMI). The dual-task effect (DTE) quantified the impact of cognitive load. In the iVR condition (C4-C6), gait speed, stride length, and swing-time variability discriminated both PwFMD and PwPD from the HCs with good accuracy (AUC > 0.8), particularly under higher dual-task load (C5 and C6), whereas no parameter reliably differentiated the PwFMD from the PwPD using ROC analysis (AUC < 0.7). Adjusted ANOVA revealed significant group × condition interactions for multiple gait parameters (P < 0.05). DTE analysis revealed distinct responses to cognitive load: dual-task cost was greater in PwPD than in PwFMD, which was often comparable to the HCs, particularly under cognitive dual-task conditions (C3 and C6). iVR revealed context-dependent gait abnormalities and differential responses to cognitive load in PwFMD and PwPD, which suggests its use as a paradigm to probe underlying mechanisms. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
To conduct a case-control study to investigate melanopsin-mediated post-illumination pupillary response (PIPR) in patients with Parkinson's disease (PD), video-polysomnography-confirmed isolated/idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD), and age-matched healthy controls (HC). PIPR was measured at 6 s after light offset (PIPR-6s). Net PIPR-6s was calculated by subtracting the red-light response from the blue-light response. Participants also underwent 1-week actigraphy, overnight urinary 6-sulfatoxymelatonin assessment, and cognitive testing using the Hong Kong Montreal Cognitive Assessment (HK-MoCA). We recruited 135 participants (mean age 64.4 ± 5.7 years; 56% male), with 45 in each group. Net PIPR-6s was 23.8 ± 9.4% in HC, 18.6 ± 10.8% in iRBD, and 13.3 ± 9.6% in PD (P < 0.001; HC > iRBD > PD). Net PIPR-6s was positively associated with circadian rest-activity rhythm amplitude, mesor, and HK-MoCA score. Attenuated PIPR may reflect early dysfunction in melanopsin-mediated phototransduction in the prodromal stage of synucleinopathy. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Altered immune responses including increased neutrophils have been reported in Parkinson's disease (PD); however, the role of neutrophil extracellular traps (NETs) remains unclear. The aim of this study was to evaluate the contribution of NETs to the systemic immunity and central nervous system (CNS) in PD pathogenesis. Transcriptomic analysis from the Parkinson's Progression Markers Initiative (PPMI) cohort was performed. Serum NETs were measured by myeloperoxidase (MPO)-DNA and citrullinated histone H3 (CitH3)-DNA complexes using enzyme-linked immunosorbent assay (ELISA). In addition, NET structures in postmortem brains of individuals with PD and multiple system atrophy (MSA) were quantified using ELISA and visualized by confocal microscopy. Differential expression gene analysis showed significant systemic upregulation of PADI4 expression, which encodes the NET-priming enzyme peptidylarginine deiminase 4, in patients with PD compared with control subjects. In the regional cross-sectional cohort, serum MPO-DNA complexes were reduced in patients with PD compared with control subjects and showed a graded reduction with disease severity; this reduction was independently replicated using a CitH3-DNA ELISA. In contrast, NET structures were markedly increased in postmortem brain tissues from individuals with PD and MSA compared with control subjects. Confocal imaging further confirmed the presence of NETs in the PD brain cortex, with an increased density in the substantia nigra and in close proximity to Lewy bodies. These findings demonstrated systemic priming of NET-associated pathways accompanied by reduced circulating NET complexes in PD, alongside substantial NETs deposition within the CNS. Together, these observations identify the PADI4-NET axis as a candidate immune feature of PD that warrants further mechanistic investigation. © 2026 International Parkinson and Movement Disorder Society.
Parkinson's disease (PD) is a progressive neurodegenerative disorder. Neurotrophic therapeutic approaches have been limited in part by incomplete delivery to the putamen. We developed image-guided convection-enhanced delivery with real-time monitoring to improve intraputaminal distribution of neurotrophic gene therapy. To evaluate the 5-year safety and tolerability of bilateral putaminal delivery of adeno-associated virus serotype 2 encoding glial cell line-derived neurotrophic factor (AAV2-GDNF), and to describe exploratory long-term clinical outcomes. This was a single-center, open-label, phase 1, dose-escalation study in adults with advanced PD. Thirteen participants received bilateral putaminal infusions across three dose cohorts (six low-dose, six medium-dose, one high-dose) and were followed for 5 years. Adverse events, including serious adverse events, were collected, and their relationship to the study agent was determined. Longitudinal clinical outcomes were analyzed with a mixed-effects model. Across follow-up, 562 adverse events were recorded; 45 were considered possibly or probably related to the study drug. The 13 serious adverse events that occurred were not attributed to the study drug. One participant died 45 months after infusion from aspiration pneumonia following cervical spine surgery at an outside institution. The study drug had a mean putaminal coverage of 26% ± 10%. Exploratory clinical measures did not change significantly between baseline and final follow-up. Bilateral putaminal neurotrophic gene therapy delivered with real-time image guidance was well tolerated over 5 years, without protocol-defined stopping events. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
NKX2-1-related disorders (NKX2-1-RDs) classically present with a triad of neurological, endocrine, and pulmonary manifestations, including benign hereditary chorea. However, in a fraction of patients, NKX2-1 coding variants are not detected, and variants outside the NKX2-1 locus have been reported. The objective of this study was to evaluate the clinical spectrum and frequency of regulatory variants in NKX2-1-RDs. Eight families carrying structural variants near NKX2-1 without disruption of the coding sequence were recruited, and clinical data were systematically collected. Regulatory activity was assessed using EpiMap data. Frequency and diagnostic yield were evaluated in a cohort of 26 individuals with molecularly confirmed NKX2-1-RD. Eight families comprising 13 affected individuals were identified: five with downstream deletions and three with complex structural rearrangements. Neurological manifestations were universal, including chorea, myoclonus, and ataxia, while cognitive or behavioral abnormalities occurred in a subset. Individuals with deletions rarely presented extraneurological features, whereas all carriers of complex structural variants showed the complete triad. All deletions and breakpoints were located downstream of NKX2-1. The core shared deleted region showed open chromatin and H3K27ac peaks in fetal brain, lung, and thyroid tissues, suggesting regulatory activity. Regulatory variants accounted for 27% of NKX2-1-RD diagnoses in our institutions. Exome sequencing combined with copy-number variant analysis captured 92% of diagnoses when MBIP was evaluated as a target for downstream variants. Downstream regulatory variants are a substantial cause of NKX2-1-RDs. Diagnostic strategies should include this regulatory region and systematic structural variant detection, particularly when coding variants have been excluded. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Recently, PCDHGB1 has been identified as a novel causative gene of dystonia predominantly affecting the cervical muscles. However, no large cohort study has been conducted to confirm the association. The objective of the study was to systematically evaluate the genetic associations of PCDHGB1 with dystonia in a large Chinese dystonia cohort. We analyzed rare variants of PCDHGB1 in a discovery cohort, including 878 dystonia patients, and a validation cohort, including 509 dystonia patients, using whole-exome sequencing. The overrepresentation of rare variants in patients was examined using Fisher's exact test at allele and gene levels. Twenty-seven rare variants of PCDHGB1 were identified in 55 individuals in the discovery cohort, including 3 frameshift variants (p.Leu177Valfs*7, p.Arg635Profs*24, p.Asp797Glufs*51) and 24 missense variants. Another 10 rare variants were detected in 12 patients in the validation cohort, including 1 frameshift variant (p.Leu709Argfs*13) and 9 missense variants. Fourteen patients carried the frameshift variant p.Leu177Valfs*7. Thirteen patients carried the p.Met111Val variant, including 3 patients from one family. At variant level, p.Pro773Ser and p.Arg408Gln were significantly associated with a higher risk of dystonia, whereas 15 variants (including p.Arg635Profs*24, p.Asp797Glufs*51, p.Leu709Argfs*13, and 12 missense variants) were nominally associated with a higher risk of dystonia. Gene-based burden analysis detected the enrichment of ultra-rare variants of PCDHGB1 in dystonia. Western blot experiments revealed that these four frameshift variants (p.Leu177Valfs*7, p.Arg635Profs*24, p.Asp797Glufs*51, p.Leu709Argfs*13) induced a truncated PCDHGB1 protein. Our study supplemented the evidence on the role of PCDHGB1 in dystonia and expanded the genotypic and phenotypic spectrum of PCDHGB1. © 2026 International Parkinson and Movement Disorder Society.
Dystonia frequently coexists with Parkinson's disease (PD), yet the extent of genetic overlap remains insufficiently explored. The aim was to examine whether rare variants in dystonia-related genes are associated with PD or early-onset PD (EOPD). We curated 44 dystonia-related genes using the Online Mendelian Inheritance in Man (OMIM) and the Movement Disorder Society report on hereditary dystonia. Whole-genome sequencing data from 5315 PD patients, including 300 EOPD patients, and 36,902 controls across the Accelerating Medicines Partnership-Parkinson's Disease (AMP-PD) and UK Biobank European cohorts were analyzed. Rare-variant burden analysis was performed using the optimized sequence kernel association test (SKAT-O) and MetaSKAT. In the analyses of all PD patients, no association survived multiple-testing correction. Conversely, exploratory EOPD analyses identified five significant genes (ATP5MC3, DNAJC12, KMT2B, TBC1D24, TMEM151A); however, these signals were driven by small numbers of variants and were not robust to leave-one-variant-out analyses. Rare variants in dystonia-related genes are not major contributors to overall PD risk. Signals observed in the EOPD subset require replication in larger cohorts. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
In the classical model of basal ganglia circuitry, striatal spiny projection neurons of the direct and indirect pathways (dSPNs, iSPNs) promote and suppress movement, respectively, and exhibit unbalanced activity levels during hypokinetic or hyperkinetic conditions. Most therapies for these conditions are thought to work by rebalancing the relative activity of dSPNs and iSPNs toward normal levels. However, the mechanism of amantadine, which uniquely improves both hypokinetic and hyperkinetic conditions, is poorly understood. Our aim was to determine whether amantadine restores motor function by normalizing the balance of dSPN and iSPN activity or through a distinct mechanism. We used dual-color two-photon Ca2+ imaging in the 6-hydroxydopamine (6-OHDA) mouse model of Parkinson's disease to concurrently monitor dSPN and iSPN dynamics across healthy, hypokinetic (parkinsonian), and hyperkinetic (dyskinetic) conditions. We evaluated both dSPN/iSPN activity balance and action-specific neural ensemble activity in the dorsolateral striatum. In hypokinetic conditions, levodopa rescued the dSPN/iSPN imbalance but failed to restore the disrupted activity of the locomotion-specific ensemble. Conversely, amantadine improved locomotion-specific ensemble activity without normalizing the dSPN/iSPN imbalance. In hyperkinetic conditions, forelimb dyskinesias were characterized by neural activity patterns distinct from those encoding locomotion. Amantadine selectively suppressed the resting activity of forelimb dyskinesia ensembles without affecting locomotion-coding ensembles or restoring pathway balance. Levodopa and amantadine may act through distinct mechanisms, with levodopa normalizing pathway balance and amantadine modulating action-specific neural ensembles. These findings support the importance of action-coding disruptions during hypokinetic and hyperkinetic conditions and suggest that correcting them can restore motor function. © 2026 International Parkinson and Movement Disorder Society.
Progressive supranuclear palsy (PSP) is a tauopathy for which there is limited understanding of epidemiological risk factors. The objective of this study was to identify premorbid nonmedical and medical risk factors for PSP diagnosis in a large prospective population-based cohort. We performed a matched nested case-control study using the UK Biobank (UKB) cohort consisting of >500,000 adults aged 37 to 73 years. PSP diagnoses were identified from 2007 to censor date (August 2025) and matched 1:10 by age and sex to control subjects without parkinsonism or dementia diagnoses. We derived risk factors using an iterative logistic regression approach. There were 240 incident PSP diagnoses in the UKB. In the fully adjusted model, premorbid depression (odds ratio [OR], 3.22; 95% confidence interval [CI], 2.30-4.50; P < 0.001), delirium (OR, 6.76; 95% CI, 4.08-11.19; P < 0.001), and functional gastrointestinal disorders (OR, 1.91; 95% CI, 1.39-2.63; P < 0.001) were associated with increased risk. Heavy alcohol consumption was associated with higher risk compared with moderate consumption (OR, 1.65; 95% CI: 1.21-2.26; P = 0.0017). Body mass index (BMI) and alcohol consumption had nonlinear risk profiles. Cancer diagnosis was inversely associated with PSP (OR, 0.56; 95% CI, 0.40-0.79; P < 0.001). Depression and delirium diagnoses remained significant 5 to 10 years before diagnosis. In this large prospective cohort, PSP was associated with premorbid lifestyle practices and neuropsychiatric diagnoses years before diagnosis. This suggests a long premotor phase and highlights opportunities for earlier diagnosis and further mechanistic investigation. The inverse association with cancer mirrors the relationship seen in other neurodegenerative conditions and may point toward shared mechanisms. © 2026 International Parkinson and Movement Disorder Society.
Hereditary spastic paraplegias (HSPs) comprise a heterogeneous group of heritable neurodegenerative disorders resulting from mutations in a wide variety of genes. HSP locomotor symptoms include lower limb weakness and spasticity that arise from progressive degeneration of corticospinal axons projecting from the motor cortex to the distal spinal cord. Ensuing gait defects typically lead to wheelchair dependence. Degeneration of other tracts can also occur, expanding the constellation of symptoms to potentially include urinary, fecal, and speech problems, as well as intellectual disability. SPG4-HSP, the most common variant, is caused by mutations in the SPAST gene, which encodes spastin, a microtubule-severing protein with membrane-related properties. Significant progress has been made in developing preclinical models for SPG4-HSP and in elucidating its mechanistic etiology. On this basis, progress is being made on developing a flexible therapeutic regimen for patients at all stages of disease progression. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
暂无摘要（点击查看详情）