Background Environmental exposures have been linked to increased risk of amyotrophic lateral sclerosis (ALS); however, their impact on disease progression remains unclear. This study examined whether prior environmental and occupational exposures influenced functional decline in patients with an established ALS diagnosis.Methods We conducted a retrospective cohort analysis using the National ALS Registry from 2010 to 2024. Participants with complete exposure histories were included. Disease progression was measured with the ALS Functional Rating Scale-Revised (ALSFRS-R) at baseline and every 3 months. Mixed-effects linear regression models assessed associations between exposures and ALSFRS-R decline, adjusting for age, sex and time since diagnosis.Results The cohort included 8618 participants with ALS. The median time from diagnosis to enrolment was 2 years (IQR= 1.1–2.9), with a median of 1 year of follow-up (IQR=1–4). Exposure to herbicides (β=−0.57. IC95%=−0.86 to −0.28, p<0.001), metal dust and fumes (β=−0.28, IC95%=−0.51 to −0.04, p=0.020) and oil paint (β=−0.27, IC95%=−0.48 to −0.06, p=0.011) prior to diagnosis were each associated with accelerated decline. Head injury was associated with an overall lower ALSFRS-R score (β=−1.74, IC95%=−2.21 to −1.27, <0.001), based on our non-linear mixed effects model.Conclusion Environmental and occupational exposures, particularly herbicides, metal dust/fumes and oil-based paints, were associated with faster ALS progression, and head injury was associated with overall worse function.

The Deep Brain Stimulation (DBS) Think Tank XIII was held September 2-4th, 2025, in Gainesville, Florida, at the Norman Fixel Institute for Neurological Diseases at the University of Florida. The theme was "The Evolving Landscape of DBS: New Indications, New Goals." This theme was a continuation of the DBS Think Tank XI and XII, which were focused on emerging technology and pushing the horizon of indications. Since its founding in 2012, the DBS Think Tank has provided a global forum for leading clinicians, engineers, and researchers in both in industry and academia to present, discuss, and debate the current state of DBS technologies as well as to consider important logistics and ethical challenges. Over the course of three days, members of each panel presented and facilitated discussions on the cutting edge of DBS research. The keynote speaker was Dr. Kamil Uğurbil of the University of Minnesota, who led the first group of researchers to demonstrate the feasibility of imaging the human brain using fMRI technology and who was a pioneer in the development of high-field human MRI scanning. Nobel laureate Dr. Stanley Prusiner, from the University of California, San Francisco, used the story of the discovery of prions to demonstrate the power of pursuing a finding even when the idea conflicted with the prevailing state of the field. The think tank was divided into sections, including: Next Generation Neuromodulation for Gait, Brain Networks and Neuromodulation, Neuroscience & Society, Interventional Psychiatry & Behavior, Devices for Closing the Loop, Physiology & Closing the Loop, and A Roadmap for Genetics & Neuromodulation.

Importance:Persons with Parkinson walk slowly, with short steps, reduced arm swing, and altered stride variability. Walking to a metronome or music may increase velocity, stride length, and cadence, yet few studies have directly compared the efficacy of these techniques. Objective:To determine the optimal auditory cue to improve Parkinson gait. Design, Setting, and Participants:This case-control study was conducted among persons with Parkinson disease (using medication) and healthy older adult controls at University of Florida Applied Neuromechanics laboratory in 2017. Changes in gait in participants with Parkinson disease and controls were compared with walking with no cue: walking to a regular metronome, walking to a fractal metronome, and walking to music. Condition order was randomized. Cueing frequency was set to natural cadence. Post hoc analyses restricted to participants with Parkinson disease were performed in 2026. Exposures:Auditory cueing with a regular metronome, fractal metronome, or music while walking. Main Outcomes and Measures:Outcomes of interest were stride time detrended fluctuation analysis (DFA), velocity, stride length, and arm swing velocity. Spatiotemporal gait measures and DFA of stride time were compared using repeated measures multivariate analysis of variance. Results:Analyses included 15 participants with Parkinson disease (mean [SD] age, 69 [6] years; 11 [73%] male; mean [SD] Hoehn and Yahr Parkinson disease stage. 2.3 [0.6]; mean [SD] age of onset, 63 [7] years) and 15 controls (mean [SD] age, 69 [5] years; 11 [73%] male). Stride time DFA was increased during the fractal metronome condition (α = 0.200; SE, 0.024; P < .001) vs no cue, the regular metronome (α = 0.320; SE, 0.032; P < .001), and music (α = 0.219; SE, 0.030; P < .001); worsened with the regular metronome vs no cue (α = -0.120; SE, 0.037; P = .003); and was not statistically different during music vs no cue (α = -0.019; SE, 0.031; P = .54). Music was associated with increased velocity (mean [SE] change, 0.041 [0.015] m/s; P = .01), stride length (mean [SE] change, 0.047 [0.013] m; P = .001), and arm swing velocity (mean [SE] change, 27.10 [7.33] °/s; P = .001) compared with no cue; velocity (mean [SE] change, 0.030 [0.011] m/s; P = .03), stride length (mean [SE] change, 0.034 [0.009] m; P = .002), and arm swing velocity (mean [SE] change, 34.7 [8.5] °g/s; P = .001) compared with the regular metronome; and increased stride length (mean [SE] change, 0.028 [0.009] m; P = .01) and arm swing velocity (mean [SE] change, 37.52 [7.89] °/s; P < .001) compared with the fractal metronome. Analyses restricted to participants with Parkinson disease found similar trends, with reduced levels of significance due to the smaller sample. Conclusions and Relevance:In this case-control study, walking to the fractal metronome was associated with improved stride time fluctuations compared with the regular metronome or music. Walking to music was associated with improved velocity, stride length, and arm swing velocity compared with either metronome condition.

BACKGROUND:Dysphagia is a known complication of Parkinson's Disease (PD). Percutaneous endoscopic gastrostomy (PEG) tube placement is a therapy for select patients with dysphagia. There is a paucity of information on the role of PEG in PD management. OBJECTIVES:To investigate the frequency and outcomes of PEG tube implantations in hospitalized patients with PD. METHODS:We performed a retrospective review of the PINC AI™ Healthcare Database of hospitalized PD patients between 2017 and 2023. PEG implantation, discharge status, and aspiration pneumonia (AP) diagnoses were collected and analyzed. The relationships between AP and PEG were evaluated using logistic regression. Generalized estimating equation (GEE) models were used to account for repeated hospitalizations and were adjusted for covariates. Odds ratios were calculated. RESULTS:There were 321,967 hospitalizations analyzed. The frequency of PEG tube placement was 1.88%. PEG implantation was associated with higher odds of AP diagnosis (OR 8.52, 95% CI 8.07-9.00; p < 0.001). Patients diagnosed with AP during hospitalization had increased odds of PEG placement compared to those with AP present on admission (OR 2.0, 95% CI 1.8-2.2; p < 0.001). PEG implantation was associated with reduced odds of discharge to hospice (OR 0.62, 95% CI 0.55-0.7; p < 0.001) and in-hospital death (OR 0.49, 95% CI 0.43-0.57; p < 0.001). CONCLUSIONS:This is the largest study of the frequency and outcomes of PEG implantation in a cohort of hospitalized PD patients. PEG implantation was associated with AP and, in adjusted GEE models, those with PEG placement were less likely to be discharged to hospice or to die in the hospital.

Abstract Tourette Syndrome and other tic disorders (TD) are common, highly heritable neurodevelopmental conditions with complex genetic architectures. We conducted a genome-wide association study of 13,247 TD cases and 536,217 European ancestry controls and identified six independent genome-wide significant loci, including a pleiotropic signal at 3p21 shared with attention-deficit/hyperactivity disorder, among other traits. Gene prioritization highlighted 20 genes, including PCDH9, HCN1, NCKIPSD, WDR6, DALRD3 , and CELSR3 . Integrative analyses provide genetic support for the role of cortico-striato-thalamo-cortical circuits in TD pathophysiology and further localize TD genetic risk to specific cell types, including dopamine D1- and D2-receptor-positive medium spiny neurons, cortical pyramidal neurons, and oligodendrocyte-lineage cells. We further demonstrate extensive genetic correlations with neurodevelopmental and psychiatric traits, but not with neurological disorders. These findings advance our understanding of the genetic basis of TD, pinpointing specific genes and cell types that drive pathophysiology and providing a foundation for future mechanistic studies.

BACKGROUND:The differential diagnosis of progressive ataxia is broad. Multiple degenerative, inherited, and acquired causes of ataxia must be considered. The presence of chorea as part of the clinical phenotype provides invaluable clinical information which may help to narrow the differential. OBJECTIVES:There are a limited number of conditions with both prominent chorea and cerebellar ataxia, and it is essential for clinicians to recognize these disorders to direct early disease-specific treatment. We aim to identify these conditions and propose a diagnostic approach. METHODS:We conducted a literature search on PubMed from January 2000 to January 2025 using search terms including "ataxia," "cerebellar ataxia," "chorea," and "ataxia-chorea syndromes." RESULTS:We identify and examine the key clinical features of several inherited disorders with this unique clinical phenotype, including spinocerebellar ataxias, Huntington's disease, dentatorubral-pallidoluysian atrophy, ataxia telangiectasia, disorders of brain iron metabolism, Wilson's disease, Niemann-Pick disease type C, ataxia with oculomotor apraxia, glucose transporter type 1 deficiency, mitochondrial cytopathies, along with other rare genetic and metabolic disorders. We provide insight into diagnostic approach and genetic testing with focus on identifying treatable conditions. CONCLUSIONS:Features unique to each disorder are discussed, along with current treatment and diagnostic considerations.

OBJECTIVES:Deep brain stimulation (DBS) of the ventralis intermedius nucleus of the thalamus (VIM DBS) effectively suppresses upper limb tremor in the setting of essential tremor (ET); however, its effect on motor learning remains unclear. This study aimed to evaluate the influence of DBS on movement consolidation, an important feature of motor learning. MATERIALS AND METHODS:A total of 16 individuals with ET undergoing VIM DBS treatment and 16 healthy controls (HC) matched for age and sex participated in this study. Participants with ET performed a goal-directed ankle dorsiflexion task over two consecutive days. On day 1, a group of participants with ET (n = 8) practiced the task with DBS off (DBS OFF), whereas the comparison group (n = 8) practiced with DBS on (DBS ON). Task retention was assessed on day 2 with the alternate condition for each group. Spatial accuracy, movement smoothness (Jerk), and tibialis anterior (TA) muscle activity were recorded during practice (day 1) and retention (day 2) for both groups. RESULTS:During the practice session, spatial error and movement smoothness were not significantly different among the three groups. However, on retention, spatial error and Jerk magnitude were greater in the DBS OFF group than in the DBS ON group and HC group. A significant positive association was found between practice and retention Jerk magnitude (R2 = 0.48). All participants manifested 4-to-8-Hz oscillations in the TA muscle, which predicted Jerk magnitude during both practice (R2 = 0.37) and retention (R2 = 0.27). CONCLUSIONS:These findings suggest that thalamic neurostimulation improves consolidation and may influence other motor learning processes. The presence of 4-to-8-Hz TA oscillations in all individuals with ET and their association with movement smoothness highlight a potential area of interest for further research.

BackgroundDifferentiating dystonic tremor (DT) from Parkinson's disease (PD) remains challenging, particularly when dystonic signs are subtle, and DT is a major contributor to scans without evidence of dopaminergic deficit. Although dopamine transporter imaging can support the distinction, it is costly and not universally accessible. Simple diagnostic indicators less reliant on subjective clinical interpretation are needed.MethodsIn a dopamine transporter imaging-supported cohort (n = 102; DT, 51; PD, 51), we used accelerometry to characterize ordinal patterns of tremor amplitude across rest, postural, and kinetic (spiral drawing) conditions. Candidate ordinal rules were evaluated, and the rule with the highest classification accuracy was selected for subsequent blinded visual assessment by three raters within the same cohort.ResultsAccelerometry showed greater kinetic tremor amplitude in DT and greater rest tremor amplitude in PD, whereas postural tremor amplitude did not differ significantly between groups. Among candidate ordinal rules, the pairwise comparison of kinetic versus rest tremor amplitude achieved the highest overall diagnostic performance for identifying DT (90% sensitivity, 85% specificity, 88% accuracy). Blinded visual classification of this rule showed excellent inter-rater agreement (Fleiss' κ = 0.92), high concordance with accelerometer-based classification (Cohen's κ = 0.86), and 90% sensitivity, 88% specificity, and 89% accuracy.ConclusionsA simple visual comparison of tremor amplitude during spiral drawing versus at rest required no specialized equipment and showed high reproducibility in blinded ratings. Although probabilistic and requiring validation in independent cohorts, this approach may serve as a practical bedside adjunct for distinguishing DT from PD.

This Perspective outlines the challenges addressed at the first Annual Parkinson's Disease (PD) Prevention Think Tank, held on November 20-21, 2025 in Gainesville, Florida at the Fixel Institute. Over the course of two days, attendees from a wide variety of disciplines, including movement disorders neurology, environmental sciences, agriculture, public policy, public health, patient advocate groups, and more, discussed the current state of primary prevention research in PD, examined the lessons learned from prevention research in other disorders, and identified necessary regulatory and policy actions for moving toward primary prevention of PD. Eight key components of primary prevention are identified (8 C's): accurately Count incidence and prevalence, Conduct longitudinal cohort studies, induce policy Change, Counsel on individual behavior change, Communicate clearly with the general public and with key stakeholders, form multi-centric Coalitions across neurodegenerative disorders, apply Cross-disciplinary approaches, and provide sustained financial Commitment to support ongoing prevention and mitigation efforts. These proceedings serve as an initial call-to-action for at-risk individuals, the clinicians who care for them, and for policymakers.

Background Urinary tract infections (UTIs) are common complications among hospitalized patients with Parkinson's disease (PD) and are associated with delirium and prolonged hospitalization. Objectives To determine the prevalence of UTI, identify modifiable risk factors, and evaluate associated outcomes among hospitalized patients with PD. Methods We conducted a retrospective cohort study using the PINC-AI Healthcare Database including PD-related hospitalizations from 2019 to 2023. UTIs diagnosed on admission or during hospitalization were identified, and multivariable analyses were performed. Results Among more than 321,000 PD hospitalizations, 18.9% were associated with UTI. Emergent admission, inter-facility transfer, dementia, and indwelling urinary catheter use were independently associated with UTI, whereas male sex was protective. UTI was associated with prolonged length of stay and delirium. Conclusions UTIs are frequent among hospitalized patients with PD and are associated with several modifiable risk factors. These findings may inform PD-specific inpatient strategies for UTI prevention and risk stratification.

Risk stratification during hospitalization may support real-world discharge planning. We developed and validated machine learning models and an interpretable risk score to predict discharge destination among patients hospitalized with Parkinson's disease using a nationwide administrative claims database. Adults aged ≥50 years hospitalized between November 2017 and June 2023 were included, and the first hospitalization was defined as the index admission. Discharge destination was categorized as home, facility, or in-hospital death. The dataset was randomly divided into training (80%) and testing (20%) cohorts. Random forest models were constructed for all discharge outcomes, and an elastic net logistic regression model was developed for facility discharge. Among 281,664 index admissions, 48.0% were discharged home, 44.8% to a facility, and 7.2% died in hospital. The random forest models achieved AUCs of 0.775 for home discharge, 0.774 for facility discharge, and 0.832 for mortality. The elastic net model demonstrated an AUC of 0.752. A seven-item risk score identified a high-risk group with a 73.8% facility discharge rate compared with 40.6% in the low-risk group. These models provide clinically interpretable risk stratification to support multidisciplinary discharge planning.

Background Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by motor and vocal tics that vary widely across individuals. Current clinical assessments primarily rely on subjective rating scales, limiting the precision of tic evaluation and treatment outcome monitoring. To improve clinical decision-making, objective, reliable detection methods are needed. Objectives This study compared the tic-detection performance of video and electromyography (EMG)-based algorithms. We hypothesized that there would be similar accuracy across modalities and that applying multimodal integration would yield potential benefits. Methods A total of 286 video and EMG sessions were recorded synchronously from 14 participants over three months. Recordings were labeled as “Rest,” “Tic,” and “Move” using a video object detection algorithm and by applying an EMG double-threshold method. Video-based detection was used as the reference for comparison. Results Overall agreement between modalities was 71.8%. EMG achieved 61.7% accuracy for “Rest” (precision: 72.4%, recall: 75.3%, F1-score: 73.8%). Despite an 81.6% accuracy, EMG performed poorly in detecting tics (precision: 15.1%, recall: 5.3%, F1-score: 7.9%) and voluntary movement (accuracy: 72.2%, precision: 14.5%, recall: 21.7%, F1-score: 17.4%). A Pearson correlation of 0.14 was found between tic frequencies captured by both EMG and video detectors, suggesting a weak positive relationship. Conclusion While EMG shows promise for detecting tics at rest, its overall stand-alone performance for tic identification was limited. These findings highlight the potential benefits of integrating video and EMG modalities to improve the accuracy and reliability of tic detection and monitoring in the setting of TS.

Background:Deep brain stimulation has emerged as an effective investigational treatment for select cases of severe Gilles de la Tourette Syndrome. Defining the optimal stimulation sites within different targets and the specific tic improvement network across targets will be important to guide neuromodulation therapies. Methods:This retrospective multi-center cohort study analyzed stimulation locations in patients who received bilateral deep brain stimulation for Gilles de la Tourette Syndrome across 12 centers world-wide. The brain targets included the thalamus (n=43), pallidum (n=56) and subthalamic nucleus (n=16). The median follow-up period was 6 months. Imaging data were processed using a dedicated pipeline and a recently introduced voxel-wise sweetspot mapping technique. Since tic response landscapes visually resembled streamline tract connections, we carried out extensive anatomical delineations of pallidothalamic and thalamostriatal fibers. This anatomical information was used to interpret sweetspot landscapes across the three target regions. Results:Tic response maps revealed three tic-response peaks in both thalamus and pallidum. Based on thalamic and pallidal response maps, outcomes in the subthalamic DBS cohort, stimulated between the two other targets, could be explained (R=0.58, p=0.019). Across the three targets, response maps followed the anatomical course of three bundles. Namely, specific subregions of the ansa lenticularis, the fasciculus lenticularis, and projections from the posterior intralaminar thalamic nuclei to the lentiform nucleus. Stimulation overlaps with these bundles explained 19% of the variance in tic improvement across the three targets. Response maps could explain variance in an independent test cohort (n=8, R=0.70, p=0.026). Response maps were also calculated for obsessive compulsive behavior, which revealed similarities to the tic response sites in pallidum but clearly distinct results and generally less efficacy in the thalamus. Conclusion:Our analyses identified tic response targets that followed the course of known structural projections interconnecting pallidum and thalamus.

OBJECTIVE:Individuals with essential tremor (ET) face a higher risk of falls, but their obstacle navigation and the effects of thalamic deep brain stimulation (DBS) remain poorly understood. METHODS:Fourteen ET with DBS and 10 healthy older adults (OA) completed an overground walk with obstacle clearance. We measured (1) foot clearance, (2) tremor, (3) EMG-EMG synchrony, (4) total time duration, (5) dysmetria, (6) MoCA, and (7) BDI. RESULTS:ET exhibited lower leading and trailing foot clearance than OA. With DBS ON, both the leading and trailing foot clearance significantly increased relative to DBS OFF. The DBS-induced increase in leading foot clearance was significantly associated with the reduction in axial tremor (R2 = 0.54) and with the increase in EMG-EMG synchrony in the axial muscles (R2 = 0.42). The DBS-induced reduction in total time duration was significantly associated with the increase in leading foot clearance (R2 = 0.37), and with the reduction in axial tremor (R2 = 0.44). Dysmetria, MoCA, and BDI scores were not associated with foot clearance. CONCLUSIONS:Thalamic neurostimulation increases obstacle clearance in individuals with ET, likely by mitigating axial tremor. SIGNIFICANCE:These findings highlight the importance of targeting axial tremor when optimizing DBS settings, as this could improve its therapeutic efficacy in mitigating fall risk.

BACKGROUND:Orthostatic hypotension (OH) is a frequent autonomic feature of Parkinson's disease (PD), yet its long-term clinical consequences remain insufficiently characterized, particularly regarding falls and major vascular events. METHODS:Adults aged ≥50 years with PD who had a 2018 hospitalization or outpatient visit and received antiparkinsonian medication were included; the first encounter served as the index. Patients with vascular events in the prior 12 months were excluded. Five-year risks were assessed using inverse probability of treatment weighting (IPTW) and propensity score matching (PSM). Logistic regression estimated ORs, negative binomial models assessed fall counts, and OH pharmacotherapy effects were evaluated. RESULTS:Among 111,368 patients with PD who met the inclusion criteria, 2598 had OH. OH was independently associated with higher 5-year fall risk (adjusted OR 1.35, 95 % CI 1.21-1.51) and more cumulative falls (IRR 1.22, 95 % CI 1.20-1.24). These associations persisted in PSM analyses. In contrast, OH was not associated with major vascular events (adjusted OR 0.99, 95 % CI 0.86-1.14). Traditional cardiovascular risk factors, including hypertension, dyslipidemia, and diabetes, were strongly associated with vascular outcomes. Among patients with OH, pharmacotherapy was associated with higher fall risk (adjusted OR 1.34, 95 % CI 1.10-1.64) but not with vascular events. Findings were consistent across sensitivity analyses. CONCLUSIONS:In this national PD cohort, both OH and its pharmacotherapy increased long-term fall risk but showed no association with major vascular events. These findings indicate distinct outcome profiles of OH, underscoring the need for focused fall-prevention and further evaluation of vascular safety.

BACKGROUND:Deep brain stimulation (DBS) has been shown to provide benefits for dystonia beyond 15 years. However, the long-term biological response to chronically implanted DBS hardware and its structural integrity over such extended periods remain poorly characterized. Pathological examination of explanted leads and especially those implanted for over a decade or more has been rarely performed. OBJECTIVE:The aim was to document the pathological findings of bilaterally explanted globus pallidus pars interna (GPi) DBS leads after 15 years of continuous therapy in a patient with DYT-1 dystonia. METHODS:We present the case of a 23-year-old woman with genetically confirmed DYT-1 dystonia who underwent bilateral GPi DBS implantation at the age of 8. After 15 years of stable therapeutic benefit, she experienced progressive functional decline despite extensive reprogramming attempts. Bilateral lead revision was performed, and the explanted DBS leads were examined macroscopically and microscopically. RESULTS:The explanted leads demonstrated striking macroscopic abnormalities, including membrane coating and mild contact degradation. Microscopic examination revealed extensive fibrous tissue encapsulation and adherent coagulated brain tissue, suggestive of a mild chronic foreign body response. The left DBS lead revealed a decreased electrical impedance, and this was correlated with contact degradation. Despite lead revision, no definitive symptom improvement occurred after 9 months. CONCLUSIONS:These findings suggest that DBS leads may maintain therapeutic function despite significant biological and structural changes over a 15-year period. Hardware integrity in this case did not correlate with clinical effectiveness.

Background: Frontotemporal dementia (FTD) is a common form of early-onset dementia, and little is known about potential modifiable FTD risk factors. We sought to determine if exposure to ambient particulate matter with a diameter less than 2·5 μm (PM2·5) and exposure to nitrogen dioxide (NO2) was associated with risk of FTD diagnosis. Methods: We conducted a population-based, nested case-control study within a source population of all individuals aged 35-95 years residing in Denmark between January 1, 2001, and December 31, 2021. Cases were identified from hospital diagnoses with FTD and matched on sex and birth date with 10 controls randomly selected using risk-set sampling. We used conditional logistic regression to estimate incidence rate ratios (IRRs) for the associations of exposure to PM2·5 or NO2. Each matched case-control set formed a separate stratum. Models were adjusted for confounding factors and stratified by age and sex. Findings: There were 3,572 incident cases of FTD identified with 35,720 matched controls (median, interquartile range [IQR] age at FTD diagnosis: 74 years [67-80];50·4% females). In adjusted models, each 5 µg/m³ increase in PM2·5 was associated with a greater rate of FTD (IRR=1·80; 95%CI:1·42–2·27). The association was stronger in females (IRR=2·24; 95%CI:1·63-3·07) compared to males (IRR=1·42; 95%CI:1·03-1·96)(p=0·040). Each 10 µg/m³ increase in NO₂ was associated with 1·14-times greater rate of FTD (95%CI:1·02–1·28) with no significant difference between females (IRR=1·22; 95%-CI:1·05-1·41) and males (IRR=1·07;95%CI:0·92-1·24)(p=0·171). Interpretation: Exposure to PM2·5 and NO2 were each associated with a higher risk of FTD. These findings strengthen the evidence supporting an association of air pollution with neurodegeneration and specifically with FTD.