臨床試験・研究

BACKGROUND

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

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

METHODS

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

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

RESULTS

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

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

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

CONCLUSION

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

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

OBJECTIVE

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

METHODS

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

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

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

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

RESULTS

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

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

The overall evidence certainty was rated as moderate.

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

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

CONCLUSION

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

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

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

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.

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.

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.

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.

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.

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.

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 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.

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.

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

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.

脳深部刺激（DBS）は運動障害の運動症状に効果的ですが、その機序が十分に解明されないまま言語（発話）機能を損なうことがしばしばあります。

研究陣はPROSPEROに事前登録した系統的レビューとメタ分析を行い、2024年8月までの文献を対象としました（CRD42024527738）。

2,726編をスクリーニングし、パーキンソン病131編・本態性振戦32編・ジストニア21編、計184編を対象に、聴覚印象・音響・患者報告による発話評価を検討しました。

メタ分析の結果、パーキンソン病の視床下核DBSは最良の薬物治療と比べて発話明瞭度が低下していました（効果量-0.24、95%信頼区間-0.46〜-0.03、p=0.027）。

縦断解析では、刺激オン下で状態依存的な悪化がみられました（統一パーキンソン病評価尺度パートIII項目18の月次変化：服薬オン時+0.016、p<0.001／服薬オフ時+0.002、p=0.50）。

本態性振戦では、DBSは声の振戦を一貫して抑えましたが、とくに両側刺激で構音障害のリスクが高まりました。

ジストニアの結果はばらつきがより大きいものでした。

疾患を横断して見ると、持続発声の指標は改善する一方、連続発話の成績は悪化しており、複雑な運動課題ほど選択的に影響を受けることが示されました。

神経解剖学的マッピングにより、互いに排他的でない2つの機序が特定されました — 皮質延髄路への電流拡散による痙性発話の特徴と、小脳視床皮質路への拡散による運動失調様の特徴です。

動作減少型・吃音様の表現型もみられましたが、これは特定の神経線維束への拡散というより、ネットワークレベルの相互作用を反映していると考えられます。

こうした線維束を介した変化やネットワークレベルの変化は、大脳半球の左右差・服薬状態・長期的な可塑性と相互作用し、複雑な臨床像を生み出しているとみられます。

研究陣は、系統的なスクリーニング・表現型の特定・的を絞った刺激設定の調整を組み合わせた臨床的な枠組みを示しました。

発話評価の強化、正確な電場マッピング、適応型DBSの導入により、精密DBS治療において発話機能と運動機能の両方を最適化する個別化ケアが可能になるかもしれません。

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

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).

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

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.

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.

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

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.

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

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).

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

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.

脳深部刺激（DBS）は運動障害の運動症状に効果的ですが、その機序が十分に解明されないまま言語（発話）機能を損なうことがしばしばあります。

研究陣はPROSPEROに事前登録した系統的レビューとメタ分析を行い、2024年8月までの文献を対象としました（CRD42024527738）。

2,726編をスクリーニングし、パーキンソン病131編・本態性振戦32編・ジストニア21編、計184編を対象に、聴覚印象・音響・患者報告による発話評価を検討しました。

メタ分析の結果、パーキンソン病の視床下核DBSは最良の薬物治療と比べて発話明瞭度が低下していました（効果量-0.24、95%信頼区間-0.46〜-0.03、p=0.027）。

縦断解析では、刺激オン下で状態依存的な悪化がみられました（統一パーキンソン病評価尺度パートIII項目18の月次変化：服薬オン時+0.016、p<0.001／服薬オフ時+0.002、p=0.50）。

本態性振戦では、DBSは声の振戦を一貫して抑えましたが、とくに両側刺激で構音障害のリスクが高まりました。

ジストニアの結果はばらつきがより大きいものでした。

疾患を横断して見ると、持続発声の指標は改善する一方、連続発話の成績は悪化しており、複雑な運動課題ほど選択的に影響を受けることが示されました。

神経解剖学的マッピングにより、互いに排他的でない2つの機序が特定されました — 皮質延髄路への電流拡散による痙性発話の特徴と、小脳視床皮質路への拡散による運動失調様の特徴です。

動作減少型・吃音様の表現型もみられましたが、これは特定の神経線維束への拡散というより、ネットワークレベルの相互作用を反映していると考えられます。

こうした線維束を介した変化やネットワークレベルの変化は、大脳半球の左右差・服薬状態・長期的な可塑性と相互作用し、複雑な臨床像を生み出しているとみられます。

研究陣は、系統的なスクリーニング・表現型の特定・的を絞った刺激設定の調整を組み合わせた臨床的な枠組みを示しました。

発話評価の強化、正確な電場マッピング、適応型DBSの導入により、精密DBS治療において発話機能と運動機能の両方を最適化する個別化ケアが可能になるかもしれません。

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.

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

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

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

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

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

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

BACKGROUND

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

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

OBJECTIVES

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

METHODS

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

We compared hourly acceleration patterns and classification performance across cohorts.

RESULTS

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

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

No pair of cohorts demonstrated statistical equivalence.

CONCLUSIONS

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

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

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

BACKGROUND

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

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

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

OBJECTIVES

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

METHODS

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

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

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

Symptom progression was analyzed using correlation analyses and MLMs.

RESULTS

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

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

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

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

CONCLUSIONS

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

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

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

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

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

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

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

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

Levodopa reduced stepping frequency variability, implying improved stepping rhythmicity.

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

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

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

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

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

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

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

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.

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

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

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

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

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

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.

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

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

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

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

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

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

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

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

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

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

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

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.

多様な祖先系統にわたるパーキンソン病の病因への遺伝的関与を解明することは、グローバルな文脈で標的治療を開発するうえで重要な優先課題である。

我々は、遺伝学的に推定されたアフリカ系またはアフリカ系混血系統の710例の症例と11,827例の対照において、疾患を引き起こす可能性のあるタンパク質改変・スプライシング変異について、これまでで最大規模のシークエンシング解析を実施した。

早期発症例および家族性症例を優先して、コピー数変異(CNV)およびホモ接合性領域(runs of homozygosity)を検討した。

本研究では、パーキンソン病患者において最も頻度の高い変異として希少GBA1コーディング変異を同定し、症例コホートにおける頻度は4%であった。

同定された18種類のGBA1変異のうち、10種類は病原性または病原性の可能性ありと既に分類されており、4種類は新規変異、4種類は臨床的意義不明とされた。

アシュケナージ系ユダヤ人集団および欧州系集団で最も一般的に知られる疾患関連GBA1変異(p.Asn409Ser、p.Leu483Pro、p.Thr408Met、p.Glu365Lys)は、アフリカ系およびアフリカ系混血系統のパーキンソン病症例では同定されなかった。

同様に、LRRK2 p.Gly2019Serやp.Gly2385Argを含む欧州系・アジア系集団で知られる疾患原因変異スペクトラムは、西アフリカ系集団におけるパーキンソン病の病因において主要な役割を果たしていないと考えられた。

しかしながら、臨床的意義不明の新規ヘテロ接合性LRRK2ミスセンス変異を3種類同定し、うち2種類(p.Glu268Alaおよびp.Arg1538Cys)はアフリカ系集団の参照データセットにおいてより高頻度にみられた。

構造変異解析により、アフリカ系およびアフリカ系混血症例においてPRKNのCNVが0.7%の頻度で存在することが明らかとなり、検出されたCNVの66%は早期発症例における複合ヘテロ接合体またはホモ接合体であり、これらの集団における若年性パーキンソン病の遺伝的背景についてさらなる知見を与えた。

ショートタンデムリピート解析では、アフリカ系パーキンソン病患者3例において病原性範囲(CAGリピート数45超)のATXN3 CAGリピート伸長が同定された。

今回検討した遺伝子における新規の遺伝的variationは、その病原性の可能性を解明するため、さらなる再現研究および機能的な優先度評価が求められる。

本研究では、十分に研究されてこなかった集団におけるパーキンソン病の病因に関連しうる、既知および新規のコーディング・スプライシング変異について、これまでで最も包括的な遺伝カタログを作成し、さらに集団特異的な影響を検討するためグローバルおよびローカルな祖先系統解析を実施した。

本研究は、精密医療が発展する時代において標的治療の開発を導く可能性を持つ。

遺伝学研究の対象を十分に代表されてこなかった集団にまで広げることで、将来のパーキンソン病治療が有効であるだけでなく、多様な祖先集団のニーズに応える包摂的なものとなることを期待する。

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

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

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

METHODS

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

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

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

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

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

FINDINGS

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

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

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

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

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

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

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

INTERPRETATION

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

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

FUNDING

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

BACKGROUND

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

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

OBJECTIVE

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

METHODS

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

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

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

Model interpretability was examined with SHapley Additive exPlanations.

RESULTS

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

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

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

CONCLUSIONS

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

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

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

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.

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.

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.

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.

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

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

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

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

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

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

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

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

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

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.

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

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

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

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

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

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

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

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

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

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

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

BACKGROUND

Pain affects up to 87% of people with multiple system atrophy (MSA), but it remains unclear which types of pain contribute most to the overall burden.

OBJECTIVE

To estimate the frequency of different types of pain in MSA individuals.

METHODS

In 2023, individuals with MSA completed a web-based survey that included the King's Parkinson's Disease Pain Questionnaire (KPPQ) and additional questions addressing pain related to MSA core features (eg, coat-hanger pain, pain due to bladder-issues, cold extremities, bruises, and pressure sores).

Respondents were matched by age, gender, and disease duration with historical cohorts of individuals with Parkinson's disease (PD) and healthy controls (n = 96 each) who had previously completed the KPPQ.

RESULTS

One hundred and fifty-seven MSA individuals with pain completed the survey.

The most frequently reported KPPQ types of pain were nocturnal pain (73%), musculoskeletal pain (63%), and fluctuation-related pain (62%).

Common additional pain sources included coat-hanger pain (59%), cold extremities (48%), and bruises (44%).

All KPPQ pain types were significantly more frequent in MSA than in healthy controls, except for musculoskeletal pain (63% vs. 66%, P = 0.722).

Compared with PD, MSA individuals reported less musculoskeletal (63% vs. 78%, P = 0.023), but more orofacial pain (32% vs. 12%, P < 0.001) on the KPPQ.

CONCLUSIONS

MSA is associated with both non-specific and disease-related pain types, which may be neuropathic, nociceptive, nociplastic, or mixed in nature.

These findings inform the development of tailored tools for identifying distinct pain sources in MSA, as each may require a specific therapeutic approach, including targeted treatment of motor and non-motor symptoms. © 2026 The Author(s).

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

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

BACKGROUND

The cerebrospinal fluid alpha-synuclein seed amplification assay (CSFasynSAA) detects alpha-synuclein aggregation in over 90% of individuals with sporadic PD (sPD).

However, the clinical characteristics of sPD with negative CSFasynSAA remain undefined.

OBJECTIVES

Describe clinical and neuroimaging characteristics of CSFasynSAA-negative sPD individuals in the Parkinson's Progression Markers Initiative (PPMI).

METHODS

We identified sPD PPMI participants with a negative CSFasynSAA (SAA-, n = 80) or positive CSFasynSAA (SAA+, n = 856) result at baseline.

For comparative analysis between groups, we used a reduced dataset (n = 79 SAA- and n = 237 SAA+) propensity-score matched on age, sex, and time since clinical diagnosis.

Clinical parameters, dopamine transporter-single photon emission computed tomography (DAT-SPECT), and magnetic resonance imaging (MRI) brain volumetrics were analyzed.

RESULTS

The SAA- and matched SAA+ groups had similar motor performance on the Movement Disorder Society Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III) and similar cognitive performance on the Montreal Cognitive Assessment (MoCA) at baseline.

The proportion with severe hyposmia was 12% for SAA- versus 73% for SAA+ (P < 0.001).

Per PPMI enrollment criteria all participants were classified as having an abnormal DAT-SPECT.

There were no significant differences in median quantitative DAT-SPECT measures between groups.

The SAA- group showed a higher degree of atrophy in subcortical brain regions including substantia nigra.

Longitudinally, 14.3% of SAA- participants had a change in diagnosis versus 0.9% of SAA+ participants.

CONCLUSIONS

At baseline, SAA- sPD PPMI participants have a substantially lower rate of hyposmia, but otherwise cannot be readily distinguished from SAA+ participants based on clinical characteristics.

However, SAA- participants have a greater degree of subcortical brain atrophy, and approximately one out of seven SAA- participants received a change in diagnosis. © 2026 The Author(s).

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

IMPORTANCE

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

OBJECTIVE

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

DESIGN, SETTING, AND PARTICIPANTS

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

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

Data analysis was completed from July 2024 to May 2025.

INTERVENTION

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

MAIN OUTCOMES AND MEASURES

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

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

RESULTS

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

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

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

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

CONCLUSIONS AND RELEVANCE

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

TRIAL REGISTRATION

ClinicalTrials.gov Identifier: NCT04201093.

BACKGROUND

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

OBJECTIVES

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

METHODS

New users of CCBs were identified using drug reimbursement databases.

We validated incident PD using several data sources.

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

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

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

RESULTS

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

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

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

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

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

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

DISCUSSION

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

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

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

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

BACKGROUND

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

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

OBJECTIVES

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

METHODS

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

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

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

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

RESULTS

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

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

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

CONCLUSIONS

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

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

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

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

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

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

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

Levodopa reduced stepping frequency variability, implying improved stepping rhythmicity.

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

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

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

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

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

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

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

BACKGROUND AND OBJECTIVES

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

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

METHODS

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

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

DISCUSSION

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

IMPORTANCE

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

OBJECTIVE

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

DESIGN, SETTING, AND PARTICIPANTS

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

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

Data analysis was completed from July 2024 to May 2025.

INTERVENTION

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

MAIN OUTCOMES AND MEASURES

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

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

RESULTS

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

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

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

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

CONCLUSIONS AND RELEVANCE

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

TRIAL REGISTRATION

ClinicalTrials.gov Identifier: NCT04201093.

OBJECTIVE

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

BACKGROUND

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

METHODS

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

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

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

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

RESULTS

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

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

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

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

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

CONCLUSIONS

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

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

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

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

BACKGROUND

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

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

OBJECTIVES

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

METHODS

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

PRIMARY OUTCOMES

enrollment and program completion rates.

SECONDARY OUTCOMES

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

RESULTS

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

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

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

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

CONCLUSIONS

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

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

Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2025 The Author(s).

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

Perineuronal nets are specialized extracellular matrix structures forming preferentially around parvalbumin interneurons to regulate plasticity.

While cortical perineuronal nets have been implicated in sensory plasticity and memory modulation, perineuronal nets of the primary motor cortex have been largely overlooked.

We found that transient reduction of primary motor cortex perineuronal nets by chondroitinase ABC (ChABC) treatment in otherwise healthy adult mice resulted in temporary deficits in motor function.

In a mouse model of Parkinson's disease based on unilateral 6-hydroxydopamine lesions of the midbrain, perineuronal net levels were decreased in both primary motor cortex hemispheres 2 weeks post-lesion, yet returned to baseline within 5 weeks.

We discovered that subsequent transient reduction of primary motor cortex perineuronal nets through ChABC treatment could unlock motor recovery when coupled with motor stimulation.

This recovery was associated with a bilateral increase in perineuronal-net-enwrapped parvalbumin interneurons and a rebalancing of parvalbumin cell soma excitatory synaptic markers.

These findings reveal distinct roles of perineuronal net plasticity-first in response to the initial midbrain lesion and then during rescue after ChABC treatment-suggesting that primary motor cortex perineuronal nets play a nuanced role in regulating motor function.

This duality positions perineuronal nets as potential therapeutic targets for motor rehabilitation strategies in Parkinson's disease.

Traditional clinical assessments in Parkinson's disease (PD) trials are limited by subjectivity and inter-rater variability.

Digital health technologies (DHT) offer an objective continuous assessment of motor symptoms and are increasingly used in clinical research.

This review evaluated the role of DHTs as outcome tools in pharmacological trials for PD.

A systematic search of MEDLINE and Embase was conducted according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, covering studies up to August 31, 2025.

Eligible studies included randomized controlled trials, open-label or crossover designs, and observational studies using DHTs to assess motor outcome variables in PD.

Studies focusing only on technology development or with fewer than 10 participants were excluded.

Data extracted included study design, DHT type, assessment setting, and motor parameters measured.

Study quality was appraised using an eight-criterion tool, and level of evidence was rated using the Oxford Centre for Evidence-Based Medicine framework.

A total of 42 studies were included, covering 26 distinct DHTs.

These comprised 11 wearable sensors and 15 nonwearable systems such as motion capture platforms and force-sensing assessments.

DHTs were used to measure bradykinesia, tremor, gait, balance, and nocturnal motor symptoms in both supervised and unsupervised settings.

Fifteen studies were rated as high quality, 14 moderate, and 13 low.

Among currently available tools, only Opal reached the threshold of Level 1a evidence.

Other validated tools included the Parkinson's Kinetigraph, Actiwatch, and Roche PD Mobile Application (Level 1b).

DHTs offer valuable tools for objective assessment in PD trials, though broader adoption requires greater standardization and regulatory alignment. © 2025 International Parkinson and Movement Disorder Society.

腸内細菌叢の組成変化とパーキンソン病を結びつける有力な根拠が蓄積されており、これを受けて近年、腸内細菌の乱れ(dysbiosis)を標的とし、腸脳相関(gut-brain axis)の調節を目的としたパーキンソン病患者を対象とする糞便微生物移植(FMT)のランダム化比較試験がいくつか実施されている。

FMT試験の一部では、腸内細菌叢を介した短鎖脂肪酸をはじめとする代謝物への作用や全身性炎症の軽減を通じてと考えられる、パーキンソン病患者の運動症状・非運動症状の改善が観察されている。

これらの知見は興味深く、新たな治療パラダイムを切り開く可能性を秘めている一方で、ドナーの選定、ドナー微生物叢の最適なスクリーニング・選択、投与経路、移植の時期と頻度といった重要な課題に取り組む必要がある。

今後のFMT試験では、血液・代謝物・尿および機能的神経画像のバイオマーカーを組み込み、食事・生活習慣に関連する併存疾患・服薬状況やその他の変数を統制したうえで、腸内細菌と脳の転帰との相互作用をより長期にわたって前向きに評価することが望ましいと提言する。

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.

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.

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.