Freezing of gait (FOG) is a common and enigmatic feature of Parkinson's disease (PD) because of its episodic and unpredictable nature. It is now clear that FOG is not a monolithic phenomenon but instead exhibits substantial heterogeneity across patients, suggesting the existence of subtypes. Among the heterogeneous features are levodopa response patterns and nonmotor features, cognitive impairment and anxiety/depression. It remains an open question as to whether these phenotypes are the result of different pathophysiology. In this paper, we develop the hypothesis that levodopa response patterns may identify FOG subpopulations tied to nonmotor symptoms and alterations in different neurotransmitter systems. Here, we review the levodopa response patterns of FOG seen in PD based on a rigorous levodopa challenge paradigm using a 40% higher dose of levodopa and blood levodopa levels to demonstrate that the majority of patients are either levodopa responsive (OFF-FOG) or unresponsive (ONOFF-FOG). The literature demonstrates that executive and affective changes are not universal in FOG and actually relate closely to levodopa response patterns, OFF-FOG is associated with affective disorders, and ONOFF-FOG is related to cognitive decline. In turn, OFF-FOG and affective disorders appear to be associated with brain noradrenergic degeneration, whereas ONOFF-FOG and cognitive decline are associated with cholinergic loss. These observations suggest different therapeutic targets by subtype. We suggest that levodopa challenge testing may help stratify FOG patients in trials and mechanistic studies.

Freezing of gait (FOG) is among the most debilitating symptoms of Parkinson disease and related disorders, often resulting in falls and a loss of independence. FOG has an episodic and heterogeneous nature that makes it difficult to measure and treat. The field currently lacks a consensus on how to precisely define this phenomenon. For this reason, the International Consortium for Freezing of Gait convened a group of experts to establish an updated ‘clinical’ definition of FOG for use in the clinical setting and a ‘technical’ definition for assessors to use when scoring FOG episodes from video recordings as an outcome in fundamental research and clinical trials. Guidelines on how to classify people with Parkinson disease into subgroups of those with or without FOG (non-FOG) are also provided. This position paper presents these new definitions and guidelines, offering a foundation for harmonizing the study and management of FOG. Freezing of gait (FOG) is among the most debilitating symptoms of Parkinson disease. This Consensus Statement from the International Consortium for Freezing of Gait presents new guidelines for the definition and assessment of FOG, with the aim of harmonizing the study and management of the condition.

PURPOSE OF REVIEW:Balance depends on accurate perception of self-motion and verticality and on multisensory integration for stance, and gait. In Parkinson's disease, balance is commonly impaired and variably affected by treatment. Although vestibular and multisensory contributions are increasingly recognized, progress is limited by fragmented evidence, inconsistent methods, and artifact-prone measures. We provide a consensus roadmap across four domains - video-oculography/vHIT, VEMPs, posturography, and perceptual paradigms - to improve clinical translation of balance research in Parkinson's disease. RECENT FINDINGS:An interdisciplinary taskforce conducted a comprehensive literature review and a modified Delphi process (≥80% agreement), using virtual meetings, surveys, and an in-person consensus session. Oculography/vHIT shows largely preserved aVOR in Parkinson's disease but is vulnerable to Parkinson's disease specific artifacts, requiring standardization. VEMPs relate to brainstem and non-motor features but are limited by EMG-dependent confounds. Posturography reveals impaired multisensory integration with visual dependence and cholinergic contributions; reactive-capacity measures outperform sway alone. Perceptual paradigms show task-specific distortions and increased variability linked to axial/postural syndromes. SUMMARY:This consensus offers a practical roadmap, de-emphasize aVOR/vHIT as primary unsteadiness outcomes; use VEMPs as ancillary measures; prioritize posturography probing adaptability and reactive stepping; integrate wearables and neurochemical imaging; and adopt consortium-level minimum datasets to enable reproducible, phenotype-aware advances in Parkinson's disease balance research.

Abstract Background Freezing of gait (FOG) is a disabling and often underrecognized feature of Parkinson’s disease (PD). Objective gait analysis may improve characterization of this motor symptom. Objective To compare quantitative 3D gait parameters in PD with FOG (PD F ) and PD without FOG (PD NF ) in a routine clinical cohort. Methods: We retrospectively analyzed a sequential sample of 180 patients with PD referred for motion analysis between 2020 and 2024. All patients underwent 3D motion capture in the off-medication state. Eighteen gait outcomes spanning pace, rhythm, postural control, variability, and asymmetry domains were derived from steady-state walking tasks. FOG status was determined using physician documentation and Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) items. Group differences between PD F (n=99) and PD NF (n=81) were evaluated using independent samples t-tests, with outcomes adjusted for disease duration and corrected for multiple comparisons. A secondary analysis among PD F compared those in Hoehn and Yahr (HCY) stage ≥III to those in HCY ≤II. Results: PD F had longer disease duration, higher OFF MDS-UPDRS III scores, and higher Hoehn and Yahr stage than PD NF but were similar in age and sex. After adjusting for disease duration and multiplicity, PD F demonstrated reduced step length, stride length, and forward velocity, and greater cadence variability, while most postural control, and asymmetry measures were comparable between groups. Among PD F , advanced HCY stage was associated with impaired pace and rhythm, similar to previous reports among PD in general. Conclusion: In this large, sequential, clinically referred cohort, FOG was associated with more advanced PD and specific impairments in pace and gait variability. These findings support comprehensive 3D gait analysis as an objective tool to better delineate FOG-related gait abnormalities and identify features that may predict FOG, informing targeted interventions.

BACKGROUND:Cervical dystonia (CD) motor severity is typically quantified with the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). An expanded version of the Motor Severity section of the TWSTRS ("TWSTRS-Delphi") has been previously evaluated for its clinimetric properties but not for inter- and intrarater reliability. OBJECTIVE:In this study we quantified inter- and intrarater reliability of the Motor Severity section of the TWSTRS-Delphi for CD. METHODS:Ten raters familiar with the TWSTRS-Delphi and ten raters unfamiliar with it independently scored standardized videos from 90 patients with CD. We computed one-way random intraclass correlation coefficient (ICC, absolute agreement) for total and item scores. We repeated assessments and calculations with a subset of raters to assess intrarater reliability. RESULTS:Interrater reliability for the Total score was good for Familiar raters (ICC = 0.697) and fair for Unfamiliar raters (ICC = 0.566). Most individual items achieved fair-excellent interrater agreement in both groups (Familiar 0.415-0.763; Unfamiliar 0.416-0.769). Sagittal Shift, Duration, and Sensory Tricks showed poor agreement. Intrarater reliability was fair-excellent for most items in both groups (Familiar 0.494-0.927; Unfamiliar 0.413-0.877), but poor for Sagittal Shift and Duration among Familiar raters. CONCLUSIONS:The TWSTRS-Delphi yields reproducible Total and item scores across movement disorder raters. The data pinpoint Sagittal Shift, Duration, and Sensory Tricks as the principal sources of between-rater variability, defining immediate priorities for scale modification and focused training.

Inhibition of cAbl tyrosine kinase reduces α-synuclein aggregation, protects dopaminergic neurons, and improves motor function in animal models of Parkinson's Disease (PD). PROSEEK was a Phase 2, randomized, double-blind, placebo-controlled study of the effects on disease progression of Vodobatinib, a brain-penetrant c-Abl inhibitor, in 513 participants with early PD not on symptomatic treatment other than a stable dose of a MAO-B inhibitor. Recently diagnosed subjects with confirmatory Dopamine Transporter Single Photon Emission Computed Tomography (DaT-SPECT) scans were randomized to daily Vodobatinib 384 mg, 192 mg, or placebo. The primary endpoint in Part 1 was the change from baseline to Week 40 in the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III total score; Part 2 was an optional 36-week extension. There was a high, dose-related rate of early withdrawal. The mean score of completers in the placebo group was slightly lower than at baseline of the entire cohort. Comparisons with either dose group favored the placebo. Serum neurofilament light chains increased significantly in both Vodobatinib groups, supporting inefficacy in PD.

Tremor is a common movement disorder associated with conditions like Parkinson's disease and Essential tremor, traditionally diagnosed through expert clinician assessment. Current automated detection methods rely on frequency-domain features informed by clinical expertise. In this work, we present an explainable, two-stage hierarchical framework for tremor detection in the time domain that learns tremor patterns directly from 3D kinematic marker time-series data across entire tremor-provoking trials. Our framework combined a deep convolutional and long short-term memory network to learn tremor representations from short, discrete, non-overlapping time segments of kinematic time series data from trials, which are then processed by a vision transformer that models their long-term temporal dynamics of time segment features for trial (session) level classification. Evaluated across nine body parts, the framework achieved F1-scores of 0.594 - 0.947 depending on body parts (average: 0.765), falling short of the frequency-domain state-of-the-art performance (0.909) while requiring minimal preprocessing. Attention weights and gradient-based class activation maps (Grad-CAM) identified time-domain features of tremor across body parts. This proof of concept demonstrated the feasibility of data-driven time-domain modeling for tremor detection across anatomically diverse body parts, while reducing reliance on expert-engineered spectral features and providing posthoc interpretability of temporal and anatomical patterns of tremor.

Freezing of gait (FOG), a common, perplexing gait disorder observed in Parkinson's disease (PD), is a leading cause of injurious falls and contributes significantly to social isolation. Unlike other PD cardinal features, FOG appears to develop independently, and its heterogeneity presents challenges for both definition and measurement. The pathophysiological mechanisms underlying FOG remain poorly understood, limiting the development of effective treatments. Although the roles of specific, targetable biomarkers in FOG development remain unidentified, evidence suggests that it is likely multimodal, potentially involving extranigral transmitter circuits. The diversity of FOG phenotypes may also reflect underlying differences in pathophysiology. In this paper, we first present evidence that FOG may occur independently of dopaminergic influence. We then review an expanding body of research supporting the hypothesis that FOG arises from a dysfunctional pathophysiological feedback loop, involving norepinephrine (NE) depletion, neuroinflammation, and amyloid-β (Aβ) accumulation. This biological disruption occurs concurrently with, but distinct from, the primary dopaminergic pathology of PD. When they occur on the background of dopamine loss, the interactions between NE, Aβ, and inflammation, as observed in Alzheimer's disease models, may similarly play a critical role in the development of FOG in PD and could serve as pathobiological markers. The proposed changes in the pathophysiological loop might even precede its onset, highlighting the need for further investigation. A deeper understanding of the involvement of Aβ, NE, and inflammatory markers in FOG could pave the way for rapid clinical trials to test existing amyloid-clearing therapies and noradrenergic drugs in appropriate patient populations.

LRRK2-PD represents the most common form of autosomal dominant Parkinson’s disease. We identified the LRRK2 p.L1795F variant in three families and six additional unrelated cases using genetic data from over 50,000 individuals. Carriers with available genotyping data shared a common haplotype. The clinical presentation resembles other LRRK2-PD forms. Combined with published functional evidence showing strongly enhanced LRRK2 kinase activity, we provide evidence that LRRK2 p.L1795F is pathogenic.

Background:Paroxysmal abdominalgia (PxA) is an underrecognized, debilitating form of abdominal pain that manifests during wearing-off (WO) periods in Parkinson's disease (PD). Despite its profound impact, PxA remains poorly described, complicating diagnosis and management. Methods:We conducted a retrospective case series of patients with PD and recurrent abdominal pain linked to WO episodes. Demographic, clinical, and detailed pain data were extracted from records. Patients with alternative gastrointestinal (GI) causes were excluded. Data were analyzed descriptively and compared with existing literature. Results:Five patients (3 males, mean disease duration 14.4 years) met inclusion criteria. PxA was characterized by severe abdominal pain-described as twisting, squeezing, or tightness-that consistently occurred during WO states and frequently led to emergency department visits and repeated GI evaluations which were unremarkable. Symptoms were often associated with anxiety and panic attacks. Standard analgesics and GI therapies were largely ineffective. Extra carbidopa/levodopa doses provided variable relief; apomorphine bolus injections and continuous subcutaneous foslevodopa/foscarbidopa infusion appeared to offer significant benefit in eligible patients. PxA symptoms aligned best with the nociplastic category of the PD Pain Classification System. Conclusions:PxA is a severe, non-motor complication of PD that likely represents a form of nociplastic pain linked to dopaminergic fluctuations. Increased awareness is needed to reduce misdiagnosis and inappropriate interventions. Further research is required to elucidate underlying mechanisms and guide targeted therapy.

Mutant huntingtin (mHTT) aggregates represent a key pharmacodynamic biomarker of Huntington's disease (HD). The development of positron emission tomography (PET) tracers targeting mHTT addresses a critical unmet need by enabling the noninvasive quantification of pathological burden in vivo. The first-generation tracer, [11C]-CHDI-180R, a benzoxazole derivative, laid the foundation for this effort. Subsequent analogs such as [11C]-CHDI-626 and [18F]-CHDI-650 were developed to improve in vivo performance; however, key challenges including limited metabolic stability and suboptimal selectivity persisted. To address these limitations, a recent study introduced a new class of isoindolinone-derived candidate tracers, including [11C]-CHDI-009, [18F]-CHDI-385, and [18F]-CHDI-386, identified through systematic structure-activity relationship (SAR) optimization. These next-generation tracers exhibit markedly enhanced binding affinity, selectivity, and translational potential, offering valuable tools to investigate mHTT pathology and its role in HD progression.

Freezing of gait (FOG) is a debilitating motor symptom that commonly occurs in Parkinson disease, atypical parkinsonism and other neurodegenerative conditions. Management of FOG is complex and requires a multifaceted approach that includes pharmacological, surgical and non-pharmacological interventions. In this Expert Recommendation, we provide state-of-the-art practical recommendations for the management of FOG, based on the latest insights into the pathophysiology of the condition. We propose two complementary treatment flows, both of which are linked to the pathophysiology and tailored to specific FOG phenotypes. The first workflow focuses on the reduction of excessive inhibitory outflow from the basal ganglia through use of dopaminergic medication or advanced therapies such as deep brain stimulation and infusion therapy. The second workflow focuses on facilitation of processing across cerebral compensatory networks by use of non-pharmacological interventions. We also highlight interventions that have potential for FOG but are not supported by sufficient evidence to recommend for clinical application. Our updated recommendations are intended to enable effective symptomatic relief once FOG has developed, but we also consider potential targets for preventive approaches. The recommendations are based on scientific evidence where available, supplemented with practice-based evidence informed by our clinical experience. Freezing of gait is a debilitating motor symptom that commonly occurs in Parkinson disease, atypical parkinsonism and other neurodegenerative conditions, the management of which is complex. This Expert Recommendation provides updated, state-of-the-art recommendations for the management of freezing of gait, based on the latest insights into the pathophysiology of the condition.

Objective gait assessment in Parkinson's Disease (PD) is limited by the absence of large, diverse, and clinically annotated motion datasets. We introduce CARE-PD, the largest publicly available archive of 3D mesh gait data for PD, and the first multi-site collection spanning 9 cohorts from 8 clinical centers. All recordings (RGB video or motion capture) are converted into anonymized SMPL meshes via a harmonized preprocessing pipeline. CARE-PD supports two key benchmarks: supervised clinical score prediction (estimating Unified Parkinson's Disease Rating Scale, UPDRS, gait scores) and unsupervised motion pretext tasks (2D-to-3D keypoint lifting and full-body 3D reconstruction). Clinical prediction is evaluated under four generalization protocols: within-dataset, cross-dataset, leave-one-dataset-out, and multi-dataset in-domain adaptation. To assess clinical relevance, we compare state-of-the-art motion encoders with a traditional gait-feature baseline, finding that encoders consistently outperform handcrafted features. Pretraining on CARE-PD reduces MPJPE (from 60.8mm to 7.5mm) and boosts PD severity macro-F1 by 17 percentage points, underscoring the value of clinically curated, diverse training data. CARE-PD and all benchmark code are released for non-commercial research at https://neurips2025.care-pd.ca/.

BACKGROUND:Dopamine dysregulation syndrome (DDS) is a debilitating complication of Parkinson's disease (PD) dopamine replacement therapy (DRT) in which patients pathologically and/or compulsively use dopaminergic drugs to treat motor symptoms. Studies examining DDS outcomes following deep brain stimulation (DBS) are limited and have focused on subthalamic targeting. CASES:Here, we present DDS outcomes in six patients from the Emory Movement Disorders clinic who underwent unilateral or bilateral DBS implantation of the globus pallidus internus (GPi). Despite motor improvements and/or initial reductions in DRT dosing, all six patients continued to meet clinical criteria for DDS 6 months post-surgery, displaying persistent pathological medication use, mood disturbances, and social impairment. Anxiety surrounding levodopa use was the most persistent DDS feature following surgery. CONCLUSION:These results indicate that pallidal DBS is not a suitable treatment for DDS and its associated symptoms.

Freezing of gait (FOG) is a debilitating symptom of Parkinson's disease (PD) and a common cause of injurious falls. Recent advances in wearable-based human activity recognition (HAR) enable FOG detection, but bias and fairness in these models remain understudied. Bias refers to systematic errors leading to unequal outcomes, while fairness refers to consistent performance across subject groups. Biased models could systematically underserve patients with specific FOG phenotypes or demographics, potentially widening care disparities. We systematically evaluated bias and fairness of state-of-the-art HAR models for FOG detection across phenotypes and demographics using multi-site datasets. We assessed four mitigation approaches: conventional methods (threshold optimization and adversarial debiasing) and transfer learning approaches (multi-site transfer and fine-tuning large pretrained models). Fairness was quantified using demographic parity ratio (DPR) and equalized odds ratio (EOR). HAR models exhibited substantial bias (DPR EOR < 0.8) across age, sex, disease duration, and critically, FOG phenotype. Phenotype-specific bias is particularly concerning as tremulous and akinetic FOG require different clinical management. Conventional bias mitigation methods failed: threshold optimization (DPR=-0.126, EOR=+0.063) and adversarial debiasing (DPR=-0.008, EOR=-0.001) showed minimal improvement. In contrast, transfer learning from multi-site datasets significantly improved fairness (DPR=+0.037, p<0.01; EOR=+0.045, p<0.01) and performance (F1-score=+0.020, p<0.05). Transfer learning across diverse datasets is essential for developing equitable HAR models that reliably detect FOG across all patient phenotypes, ensuring wearable-based monitoring benefits all individuals with PD.