Ensayos clínicos e investigación

BACKGROUND

Oxidative stress is central to type 2 diabetes mellitus (T2DM) and Parkinson's disease (PD).

However, the utility of biomarkers for lipid peroxidation (F2-isoprostanes) and DNA damage (8-OHdG) in the comorbidity of PD and T2DM remains unclear.

METHODS

We conducted a systematic review and meta-analysis of 54 unique studies of human subjects aged ≥ 50 years (n = 7,521: 3,522 with T2DM, 722 with PD, and 3,277 controls), measuring biomarkers in serum, plasma, or leukocytes.

Mixed-effects models quantified standardized differences (Hedges' g) across subgroups.

RESULTS

In T2DM, F2-isoprostanes (g = 1.60, 95% CI: 0.95-2.25) and 8-OHdG (g = 2.64, 95% CI: 2.13-3.14) were markedly elevated (p g = 5.24).

In PD, 8-OHdG was moderately elevated (g = 0.78, 95% CI: 0.18-1.39; p = 0.011), particularly in randomized controlled trials and plasma samples, whereas F2-isoprostanes were not significantly elevated (g = 0.47, 95% CI: -0.43-1.38).

High heterogeneity in T2DM (I2 > 90%) reflected methodological variability.

CONCLUSION

Distinct profiles - both markers elevated in T2DM but only 8-OHdG in PD - underscore 8-OHdG's potential in PD-T2DM comorbidity.

Future research should focus on standardized assays, multi-compartmental or multi-modal sampling, and longitudinal studies to clarify mechanisms and therapeutic targets.

OBJECTIVE

Given the persistent absence of direct head-to-head trials, this study aimed to evaluate the comparative efficacy, safety, and cost-effectiveness of rasagiline versus selegiline as early-stage monotherapy for Parkinson's disease (PD), informing clinical selection and healthcare policies in China.

METHODS

A systematic search of PubMed, Embase, and the Cochrane Library identified randomized controlled trials (RCTs) up to April 2026.

Focusing on short-term outcomes (10-16 weeks), an adjusted indirect treatment comparison (ITC) using placebo as a common anchor evaluated symptom improvement (UPDRS total scores) and adverse event (AE) incidence.

For economic evaluation, a 2-year Markov model was constructed from a Chinese healthcare-system perspective.

The incremental cost-effectiveness ratio (ICER) was calculated alongside robust sensitivity analyses.

RESULTS

Ten RCTs (rasagiline: 6; selegiline: 4) were included.

The ITC revealed no statistically significant differences between rasagiline and selegiline in short-term symptomatic relief (Mean Difference = -0.82, 95% CI [-2.08, 0.44], p = 0.203) or AE risk (Odds Ratio = 0.83, 95% CI [0.50, 1.38], p = 0.475).

The overall evidence certainty was rated as moderate.

Economically, the base-case simulation indicated rasagiline yielded a marginal benefit of 0.0088 QALYs over selegiline but incurred an additional 17,111.10 Yuan.

This resulted in an ICER of 1,951,505.55 Yuan/QALY, substantially exceeding the conventional willingness-to-pay threshold.

CONCLUSION

Supported by moderate-certainty evidence, rasagiline and selegiline provide comparable short-term efficacy and safety for early-stage PD monotherapy.

However, at its current pricing, rasagiline is not cost-effective.

Significant price reductions or definitive proof of long-term superiority are required to justify its economic value.

BACKGROUND AND OBJECTIVES

Pain associated with foot dystonia is a common and disabling symptom of Parkinson disease (PD), often occurring during OFF periods, yet frequently refractory to medication optimization.

Evidence supporting treatments for dystonia-related pain in PD remains limited.

This study evaluated the efficacy and safety of onabotulinumtoxinA (BTXA) for pain associated with foot dystonia in patients with PD.

METHODS

This single-center, randomized, double-blind, placebo-controlled trial assessed outcomes at 6 and 12 weeks, followed by a 12-week open-label extension.

Adults with unilateral PD and painful foot dystonia refractory to medication optimization were randomized 1:1 to receive BTXA (100 units) or placebo using a guided injection protocol targeting the tibialis posterior, extensor hallucis longus, and flexor digitorum brevis.

The primary outcome was change from baseline in dystonia-related pain assessed using Item 5 of the King's Parkinson's Disease Pain Scale (KPPS).

Secondary outcomes included responder rates (≥30% pain reduction), KPPS Domain 3 total score, KPPS Item 5 pain severity and frequency subitems, Visual Analogue Scale (VAS) pain, Clinical Global Impression, motor outcomes (Movement Disorder Society-Unified Parkinson's Disease Rating Scale III and IV), quality of life, and safety.

RESULTS

Thirty-three participants were randomized (BTXA, n = 16; placebo, n = 17).

BTXA resulted in significantly greater reduction in dystonia-related pain assessed by KPPS Item 5 total score compared with placebo at 6 weeks (mean difference -3.60), with effects sustained at 12 weeks (p p < 0.001).

No differences were observed in motor outcomes, quality of life, or adverse events, which were mild.

DISCUSSION

BTXA reduced pain associated with foot dystonia in PD without adversely affecting motor outcomes and was well tolerated, supporting its use as a targeted treatment for this disabling symptom.

TRIAL REGISTRATION INFORMATION

NCT04277247.

BACKGROUND

Parkinson's disease (PD) is a chronic progressive neurodegenerative disease with debilitating clinical presentations.

Common therapeutic approaches for symptomatic improvement are often effective for a temporary period of time, after which patients often experience progressive disabilities.

Cell replacement therapy is a potential therapeutic method that aims to replace depleted mesencephalic dopaminergic (DA) neurons, which may control symptoms and halt disease progression.

Preclinical studies have investigated the efficacy of these PSC-derived DA cells in animal models of PD.

METHODS

In this study, we comprehensively examine preclinical data on the therapeutic effect of primate PSC-derived DA progenitors on motor deficits in animal models of PD as a precursor for conducting human clinical trials.

Relevant articles published before August 14th, 2023, were obtained from PubMed, Scopus, and Web of Science.

RESULTS

Through several rounds of screening, 46 studies that met our inclusion criteria were included in this study.

The quality of each study was assessed using CAMARADES and SYRCLE approaches.

Although no included studies were judged to have an overall high risk of bias, several studies exhibited domain-specific methodological limitations.

The analyzed studies demonstrate that cell therapy significantly improves motor dysfunction in rodent and non-human primate models of PD.

CONCLUSION

This systematic review and meta-analysis demonstrate that PSC-based cell therapy significantly improves motor dysfunction in rodent and NHP models of PD and could be a promising approach for halting disease progression, improving behavioral manifestations of the disease, and increasing the overall quality of life in PD.

Parkinson's disease (PD) is a neurodegenerative condition primarily characterized by motor deficits, yet cognitive impairments are increasingly recognized.

While deficits in executive functioning are well documented even in the absence of cognitive decline, evidence of attentional deficits in PD remains inconsistent, and the role of motor symptom lateralization is unclear.

In this systematic review and meta-analysis, we examined visual attention in right-handed, cognitively unimpaired idiopathic PD patients, focusing on the canonical attentional domains (sustained, selective, divided) and processes (alerting, endogenous and exogenous orienting, reorienting), as well as visuospatial bias.

Four databases were searched for studies comparing PD patients with healthy controls.

Meta-analytic estimates were derived using Hedges' g within random-effects models, and studies that could not be quantitatively integrated were summarized narratively.

In addition, studies directly comparing patients with left- and right-predominant motor symptoms (LPD vs.

RPD) were reviewed qualitatively.

Across 51 studies, PD patients exhibited deficits in sustained, selective, and divided attention.

Among attentional processes, only exogenous orienting was impaired, whereas alerting, endogenous orienting, and reorienting were preserved.

Findings from the few studies examining visuospatial bias indicated small, context-dependent shifts in spatial attention rather than a consistent directional bias.

These findings indicate that PD patients show visual-attentional impairments, particularly under high-demand conditions, while basic alertness and voluntary orienting appear preserved.

Exogenous orienting deficits and subtle rightward spatial tendencies in LPD suggest disruption of right-hemisphere attentional networks.

These results have implications for early cognitive assessment, rehabilitation strategies, and understanding the neural bases of attentional dysfunction in PD.

BACKGROUND AND OBJECTIVES

Evidence for the effect of physical activity on disease progression in Parkinson disease (PD) remains limited.

We aimed to examine whether physical activity is associated with the rate of motor and cognitive progression in PD and to identify specific components of physical activity underlying these associations.

METHODS

In this longitudinal cohort study, we analyzed data from individuals with mild-to-moderate PD enrolled in the Cincinnati Cohort Biomarker Program between January 2019 and February 2025.

Physical activity was assessed using standardized interviews and quantified as total physical activity time (TPT), total physical activity volume (TPV), and vigorous physical activity time (VPT).

Longitudinal associations between physical activity and annual changes in Movement Disorder Society-Unified Parkinson's Disease Rating Scale, part III (MDS-UPDRS-III; higher is worse) and Montreal Cognitive Assessment (MoCA; higher is better) scores were assessed using linear mixed-effects models adjusted for demographic and disease-related covariates.

We compared predicted severity trajectories across tertiles of TPT and used residualized analyses to evaluate the independent effects of activity intensity and timing.

RESULTS

A total of 294 individuals with PD (mean age, 66.4 years; 33.0% female) were included, with up to 5 years of follow-up for MoCA and 7 years for MDS-UPDRS-III.

Higher TPT, TPV, and VPT were each associated with slower cognitive decline and motor progression.

The annual MoCA change was -0.478, -0.090, and -0.007 points in the low, mid, and high TPT tertiles, respectively, with corresponding annual MDS-UPDRS-III changes of 0.143, -0.225, and -0.783.

Compared with the lowest tertile, the highest tertile showed slower cognitive (β = 0.470; 95% CI 0.203-0.737; p p = 0.048) progression.

In residualized analyses, recent physical activity remained associated with longitudinal changes in both MoCA and MDS-UPDRS-III scores after accounting for previous 10-year physical activity, whereas vigorous physical activity was no longer associated with outcomes after adjustment for total physical activity time.

DISCUSSION

Higher levels of physical activity were associated with slower cognitive and motor progression in PD.

The beneficial associations of moderate-to-vigorous physical activity may be related to activity duration and ongoing engagement.

Limitations include the observational design, self-reported physical activity, and potential selection bias.

BACKGROUND AND OBJECTIVES

The gold standard for Parkinson disease (PD) diagnosis is postmortem examination, based on the presence and distribution of pathologic α-synuclein (Lewy pathology) across brain regions.

Whether pathologic α-synuclein Braak staging reflects clinical disease progression remains uncertain.

We examined the relationship between Braak stage with clinical indices of PD progression in an autopsy-proven cohort.

METHODS

We performed a retrospective clinicopathologic analysis of autopsy-confirmed PD cases from the Parkinson's UK Brain Bank (Imperial College London).

Clinical records were systematically reviewed to extract age at symptom onset, disease duration, brain weight, Hoehn and Yahr (H&Y) stage at death, and key clinical features.

Normality was assessed using Shapiro-Wilk tests; comparisons across Braak stages used Kruskal-Wallis tests.

Correlations with Braak stage were examined using Spearman correlation with 95% CIs.

Prevalence of major copathologies was summarized descriptively.

RESULTS

Of 119 clinically diagnosed PD cases, we included all 61 with autopsy confirmation and available Braak staging.

Mean ± SD age at death was 79.1 ± 7.4 years, disease duration was 13.5 ± 5.8 years, H&Y stage at death was 4.0 ± 0.8, and brain weight was 1,234.2 ± 108 g.

Braak stage was not correlated with H&Y at death (ρ = 0.146, 95% CI -0.11 to 0.39, p = 0.262), age at death (ρ = -0.210, 95% CI -0.47 to 0.07, p = 0.104), disease duration (ρ = 0.035, 95% CI -0.23 to 0.29, p = 0.787), or brain weight (ρ = 0.2, 95% CI -0.07 to 0.42, p = 0.139).

There were no differences across Braak stages in disease duration (p = 0.925), age at death (p = 0.356), brain weight (p = 0.279), or H&Y stage (p = 0.603).

By contrast, brain weight correlated negatively with age at death (ρ = -0.352, 95% CI -0.57 to -0.09, p = 0.005).

Copathologies were common, including entorhinal/allocortical tau (B1-B2) in 82%, small vessel disease in 60%, β-amyloid (Thal ≥1) in 58%, and cerebral amyloid angiopathy in 25%.

The prevalence of copathologies did not differ across Braak stages.

DISCUSSION

Braak stage was not associated with H&Y at death, disease duration, age at death, or brain weight in autopsy-proven PD patients.

These findings provide evidence that pathologic α-synuclein-based staging does not represent a model of clinical progression in PD.

The quantification of both monomeric and pathologic α-synuclein may be needed to overcome the clinical limitations of pathology-based staging.

OBJECTIVE

To synthesize the evidence on the efficacy and safety of mirabegron and intradetrusor onabotulinumtoxinA (BoNT-A) as separate interventions for overactive bladder (OAB) in Parkinson's disease (PD).

METHODS

A systematic review and meta-analysis with parallel synthesis of two distinct interventions was conducted of randomized and observational studies involving adults with idiopathic PD and OAB treated with mirabegron or BoNT-A.

Primary outcomes included mean change in 24-h voiding frequency, nocturia, urgency, and incontinence.

Secondary outcomes were postvoid residual (PVR) volume and adverse events.

Pooled outcomes were reported as mean differences (MDs), representing the change in symptoms from baseline to follow-up; negative MDs indicate a reduction in symptom frequency.

RESULTS

No direct head-to-head comparative trials of mirabegron versus BoNT-A were identified; however, eight single-arm pre-post studies met the inclusion criteria.

Pooled analysis showed reductions in 24-h urinary frequency (MD -4.48; 95% CI -8.45 to -0.52), nocturia (MD -1.36; 95% CI -2.68 to -0.05), urgency (MD -2.68; 95% CI -7.08 to 1.72), and incontinence (MD -1.24; 95% CI -1.98 to -0.50).

BoNT-A was associated with a mean increase in PVR (+43 mL), whereas mirabegron was associated with minimal change (+3 mL).

Adverse events were generally mild with mirabegron (e.g., dizziness, constipation, hypertension), whereas BoNT-A was associated with transient urinary retention and urinary tract infection.

The certainty of evidence across outcomes was low to moderate and therefore should be interpreted with caution.

CONCLUSION

Currently, no studies have directly compared the benefits of mirabegron versus BoNT-A.

Available study data confirm that both mirabegron and BoNT-A were associated with directional reductions in several OAB symptoms in PD.

However, urgency and most subgroup analyses did not reach statistical significance.

The overall certainty of evidence was low to moderate due to small sample sizes, heterogeneity, and short follow-up.

These findings are hypothesis-generating and should be confirmed in larger, randomized controlled trials with longer follow-up and ideally comparing effects head-to-head.

PROSPERO Registration: CRD420251181682.

INTRODUCTION

Bilateral electrode implantation is the primary approach for deep brain stimulation (DBS) in Parkinson's disease (PD).

However, it may lead to gait deterioration in some patients.

This study aimed to investigate the efficacy of unilateral DBS on gait in PD patients as an alternative with fewer side effects and lower costs.

METHODS

We systematically searched four major clinical databases to evaluate the effects of unilateral DBS on UPDRS gait score, gait velocity, stride length, cadence, and gait initiation in PD patients.

Twenty-three studies were included in the review, selected from an initial pool of 2,415 studies.

We also performed a meta-analysis to assess the impact of unilateral DBS on gait velocity and compare its efficacy to bilateral stimulation.

The study protocol was registered at PROSPERO with the registration code: CRD42024585359.

RESULTS

The included studies assessed gait measures in patients receiving unilateral DBS targeting the STN, globus pallidus internus, pedunculopontine nucleus, and ventral intermediate nucleus.

According to the systematic review of clinical evidence, unilateral DBS can improve the UPDRS gait score, freezing of gait, and gait velocity, although to a lesser extent than bilateral stimulation.

The meta-analysis revealed a nonsignificant positive pooled effect on gait velocity in the unilateral DBS condition compared to the control condition and no significant difference when compared to bilateral DBS.

CONCLUSION

Unilateral DBS shows promise for improving gait in PD, as an alternative with lower costs and side effects, especially in early-stage or asymmetric cases.

The association between pesticide exposure and Parkinson's disease (PD) is substantial, but heterogeneity in methodology and lack of categorization according to the type of exposure and pesticide classes in previous meta-analyses impair the interpretation of data.

This study aims to update evidence of the association between pesticide exposure and PD.

We conducted a systematic review and meta-analysis of studies investigating associations between pesticide exposure and PD according to the type of pesticide exposure and pesticide class.

We searched PubMed, EMBASE, and Web of Science until July 2024.

Reviewers screened titles and abstracts.

Afterward, reviewers reanalyzed the selection criteria and extracted the data based on the full paper.

Meta-analyses were conducted to assess the association between pesticide exposure and PD.

A total of 124 studies were eligible.

There is a lack of diversity in the populations represented and a high variability in methodology among the included studies.

Considering only studies with any type of exposure, we found a positive association of PD with any pesticide class and herbicides.

Occupational exposure was associated with PD for all pesticide classes except for fungicides.

Exclusive household pesticide exposure was also associated with PD.

Pesticide exposure remains a significant environmental risk factor for the development of PD, regardless of the type of exposure.

Herbicides are the pesticide class with the most substantial evidence of association with the disease.

Further studies with new methods of pesticide exposure measurement, innovative design studies, and the inclusion of underrepresented populations are still needed.

BACKGROUND AND OBJECTIVES

Recent reports have suggested that levodopa exposure may contribute to freezing of gait (FOG), but this relationship remains controversial because of confounding by disease severity and duration.

Our goal was to assess the relationship between levodopa use and FOG incidence and severity.

METHODS

We studied 2 prospective, multicentric cohorts: NS-Park and Parkinson's Progression Markers Initiative (PPMI).

Patients with ≥2 visits were selected.

Three nested subcohorts were defined based on disease duration, baseline FOG, and levodopa exposure.

FOG was assessed using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II 2.13.

Analyses included mixed-effects ordered logistic regression to evaluate FOG severity and Kaplan-Meier and Cox proportional hazards models to assess incident FOG.

Models adjusted for disease duration, Hoehn and Yahr (H&Y) stage, and MDS-UPDRS Part III scores.

RESULTS

A total of 25,602 patients with Parkinson disease from the NS-Park (mean age 68.3 ± 29.1, 42% female) and 1,441 from the PPMI (mean age 62.9 ± 9.8, 37% female) cohorts were included.

In unadjusted analyses with the NS-Park cohort, levodopa use was associated with higher FOG severity and incidence, but this association was no longer statistically significant in the PPMI cohort.

In mixed-effects ordinal logistic regression models adjusting for disease duration/severity, levodopa status showed a nonsignificant effect size on FOG (NS-Park odds ratio [OR] 1.84, 95% CI 0.94-3.61, p = 0.074; PPMI OR 0.76, 95% CI 0.38-1.51, p = 0.430), while disease duration (NS-Park OR 4.4, 95% CI 3.01-6.29, p = 6.0e-15; PPMI OR 6.97, 95% CI 5.05-9.63, p = 4.7e-32), Hoehn & Yahr stage (NS-Park OR 6.8, 95% CI 3.52-13.08, p = 1.059e-08; PPMI OR 1.5, 95% CI 0.96-2.22, p = 0.073), and MDS-UPDRS-III score (NS-Park OR 1.85, 95% CI 1.38-2.49, p = 4.34e-05; PPMI OR 2.00, 95% CI 1.67-2.39, p = 2.4e-14) were independently associated with greater FOG severity.

No statistically significant association was observed between future levodopa exposure and de novo FOG incidence.

In turn, FOG incidence was driven by the H&Y (NS-Park: hazard ratio [HR] 1.94, 95% CI 1.68-2.23; PPMI: HR 1.78, 95% CI 1.47-2.17) and MDS-UPDRS III (NS-Park: HR 1.40, 95% CI 1.07-1.83; PPMI: HR 1.26, 95% CI 1.17-1.36).

DISCUSSION

No significant or consistent association between levodopa exposure and FOG severity or incidence was observed after adjustment for disease duration and severity, with the effect estimates significantly attenuated despite residual uncertainty.

Language often incorporates mechanistic assumptions.

Terms used to describe protein behavior and properties, such as "accumulation," "replication," "propagation," and "strains," largely borrowed from prion biology and investigated in animal models, have shaped how Parkinson disease is understood.

Similarly, clinical constructs such as "phenoconversion," "prodrome," "resilience," and "copathology" embed assumptions about disease onset and pathogenicity.

In this article, we explore how our vocabulary has contributed to the transformation of hypotheses into widely accepted conventions.

We argue that greater precision in language may help clarify the difference between observation and inference: Aggregated proteins can be described as pathologic deposits representing the insoluble fraction of proteins no longer in their soluble functional state, their variants as polymorphs rather than "strains," and seeding phenomena as nucleation-dependent aggregation or precipitation rather than replication.

Such distinctions avoid conflating pathologic observations with etiology and have implications for biomarker interpretation, taxonomy, and therapeutic innovation.

Transposable elements (TEs) (mobile genetic elements comprising ∼45% of the human genome) have recently emerged as potential contributors to Parkinson's disease (PD); however their role and sex-specific impact remain poorly understood.

Here, we present the first integrative meta-analysis of TE expression across 4 substantia nigra single-nucleus RNA-seq datasets, comprising a total of 66 donors, generating a cell-type-resolved atlas of TE dysregulation in PD.

We identified widespread TE activation across major brain cell types (i.e. neurons, astrocytes, oligodendrocytes and microglia), with marked upregulation of L1s in neurons and HERVs in oligodendrocytes.

Sex-stratified analyses revealed distinct male- and female-biased TE signatures, indicating regulatory programs uniquely affected in each sex, including MIR elements in microglia and Alu subfamilies in neurons.

Correlation and genomic proximity analyses also uncovered TE-gene associations linked to important PD pathways such as neuroinflammation or myelination.

Collectively, our study positions TEs as potential sex-modulated contributors to PD pathology and also provides a public web resource (PATOSS) to explore PD-associated TE transcriptional deregulation.

BACKGROUND AND OBJECTIVES

Small fiber pathology is an intrinsic feature of Parkinson disease (PD), yet its relevance to central neurodegeneration remains unclear.

Given that cognitive impairment is a major manifestation of disease progression closely linked to cortical structural changes, we aimed to determine whether peripheral skin denervation is associated with cognitive impairment and brain atrophy in PD.

METHODS

In this cross-sectional study at a movement disorders center in China, patients with PD and healthy controls (HCs) were recruited.

Key inclusion criteria included a clinical PD diagnosis based on the Movement Disorder Society criteria and an age range of 50-99 years.

Patients were classified into normal cognition (PD-NC), mild cognitive impairment (PD-MCI), and patients develop dementia (PDD).

All participants underwent skin biopsy for quantification of intraepidermal nerve fiber density (IENFD), neuropsychological assessments, and structural MRI.

Multivariable regression and mediation analyses examined associations among IENFD, cognition, and brain volumes.

RESULTS

A total of 155 patients with PD (mean age, 63.4 years; 52% female; PD-NC: n = 75; PD-MCI: n = 40; PDD: n = 40) and 50 HCs (mean age, 60.3 years; 50% female) were included.

IENFD demonstrated a progressive decline across the PD cognitive spectrum (HC: 7.18 ± 2.44; PD-NC: 5.89 ± 2.05; PD-MCI: 4.65 ± 1.33; PDD: 3.40 ± 1.15 fibers/mm).

IENFD positively correlated with global and 5 domain-specific cognitive scores (β = 0.170-0.387, p p < 0.05), which statistically mediated the associations between IENFD and cognitive performance (proportion mediated for global cognition: 8.0%-10.2%).

DISCUSSION

Our study suggests that skin denervation is closely associated with cognitive impairment in PD and that regional brain atrophy statistically mediates this relationship.

These findings provide novel evidence for the peripheral-central axis in PD, suggesting that small fiber pathology may mirror central neurodegeneration.

Future multicenter and longitudinal studies are required for validation.

White matter lesions are associated with cognitive impairment in Parkinson's disease, but the underlying neurobiological mechanisms remain unclear.

One hypothesis is that strategically located white matter lesions disrupt long-range white matter pathways crucial for cognitive functioning, particularly cholinergic projections from the basal forebrain, contributing to cognitive decline.

Using volumetric measures of basal forebrain nuclei (T1 MRI proxy for brain cholinergic projection nuclei), quantitative white matter lesion assessments (fluid-attenuated inversion recovery MRI) and a presynaptic cholinergic marker (18F-FEOBV PET), we tested a mechanistic model of white matter lesion effects on basal forebrain cholinergic projections and nuclei, and how these disruptions relate to cognition.

We analysed data from 127 mid-to-advanced-stage patients with Parkinson's disease without dementia.

Periventricular and deep white matter lesion burdens were quantified with the UBO Detector pipeline.

Cognitive function was assessed across five domains using z-scores from a control group matched for age and education.

Voxel-wise analyses examined associations between white matter lesion burden and cholinergic synaptic density, followed by mediation analyses testing whether cholinergic alterations mediated the relationship between white matter lesions and cognition, while correcting for sex, levodopa equivalent dose and disease duration.

Voxel-wise analyses revealed that higher periventricular lesions burden was associated with reduced 18F-FEOBV uptake in an insular-limbic-frontal-cingulum cluster, while deep lesions showed more topographically limited associations that disappeared after adjusting for periventricular burden.

Periventricular lesions affected lateral and external Ch4 cholinergic projection pathways (81%-88% of patients), more frequently than deep white matter lesions (25%-47% of patients), except for the external capsule, which was equally affected by both.

Cognitive performance (global cognition, memory, executive function and attention) was associated with both periventricular lesion burden and 18F-FEOBV uptake within the insular-limbic-frontal-cingulum cluster, as well as with basal forebrain volume.

Mediation analyses indicated that periventricular lesions had a direct effect on cortical terminal integrity (18F-FEOBV) and an indirect, presumably retrograde degeneration effect via basal forebrain atrophy.

The effect of periventricular lesions on insular-limbic-frontal-cingulum cholinergic terminal density was a strong mediator of the association between lesion burden and cognitive performance.

A weaker mediation effect via the basal forebrain emerged for global cognition, whereas mediation was more robust for memory and executive functioning.

Our findings indicate that periventricular white matter lesions contribute to cognitive vulnerability in Parkinson's disease without dementia through impacts on basal forebrain cholinergic projections.

White matter lesion burden may represent a mechanistically meaningful biomarker for predicting cognitive trajectories and informing targeted interventions in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative condition primarily characterized by motor deficits, yet cognitive impairments are increasingly recognized.

While deficits in executive functioning are well documented even in the absence of cognitive decline, evidence of attentional deficits in PD remains inconsistent, and the role of motor symptom lateralization is unclear.

In this systematic review and meta-analysis, we examined visual attention in right-handed, cognitively unimpaired idiopathic PD patients, focusing on the canonical attentional domains (sustained, selective, divided) and processes (alerting, endogenous and exogenous orienting, reorienting), as well as visuospatial bias.

Four databases were searched for studies comparing PD patients with healthy controls.

Meta-analytic estimates were derived using Hedges' g within random-effects models, and studies that could not be quantitatively integrated were summarized narratively.

In addition, studies directly comparing patients with left- and right-predominant motor symptoms (LPD vs.

RPD) were reviewed qualitatively.

Across 51 studies, PD patients exhibited deficits in sustained, selective, and divided attention.

Among attentional processes, only exogenous orienting was impaired, whereas alerting, endogenous orienting, and reorienting were preserved.

Findings from the few studies examining visuospatial bias indicated small, context-dependent shifts in spatial attention rather than a consistent directional bias.

These findings indicate that PD patients show visual-attentional impairments, particularly under high-demand conditions, while basic alertness and voluntary orienting appear preserved.

Exogenous orienting deficits and subtle rightward spatial tendencies in LPD suggest disruption of right-hemisphere attentional networks.

These results have implications for early cognitive assessment, rehabilitation strategies, and understanding the neural bases of attentional dysfunction in PD.

The association between pesticide exposure and Parkinson's disease (PD) is substantial, but heterogeneity in methodology and lack of categorization according to the type of exposure and pesticide classes in previous meta-analyses impair the interpretation of data.

This study aims to update evidence of the association between pesticide exposure and PD.

We conducted a systematic review and meta-analysis of studies investigating associations between pesticide exposure and PD according to the type of pesticide exposure and pesticide class.

We searched PubMed, EMBASE, and Web of Science until July 2024.

Reviewers screened titles and abstracts.

Afterward, reviewers reanalyzed the selection criteria and extracted the data based on the full paper.

Meta-analyses were conducted to assess the association between pesticide exposure and PD.

A total of 124 studies were eligible.

There is a lack of diversity in the populations represented and a high variability in methodology among the included studies.

Considering only studies with any type of exposure, we found a positive association of PD with any pesticide class and herbicides.

Occupational exposure was associated with PD for all pesticide classes except for fungicides.

Exclusive household pesticide exposure was also associated with PD.

Pesticide exposure remains a significant environmental risk factor for the development of PD, regardless of the type of exposure.

Herbicides are the pesticide class with the most substantial evidence of association with the disease.

Further studies with new methods of pesticide exposure measurement, innovative design studies, and the inclusion of underrepresented populations are still needed.

White matter lesions are associated with cognitive impairment in Parkinson's disease, but the underlying neurobiological mechanisms remain unclear.

One hypothesis is that strategically located white matter lesions disrupt long-range white matter pathways crucial for cognitive functioning, particularly cholinergic projections from the basal forebrain, contributing to cognitive decline.

Using volumetric measures of basal forebrain nuclei (T1 MRI proxy for brain cholinergic projection nuclei), quantitative white matter lesion assessments (fluid-attenuated inversion recovery MRI) and a presynaptic cholinergic marker (18F-FEOBV PET), we tested a mechanistic model of white matter lesion effects on basal forebrain cholinergic projections and nuclei, and how these disruptions relate to cognition.

We analysed data from 127 mid-to-advanced-stage patients with Parkinson's disease without dementia.

Periventricular and deep white matter lesion burdens were quantified with the UBO Detector pipeline.

Cognitive function was assessed across five domains using z-scores from a control group matched for age and education.

Voxel-wise analyses examined associations between white matter lesion burden and cholinergic synaptic density, followed by mediation analyses testing whether cholinergic alterations mediated the relationship between white matter lesions and cognition, while correcting for sex, levodopa equivalent dose and disease duration.

Voxel-wise analyses revealed that higher periventricular lesions burden was associated with reduced 18F-FEOBV uptake in an insular-limbic-frontal-cingulum cluster, while deep lesions showed more topographically limited associations that disappeared after adjusting for periventricular burden.

Periventricular lesions affected lateral and external Ch4 cholinergic projection pathways (81%-88% of patients), more frequently than deep white matter lesions (25%-47% of patients), except for the external capsule, which was equally affected by both.

Cognitive performance (global cognition, memory, executive function and attention) was associated with both periventricular lesion burden and 18F-FEOBV uptake within the insular-limbic-frontal-cingulum cluster, as well as with basal forebrain volume.

Mediation analyses indicated that periventricular lesions had a direct effect on cortical terminal integrity (18F-FEOBV) and an indirect, presumably retrograde degeneration effect via basal forebrain atrophy.

The effect of periventricular lesions on insular-limbic-frontal-cingulum cholinergic terminal density was a strong mediator of the association between lesion burden and cognitive performance.

A weaker mediation effect via the basal forebrain emerged for global cognition, whereas mediation was more robust for memory and executive functioning.

Our findings indicate that periventricular white matter lesions contribute to cognitive vulnerability in Parkinson's disease without dementia through impacts on basal forebrain cholinergic projections.

White matter lesion burden may represent a mechanistically meaningful biomarker for predicting cognitive trajectories and informing targeted interventions in Parkinson's disease.

Preclinical and epidemiologic data suggest that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may reduce the risk of Parkinson's disease and related disorders (PDRD), yet clinical trial findings have been mixed, raising the possibility of biologically meaningful heterogeneity.

We tested whether interindividual differences in systemic GLP1R expression are associated with PDRD risk among adults with type 2 diabetes initiating GLP-1RAs.

We conducted an electronic health record-based new-user cohort study in the National Institutes of Health All of Us Research Program, focusing on adults with type 2 diabetes aged 50 years or older who initiated a GLP-1RA between 2005 and 2023 and had no prior PDRD or Alzheimer's disease and related dementias (ADRD).

Systemic GLP1R expression was genetically proxied by a 15-variant cis-expression quantitative trait locus (cis-eQTL) genetic risk score dichotomized at the cohort median.

Follow-up ended at the earliest of incident PDRD, death or 1 October 2023.

Hazard ratios (HR) were estimated using multivariable Cox proportional hazards models adjusting for baseline covariates, and incidence rates and rate differences per 1000 person-years were estimated using Poisson models.

Prespecified sensitivity analyses excluded early outcome events and short drug exposure; an exploratory analysis evaluated incident ADRD.

The cohort included 7039 initiators (3520 high versus 3519 low genetic score; mean age 61.7 ± 8.4 years; 59.8% female; mean follow-up 3.8 ± 3.1 years).

Compared with the low-score group, the high-score group had a lower hazard of incident PDRD [HR 0.78; 95% confidence interval (CI) 0.62 to 0.98] and a lower incidence rate (rate difference -1.36 per 1000 person-years; 95% CI -2.51 to -0.20).

Associations were consistent across sensitivity analyses.

No association was observed for incident ADRD (HR 1.02; 95% CI 0.81 to 1.28).

These findings link a mechanism-anchored genetic proxy for higher systemic GLP1R expression to a lower risk of incident PDRD among GLP-1RA-treated adults with type 2 diabetes.

Systemic GLP1R-mediated pathways may be relevant to interindividual differences in observed PDRD risk, and genetic instruments for GLP1R expression may inform hypotheses for future PDRD trial design.

Rigidity, along with bradykinesia and tremor, is recognized as one of the core motor symptoms fundamental to the clinical diagnosis of Parkinson's disease.

Despite its diagnostic relevance, rigidity has received comparatively less systematic investigation than other motor symptoms, resulting in gaps in our understanding of its phenomenology, neurophysiological correlates and response to therapeutic interventions such as deep brain stimulation.

This narrative review aims critically to examine and clarify the current conceptual ambiguities, assessment strategies and pathophysiological underpinnings associated with rigidity in Parkinson's disease.

We begin by discussing the wide range of phenomena described by the term 'rigidity' in neurological and non-neurological fields and highlight the inconsistencies that arise in its clinical interpretation.

We review and compare the clinical and instrumental approaches that are currently used to assess rigidity, emphasizing their respective strengths, limitations and contributions to a more precise characterization of rigidity in Parkinson's disease.

We end with a summary of molecular, neuroimaging and neurophysiological insights into the pathophysiology of rigidity.

In summary, we seek to consolidate existing knowledge, underscore unresolved questions and suggest new solutions for existing gaps with the hope of providing a conceptual and methodological foundation to guide future clinical and experimental research in the field.

Parkinson's disease (PD) is the second leading neurodegenerative disease, pathologically characterized by the accumulation of alpha-synuclein in the brain and the loss of dopaminergic neurons in the substantia nigra pars compacta.

Despite the intensive efforts to identify diagnostic biomarkers for PD and nominating prospective candidates such as such as CSF α-synuclein seed amplification assay or α-/β-synuclein ratio, establishment of minimally invasive biomarkers remains the focus of PD research.

We leveraged transcriptomic data from 4343 participants from four independent datasets to robustly identify PD-associated transcripts.

Following the differential abundance analyses, we integrated our findings with several brain transcriptomic, CSF proteomic, plasma proteomic and genomic data to add biological context.

We further leveraged our findings to develop predictive models that could differentiate between PD and healthy controls.

We identified 296 differentially expressed transcripts, 28 of which were transcribed from known PD-associated loci.

Furthermore, we found a significant overlap between our findings and transcripts dysregulated in brain, as well as proteins that differentially accumulate in CSF.

Our results suggested that expression of the identified transcripts was affected by genetic background, including ancestry and PD-related mutations, and nearly half of the identified transcripts were dysregulated before symptom onset.

The differentially expressed transcripts were utilized to develop three predictive models that distinguished PD from healthy controls with an area under the receiver operating characteristic curve of 0.727-0.733.

The predictive models detected transcriptomic PD signatures even before symptom onset.

Overall, two transcripts, DLD and CD55, showed particular promise as early stage, minimally invasive PD biomarkers.

DLD was significantly related to PD in the expression quantitative trait loci (eQTL) analyses, and we identified a putative eQTL for CD55.

Their protein products differentially accumulated in CSF, and both DLD and CD55 were included in all three predictive models.

Having performed the largest transcriptomic study of PD to date, we demonstrate that the transcriptome can be leveraged to develop minimally invasive biomarkers that may aid in diagnosing the disease.

BACKGROUND

Levodopa-induced dyskinesia (LID) is a complication of Parkinson's disease (PD) treatment.

While the placebo effect is a known component in PD clinical trials, its specific magnitude in the context of LID is not well characterized.

OBJECTIVE

To quantify the magnitude of the placebo response in LID trials and to identify potential moderators of this effect.

METHODS

We conducted a systematic review and meta-analysis of double-blind, placebo-controlled trials in patients with PD and LID.

The primary outcome was the change in dyskinesia severity in the placebo arm, pooled using random-effects model.

RESULTS

Thirty one publications, comprising 1329 patients, were included.

Data were stratified by reporting methodology: 16 studies provided primary LS mean change data, 11 provided simple change and the remaining studies contributing solely to subgroup analyses.

The primary meta-analysis, revealed a statistically significant placebo response of moderate magnitude (pooled SMD = -0.48, p 2 = 47.6%).

Subgroup analyses showed this corresponded to clinically measurable improvements, including a mean reduction of -6.78 points on the UDysRS and an increase of +1.27 h in "Good On Time." Meta-regression identified that a larger placebo effect was significantly associated with older patient age (p = 0.014), a higher proportion of female participants (p = 0.016), and shorter study duration (p = 0.006).

CONCLUSION

The placebo response in LID is a consistent, clinically relevant phenomenon modulated by patient demographics and trial duration.

Quantifying this response is essential for design and accurate interpretation of future trials.

ANTECEDENTES

La enfermedad de Parkinson (EP) causa una discapacidad motora y no motora progresiva.

Aunque el tratamiento farmacológico es la primera opción, la respuesta disminuye con el tiempo.

La estimulación cerebral profunda (ECP) trata eficazmente la EP avanzada, y datos recientes sugieren beneficios cuando se aplica antes.

OBJETIVOS

Revisar sistemáticamente los estudios y realizar un metaanálisis de los ensayos controlados aleatorizados que comparan la ECP subtalámica más el mejor tratamiento médico (MTM) con el MTM solo en la EP temprana.

MÉTODOS

Realizamos una revisión sistemática y un metaanálisis de acuerdo con PRISMA, con un protocolo registrado en PROSPERO (CRD420251014105).

Se buscaron en MEDLINE, Embase y la Biblioteca Cochrane estudios publicados entre 2002 y 2025 que compararan la ECP temprana con el MTM en la EP "temprana".

La definición de "temprana" varió, pero habitualmente correspondía a una duración de la enfermedad de 4 a 8 años o a la aparición de complicaciones motoras sin discapacidad importante.

Se incluyeron ensayos controlados aleatorizados, análisis secundarios, estudios observacionales y ensayos no publicados; los metaanálisis se limitaron a las comparaciones aleatorizadas de ECP temprana más MTM frente a MTM solo.

RESULTADOS

Los estudios incluyeron pacientes más jóvenes con una duración de la EP de hasta 8 años y complicaciones motoras tempranas.

Los datos combinados de los ensayos controlados aleatorizados mostraron un beneficio consistente en la calidad de vida.

Los resultados motores y los relacionados con la medicación favorecieron, en cuanto a la dirección del efecto, a la ECP temprana del núcleo subtalámico, pero siguieron siendo heterogéneos e imprecisos.

Los estudios sugieren que la seguridad es, en términos generales, comparable a la de la ECP aplicada según las indicaciones habituales.

CONCLUSIONES

Ofrecer ECP antes de que aparezca una discapacidad avanzada, en particular a pacientes menores de 60 años, con menos de 10 años desde el diagnóstico, estadio de Hoehn-Yahr de 3 o menor, complicaciones motoras tempranas y sin demencia, podría ayudar a retrasar la pérdida de calidad de vida frente al MTM solo.

Dado el reducido número de ensayos y la heterogeneidad considerable, se necesitan más estudios aleatorizados a gran escala para confirmar la seguridad, definir el momento óptimo en la EP temprana y aclarar qué subgrupos se benefician más.

BACKGROUND

Multiple system atrophy (MSA) is a rare neurodegenerative synucleinopathy whose epidemiological risk factors remain poorly characterized.

OBJECTIVES

To characterize pre-diagnostic features and identify candidate risk factors for coding-based incident MSA in the UK Biobank (UKB), compared with Parkinson's disease (PD) and healthy controls.

METHODS

Iterative logistic regression models were used to derive risk factors from sociodemographic, lifestyle, environmental, and medical factors, adjusting for baseline age and sex, with Benjamini-Hochberg correction in the fully adjusted model.

Candidate risk factors were evaluated in multivariate models at baseline and using 5- and 10-year latency windows to assess reverse causation.

RESULTS

We identified 114 coding-based incident MSA diagnoses, 1139 age- and sex-matched incident PD cases, and 1075 matched controls.

We identified several baseline associations that attenuated with latency windows, including antihistamine use, alcohol use, and reduced physical activity, suggesting reverse causation.

Statin use was associated with reduced risk at baseline (odds ratio [OR] 0.34, 95% confidence interval [95% CI] 0.17-0.69) and 5 years' latency but attenuated at 10 years, and was discordant with findings of reduced risk with moderately elevated cholesterol (OR 0.41, 95% CI 0.24-0.72).

Rural living was the only candidate exposure whose effect strengthened with longer latency windows (5-year OR 2.73, 95% CI 1.32-5.65).

CONCLUSIONS

Coding-based incident MSA in the UKB exhibits a long pre-diagnostic phase consistent with autonomic and lifestyle changes several years prior to the diagnosis of an autonomic or parkinsonian disorder.

Rural living may be an environmental signal warranting further investigation. © 2026 International Parkinson and Movement Disorder Society.

BACKGROUND

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.

OBJECTIVE

Our aim was to determine whether amantadine restores motor function by normalizing the balance of dSPN and iSPN activity or through a distinct mechanism.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.

BACKGROUND

Alzheimer's disease (AD) co-pathology contributes to dementia in PD, but its role in earlier cognitive impairment remains uncertain.

OBJECTIVE

To determine if p-tau217, a biomarker of early AD, is associated with cognitive impairment in PD.

METHODS

Plasma p-tau217 levels in 167 PD patients without dementia and 63 controls were related to performance on standard neuropsychological testing, and to cognitive impairment as defined by a MoCA score <26 and by self-report.

Plasma GFAP, NfL and APOE ε4 carrier status were also examined.

RESULTS

No significant differences in p-tau217, GFAP and NfL level were observed between groups (pFDR > 0.08).

Higher p-tau217 was associated with worse visuospatial function and greater self-reported cognitive impairment, but these associations did not survive correction (pFDR > 0.08).

There was no association with cognitive impairment (pFDR > 0.08).

CONCLUSION

These results suggest that co-morbid AD pathology is not a major contributor to early cognitive changes in this sample of PD patients without dementia. © 2026 The Author(s).

Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BACKGROUND

The Movement Disorder Society (MDS) research criteria for possible prodromal multiple system atrophy (PP-MSA) have not been prospectively validated.

OBJECTIVE

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.

BACKGROUND

Magnetic resonance imaging (MRI)-guided focused ultrasound (MRgFUS) thalamotomy provides durable tremor control for most patients with essential tremor (ET) and tremor-dominant Parkinson's disease (TdPD), but tremor can recur.

OBJECTIVES

To evaluate the safety, efficacy, and lesion characteristics of repeat MRgFUS thalamotomy for tremor recurrence.

METHODS

We retrospectively analyzed patients undergoing repeat ipsilateral MRgFUS thalamotomy.

Clinical Rating Scale for Tremor-Part A (CRST-A) assessed tremor severity preoperatively and 1 day, 1 week, 1 month, 3 months, and 1 year after retreatment.

Outcomes, side effects, lesion volumes and locations, and treatment parameters were compared with initial procedures and an institutional one-time MRgFUS cohort (n = 535).

RESULTS

Thirty patients (26 ET, 4 TdPD) underwent repeat thalamotomy with ≥3 months follow-up.

Mean CRST-A improved from 5.37 preoperatively to 0.27 at day 1 (94.9% improvement), 2.00 (64.4%) at 3 months, and 2.50 (38.8%) at 1 year (all P ≤ 0.003 vs. baseline).

Tremor recurred at similar rates after initial and repeat treatments.

Repeat lesions were larger (526.3 vs. 414.1 mm3, P = 0.025) and shifted anteriorly (+1.2 mm, P = 0.003).

Initial lesion volume in retreatment patients was similar to the one-time cohort.

Compared with initial treatments, patients more often experienced any side effect at 1 month (P = 0.023) and had more side effects at 1 month (P < 0.001) and 3 months (P = 0.014) after repeat treatment.

Patient satisfaction was high and 85% of patients would choose retreatment again.

CONCLUSIONS

Repeat ipsilateral MRgFUS thalamotomy restored tremor control after recurrence and achieved high patient satisfaction, despite increased side effects after repeat treatment and similar tremor progression rates after initial and repeat procedures. © 2026 International Parkinson and Movement Disorder Society.

AIMS

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).

METHODS

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).

RESULTS

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  iRBD > PD).

Net PIPR-6s was positively associated with circadian rest-activity rhythm amplitude, mesor, and HK-MoCA score.

CONCLUSION

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.

The purpose of this study was to use the meta-analytic approach to investigate the ability of Inertial Measurement Unit-based commercial system measured gait variability and asymmetry in distinguishing individuals with Parkinson's disease (PD) from healthy controls (HC).

Cross-sectional studies included using commercial IMU-based systems measuring gait variability or asymmetry at any stage of PD patients and healthy adults were included.

Studies were determined by searching for four electronic databases and cross-referencing.

Dual selection and data abstraction of studies were conducted.

Hedges' g standardized mean difference was calculated for each variable and pooled using inverse heterogeneity mode.

Statistically significant was determined by two tailed z-alpha values ≤0.05 and non-overlapping 95% CI.

Heterogeneity was estimated using Q and I2 with alpha values ≤0.10 for Q considered statistically significant.

Small-study effects were examined using doi plots and LFK index.

A total of 1,725 studies were screened.

Eventually, 9 studies representing up to 571 PD patients and 470 HC met the inclusion criteria.

Overall gait variability was significantly greater in individuals with PD than in HC (Hedges' g = 0.368, 95% CI 0.139-0.597).

The multi-IMU subgroup also showed significantly greater gait variability (Hedges' g = 0.397, 95% CI 0.221-0.574), whereas the one-IMU subgroup did not.

However, the between-subgroup difference was not statistically significant, and the multi-IMU prediction interval included null.

The primary analysis detected no statistically significant overall difference in gait asymmetry (Hedges' g = 0.180, 95% CI -0.012-0.373).

These findings provide preliminary evidence of an average group-level difference in gait variability but hard to establish individual-level discrimination, clinical utility, or the superiority of multi-IMU systems.

BACKGROUND

Magnetic resonance imaging (MRI)-guided focused ultrasound (MRgFUS) thalamotomy provides durable tremor control for most patients with essential tremor (ET) and tremor-dominant Parkinson's disease (TdPD), but tremor can recur.

OBJECTIVES

To evaluate the safety, efficacy, and lesion characteristics of repeat MRgFUS thalamotomy for tremor recurrence.

METHODS

We retrospectively analyzed patients undergoing repeat ipsilateral MRgFUS thalamotomy.

Clinical Rating Scale for Tremor-Part A (CRST-A) assessed tremor severity preoperatively and 1 day, 1 week, 1 month, 3 months, and 1 year after retreatment.

Outcomes, side effects, lesion volumes and locations, and treatment parameters were compared with initial procedures and an institutional one-time MRgFUS cohort (n = 535).

RESULTS

Thirty patients (26 ET, 4 TdPD) underwent repeat thalamotomy with ≥3 months follow-up.

Mean CRST-A improved from 5.37 preoperatively to 0.27 at day 1 (94.9% improvement), 2.00 (64.4%) at 3 months, and 2.50 (38.8%) at 1 year (all P ≤ 0.003 vs. baseline).

Tremor recurred at similar rates after initial and repeat treatments.

Repeat lesions were larger (526.3 vs. 414.1 mm3, P = 0.025) and shifted anteriorly (+1.2 mm, P = 0.003).

Initial lesion volume in retreatment patients was similar to the one-time cohort.

Compared with initial treatments, patients more often experienced any side effect at 1 month (P = 0.023) and had more side effects at 1 month (P < 0.001) and 3 months (P = 0.014) after repeat treatment.

Patient satisfaction was high and 85% of patients would choose retreatment again.

CONCLUSIONS

Repeat ipsilateral MRgFUS thalamotomy restored tremor control after recurrence and achieved high patient satisfaction, despite increased side effects after repeat treatment and similar tremor progression rates after initial and repeat procedures. © 2026 International Parkinson and Movement Disorder Society.

Depression is one of the most common and disabling non-motor symptoms in Parkinson's disease (PD), yet its genetic basis remains poorly understood.

Here, we investigate the genetic contributions to depression in PD by estimating the burden from common as well as low-frequency single nucleotide polymorphisms (SNPs) within genes previously implicated in PD or depression risk among European ancestry PD patients from three population-based studies.

Using gene-based association analyses (SKAT, Burden, and SKAT-O) in the PASIDA, PEG, and PPMI studies, we evaluated SNP sets in gene regions previously linked to PD or depression.

Among PD-related genes, meta-analysis identified a significant association between KRTCAP2 and self-reported depression diagnosis in PD (SKAT-O p = 4.33 × 10⁻⁵), which remained significant after false discovery rate correction.

A higher genetic burden in KRTCAP2 was associated with 20% increased odds of depression (OR = 1.20, 95% CI: 1.04-1.38).

TRAF5 and LRRK2 showed marginal associations.

Among depression-related genes, SPPL3 and ERBB4 were associated with depression diagnosis history, and FNIP2 was associated with current depressive symptoms.

The PD polygenic risk score was not associated with depression in PD, while a higher depression polygenic risk score was significantly associated with increased odds of depression diagnosis in both cohorts and the meta-analysis (OR = 1.26, 95% CI: 1.13-1.40).

Our findings highlight immune-related genes such as KRTCAP2 and TRAF5 as potential contributors to depression in PD.

Additionally, the depression PRS shows statistically significant association with depression diagnosis in PD, suggesting that a general depression-related genetic liability contributes to this non-motor feature in PD.

Together, these results suggest that depression in PD may involve both shared and disease-specific genetic mechanisms, offering new insights into its pathogenesis and potential therapeutic targets.

IMPORTANCE

Transportation noise has been proposed as a risk factor for Parkinson disease (PD), but epidemiological evidence remains limited and inconsistent.

OBJECTIVE

To investigate whether long-term residential exposure to road traffic noise is associated with a higher risk of PD.

DESIGN, SETTING, AND PARTICIPANTS

This was a Danish nationwide prospective cohort study with follow-up from 2000 to 2017.

Danish residents 40 years and older were eligible.

Analyses were conducted from April to May 2026.

EXPOSURES

Based on complete residential address history from 1990 onward, 10-year time-weighted residential exposure to road traffic noise (LDEN) at the most and least exposed facades were assessed for all participants.

MAIN OUTCOME AND MEASURES

Incident PD cases during follow-up were identified in the National Patient Register.

Analyses were conducted using Cox proportional hazards models.

RESULTS

Of 3 542 488 eligible individuals, 438 911 were excluded (prevalent PD, incomplete address history, or missing covariates), leaving 3 103 577 participants (mean [SD] baseline age, 50.9 [11.7] years, 1 588 658 female [51.2%]).

Among 3 103 577 participants, 20 587 developed PD during follow-up.

Road traffic noise at the most exposed facade (LDEN-Max) was associated with a hazard ratio (HR) of 1.03 (95% CI, 1.00-1.05) per interquartile increment of 11.5 dB in models adjusted for individual- and area-level sociodemographics, air pollution (fine particulate matter with a diameter of 2.5 µm or less [PM2.5] and ultrafine particles), and green space covariates.

Having a difference between noise at the most and least exposed facades (Δnoise, indicator of having a quiet side) of 10 dB or more was associated with a decline in PD risk across different levels of LDEN-Max above 50 dB.

Also, accounting for Δnoise strengthened the association between LDEN-Max and PD (HR, 1.06; 95% CI, 1.02-1.09).

Noise at the least exposed facade was associated with PD, with an HR of 1.04 (95% CI, 1.02-1.07) per interquartile increment of 8.9 dB.

Associations were consistent across strata of sex, education, income, cohabiting status, and population density and after additional adjustment for smoking and physical activity in a subpopulation.

CONCLUSIONS AND RELEVANCE

Results of this cohort study show that long-term exposure to road traffic noise was associated with higher PD risk.

Having a quiet facade mitigated this association.

These findings suggest noise as a novel risk factor for PD and support mitigation strategies ensuring a quiet residential side.

BACKGROUND

Parkinson's disease is the second most common neurodegenerative disorder, with environmental factors influencing the risk.

The role of dairy consumption is controversial, despite repeated with Parkinson's disease in epidemiological studies.

OBJECTIVES

We conducted a systematic review and meta-analysis to evaluate sex-specific associations between dairy intake and Parkinson's disease risk.

METHODS

A literature search was performed using the Medline and EMBASE databases.

Out of 649 studies, eight cohort studies were included in the systematic review, covering 578,736 participants and 4816 Parkinson's disease cases from seven countries.

For the meta-analyses, a Restricted Maximum Likelihood random effect model was used to derive the pooled estimates stratified by sex for six prospective cohort studies comparing the highest versus the lowest intake quantile.

Results revealed a sex-specific effect of dairy intake, a significant association with a higher risk of Parkinson's disease in males (HR 1.28, 1.05-1.56), whereas no association was observed in females (HR 1.02, 0.80-1.30).

For milk intake only, estimates were 1.36 (0.97-1.90) for males and 1.19 (0.94-1.51) for females.

CONCLUSION

Our meta-analysis found an association between dairy consumption and Parkinson's disease risk in males, but not in females.

There was also an almost significant association between milk intake and risk of Parkinson's disease, which was stronger in males than in females.

However, the evidence for this association remains weak.

Further studies with larger sex-stratified samples across diverse countries are needed to clarify sex differences and establish significant associations.

ANTECEDENTES

Las iniciativas de secuenciación a gran escala han generado amplios recursos genómicos esenciales para interpretar variantes, pero su uso eficaz suele requerir conocimientos de bioinformática.

Para facilitar la identificación de variantes de riesgo y causantes de enfermedad en la enfermedad de Parkinson (EP), desarrollamos un navegador de datos genómicos agregados de acceso abierto.

MÉTODOS

Realizamos una identificación conjunta y uniforme de variantes para armonizar datos de secuenciación del genoma completo (WGS) de AMP-PD Release 4, varias publicaciones de datos de GP2 y controles adicionales del Alzheimer’s Disease Sequencing Project.

También se incluyeron datos de secuenciación del exoma clínico (CES) de GP2 Release 8.

RESULTADOS

El conjunto integrado incluyó 31.665 muestras de WGS y 9.559 de CES, correspondientes a 11 ascendencias y más de 300 millones de variantes.

CONCLUSIONES

El navegador genómico GP2 es una plataforma ligera y flexible que ofrece resúmenes intuitivos por gen y por variante, con frecuencias alélicas desglosadas por ascendencia y anotaciones funcionales.

Es de código abierto y está disponible gratuitamente en https://gp2.broadinstitute.org, lo que facilita el acceso amplio a los datos genómicos de la EP y respalda la investigación mundial.

BACKGROUND

The genetic architecture of Parkinson's disease varies considerably across ancestries, yet most previous genetic studies have focused on individuals of European ancestry.

We aimed to characterise the distribution of established Parkinson's disease causal variants, as well as risk-associated variants with clinical implications (ie, variants in genes involved in pathways targeted by ongoing clinical trials), across ancestrally diverse populations.

METHODS

We conducted a multi-ancestry, observational, cross-sectional genetic study using retrospective data from the Global Parkinson's Genetics Program (GP2) release 11 (released in December, 2025).

The study investigated causal and risk variants, including copy number variants, in established Parkinson's disease and parkinsonism-associated genes, following the recommendations of the Movement Disorder Society (MDS) Task Force on the Nomenclature of Genetic Movement Disorders, including GBA1, LRRK2, SNCA, VPS35, RAB32, PINK1, PRKN, PARK7, ATP13A2, DCTN1, DNAJC6, FBXO7, JAM2, RAB39B, SLC20A2, SYNJ1, VPS13C, and WDR45.

Individuals with Parkinson's disease were diagnosed based on established clinical criteria, including the Parkinson's UK Brain Bank or MDS diagnostic criteria (or both), and healthy control participants were defined as individuals without evidence of neurodegenerative disease and unrelated to participants with Parkinson's disease.

We analysed genome and exome sequencing and array genotyping data of 99 783 individuals, including 58 559 individuals with Parkinson's disease and 41 224 controls, from 11 genetically inferred ancestries (African, African admixed, Ashkenazi Jewish, Latino and Indigenous people of the Americas, central Asian, complex admixture, east Asian, European, Finnish, Middle Eastern, and south Asian), defined using reference population-based ancestry inference methods.

We calculated allele frequencies for all investigated variants in individuals with Parkinson's disease and controls, both overall and stratified by ancestry.

FINDINGS

Approximately 29% of individuals (29 001 of 99 783; 15 443 [26·4%] of 58 559 individuals with Parkinson's disease and 13 558 [32·9%] of 41 224 controls) were from under-represented populations (ie, non-European and non-Ashkenazi Jewish).

Our findings indicated both shared genetic contributors across ancestries as well as ancestry-specific differences in variant frequencies and the spectrum of variants within Parkinson's disease-associated genes.

Overall, 1217 (2·1%) of 58 559 individuals with Parkinson's disease carried a causal variant, with substantial variations across ancestries ranging from ten (0·4%) of 2844 African individuals to 251 (10·7%) of 2343 individuals of Ashkenazi Jewish ancestry.

Risk variants in GBA1 and LRRK2 were identified in 6893 (11·8%) of 58 559 individuals with Parkinson's disease and 3578 (8·7%) of 41 224 controls.

GBA1 risk variants were most frequent overall and identified across all ancestries, but variant frequency and spectra differed substantially between ancestries, from 195 (4·1%) of 4773 in the east Asian ancestry group to 1505 (52·9%) of 2844 in the African ancestry group.

Similarly, LRRK2 causal and risk variants showed ancestry-specific enrichment, with the highest frequencies of causal variants in the Ashkenazi Jewish (250 [10·7%] of 2343) and Middle Eastern (59 [4·4%] of 1347) ancestry groups, whereas risk variants were predominantly identified in the east Asian ancestry group (601 [12·6%] of 4773).

Carriers of biallelic causal variants in PRKN, commonly including deletions and duplications, were also identified across all ancestries except Ashkenazi Jewish; the highest frequency was in the Middle Eastern ancestry group (17 [1·3%] of 1347), and frequencies in all other ancestries were less than 1%.

INTERPRETATION

This large-scale, multi-ancestry genetic study offers crucial insights into the population-specific genetic architecture of Parkinson's disease.

Whereas clinical trials targeting GBA1 and LRRK2 variant carriers are primarily performed in Europe and the USA, increased ancestral diversity in Parkinson's disease research will be crucial to improve diagnostic accuracy, enhance our understanding of disease mechanisms across populations, and ensure equitable application of and access to emerging genetically informed therapies.

FUNDING

Aligning Science Across Parkinson's (ASAP) through the Global Parkinson's Genetics Program (GP2).

BACKGROUND

Current dopaminergic therapies for Parkinson's disease carry significant limitations: levodopa can cause long-term motor complications, while D2/D3 receptor-targeting dopamine agonists can produce non-motor adverse effects.

Tavapadon is an oral, once-daily, selective D1/D5 agonist that might improve Parkinson's disease motor symptoms.

We aimed to evaluate the safety, tolerability and efficacy of flexible-dose tavapadon in people with early-stage Parkinson's disease.

METHODS

TEMPO-2 was a phase 3, randomised, double-blind, placebo-controlled trial conducted at 75 clinical sites (both hospital or academic and community settings) across 13 countries.

Adults aged 40-80 years with early-stage Parkinson's disease (<3 years' disease duration) who were treatment-naive or had less than 3 months of previous dopaminergic treatment were eligible.

Participants were randomly assigned 1:1 to flexible-dose tavapadon (5-15 mg) or placebo orally once daily for 27 weeks.

The primary endpoint was change from baseline to week 26 in the combined score of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts II and III (reflecting activities of daily living and motor performance).

Safety endpoints included adverse events, clinical laboratory values, vital signs, and electrocardiograms.

The primary endpoint was assessed in the modified intent-to-treat population (participants who received one dose or more of study drug and had both a baseline and one or more post-baseline MDS-UPDRS assessments) and safety was assessed in the safety analysis set (all participants who received one dose or more of tavapadon or placebo).

This study is registered with ClinicalTrials.gov (NCT04223193) and is now complete.

FINDINGS

Between Jan 6, 2020, and Feb 22, 2024, 473 individuals were screened and 304 were randomly assigned to receive tavapadon 5-15 mg (n=151) or placebo (n=153).

The majority of participants were male (169 [56%] of 304 male; 135 [44%] of 304 female), the mean age was 62·9 (SD 9·2) years, and the mean disease duration was 0·86 (0·79) years. 80 (26%) of 304 participants discontinued from the trial (57 [38%] of 151 on tavapadon and 23 [15%] of 153 on placebo), most commonly due to adverse events (42 [14%] of 304; 36 [24%] of 151 on tavapadon and six [4%] of 153 on placebo).

The primary endpoint of change from baseline to week 26 in the MDS-UPDRS Parts II and III combined score was significantly improved with tavapadon versus placebo (least squares mean [LSM] decrease of 10·3 [95% CI -12·2 to -8·3] points vs 1·2 [-2·9 to 0·6] points; LSM treatment difference -9·1 [95% CI -11·7 to -6·5]; p10% of participants) were nausea (45 [30%] of 151] vs five [3%] of 153), headache (25 [17%] vs eight [5%]), and dizziness (24 [16%] vs five [3%]).

INTERPRETATION

Tavapadon showed significant and clinically meaningful improvements in Parkinson's disease motor symptoms, with low incidence of somnolence and impulse control disorders.

However, the short observation period limits conclusions about long-term tolerability.

An ongoing extension study aims to confirm its long-term safety and efficacy.

FUNDING

AbbVie.

The progressive age-related aggregation of soluble α-synuclein into toxic oligomers and insoluble amyloid fibrils causes Parkinson's disease, Lewy body dementia and multiple system atrophy, all of which are neurodegenerative diseases without a cure.

Because α-synuclein is a self-antigen, pathogenic α-synuclein aggregates do not elicit a strong immune response.

Recent advances in structural biology elucidating the structure of α-synuclein fibrils have allowed us to design engineered protein fibrils that model conformational epitopes present on the surface of α-synuclein fibrils.

HET-s is a soluble fungal protein capable of forming amyloid fibrils.

We used HET-s(218-298) fibrils and four modified derivatives, each displaying a selected conformational epitope present on the surface of α-synuclein fibrils, to vaccinate TgM83+/- mice, a model for Parkinson's disease-like synucleinopathies.

Fibrillar vaccine candidates significantly extended the survival of immunized TgM83+/- mice by ≤38% after intraperitoneal challenge and ≤42% after intragastric challenge with α-synuclein fibrils.

Fully immunized mice developed antibodies that recognized α-synuclein fibrils and brain homogenates from patients with dementia with Lewy bodies, multiple system atrophy and Parkinson's disease.

Fibrillar vaccine candidates that mimic conformational epitopes on the surface of pathological α-synuclein fibrils have the ability to induce immunity and protection against Parkinson's disease and other synucleinopathies.

IMPORTANCE

Accurate diagnosis of neurodegenerative movement disorders is challenging because of a lack of in vivo biomarkers, overlapping clinical features, and a delay in the emergence of pathognomonic features.

OBJECTIVE

To evaluate clinicopathological correlation, diagnostic accuracy, genetic association with pathology, and ancestry-related differences in a multiancestry brain bank cohort.

DESIGN, SETTING, AND PARTICIPANTS

This was a multicenter, retrospective, autopsy-confirmed cross-sectional brain bank study on donors enrolled between 1985 and 2024.

Included were donors from 11 academic brain banks in the UK, US, and Australia.

Among brain donors with available genetic data from participating brain banks, included were individuals with clinical diagnoses of Parkinson disease, Parkinson disease dementia, dementia with Lewy bodies (DLB), progressive supranuclear palsy, corticobasal syndrome, multiple system atrophy, or neurologically normal controls.

EXPOSURES

Genetic variant carrier status and clinical diagnostic category.

MAIN OUTCOMES AND MEASURES

Outcomes included clinical diagnostic accuracy, Lewy body and Alzheimer disease pathology burden, survival, association with genetic variants, and genetically inferred ancestry.

RESULTS

Among 5648 brain donors with available genetic data, a total of 3353 eligible donors (mean [SD] age at death, 76.8 [10.6] years; 2072 male [61.8%]) were included.

Misdiagnosis rates for movement disorders ranged approximately from 10% to 20%.

Clinical diagnoses of dementia with parkinsonism (ie, Parkinson disease dementia and DLB) were more strongly associated with Lewy body pathology than Parkinson disease without dementia (odds ratio [OR], 1.96; 95% CI, 1.30-3.04; P = 7.2 × 10-4).

Lewy pathology was identified in 33 of 745 of neurologically normal controls (4.4%).

Alzheimer disease copathology was present in 426 of 1064 cases (40.0%) with Lewy body disease.

Carriers of the GBA1 variant exhibited greater Lewy body burden compared with noncarriers (OR, 1.94; 95% CI, 1.24-3.03; P = .01) or carriers of the LRRK2 variant (OR, 7.44; 95% CI, 2.16-25.64; P = .01).

Pathological diagnoses differed by ancestry, with South Asian donors more likely to have progressive supranuclear palsy pathology and Ashkenazi Jewish donors more likely to have Lewy body disease (χ22 = 35.5; P < .001), independent of GBA1 and LRRK2 variant status.

CONCLUSIONS AND RELEVANCE

Findings of this cross-sectional brain bank study highlight the value of integrating genetic and pathological data to improve diagnostic accuracy.

The high prevalence of Alzheimer disease copathology and ancestry-associated differences in pathology point to the need for biologically informed diagnostic tools.

These results suggest supporting the integration of genetically and pathologically stratified approaches, correlating pathology with in vivo biomarkers, for future therapeutic trials.

Parkinson's disease (PD) has been historically defined as a disease of striatal dopamine deficiency secondary to degeneration of dopaminergic neurons in the substantia nigra pars compacta, related to the presence of Lewy bodies and Lewy neurites.

Since the discovery of pathogenic variants in the gene encoding α-synuclein, as well as the finding that α-synuclein is a major constituent of Lewy pathology, PD is considered as a prototypical synucleinopathy.

However, neuropathological studies consistently show that most people with PD display copathologies, many of which are linked to specific clinical features and outcomes.

In this review, we summarize the spectrum and frequency of these co- and multi-pathologies in idiopathic and genetic PD and their impact on disease initiation and progression.

Additionally, we also discuss how this multi-pathological landscape may impact biomarker research and the implementation of emerging disease-modifying therapies. © 2026 The Author(s).

Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BACKGROUND

Models trained on accelerometer data have been proposed for detecting prodromal Parkinson's disease (PD).

However, uncertainties in diagnosis timing in the UK Biobank (UKBB) may affect generalizability to other cohorts.

OBJECTIVES

The aim of the study was to evaluate the performance of previously published models for prodromal PD detection in other international cohorts.

METHODS

We applied the models to data from German and British cohorts of individuals with isolated or idiopathic rapid eye movement sleep behavior disorder and healthy controls.

We compared hourly acceleration patterns and classification performance across cohorts.

RESULTS

The British cohort exhibited visually similar activity patterns to UK Biobank but weaker statistical differences and reduced model performance.

The German cohort showed no significant group differences and lower performance.

No pair of cohorts demonstrated statistical equivalence.

CONCLUSIONS

Models trained on UK Biobank data may capture early clinical disease rather than universal prodromal markers.

Prospective validation in well-characterized cohorts is essential before clinical translation. © 2026 The Author(s).

Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BACKGROUND

Treatment of Parkinson's disease (PD) with levodopa results in a sustained reduction of symptoms.

Although the plasma half-life of levodopa is short, it elicits a lasting effect, the long-duration levodopa response (LDR).

A decrease in LDR as PD progresses has been linked to motor complications, but long-term data on the LDR and its clinical implications remain scarce.

OBJECTIVES

The aim is to analyze the magnitude and impact of the LDR over time using data from the Parkinson's Disease Progression Marker Initiative (PPMI).

METHODS

First, therapy-naïve Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) scores were predicted using a mixed linear model (MLM) from n = 245 untreated people with PD (PwPD).

This model yielded an increase of MDS-UPDRS III scores of 2.65 points per year.

Using this model, we then calculated LDR and short-duration response in longitudinal data of 148 initially therapy-naïve PwPD.

Symptom progression was analyzed using correlation analyses and MLMs.

RESULTS

In the 98 PwPD with observed LDR, the LDR accounted for approximately half of the total levodopa response.

No significant change in LDR magnitude was observed over up to 10 years (analysis of variance, P = 0.14; generalized estimating equations, P = 0.26).

The LDR magnitude was not associated with the onset of motor complications.

PwPD with absent LDR (n = 50) progressed faster than PwPD with observed LDR in several motor and non-motor domains.

CONCLUSIONS

The LDR is a stable component of the levodopa response and needs to be considered in clinical trials.

These findings argue against a declining LDR as a major driver of motor fluctuations in PD. © 2026 The Author(s).

Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Deep brain stimulation (DBS) effectively treats motor symptoms in movement disorders but often compromises speech through incompletely defined mechanisms.

We conducted a PROSPERO-registered systematic review and meta-analysis of publications through August 2024 (CRD42024527738).

Among 2726 screened records, we included 184 studies: 131 in Parkinson's disease (PD), 32 in essential tremor (ET), and 21 in dystonia, assessing perceptual, acoustic, and patient-reported speech outcomes.

Meta-analyses showed that subthalamic nucleus DBS in PD resulted in poorer speech intelligibility compared with best medical treatment (effect size -0.24; 95% confidence interval: -0.46 to -0.03; P = 0.027), with state-dependent decline under active stimulation on longitudinal analysis (Unified Parkinson's Disease Rating Scale Part III item 18 monthly change: medication on +0.016, P < 0.001; medication off +0.002, P = 0.50).

In ET, DBS consistently suppressed vocal tremor but increased the risk of dysarthria, particularly with bilateral stimulation.

Dystonia outcomes showed greater heterogeneity.

Across disorders, sustained phonation measures improved, whereas connected speech performance worsened, indicating selective vulnerability of complex motor tasks.

Neuroanatomical mapping identified two nonexclusive mechanisms: current spread to corticobulbar fibers producing spastic speech features and to the cerebellothalamocortical pathway producing ataxic features.

Hypokinetic and stuttering-like phenotypes also occurred but likely reflect network-level interactions rather than tract-specific spread.

These tract-mediated and network-level alterations appear to interact with hemispheric lateralization, medication state, and longer-term plasticity to produce complex clinical phenotypes.

We outline a clinical framework integrating systematic screening, phenotype identification, and targeted programming adjustments.

Enhanced speech assessment, precise field mapping, and adaptive DBS paradigms may promote individualized care that optimizes speech and motor function in precision DBS therapy. © 2026 The Author(s).

Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Deep brain stimulation (DBS) of the subthalamic nucleus improves motor symptoms in patients with Parkinson's disease.

Using functional MRI, optimal DBS response networks have been characterized.

However, neural activity associated with Parkinsonian symptoms is magnitudes faster than what can be resolved by this method.

Although both spatial and temporal domains of these networks appear crucial, no single study has yet investigated both domains simultaneously.

Here, we aimed at closing this gap by analysing electrophysiological data from a total of n = 127 hemispheres.

Using subthalamic local field potentials that were recorded concurrently alongside whole-brain magnetoencephalography in a multi-centre cohort of patients who underwent subthalamic DBS for the treatment of Parkinson's disease (n = 100 hemispheres), we analysed the DBS response network in both spatial and temporal domains.

In every cortical vertex, cortico-subthalamic coupling was correlated with stimulation outcomes.

This network spatially resembled functional MRI-based findings (R = 0.40, P = 0.039) and explained significant amounts of variance in clinical outcomes (βstd = 0.30, P = 0.002), whereas theta-alpha and low beta coupling did not show significant associations with DBS response (theta-alpha: βstd = -0.02, P = 0.805; low beta: βstd = -0.08, P = 0.426).

The 'optimal' high beta coupling map was robust when subjected to various cross-validation designs (10-fold cross-validation: R = 0.29, P = 0.009; split-half design: R = 0.31, P = 0.026) and was able to predict outcomes across DBS centres [R = 0.74; P(1) = 8.9 × 10-5].

We identified a DBS response network that resembles the previously defined MRI network and operates in the high beta band.

Maximal connectivity to this network was associated with optimal DBS outcomes and was able to cross-predict clinical improvements across DBS surgeons and centres.

Freezing of gait (FOG) is a devastating symptom of Parkinson's disease (PD) often resulting in disabling falls and loss of independence.

It affects half of patients, yet current therapeutic strategies are insufficient, and the underlying neural mechanisms remain poorly understood.

This study investigated beta oscillation dynamics in the subthalamic nucleus (STN) during different movement states (sitting, standing and stepping), while examining the effects of levodopa.

Specifically, it aimed to identify pathological activity during stepping by analysing the relationship between the STN and leg muscles and how this is modulated by levodopa.

Local field potentials (LFPs) in the STN and leg muscle activity measured as EMG of the gastrocnemius and peroneus longus were recorded in 14 PD patients during sitting, standing and stepping, ON and OFF levodopa.

Levodopa reduced stepping frequency variability, implying improved stepping rhythmicity.

Low-beta (12-20 Hz) and high-beta (21-35 Hz) were differentially modulated by stepping movements and levodopa, with reduced high-beta and increased low-beta during stepping compared with standing and sitting.

In contrast, levodopa reduced low-beta but increased high-beta activity, highlighting a potential physiological function of high-beta in the STN.

Additionally, step-phase-specific effects of levodopa were observed including reduced broad-beta band activity in the STN and leg muscles during the late stance and lift-off phase of the contralateral leg when ON medication.

Furthermore, STN beta bursts were associated with increased muscle activation at movement initiation, potentially reducing the ability to move freely.

This study observed different effects of movement status (sitting versus stepping versus standing) on the average amplitude of low- versus high-beta frequency bands, suggesting they may serve distinct functional roles.

Furthermore, there is a step-phase-specific effect of levodopa on STN LFPs, EMGs and intermuscular coherence during stepping.

These findings offer insight for developing phase-specific stimulation strategies targeting STN beta oscillations during gait.

Parkinson's disease (PD) is a neurodegenerative condition primarily characterized by motor deficits, yet cognitive impairments are increasingly recognized.

While deficits in executive functioning are well documented even in the absence of cognitive decline, evidence of attentional deficits in PD remains inconsistent, and the role of motor symptom lateralization is unclear.

In this systematic review and meta-analysis, we examined visual attention in right-handed, cognitively unimpaired idiopathic PD patients, focusing on the canonical attentional domains (sustained, selective, divided) and processes (alerting, endogenous and exogenous orienting, reorienting), as well as visuospatial bias.

Four databases were searched for studies comparing PD patients with healthy controls.

Meta-analytic estimates were derived using Hedges' g within random-effects models, and studies that could not be quantitatively integrated were summarized narratively.

In addition, studies directly comparing patients with left- and right-predominant motor symptoms (LPD vs.

RPD) were reviewed qualitatively.

Across 51 studies, PD patients exhibited deficits in sustained, selective, and divided attention.

Among attentional processes, only exogenous orienting was impaired, whereas alerting, endogenous orienting, and reorienting were preserved.

Findings from the few studies examining visuospatial bias indicated small, context-dependent shifts in spatial attention rather than a consistent directional bias.

These findings indicate that PD patients show visual-attentional impairments, particularly under high-demand conditions, while basic alertness and voluntary orienting appear preserved.

Exogenous orienting deficits and subtle rightward spatial tendencies in LPD suggest disruption of right-hemisphere attentional networks.

These results have implications for early cognitive assessment, rehabilitation strategies, and understanding the neural bases of attentional dysfunction in PD.

BACKGROUND AND OBJECTIVES

The gold standard for Parkinson disease (PD) diagnosis is postmortem examination, based on the presence and distribution of pathologic α-synuclein (Lewy pathology) across brain regions.

Whether pathologic α-synuclein Braak staging reflects clinical disease progression remains uncertain.

We examined the relationship between Braak stage with clinical indices of PD progression in an autopsy-proven cohort.

METHODS

We performed a retrospective clinicopathologic analysis of autopsy-confirmed PD cases from the Parkinson's UK Brain Bank (Imperial College London).

Clinical records were systematically reviewed to extract age at symptom onset, disease duration, brain weight, Hoehn and Yahr (H&Y) stage at death, and key clinical features.

Normality was assessed using Shapiro-Wilk tests; comparisons across Braak stages used Kruskal-Wallis tests.

Correlations with Braak stage were examined using Spearman correlation with 95% CIs.

Prevalence of major copathologies was summarized descriptively.

RESULTS

Of 119 clinically diagnosed PD cases, we included all 61 with autopsy confirmation and available Braak staging.

Mean ± SD age at death was 79.1 ± 7.4 years, disease duration was 13.5 ± 5.8 years, H&Y stage at death was 4.0 ± 0.8, and brain weight was 1,234.2 ± 108 g.

Braak stage was not correlated with H&Y at death (ρ = 0.146, 95% CI -0.11 to 0.39, p = 0.262), age at death (ρ = -0.210, 95% CI -0.47 to 0.07, p = 0.104), disease duration (ρ = 0.035, 95% CI -0.23 to 0.29, p = 0.787), or brain weight (ρ = 0.2, 95% CI -0.07 to 0.42, p = 0.139).

There were no differences across Braak stages in disease duration (p = 0.925), age at death (p = 0.356), brain weight (p = 0.279), or H&Y stage (p = 0.603).

By contrast, brain weight correlated negatively with age at death (ρ = -0.352, 95% CI -0.57 to -0.09, p = 0.005).

Copathologies were common, including entorhinal/allocortical tau (B1-B2) in 82%, small vessel disease in 60%, β-amyloid (Thal ≥1) in 58%, and cerebral amyloid angiopathy in 25%.

The prevalence of copathologies did not differ across Braak stages.

DISCUSSION

Braak stage was not associated with H&Y at death, disease duration, age at death, or brain weight in autopsy-proven PD patients.

These findings provide evidence that pathologic α-synuclein-based staging does not represent a model of clinical progression in PD.

The quantification of both monomeric and pathologic α-synuclein may be needed to overcome the clinical limitations of pathology-based staging.

Rigidity, along with bradykinesia and tremor, is recognized as one of the core motor symptoms fundamental to the clinical diagnosis of Parkinson's disease.

Despite its diagnostic relevance, rigidity has received comparatively less systematic investigation than other motor symptoms, resulting in gaps in our understanding of its phenomenology, neurophysiological correlates and response to therapeutic interventions such as deep brain stimulation.

This narrative review aims critically to examine and clarify the current conceptual ambiguities, assessment strategies and pathophysiological underpinnings associated with rigidity in Parkinson's disease.

We begin by discussing the wide range of phenomena described by the term 'rigidity' in neurological and non-neurological fields and highlight the inconsistencies that arise in its clinical interpretation.

We review and compare the clinical and instrumental approaches that are currently used to assess rigidity, emphasizing their respective strengths, limitations and contributions to a more precise characterization of rigidity in Parkinson's disease.

We end with a summary of molecular, neuroimaging and neurophysiological insights into the pathophysiology of rigidity.

In summary, we seek to consolidate existing knowledge, underscore unresolved questions and suggest new solutions for existing gaps with the hope of providing a conceptual and methodological foundation to guide future clinical and experimental research in the field.

BACKGROUND

Real-world gait assessment has gained momentum in populations with walking impairments, offering insights beyond standardized tests and supporting the integration of remote monitoring into clinical care.

However, its potential remains limited by the lack of validated population- and context-specific digital biomarkers.

OBJECTIVE

The primary objective was to summarize and critically evaluate the current state of real-world gait assessment using wearable sensors in Parkinson disease (PD) and stroke, addressing methodological approaches, sensor configurations, validation strategies, and outcome reporting.

The secondary objective was to quantify methodological heterogeneity by reporting pooled means with 95% confidence intervals (CIs) and prediction intervals (PIs) of commonly reported gait parameters.

METHODS

PubMed, Scopus, Web of Science, and Embase were searched for English-language studies published up to April 20, 2026.

Eligible studies used wearable sensors to assess gait quality parameters in real-world settings in at least 5 individuals with PD or poststroke.

Laboratory- or rehabilitation-only studies, non-peer-reviewed articles, abstracts, and studies before 2014 were excluded.

Methodological quality was assessed with a checklist adapted from Hubble et al.

Gait features available in at least 5 reports were included in a meta-analysis using a random-effects model with Hartung-Knapp-Sidik-Jonkman adjustment, deriving 95% CIs and PIs to characterize the pooled estimate and its dispersion.

RESULTS

Of 2489 records, 43 reports were included: 37 on PD (2774 participants; mean age 67.89, SD 8.68 years) and 6 on stroke (217 participants; mean age 63.83, SD 11.84 years).

Methodological quality was high, but external validity was consistently the weakest domain in both populations.

Sensor configurations most commonly consisted of a lower back accelerometer.

In total, 13 distinct walking bout definitions were identified, whereas 17 reports provided none, indicating substantial terminological heterogeneity.

In PD, 4 gait parameters met the meta-analysis threshold, each showing a PI far wider than its CI, precluding generalization to future settings.

For example, gait speed pooled at 0.84 m/s (95% CI 0.77-0.91; 95% PI 0.56-1.12), and number of steps per day at 7202 (95% CI 3975-10,429), the latter with a PI extending below zero, a mathematically impossible range reflecting extreme dispersion.

No stroke parameter was reported consistently enough to permit meta-analysis, underscoring a critically underdeveloped evidence base.

CONCLUSIONS

Unlike previous reviews focusing on single diseases or specific hardware, this review contrasts PD and stroke to highlight shared methodological challenges.

Real-world gait assessment in PD is advancing but fragmented, whereas the stroke evidence base remains sparse.

The observed variance is compounded by procedural and algorithmic inconsistencies that cannot currently be separated from genuine clinical differences.

The methodological groundwork established in PD offers a foundation for early adoption of standardized terminology, validation procedures, and core outcomes, essential for transitioning wearable sensors from exploratory tools to reliable clinical and remote-monitoring instruments.

BACKGROUND

The genetic architecture of Parkinson's disease varies considerably across ancestries, yet most previous genetic studies have focused on individuals of European ancestry.

We aimed to characterise the distribution of established Parkinson's disease causal variants, as well as risk-associated variants with clinical implications (ie, variants in genes involved in pathways targeted by ongoing clinical trials), across ancestrally diverse populations.

METHODS

We conducted a multi-ancestry, observational, cross-sectional genetic study using retrospective data from the Global Parkinson's Genetics Program (GP2) release 11 (released in December, 2025).

The study investigated causal and risk variants, including copy number variants, in established Parkinson's disease and parkinsonism-associated genes, following the recommendations of the Movement Disorder Society (MDS) Task Force on the Nomenclature of Genetic Movement Disorders, including GBA1, LRRK2, SNCA, VPS35, RAB32, PINK1, PRKN, PARK7, ATP13A2, DCTN1, DNAJC6, FBXO7, JAM2, RAB39B, SLC20A2, SYNJ1, VPS13C, and WDR45.

Individuals with Parkinson's disease were diagnosed based on established clinical criteria, including the Parkinson's UK Brain Bank or MDS diagnostic criteria (or both), and healthy control participants were defined as individuals without evidence of neurodegenerative disease and unrelated to participants with Parkinson's disease.

We analysed genome and exome sequencing and array genotyping data of 99 783 individuals, including 58 559 individuals with Parkinson's disease and 41 224 controls, from 11 genetically inferred ancestries (African, African admixed, Ashkenazi Jewish, Latino and Indigenous people of the Americas, central Asian, complex admixture, east Asian, European, Finnish, Middle Eastern, and south Asian), defined using reference population-based ancestry inference methods.

We calculated allele frequencies for all investigated variants in individuals with Parkinson's disease and controls, both overall and stratified by ancestry.

FINDINGS

Approximately 29% of individuals (29 001 of 99 783; 15 443 [26·4%] of 58 559 individuals with Parkinson's disease and 13 558 [32·9%] of 41 224 controls) were from under-represented populations (ie, non-European and non-Ashkenazi Jewish).

Our findings indicated both shared genetic contributors across ancestries as well as ancestry-specific differences in variant frequencies and the spectrum of variants within Parkinson's disease-associated genes.

Overall, 1217 (2·1%) of 58 559 individuals with Parkinson's disease carried a causal variant, with substantial variations across ancestries ranging from ten (0·4%) of 2844 African individuals to 251 (10·7%) of 2343 individuals of Ashkenazi Jewish ancestry.

Risk variants in GBA1 and LRRK2 were identified in 6893 (11·8%) of 58 559 individuals with Parkinson's disease and 3578 (8·7%) of 41 224 controls.

GBA1 risk variants were most frequent overall and identified across all ancestries, but variant frequency and spectra differed substantially between ancestries, from 195 (4·1%) of 4773 in the east Asian ancestry group to 1505 (52·9%) of 2844 in the African ancestry group.

Similarly, LRRK2 causal and risk variants showed ancestry-specific enrichment, with the highest frequencies of causal variants in the Ashkenazi Jewish (250 [10·7%] of 2343) and Middle Eastern (59 [4·4%] of 1347) ancestry groups, whereas risk variants were predominantly identified in the east Asian ancestry group (601 [12·6%] of 4773).

Carriers of biallelic causal variants in PRKN, commonly including deletions and duplications, were also identified across all ancestries except Ashkenazi Jewish; the highest frequency was in the Middle Eastern ancestry group (17 [1·3%] of 1347), and frequencies in all other ancestries were less than 1%.

INTERPRETATION

This large-scale, multi-ancestry genetic study offers crucial insights into the population-specific genetic architecture of Parkinson's disease.

Whereas clinical trials targeting GBA1 and LRRK2 variant carriers are primarily performed in Europe and the USA, increased ancestral diversity in Parkinson's disease research will be crucial to improve diagnostic accuracy, enhance our understanding of disease mechanisms across populations, and ensure equitable application of and access to emerging genetically informed therapies.

FUNDING

Aligning Science Across Parkinson's (ASAP) through the Global Parkinson's Genetics Program (GP2).

BACKGROUND

Differentiating progressive supranuclear palsy (PSP) from Parkinson's disease (PD) can be clinically challenging.

In the neuroimaging field, radiomics has emerged as a promising approach to capture subtle microstructural and textural image alterations, improving differential diagnoses.

OBJECTIVE

To assess the diagnostic value of brainstem radiomic features from T1-weighted magnetic resonance imaging (MRI) in distinguishing PSP from PD patients.

METHODS

This study included 433 participants from two independent cohorts: an Italian training cohort (84 PSP and 177 PD) and an international validation cohort (68 PSP and 104 PD).

Radiomic features including first-order, shape, and texture descriptors were extracted with PyRadiomics from brainstem segmentations generated by the automated deep-learning-based AssemblyNet pipeline.

Classification models (Decision Tree, Support Vector Machine, Random Forest, and XGBoost) were trained using nested cross-validation and tested on the independent cohort.

Model interpretability was examined with SHapley Additive exPlanations.

RESULTS

Radiomics-based models yielded high and consistent performance in distinguishing PSP from PD, higher than brainstem volume.

In the validation cohort, Random Forest and XGBoost achieved the best performance (area under the curve [AUC]: 0.93 and 0.94, respectively).

Texture- and intensity-based radiomic features emerged as the most informative predictors, while shape descriptors showed lower relevance in discrimination between PSP and PD.

CONCLUSIONS

Brainstem radiomics extracted from routine T1-weighted MRI demonstrated excellent classification performance in distinguishing PSP from PD patients and generalized robustly across independent datasets.

Texture-based features captured microstructural disorganization not reflected by automated volumetry, underscoring the added value of radiomics for differential diagnosis in atypical parkinsonism and for integration in future multimodal biomarker frameworks. © 2026 The Author(s).

Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BACKGROUND

Emerging evidence implicates neuroinflammation in progressive supranuclear palsy (PSP) pathophysiology, with elevated cyto-chemokines suggesting natural killer (NK) cell involvement.

METHODS

We characterized peripheral NK in PSP (N = 11) versus Parkinson's disease (PD, N = 10) and healthy controls (HC, N = 8) at both immunophenotypic and transcriptional levels.

RESULTS

PSP patients showed significantly reduced CD3-CD56 + NK frequency (1.35% ± 0.98%) compared with HC (2.96% ± 1.14%) and PD (2.03% ± 0.86%), specifically affecting the immunoregulatory CD56brightCD16-/dim subset.

PSP NK cells exhibited elevated CX3CR1 expression, suggesting enhanced migratory capacity toward inflamed tissues.

Transcriptomic analysis of primary NK cells revealed 208 DEG with significant enrichment in angiogenesis pathways, particularly vascular endothelial growth factor-A (VEGF-A).

Plasma VEGF-A measurements demonstrated a disease-specific pattern: inverse correlation with severity in PSP versus direct correlation in PD.

CONCLUSIONS

These findings identify a potentially disease-specific transcriptional signature with repercussions on the cyto-chemokine plasma profile.

Further investigation of the NK cell-mediated immune response in PSP may provide new insights into disease mechanisms and open avenues for immunomodulatory therapeutic strategies. © 2026 The Author(s).

Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

INTRODUCTION

Creativity in Parkinson's disease (PD) has aroused research interest due to its neurological underpinnings, which involve brain regions crucial for creative and divergent thinking (a core-process of creative thinking), and because of some patients who displayed an increased artistic drive following dopaminergic treatment.

From a cognitive point of view, creative thinking underlies several cognitive abilities, such as executive functions and memory.

Therefore, a better understanding of whether it is increased (or, at least, preserved) in PD patients can provide useful insights for sustaining cognitive functioning.

The aim of the present study was to investigate whether PD patients regularly assuming dopaminergic medications present higher divergent thinking skills than healthy controls.

METHODS

A meta-analysis was conducted according to the PRISMA guidelines to provide a statistical synthesis of the studies.

Study quality was assessed using the QUADAS -2 tool.

RESULTS

Ten studies were included in the meta-analysis, which indicated the absence of significant differences between PD patients and healthy controls in tasks assessing divergent thinking (Cohen's d = -0,095 (95% CI: -0,308, 0,118)).

CONCLUSIONS

Such findings support the notion that divergent thinking can be spared by the disease, maybe constituting a possible resource for patients' cognitive functioning, as it involves those cognitive abilities that can compensate impairments in PD.

Clinical implications and guidance to further studies and interventions to support PD patients' cognition were discussed.

IMPORTANCE

Pure autonomic failure (PAF) can be the prodromal presentation of Parkinson disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), although phenoconversion rates and predictors have not been systematically reported.

OBJECTIVE

To estimate phenoconversion rates for MSA, PD, and DLB separately and grouped as central α-synucleinopathies and identify clinical predictors of phenoconversion in patients with PAF.

DATA SOURCES

PubMed and Embase databases from inception to June 2025.

STUDY SELECTION

Longitudinal studies including patients with confirmed PAF reporting data on incidence and/or predictors of phenoconversion.

DATA EXTRACTION AND SYNTHESIS

Studies were screened and data extracted by 2 independent investigators according to PRISMA guidelines.

A meta-analysis was performed using generic inverse-variance random-effects models.

MAIN OUTCOMES AND MEASURES

PD, DLB, MSA, and central α-synucleinopathy phenoconversion incidence rates as per 100 person-years were the main outcomes.

Incidence rates were log transformed and pooled using a random-effects meta-analysis.

Clinical predictors of phenoconversion were reported as secondary outcomes.

Prediction intervals and meta-regression explored study-level moderators.

RESULTS

A total of 9 studies comprising 900 individuals with PAF (mean [SD] age at onset, 63.1 [4.3] years; 63.8% male) were included.

During the mean (SD) 6.4 (2.0) years of follow-up, 270 of 900 individuals with PAF (30%) experienced phenoconversion to a central α-synucleinopathy (12% to MSA, 11% to DLB, 7% to PD) with a pooled incidence rate of 5.09 per 100 person-years (95% CI, 3.79-6.85; approximately 5% per year).

Phenoconversion rates for MSA (pooled incidence rate, 1.96; 95% CI, 1.29-2.99) were highest in the first years of follow-up, whereas Lewy body disorders showed more constant phenoconversion rates (DLB pooled incidence rate, 1.56; 95% CI, 0.94-2.61; PD pooled incidence rate, 1.35; 95% CI, 0.75-2.41).

Hyposmia was the only predictor with diagnostic value to distinguish between those with phenoconversion to PD and DLB (hyposmia pooled risk ratio, 1.88; 95% CI, 1.26-2.97) and MSA, although rapid eye movement sleep behavior disorder (RBD) and subtle motor signs were consistent predictors of phenoconversion to any central α-synucleinopathy.

Heterogeneity was partly explained by follow-up duration.

CONCLUSIONS AND RELEVANCE

Findings of this systematic review and meta-analysis suggest that PAF may be a prodromal presentation of PD, DLB, or MSA with phenoconversion incidence rates similar to those of RBD.

A combination of clinical (RBD, subtle motor signs, hyposmia) and in-development biomarkers may help refine the phenoconversion trajectories of people with PAF providing an invaluable opportunity for early diagnosis and intervention.

BACKGROUND

[18F]Fluorodeoxyglucose positron emission tomography ([18F]FDG PET) represents an endorsed neurodegeneration biomarker in neuronal α-synucleinopathies.

Idiopathic/isolated rapid eye movement (REM) sleep behavior disorder (iRBD) represents a prodromal stage of such disorders.

OBJECTIVES

To assess [18F]FDG PET as a neurodegeneration biomarker, using published brain metabolic disease-related patterns, and a regional-based approach, across the prodromal to overt α-synucleinopathy continuum.

METHODS

We included 83 prodromal subjects with iRBD, comprising non-converters (n = 56) and converters (n = 27) to an overt α-synucleinopathy (either Parkinson's disease [PD] or dementia with Lewy bodies [DLB]) according to the last available follow-up, and 85 subjects with PD (n = 40) and DLB (n = 45).

For comparison, we enrolled a group of healthy subjects (n = 41).

Participants underwent brain [18F]FDG PET at baseline.

Analysis of covariance was used to test the ability of previously published [18F]FDG PET disease-related patterns in characterizing neurodegeneration levels along the prodromal to overt α-synucleinopathy continuum, and across the motor-predominant (parkinsonism-first) and the cognitive-predominant (dementia-first) clinical trajectories.

We further assessed metabolic changes using a regional-based approach.

RESULTS

All disease-related patterns effectively discriminated clinical stages, from prodromal to overt α-synucleinopathies, with comparable performance. [18F]FDG PET significantly distinguished all groups along the cognitive-predominant pathway; whereas in the motor-predominant pathway, converter patients were not significantly discriminated from non-converters.

Regionally, the inferior parietal, precuneus, and middle frontal areas exhibited the most prominent decrease in [18F]FDG uptake with progression, alongside relative parallel progressive increases in the cerebellum, pons, parahippocampal areas, putamen, and pallidum.

CONCLUSIONS

[18F]FDG PET disease-related patterns efficiently characterize neurodegeneration from prodromal to overt α-synucleinopathy, best assessing the cognitive-predominant (dementia-first) pathway. © 2026 The Author(s).

Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

OBJECTIVES

Early-onset Parkinson disease (EOPD) is associated with stronger genetic contributions than late-onset Parkinson disease (LOPD).

However, the complex interplay between genetic susceptibility, family history, and environmental factors remains incompletely understood.

This study assesses familial aggregation of PD and essential tremor (ET) among relatives of patients with EOPD and compares it with patients with LOPD.

METHODS

Patients with EOPD evaluated at the Mayo Clinic were identified, whereas patients with LOPD were identified through the Rochester Epidemiology Project record-linkage system.

All cases with symptom onset between 1991 and 2020 were included.

DISCUSSION

The higher prevalence of PD and ET family history in the EOPD cohort supports a stronger genetic contribution and may reflect enrichment for high-penetrance monoallelic variants.

Conversely, the higher frequency of affected siblings in the LOPD cohort suggests a polygenic inheritance pattern with greater environmental contribution.

Parkinson's disease is associated with extensive structural brain changes.

Recent work has proposed that the spatial pattern of disease pathology is shaped by both network spread and local vulnerability.

However, few studies have assessed these biological frameworks in large patient samples across disease stages.

Analysing the largest imaging cohort in Parkinson's disease to date (n = 3096 patients), we investigated the roles of network architecture and local brain features by relating regional abnormality maps to normative profiles of connectivity, intrinsic networks, cytoarchitectonics, neurotransmitter receptor densities and gene expression.

We found widespread cortical and subcortical atrophy in Parkinson's disease to be associated with advancing disease stage, longer time since diagnosis and poorer global cognition.

Structural brain connectivity best explained cortical atrophy patterns in Parkinson's disease and across disease stages.

These patterns were robust among individual patients.

The precuneus, lateral temporal cortex and amygdala were identified as likely network-based epicentres, with high convergence across disease stages.

Individual epicentres varied significantly among patients, yet they consistently localized to the default mode and limbic networks.

Furthermore, we showed that regional overexpression of genes implicated in synaptic structure and signalling conferred increased susceptibility to brain atrophy in Parkinson's disease.

In summary, this study demonstrates in a well-powered sample that structural brain abnormalities in Parkinson's disease across disease stages and within individual patients are influenced by both network spread and local vulnerability.

PURPOSE

This review aims to examine the effects of Lee Silverman Voice Treatment® BIG (LSVT® BIG) on motor impairments, activities of daily living (ADLs), and quality of life (QoL) in patients with Parkinson's disease (PD).

METHODS

PsycINFO, PubMed, EMBASE, SCOPUS, PEDro, CINAHL, and Web of Science were searched until June 2025.

Studies were included if they included patients with PD, administered LSVT® BIG, and assessed motor symptoms, ADLs, and QoL.

The PEDro scale was used to assess methodological quality, and pooled effect sizes were calculated using Cohen's d and random-effects models.

RESULTS

Ten studies (300 participants) met the inclusion criteria.

No significant effects in the Time-Up & Go (TUG) test (SMD: 0.050, 95% CI: -0.550 to 0.650, p = 0.870) and the 10-Minute Walk Test (10MWT) (SMD: 0.415, 95% CI: -0.198 to 1.027, p = 0.184) were reported.

Other outcome measures revealed significant improvements in balance, gait cycle symmetry, and manual dexterity in patients with PD.

CONCLUSIONS

The initial findings revealed that LSVT® BIG improves balance and gait in patients with PD.

The evidence for the effects of LSVT® BIG on manual dexterity and overall ADLs is mixed and inconclusive for QoL.

Further high-quality studies with long-term follow-ups are needed.

GBA1 variants are common genetic risk factors for Parkinson's disease and also for dementia with Lewy bodies.

New evidence highlights the relationship between the different GBA1 variants and their associated clinical presentation and disease progression, although penetrance is low and the majority of carriers do not develop a synucleinopathy.

The clinical profile of GBA1-associated Parkinson's disease is characterised by a faster rate of progression with more severe cognitive and autonomic dysfunction than idiopathic Parkinson's disease, particularly in those carrying severe pathogenic variants.

The mechanisms involved in phenotypic conversion and disease progression in carriers of GBA1 variants are being elucidated, and this knowledge could be translated into clinically relevant biomarker profiles.

GBA1 has become a target for intervention for both GBA1-associated Parkinson's disease and idiopathic Parkinson's disease, with therapeutic strategies aiming to prevent or slow disease progression via pharmacological chaperones, enzymatic allosteric activators, metabolic interventions, and modulation of gene expression.

Primary results from the 24-week EPSILON study (NCT04978597) showed that adding opicapone to levodopa in non-fluctuating Parkinson's patients significantly improved motor impairment without increasing the development of motor complications versus placebo.

All participants finishing the double-blind phase became eligible for open-label treatment with opicapone.

Symptomatic efficacy of opicapone was maintained with 1-year open-label treatment (adjusted-mean ± SE change in MDS-UPDRS motor score from double-blind baseline to Week 76: -7.4 ± 0.81); participants who switched from placebo to opicapone had a motor improvement of -6.1 ± 0.79.

At Week 76, 80.2% of opicapone-opicapone-treated participants remained motor complication-free versus 69.7% in the placebo-opicapone group (p = 0.1).

BACKGROUND AND OBJECTIVES

Recent reports have suggested that levodopa exposure may contribute to freezing of gait (FOG), but this relationship remains controversial because of confounding by disease severity and duration.

Our goal was to assess the relationship between levodopa use and FOG incidence and severity.

METHODS

We studied 2 prospective, multicentric cohorts: NS-Park and Parkinson's Progression Markers Initiative (PPMI).

Patients with ≥2 visits were selected.

Three nested subcohorts were defined based on disease duration, baseline FOG, and levodopa exposure.

FOG was assessed using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II 2.13.

Analyses included mixed-effects ordered logistic regression to evaluate FOG severity and Kaplan-Meier and Cox proportional hazards models to assess incident FOG.

Models adjusted for disease duration, Hoehn and Yahr (H&Y) stage, and MDS-UPDRS Part III scores.

RESULTS

A total of 25,602 patients with Parkinson disease from the NS-Park (mean age 68.3 ± 29.1, 42% female) and 1,441 from the PPMI (mean age 62.9 ± 9.8, 37% female) cohorts were included.

In unadjusted analyses with the NS-Park cohort, levodopa use was associated with higher FOG severity and incidence, but this association was no longer statistically significant in the PPMI cohort.

In mixed-effects ordinal logistic regression models adjusting for disease duration/severity, levodopa status showed a nonsignificant effect size on FOG (NS-Park odds ratio [OR] 1.84, 95% CI 0.94-3.61, p = 0.074; PPMI OR 0.76, 95% CI 0.38-1.51, p = 0.430), while disease duration (NS-Park OR 4.4, 95% CI 3.01-6.29, p = 6.0e-15; PPMI OR 6.97, 95% CI 5.05-9.63, p = 4.7e-32), Hoehn & Yahr stage (NS-Park OR 6.8, 95% CI 3.52-13.08, p = 1.059e-08; PPMI OR 1.5, 95% CI 0.96-2.22, p = 0.073), and MDS-UPDRS-III score (NS-Park OR 1.85, 95% CI 1.38-2.49, p = 4.34e-05; PPMI OR 2.00, 95% CI 1.67-2.39, p = 2.4e-14) were independently associated with greater FOG severity.

No statistically significant association was observed between future levodopa exposure and de novo FOG incidence.

In turn, FOG incidence was driven by the H&Y (NS-Park: hazard ratio [HR] 1.94, 95% CI 1.68-2.23; PPMI: HR 1.78, 95% CI 1.47-2.17) and MDS-UPDRS III (NS-Park: HR 1.40, 95% CI 1.07-1.83; PPMI: HR 1.26, 95% CI 1.17-1.36).

DISCUSSION

No significant or consistent association between levodopa exposure and FOG severity or incidence was observed after adjustment for disease duration and severity, with the effect estimates significantly attenuated despite residual uncertainty.

BACKGROUND

Lysosomal dysfunction is central to Parkinson's disease (PD) pathogenesis, with GBA1 representing the strongest established genetic risk factor.

Numerous other genes involved in lysosomal sphingolipid, glycosphingolipid, and ceramide metabolism have been proposed as contributors to PD, highlighting the need for genetic analyses across these pathways.

OBJECTIVES

The aim was to evaluate the contribution of rare variants across lysosomal genes to PD risk.

METHODS

We analyzed rare variants (minor allele frequency ≤0.01) across 36 lysosomal genes in 8267 individuals with PD and 68,208 controls, including 793 early-onset PD (≤50 years) cases.

Targeted sequencing was performed in four cohorts at McGill University (3456 cases and 2664 controls) and combined with whole-genome sequencing data from the United Kingdom (UK) Biobank (2848 cases, 62,451 controls) and the Accelerating Medicines Partnership-PD cohort (1963 cases, 3093 controls).

Associations were tested using Sequence Kernel Association Test-Optimal across variant classes (rare variants, nonsynonymous, loss-of-function, and predicted damaging variants with combined annotation-dependent depletion score >20), followed by meta-analysis across cohorts.

Domain-level analyses were performed for variants located within protein domains.

False discovery rate (FDR) correction was applied.

RESULTS

Meta-analysis identified a significant association between rare variants in ST3GAL3 and Parkinson's disease (Pfdr = 0.04).

Domain-based analyses showed enrichment of nonsynonymous variants within the β-acetyl-hexosaminidase-like domain of HEXA (P = 8.0 × 10-4), although this signal did not survive correction (Pfdr = 0.154).

In early-onset PD, domain-based analyses identified significant associations in NAGLU (Pfdr = 7.3 × 10-6) and ST3GAL5 (Pfdr = 0.03).

CONCLUSIONS

Rare variants across multiple lysosomal pathways, particularly those related to sialylation, ganglioside metabolism, ceramide biology, and lysosomal proteolysis, may contribute to PD susceptibility beyond GBA1, highlighting pathways for future replication and investigation. © 2026 The Author(s).

Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BACKGROUND

Pain is a frequent and heterogeneous non-motor symptom of Parkinson's disease (PD).

Identifying its various underlying mechanisms remains challenging, while such mechanisms are likely to drive proper therapeutic management.

Among the various PD-related pain subtypes, primary Parkinsonian pain (PPP) is particularly difficult to identify and differentiate from musculoskeletal pain, due to the absence of positive diagnostic criteria.

OBJECTIVES

The aim is to develop and validate the "Primary Parkinsonian Pain Diagnostic Questionnaire" (3PDQ), a self-reported tool for identifying PPP in PD.

METHODS

The 3PDQ was developed through literature review and expert consensus, and refined based on patient feedback.

In this multicentric study, 227 PD patients with chronic pain were recruited from 11 French Parkinson's Expert Centers; 179 were analyzed after cases were excluded where two independent expert raters made discordant types of pain diagnoses.

Psychometric validation followed COSMIN standards, assessing acceptability, internal consistency, reproducibility, and diagnostic accuracy versus expert diagnosis.

RESULTS

PPP was diagnosed in 36.3% of patients, whereas musculoskeletal pain was the most frequent pain subtype (42.5%).

The final 11-item 3PDQ showed good acceptability (96.5% computable data), satisfactory internal consistency (Kuder-Richardson = 0.71), and excellent test-retest reliability (Lin's concordance = 0.82).

The questionnaire demonstrated good discrimination between PPP and musculoskeletal pain (AUC = 0.82), with sensitivity = 82%, specificity = 74%, and a negative predictive value = 82%.

CONCLUSIONS

The 3PDQ is the first validated self-reported tool for diagnosing PPP in PD.

It provides a reliable, clinically feasible tool to facilitate pain phenotyping and supports the development of mechanism-based treatment strategies. © 2026 International Parkinson and Movement Disorder Society.

BACKGROUND

SUNRISE-PD was a dose-escalating, phase 1/2 study investigating a second-generation lentiviral vector gene therapy delivering the genes for dopamine synthesis (OXB-102) to treat Parkinson's disease (PD).

The trial was prematurely terminated due to insolvency of the sponsor.

OBJECTIVES

The aim was to provide an investigator-led description of the clinical course for the 6 patients enrolled in the OXB-102 trial.

METHODS

Individual patient data were extracted, compiled, and summarized from investigator records.

RESULTS

Six patients received a low (n = 2) and a higher (n = 4) dose of the OXB-102 gene therapy.

There were eight serious adverse events (SAE), of which only one was considered definitely related to the intervention.

All SAEs were transient and resolved without sequelae.

Efficacy data were limited, but some stabilization of motor function was observed in most of the patients.

CONCLUSION

This novel dopamine gene therapy appears safe in patients with moderate-to-severe PD, with some possible stabilizing effects on their clinical course. © 2026 The Author(s).

Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BACKGROUND

Magnetic resonance imaging (MRI) relaxometry using R 2 * measurement is a promising non-invasive marker of brain iron-related changes in Parkinson's disease (PD).

Although longitudinal susceptibility MRI studies have demonstrated progression over time, the stage-dependent dynamics of R 2 * changes across the full spectrum of PD duration remain incompletely characterized.

OBJECTIVES

The goal was to assess 1-year longitudinal R 2 * changes across PD stages within a multicenter framework, compared with healthy controls (HC).

METHODS

In this prospective multicenter study, 95 PD patients and 65 age- and sex-matched HC underwent 3 T MRI and clinical evaluation at baseline and 1 year.

PD patients were stratified by disease duration (15 years).

R 2 * values were extracted from basal ganglia regions, focusing primarily on the substantia nigra (SN).

Motor and non-motor assessments, performed in the on-medication state, included the Movement Disorder Society-Unified Parkinson's Disease Rating Scale, Montreal Cognitive Assessment, and mood/apathy scales.

RESULTS

SN R 2 * increased significantly over 1 year across PD patients (+5% within-group) and HC (+2% within-group), resulting in a +3% greater longitudinal change in PD versus HC (P  R 2 * changes were observed in patients with longer disease duration (r = 0.28; P = 0.006).

Significant R 2 * changes were also detected in other basal ganglia regions.

No significant change in motor or non-motor disability in the on-medication state was observed over 1 year.

CONCLUSIONS

SN R 2 * increased over 1 year in PD across disease stages, with larger changes in more advanced patients and no evidence of an early plateau.

These findings support the potential of R 2 * as a sensitive imaging marker of PD progression over short intervals. © 2026 International Parkinson and Movement Disorder Society.

BACKGROUND

Previous studies on calcium channel blockers (CCBs) and Parkinson's disease (PD) risk reached conflicting conclusions.

OBJECTIVES

We examined the relationship between CCBs and PD in the E3N cohort of French women followed for 15 years (2004-2018), while taking into account the potential for reverse causation.

METHODS

New users of CCBs were identified using drug reimbursement databases.

We validated incident PD using several data sources.

We described trajectories of CCBs use using mixed logistic models within a nested case-control study.

We used Cox proportional hazards models for time-varying variables to estimate the association between CCBs (overall, amlodipine, non-amlodipine dihydropyridines [DiCCBs], non-dihydropyridines [non-DiCCBs]) and PD.

Main analyses used a 5-year lag; sensitivity analyses without a lag were performed for comparison.

RESULTS

Among 82,605 women, 603 developed PD and 13,022 used CCBs.

Women who started non-DiCCBs had higher PD risk than never users (hazard ratio [HR] = 1.56; 95% confidence interval [95% CI] = 0.99-2.46; P-trend ≤ 0.02).

Among non-DiCCBs, diltiazem was associated with PD (HR = 2.20 [95% CI = 1.19-4.04]).

There were no significant associations for CCBs overall, amlodipine, and non-amlodipine DiCCBs.

In analyses without a lag, amlodipine (HR = 1.45 [95% CI = 1.13-1.87]) and diltiazem (HR = 1.63 [95% CI = 1.02-2.60]) were associated with PD.

Results are consistent with trajectories of CCBs prescriptions in PD patients and controls.

DISCUSSION

Overall, CCBs were not associated with PD but women who started using diltiazem had higher PD incidence in lagged analyses.

Diltiazem and amlodipine were associated with PD in analyses without a lag.

These findings are consistent with case reports of parkinsonism induced by specific CCBs and warrant further studies and surveillance. © 2026 The Author(s).

Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Freezing of gait (FOG) is a devastating symptom of Parkinson's disease (PD) often resulting in disabling falls and loss of independence.

It affects half of patients, yet current therapeutic strategies are insufficient, and the underlying neural mechanisms remain poorly understood.

This study investigated beta oscillation dynamics in the subthalamic nucleus (STN) during different movement states (sitting, standing and stepping), while examining the effects of levodopa.

Specifically, it aimed to identify pathological activity during stepping by analysing the relationship between the STN and leg muscles and how this is modulated by levodopa.

Local field potentials (LFPs) in the STN and leg muscle activity measured as EMG of the gastrocnemius and peroneus longus were recorded in 14 PD patients during sitting, standing and stepping, ON and OFF levodopa.

Levodopa reduced stepping frequency variability, implying improved stepping rhythmicity.

Low-beta (12-20 Hz) and high-beta (21-35 Hz) were differentially modulated by stepping movements and levodopa, with reduced high-beta and increased low-beta during stepping compared with standing and sitting.

In contrast, levodopa reduced low-beta but increased high-beta activity, highlighting a potential physiological function of high-beta in the STN.

Additionally, step-phase-specific effects of levodopa were observed including reduced broad-beta band activity in the STN and leg muscles during the late stance and lift-off phase of the contralateral leg when ON medication.

Furthermore, STN beta bursts were associated with increased muscle activation at movement initiation, potentially reducing the ability to move freely.

This study observed different effects of movement status (sitting versus stepping versus standing) on the average amplitude of low- versus high-beta frequency bands, suggesting they may serve distinct functional roles.

Furthermore, there is a step-phase-specific effect of levodopa on STN LFPs, EMGs and intermuscular coherence during stepping.

These findings offer insight for developing phase-specific stimulation strategies targeting STN beta oscillations during gait.

BACKGROUND AND OBJECTIVES

The prevalence of Parkinson disease (PD), multiple sclerosis (MS), and motor neuron diseases (MNDs) is rising globally.

However, it is unclear to what degree this is related to an increase in incidence or to improved survival after diagnosis.

METHODS

We performed 2 nationwide, population-based, retrospective cohort studies, including all individuals living in Sweden between 2001 and 2016 and living in France between 2009 and 2022, respectively.

Pooled mixed-effects regression models, with country as a random effect, were used to determine temporal trends in prevalence, crude and age-standardized and sex-standardized incidence, and age and life expectancy at diagnosis.

DISCUSSION

These findings indicate that the rising MS prevalence is largely survival-driven and the rising MND prevalence reflects a true increase in incidence, whereas PD prevalence grows modestly, largely independent of incidence.

Depending on the mechanism that drives prevalence, whether increased incidence reflecting changing risk factor exposures, improved survival due to therapeutic advances, or demographic aging of the population, inferences about underlying causes differ substantially between PD, MS, and MNDs, with direct implications for health care planning and etiologic research.

GBA1 variants are common genetic risk factors for Parkinson's disease and also for dementia with Lewy bodies.

New evidence highlights the relationship between the different GBA1 variants and their associated clinical presentation and disease progression, although penetrance is low and the majority of carriers do not develop a synucleinopathy.

The clinical profile of GBA1-associated Parkinson's disease is characterised by a faster rate of progression with more severe cognitive and autonomic dysfunction than idiopathic Parkinson's disease, particularly in those carrying severe pathogenic variants.

The mechanisms involved in phenotypic conversion and disease progression in carriers of GBA1 variants are being elucidated, and this knowledge could be translated into clinically relevant biomarker profiles.

GBA1 has become a target for intervention for both GBA1-associated Parkinson's disease and idiopathic Parkinson's disease, with therapeutic strategies aiming to prevent or slow disease progression via pharmacological chaperones, enzymatic allosteric activators, metabolic interventions, and modulation of gene expression.

Primary results from the 24-week EPSILON study (NCT04978597) showed that adding opicapone to levodopa in non-fluctuating Parkinson's patients significantly improved motor impairment without increasing the development of motor complications versus placebo.

All participants finishing the double-blind phase became eligible for open-label treatment with opicapone.

Symptomatic efficacy of opicapone was maintained with 1-year open-label treatment (adjusted-mean ± SE change in MDS-UPDRS motor score from double-blind baseline to Week 76: -7.4 ± 0.81); participants who switched from placebo to opicapone had a motor improvement of -6.1 ± 0.79.

At Week 76, 80.2% of opicapone-opicapone-treated participants remained motor complication-free versus 69.7% in the placebo-opicapone group (p = 0.1).

Adaptive deep brain stimulation (aDBS) represents an important evolution in the treatment of Parkinson's disease (PD), building on conventional DBS (cDBS) by adjusting stimulation in response to real-time physiological signals.

By enabling dynamic targeting of disease-related neural activity, aDBS offers the potential for more precise modulation of motor symptoms.

Additional anticipated advantages include reduced stimulation-related side effects and improved energy efficiency, supporting long-term device performance.

Although clinical uptake is still at an early stage, growing experience has highlighted both opportunities and areas requiring further refinement.

Key challenges include inter-individual variability in biomarker expression, diversity in programming approaches, and ongoing debate regarding optimal thresholds and response latencies.

The clinical significance of short-term local field potential (LFP) recordings continues to be actively investigated, particularly in the context of signal artifacts, physiological variability, and current hardware limitations.

Beyond technical considerations, factors such as patient selection, ethical frameworks, and cost-effectiveness remain important determinants of broader implementation.

Continued progress will depend on the development of robust and flexible control strategies that incorporate multimodal biomarkers, including wearable-derived motor metrics and patient-reported outcomes, to support personalized therapy.

With an expanding evidence base and recent regulatory approvals, aDBS is increasingly transitioning from an experimental concept to a viable clinical tool.

Future efforts should prioritize the translation of research paradigms into scalable clinical workflows that effectively balance automation with individualized patient care. © 2026 The Author(s).

Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

IMPORTANCE

Tavapadon is an oral, once-daily, selective D1/D5 agonist that may improve Parkinson disease (PD) motor symptoms while minimizing adverse events (AEs) associated with D2/D3 receptor activation.

OBJECTIVE

To evaluate the efficacy, safety, and tolerability of tavapadon in adults with early PD.

DESIGN, SETTING, AND PARTICIPANTS

TEMPO-1 was a phase 3, double-blind, placebo-controlled randomized clinical trial conducted at 102 sites across 12 countries between December 2019 and June 2024.

Adults with early PD (<3 years' disease duration) who were treatment naive or had less than 3 months of prior dopaminergic treatment were eligible for enrollment.

Data analysis was completed from July 2024 to May 2025.

INTERVENTION

Participants were randomized 1:1:1 to receive 1 of 2 fixed doses of tavapadon (5 or 15 mg once daily) or placebo for 27 weeks, followed by a 4-week safety follow-up period.

MAIN OUTCOMES AND MEASURES

The primary end point was least-squares mean (LSM) change from baseline to week 26 in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) parts II and III combined score.

Key secondary end points were LSM change from baseline to week 26 in MDS-UPDRS part II scores and the proportion of participants with a score of "much improved" or "very much improved" on the Patient Global Impression of Change.

RESULTS

Overall, 751 adults with early PD who were treatment naive or had less than 3 months of prior dopaminergic treatment were screened, and 529 participants were enrolled (187 female participants [35.3%]; mean [SD] age, 63.7 [9.6] years; mean [SD] disease duration, 0.7 [0.8] years) and randomized to receive tavapadon, 5 mg (n = 177), tavapadon, 15 mg (n = 177), or placebo (n = 175).

The change from baseline to week 26 in the MDS-UPDRS parts II and III combined score was significantly improved in participants treated with both the 5-mg dose of tavapadon (9.7-point decrease vs 1.8-point increase with placebo; treatment difference, -11.5 points; 95% CI, -13.8 to -9.2; P < .001; d = 1.14) and 15-mg dose of tavapadon (10.2-point decrease vs 1.8-point increase with placebo; treatment difference, -12.1 points; 95% CI, -14.4 to -9.8; P < .001; d = 1.20).

Tavapadon had a favorable safety profile; most AEs were nonserious and mild to moderate in severity.

Common AEs with tavapadon were nausea (90 of 354 with tavapadon [25.4%]), headache (59 of 354 [16.7%]), and dizziness (45 of 354 [12.7%]).

CONCLUSIONS AND RELEVANCE

In the TEMPO-1 randomized clinical trial, tavapadon improved motor function in participants with early PD and was well tolerated with a favorable safety profile.

TRIAL REGISTRATION

ClinicalTrials.gov Identifier: NCT04201093.

OBJECTIVE

Investigate the efficacy of immediate-release (IR) amantadine in reducing the risk of peak-dose dyskinesia in early Parkinson's disease (PD) as add-on to levodopa.

BACKGROUND

While the use of amantadine to manage dyskinesia in PD is well supported by controlled clinical trials, data on its efficacy in patients without motor complications remain limited.

METHODS

This 22-month, multicenter, randomized, placebo-controlled trial (NCT01538329) enrolled early PD patients on stable levodopa (≥150 mg/day for ≤1 year) without motor complications.

The study included three double-blind phases: an 18-month treatment phase with adjunct amantadine-IR (200 mg/day) or placebo (Period 1), a 3-month delayed-start phase where all participants received amantadine-IR (Period 2), and a 1-month washout with placebo (Period 3).

The primary outcome was dyskinesia incidence at month 18; secondary outcomes included dyskinesia rates at the end of Periods 2 and 3 to assess potential long-lasting mechanisms of the drug.

Exploratory outcomes investigated the potential effects of amantadine-IR on motor and non-motor symptoms and quality of life.

RESULTS

A total of 207 patients were randomized to amantadine-IR (N = 99) or placebo (N = 108).

Significantly fewer patients in the amantadine-IR group developed dyskinesia versus placebo during Period 1 (11% vs. 22%, P = 0.025), while the mean daily dose of levodopa (95% CI) increased by 70 (21-119) mg less (P = 0.005).

The proportion of patients with dyskinesia was less in the amantadine-IR group versus placebo at the end of Periods 2 and 3, but the difference was not statistically significant (12% vs. 20%, P = 0.13 and 16% vs. 22%, P = 0.23, respectively).

Mild but significant positive effects on freezing of gait, fatigue, and quality of life were observed during Period 1.

The safety profile of amantadine-IR was in line with previous reports.

CONCLUSIONS

Adjunctive amantadine-IR in early PD halved dyskinesia incidence over 18 months.

Long-lasting mechanisms could not be demonstrated and merit further investigation.

Exploratory positive findings on the potential benefit of amantadine-IR on symptoms like freezing of gait and fatigue also call for further investigation. © 2025 The Author(s).

Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BACKGROUND

The optimal design for care delivery in Parkinson's disease (PD) that addresses changing needs of the lived experience is unclear.

There is a critical need for care models to be implemented and transferable across diverse healthcare systems with agility.

OBJECTIVES

We aimed to evaluate the multinational implementation and impact of a novel pragmatic integrated care delivery program for PD (iCARE-PD).

METHODS

We conducted a multinational prospective observational study with a pre-post design (six national PD tertiary centers) of a 4-month integrated care program focused on individualized care plans, enhanced system navigation, and self-care support.

PRIMARY OUTCOMES

enrollment and program completion rates.

SECONDARY OUTCOMES

transnational feasibility of program implementation, processes outcomes, acceptability, and preliminary estimates of health-related outcomes changes.

RESULTS

Between May 2021 and February 2023, we enrolled 202 participants ("Newly Diagnosed," n = 43; "Intermediate," n = 54; "Complex Care Needs," n = 105).

Median site enrollment rate was 69.6% (range: 21.1-100), and the program completion rate was 96.5%.

Overall, there was a positive change in Patient Assessment of Chronic Illness Care + (PACIC+ total score: 0.48; 95% confidence interval [CI]: 0.34, 0.61; P < 0.0001).

We found a positive score change in the MDS-UPDRS Part II + III nontremor (4.03; 95% CI: 6.55, 1.52; P = 0.0018) in the "Complex Care Needs" group.

CONCLUSIONS

The iCARE-PD model was successfully implemented across a social, cultural, and healthcare system diversity, with high program completion rates and improved care quality perceived by participants living at distinct stages of PD.

The findings provide valuable insights about the transferability potential and impact of a pragmatic integrated care model centered in the community, with applicability to other chronic movement disorders. © 2025 The Author(s).

Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2025 The Author(s).

Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Perineuronal nets are specialized extracellular matrix structures forming preferentially around parvalbumin interneurons to regulate plasticity.

While cortical perineuronal nets have been implicated in sensory plasticity and memory modulation, perineuronal nets of the primary motor cortex have been largely overlooked.

We found that transient reduction of primary motor cortex perineuronal nets by chondroitinase ABC (ChABC) treatment in otherwise healthy adult mice resulted in temporary deficits in motor function.

In a mouse model of Parkinson's disease based on unilateral 6-hydroxydopamine lesions of the midbrain, perineuronal net levels were decreased in both primary motor cortex hemispheres 2 weeks post-lesion, yet returned to baseline within 5 weeks.

We discovered that subsequent transient reduction of primary motor cortex perineuronal nets through ChABC treatment could unlock motor recovery when coupled with motor stimulation.

This recovery was associated with a bilateral increase in perineuronal-net-enwrapped parvalbumin interneurons and a rebalancing of parvalbumin cell soma excitatory synaptic markers.

These findings reveal distinct roles of perineuronal net plasticity-first in response to the initial midbrain lesion and then during rescue after ChABC treatment-suggesting that primary motor cortex perineuronal nets play a nuanced role in regulating motor function.

This duality positions perineuronal nets as potential therapeutic targets for motor rehabilitation strategies in Parkinson's disease.

Transposable elements (TEs) (mobile genetic elements comprising ∼45% of the human genome) have recently emerged as potential contributors to Parkinson's disease (PD); however their role and sex-specific impact remain poorly understood.

Here, we present the first integrative meta-analysis of TE expression across 4 substantia nigra single-nucleus RNA-seq datasets, comprising a total of 66 donors, generating a cell-type-resolved atlas of TE dysregulation in PD.

We identified widespread TE activation across major brain cell types (i.e. neurons, astrocytes, oligodendrocytes and microglia), with marked upregulation of L1s in neurons and HERVs in oligodendrocytes.

Sex-stratified analyses revealed distinct male- and female-biased TE signatures, indicating regulatory programs uniquely affected in each sex, including MIR elements in microglia and Alu subfamilies in neurons.

Correlation and genomic proximity analyses also uncovered TE-gene associations linked to important PD pathways such as neuroinflammation or myelination.

Collectively, our study positions TEs as potential sex-modulated contributors to PD pathology and also provides a public web resource (PATOSS) to explore PD-associated TE transcriptional deregulation.

Rigidity, along with bradykinesia and tremor, is recognized as one of the core motor symptoms fundamental to the clinical diagnosis of Parkinson's disease.

Despite its diagnostic relevance, rigidity has received comparatively less systematic investigation than other motor symptoms, resulting in gaps in our understanding of its phenomenology, neurophysiological correlates and response to therapeutic interventions such as deep brain stimulation.

This narrative review aims critically to examine and clarify the current conceptual ambiguities, assessment strategies and pathophysiological underpinnings associated with rigidity in Parkinson's disease.

We begin by discussing the wide range of phenomena described by the term 'rigidity' in neurological and non-neurological fields and highlight the inconsistencies that arise in its clinical interpretation.

We review and compare the clinical and instrumental approaches that are currently used to assess rigidity, emphasizing their respective strengths, limitations and contributions to a more precise characterization of rigidity in Parkinson's disease.

We end with a summary of molecular, neuroimaging and neurophysiological insights into the pathophysiology of rigidity.

In summary, we seek to consolidate existing knowledge, underscore unresolved questions and suggest new solutions for existing gaps with the hope of providing a conceptual and methodological foundation to guide future clinical and experimental research in the field.

BACKGROUND

Unilateral focused ultrasound subthalamotomy (STN-FUS) improves motor features of Parkinson's disease (PD) for up to 3 years.

OBJECTIVES

To assess the efficacy of unilateral STN-FUS in PD 5 years post-procedure.

METHODS

Prospective, open-label study including PD patients treated with STN-FUS.

PRIMARY OUTCOME

change from baseline in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III) off-medication for the treated side.

SECONDARY OUTCOMES

global motor state, motor complications, functional disability, quality of life, medication, and safety.

RESULTS

Forty-five patients were included; 32 completed 5 years of follow-up.

While off-medication, the MDS-UPDRS-III on the treated side showed 54% improvement from baseline (19.0 [95% CI 17.9-20.1] to 8.8 [7.5-10.1], P < 0.001).

The total MDS-UPDRS-III was reduced by 27% (37.1 [34.9-39.3] to 27.1 [24.3-29.9], P < 0.001).

At 5 years, motor complications, quality of life, and functional disability were equivalent to baseline.

Levodopa equivalent daily dose (LEDD) increased from 739.2 (650.1-828.4) to 1053.3 (946.3-1160.3) milligrams (P < 0.001).

Mild-to-moderate levodopa-induced dyskinesias (n = 7) were reported.

No late adverse events occurred.

CONCLUSION

Unilateral STN-FUS for PD may provide sustained motor benefits after 5 years. © 2026 International Parkinson and Movement Disorder Society.

BACKGROUND

Current dopaminergic therapies for Parkinson's disease carry significant limitations: levodopa can cause long-term motor complications, while D2/D3 receptor-targeting dopamine agonists can produce non-motor adverse effects.

Tavapadon is an oral, once-daily, selective D1/D5 agonist that might improve Parkinson's disease motor symptoms.

We aimed to evaluate the safety, tolerability and efficacy of flexible-dose tavapadon in people with early-stage Parkinson's disease.

METHODS

TEMPO-2 was a phase 3, randomised, double-blind, placebo-controlled trial conducted at 75 clinical sites (both hospital or academic and community settings) across 13 countries.

Adults aged 40-80 years with early-stage Parkinson's disease (<3 years' disease duration) who were treatment-naive or had less than 3 months of previous dopaminergic treatment were eligible.

Participants were randomly assigned 1:1 to flexible-dose tavapadon (5-15 mg) or placebo orally once daily for 27 weeks.

The primary endpoint was change from baseline to week 26 in the combined score of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts II and III (reflecting activities of daily living and motor performance).

Safety endpoints included adverse events, clinical laboratory values, vital signs, and electrocardiograms.

The primary endpoint was assessed in the modified intent-to-treat population (participants who received one dose or more of study drug and had both a baseline and one or more post-baseline MDS-UPDRS assessments) and safety was assessed in the safety analysis set (all participants who received one dose or more of tavapadon or placebo).

This study is registered with ClinicalTrials.gov (NCT04223193) and is now complete.

FINDINGS

Between Jan 6, 2020, and Feb 22, 2024, 473 individuals were screened and 304 were randomly assigned to receive tavapadon 5-15 mg (n=151) or placebo (n=153).

The majority of participants were male (169 [56%] of 304 male; 135 [44%] of 304 female), the mean age was 62·9 (SD 9·2) years, and the mean disease duration was 0·86 (0·79) years. 80 (26%) of 304 participants discontinued from the trial (57 [38%] of 151 on tavapadon and 23 [15%] of 153 on placebo), most commonly due to adverse events (42 [14%] of 304; 36 [24%] of 151 on tavapadon and six [4%] of 153 on placebo).

The primary endpoint of change from baseline to week 26 in the MDS-UPDRS Parts II and III combined score was significantly improved with tavapadon versus placebo (least squares mean [LSM] decrease of 10·3 [95% CI -12·2 to -8·3] points vs 1·2 [-2·9 to 0·6] points; LSM treatment difference -9·1 [95% CI -11·7 to -6·5]; p10% of participants) were nausea (45 [30%] of 151] vs five [3%] of 153), headache (25 [17%] vs eight [5%]), and dizziness (24 [16%] vs five [3%]).

INTERPRETATION

Tavapadon showed significant and clinically meaningful improvements in Parkinson's disease motor symptoms, with low incidence of somnolence and impulse control disorders.

However, the short observation period limits conclusions about long-term tolerability.

An ongoing extension study aims to confirm its long-term safety and efficacy.

FUNDING

AbbVie.

Parkinson's disease (PD) has been historically defined as a disease of striatal dopamine deficiency secondary to degeneration of dopaminergic neurons in the substantia nigra pars compacta, related to the presence of Lewy bodies and Lewy neurites.

Since the discovery of pathogenic variants in the gene encoding α-synuclein, as well as the finding that α-synuclein is a major constituent of Lewy pathology, PD is considered as a prototypical synucleinopathy.

However, neuropathological studies consistently show that most people with PD display copathologies, many of which are linked to specific clinical features and outcomes.

In this review, we summarize the spectrum and frequency of these co- and multi-pathologies in idiopathic and genetic PD and their impact on disease initiation and progression.

Additionally, we also discuss how this multi-pathological landscape may impact biomarker research and the implementation of emerging disease-modifying therapies. © 2026 The Author(s).

Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BACKGROUND

Parkinson's disease management is often complicated by motor fluctuations and dyskinesia.

Although deep brain stimulation addresses these symptoms, its use is limited by invasiveness, potential device failure, and the need for ongoing maintenance.

Magnetic resonance-guided focused ultrasound (MRgFUS) provides incisionless, image-guided ablation as an alternative.

However, the benefits and harms of staged, bilateral MRgFUS pallidothalamic tractotomy have not been evaluated systematically in prospective multicentre studies.

METHODS

In this prospective, multicentre, single-arm study, adults with idiopathic, levodopa-responsive Parkinson's disease and motor complications (Movement Disorders Society Unified Parkinson's Disease Rating Scale [MDS-UPDRS] part IV item 4.2 or 4.4 score ≥2) were enrolled at nine investigational centres (six in the USA, two in Spain, and one in Taiwan).

Participants underwent unilateral MRgFUS pallidothalamic tractotomy to the symptom-dominant side.

Contralateral pallidothalamic tractotomy followed a minimum of 6 months later for participants meeting prespecified criteria.

The primary efficacy endpoint was percent change from baseline to 3 months after the second procedure in the summed MDS-UPDRS part III off-medication upper and lower extremity (ULE) motor scores.

Safety outcomes were incidence, severity, and persistence of treatment-related adverse events in the 12 months after each procedure.

Safety and efficacy of unilateral treatment were evaluated in the unilateral intention-to-treat (ITT) and safety populations, defined as all patients receiving one or more sonications during the first procedure.

The primary outcome and safety of bilateral treatment were evaluated in the bilateral modified ITT (mITT) and safety populations, which required one or more sonications during the second procedure, a baseline motor assessment, and at least one post-bilateral motor assessment.

This trial is registered at ClinicalTrials.gov, NCT04728295 and is active, not recruiting.

FINDINGS

Between July 12, 2021, and Nov 1, 2023, 54 patients received unilateral treatment and 40 proceeded to bilateral treatment (63 [67%] were male and 31 [33%] were female) and were included in the primary analysis; 36 completed 12-month follow-up after the second procedure.

Median bilateral ULE motor scores decreased from 33·0 points (IQR 28·0-40·5) at baseline to 21·0 points (15·0-25·5) at month 3 post-bilateral treatment, a median within-patient change of 10·5 points (5·7-20·0), representing a 32% (18-52) improvement (p<0·0001).

Benefits became apparent within 1 month of the first procedure and lasted through to 12 months after the second procedure.

Treatment-related adverse events occurred in 21 (39%) of 54 patients after unilateral treatment; one (2%) had a persistent moderate adverse event at 6 months.

After bilateral treatment, 22 (55%) of 40 patients had treatment-related adverse events; ten (25%) had persistent moderate or severe adverse events at 12 months, mainly affecting speech, gait, and balance.

One (3%) patient developed severe persistent anarthria.

INTERPRETATION

Unilateral MRgFUS pallidothalamic tractotomy demonstrated safety and efficacy for Parkinson's disease motor complications; however, bilateral treatment offered small motor gains while increasing persistent moderate or severe adverse events.

Post-bilateral treatment complications in speech, gait, and balance are consistent with historical data for bilateral ablative procedures for movement disorders.

Although unilateral MRgFUS pallidothalamic tractotomy was beneficial in our study, bilateral procedures demand rigorous patient selection and counselling regarding cumulative risks.

FUNDING

Insightec.

BACKGROUND

[18F]Fluorodeoxyglucose positron emission tomography ([18F]FDG PET) represents an endorsed neurodegeneration biomarker in neuronal α-synucleinopathies.

Idiopathic/isolated rapid eye movement (REM) sleep behavior disorder (iRBD) represents a prodromal stage of such disorders.

OBJECTIVES

To assess [18F]FDG PET as a neurodegeneration biomarker, using published brain metabolic disease-related patterns, and a regional-based approach, across the prodromal to overt α-synucleinopathy continuum.

METHODS

We included 83 prodromal subjects with iRBD, comprising non-converters (n = 56) and converters (n = 27) to an overt α-synucleinopathy (either Parkinson's disease [PD] or dementia with Lewy bodies [DLB]) according to the last available follow-up, and 85 subjects with PD (n = 40) and DLB (n = 45).

For comparison, we enrolled a group of healthy subjects (n = 41).

Participants underwent brain [18F]FDG PET at baseline.

Analysis of covariance was used to test the ability of previously published [18F]FDG PET disease-related patterns in characterizing neurodegeneration levels along the prodromal to overt α-synucleinopathy continuum, and across the motor-predominant (parkinsonism-first) and the cognitive-predominant (dementia-first) clinical trajectories.

We further assessed metabolic changes using a regional-based approach.

RESULTS

All disease-related patterns effectively discriminated clinical stages, from prodromal to overt α-synucleinopathies, with comparable performance. [18F]FDG PET significantly distinguished all groups along the cognitive-predominant pathway; whereas in the motor-predominant pathway, converter patients were not significantly discriminated from non-converters.