Essais cliniques et recherche

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.

CONTEXTE ET OBJECTIFS

Des rapports récents ont suggéré que l'exposition à la lévodopa pourrait contribuer au freezing de la marche (FOG), mais cette relation reste controversée en raison de facteurs de confusion liés à la sévérité et à la durée de la maladie.

Notre objectif était d'évaluer la relation entre l'usage de la lévodopa et l'incidence et la sévérité du FOG.

MÉTHODES

Nous avons étudié 2 cohortes prospectives multicentriques : NS-Park et Parkinson's Progression Markers Initiative (PPMI).

Les patients ayant au moins 2 visites ont été sélectionnés.

Trois sous-cohortes emboîtées ont été définies selon la durée de la maladie, le FOG initial et l'exposition à la lévodopa.

Le FOG a été évalué à l'aide de l'item 2.13 de la partie II de l'échelle MDS-UPDRS (Movement Disorder Society-Unified Parkinson's Disease Rating Scale).

Les analyses ont inclus une régression logistique ordonnée à effets mixtes pour évaluer la sévérité du FOG, ainsi que des modèles de Kaplan-Meier et de Cox pour évaluer l'incidence du FOG.

Les modèles étaient ajustés sur la durée de la maladie, le stade de Hoehn et Yahr (H&Y) et les scores de la partie III du MDS-UPDRS.

RÉSULTATS

Au total, 25 602 patients atteints de la maladie de Parkinson de la cohorte NS-Park (âge moyen 68,3 ± 29,1 ans, 42 % de femmes) et 1 441 de la cohorte PPMI (âge moyen 62,9 ± 9,8 ans, 37 % de femmes) ont été inclus.

Dans les analyses non ajustées de la cohorte NS-Park, l'usage de la lévodopa était associé à une sévérité et une incidence plus élevées du FOG, mais cette association n'était plus statistiquement significative dans la cohorte PPMI.

Dans les modèles de régression logistique ordinale à effets mixtes ajustés sur la durée/sévérité de la maladie, le statut lévodopa montrait un effet non significatif sur le FOG (NS-Park : rapport de cotes [OR] 1,84, IC à 95 % 0,94-3,61, p = 0,074 ; PPMI : OR 0,76, IC à 95 % 0,38-1,51, p = 0,430), tandis que la durée de la maladie (NS-Park : OR 4,4, IC à 95 % 3,01-6,29, p = 6,0e-15 ; PPMI : OR 6,97, IC à 95 % 5,05-9,63, p = 4,7e-32), le stade de Hoehn & Yahr (NS-Park : OR 6,8, IC à 95 % 3,52-13,08, p = 1,059e-08 ; PPMI : OR 1,5, IC à 95 % 0,96-2,22, p = 0,073) et le score MDS-UPDRS-III (NS-Park : OR 1,85, IC à 95 % 1,38-2,49, p = 4,34e-05 ; PPMI : OR 2,00, IC à 95 % 1,67-2,39, p = 2,4e-14) étaient indépendamment associés à une sévérité plus élevée du FOG.

Aucune association statistiquement significative n'a été observée entre une exposition future à la lévodopa et l'incidence d'un FOG de novo.

L'incidence du FOG était quant à elle déterminée par le stade H&Y (NS-Park : rapport de risque [HR] 1,94, IC à 95 % 1,68-2,23 ; PPMI : HR 1,78, IC à 95 % 1,47-2,17) et le score MDS-UPDRS III (NS-Park : HR 1,40, IC à 95 % 1,07-1,83 ; PPMI : HR 1,26, IC à 95 % 1,17-1,36).

DISCUSSION

Aucune association significative ou cohérente entre l'exposition à la lévodopa et la sévérité ou l'incidence du FOG n'a été observée après ajustement sur la durée et la sévérité de la maladie, les estimations d'effet étant significativement atténuées malgré une incertitude résiduelle.

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.

BACKGROUND

Parkinson's disease (PD) causes progressive motor and non-motor disability.

Although pharmacotherapy is first-line, responses diminish over time.

Deep brain stimulation (DBS) effectively treats advanced PD, and recent data suggest benefits when applied earlier.

OBJECTIVES

To systematically review studies and meta-analyze randomized controlled trials comparing subthalamic DBS plus best medical therapy (BMT) with BMT alone in early PD.

METHODS

We conducted a systematic review and meta-analysis according to PRISMA, with a protocol registered in PROSPERO (CRD420251014105).

MEDLINE, Embase, and the Cochrane Library (2002-2025) were searched for studies comparing early DBS with BMT in "early" PD. "Early" was variably defined, commonly disease duration 4-8 years or onset of motor complications without significant disability.

We included RCTs, secondary analyses, observational studies, and unpublished trials; meta-analyses were restricted to randomized comparisons of early DBS plus BMT versus BMT alone.

RESULTS

Studies included younger patients with ≤8 years' PD duration and early motor complications.

Pooled RCT data showed a consistent quality-of-life benefit, while motor and medication outcomes directionally favored early STN-DBS but remained heterogeneous and imprecise.

Studies suggest safety is broadly comparable to standard-indication DBS.

CONCLUSIONS

Offering DBS before advanced disability-particularly in patients <60 years, <10 years from diagnosis, Hoehn-Yahr stage ≤3, early motor complications, and no dementia-may help delay loss of quality of life versus BMT alone.

Given few trials and substantial heterogeneity, further large-scale randomized studies are needed to confirm safety, define optimal timing in early PD, and clarify which subgroups benefit most.

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.

BACKGROUND

Large-scale sequencing initiatives have generated extensive genomic resources essential for variant interpretation, yet their effective use often requires bioinformatics expertise.

To support identification of Parkinson's disease (PD) risk and disease-causing variants, we developed an open-access, summary-level genomic data browser.

METHODS

We performed uniform joint variant calling to harmonize whole-genome sequencing (WGS) data from AMP-PD Release 4, GP2 Data Releases, and additional controls from the Alzheimer's Disease Sequencing Project.

Clinical-exome sequencing (CES) data from GP2 Release 8 were also included.

RESULTS

The integrated dataset included 31,665 WGS and 9,559 CES samples, spanning 11 ancestries and over 300 million variants.

CONCLUSIONS

The GP2 Genome Browser is a lightweight, flexible platform providing intuitive gene- and variant-level summaries with ancestry-stratified allele frequencies and functional annotations.

It is open source and freely accessible at https://gp2.broadinstitute.org, enabling broad access to PD genomic data and supporting global research efforts. © 2026 The Author(s).

Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2026 The Author(s).

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

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.

Le blocage de la marche (freezing of gait, FOG) est un symptôme dévastateur de la maladie de Parkinson (MP), qui entraîne souvent des chutes invalidantes et une perte d’autonomie.

Il touche la moitié des personnes atteintes, or les stratégies thérapeutiques actuelles sont insuffisantes et les mécanismes neuronaux sous-jacents restent mal compris.

Cette étude a examiné la dynamique des oscillations bêta dans le noyau subthalamique (NST) au cours de différents états moteurs (assis, debout et marche sur place), tout en évaluant les effets de la lévodopa.

Elle visait plus précisément à identifier une activité pathologique durant le pas en analysant la relation entre le NST et les muscles des jambes, ainsi que la façon dont celle-ci est modulée par la lévodopa.

Les potentiels de champ locaux (LFP) du NST et l’activité des muscles des jambes, mesurée par EMG du gastrocnémien et du long fibulaire, ont été enregistrés chez 14 participants atteints de MP en position assise, debout et lors du pas, sous lévodopa (ON) et sans lévodopa (OFF).

La lévodopa a réduit la variabilité de la fréquence des pas, ce qui traduit une meilleure rythmicité de la marche.

Les bandes bêta basse (12-20 Hz) et bêta haute (21-35 Hz) étaient modulées différemment par les mouvements de marche et par la lévodopa, avec une diminution de la bêta haute et une augmentation de la bêta basse durant le pas par rapport à la station debout et à la position assise. À l’inverse, la lévodopa a réduit l’activité bêta basse mais augmenté l’activité bêta haute, ce qui met en évidence une fonction physiologique possible de la bêta haute dans le NST.

De plus, des effets de la lévodopa propres à chaque phase du pas ont été observés, notamment une réduction de l’activité de la bande bêta large dans le NST et dans les muscles des jambes durant la fin de la phase d’appui et le décollement du pied de la jambe controlatérale sous traitement.

Par ailleurs, les bouffées bêta du NST étaient associées à une activation musculaire accrue à l’initiation du mouvement, ce qui pourrait réduire la capacité à se mouvoir librement.

Cette étude a mis en évidence des effets différents de l’état moteur (assis, marche sur place ou debout) sur l’amplitude moyenne des bandes de fréquence bêta basse et bêta haute, ce qui suggère qu’elles pourraient remplir des rôles fonctionnels distincts.

En outre, il existe un effet de la lévodopa propre à chaque phase du pas sur les LFP du NST, les EMG et la cohérence intermusculaire durant la marche.

Ces résultats éclairent le développement de stratégies de stimulation adaptées à la phase du pas et ciblant les oscillations bêta du NST pendant la marche.

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.

Les variants du gène GBA1 sont des facteurs de risque génétiques fréquents de la maladie de Parkinson, ainsi que de la démence à corps de Lewy.

De nouvelles données mettent en lumière la relation entre les différents variants de GBA1 et le tableau clinique et l’évolution de la maladie qui leur sont associés, bien que la pénétrance soit faible et que la majorité des porteurs ne développent pas de synucléinopathie.

Le profil clinique de la maladie de Parkinson associée à GBA1 se caractérise par une progression plus rapide, avec des troubles cognitifs et une dysautonomie plus sévères que dans la maladie de Parkinson idiopathique, en particulier chez les porteurs de variants pathogènes sévères.

Les mécanismes en jeu dans la conversion phénotypique et la progression de la maladie chez les porteurs de variants de GBA1 sont en voie d’élucidation, et ces connaissances pourraient se traduire par des profils de marqueurs biologiques cliniquement pertinents.

GBA1 est devenu une cible d’intervention à la fois pour la maladie de Parkinson associée à GBA1 et pour la maladie de Parkinson idiopathique, avec des stratégies thérapeutiques visant à prévenir ou à ralentir la progression de la maladie au moyen de chaperons pharmacologiques, d’activateurs allostériques enzymatiques, d’interventions métaboliques et de la modulation de l’expression génique.

Les résultats principaux de l’étude EPSILON de 24 semaines (NCT04978597) ont montré que l’ajout d’opicapone à la lévodopa, chez des personnes atteintes de la maladie de Parkinson sans fluctuations, améliorait significativement l’atteinte motrice sans augmenter l’apparition de complications motrices par rapport au placebo.

Tous les participants ayant terminé la phase à double insu devenaient admissibles à un traitement en ouvert par opicapone.

L’efficacité symptomatique de l’opicapone s’est maintenue après 1 an de traitement en ouvert (variation moyenne ajustée ± ET du score moteur du MDS-UPDRS entre la valeur initiale de la phase à double insu et la semaine 76 : -7.4 ± 0.81); les participants passés du placebo à l’opicapone ont présenté une amélioration motrice de -6.1 ± 0.79. À la semaine 76, 80.2% des participants traités par opicapone-opicapone demeuraient exempts de complications motrices, contre 69.7% dans le groupe placebo-opicapone (p = 0.1).

CONTEXTE ET OBJECTIFS

Des rapports récents ont suggéré que l'exposition à la lévodopa pourrait contribuer au freezing de la marche (FOG), mais cette relation reste controversée en raison de facteurs de confusion liés à la sévérité et à la durée de la maladie.

Notre objectif était d'évaluer la relation entre l'usage de la lévodopa et l'incidence et la sévérité du FOG.

MÉTHODES

Nous avons étudié 2 cohortes prospectives multicentriques : NS-Park et Parkinson's Progression Markers Initiative (PPMI).

Les patients ayant au moins 2 visites ont été sélectionnés.

Trois sous-cohortes emboîtées ont été définies selon la durée de la maladie, le FOG initial et l'exposition à la lévodopa.

Le FOG a été évalué à l'aide de l'item 2.13 de la partie II de l'échelle MDS-UPDRS (Movement Disorder Society-Unified Parkinson's Disease Rating Scale).

Les analyses ont inclus une régression logistique ordonnée à effets mixtes pour évaluer la sévérité du FOG, ainsi que des modèles de Kaplan-Meier et de Cox pour évaluer l'incidence du FOG.

Les modèles étaient ajustés sur la durée de la maladie, le stade de Hoehn et Yahr (H&Y) et les scores de la partie III du MDS-UPDRS.

RÉSULTATS

Au total, 25 602 patients atteints de la maladie de Parkinson de la cohorte NS-Park (âge moyen 68,3 ± 29,1 ans, 42 % de femmes) et 1 441 de la cohorte PPMI (âge moyen 62,9 ± 9,8 ans, 37 % de femmes) ont été inclus.

Dans les analyses non ajustées de la cohorte NS-Park, l'usage de la lévodopa était associé à une sévérité et une incidence plus élevées du FOG, mais cette association n'était plus statistiquement significative dans la cohorte PPMI.

Dans les modèles de régression logistique ordinale à effets mixtes ajustés sur la durée/sévérité de la maladie, le statut lévodopa montrait un effet non significatif sur le FOG (NS-Park : rapport de cotes [OR] 1,84, IC à 95 % 0,94-3,61, p = 0,074 ; PPMI : OR 0,76, IC à 95 % 0,38-1,51, p = 0,430), tandis que la durée de la maladie (NS-Park : OR 4,4, IC à 95 % 3,01-6,29, p = 6,0e-15 ; PPMI : OR 6,97, IC à 95 % 5,05-9,63, p = 4,7e-32), le stade de Hoehn & Yahr (NS-Park : OR 6,8, IC à 95 % 3,52-13,08, p = 1,059e-08 ; PPMI : OR 1,5, IC à 95 % 0,96-2,22, p = 0,073) et le score MDS-UPDRS-III (NS-Park : OR 1,85, IC à 95 % 1,38-2,49, p = 4,34e-05 ; PPMI : OR 2,00, IC à 95 % 1,67-2,39, p = 2,4e-14) étaient indépendamment associés à une sévérité plus élevée du FOG.

Aucune association statistiquement significative n'a été observée entre une exposition future à la lévodopa et l'incidence d'un FOG de novo.

L'incidence du FOG était quant à elle déterminée par le stade H&Y (NS-Park : rapport de risque [HR] 1,94, IC à 95 % 1,68-2,23 ; PPMI : HR 1,78, IC à 95 % 1,47-2,17) et le score MDS-UPDRS III (NS-Park : HR 1,40, IC à 95 % 1,07-1,83 ; PPMI : HR 1,26, IC à 95 % 1,17-1,36).

DISCUSSION

Aucune association significative ou cohérente entre l'exposition à la lévodopa et la sévérité ou l'incidence du FOG n'a été observée après ajustement sur la durée et la sévérité de la maladie, les estimations d'effet étant significativement atténuées malgré une incertitude résiduelle.

CONTEXTE

Le dysfonctionnement lysosomal joue un rôle central dans la pathogenèse de la maladie de Parkinson (MP), et GBA1 constitue le facteur de risque génétique établi le plus important.

De nombreux autres gènes participant au métabolisme des sphingolipides, glycosphingolipides et céramides lysosomaux ont été proposés comme facteurs contributifs, ce qui justifie des analyses génétiques de ces voies.

OBJECTIF

Évaluer la contribution des variants rares des gènes lysosomaux au risque de MP.

MÉTHODES

Nous avons analysé les variants rares (fréquence allélique mineure ≤ 0,01) de 36 gènes lysosomaux chez 8 267 personnes atteintes de MP et 68 208 témoins, dont 793 cas de MP à début précoce (≤ 50 ans).

Un séquençage ciblé a été réalisé dans quatre cohortes de l’Université McGill (3 456 cas et 2 664 témoins), puis combiné aux données de séquençage du génome entier de la UK Biobank (2 848 cas et 62 451 témoins) et de la cohorte Accelerating Medicines Partnership–PD (1 963 cas et 3 093 témoins).

Les associations entre classes de variants (rares, non synonymes, avec perte de fonction ou prédits délétères avec un score CADD > 20) ont été évaluées par le test SKAT-O, puis par méta-analyse entre cohortes.

Des analyses par domaine protéique ont été menées et une correction du taux de fausses découvertes (FDR) a été appliquée.

RÉSULTATS

La méta-analyse a mis en évidence une association significative entre les variants rares de ST3GAL3 et la MP (P corrigé par FDR = 0,04).

Les analyses par domaine ont montré un enrichissement en variants non synonymes dans le domaine de type β-acétyl-hexosaminidase de HEXA (P = 8,0 × 10⁻⁴), mais ce signal ne résistait pas à la correction (P corrigé par FDR = 0,154).

Dans la MP à début précoce, ces analyses ont identifié des associations significatives pour NAGLU (P corrigé par FDR = 7,3 × 10⁻⁶) et ST3GAL5 (P corrigé par FDR = 0,03).

CONCLUSIONS

Des variants rares touchant plusieurs voies lysosomales, notamment celles liées à la sialylation, au métabolisme des gangliosides et des céramides ainsi qu’à la protéolyse lysosomale, pourraient contribuer à la susceptibilité à la MP au-delà de GBA1.

Ces voies méritent d’être reproduites et étudiées plus avant.

CONTEXTE

La douleur est un symptôme non moteur fréquent et hétérogène de la maladie de Parkinson (MP).

Ses différents mécanismes sont difficiles à reconnaître, alors qu’ils orientent probablement le traitement.

Parmi les sous-types de douleur liés à la MP, la douleur parkinsonienne primaire (DPP) est particulièrement difficile à distinguer de la douleur musculosquelettique en l’absence de critères diagnostiques positifs.

OBJECTIF

Élaborer et valider le Primary Parkinsonian Pain Diagnostic Questionnaire (3PDQ), un outil auto-administré pour identifier la DPP dans la MP.

MÉTHODES

Le 3PDQ a été élaboré à partir de la littérature et d’un consensus d’experts, puis ajusté selon les commentaires de patients.

Cette étude multicentrique a recruté 227 personnes atteintes de MP et souffrant de douleur chronique dans 11 centres experts français; 179 ont été analysées après exclusion des cas où deux évaluateurs experts indépendants n’étaient pas d’accord sur le type de douleur.

La validation psychométrique a suivi les normes COSMIN et a porté sur l’acceptabilité, la cohérence interne, la reproductibilité et l’exactitude diagnostique par rapport au diagnostic des experts.

RÉSULTATS

La DPP a été diagnostiquée chez 36,3% des participants, tandis que la douleur musculosquelettique était le sous-type le plus fréquent (42,5%).

La version finale à 11 items du 3PDQ présentait une bonne acceptabilité (96,5% de données exploitables), une cohérence interne satisfaisante (Kuder-Richardson = 0,71) et une excellente fidélité test-retest (concordance de Lin = 0,82).

Le questionnaire distinguait bien la DPP de la douleur musculosquelettique (aire sous la courbe = 0,82), avec une sensibilité de 82%, une spécificité de 74% et une valeur prédictive négative de 82%.

CONCLUSIONS

Le 3PDQ est le premier outil auto-administré validé pour diagnostiquer la DPP dans la MP.

Il peut faciliter la caractérisation clinique des types de douleur et soutenir le développement de stratégies thérapeutiques fondées sur leurs mécanismes.

CONTEXTE

SUNRISE-PD était une étude de phase 1/2 à doses croissantes portant sur OXB-102, une thérapie génique de deuxième génération utilisant un vecteur lentiviral qui apporte les gènes nécessaires à la synthèse de dopamine pour traiter la maladie de Parkinson (MP).

L’essai a été interrompu prématurément en raison de l’insolvabilité du promoteur.

OBJECTIF

Décrire, sous la conduite des investigateurs, l’évolution clinique des six patients inscrits à l’essai OXB-102.

MÉTHODES

Les données individuelles des patients ont été extraites des dossiers des investigateurs, rassemblées et résumées.

RÉSULTATS

Six patients ont reçu une faible dose (n = 2) ou une dose plus élevée (n = 4) de la thérapie génique OXB-102.

Huit événements indésirables graves ont été rapportés; un seul a été considéré comme certainement lié à l’intervention.

Tous ont été transitoires et se sont résolus sans séquelles.

Les données d’efficacité étaient limitées, mais une certaine stabilisation de la fonction motrice a été observée chez la plupart des patients.

CONCLUSION

Cette nouvelle thérapie génique visant la synthèse de dopamine semble sûre chez les patients atteints d’une MP modérée à sévère, avec un possible effet stabilisateur sur leur évolution clinique.

L’effectif et les données d’efficacité limités ne permettent pas de conclure à une efficacité démontrée.

Contexte

La relaxométrie par IRM utilisant la mesure du R2* est un marqueur non invasif prometteur des changements liés au fer cérébral dans la maladie de Parkinson.

Bien que des études longitudinales de susceptibilité magnétique aient montré une progression dans le temps, la dynamique du R2* selon le stade, sur l’ensemble des durées de la maladie, reste incomplètement caractérisée.

Objectifs

Évaluer, dans un cadre multicentrique, l’évolution du R2* sur un an selon le stade de la maladie de Parkinson, en comparaison avec des témoins sains.

Méthodes

Dans cette étude prospective multicentrique, 95 patients atteints de la maladie de Parkinson et 65 témoins sains appariés en âge et en sexe ont eu une IRM à 3 teslas et une évaluation clinique à l’inclusion puis à 1 an.

Les patients ont été stratifiés selon la durée de la maladie.

Les valeurs de R2* ont été extraites des régions des ganglions de la base, en particulier la substance noire.

Les évaluations motrices et non motrices, réalisées sous traitement, comprenaient l’échelle MDS-UPDRS, le Montreal Cognitive Assessment et des échelles d’humeur et d’apathie.

Résultats

Le R2* de la substance noire a augmenté de façon significative sur un an, aussi bien chez les patients (+5 % au sein du groupe) que chez les témoins sains (+2 % au sein du groupe), soit une augmentation longitudinale supplémentaire de 3 % chez les patients par rapport aux témoins.

Les changements de R2* étaient plus marqués chez les patients ayant une durée de maladie plus longue (r = 0,28 ; p = 0,006).

Des changements significatifs du R2* ont également été observés dans d’autres régions des ganglions de la base.

Aucun changement significatif du handicap moteur ou non moteur sous traitement n’a été observé sur un an.

Conclusions

Le R2* de la substance noire a augmenté sur un an dans la maladie de Parkinson, quel que soit le stade, avec des changements plus marqués chez les patients à un stade plus avancé et sans signe de plateau précoce.

Ces résultats confortent le potentiel du R2* comme marqueur d’imagerie sensible de la progression de la maladie de Parkinson sur de courts intervalles.

Contexte

Les études précédentes sur les inhibiteurs calciques (ICa) et le risque de maladie de Parkinson sont arrivées à des conclusions contradictoires.

Objectifs

Examiner le lien entre les ICa et la maladie de Parkinson dans la cohorte française E3N (femmes suivies pendant 15 ans, de 2004 à 2018), en tenant compte d’une éventuelle causalité inverse.

Méthodes

Les nouvelles utilisatrices d’ICa ont été identifiées à partir des bases de remboursement de médicaments.

Les cas incidents de maladie de Parkinson ont été validés à l’aide de plusieurs sources de données.

Les trajectoires d’utilisation des ICa ont été décrites par des modèles logistiques mixtes dans une étude cas-témoins nichée.

Des modèles de Cox à variables dépendantes du temps ont estimé l’association entre les ICa (ensemble, amlodipine, dihydropyridines autres que l’amlodipine [DiCCB], non-dihydropyridines [non-DiCCB]) et la maladie de Parkinson.

Les analyses principales utilisaient un délai de 5 ans ; des analyses de sensibilité sans délai ont servi de comparaison.

Résultats

Sur 82 605 femmes, 603 ont développé une maladie de Parkinson et 13 022 ont utilisé des ICa.

Les femmes ayant débuté un non-DiCCB avaient un risque plus élevé que celles n’en ayant jamais pris (rapport de risque = 1,56 ; IC à 95 % : 0,99–2,46 ; p de tendance ≤ 0,02).

Parmi les non-DiCCB, le diltiazem était associé à la maladie de Parkinson (rapport de risque = 2,20 ; IC à 95 % : 1,19–4,04).

Aucune association significative n’a été trouvée pour les ICa dans leur ensemble, l’amlodipine ou les DiCCB autres que l’amlodipine.

Dans les analyses sans délai, l’amlodipine (rapport de risque = 1,45 ; IC à 95 % : 1,13–1,87) et le diltiazem (rapport de risque = 1,63 ; IC à 95 % : 1,02–2,60) étaient associés à la maladie.

Ces résultats sont cohérents avec les trajectoires de prescription des ICa observées chez les patientes et les témoins.

Discussion

Dans l’ensemble, les ICa n’étaient pas associés à la maladie de Parkinson, mais les femmes ayant débuté le diltiazem avaient une incidence plus élevée dans les analyses avec délai.

Le diltiazem et l’amlodipine étaient associés à la maladie dans les analyses sans délai.

Ces résultats concordent avec des cas rapportés de parkinsonisme induit par certains inhibiteurs calciques et justifient des études et une surveillance complémentaires.

Le blocage de la marche (freezing of gait, FOG) est un symptôme dévastateur de la maladie de Parkinson (MP), qui entraîne souvent des chutes invalidantes et une perte d’autonomie.

Il touche la moitié des personnes atteintes, or les stratégies thérapeutiques actuelles sont insuffisantes et les mécanismes neuronaux sous-jacents restent mal compris.

Cette étude a examiné la dynamique des oscillations bêta dans le noyau subthalamique (NST) au cours de différents états moteurs (assis, debout et marche sur place), tout en évaluant les effets de la lévodopa.

Elle visait plus précisément à identifier une activité pathologique durant le pas en analysant la relation entre le NST et les muscles des jambes, ainsi que la façon dont celle-ci est modulée par la lévodopa.

Les potentiels de champ locaux (LFP) du NST et l’activité des muscles des jambes, mesurée par EMG du gastrocnémien et du long fibulaire, ont été enregistrés chez 14 participants atteints de MP en position assise, debout et lors du pas, sous lévodopa (ON) et sans lévodopa (OFF).

La lévodopa a réduit la variabilité de la fréquence des pas, ce qui traduit une meilleure rythmicité de la marche.

Les bandes bêta basse (12-20 Hz) et bêta haute (21-35 Hz) étaient modulées différemment par les mouvements de marche et par la lévodopa, avec une diminution de la bêta haute et une augmentation de la bêta basse durant le pas par rapport à la station debout et à la position assise. À l’inverse, la lévodopa a réduit l’activité bêta basse mais augmenté l’activité bêta haute, ce qui met en évidence une fonction physiologique possible de la bêta haute dans le NST.

De plus, des effets de la lévodopa propres à chaque phase du pas ont été observés, notamment une réduction de l’activité de la bande bêta large dans le NST et dans les muscles des jambes durant la fin de la phase d’appui et le décollement du pied de la jambe controlatérale sous traitement.

Par ailleurs, les bouffées bêta du NST étaient associées à une activation musculaire accrue à l’initiation du mouvement, ce qui pourrait réduire la capacité à se mouvoir librement.

Cette étude a mis en évidence des effets différents de l’état moteur (assis, marche sur place ou debout) sur l’amplitude moyenne des bandes de fréquence bêta basse et bêta haute, ce qui suggère qu’elles pourraient remplir des rôles fonctionnels distincts.

En outre, il existe un effet de la lévodopa propre à chaque phase du pas sur les LFP du NST, les EMG et la cohérence intermusculaire durant la marche.

Ces résultats éclairent le développement de stratégies de stimulation adaptées à la phase du pas et ciblant les oscillations bêta du NST pendant la marche.

Contexte et objectifs

La prévalence de la maladie de Parkinson (MP), de la sclérose en plaques (SEP) et des maladies du motoneurone (MMN) augmente à l’échelle mondiale.

On ignore toutefois dans quelle mesure cette hausse est liée à une augmentation de l’incidence ou à une amélioration de la survie après le diagnostic.

Méthodes

Nous avons réalisé 2 études de cohorte rétrospectives, nationales et en population générale, incluant respectivement toutes les personnes vivant en Suède entre 2001 et 2016 et toutes celles vivant en France entre 2009 et 2022.

Des modèles de régression à effets mixtes regroupés, avec le pays comme effet aléatoire, ont été utilisés pour déterminer les tendances temporelles de la prévalence, de l’incidence brute et standardisée selon l’âge et le sexe, ainsi que de l’âge et de l’espérance de vie au moment du diagnostic.

Discussion

Ces résultats indiquent que la hausse de la prévalence de la SEP est largement attribuable à l’allongement de la survie et que la hausse de la prévalence des MMN reflète une véritable augmentation de l’incidence, tandis que la prévalence de la MP croît modestement, en grande partie indépendamment de l’incidence.

Selon le mécanisme qui sous-tend la prévalence — une incidence accrue traduisant une évolution de l’exposition aux facteurs de risque, une meilleure survie grâce aux progrès thérapeutiques ou le vieillissement démographique de la population —, les conclusions sur les causes sous-jacentes diffèrent considérablement entre la MP, la SEP et les MMN, avec des implications directes pour la planification des soins de santé et la recherche étiologique.

Les variants du gène GBA1 sont des facteurs de risque génétiques fréquents de la maladie de Parkinson, ainsi que de la démence à corps de Lewy.

De nouvelles données mettent en lumière la relation entre les différents variants de GBA1 et le tableau clinique et l’évolution de la maladie qui leur sont associés, bien que la pénétrance soit faible et que la majorité des porteurs ne développent pas de synucléinopathie.

Le profil clinique de la maladie de Parkinson associée à GBA1 se caractérise par une progression plus rapide, avec des troubles cognitifs et une dysautonomie plus sévères que dans la maladie de Parkinson idiopathique, en particulier chez les porteurs de variants pathogènes sévères.

Les mécanismes en jeu dans la conversion phénotypique et la progression de la maladie chez les porteurs de variants de GBA1 sont en voie d’élucidation, et ces connaissances pourraient se traduire par des profils de marqueurs biologiques cliniquement pertinents.

GBA1 est devenu une cible d’intervention à la fois pour la maladie de Parkinson associée à GBA1 et pour la maladie de Parkinson idiopathique, avec des stratégies thérapeutiques visant à prévenir ou à ralentir la progression de la maladie au moyen de chaperons pharmacologiques, d’activateurs allostériques enzymatiques, d’interventions métaboliques et de la modulation de l’expression génique.

Les résultats principaux de l’étude EPSILON de 24 semaines (NCT04978597) ont montré que l’ajout d’opicapone à la lévodopa, chez des personnes atteintes de la maladie de Parkinson sans fluctuations, améliorait significativement l’atteinte motrice sans augmenter l’apparition de complications motrices par rapport au placebo.

Tous les participants ayant terminé la phase à double insu devenaient admissibles à un traitement en ouvert par opicapone.

L’efficacité symptomatique de l’opicapone s’est maintenue après 1 an de traitement en ouvert (variation moyenne ajustée ± ET du score moteur du MDS-UPDRS entre la valeur initiale de la phase à double insu et la semaine 76 : -7.4 ± 0.81); les participants passés du placebo à l’opicapone ont présenté une amélioration motrice de -6.1 ± 0.79. À la semaine 76, 80.2% des participants traités par opicapone-opicapone demeuraient exempts de complications motrices, contre 69.7% dans le groupe placebo-opicapone (p = 0.1).

La stimulation cérébrale profonde adaptative (aDBS) représente une évolution importante du traitement de la maladie de Parkinson (MP) : elle s’appuie sur la stimulation cérébrale profonde conventionnelle (cDBS) en ajustant la stimulation en fonction de signaux physiologiques enregistrés en temps réel.

En permettant un ciblage dynamique de l’activité neuronale liée à la maladie, l’aDBS offre la possibilité d’une modulation plus précise des symptômes moteurs.

Parmi les autres avantages attendus figurent une réduction des effets indésirables liés à la stimulation et une meilleure efficacité énergétique, favorisant la performance du dispositif à long terme.

Bien que l’adoption clinique n’en soit qu’à ses débuts, l’expérience croissante a mis en lumière à la fois des possibilités et des aspects qui doivent encore être affinés.

Les principaux défis comprennent la variabilité interindividuelle de l’expression des marqueurs biologiques, la diversité des approches de programmation et le débat en cours sur les seuils et les délais de réponse optimaux.

La signification clinique des enregistrements de potentiels de champ locaux (LFP) à court terme continue d’être activement étudiée, en particulier dans le contexte des artéfacts de signal, de la variabilité physiologique et des limites actuelles du matériel.

Au-delà des considérations techniques, des facteurs tels que la sélection des personnes candidates, les cadres éthiques et le rapport coût-efficacité demeurent des déterminants importants d’une mise en œuvre plus large.

Les progrès à venir dépendront de l’élaboration de stratégies de contrôle robustes et souples intégrant des marqueurs biologiques multimodaux, dont des mesures motrices issues de dispositifs portables et des résultats rapportés par les personnes concernées, afin de soutenir un traitement personnalisé.

Avec un corpus de données en expansion et de récentes approbations réglementaires, l’aDBS passe de plus en plus du concept expérimental à l’outil clinique viable.

Les efforts futurs devraient donner la priorité à la traduction des paradigmes de recherche en parcours cliniques déployables à grande échelle, qui équilibrent efficacement l’automatisation et l’individualisation des soins. © 2026 The Author(s).

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

Importance

Le tavapadon est un agoniste sélectif D1/D5 par voie orale, administré une fois par jour, susceptible d’améliorer les symptômes moteurs de la maladie de Parkinson (MP) tout en réduisant au minimum les événements indésirables (EI) associés à l’activation des récepteurs D2/D3.

Objectif

Évaluer l’efficacité, l’innocuité et la tolérabilité du tavapadon chez des adultes atteints d’une MP au stade précoce.

Plan de l’étude, cadre et participants

TEMPO-1 était un essai clinique randomisé de phase 3, à double insu et contrôlé par placebo, mené dans 102 sites répartis dans 12 pays entre décembre 2019 et juin 2024.

Les adultes atteints d’une MP au stade précoce (durée d’évolution < 3 ans) n’ayant jamais reçu de traitement ou ayant reçu moins de 3 mois de traitement dopaminergique antérieur étaient admissibles.

L’analyse des données a été réalisée de juillet 2024 à mai 2025.

Intervention

Les participants ont été randomisés selon un rapport 1:1:1 pour recevoir l’une de 2 doses fixes de tavapadon (5 ou 15 mg une fois par jour) ou un placebo pendant 27 semaines, suivies d’une période de suivi d’innocuité de 4 semaines.

Principaux critères de jugement et mesures

Le critère de jugement principal était la variation de la moyenne des moindres carrés (MMC) entre la valeur initiale et la semaine 26 du score combiné des parties II et III de la Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS).

Les principaux critères de jugement secondaires étaient la variation MMC entre la valeur initiale et la semaine 26 des scores de la partie II du MDS-UPDRS, ainsi que la proportion de participants ayant obtenu la mention « nettement amélioré » ou « très nettement amélioré » à l’échelle Patient Global Impression of Change.

Résultats

Au total, 751 adultes atteints d’une MP au stade précoce, n’ayant jamais reçu de traitement ou ayant reçu moins de 3 mois de traitement dopaminergique antérieur, ont été présélectionnés, et 529 participants ont été inclus (187 femmes [35.3%]; âge moyen [ÉT], 63.7 [9.6] ans; durée moyenne [ÉT] d’évolution de la maladie, 0.7 [0.8] an) puis randomisés pour recevoir du tavapadon à 5 mg (n = 177), du tavapadon à 15 mg (n = 177) ou un placebo (n = 175).

La variation entre la valeur initiale et la semaine 26 du score combiné des parties II et III du MDS-UPDRS était significativement améliorée chez les participants traités par la dose de 5 mg de tavapadon (diminution de 9.7 points vs augmentation de 1.8 point sous placebo; différence de traitement, -11.5 points; IC à 95%, -13.8 à -9.2; P < .001; d = 1.14) comme par la dose de 15 mg de tavapadon (diminution de 10.2 points vs augmentation de 1.8 point sous placebo; différence de traitement, -12.1 points; IC à 95%, -14.4 à -9.8; P < .001; d = 1.20).

Le tavapadon présentait un profil d’innocuité favorable; la plupart des EI étaient non graves et d’intensité légère à modérée.

Les EI courants sous tavapadon étaient les nausées (90 sur 354 sous tavapadon [25.4%]), les céphalées (59 sur 354 [16.7%]) et les étourdissements (45 sur 354 [12.7%]).

Conclusions et portée

Dans l’essai clinique randomisé TEMPO-1, le tavapadon a amélioré la fonction motrice chez les participants atteints d’une MP au stade précoce et a été bien toléré, avec un profil d’innocuité favorable.

Enregistrement de l’essai

Identifiant ClinicalTrials.gov : NCT04201093.

Objectif

Évaluer l’efficacité de l’amantadine à libération immédiate (LI) pour réduire le risque de dyskinésies de pic de dose au stade précoce de la maladie de Parkinson (MP), en association avec la lévodopa.

Contexte

Si l’utilisation de l’amantadine pour prendre en charge les dyskinésies dans la MP est bien étayée par des essais cliniques contrôlés, les données sur son efficacité chez les personnes sans complications motrices demeurent limitées.

Méthodes

Cet essai multicentrique de 22 mois, randomisé et contrôlé par placebo (NCT01538329), a recruté des personnes atteintes d’une MP au stade précoce sous lévodopa à dose stable (≥150 mg/jour depuis ≤1 an) et sans complications motrices.

L’étude comportait trois phases à double insu : une phase de traitement de 18 mois avec adjonction d’amantadine-LI (200 mg/jour) ou de placebo (période 1), une phase à début différé de 3 mois durant laquelle tous les participants recevaient de l’amantadine-LI (période 2) et un sevrage d’un mois sous placebo (période 3).

Le critère de jugement principal était l’incidence des dyskinésies au mois 18; les critères secondaires comprenaient les taux de dyskinésies à la fin des périodes 2 et 3, afin d’évaluer d’éventuels mécanismes durables du médicament.

Les critères exploratoires ont porté sur les effets potentiels de l’amantadine-LI sur les symptômes moteurs et non moteurs ainsi que sur la qualité de vie.

Résultats

Au total, 207 participants ont été randomisés dans le groupe amantadine-LI (N = 99) ou placebo (N = 108).

Significativement moins de participants du groupe amantadine-LI ont développé des dyskinésies par rapport au placebo durant la période 1 (11% vs 22%, P = 0.025), tandis que la dose quotidienne moyenne de lévodopa (IC à 95%) a augmenté de 70 (21-119) mg de moins (P = 0.005).

La proportion de participants présentant des dyskinésies était plus faible dans le groupe amantadine-LI que sous placebo à la fin des périodes 2 et 3, mais la différence n’était pas statistiquement significative (12% vs 20%, P = 0.13 et 16% vs 22%, P = 0.23, respectivement).

Des effets positifs légers mais significatifs sur le blocage de la marche (freezing), la fatigue et la qualité de vie ont été observés durant la période 1.

Le profil d’innocuité de l’amantadine-LI était conforme aux données antérieures.

Conclusion

L’adjonction d’amantadine-LI au stade précoce de la MP a réduit de moitié l’incidence des dyskinésies sur 18 mois.

Des mécanismes durables n’ont pas pu être démontrés et méritent d’être étudiés davantage.

Les résultats exploratoires positifs quant au bénéfice potentiel de l’amantadine-LI sur des symptômes tels que le blocage de la marche et la fatigue appellent également des recherches supplémentaires. © 2025 The Author(s).

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

Contexte

La conception optimale de l’organisation des soins dans la maladie de Parkinson (MP), qui répondrait à l’évolution des besoins vécus au quotidien, demeure incertaine.

Il est essentiel de disposer de modèles de soins pouvant être mis en œuvre avec souplesse et transférés entre des systèmes de santé variés.

Objectifs

Nous avons cherché à évaluer la mise en œuvre multinationale et l’incidence d’un nouveau programme pragmatique de soins intégrés pour la MP (iCARE-PD).

Méthodes

Nous avons mené une étude observationnelle prospective multinationale avec un devis avant-après (six centres nationaux tertiaires spécialisés en MP) portant sur un programme de soins intégrés de 4 mois axé sur des plans de soins individualisés, une meilleure navigation dans le système de santé et un soutien à l’autoprise en charge.

Critères de jugement principaux

taux de recrutement et taux d’achèvement du programme.

Critères de jugement secondaires

faisabilité transnationale de la mise en œuvre du programme, résultats de processus, acceptabilité et estimations préliminaires des changements des résultats de santé.

Résultats

Entre mai 2021 et février 2023, nous avons recruté 202 participants (« nouvellement diagnostiqués », n = 43; « intermédiaires », n = 54; « besoins de soins complexes », n = 105).

Le taux médian de recrutement par site était de 69.6% (étendue : 21.1-100) et le taux d’achèvement du programme, de 96.5%.

Globalement, un changement positif a été observé au questionnaire Patient Assessment of Chronic Illness Care + (score total PACIC+ : 0.48; intervalle de confiance [IC] à 95% : 0.34, 0.61; P < 0.0001).

Nous avons constaté un changement de score positif au MDS-UPDRS parties II + III hors tremblement (4.03; IC à 95% : 6.55, 1.52; P = 0.0018) dans le groupe « besoins de soins complexes ».

Conclusion

Le modèle iCARE-PD a été mis en œuvre avec succès dans des contextes sociaux, culturels et de systèmes de santé variés, avec des taux élevés d’achèvement du programme et une amélioration de la qualité des soins perçue par des participants se trouvant à des stades différents de la MP.

Ces résultats fournissent des enseignements précieux sur le potentiel de transférabilité et l’incidence d’un modèle de soins intégrés pragmatique et ancré dans la communauté, applicable à d’autres troubles du mouvement chroniques. © 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.

Les filets périneuronaux sont des structures spécialisées de la matrice extracellulaire qui se forment préférentiellement autour des interneurones à parvalbumine afin de réguler la plasticité.

Alors que les filets périneuronaux corticaux ont été impliqués dans la plasticité sensorielle et la modulation de la mémoire, ceux du cortex moteur primaire ont été largement négligés.

Nous avons constaté que la réduction transitoire des filets périneuronaux du cortex moteur primaire par un traitement à la chondroïtinase ABC (ChABC), chez des souris adultes par ailleurs en bonne santé, entraînait des déficits temporaires de la fonction motrice.

Dans un modèle murin de la maladie de Parkinson fondé sur des lésions unilatérales du mésencéphale par la 6-hydroxydopamine, les taux de filets périneuronaux étaient diminués dans les deux hémisphères du cortex moteur primaire 2 semaines après la lésion, mais revenaient à leur valeur initiale en moins de 5 semaines.

Nous avons découvert qu’une réduction transitoire ultérieure des filets périneuronaux du cortex moteur primaire par traitement à la ChABC pouvait débloquer une récupération motrice lorsqu’elle était associée à une stimulation motrice.

Cette récupération était associée à une augmentation bilatérale des interneurones à parvalbumine entourés d’un filet périneuronal et à un rééquilibrage des marqueurs synaptiques excitateurs du soma des cellules à parvalbumine.

Ces résultats révèlent des rôles distincts de la plasticité des filets périneuronaux — d’abord en réponse à la lésion initiale du mésencéphale, puis lors de la récupération après le traitement par ChABC — ce qui suggère que les filets périneuronaux du cortex moteur primaire jouent un rôle nuancé dans la régulation de la fonction motrice.

Cette dualité fait des filets périneuronaux des cibles thérapeutiques potentielles pour les stratégies de rééducation motrice dans la maladie de Parkinson.

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.

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.