Essais cliniques et recherche

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

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.

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.

CONTEXT

Evidence suggests a link between diet and Parkinson's disease (PD).

OBJECTIVE

We conducted a dose-response meta-analysis of prospective cohort studies to examine the association of food-group intakes and dietary patterns with PD incidence.

DATA SOURCES

After searching PubMed, Scopus, and Web of Science, 29 cohort studies with 1 307 337 participants met the eligibility criteria.

DATA EXTRACTION

Quantitative exposure levels and the most adjusted risk estimates and 95% CIs were extracted.

DATA ANALYSIS

Linear and nonlinear dose-response analyses and highest vs lowest intake comparisons were conducted using STATA and RevMan.

Risk of bias was assessed by the Newcastle-Ottawa quality-assessment tool.

RESULTS

Dairy, low-fat dairy, milk, and cheese indicated a positive dose-response association with PD risk.

High consumption of dairy, low-fat dairy, and milk demonstrated 26% (odd ratio [OR], 1.26; 95% CI, 1.12-1.41), 30% (OR, 1.30; 95% CI, 1.06-1.58), and 23% (OR, 1.23; 95% CI, 1.07-1.43) increased PD risk compared with the lowest intake categories, respectively.

Linear dose-response analysis showed a 5%-7% increased risk for every 100-g/day dairy and low-fat dairy intake, 4% increased risk per 10-g cheese/day, and 13% increased risk per 1 cup milk/day.

Sex-based subgroup analysis revealed stronger associations in men for dairy and, to a lesser extent, for low-fat dairy, milk, yogurt, and cheese.

Legumes/nuts were the only group that showed a reduced PD risk (OR, 0.71; 95% CI, 0.62-0.81).

Both healthy and unhealthy dietary patterns showed dose-response associations with PD risk.

Also, in the highest vs lowest comparison, adherence to healthy diets was associated with a 37% reduction in PD risk (OR, 0.63; 95% CI, 0.54-0.74), while adherence to unhealthy diets was linked to a 40% increased PD risk (OR, 1.40; 95% CI, 1.07-1.83).

CONCLUSION

These findings underscore the importance of diet in the prevention or development of PD.

While adherence to healthy diets was associated with reduced PD risk, dairy consumption, despite being part of healthy diets, was linked to increased risk, highlighting the need for more nuanced dietary guidance.

SYSTEMATIC REVIEW REGISTRATION

PROSPERO no.

CRD420251026654.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by widespread structural brain alterations, yet the specific patterns of brain atrophy and their underlying genetic mechanisms remain incompletely understood.

Here, we integrated large-scale neuroimaging meta-analysis with population-scale imaging genetics to systematically characterize the genetic architecture linking gray matter volume (GMV) abnormalities to PD.

We first performed a meta-analysis of structural MRI studies comprising 3212 patients with PD and 2056 controls, identifying robust patterns of GMV reduction and assessing differences across medication states.

Using these meta-analytically defined regions as imaging phenotypes, we extracted GMV measures from the UK Biobank and conducted genome-wide association analysis (GWAS).

This analysis identified 12 significant SNPs associated with PD-related GMV atrophy.

Furthermore, we performed pleiotropy analysis and identified 22 SNPs jointly associated with PD risk and GMV reduction.

Functional enrichment analyses revealed that these shared genes converge on pathways involved in clathrin-mediated endocytosis and synaptic vesicle recycling.

Spatiotemporal transcriptomic profiling further characterized the developmental expression patterns of these genes, while molecular docking analyses suggested potential therapeutic targets.

Together, these findings provide a comprehensive characterization of the genetic architecture linking brain structural abnormalities to PD, offering new molecular insights into the mechanisms underlying neurodegenerative brain damage and potential avenues for therapeutic intervention.

BACKGROUND AND OBJECTIVES

White matter hyperintensities (WMHs) are common neuroimaging markers of cerebrovascular pathology in aging and neurodegeneration.

Despite their clinical relevance, WMH are typically quantified using global burden measures that assume a relatively homogeneous pathologic process.

However, growing evidence suggests substantial biological heterogeneity across lesions.

We aimed to identify lesion-level WMH subtypes beyond anatomic location and evaluate their associations with neurodegeneration and vascular risk.

METHODS

We conducted a longitudinal observational study analyzing 3224 MRI scans from 403 participants spanning cognitively normal aging, mild cognitive impairment, Alzheimer, and Parkinson disease.

Imaging at baseline and 2-year follow-up included structural, diffusion, and resting-state MRI.

A total of 2107 WMH lesions were identified, and lesion-wise longitudinal changes were used to derive subtypes using unsupervised clustering.

Associations with neurodegeneration and vascular risk factors were assessed using multivariable models with false discovery rate correction.

RESULTS

Three lesion subtypes (L1-L3) were identified, frequently coexisting within the same individual.

L1 lesions were the most prevalent (48.1%), predominated in cognitively normal individuals, and exhibited relatively stable trajectories without association with brain atrophy.

L2 lesions represented a less frequent (11.3%) unstable subtype associated with weight gain (odds ratio [OR] 1.33, 95% CI 1.22-1.45; pFDR ≤ 0.001), suggesting metabolic vulnerability.

L3 lesions (40.6%) represented an unstable subtype associated with brain atrophy (β = -0.11, 95% CI -0.16 to -0.05; pFDR pFDR pFDR = 0.006).

Global WMH burden was no longer associated with brain atrophy after accounting for L3 lesion burden.

Clustering robustness was supported by sensitivity analyses excluding anatomical location and by external validation in an independent cohort reproducing the main atrophy-related findings.

DISCUSSION

WMH are not a homogeneous entity but comprise biologically distinct lesion subtypes with differential neurobiological and clinical significance.

Lesion composition may therefore offer a more informative framework than global WMH burden for understanding cerebrovascular contributions to aging and neurodegeneration, with potential implications for risk stratification, clinical interpretation, and targeted interventions.

We aimed to compare the effect of transcranial direct current stimulation (tDCS) compared with sham or conventional interventions on motor functions and activity in individuals with Parkinson's disease.

Two independent reviewers searched four databases (PubMed, Embase, Scopus, and Cochrane Library) from inception to April 2026.

We only included randomized controlled trials comparing active tDCS (alone or with training) versus sham tDCS (alone or with training) on walking speed, functional mobility, Parkinson motor symptoms, activities of daily living, quality of life (QoL), dropouts, and adverse events.

Two authors independently extracted data, including study source and design, participant and intervention characteristics, and outcomes.

We computed a mean difference with a random-effects model.

Subgroup analyses were performed for outcomes with greater than or equal to 10 experimental study arms, accounting for intervention protocol and stimulation site.

We assessed the risk of bias using ROB 2 tool, and the certainty of evidence using Grading of Recommendations Assessment, Development, and Evaluation.

Seventeen randomized controlled trials ( n  = 553) were included.

Pooled analyses showed little to no effect on walking speed (mean difference: 0.04 m/s 2 , 95% confidence interval: -0.03 to 0.11), functional mobility (mean difference: 0.67 s gained on the Timed Up and Go test, 95% confidence interval: -0.64 to 2.02), and other outcomes.

Subgroup analyses based on stimulation site and intervention protocol revealed no differences.

Adverse events were minor and infrequent, and dropout rates did not differ between groups.

The overall certainty of evidence ranged from very low to low.

Current evidence suggests that the effect of tDCS on gait, activities of daily living, or quality of life is probably not superior to other conventional interventions in individuals with Parkinson's disease.

BACKGROUND AND OBJECTIVES

Parkinson disease (PD) is a progressive neurodegenerative disease in which gait impairment is a common and disabling clinical feature.

We aimed to characterize the independent and mediated contributions of striatal dopamine transporter (DAT) availability and gray matter (GM) volume to quantitative gait impairment in de novo PD.

METHODS

In this prospective study, we consecutively recruited patients with de novo PD fulfilling the UK Brain Bank clinical criteria and healthy controls (HCs) without focal neurologic symptoms and parkinsonism at Wonju Severance Christian Hospital.

All participants underwent GAITRite-based gait analysis, and patients further underwent brain MRI for GM volumetry, 18F-FP-CIT PET for striatal DAT availability, and motor and cognitive assessments.

After exploratory gait-related correlation analyses, causal mediation analyses tested whether the effects of neuroimaging biomarkers on gait parameters were mediated by cognition or motor symptom severity.

RESULTS

A total of 122 patients with de novo PD (mean age, 69.66 years; 45.90% female) and 177 HCs (mean age, 72.07 years; 51.41% female) were enrolled.

Compared with HCs, patients with PD showed slower velocity, shorter step/stride lengths, reduced swing and single-support time, increased double-support time, and greater dispersion across multiple gait domains.

Limbic-related GM volumes were associated with step/stride lengths and temporal phase composition, and these associations were substantially mediated by global cognition (representative ACMEs [95% CIs] for stride length: posterior cingulate cortex, 1.9559 [0.5606-4.2238]; hippocampus, 3.6722 [1.0707-8.2118]; thalamus, 2.8794 [0.0408-7.2535]; amygdala, 4.9696 [1.8241-10.3405]; proportions mediated, 19%-50%).

Lower putaminal DAT availability was associated with greater stance time and double-support time variability, whereas lower caudate DAT availability was associated with longer swing and single-support time and altered phase parameters.

These associations were not significantly mediated by bradykinesia/rigidity scores; direct effects remained significant (ADEs [95% CIs]: caudate-swing time, -0.0237 [-0.0428 to -0.0086]; putamen-double-support time variability, -2.0249 [-3.1445 to -0.8835]).

DISCUSSION

These findings support a dual-pathway model of gait regulation in patients with de novo PD, where striatal dopaminergic denervation directly affects gait rhythmicity, whereas limbic system atrophy affects gait through direct and cognition-mediated pathways.

This medication-naïve cohort may limit generalizability to the broader PD spectrum.

BACKGROUND

Parkinson's disease (PD), multiple sclerosis (MS) and motor neurone disease (MND) are progressive and debilitating diseases that are increasing in prevalence globally.

Some primary studies show an increased risk from long-term outdoor air pollution exposure, while others contradict this association.

METHODS

A systematic review and meta-analysis were undertaken to assess the associations of long-term (≥1 year) outdoor air pollution exposure with PD, MS and MND incidence.

We searched eight databases for publications up to July 2025.

Primary case-control, cohort, cross-sectional or ecological studies investigating the association between long-term air pollution exposure and adult (>18 years old) PD, MS, or MND incidence were included.

Meta-analyses were carried out using random-effects models with assessment of heterogeneity, meta-bias and shape of the exposure-response functions.

PROSPERO (CRD42023417961).

RESULTS

Of 42 papers included, 26, 3 and 3 were meta-analysed for PD, MS, and MND outcomes, respectively. 19 studies from North America, 12 from Europe and 10 from Asia were meta-analysed.

For every 5 μg/m3 and 15 μg/m3 increase of Particulate Matter 2.5 (PM2.5) and PM10 concentration, estimated (95% Confidence Interval) PD risk was 10% (1.10; 1.03-1.19) and 18% (1.18; 1.01-1.38), respectively but effects varied across settings (Prediction Interval: 0.80-1.52 for PM2.5 and 0.41-3.36 for PM10), with the largest estimated risk for PM2.5 in Asia (1.19; 1.01-1.41).

There was no clear evidence that PM2.5 (1.01; 0.77-1.32) or nitrogen dioxide (NO2, 0.98, 95% CI: 0.95-1.01) were associated with MS risk or PM2.5 with MND risk (1.07, 95% CI: 0.86-1.33).

CONCLUSION

This systematic review reports increased PD risk from long-term PM2.5 and PM10 exposure.

No association was observed for MS and MND from a very limited evidence base.

The neurodegenerative diseases investigated here are rare and therefore alternatives to insufficiently powered cohort studies are needed to strengthen the evidence on risk.

OBJECTIVES

To compare the effects of combined exercise and cognitive interventions with those of exercise alone on cognitive function and quality of life in people with Parkinson's disease.

METHOD

Six electronic databases were systematically searched for randomized controlled trials (RCTs) published up to January 2025, in strict accordance with the PRISMA guidelines.

Two independent reviewers assessed the risk of bias using the Cochrane Risk of Bias 2 tool, and pairwise meta‑analyses were performed to synthesize the extracted data.

RESULTS

Fourteen RCTs were included in this meta-analysis.

Combined interventions significantly improved global cognitive function compared with exercise alone.

Moreover, combined interventions lasting more than 12 weeks offered significant advantages over exercise‑only regimens in terms of global cognition and executive function.

Additionally, combined interventions yielded significant beneficial effects on executive function in individuals with Parkinson's disease and mild cognitive impairment.

No statistically significant between-group differences were observed in the domains of attention, memory, or quality of life.

CONCLUSION

Combined exercise and cognitive interventions are superior to exercise alone for patients with Parkinson's disease, and their beneficial effects on global cognitive function are not influenced by the specific intervention format.

BACKGROUND

Parkinson's disease (PD) is the second most common neurodegenerative disorder, yet effective disease-modifying therapies remain elusive.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used in the management of type 2 diabetes mellitus (T2DM), have shown neuroprotective potential in preclinical studies.

However, real-world evidence on the association between GLP-1RAs use and PD risk remains inconsistent and has not been systematically synthesized.

This systematic review and meta-analysis aimed to evaluate this association using large-scale real-world data.

METHODS

We systematically searched PubMed, Embase, the Cochrane Library, and Web of Science from database inception to March 18, 2026, for cohort and case-control studies exploring the association between GLP-1RA exposure and PD risk among patients with T2DM.

Study selection, data extraction, and methodological quality assessment were independently conducted by two reviewers.

All meta-analyses were performed using Stata 15.0 software.

RESULTS

A total of six studies were included, involving 452,763 participants.

The meta-analysis revealed that GLP-1RA exposure was significantly associated with a reduced risk of PD in patients with T2DM (HR = 0.68, 95%CI (0.54,0.85), P = 0.001).

Subgroup analyses demonstrated that compared with dipeptidyl peptidase-4 (DPP-4) inhibitors, metformin, and other hypoglycemic drugs, GLP-1RAs were linked to a lower risk of incident PD (DPP-4 inhibitors: HR = 0.60, 95%CI (0.43,0.83), P = 0.001; Metformin: HR = 0.83, 95%CI (0.73,0.95), P = 0.006; Other: HR = 0.73, 95%CI (0.60,0.87), P = 0.002).

CONCLUSIONS

This meta-analysis based on large-scale real-world data indicates that GLP-1RA exposure is associated with a lower risk of PD in patients with T2DM, with robust and consistent results across diverse comparator groups.

These findings support the hypothesis that GLP-1RAs may confer neuroprotective properties, a finding that merits further rigorous investigation.

Nevertheless, given the inherent limitations inherent to observational study designs and the possibility of residual confounding in the included studies, the present results should be regarded as preliminary and hypothesis-generating rather than conclusive.

Future large-scale prospective cohort studies with standardized methodologies, as well as well-designed randomized controlled trials, are warranted to validate these findings and clarify whether the observed inverse association reflects a causal neuroprotective effect of GLP-1RAs.

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.

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).

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.

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.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by widespread structural brain alterations, yet the specific patterns of brain atrophy and their underlying genetic mechanisms remain incompletely understood.

Here, we integrated large-scale neuroimaging meta-analysis with population-scale imaging genetics to systematically characterize the genetic architecture linking gray matter volume (GMV) abnormalities to PD.

We first performed a meta-analysis of structural MRI studies comprising 3212 patients with PD and 2056 controls, identifying robust patterns of GMV reduction and assessing differences across medication states.

Using these meta-analytically defined regions as imaging phenotypes, we extracted GMV measures from the UK Biobank and conducted genome-wide association analysis (GWAS).

This analysis identified 12 significant SNPs associated with PD-related GMV atrophy.

Furthermore, we performed pleiotropy analysis and identified 22 SNPs jointly associated with PD risk and GMV reduction.

Functional enrichment analyses revealed that these shared genes converge on pathways involved in clathrin-mediated endocytosis and synaptic vesicle recycling.

Spatiotemporal transcriptomic profiling further characterized the developmental expression patterns of these genes, while molecular docking analyses suggested potential therapeutic targets.

Together, these findings provide a comprehensive characterization of the genetic architecture linking brain structural abnormalities to PD, offering new molecular insights into the mechanisms underlying neurodegenerative brain damage and potential avenues for therapeutic intervention.

BACKGROUND

Diabetes mellitus is recognised as a risk factor for Parkinson's disease (PD); however, comparative evidence regarding PD risk across antidiabetic drug classes remains limited and inconsistent.

We aimed to compare the risk of PD across different antidiabetic classes, with stratified analyses by age, sex, and cardiovascular disease (CVD) status.

METHODS

We searched the Cochrane Library, Embase, and PubMed until August 2025 for studies assessing the association between antidiabetic drugs and PD incidence.

We performed a Bayesian network meta-analysis, estimating effect sizes as risk ratios with 95% credible intervals.

We performed prespecified subgroup analyses according to age, sex, and CVD status.

RESULTS

We included nine observational cohort studies, totalling 712 287 patients.

No antidiabetic class demonstrated a statistically significant difference in PD risk.

Rank probability analyses suggested that sodium-glucose co-transporter-2 inhibitors (SGLT2i) tended to rank lowest in PD risk among older adults (≥75 years), while glucagon-like peptide-1 receptor agonist (GLP-1RA) ranked lowest in patients aged <75 years.

In patients with CVD, metformin showed relatively higher-ranking probabilities for PD risk compared with SGLT2i.

In contrast, metformin, sulfonylureas, and α-glucosidase inhibitors were consistently associated with higher ranking probabilities for PD risk compared to newer agents.

CONCLUSIONS

Our analysis suggests that antidiabetic drugs may exert effects beyond glycaemic control and could influence neurodegenerative risk.

Furthermore, SGLT2i and GLP-1RA were consistently associated with lower PD risk, suggesting potential neuroprotective effects.

While our results indicate the potential importance of antidiabetic drug selection in patients at risk for neurodegenerative diseases, further large-scale, controlled studies should validate these associations and clarify potential mechanisms.

REGISTRATION

PROSPERO: CRD420251130232.

BACKGROUND

In 2015, we reported a family with Parkinson's disease resulting from the RAB39B p.G192R (c.574G>A) variant.

Since then, two affected brothers from the family have undergone autopsy.

OBJECTIVES

To characterize neuropathological findings, assess intracellular distribution of RAB39B protein, and examine the effect of p.G192R on α-synuclein and tau.

METHODS

Detailed neuropathological assessments were performed on both siblings.

Dopaminergic neurons were generated from induced pluripotent stem cells (iPSCs) from an affected and unaffected male in this kindred.

Western blots were performed to measure RAB39B, α-synuclein, phospho-α-synuclein, and phospho-tau.

RESULTS

The younger brother had neocortical stage Lewy body disease (LBD) pathology and an unusual pattern and burden of four-repeat (4R) tau pathology that included neocortical neurofibrillary tangles, pretangles, and neurites in the absence of β-amyloid pathology.

The older brother's brain showed a similar pattern of 4R tau pathology but had no LBD pathology.

Robust RAB39B immunostaining was seen in p.G192R carriers and non-carriers.

In p.G192R iPSC-derived neurons, RAB39B protein was reduced by ~50% and disproportionately diminished in peripheral cell processes compared with cell bodies.

Aberrant forms of both α-synuclein and tau were observed in p.G192R neurons.

CONCLUSIONS

The intrafamilial pathological heterogeneity observed here is unusual for monogenic parkinsonism and suggests that mechanisms underlying RAB39B-related neurodegeneration might be complex.

Our results from iPSC-neurons provide additional support that RAB39B p.G192R promotes α-synuclein and tau co-pathology.

Further work in model systems based on RAB39B p.G192R might offer important insights into the interplay between α-synuclein and tau that are applicable to multiple neurodegenerative disorders. © 2026 The Author(s).

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

This article has been contributed to by U.S.

Government employees and their work is in the public domain in the USA.

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.

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.

This invited perspective paper celebrating the 40th anniversary of Movement Disorders demonstrates that the topic of physical activity and exercise as a treatment for Parkinson's disease did not feature before 2002 in this journal.

The topic of physical activity and exercise garnered increasing recognition over the next two decades with several important papers published in Movement Disorders.

As of 2026, there are four well-recognized treatments for Parkinson's disease: (1) exercise and physical activity; (2) general lifestyle modifications, including avoiding harmful environmental toxins; (3) medication; and (4) surgery and devices.

The paper concludes by suggesting a variety of questions, the answers to which will improve clinicians' ability to help patients understand and implement the full Parkinson's exercise prescription. © 2026 The Author(s).

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

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).

Sex differences, in terms of prevalence, symptoms and disease progression, are established in the aetiology of complex neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease, but the underlying biology driving these differences remains poorly understood.

There is emerging evidence from genetic and functional analyses affirming the role of the immune system in such diseases, but a thorough assessment of sex differences in the link between the immune system and neurodegenerative diseases remains lacking.

Here, we applied a robust causal inference approach, two-sample Mendelian randomization, to evaluate the causal effect of immune-related protein levels on three neurodegenerative diseases with large-scale sex-stratified genome-wide association data available: amyotrophic lateral sclerosis (females = 10 895 cases, 57 062 controls; males = 15 547 cases, 50 145 controls); Parkinson's disease (females = 7947 cases, 90 662 controls; males = 13 020 cases, 89 660 controls); and Alzheimer's disease (females = 18 822 cases, 281 415 controls; males = 17 293 cases, 213 339 controls).

As exposures, we focused on 932 immune system-related proteins with significant protein cis-quantitative trait loci (false discovery rate cut-off < 0.01) from a large sex-combined plasma protein dataset (n = 33 477), for which corresponding genes were included in the Immunology Database and Analysis Portal gene list.

We tested for a causal relationship between genetically predicted levels of each of these proteins and each neurodegenerative disease in sex-stratified and sex-combined data, followed by colocalization and estimation of sex-differential effects.

We additionally performed exploratory analyses using sex-combined CSF protein cis-quantitative trait loci (n = 971) as exposures.

We observed evidence for a sex-differential causal relationship between FCGR2A and Parkinson's disease and between CD2AP, MAMDC2, PCDH17 or CSF3 and Alzheimer's disease.

We validated significant results using two independent protein cis-quantitative trait loci datasets for those plasma proteins available.

After performing sensitivity analyses, we validated the potential causal relationships of OMG on Parkinson's disease and of GRN, SERPINF2 and TREM2 on Alzheimer's disease.

Mendelian randomization with CSF protein cis-quantitative trait loci showed a potential causal effect of ADGRE2, GPNMB and COLEC11 on Parkinson's disease and of CD33 on Alzheimer's disease, without evidence of sex-differential effects.

Finally, we substantiated our findings of protein-disease pairs using triangulation, specifically reporting independent supporting evidence from the literature and drug-related databases.

Overall, our results point to potential causal effects of genetically predicted levels of immune system-related plasma and CSF proteins in Alzheimer's disease and Parkinson's disease, some of which may be considered as potential candidates for drug development.

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.

BACKGROUND

Parkinson's disease (PD), multiple sclerosis (MS) and motor neurone disease (MND) are progressive and debilitating diseases that are increasing in prevalence globally.

Some primary studies show an increased risk from long-term outdoor air pollution exposure, while others contradict this association.

METHODS

A systematic review and meta-analysis were undertaken to assess the associations of long-term (≥1 year) outdoor air pollution exposure with PD, MS and MND incidence.

We searched eight databases for publications up to July 2025.

Primary case-control, cohort, cross-sectional or ecological studies investigating the association between long-term air pollution exposure and adult (>18 years old) PD, MS, or MND incidence were included.

Meta-analyses were carried out using random-effects models with assessment of heterogeneity, meta-bias and shape of the exposure-response functions.

PROSPERO (CRD42023417961).

RESULTS

Of 42 papers included, 26, 3 and 3 were meta-analysed for PD, MS, and MND outcomes, respectively. 19 studies from North America, 12 from Europe and 10 from Asia were meta-analysed.

For every 5 μg/m3 and 15 μg/m3 increase of Particulate Matter 2.5 (PM2.5) and PM10 concentration, estimated (95% Confidence Interval) PD risk was 10% (1.10; 1.03-1.19) and 18% (1.18; 1.01-1.38), respectively but effects varied across settings (Prediction Interval: 0.80-1.52 for PM2.5 and 0.41-3.36 for PM10), with the largest estimated risk for PM2.5 in Asia (1.19; 1.01-1.41).

There was no clear evidence that PM2.5 (1.01; 0.77-1.32) or nitrogen dioxide (NO2, 0.98, 95% CI: 0.95-1.01) were associated with MS risk or PM2.5 with MND risk (1.07, 95% CI: 0.86-1.33).

CONCLUSION

This systematic review reports increased PD risk from long-term PM2.5 and PM10 exposure.

No association was observed for MS and MND from a very limited evidence base.

The neurodegenerative diseases investigated here are rare and therefore alternatives to insufficiently powered cohort studies are needed to strengthen the evidence on risk.

The basal ganglia and sensorimotor cortex are essential nodes of a network that supports motor control.

In Parkinson's disease, disruptions in this network lead to rigidity and slowness during movement execution.

Deep brain stimulation (DBS) of the basal ganglia has proved effective in alleviating Parkinson's disease-related hypokinetic symptoms, and sensing-enabled neurostimulators now afford the opportunity to detect cortico-basal oscillations during motion.

However, the specific contributions of these motor network nodes to chronic, naturalistic movement and the effects of DBS on circuit dynamics are not well understood.

To address these gaps, we recorded >530 h of cortical and subcortical signals from 15 Parkinson's disease patients (27 hemispheres) during unsupervised, unconstrained daily activities and subthalamic or pallidal DBS.

Synchronized wrist-worn accelerometers tracked forearm speeds, supporting the evaluation of neural biomarkers related to motion.

Our study validated and extended the known relationship between cortical and subcortical beta power (13-30 Hz) and movement.

We showed that cortical low (13-20 Hz) and high (21-30 Hz) beta movement-related desynchronization effectively distinguished between mobile and stationary states.

In the subthalamic nucleus and globus pallidus interna, high beta movement-related desynchronization and gamma (40-80 Hz) movement-related synchronization exhibited significant group-level correlations with movement kinematics.

When stimulated at 130 Hz, cortical stimulation-entrained gamma oscillations at the half-harmonic (∼65 Hz) were observed.

Furthermore, cortical entrained gamma movement-related synchronization was a stronger predictor of motion than broadband gamma movement-related synchronization.

We developed machine learning models to predict naturalistic movement over extended periods using spectral features from brief neural recordings (0.5-8 s epochs).

Cortical models outperformed subcortical models, although combining cortico-basal signals yielded the highest model performance (area under the curve > 0.85 for binary movement state classifiers; Pearson's r statistic > 0.68 for continuous forearm speed regressors).

Higher DBS current amplitudes were associated with reduced beta movement-related desynchronization and low gamma (40-60 Hz) movement-related synchronization in the subthalamic nucleus and globus pallidus interna.

This negatively impacted the accuracy of the subcortical models, whereas cortical and cortico-basal model performance remained stable across stimulation amplitudes.

Our study demonstrates that cortico-basal nodes of the motor network encode complementary kinematic information, which can be integrated to enhance the accuracy and stability of chronic, naturalistic movement decoding during deep brain stimulation.

These insights support the development and integration of therapeutic brain-computer interfaces with closed-loop, adaptive DBS to leverage rapid and precise movement-predictive models for the treatment of motor network disorders.

Parkinson's disease is a common multisystem movement disorder characterized by accumulation of neurotoxic Lewy body aggregates, neuronal loss and gliosis of vulnerable populations.

The gene encoding α-synuclein (SNCA) is the greatest genetic risk factor for sporadic Parkinson's disease.

Misfolding and overexpression of SNCA (α-Syn) underlie pathognomonic features of Parkinson's disease, including insoluble Lewy body aggregates and midbrain dopaminergic (mbDA) neurodegeneration.

We recently identified an SNCA intronic sequence that harbours variation associated with Parkinson's disease risk and demonstrated its role as a neuronal cis-regulatory element (CRE).

CRISPR-mediated engineering was used to establish a mouse model lacking this intronic CRE sequence (SncaEnh+37).

Single molecule fluorescent in situ hybridization (smFISH) was used to assess changes on Snca transcription in mbDA neurons.

Intrastriatal injection of α-Syn preformed fibrils was used to seed Parkinson's disease pathology (or PBS vehicle) in these mice.

Cohorts of mice harbouring two, one or zero CRE deleted alleles of SncaEnh+37 were evaluated for motor deficits in standard assays (pole descent, rotarod, grip strength).

Immunohistochemistry, unbiased stereology and western blotting were employed to evaluate the impact of neuronal integrity, Lewy body acquisition and glial activation in the substantia nigra.

Mice deficient in SncaEnh+37 exhibit significantly reduced Snca transcription in mbDA neurons.

In animals challenged with intrastriatal delivery of α-Syn preformed fibrils, SncaEnh+37 deficient animals are largely protected from motor deficits.

Further, we demonstrate that mice lacking this Snca enhancer are protected against Parkinson's disease-relevant histopathology, including DA neurodegeneration, Lewy body acquisition and evidence of neuroinflammatory response.

By targeting a cell-dependent Snca CRE, we directly reduced the onset, severity and progression of Parkinson's disease pathology in mice.

The demonstration that cell-type-dependent modulation of key genes in disease progression can be leveraged to mitigate risk introduces a potentially powerful therapeutic avenue for Parkinson's disease.

BACKGROUND

Adaptive deep brain stimulation (aDBS) using subthalamic nucleus (STN) beta-band oscillations as a biomarker for the akinetic-rigid symptoms of Parkinson's disease has been proposed to improve the efficacy of stimulation and decrease adverse effects.

However, most studies validating STN beta oscillations as a biomarker used perioperative, off medication, and OFF stimulation conditions, limiting their potential relevance to real-world aDBS deployment.

OBJECTIVE

We evaluated how stimulation and dopaminergic medication affect beta-range STN oscillatory activity and its ability to predict the hypokinetic parkinsonian state.

METHODS

In six patients with Parkinson's disease who experienced residual levodopa-related motor fluctuations despite standard-of-care DBS, we studied medication cycle-induced fluctuations of peak STN beta oscillation power during active DBS.

We evaluated the magnitude of beta oscillation fluctuations, the frequency of peak beta activity, and the ability to predict the off medication state.

Neural signals were collected in the clinic during a medication challenge and at home during naturalistic medication cycles.

RESULTS

Medication-induced beta oscillation fluctuations were smaller in the presence of therapeutic DBS compared with when the stimulator was off (P = 0.008).

Therapeutic stimulation also decreased the frequency of peak beta activity (P < 0.001).

As a result, the beta frequencies with the highest power in the OFF stimulation/off medication state were less accurate than other beta-range bands at predicting the patient's off medication state during active stimulation (P = 0.02).

CONCLUSIONS

The spectral characteristics of STN beta oscillations and their performance as a biomarker in aDBS for Parkinson's disease are influenced by the stimulation and medication conditions in which it is implemented. © 2026 International Parkinson and Movement Disorder Society.

BACKGROUND

Transcranial temporal interference stimulation (TIs) targeting the subthalamic nucleus (STN) is a novel noninvasive neuromodulation approach with potential to improve motor symptoms in Parkinson's disease (PD).

However, its underlying neuroimaging mechanisms remain unclear.

Changes in functional connectivity (FC) of the STN and the cortical-basal ganglia-thalamic-cortical (CBTC) circuit are central to PD pathophysiology.

OBJECTIVE

This randomized, double-blind, crossover study aimed to examine the effects of STN-TIs on FCs of the STN and regions in the CBTC circuit in PD.

METHODS

23 participants with mild-to-moderate PD received a 20-minute session of 130 Hz TIs targeting the STN of the contralateral hemisphere of the patient's severely affected side (or the dominant side in case of bilateral disturbance), and active sham stimulation in randomized order.

Resting-state functional magnetic resonance imaging (fMRI) and Part III of Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS-III) were completed before and after stimulation.

The STN and regions in the CBTC circuit were defined as regions of interest (ROI) for ROI-to-ROI FC analysis.

RESULTS

Compared to sham stimulation, 130 Hz STN-TIs induced a connectivity-specific effect, including the decreased FCs between the targeted side of STN and putamen (P = 0.004-0.046) and caudate (P < 0.001), and increased FC between the targeted side of STN and M1 (P = 0.002-0.004).

No severe side effects were reported.

CONCLUSIONS

Our study provides preliminary but novel evidence for the potential modulatory effect of STN-TIs on resting-state neural activities in the motor circuit. © 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.

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.

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

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.

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.

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

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) 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.

IntroductionParkinson's disease is associated with increased mortality and hospitalisations are common at the end of life.

However, limited evidence exists regarding the place of death and its influencing factors in people with Parkinson's disease (PwPD).ObjectivesTo identify and analyse factors associated with place of death in PwPD.MethodsWe systematically searched three electronic databases (MEDLINE, EMBASE, PsycINFO) for studies reporting on the place of death of PwPD.

No restrictions on time or language were applied.

Where possible, meta-analyses were conducted using random-effects meta-regression adjusted for country-level long-term care and hospital bed availability.

Results are presented as odds ratios (OR) for place of death with 95% confidence intervals.

Sensitivity analyses were performed to explore heterogeneity.Results33 studies were analysed, including over 1,200,000 individuals across five continents and reporting on individual, illness-level, service-level, and environmental factors.

Hospital death was more likely among men (OR = 1.34; 95% CI: 1.21-1.49), married individuals (OR = 1.16; 95% CI: 1.07-1.26), and those under 85 years (OR = 1.29; 95% CI: 1.20-1.39).

Lower-quality evidence suggested a higher likelihood of hospital death among non-white individuals, while receipt of palliative care was associated with reduced odds.ConclusionsThis systematic review and meta-analysis identify key factors associated with hospital death in PwPD that can inform clinical decision-making and policy planning.

Our findings may support the development of targeted screening interventions and help clinicians and policymakers allocate resources effectively.

Further research is needed to address gaps in evidence across different care settings.Plain language titlePlace of death in Parkinson's disease and related factors.

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.

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.

BACKGROUND

Parkinson's disease (PD) is characterized by large-scale disruptions in beta and gamma oscillations.

Although subcortical beta power is an established biomarker for current adaptive deep brain stimulation (aDBS), it may not fully capture the global pathophysiological burden and the macroscale hierarchical reorganization of the cortex.

OBJECTIVE

We characterize the frequency-specific reorganization of the cortical hierarchy across resting and motor states using functional gradients.

We sought to identify topographic biomarkers that emerge across different behavioral states and determine whether these hierarchical features provide predictive power for global motor severity.

METHODS

High-density electroencephalography and magnetic resonance imaging-based source reconstruction were employed in patients with PD (n = 35) and healthy control subjects (n = 34).

To characterize cortical connectivity transitions, we applied a manifold learning framework to derive frequency-specific functional gradients.

We quantified the diagnostic and predictive utility of these hierarchical features and performed transcriptomic enrichment analysis to validate the biological relevance of the alterations.

RESULTS

Patients with PD exhibited a macroscale reorganization of the cortical hierarchy that was both frequency specific and state dependent.

These gradient-based biomarkers effectively differentiated patient groups and significantly predicted global Unified Parkinson's Disease Rating Scale Part III severity.

Findings showed a robust framework with distinct topographical signatures, manifesting as a redistribution of informative signals across cortical regions.

CONCLUSIONS

This work demonstrates that PD induces a macroscale reorganization of the cortical hierarchy.

State-dependent topographical biomarkers effectively predict clinical severity and align with the disease pathological landscape.

By identifying optimal sensing sites across distributed networks, our findings provide a principled reference to support next-generation, cortical-guided aDBS. © 2026 The Author(s).

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

Pathogenic GAA repeat expansions in FGF14 are an established cause of late-onset cerebellar ataxia, but have not been linked to Parkinson's disease.

Given emerging evidence that repeat expansions in ataxia-associated genes like RFC1 can contribute to atypical or familial forms of Parkinson's disease, we investigated whether FGF14 expansions might play a similar role.

Using long-read whole-genome sequencing, we analysed 411 individuals with Parkinson's disease and 197 neurologically healthy controls from the Parkinson's Progression Markers Initiative (PPMI) cohort, together with 1429 additional controls from the National Institutes of Health (NIH) Center for Alzheimer's Disease and Related Dementias (CARD) initiative, the 1000 Genomes Project, and the All of Us program, representing globally diverse populations.

We identified pathogenic FGF14 GAA repeat expansions in five individuals with Parkinson's disease and one control subject.

All five individuals fit the clinical criteria of Parkinson's disease and showed typical patterns of neurodegeneration on DaTSCAN imaging; α-synuclein aggregation was confirmed by a positive seeding assay among four individuals with available data.

These findings broaden the phenotypic spectrum of FGF14 repeat-associated disease and suggest a rare, previously unrecognized genetic contributor to Parkinson's disease.

To our knowledge, this is the first report implicating FGF14 in Parkinson's disease and underscores the utility of long-read sequencing for detecting hidden forms of pathogenic variation in unresolved cases.

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

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.

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.

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.

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.

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.

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.

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.

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).

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.

BACKGROUND AND OBJECTIVES

Glucocerebrosidase (GBA1) pathogenic variants are strongly associated with Parkinson disease (PD); however, insufficient data exist on the prevalence of PD among patients with Gaucher disease type 1 (GD1) (biallelic pathogenic GBA1 variants).

Also, penetrance estimates in patients with GD are lower than expected given their severely diminished enzymatic activity.

We aimed to estimate the age-specific risk of PD in patients with GD1, overall and by GBA1 genotype.

METHODS

Participants were patients with GD1 in the International Collaborative Gaucher Group Gaucher Registry, a global GD database, as of February 2024.

We longitudinally collected data on clinical diagnosis of PD and dementia with Lewy bodies (DLB) and report of motor (rest tremor, falls) and nonmotor (cognitive impairment, REM sleep behavior disorder, loss of sense of smell, autonomic dysfunction) signs/symptoms.

In addition to a conservative physician-based PD and DLB diagnosis, we created a liberal definition of possible parkinsonian syndrome (pPS; ≥2 signs/symptoms, PD, or DLB) to test whether previous low penetrance estimates stem from underdiagnosis.

Patients were classified as pPS at earliest of the following dates: PD diagnosis, DLB diagnosis, or report of second sign/symptom.

We separately estimated age-specific prevalence of PD and pPS using Kaplan-Meier survival curves.

RESULTS

Among 1,618 patients with GD1 (median age at last follow-up 47.8 years; 53% female), 51 were diagnosed with PD and 86 as pPS.

The age-specific prevalence (95% CI) of PD and pPS was 4.0% (2.7-5.7) and 6.0% (4.5-7.9) at 60 years and 12.2% (8.6-17.0) and 22.9% (17.1-30.1) at 80 years, respectively.

Patients with 2 mild pathogenic GBA1 variants had a qualitatively lower prevalence of PD and pPS vs patients with one mild variant.

DISCUSSION

In this large cohort of 1,618 patients, approximately one-in-nine patients with GD1 were diagnosed with PD and more than one-in-five patients were diagnosed with PD/DLB or experienced movement disorder symptoms by 80 years.

Most patients were from North America and Europe; generalizability to other regions is unknown.

Our finding that most patients remain free of PD despite very low residual enzyme activity informs the hypothesis that acid ß-glucosidase levels directly predict risk of PD.

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.

OBJECTIVE

To evaluate the effectiveness of sequential and simultaneous motor and cognitive treatment on motor functions, activities of daily living, and quality of life in people with Parkinson's disease.

DESIGN

Systematic review and meta-analysis.

SUBJECTS/PATIENTS

Patients with Parkinson's disease.

METHODS

A search was conducted in PubMed, Embase, Scopus, Web of Science, and Cochrane Library.

Functional mobility was assessed as the main outcome, and balance, gait, activities of daily living, and quality of life as secondary outcomes.

Meta-analyses were conducted using mean difference or standardized mean difference with 95% confidence intervals and fixed or random effect models.

Heterogeneity was explored, setting a cut-off value of I2 = 50%.

RESULTS

Sixteen studies were included, with 8 -eligible for meta-analysis.

Results showed that sequential combined treatment offered no clear advantage over motor rehabilitation alone for functional mobility, although a significant benefit was found for activities of daily living.

Results on simultaneous combined treatment suggested improvements in quality of life, but no significant differences between treatments for functional mobility.

CONCLUSION

Motor-cognitive approaches may enhance prefrontal cortex efficiency, supporting complex motor tasks and reducing the risk of falls.

Future research should elucidate neural mechanisms and compare simultaneous and sequential strategies to develop personalized, multidisciplinary rehabilitation protocols.

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.

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.

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.

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.

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).

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.

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.

De nombreuses données établissent un lien entre les altérations de la composition du microbiote intestinal et la maladie de Parkinson, ce qui a conduit à plusieurs essais contrôlés randomisés récents de transplantation de microbiote fécal (TMF) chez des personnes atteintes de la maladie de Parkinson, ciblant la dysbiose intestinale dans le but de moduler l’axe intestin-cerveau.

Certains essais de TMF ont observé une amélioration des symptômes moteurs et non moteurs chez des personnes atteintes de la maladie de Parkinson, possiblement par une augmentation, liée au microbiote, des acides gras à chaîne courte ou d’autres métabolites, ainsi que par une réduction de l’inflammation systémique.

Bien que ces résultats soient enthousiasmants et puissent ouvrir un nouveau paradigme thérapeutique, des questions cruciales restent à résoudre concernant la sélection des donneurs, le dépistage et la sélection optimaux du microbiote du donneur, les voies d’administration ainsi que le moment et la fréquence des transplantations.

Nous proposons que les futurs essais de TMF intègrent des marqueurs biologiques sanguins, métaboliques, urinaires et de neuro-imagerie fonctionnelle, et qu’ils contrôlent l’alimentation, les comorbidités liées au mode de vie, la prise de médicaments ou d’autres variables potentielles, afin d’assurer une évaluation optimale des interactions entre les microbes intestinaux et les effets cérébraux, de façon prospective et sur une plus longue période.

Les évaluations cliniques traditionnelles dans les essais sur la maladie de Parkinson (MP) sont limitées par leur subjectivité et par la variabilité entre évaluateurs.

Les technologies numériques de santé (TNS) offrent une évaluation objective et continue des symptômes moteurs et sont de plus en plus utilisées en recherche clinique.

Cette revue a évalué le rôle des TNS comme outils de mesure des résultats dans les essais pharmacologiques portant sur la MP.

Une recherche systématique dans MEDLINE et Embase a été menée conformément aux lignes directrices PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), couvrant les études publiées jusqu’au 31 août 2025.

Les études admissibles comprenaient des essais contrôlés randomisés, des devis en ouvert ou croisés et des études observationnelles utilisant des TNS pour évaluer des variables motrices dans la MP.

Les études portant uniquement sur le développement technologique ou comptant moins de 10 participants ont été exclues.

Les données extraites comprenaient le devis de l’étude, le type de TNS, le cadre d’évaluation et les paramètres moteurs mesurés.

La qualité des études a été appréciée à l’aide d’un outil à huit critères, et le niveau de preuve a été coté selon le cadre de l’Oxford Centre for Evidence-Based Medicine.

Au total, 42 études ont été incluses, portant sur 26 TNS distinctes.

Celles-ci comprenaient 11 capteurs portables et 15 systèmes non portables, tels que des plateformes de capture de mouvement et des évaluations par capteurs de force.

Les TNS ont servi à mesurer la bradykinésie, le tremblement, la marche, l’équilibre et les symptômes moteurs nocturnes, en contexte supervisé comme non supervisé.

Quinze études ont été jugées de qualité élevée, 14 de qualité modérée et 13 de qualité faible.

Parmi les outils actuellement disponibles, seul Opal atteignait le seuil du niveau de preuve 1a.

Les autres outils validés comprenaient le Parkinson’s Kinetigraph, l’Actiwatch et la Roche PD Mobile Application (niveau 1b).

Les TNS constituent des outils précieux pour une évaluation objective dans les essais sur la MP, même si une adoption plus large exige une standardisation accrue et une harmonisation réglementaire. © 2025 International Parkinson and Movement Disorder Society.

BACKGROUND

Phase-amplitude coupling (PAC) in the beta-gamma range has emerged as a promising electrophysiological biomarker of Parkinson's disease (PD).

OBJECTIVE

This study aims to investigate how levodopa and locomotion modulate cortical (central electroencephalogram [cEEG]) and corticomuscular (cEEG-gEMG [gastrocnemius electromyography]) beta-gamma PAC in patients with PD.

METHODS

Thirty patients with PD underwent simultaneous cEEG and gEMG recordings during sitting, standing, and free walking in both off and on dopaminergic states.

Spectral features and PAC analyses were conducted to assess the effects of levodopa, locomotion, and their associations with motor symptoms.

RESULTS

In the off levodopa state, patients showed prolonged gait cycle intervals and shorter step lengths, correlating with higher Movement Disorder Society-revised Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) scores.

The cEEG beta-gamma PAC during sitting and standing, and cEEG-gEMG beta-gamma PAC during walking, positively correlated with UPDRS-III in the off levodopa state.

The cEEG alpha/low beta-gamma and cEEG-gEMG low beta-gamma PAC increased from on to off levodopa while walking, with the latter correlating with reduced step length.

Step event-related PAC analysis unveiled a dynamic enhancement of alpha/beta cEEG-gamma gEMG PAC around heel strikes in on levodopa compared with off.

CONCLUSIONS

Both cortical and corticomuscular beta-gamma PACs are modulated by levodopa and locomotion, with low beta-gamma corticomuscular PAC specifically linked to gait dysfunction.

Moreover, the levodopa-related enhancement of alpha/beta-gamma PAC during heel strikes highlights the functional relevance of dopaminergic modulation during gait.

These findings highlight the potential of PAC as a biomarker for PD, particularly in the development of gait phase-locked adaptive deep brain stimulation strategies for patients with PD guided by noninvasive PAC monitoring. © 2025 The Author(s).

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

Gait problems in people with Parkinson's disease are increasingly common as disease progresses.

Symptoms include freezing of gait (FoG) and a predisposition to falls.

The causative pathophysiology is not completely understood.

In this study, PET with 18F-fluoroethoxybenzovesamicol (18F-FEOBV), a presynaptic marker of cholinergic terminal density, and 18F-fluorodeoxyglucose (18F-FDG) was performed in a cohort of people with Parkinson's disease and gait disorder to derive spatial covariance networks of cholinergic and metabolic activity and to evaluate the correlation of such networks against the frequency of FoG and other gait measures.

Fourteen patients with Parkinson's disease and FoG in the ON motor state underwent PET using 18F-FEOBV and 18F-FDG on two separated days.

Following spatial normalization, functional networks were derived by principal component analysis.

The individual expression of linear combinations of principal components was subsequently correlated with measures of FoG in the ON motor state (ON-FoG) and a lower body and gait subsection of the Unified Parkinson's Disease Rating Scale part III.

Gait measures were derived from home-worn measures using a triaxial accelerometer.

We found a derived pattern of 18F-FEOBV binding that was correlated with ON-FoG (R2 = 0.46975, P = 0.045) and with other lower body and gait signs (R2 = 0.78591, P = 0.0077).

Lower levels of cholinergic activity in the thalamus, hippocampus, striatum, anterior cingulate and areas of the brainstem consistent with the mesencephalic locomotor region were associated with worse ON-FoG and gait disturbances.

The derived pattern was not associated with overall disease duration or progression as assessed by standard motor scores.

There was no correlation between 18F-FEOBV and OFF-FoG.

For 18F-FDG, no correlation between covariance patterns and gait assessments could be found.

However, a statistically significant correlation was found for a subset of lower body and gait symptoms (R2 = 0.78306, P = 0.002).

These results exhibit a correlation between lower levels of cholinergic function in locomotor-related areas of the brainstem and objective measures of dopamine medication ON-FoG, potentially indicating a causative link between the two.

No association was found with OFF-FoG.

Taken together, our results provide support for the role of the cholinergic system in the occurrence of dopamine medication ON-FoG.

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

[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.

BACKGROUND

Neuroinflammation, measured using [11C](R)-PK11195 positron emission tomography (PET), has been reported in isolated rapid-eye-movement sleep behavior disorder (iRBD), but its temporal progression is unknown.

OBJECTIVE

The aim was to assess longitudinal progression of neuroinflammation in iRBD patients and its relationship with phenoconversion into Parkinson's disease (PD) or dementia with Lewy bodies (DLB).

METHODS

Sixteen iRBD patients received longitudinal [11C](R)-PK11195 PET scans over 3 years and were followed up clinically for 8 years to record phenoconversion into PD and DLB.

RESULTS

We found significant progression of neuroinflammation in the putamen among other regions, with a trend to cortical increase over 3 years.

During the clinical follow-up, 7 patients converted, and subgroup analyses suggested that the converters differed in progression patterns, with PD converters exhibiting increases and DLB exhibiting decreases in inflammation.

CONCLUSION

This exploratory study suggests that progression of neuroinflammation in iRBD patients depends on their clinical trajectories, and this could be impactful in immune-modifying treatments. © 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.

INTRODUCTION

As Parkinson's disease (PD) advances, limitations of oral medication include pill burden, increasing "Off" time, and "On" time with bothersome dyskinesia.

Deep brain stimulation (DBS) can improve motor complications, but disease progression may warrant further intervention later.

An approved nonsurgical option, continuous subcutaneous infusion of foslevodopa/foscarbidopa (LDp/CDp), has been shown to improve motor fluctuations, though the impact of prior DBS on its efficacy and safety is unknown.

METHODS

Post hoc analysis of a 52-week open-label phase 3 trial (NCT03781167) evaluated baseline characteristics, safety, and efficacy in patients treated with LDp/CDp with or without prior DBS.

Fisher's exact test, t test, Wilcoxon rank-sum test, and analysis of covariance were performed.

RESULTS

Twenty-four (9.8%) of 244 patients received prior DBS.

Both groups had similar baseline characteristics, although prior patients treated with DBS had significantly more time since diagnosis and more "speech" and "gait" impairment (Movement Disorders Society-Unified Parkinson's Disease Rating Scale [MDS-UPDRS] Parts II/III single items).

Both groups showed significant within-group improvements in "Off" time and "On" time without dyskinesia, and the between-group difference for these improvements was not significant, indicating LDp/CDp had efficacy regardless of DBS exposure.

The no DBS group had significant improvement in sleep and quality of life, while the prior DBS group had nonsignificant trends in the same direction.

The no DBS group had significant improvement in MDS-UPDRS Part II score but worsening in Part III score, as expected with advancing disease; change from baseline in the prior DBS group was not significant.

The safety data were similar in both groups, with the only significant difference being a higher percentage of prior patients treated with DBS experiencing severe treatment-emergent adverse events than no DBS (45.8% vs 23.6%).

CONCLUSION

While limited by small prior DBS patient numbers, this post hoc study suggests generally similar overall baseline, safety, and efficacy profiles in LDp/CDp-treated prior DBS and no DBS.

TRIAL REGISTRATION

ClinicalTrials.gov identifier NCT03781167.

BACKGROUND

Soon after the advent of cinematography in 1895, neurologists began exploring its use as a permanent record of physical signs and as a teaching aid.

We present the first known Spanish film on movement disorders, recorded in 1915.

METHODS

We describe and analyze the patients shown in the film within its historical context.

RESULTS

The first section of the film is a teaching session in which a fixed camera records the patients and the professor, surrounded by students.

It presents 10 patients, including parkinsonian and catatonic patients.

In the second section, a mobile camera follows two cases in more detail: a patient with probable Huntington's disease (HD), and an impressive case of paradoxical kinesia in Parkinson's disease (PD).

CONCLUSIONS

The didactic value of the film is exceptional.

It presents the first reported Spanish case of HD, and the first documented case of paradoxical kinesia in PD, 6 years before its written description in 1921. © 2026 International Parkinson and Movement Disorder Society.

Understanding the genetic foundations of dementia is critical to unraveling its complex molecular basis.

Given that a clinical diagnosis of Alzheimer's disease (AD) dementia often results from interplay between multiple underlying neuropathologic co-morbidities, previous genome-wide association studies (GWAS) of clinically diagnosed AD are restricted in their ability to translate genetic associations to potential targeted therapeutics.

The current study seeks to address these limitations by presenting the largest GWAS to date (n = 12,509) of neuropathologic hallmarks of AD and AD related dementias (ADRDs).

We further performed a candidate-variant analysis using loci previously identified in GWAS of clinically diagnosed AD dementia and Parkinson's disease (PD).

Finally, we conducted heritability and genetic correlation analyses using linkage disequilibrium (LD) score regression.

We found broad genome-wide significant associations with APOE across AD and ADRDs but not cerebrovascular disease and vascular brain injury.

We further identified 12 significant loci across 10 neuropathologic phenotypes, including 5 loci previously implicated in GWAS of clinical AD and ADRDs (variants on BIN1, PICALM/ EED, TMEM106B, GRN, and SNCA/ SNCA-AS1) and 7 novel genome-wide associations (variants on EPHA5, PSMG1, LINC00276, VAPA, LINC00290, DOCK4 and SLAIN2/ SLC10A4).

Our analysis of AD and PD clinical candidate variants demonstrated several that were associated with AD neuropathologic change and Lewy body disease, as well as substantial overlap with neuropathologic lesions other than the primary neuropathologic hallmarks of these diseases.

Heritability analyses demonstrated heritability that was high for amyloid plaques (78%) relative to prior clinical AD heritability analyses, intermediate for TDP-43 inclusions (41%), and low for remaining AD and ADRD pathologic features.

This study underscores the importance of investigating the underlying neuropathologic hallmarks of AD and ADRDs as a step toward refining the translation of genetic associations to biomarker interpretation and development of targeted therapeutics.

Focused ultrasound is rapidly emerging as a novel technology for the development of symptomatic therapies and supporting disease-modifying treatments for Parkinson's disease (PD).