임상시험·연구

BACKGROUND

Oxidative stress is central to type 2 diabetes mellitus (T2DM) and Parkinson's disease (PD). However, the utility of biomarkers for lipid peroxidation (F2-isoprostanes) and DNA damage (8-OHdG) in the comorbidity of PD and T2DM remains unclear.

METHODS

We conducted a systematic review and meta-analysis of 54 unique studies of human subjects aged ≥ 50 years (n = 7,521: 3,522 with T2DM, 722 with PD, and 3,277 controls), measuring biomarkers in serum, plasma, or leukocytes. Mixed-effects models quantified standardized differences (Hedges' g) across subgroups.

RESULTS

In T2DM, F2-isoprostanes (g = 1.60, 95% CI: 0.95-2.25) and 8-OHdG (g = 2.64, 95% CI: 2.13-3.14) were markedly elevated (p g = 5.24). In PD, 8-OHdG was moderately elevated (g = 0.78, 95% CI: 0.18-1.39; p = 0.011), particularly in randomized controlled trials and plasma samples, whereas F2-isoprostanes were not significantly elevated (g = 0.47, 95% CI: -0.43-1.38). High heterogeneity in T2DM (I2 > 90%) reflected methodological variability.

CONCLUSION

Distinct profiles - both markers elevated in T2DM but only 8-OHdG in PD - underscore 8-OHdG's potential in PD-T2DM comorbidity. Future research should focus on standardized assays, multi-compartmental or multi-modal sampling, and longitudinal studies to clarify mechanisms and therapeutic targets.

INTRODUCTION

Bilateral electrode implantation is the primary approach for deep brain stimulation (DBS) in Parkinson's disease (PD). However, it may lead to gait deterioration in some patients. This study aimed to investigate the efficacy of unilateral DBS on gait in PD patients as an alternative with fewer side effects and lower costs.

METHODS

We systematically searched four major clinical databases to evaluate the effects of unilateral DBS on UPDRS gait score, gait velocity, stride length, cadence, and gait initiation in PD patients. Twenty-three studies were included in the review, selected from an initial pool of 2,415 studies. We also performed a meta-analysis to assess the impact of unilateral DBS on gait velocity and compare its efficacy to bilateral stimulation. The study protocol was registered at PROSPERO with the registration code: CRD42024585359.

RESULTS

The included studies assessed gait measures in patients receiving unilateral DBS targeting the STN, globus pallidus internus, pedunculopontine nucleus, and ventral intermediate nucleus. According to the systematic review of clinical evidence, unilateral DBS can improve the UPDRS gait score, freezing of gait, and gait velocity, although to a lesser extent than bilateral stimulation. The meta-analysis revealed a nonsignificant positive pooled effect on gait velocity in the unilateral DBS condition compared to the control condition and no significant difference when compared to bilateral DBS.

CONCLUSION

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

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.

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

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

Current dopaminergic therapies for Parkinson's disease carry significant limitations: levodopa can cause long-term motor complications, while D2/D3 receptor-targeting dopamine agonists can produce non-motor adverse effects. Tavapadon is an oral, once-daily, selective D1/D5 agonist that might improve Parkinson's disease motor symptoms. We aimed to evaluate the safety, tolerability and efficacy of flexible-dose tavapadon in people with early-stage Parkinson's disease.

METHODS

TEMPO-2 was a phase 3, randomised, double-blind, placebo-controlled trial conducted at 75 clinical sites (both hospital or academic and community settings) across 13 countries. Adults aged 40-80 years with early-stage Parkinson's disease (<3 years' disease duration) who were treatment-naive or had less than 3 months of previous dopaminergic treatment were eligible. Participants were randomly assigned 1:1 to flexible-dose tavapadon (5-15 mg) or placebo orally once daily for 27 weeks. The primary endpoint was change from baseline to week 26 in the combined score of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts II and III (reflecting activities of daily living and motor performance). Safety endpoints included adverse events, clinical laboratory values, vital signs, and electrocardiograms. The primary endpoint was assessed in the modified intent-to-treat population (participants who received one dose or more of study drug and had both a baseline and one or more post-baseline MDS-UPDRS assessments) and safety was assessed in the safety analysis set (all participants who received one dose or more of tavapadon or placebo). This study is registered with ClinicalTrials.gov (NCT04223193) and is now complete.

FINDINGS

Between Jan 6, 2020, and Feb 22, 2024, 473 individuals were screened and 304 were randomly assigned to receive tavapadon 5-15 mg (n=151) or placebo (n=153). The majority of participants were male (169 [56%] of 304 male; 135 [44%] of 304 female), the mean age was 62·9 (SD 9·2) years, and the mean disease duration was 0·86 (0·79) years. 80 (26%) of 304 participants discontinued from the trial (57 [38%] of 151 on tavapadon and 23 [15%] of 153 on placebo), most commonly due to adverse events (42 [14%] of 304; 36 [24%] of 151 on tavapadon and six [4%] of 153 on placebo). The primary endpoint of change from baseline to week 26 in the MDS-UPDRS Parts II and III combined score was significantly improved with tavapadon versus placebo (least squares mean [LSM] decrease of 10·3 [95% CI -12·2 to -8·3] points vs 1·2 [-2·9 to 0·6] points; LSM treatment difference -9·1 [95% CI -11·7 to -6·5]; p10% of participants) were nausea (45 [30%] of 151] vs five [3%] of 153), headache (25 [17%] vs eight [5%]), and dizziness (24 [16%] vs five [3%]).

INTERPRETATION

Tavapadon showed significant and clinically meaningful improvements in Parkinson's disease motor symptoms, with low incidence of somnolence and impulse control disorders. However, the short observation period limits conclusions about long-term tolerability. An ongoing extension study aims to confirm its long-term safety and efficacy.

FUNDING

AbbVie.

The progressive age-related aggregation of soluble α-synuclein into toxic oligomers and insoluble amyloid fibrils causes Parkinson's disease, Lewy body dementia and multiple system atrophy, all of which are neurodegenerative diseases without a cure. Because α-synuclein is a self-antigen, pathogenic α-synuclein aggregates do not elicit a strong immune response. Recent advances in structural biology elucidating the structure of α-synuclein fibrils have allowed us to design engineered protein fibrils that model conformational epitopes present on the surface of α-synuclein fibrils. HET-s is a soluble fungal protein capable of forming amyloid fibrils. We used HET-s(218-298) fibrils and four modified derivatives, each displaying a selected conformational epitope present on the surface of α-synuclein fibrils, to vaccinate TgM83+/- mice, a model for Parkinson's disease-like synucleinopathies. Fibrillar vaccine candidates significantly extended the survival of immunized TgM83+/- mice by ≤38% after intraperitoneal challenge and ≤42% after intragastric challenge with α-synuclein fibrils. Fully immunized mice developed antibodies that recognized α-synuclein fibrils and brain homogenates from patients with dementia with Lewy bodies, multiple system atrophy and Parkinson's disease. Fibrillar vaccine candidates that mimic conformational epitopes on the surface of pathological α-synuclein fibrils have the ability to induce immunity and protection against Parkinson's disease and other synucleinopathies.

BACKGROUND

People with Parkinson's (PwP) who lose independence may need care in nursing homes or similar institutions if home care is insufficient. Institutionalisation has major social and financial implications. Better understanding of which PwP are most likely to be institutionalised would improve information provision, clinical risk stratification, and healthcare planning.

OBJECTIVES

To identify risk factors for institutionalisation in PwP and develop models predicting individual institutionalisation risk.

METHODS

We described institutionalisation in the Parkinson's Incidence Cohorts Collaboration, comprising 6 European incidence cohorts. We identified prognostic factors by two-stage individual-participant-data meta-analysis. Prognostic models predicting risk of institutionalisation within 7 years and 10 years were developed using the Royston-Parmar model. Heterogeneity in model performance was assessed using internal-external cross validation (IECV).

RESULTS

In 1046 PwP, the cumulative incidence of institutionalisation by 10 years was 37.2%. The incidence rate ranged from 1.7 to 6.2 per 100 person-years. Older age, higher MDS-UPDRS part 3 and lower MMSE at baseline independently predicted higher institutionalisation risk. IECV showed good discrimination in the 10-year (C-statistics 0.73-0.81) and 7-year (0.71-0.84) models. However, calibration (agreement between predictions and observed outcomes) showed under- and over-prediction across studies. After updating model intercept and coefficients (recalibration), the calibration improved.

CONCLUSION

37% of PwP entered institutional care within ten years from diagnosis. Older age, higher MDS-UPDRS part 3 and lower MMSE predicted institutionalisation. The prognostic models discriminated well, but calibration varied between cohorts. We recommend further validation before applying the models in other settings.

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.

The basal ganglia and sensorimotor cortex are essential nodes of a network that supports motor control. In Parkinson's disease, disruptions in this network lead to rigidity and slowness during movement execution. Deep brain stimulation (DBS) of the basal ganglia has proved effective in alleviating Parkinson's disease-related hypokinetic symptoms, and sensing-enabled neurostimulators now afford the opportunity to detect cortico-basal oscillations during motion. However, the specific contributions of these motor network nodes to chronic, naturalistic movement and the effects of DBS on circuit dynamics are not well understood. To address these gaps, we recorded >530 h of cortical and subcortical signals from 15 Parkinson's disease patients (27 hemispheres) during unsupervised, unconstrained daily activities and subthalamic or pallidal DBS. Synchronized wrist-worn accelerometers tracked forearm speeds, supporting the evaluation of neural biomarkers related to motion. Our study validated and extended the known relationship between cortical and subcortical beta power (13-30 Hz) and movement. We showed that cortical low (13-20 Hz) and high (21-30 Hz) beta movement-related desynchronization effectively distinguished between mobile and stationary states. In the subthalamic nucleus and globus pallidus interna, high beta movement-related desynchronization and gamma (40-80 Hz) movement-related synchronization exhibited significant group-level correlations with movement kinematics. When stimulated at 130 Hz, cortical stimulation-entrained gamma oscillations at the half-harmonic (∼65 Hz) were observed. Furthermore, cortical entrained gamma movement-related synchronization was a stronger predictor of motion than broadband gamma movement-related synchronization. We developed machine learning models to predict naturalistic movement over extended periods using spectral features from brief neural recordings (0.5-8 s epochs). Cortical models outperformed subcortical models, although combining cortico-basal signals yielded the highest model performance (area under the curve > 0.85 for binary movement state classifiers; Pearson's r statistic > 0.68 for continuous forearm speed regressors). Higher DBS current amplitudes were associated with reduced beta movement-related desynchronization and low gamma (40-60 Hz) movement-related synchronization in the subthalamic nucleus and globus pallidus interna. This negatively impacted the accuracy of the subcortical models, whereas cortical and cortico-basal model performance remained stable across stimulation amplitudes. Our study demonstrates that cortico-basal nodes of the motor network encode complementary kinematic information, which can be integrated to enhance the accuracy and stability of chronic, naturalistic movement decoding during deep brain stimulation. These insights support the development and integration of therapeutic brain-computer interfaces with closed-loop, adaptive DBS to leverage rapid and precise movement-predictive models for the treatment of motor network disorders.

Parkinson's disease is a common multisystem movement disorder characterized by accumulation of neurotoxic Lewy body aggregates, neuronal loss and gliosis of vulnerable populations. The gene encoding α-synuclein (SNCA) is the greatest genetic risk factor for sporadic Parkinson's disease. Misfolding and overexpression of SNCA (α-Syn) underlie pathognomonic features of Parkinson's disease, including insoluble Lewy body aggregates and midbrain dopaminergic (mbDA) neurodegeneration. We recently identified an SNCA intronic sequence that harbours variation associated with Parkinson's disease risk and demonstrated its role as a neuronal cis-regulatory element (CRE). CRISPR-mediated engineering was used to establish a mouse model lacking this intronic CRE sequence (SncaEnh+37). Single molecule fluorescent in situ hybridization (smFISH) was used to assess changes on Snca transcription in mbDA neurons. Intrastriatal injection of α-Syn preformed fibrils was used to seed Parkinson's disease pathology (or PBS vehicle) in these mice. Cohorts of mice harbouring two, one or zero CRE deleted alleles of SncaEnh+37 were evaluated for motor deficits in standard assays (pole descent, rotarod, grip strength). Immunohistochemistry, unbiased stereology and western blotting were employed to evaluate the impact of neuronal integrity, Lewy body acquisition and glial activation in the substantia nigra. Mice deficient in SncaEnh+37 exhibit significantly reduced Snca transcription in mbDA neurons. In animals challenged with intrastriatal delivery of α-Syn preformed fibrils, SncaEnh+37 deficient animals are largely protected from motor deficits. Further, we demonstrate that mice lacking this Snca enhancer are protected against Parkinson's disease-relevant histopathology, including DA neurodegeneration, Lewy body acquisition and evidence of neuroinflammatory response. By targeting a cell-dependent Snca CRE, we directly reduced the onset, severity and progression of Parkinson's disease pathology in mice. The demonstration that cell-type-dependent modulation of key genes in disease progression can be leveraged to mitigate risk introduces a potentially powerful therapeutic avenue for Parkinson's disease.

배경 및 목적

파킨슨병(PD)은 진행성 신경퇴행성 질환으로, 보행 장애가 흔하고 일상생활에 지장을 주는 대표적인 임상 특징입니다. 저희는 아직 약물 치료를 시작하지 않은 초발 파킨슨병(de novo PD)에서, 선조체 도파민 운반체(DAT) 가용성과 회백질(GM) 부피가 정량적 보행 장애에 미치는 독립적 기여와, 매개를 통한 기여를 규명하고자 했습니다.

방법

이 전향적 연구에서는 영국 브레인뱅크 임상 기준을 충족하는 초발 파킨슨병 환자와, 국소 신경학적 증상 및 파킨슨증이 없는 건강한 대조군(HC)을 원주세브란스기독병원에서 연속적으로 모집했습니다. 모든 참여자는 GAITRite 기반 보행 분석을 받았고, 환자군은 추가로 회백질 부피 측정을 위한 뇌 MRI, 선조체 DAT 가용성 측정을 위한 18F-FP-CIT PET, 그리고 운동·인지 평가를 받았습니다. 탐색적 보행 관련 상관분석 이후, 신경영상 생체지표가 보행 지표에 미치는 영향이 인지 기능이나 운동 증상 중증도에 의해 매개되는지를 인과매개분석(causal mediation analysis)으로 검증했습니다.

결과

초발 파킨슨병 환자 총 122명(평균 연령 69.66세, 여성 45.90%)과 건강한 대조군 177명(평균 연령 72.07세, 여성 51.41%)이 등록되었습니다. 대조군과 비교했을 때 파킨슨병 환자군은 보행 속도가 더 느렸고, 걸음 폭(step length)·활보장(stride length)이 더 짧았으며, 흔듦기(swing time)와 단일지지 시간(single-support time)이 감소하고, 양측지지 시간(double-support time)이 증가했으며, 여러 보행 영역에서 편차(변동성)도 더 컸습니다. 둘레계(limbic) 관련 회백질 부피는 걸음 폭·활보장 및 시간적 위상 구성과 관련이 있었고, 이 관련성은 전반적 인지 기능에 의해 상당 부분 매개되었습니다. 활보장에 대한 대표적 평균 인과매개효과(ACME, 95% 신뢰구간)는 다음과 같았습니다: 후측대상피질(posterior cingulate cortex) 1.9559(0.5606–4.2238), 해마(hippocampus) 3.6722(1.0707–8.2118), 시상(thalamus) 2.8794(0.0408–7.2535), 편도체(amygdala) 4.9696(1.8241–10.3405) — 매개 비율은 19%~50%였습니다. 조가비핵(putamen)의 DAT 가용성이 낮을수록 기립 시간(stance time)과 양측지지 시간의 변동성이 더 컸고, 반면 꼬리핵(caudate)의 DAT 가용성이 낮을수록 흔듦기와 단일지지 시간이 더 길어지고 위상 지표가 변화했습니다. 이러한 관련성은 서동증·경직 점수에 의해 유의하게 매개되지 않았으며, 직접효과(ADE, 95% 신뢰구간)가 유의하게 유지되었습니다: 꼬리핵–흔듦기 시간 −0.0237(−0.0428 ~ −0.0086), 조가비핵–양측지지 시간 변동성 −2.0249(−3.1445 ~ −0.8835).

논의

이 결과는 초발 파킨슨병 환자의 보행 조절에 "이중 경로" 모델이 작동함을 뒷받침합니다 — 선조체 도파민 신경의 손상은 보행 리듬에 직접 영향을 미치고, 둘레계의 위축은 직접적 경로와 인지 기능을 통한 매개 경로 양쪽으로 보행에 영향을 미칩니다. 다만 이번 연구는 약물 치료를 받지 않은 환자군만을 대상으로 했기 때문에, 전체 파킨슨병 환자군으로 일반화하는 데는 제한이 있을 수 있습니다.

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

The relationship between menopausal hormone therapy (HT) and Parkinson's disease (PD) risk remains controversial, with inconsistent findings potentially driven by differences in hormonal formulations.

METHODS

We conducted a systematic review and meta-analysis following PRISMA 2020 guidelines. MEDLINE/PubMed and EMBASE were searched between January 8 and March 14, 2026. Observational studies evaluating the association between menopausal HT and PD risk were included. Effect estimates were pooled using random-effects models. Subgroup analyses were performed according to HT formulation (estrogen-only vs. combined estrogen-progestin therapy). A multilevel meta-analysis was conducted to account for within-study dependence.

RESULTS

Fourteen studies including 753,749 participants (4,433 PD cases) were analyzed. Overall, HT was not significantly associated with PD risk (RR 1.08; 95% CI 0.94-1.23; I² = 49.4%). In subgroup analyses, combined therapy was associated with an increased PD risk (RR 1.40; 95% CI 1.07-1.82), whereas estrogen-only therapy showed no significant association (RR 1.01; 95% CI 0.81-1.27). Multilevel analysis yielded consistent results (combined: RR 1.33; 95% CI 1.00-1.77; estrogen-only: RR 1.03; 95% CI 0.83-1.27), with no statistically significant interaction between formulations (p = 0.12).

CONCLUSIONS

Combined menopausal HT was associated with an increased risk of PD, while estrogen-only therapy showed no significant association. Although differences between formulations were not statistically significant, these findings suggest that hormone composition may influence neurological outcomes and warrant further investigation into individualized HT strategies.

INTRODUCTION

Creativity in Parkinson's disease (PD) has aroused research interest due to its neurological underpinnings, which involve brain regions crucial for creative and divergent thinking (a core-process of creative thinking), and because of some patients who displayed an increased artistic drive following dopaminergic treatment. From a cognitive point of view, creative thinking underlies several cognitive abilities, such as executive functions and memory. Therefore, a better understanding of whether it is increased (or, at least, preserved) in PD patients can provide useful insights for sustaining cognitive functioning. The aim of the present study was to investigate whether PD patients regularly assuming dopaminergic medications present higher divergent thinking skills than healthy controls.

METHODS

A meta-analysis was conducted according to the PRISMA guidelines to provide a statistical synthesis of the studies. Study quality was assessed using the QUADAS -2 tool.

RESULTS

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

CONCLUSIONS

Such findings support the notion that divergent thinking can be spared by the disease, maybe constituting a possible resource for patients' cognitive functioning, as it involves those cognitive abilities that can compensate impairments in PD. Clinical implications and guidance to further studies and interventions to support PD patients' cognition were discussed.

Parkinson's disease (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.

The basal ganglia and sensorimotor cortex are essential nodes of a network that supports motor control. In Parkinson's disease, disruptions in this network lead to rigidity and slowness during movement execution. Deep brain stimulation (DBS) of the basal ganglia has proved effective in alleviating Parkinson's disease-related hypokinetic symptoms, and sensing-enabled neurostimulators now afford the opportunity to detect cortico-basal oscillations during motion. However, the specific contributions of these motor network nodes to chronic, naturalistic movement and the effects of DBS on circuit dynamics are not well understood. To address these gaps, we recorded >530 h of cortical and subcortical signals from 15 Parkinson's disease patients (27 hemispheres) during unsupervised, unconstrained daily activities and subthalamic or pallidal DBS. Synchronized wrist-worn accelerometers tracked forearm speeds, supporting the evaluation of neural biomarkers related to motion. Our study validated and extended the known relationship between cortical and subcortical beta power (13-30 Hz) and movement. We showed that cortical low (13-20 Hz) and high (21-30 Hz) beta movement-related desynchronization effectively distinguished between mobile and stationary states. In the subthalamic nucleus and globus pallidus interna, high beta movement-related desynchronization and gamma (40-80 Hz) movement-related synchronization exhibited significant group-level correlations with movement kinematics. When stimulated at 130 Hz, cortical stimulation-entrained gamma oscillations at the half-harmonic (∼65 Hz) were observed. Furthermore, cortical entrained gamma movement-related synchronization was a stronger predictor of motion than broadband gamma movement-related synchronization. We developed machine learning models to predict naturalistic movement over extended periods using spectral features from brief neural recordings (0.5-8 s epochs). Cortical models outperformed subcortical models, although combining cortico-basal signals yielded the highest model performance (area under the curve > 0.85 for binary movement state classifiers; Pearson's r statistic > 0.68 for continuous forearm speed regressors). Higher DBS current amplitudes were associated with reduced beta movement-related desynchronization and low gamma (40-60 Hz) movement-related synchronization in the subthalamic nucleus and globus pallidus interna. This negatively impacted the accuracy of the subcortical models, whereas cortical and cortico-basal model performance remained stable across stimulation amplitudes. Our study demonstrates that cortico-basal nodes of the motor network encode complementary kinematic information, which can be integrated to enhance the accuracy and stability of chronic, naturalistic movement decoding during deep brain stimulation. These insights support the development and integration of therapeutic brain-computer interfaces with closed-loop, adaptive DBS to leverage rapid and precise movement-predictive models for the treatment of motor network disorders.

Parkinson's disease is a common multisystem movement disorder characterized by accumulation of neurotoxic Lewy body aggregates, neuronal loss and gliosis of vulnerable populations. The gene encoding α-synuclein (SNCA) is the greatest genetic risk factor for sporadic Parkinson's disease. Misfolding and overexpression of SNCA (α-Syn) underlie pathognomonic features of Parkinson's disease, including insoluble Lewy body aggregates and midbrain dopaminergic (mbDA) neurodegeneration. We recently identified an SNCA intronic sequence that harbours variation associated with Parkinson's disease risk and demonstrated its role as a neuronal cis-regulatory element (CRE). CRISPR-mediated engineering was used to establish a mouse model lacking this intronic CRE sequence (SncaEnh+37). Single molecule fluorescent in situ hybridization (smFISH) was used to assess changes on Snca transcription in mbDA neurons. Intrastriatal injection of α-Syn preformed fibrils was used to seed Parkinson's disease pathology (or PBS vehicle) in these mice. Cohorts of mice harbouring two, one or zero CRE deleted alleles of SncaEnh+37 were evaluated for motor deficits in standard assays (pole descent, rotarod, grip strength). Immunohistochemistry, unbiased stereology and western blotting were employed to evaluate the impact of neuronal integrity, Lewy body acquisition and glial activation in the substantia nigra. Mice deficient in SncaEnh+37 exhibit significantly reduced Snca transcription in mbDA neurons. In animals challenged with intrastriatal delivery of α-Syn preformed fibrils, SncaEnh+37 deficient animals are largely protected from motor deficits. Further, we demonstrate that mice lacking this Snca enhancer are protected against Parkinson's disease-relevant histopathology, including DA neurodegeneration, Lewy body acquisition and evidence of neuroinflammatory response. By targeting a cell-dependent Snca CRE, we directly reduced the onset, severity and progression of Parkinson's disease pathology in mice. The demonstration that cell-type-dependent modulation of key genes in disease progression can be leveraged to mitigate risk introduces a potentially powerful therapeutic avenue for Parkinson's disease.

BACKGROUND

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.

Sex differences, in terms of prevalence, symptoms and disease progression, are established in the aetiology of complex neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease, but the underlying biology driving these differences remains poorly understood. There is emerging evidence from genetic and functional analyses affirming the role of the immune system in such diseases, but a thorough assessment of sex differences in the link between the immune system and neurodegenerative diseases remains lacking. Here, we applied a robust causal inference approach, two-sample Mendelian randomization, to evaluate the causal effect of immune-related protein levels on three neurodegenerative diseases with large-scale sex-stratified genome-wide association data available: amyotrophic lateral sclerosis (females = 10 895 cases, 57 062 controls; males = 15 547 cases, 50 145 controls); Parkinson's disease (females = 7947 cases, 90 662 controls; males = 13 020 cases, 89 660 controls); and Alzheimer's disease (females = 18 822 cases, 281 415 controls; males = 17 293 cases, 213 339 controls). As exposures, we focused on 932 immune system-related proteins with significant protein cis-quantitative trait loci (false discovery rate cut-off < 0.01) from a large sex-combined plasma protein dataset (n = 33 477), for which corresponding genes were included in the Immunology Database and Analysis Portal gene list. We tested for a causal relationship between genetically predicted levels of each of these proteins and each neurodegenerative disease in sex-stratified and sex-combined data, followed by colocalization and estimation of sex-differential effects. We additionally performed exploratory analyses using sex-combined CSF protein cis-quantitative trait loci (n = 971) as exposures. We observed evidence for a sex-differential causal relationship between FCGR2A and Parkinson's disease and between CD2AP, MAMDC2, PCDH17 or CSF3 and Alzheimer's disease. We validated significant results using two independent protein cis-quantitative trait loci datasets for those plasma proteins available. After performing sensitivity analyses, we validated the potential causal relationships of OMG on Parkinson's disease and of GRN, SERPINF2 and TREM2 on Alzheimer's disease. Mendelian randomization with CSF protein cis-quantitative trait loci showed a potential causal effect of ADGRE2, GPNMB and COLEC11 on Parkinson's disease and of CD33 on Alzheimer's disease, without evidence of sex-differential effects. Finally, we substantiated our findings of protein-disease pairs using triangulation, specifically reporting independent supporting evidence from the literature and drug-related databases. Overall, our results point to potential causal effects of genetically predicted levels of immune system-related plasma and CSF proteins in Alzheimer's disease and Parkinson's disease, some of which may be considered as potential candidates for drug development.

BACKGROUND

Current dopaminergic therapies for Parkinson's disease carry significant limitations: levodopa can cause long-term motor complications, while D2/D3 receptor-targeting dopamine agonists can produce non-motor adverse effects. Tavapadon is an oral, once-daily, selective D1/D5 agonist that might improve Parkinson's disease motor symptoms. We aimed to evaluate the safety, tolerability and efficacy of flexible-dose tavapadon in people with early-stage Parkinson's disease.

METHODS

TEMPO-2 was a phase 3, randomised, double-blind, placebo-controlled trial conducted at 75 clinical sites (both hospital or academic and community settings) across 13 countries. Adults aged 40-80 years with early-stage Parkinson's disease (<3 years' disease duration) who were treatment-naive or had less than 3 months of previous dopaminergic treatment were eligible. Participants were randomly assigned 1:1 to flexible-dose tavapadon (5-15 mg) or placebo orally once daily for 27 weeks. The primary endpoint was change from baseline to week 26 in the combined score of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts II and III (reflecting activities of daily living and motor performance). Safety endpoints included adverse events, clinical laboratory values, vital signs, and electrocardiograms. The primary endpoint was assessed in the modified intent-to-treat population (participants who received one dose or more of study drug and had both a baseline and one or more post-baseline MDS-UPDRS assessments) and safety was assessed in the safety analysis set (all participants who received one dose or more of tavapadon or placebo). This study is registered with ClinicalTrials.gov (NCT04223193) and is now complete.

FINDINGS

Between Jan 6, 2020, and Feb 22, 2024, 473 individuals were screened and 304 were randomly assigned to receive tavapadon 5-15 mg (n=151) or placebo (n=153). The majority of participants were male (169 [56%] of 304 male; 135 [44%] of 304 female), the mean age was 62·9 (SD 9·2) years, and the mean disease duration was 0·86 (0·79) years. 80 (26%) of 304 participants discontinued from the trial (57 [38%] of 151 on tavapadon and 23 [15%] of 153 on placebo), most commonly due to adverse events (42 [14%] of 304; 36 [24%] of 151 on tavapadon and six [4%] of 153 on placebo). The primary endpoint of change from baseline to week 26 in the MDS-UPDRS Parts II and III combined score was significantly improved with tavapadon versus placebo (least squares mean [LSM] decrease of 10·3 [95% CI -12·2 to -8·3] points vs 1·2 [-2·9 to 0·6] points; LSM treatment difference -9·1 [95% CI -11·7 to -6·5]; p10% of participants) were nausea (45 [30%] of 151] vs five [3%] of 153), headache (25 [17%] vs eight [5%]), and dizziness (24 [16%] vs five [3%]).

INTERPRETATION

Tavapadon showed significant and clinically meaningful improvements in Parkinson's disease motor symptoms, with low incidence of somnolence and impulse control disorders. However, the short observation period limits conclusions about long-term tolerability. An ongoing extension study aims to confirm its long-term safety and efficacy.

FUNDING

AbbVie.

BACKGROUND

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

Type 2 diabetes and Parkinson's disease (PD) share underlying pathways, including insulin resistance and neuroinflammation. While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) show neuroprotective promise in preclinical models, clinical trials have produced conflicting results. This meta-analysis systematically evaluates the efficacy and safety of GLP-1 RAs in PD, specifically distinguishing between symptomatic relief and potential disease modification.

METHODS

We searched PubMed, Scopus, Web of Science, Cochrane Library, and Embase through November 2025 for randomized, double-blind, placebo-controlled trials of GLP-1 RAs in idiopathic PD. The primary motor outcome, the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III (motor examination), was analyzed using a random-effects model and strictly stratified by "ON" versus "OFF" medication states.

RESULTS

We included four high-quality trials comprising 667 patients. GLP-1 RAs failed to significantly improve motor function in either the OFF-medication state (mean difference [MD] - 0.69; 95% confidence interval [CI] - 2.81 to 1.43; p = 0.52) or ON-medication state (MD - 0.86; 95% CI - 3.35 to 1.63; p = 0.50). Furthermore, no meaningful benefits emerged for non-motor symptoms, cognition, or quality of life. Conversely, treatment significantly increased gastrointestinal adverse events, including nausea (risk ratio [RR] = 2.48), vomiting (RR = 4.53), and clinically concerning weight loss (RR = 3.32).

CONCLUSIONS

Synthesizing the latest phase 3 data, current GLP-1 RAs offer neither disease-modifying nor symptomatic motor benefits for the broader PD population. Given the pronounced risk of weight loss, their routine use is unwarranted. Future trials must shift focus toward biologically enriched subgroups or newer-generation incretin analogs.

BACKGROUND

Previous investigations into neurodegenerative diseases demonstrated the utility of cortical diffusivity metrics in assessing microstructural changes.

OBJECTIVE

The objective of this study was to explore cortical diffusivity metrics in genetic Parkinson's disease (PD) with glucocerebrosidase 1 (GBA1) and Leucine-rich repeat kinase 2 (LRRK2) mutations, encompassing both nonmanifest carriers (NMCs) and manifest PD, and healthy control subjects (HCs).

METHODS

T1-structural and diffusion magnetic resonance imaging (MRI) scans were analyzed to calculate diffusion metrics related to cortical columnar structure (angle between the radial minicolumnar axis and the principal diffusion direction [AngleR], parallel diffusivity [ParlPD], perpendicular diffusivity of multiple components [PerpPD+]) and cortical mean diffusivity for 143 participants (60 HCs, 19 NMC GBA1, 30 NMC LRRK2, 11 PD GBA1, and 23 PD LRRK2) from the Parkinson's Progression Markers Initiative (PPMI). The first available time point including both T1-weighted and diffusion MRI acquisitions was used for each participant. Whole-brain, regional, and functional hierarchy macroregional values were used to investigate group differences. Results are reported after multiple comparison correction.

RESULTS

Grouped together, results indicated significantly lower ParlPD values in manifest PD compared with the NMC group in whole-brain analysis. Regional analyses showed a progressive reduction in cortical ParlPD across the genetic groups, primarily in mesocortex (Braak stage 4) for NMC cases, extending to neocortex (Braak stage 5) for manifest genetic PD. Subgroup analyses demonstrated a more pronounced pattern of cortical alterations in subjects with GBA1 mutations compared with patients with LRRK2 mutations.

CONCLUSIONS

Cortical diffusivity metrics effectively capture cortical architectural changes across clinical stages of genetic PD, supporting their use as microstructural markers of neurodegeneration in PD. © 2026 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.

OBJECTIVE

This systematic review and meta-analysis evaluates the efficacy of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) in improving gastric motility in patients with Parkinson's disease (PD).

MATERIALS AND METHODS

A systematic search was conducted in Scopus, Web of Science, PubMed, and Cochrane CENTRAL until December 15, 2024. Observational studies and clinical trials evaluating DBS effects on gastric motility and gastric emptying in patients with PD were included. Primary outcomes were changes in the gastrointestinal (GI) domain of the Non-Motor Symptoms Scale (NMSS) and 13CO2 excretion time (Tmax). Meta-analysis was performed using Review Manager 5.4, using a random-effects model when necessary.

RESULTS

Eight studies (N = 379) were included. Meta-analysis showed a significant reduction in NMSS-GI domain scores after DBS (MD: -1.29, 95% CI: [-2.16, -0.42], p = 0.004). Subgroup analysis revealed sustained improvements at six months (MD: -1.46, 95% CI: [-2.34, -0.57], p = 0.001) and 12 months (mean difference [MD]: -1.12, 95% CI: [-2.23, -0.01], p = 0.05). For gastric emptying (Tmax13CO2), no significant difference was found between patients on medication before DBS (with medication [WM]) and those off medication before DBS (without medication [WOM]) (MD: 2.58, 95% CI: [-3.94, 9.10], p = 0.44). However, a significant reduction in Tmax13CO2 was observed in DBS-ON-WOM vs DBS-OFF-WOM (MD: -11.71, 95% CI: [-17.41, -6.02], p < 0.0001) and DBS-ON-WOM vs WM before DBS (MD: -15.46, 95% CI: [-20.89, -10.03], p < 0.00001).

CONCLUSIONS

Meta-analysis suggests that STN-DBS significantly relieves GI symptoms and improves gastric motility in patients with PD, with sustained benefits over 12 months. Future studies should assess long-term effects and optimize stimulation parameters for autonomic dysfunction.

BACKGROUND

Leucine-rich repeat kinase 2 (LRRK2) kinase inhibition is a promising therapeutic strategy for Parkinson's disease (PD), but the functional impact of Asian-prevalent LRRK2 p.G2385R and p.R1628P variants remains unclear. Robust patient stratification and target engagement markers are needed for global LRRK2-targeted trials.

OBJECTIVE

The aim of this study was to characterize ex vivo LRRK2 activation status and its clinical correlates in patients with PD carrying LRRK2 p.G2385R and/or p.R1628P variants and in patients with idiopathic PD (iPD).

METHODS

We recruited 242 participants: patients with PD carrying LRRK2 p.G2385R (PD-G2385R; n = 57), p.R1628P (PD-R1628P; n = 61), or both (n = 5); patients with iPD (n = 61); and healthy control subjects (HCs; n = 58). Monocyte LRRK2 activity markers (pRab10Thr73 and pLRRK2Ser935) were analyzed using multiplexed quantitative immunoblotting. Clinical severity was assessed using the International Parkinson and Movement Disorder Society-Unified Parkinson's Disease Rating Scale, Clinical Impression of Severity Index for PD, and Montreal Cognitive Assessment.

RESULTS

Compared with HCs, pRab10Thr73 was elevated (indicative of LRRK2 kinase hyperactivation) in PD-G2385R (~1.2-fold, P = 0.011) and in double-variant carriers (~2.8-fold, P = 0.008), but not in PD-R1628P or iPD. Inversely correlated with pRab10Thr73 (rs = -0.611, P Ser935 was reduced (indicative of a more active LRRK2 conformation) in all PD subgroups (lowest in double-variant carriers). All double-variant carriers, the majority of single-variant carriers, and one-third of participants with iPD had pRab10Thr73 greater than the control median. Higher pRab10Thr73 correlated with better cognition.

CONCLUSIONS

LRRK2 kinase activity is enhanced in patients with PD carrying LRRK2 p.G2385R, with further elevation observed in a small group of double-variant carriers. Elevated kinase activity in a subset of iPD underscores the relevance of LRRK2 signaling and therapeutics beyond coding variants. The observed interindividual variability indicates additional genetic or environmental modifiers and highlights the need for biochemical stratification beyond genotyping in future LRRK2 trials. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Parkinson's disease (PD) and multiple system atrophy are defined by α-synuclein (αSYN)-positive inclusions - Lewy bodies (LBs) and glial cytoplasmic inclusions - yet mounting evidence indicates that these inclusions represent only a fraction of disease-relevant pathology. αSYN exists in dynamic conformational states, and soluble oligomeric assemblies, often undetectable by conventional immunohistochemistry, are increasingly implicated as key neurotoxic species. The αSYN proximity ligation assay (αSYN-PLA) enables in situ detection of widespread non-inclusion oligomeric pathology across synucleinopathies. Notably, PLA studies in LRRK2-associated PD demonstrate abundant oligomeric αSYN even in cases lacking LBs, challenging the centrality of inclusions in defining disease. In this Perspective, we outline the principles of αSYN-PLA, discuss antibody strategies and structural implications of detected species, review current evidence - including LB-negative LRRK2-PD - and consider temporal dynamics and clinical applications of PLA-positive aggregates as biomarkers and therapeutic targets. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Deep brain stimulation (DBS) of the subthalamic nucleus improves motor symptoms in patients with Parkinson's disease. Using functional MRI, optimal DBS response networks have been characterized. However, neural activity associated with Parkinsonian symptoms is magnitudes faster than what can be resolved by this method. Although both spatial and temporal domains of these networks appear crucial, no single study has yet investigated both domains simultaneously. Here, we aimed at closing this gap by analysing electrophysiological data from a total of n = 127 hemispheres. Using subthalamic local field potentials that were recorded concurrently alongside whole-brain magnetoencephalography in a multi-centre cohort of patients who underwent subthalamic DBS for the treatment of Parkinson's disease (n = 100 hemispheres), we analysed the DBS response network in both spatial and temporal domains. In every cortical vertex, cortico-subthalamic coupling was correlated with stimulation outcomes. This network spatially resembled functional MRI-based findings (R = 0.40, P = 0.039) and explained significant amounts of variance in clinical outcomes (βstd = 0.30, P = 0.002), whereas theta-alpha and low beta coupling did not show significant associations with DBS response (theta-alpha: βstd = -0.02, P = 0.805; low beta: βstd = -0.08, P = 0.426). The 'optimal' high beta coupling map was robust when subjected to various cross-validation designs (10-fold cross-validation: R = 0.29, P = 0.009; split-half design: R = 0.31, P = 0.026) and was able to predict outcomes across DBS centres [R = 0.74; P(1) = 8.9 × 10-5]. We identified a DBS response network that resembles the previously defined MRI network and operates in the high beta band. Maximal connectivity to this network was associated with optimal DBS outcomes and was able to cross-predict clinical improvements across DBS surgeons and centres.

BACKGROUND

Parkinson's disease (PD) is a common neurodegenerative disease that is a growing public health challenge. Recent evidence showed that gut microbiota dysbiosis is involved in the pathogenesis of PD, prompting interest in fecal microbiota transplantation (FMT) as a potential disease-modifying intervention. This systematic review and meta-analysis aim to evaluate the efficacy and safety of FMT in patients with PD.

METHODS

We conducted a systematic literature review using PubMed, Scopus, Web of Science, and the Cochrane Library till June 4, 2026, to identify RCTs comparing FMT with placebo or control interventions in PD. After removal of duplicates alongside title and abstract screening, followed by full-text screening, seven randomized controlled trials were included in this systematic review and meta-analysis.

RESULTS

A total of seven randomized controlled trials (RCTs) with 318 subjects were analyzed. FMT was delivered via oral capsules, nasojejunal tubes, or colonoscopy, with follow-up periods ranging from 12 to 52 weeks. The meta-analysis indicated a notable short-term enhancement in daily motor activities, as assessed by MDSUPDRS Part II, after one month (mean difference - 2.19, 95% confidence interval - 4.32 to -0.06; P = 0.044). Nevertheless, no significant estimates were noted for MDS-UPDRS Part III, aggregate MDS-UPDRS scores, motor complications, non-motor symptoms, or overall life quality at any assessed time frame. Some individual studies reported gains in cognitive ability, anxious feelings, quality of life related to constipation, and certain PDQ-39 categories, although these improvements were not uniformly observed. Overall, FMT was well tolerated by participants, with adverse reactions mostly comprising mild, self-resolving gastrointestinal issues and no major safety risks.

CONCLUSIONS

FMT is a safe treatment for individuals with PD and may offer modest short-term advantages in performing daily motor tasks. However, current evidence does not indicate lasting enhancements in overall motor capabilities, non-motor symptoms, or life quality. More extensive and sufficiently powered trials utilizing standardized FMT procedures and longer observation periods are necessary to elucidate the therapeutic benefits of FMT in Parkinson's disease.

BACKGROUND

Current dopaminergic therapies for Parkinson's disease carry significant limitations: levodopa can cause long-term motor complications, while D2/D3 receptor-targeting dopamine agonists can produce non-motor adverse effects. Tavapadon is an oral, once-daily, selective D1/D5 agonist that might improve Parkinson's disease motor symptoms. We aimed to evaluate the safety, tolerability and efficacy of flexible-dose tavapadon in people with early-stage Parkinson's disease.

METHODS

TEMPO-2 was a phase 3, randomised, double-blind, placebo-controlled trial conducted at 75 clinical sites (both hospital or academic and community settings) across 13 countries. Adults aged 40-80 years with early-stage Parkinson's disease (<3 years' disease duration) who were treatment-naive or had less than 3 months of previous dopaminergic treatment were eligible. Participants were randomly assigned 1:1 to flexible-dose tavapadon (5-15 mg) or placebo orally once daily for 27 weeks. The primary endpoint was change from baseline to week 26 in the combined score of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts II and III (reflecting activities of daily living and motor performance). Safety endpoints included adverse events, clinical laboratory values, vital signs, and electrocardiograms. The primary endpoint was assessed in the modified intent-to-treat population (participants who received one dose or more of study drug and had both a baseline and one or more post-baseline MDS-UPDRS assessments) and safety was assessed in the safety analysis set (all participants who received one dose or more of tavapadon or placebo). This study is registered with ClinicalTrials.gov (NCT04223193) and is now complete.

FINDINGS

Between Jan 6, 2020, and Feb 22, 2024, 473 individuals were screened and 304 were randomly assigned to receive tavapadon 5-15 mg (n=151) or placebo (n=153). The majority of participants were male (169 [56%] of 304 male; 135 [44%] of 304 female), the mean age was 62·9 (SD 9·2) years, and the mean disease duration was 0·86 (0·79) years. 80 (26%) of 304 participants discontinued from the trial (57 [38%] of 151 on tavapadon and 23 [15%] of 153 on placebo), most commonly due to adverse events (42 [14%] of 304; 36 [24%] of 151 on tavapadon and six [4%] of 153 on placebo). The primary endpoint of change from baseline to week 26 in the MDS-UPDRS Parts II and III combined score was significantly improved with tavapadon versus placebo (least squares mean [LSM] decrease of 10·3 [95% CI -12·2 to -8·3] points vs 1·2 [-2·9 to 0·6] points; LSM treatment difference -9·1 [95% CI -11·7 to -6·5]; p10% of participants) were nausea (45 [30%] of 151] vs five [3%] of 153), headache (25 [17%] vs eight [5%]), and dizziness (24 [16%] vs five [3%]).

INTERPRETATION

Tavapadon showed significant and clinically meaningful improvements in Parkinson's disease motor symptoms, with low incidence of somnolence and impulse control disorders. However, the short observation period limits conclusions about long-term tolerability. An ongoing extension study aims to confirm its long-term safety and efficacy.

FUNDING

AbbVie.

The progressive age-related aggregation of soluble α-synuclein into toxic oligomers and insoluble amyloid fibrils causes Parkinson's disease, Lewy body dementia and multiple system atrophy, all of which are neurodegenerative diseases without a cure. Because α-synuclein is a self-antigen, pathogenic α-synuclein aggregates do not elicit a strong immune response. Recent advances in structural biology elucidating the structure of α-synuclein fibrils have allowed us to design engineered protein fibrils that model conformational epitopes present on the surface of α-synuclein fibrils. HET-s is a soluble fungal protein capable of forming amyloid fibrils. We used HET-s(218-298) fibrils and four modified derivatives, each displaying a selected conformational epitope present on the surface of α-synuclein fibrils, to vaccinate TgM83+/- mice, a model for Parkinson's disease-like synucleinopathies. Fibrillar vaccine candidates significantly extended the survival of immunized TgM83+/- mice by ≤38% after intraperitoneal challenge and ≤42% after intragastric challenge with α-synuclein fibrils. Fully immunized mice developed antibodies that recognized α-synuclein fibrils and brain homogenates from patients with dementia with Lewy bodies, multiple system atrophy and Parkinson's disease. Fibrillar vaccine candidates that mimic conformational epitopes on the surface of pathological α-synuclein fibrils have the ability to induce immunity and protection against Parkinson's disease and other synucleinopathies.

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).

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.

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.

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.

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.

Elucidating the genetic contributions to Parkinson's disease aetiology across diverse ancestries is a critical priority for the development of targeted therapies in a global context. We conducted the largest sequencing characterization of potentially disease-causing, protein-altering and splicing mutations in 710 cases and 11 827 controls from genetically predicted African or African admixed ancestries. We explored copy number variants (CNVs) and runs of homozygosity in prioritized early onset and familial cases. Our study identified rare GBA1 coding variants to be the most frequent mutations among patients with Parkinson's disease, with a frequency of 4% in our case cohort. Of the 18 GBA1 variants identified, 10 were previously classified as pathogenic or likely pathogenic, four were novel and four were reported as of uncertain clinical significance. The most common known disease-associated GBA1 variants in the Ashkenazi Jewish and European populations, p.Asn409Ser, p.Leu483Pro, p.Thr408Met and p.Glu365Lys, were not identified among the screened Parkinson's disease cases of African and African admixed ancestry. Similarly, the European and Asian LRRK2 disease-causing mutational spectrum, including LRRK2 p.Gly2019Ser and p.Gly2385Arg genetic risk factors, did not appear to play a major role in Parkinson's disease aetiology among West African ancestry populations. However, we found three heterozygous novel missense LRRK2 variants of uncertain significance, with two (p.Glu268Ala and p.Arg1538Cys) displaying higher frequencies in the African ancestry population reference datasets. Structural variant analyses revealed the presence of PRKN CNVs with a frequency of 0.7% in African and African admixed cases, with 66% of CNVs detected being compound heterozygous or homozygous in early-onset cases, providing further insights into the genetic underpinnings in early-onset juvenile Parkinson's disease in these populations. Short tandem repeat analysis also identified ATXN3 CAG repeat expansions within the pathogenic range (CAGn > 45) in three patients with Parkinson's disease of African ancestry. Novel genetic variation among screened genes warrants further replication and functional prioritization to unravel their pathogenic potential. Here, we created the most comprehensive genetic catalogue of both known and novel coding and splicing variants potentially linked to Parkinson's disease aetiology in an underserved population and further conducted global and local ancestry analyses to further explore population-specific effects. Our study has the potential to guide the development of targeted therapies in the emerging era of precision medicine. By expanding genetics research to involve underrepresented populations, we hope that future Parkinson's disease treatments are not only effective but also inclusive, addressing the needs of diverse ancestral groups.

Pathogenic GAA repeat expansions in FGF14 are an established cause of late-onset cerebellar ataxia, but have not been linked to Parkinson's disease. Given emerging evidence that repeat expansions in ataxia-associated genes like RFC1 can contribute to atypical or familial forms of Parkinson's disease, we investigated whether FGF14 expansions might play a similar role. Using long-read whole-genome sequencing, we analysed 411 individuals with Parkinson's disease and 197 neurologically healthy controls from the Parkinson's Progression Markers Initiative (PPMI) cohort, together with 1429 additional controls from the National Institutes of Health (NIH) Center for Alzheimer's Disease and Related Dementias (CARD) initiative, the 1000 Genomes Project, and the All of Us program, representing globally diverse populations. We identified pathogenic FGF14 GAA repeat expansions in five individuals with Parkinson's disease and one control subject. All five individuals fit the clinical criteria of Parkinson's disease and showed typical patterns of neurodegeneration on DaTSCAN imaging; α-synuclein aggregation was confirmed by a positive seeding assay among four individuals with available data. These findings broaden the phenotypic spectrum of FGF14 repeat-associated disease and suggest a rare, previously unrecognized genetic contributor to Parkinson's disease. To our knowledge, this is the first report implicating FGF14 in Parkinson's disease and underscores the utility of long-read sequencing for detecting hidden forms of pathogenic variation in unresolved cases.

BACKGROUND

The 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.

Parkinson's disease (PD) risk and progression are influenced by a complex interplay of genetic, environmental, and internal factors. Environmental exposures have been understudied, primarily because of the associated complexity and inherent measurement challenges. The exposome framework, encompassing lifetime environmental exposures and biological responses, offers a way to better characterize these influences. The exposome embraces the "biography-to-biology" transition, encompassing general and specific external and internal exposures accumulating over the lifespan, and interacting with genetic factors. In other fields, machine learning has been applied to develop polyexposure scores to quantify cumulative environmental risks, although challenges remain in exposure measurement, latency, and disease heterogeneity. Advancing PD research requires refined exposome definitions, systematic data integration, validation, and collaboration to improve prediction, prevention, and personalized therapies. © 2026 International Parkinson and Movement Disorder Society.

BACKGROUND

Recessive genetic variation and extended runs of homozygosity (ROHs) may contribute to the unexplained heritability of Parkinson's disease (PD), particularly in diverse and understudied populations.

OBJECTIVE

We conducted the first large-scale, multi-ancestral investigation of PD to examine the impact of genome-wide homozygosity on disease risk and age at onset (AAO). Using genotyping, imputed, and whole-genome sequencing data from 36,127 PD cases and 19,475 controls across nine ancestral populations from the Global Parkinson's Genetics Program, we aimed to identify novel regions of homozygosity contributing to PD heritability.

METHODS

We analyzed ROHs for total length (SROH), number (NROH), average length (AVROH), and genomic inbreeding coefficient (FROH). ROHs were intersected with known PD, pallido-pyramidal syndrome, and atypical parkinsonism gene regions and risk loci to assess pleomorphic or pleiotropic contributions. Homozygosity mapping identified ROH overlaps in families, consanguineous individuals, and early-onset PD (EOPD) cases.

RESULTS

Significant differences in SROH, AVROH, NROH, and FROH were observed between case status across ancestries, persisting after excluding known PD-associated recessive genes. Our analysis revealed distinct patterns of ROH enrichment associated with AAO, suggesting recessive genetic modifiers of PD. Homozygosity mapping was used to prioritize 52 variants either segregating in families or present in individuals with consanguinity. In total, 1,559 ROHs in consanguineous individuals and EOPD overlapped known PD gene regions and risk loci.

CONCLUSIONS

ROH regions contribute to PD heritability across ancestries, partly reflecting recessive genetic architecture. Larger and more diverse whole-genome sequencing studies are needed to identify rare recessive variants influencing PD risk. © 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

Dopaminergic neurons from the substantia nigra pars compacta project their axons into the dorsal striatum, forming the nigrostriatal pathway. In Parkinson's disease (PD), dopaminergic terminals degenerate in the striatum, leading to dopamine depletion, which in turn causes alterations in the basal ganglia circuits that are essential for movement control. However, the reasons for dopaminergic neuron terminal degeneration in the striatum are still not understood. The LRRK2 gene is highly expressed in the striatum, and the LRRK2-G2019S mutation is one of the most common mutations associated with PD. It is therefore tempting to speculate that dysregulations in the striatal functionality can initiate or contribute to the dopaminergic neuron terminals' degeneration.

OBJECTIVES

We aimed to examine the phenotypic differences between healthy and patient striatum organoids carrying the LRRK2-G2019S mutation to assess whether specific alterations in the striatum that are independent of dopaminergic input could contribute to the development of the disease.

METHODS

Striatum organoids were generated using healthy and PD patient-induced pluripotent stem cell lines, and they were cultured until day 80. We evaluated the levels of striatum-specific proteins, and we performed proteomics and kinase activity analysis.

RESULTS

PD striatum organoids revealed increased abundance of DRD2, DARPP32, and CDK5. Proteomics and kinase activity analysis demonstrated an inflammatory phenotype, which was further validated by investigating the occurrence of reactive astrocytes.

CONCLUSIONS

Striatum organoids recapitulate PD-relevant phenotypes autonomously, independent of dopaminergic input. This includes a significant inflammatory phenotype. © 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).

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.

RESULTS

A total of 732 cases with EOPD and 469 with LOPD were included. EOPD patients were significantly more likely to have a positive family history of PD in parents (proportion ratio [PR] = 1.67, p = 0.049), second-degree relatives (PR = 2.54, p p p = 0.029). By contrast, patients with EOPD were less likely to have siblings with PD (PR = 0.38, p = 0.009).

DISCUSSION

The higher prevalence of PD and ET family history in the EOPD cohort supports a stronger genetic contribution and may reflect enrichment for high-penetrance monoallelic variants. Conversely, the higher frequency of affected siblings in the LOPD cohort suggests a polygenic inheritance pattern with greater environmental contribution.

Parkinson's disease is associated with extensive structural brain changes. Recent work has proposed that the spatial pattern of disease pathology is shaped by both network spread and local vulnerability. However, few studies have assessed these biological frameworks in large patient samples across disease stages. Analysing the largest imaging cohort in Parkinson's disease to date (n = 3096 patients), we investigated the roles of network architecture and local brain features by relating regional abnormality maps to normative profiles of connectivity, intrinsic networks, cytoarchitectonics, neurotransmitter receptor densities and gene expression. We found widespread cortical and subcortical atrophy in Parkinson's disease to be associated with advancing disease stage, longer time since diagnosis and poorer global cognition. Structural brain connectivity best explained cortical atrophy patterns in Parkinson's disease and across disease stages. These patterns were robust among individual patients. The precuneus, lateral temporal cortex and amygdala were identified as likely network-based epicentres, with high convergence across disease stages. Individual epicentres varied significantly among patients, yet they consistently localized to the default mode and limbic networks. Furthermore, we showed that regional overexpression of genes implicated in synaptic structure and signalling conferred increased susceptibility to brain atrophy in Parkinson's disease. In summary, this study demonstrates in a well-powered sample that structural brain abnormalities in Parkinson's disease across disease stages and within individual patients are influenced by both network spread and local vulnerability.

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.

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.

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.

PURPOSE

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

METHODS

PsycINFO, PubMed, EMBASE, SCOPUS, PEDro, CINAHL, and Web of Science were searched until June 2025. Studies were included if they included patients with PD, administered LSVT® BIG, and assessed motor symptoms, ADLs, and QoL. The PEDro scale was used to assess methodological quality, and pooled effect sizes were calculated using Cohen's d and random-effects models.

RESULTS

Ten studies (300 participants) met the inclusion criteria. No significant effects in the Time-Up & Go (TUG) test (SMD: 0.050, 95% CI: -0.550 to 0.650, p = 0.870) and the 10-Minute Walk Test (10MWT) (SMD: 0.415, 95% CI: -0.198 to 1.027, p = 0.184) were reported. Other outcome measures revealed significant improvements in balance, gait cycle symmetry, and manual dexterity in patients with PD.

CONCLUSIONS

The initial findings revealed that LSVT® BIG improves balance and gait in patients with PD. The evidence for the effects of LSVT® BIG on manual dexterity and overall ADLs is mixed and inconclusive for QoL. Further high-quality studies with long-term follow-ups are needed.

GBA1 variants are common genetic risk factors for Parkinson's disease and also for dementia with Lewy bodies. New evidence highlights the relationship between the different GBA1 variants and their associated clinical presentation and disease progression, although penetrance is low and the majority of carriers do not develop a synucleinopathy. The clinical profile of GBA1-associated Parkinson's disease is characterised by a faster rate of progression with more severe cognitive and autonomic dysfunction than idiopathic Parkinson's disease, particularly in those carrying severe pathogenic variants. The mechanisms involved in phenotypic conversion and disease progression in carriers of GBA1 variants are being elucidated, and this knowledge could be translated into clinically relevant biomarker profiles. GBA1 has become a target for intervention for both GBA1-associated Parkinson's disease and idiopathic Parkinson's disease, with therapeutic strategies aiming to prevent or slow disease progression via pharmacological chaperones, enzymatic allosteric activators, metabolic interventions, and modulation of gene expression.

Primary results from the 24-week EPSILON study (NCT04978597) showed that adding opicapone to levodopa in non-fluctuating Parkinson's patients significantly improved motor impairment without increasing the development of motor complications versus placebo. All participants finishing the double-blind phase became eligible for open-label treatment with opicapone. Symptomatic efficacy of opicapone was maintained with 1-year open-label treatment (adjusted-mean ± SE change in MDS-UPDRS motor score from double-blind baseline to Week 76: -7.4 ± 0.81); participants who switched from placebo to opicapone had a motor improvement of -6.1 ± 0.79. At Week 76, 80.2% of opicapone-opicapone-treated participants remained motor complication-free versus 69.7% in the placebo-opicapone group (p = 0.1).

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.

OBJECTIVE

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

DESIGN

Systematic review and meta-analysis.

SUBJECTS/PATIENTS

Patients with Parkinson's disease.

METHODS

A search was conducted in PubMed, Embase, Scopus, Web of Science, and Cochrane Library. Functional mobility was assessed as the main outcome, and balance, gait, activities of daily living, and quality of life as secondary outcomes. Meta-analyses were conducted using mean difference or standardized mean difference with 95% confidence intervals and fixed or random effect models. Heterogeneity was explored, setting a cut-off value of I2 = 50%.

RESULTS

Sixteen studies were included, with 8 -eligible for meta-analysis. Results showed that sequential combined treatment offered no clear advantage over motor rehabilitation alone for functional mobility, although a significant benefit was found for activities of daily living. Results on simultaneous combined treatment suggested improvements in quality of life, but no significant differences between treatments for functional mobility.

CONCLUSION

Motor-cognitive approaches may enhance prefrontal cortex efficiency, supporting complex motor tasks and reducing the risk of falls. Future research should elucidate neural mechanisms and compare simultaneous and sequential strategies to develop personalized, multidisciplinary rehabilitation protocols.

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 AND OBJECTIVES

Glucocerebrosidase (GBA1) pathogenic variants are strongly associated with Parkinson disease (PD); however, insufficient data exist on the prevalence of PD among patients with Gaucher disease type 1 (GD1) (biallelic pathogenic GBA1 variants). Also, penetrance estimates in patients with GD are lower than expected given their severely diminished enzymatic activity. We aimed to estimate the age-specific risk of PD in patients with GD1, overall and by GBA1 genotype.

METHODS

Participants were patients with GD1 in the International Collaborative Gaucher Group Gaucher Registry, a global GD database, as of February 2024. We longitudinally collected data on clinical diagnosis of PD and dementia with Lewy bodies (DLB) and report of motor (rest tremor, falls) and nonmotor (cognitive impairment, REM sleep behavior disorder, loss of sense of smell, autonomic dysfunction) signs/symptoms. In addition to a conservative physician-based PD and DLB diagnosis, we created a liberal definition of possible parkinsonian syndrome (pPS; ≥2 signs/symptoms, PD, or DLB) to test whether previous low penetrance estimates stem from underdiagnosis. Patients were classified as pPS at earliest of the following dates: PD diagnosis, DLB diagnosis, or report of second sign/symptom. We separately estimated age-specific prevalence of PD and pPS using Kaplan-Meier survival curves.

RESULTS

Among 1,618 patients with GD1 (median age at last follow-up 47.8 years; 53% female), 51 were diagnosed with PD and 86 as pPS. The age-specific prevalence (95% CI) of PD and pPS was 4.0% (2.7-5.7) and 6.0% (4.5-7.9) at 60 years and 12.2% (8.6-17.0) and 22.9% (17.1-30.1) at 80 years, respectively. Patients with 2 mild pathogenic GBA1 variants had a qualitatively lower prevalence of PD and pPS vs patients with one mild variant.

DISCUSSION

In this large cohort of 1,618 patients, approximately one-in-nine patients with GD1 were diagnosed with PD and more than one-in-five patients were diagnosed with PD/DLB or experienced movement disorder symptoms by 80 years. Most patients were from North America and Europe; generalizability to other regions is unknown. Our finding that most patients remain free of PD despite very low residual enzyme activity informs the hypothesis that acid ß-glucosidase levels directly predict risk of PD.

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.

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.

RESULTS

Annualized prevalence of PD, MS, and MNDs increased significantly between 2003 and 2022 in the pooled model (PD: prevalence ratio [PR] per year = 1.014, p p p p p p p p p p p = 0.002), while it increased significantly over the entire study period for MS (+2.35 months, p p = 0.01).

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.

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).

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.

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.

There is considerable evidence linking alterations in gut microbiome composition with Parkinson's disease, leading to several recent randomized controlled faecal microbiota transplantation (FMT) trials in patients with Parkinson's disease targeting gut dysbiosis with the aim to modulate the gut-brain axis. Some FMT trials have observed motor and non-motor symptoms improvements in patients with Parkinson's disease, possibly through microbiota linked enhanced short-chain fatty acid or other metabolite effects and reduced systemic inflammation. While the findings are exciting and can potentially open a new treatment paradigm, crital questions on donor selection, the optimal screening and selection of the donor microbiome, delivery routes and the timing and frequency of transplantation need to be addressed. We suggest that future FMT trials should incorporate blood, metabolites, urine and functional neuroimaging biological markers and to control for dietary, lifestyle comorbidities, medication intake and/or other potential variables to ensure optimal evaluation of interactions between the gut microbes and brain outcomes prospectively over a longer time frame.

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

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.

IMPORTANCE

Adaptive deep brain stimulation (aDBS) automatically adjusts stimulation amplitude in response to changes in relevant neural activity in people with Parkinson disease (PD). Whether long-term at-home aDBS is safe and delivers effective therapy in people with PD remains unknown.

OBJECTIVE

To determine the tolerability, efficacy, and safety of long-term aDBS in people with PD who were previously stable receiving continuous DBS (cDBS).

DESIGN, SETTING, AND PARTICIPANTS

This international, open-label, prospective, pivotal trial enrolled participants from December 2020 to July 2022 in the US, Canada, and Europe. Referred participants with PD were first assessed while receiving stable cDBS and those who tolerated 2 aDBS modes were randomized and blinded to 30 days in each mode (single-blind crossover design); those who tolerated only 1 mode were assessed in that mode only; assessments completed holding medication stable. Participants were given the option to continue their selected mode of aDBS for long-term follow-up (10 months). Data used for analysis were from March 2024. Multiple imputation was used if more than 5% of data was missing for the primary or secondary end points. A referred sample of 68 participants with PD, stable while receiving cDBS and medication, was included.

INTERVENTIONS

Two modes of aDBS controlled by an embedded closed-loop stimulation system: single threshold (ST-aDBS) and dual threshold (DT-aDBS).

MAIN OUTCOMES AND MEASURES

The primary end point required that at least 50% of participants meet a performance goal of on-time (ie, time when symptoms were well controlled) without troublesome dyskinesias with no less than 1-SD reduction (and post hoc threshold less than 2 hours per day reduction) reported during aDBS therapy compared to cDBS, determined from a self-reported motor diary. The secondary end point was total electrical energy delivered (TEED) compared between aDBS and cDBS. Safety assessments were conducted by characterizing adverse events (AEs), stimulation-related AEs, serious AEs, and device deficiencies.

RESULTS

A total of 68 participants enrolled (mean [SD] age, 62.2 [8.4] years; 48 [70.6%] male); 40 and 35 were evaluated with DT-aDBS and ST-aDBS, respectively. The primary end point performance goal was met in the DT-aDBS group (91% of participants) and ST-aDBS (79% of participants) with the post hoc performance threshold; no difference between aDBS modes (χ21 = 1.0; P = .51). TEED was reduced during ST-aDBS compared to cDBS (mean change, -15%; nominal P = .01) and not different from DT-aDBS. All but 1 stimulation-related AE resolved during the aDBS setup and adjustment phase with no serious device AEs through long-term follow-up. Exploratory analyses suggested improvement in on-time without troublesome dyskinesias with DT-aDBS compared to cDBS.

CONCLUSIONS AND RELEVANCE

In this study, long-term aDBS was tolerable, effective, and safe in people with PD who were previously stable while receiving cDBS.

TRIAL REGISTRATION

ClinicalTrials.gov Identifier: NCT04547712.

The global burden of Parkinson's disease is rising. Large-scale genetic studies have confirmed that extrinsic or environmental factors, rather than genetic predisposition, play a dominant role in its cause. Increasing evidence implicates three classes of toxicants-certain pesticides, the dry-cleaning chemicals trichloroethylene and perchloroethylene, and air pollution-in the development of Parkinson's disease. These toxicants are widely prevalent, impair mitochondrial or lysosomal function, or both, and contribute to, if not cause, the disease. Parkinson's disease could be thus largely preventable. Uncertainties remain regarding the relevant doses, timing, and routes of exposure, the nature of genetic and environmental interactions, the effects of combined exposures, the role of the microbiome, and the identity of other environmental risks. Methodological limitations and structural challenges hinder our understanding. However, improved measurement of toxicant exposure in individuals and the environment, long-term prospective studies, increased funding for prevention, and policy changes can precipitate the fall of the burden of Parkinson's disease.

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

Optimal outcomes from subthalamic nucleus deep brain stimulation (STN-DBS) for Parkinson's disease (PD) depend on accurate stimulation of an ideal functional target within the dorsolateral STN. Clinical programming is heuristic, and objective methods are needed to improve efficiency and consistency.

OBJECTIVES

This study aimed to investigate the feasibility and acute motor benefit of STN-DBS programming, guided by intraoperatively recorded evoked resonant neural activity (ERNA) in patients with PD.

METHODS

We assessed 12 patients with anatomically well-placed leads, 4-6 months following STN-DBS. The worst hemibody was tested off-medication. Acute motor benefit was double-blind assessed for three programming configurations: (i) chronic expert clinician settings, (ii) imaging guided, and (iii) an ERNA automated algorithm. We also compared therapeutic and side effect thresholds and the spatial distribution of fractionated current.

RESULTS

ERNA programming improved hemibody Movement Disorder Society-Unified Parkinson's Disease Rating Scale-Part III scores by 75.7% (median) compared with off-stimulation. This was not different from imaging (81.6%, P = 0.19) or clinician programming (68.8%, P = 0.33). Therapeutic thresholds (P = 0.90) and side effect thresholds (P = 0.57) did not differ across conditions. ERNA programming was 0.8-1 mm ventral and 0.3 mm posterior to imaging and clinician programming.

CONCLUSIONS

A programming algorithm based solely on ERNA achieved acute motor efficacy and tolerability equivalent to expert clinical and imaging-based approaches. ERNA recordings took <1 min, under awake and general anesthetic conditions. These findings suggest that intraoperative ERNA can provide a rapid, objective, and practical starting point for STN-DBS programming. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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.

BACKGROUND

Parkinson's disease (PD) and multiple system atrophy (MSA) show overlapping clinical features, posing diagnostic challenges. This study investigates whether distinct patterns of glymphatic dysfunction and free water (FW) accumulation can differentiate their underlying mechanisms and serve as discriminatory biomarkers.

OBJECTIVE

The objective of this study was to evaluate glymphatic function and FW pathology in PD and MSA, and to develop an integrated biomarker panel for differential diagnosis.

METHODS

We conducted a cross-sectional and longitudinal neuroimaging study involving 231 participants: 74 healthy control subjects (HCs), 79 patients with PD, and 78 patients with MSA. Glymphatic function (diffusion tensor image analysis along the perivascular space [DTI-ALPS] index and choroid plexus volume [CPV]) and FW distribution were derived from magnetic resonance imaging. Diagnostic performance was evaluated using receiver operating characteristic curves. Mediation analyses explored relationships among glymphatic impairment, FW accumulation, and clinical symptoms.

RESULTS

Both PD and MSA showed reduced DTI-ALPS and enlarged CPV versus HC. FW accumulation exhibited disease-specific patterns: cortical/midline in PD and cerebellar in MSA. Longitudinal analysis confirmed progressive FW accumulation in these regions. Spatial coupling between glymphatic dysfunction and FW was strong in PD but absent in MSA. FW mediated the relationship between glymphatic impairment and motor/autonomic symptoms in PD, but not MSA. The integrated model combining neuroimaging and clinical metrics showed excellent discriminatory power for PD and MSA (area under the curve = 0.994).

CONCLUSIONS

PD and MSA exhibit distinct glymphatic-FW pathological profiles. The coupled mechanism in PD contrasts with the uncoupled pathology in MSA, reflecting divergent pathogenesis. Multimodal imaging biomarkers demonstrate high diagnostic accuracy, showing strong potential for differential diagnosis in clinical practice. © 2026 International Parkinson and Movement Disorder Society.

INTRODUCTION

As Parkinson's disease (PD) advances, limitations of oral medication include pill burden, increasing "Off" time, and "On" time with bothersome dyskinesia. Deep brain stimulation (DBS) can improve motor complications, but disease progression may warrant further intervention later. An approved nonsurgical option, continuous subcutaneous infusion of foslevodopa/foscarbidopa (LDp/CDp), has been shown to improve motor fluctuations, though the impact of prior DBS on its efficacy and safety is unknown.

METHODS

Post hoc analysis of a 52-week open-label phase 3 trial (NCT03781167) evaluated baseline characteristics, safety, and efficacy in patients treated with LDp/CDp with or without prior DBS. Fisher's exact test, t test, Wilcoxon rank-sum test, and analysis of covariance were performed.

RESULTS

Twenty-four (9.8%) of 244 patients received prior DBS. Both groups had similar baseline characteristics, although prior patients treated with DBS had significantly more time since diagnosis and more "speech" and "gait" impairment (Movement Disorders Society-Unified Parkinson's Disease Rating Scale [MDS-UPDRS] Parts II/III single items). Both groups showed significant within-group improvements in "Off" time and "On" time without dyskinesia, and the between-group difference for these improvements was not significant, indicating LDp/CDp had efficacy regardless of DBS exposure. The no DBS group had significant improvement in sleep and quality of life, while the prior DBS group had nonsignificant trends in the same direction. The no DBS group had significant improvement in MDS-UPDRS Part II score but worsening in Part III score, as expected with advancing disease; change from baseline in the prior DBS group was not significant. The safety data were similar in both groups, with the only significant difference being a higher percentage of prior patients treated with DBS experiencing severe treatment-emergent adverse events than no DBS (45.8% vs 23.6%).

CONCLUSION

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

TRIAL REGISTRATION

ClinicalTrials.gov identifier NCT03781167.

BACKGROUND

Freezing of gait (FOG) is a debilitating motor symptom observed in the advanced stages of Parkinson's disease (PD), characterized by an abrupt inability to initiate or continue forward walking. Whole-brain functional connectivity analysis has shown promise in elucidating the underlying pathophysiology and identifying potential biomarkers in PD. However, the specific changes in local brain networks during the transition from normal gait to freezing remain unclear.

OBJECTIVES

This study aimed to investigate changes in brain network organization during the transition to FOG compared with the transition to voluntary stopping.

METHODS

Eighteen PD patients with FOG performed walking tasks designed to trigger either freezing or voluntary stop events, while undergoing simultaneous ambulatory electroencephalography (aEEG) recording. Functional connectivity was estimated using phase-locking value (PLV) across multiple frequency bands, measuring the consistency of phase synchrony between brain regions, and examined network organization using graph modularity, an index of how strongly the brain segregates into functionally specialized subnetworks, focusing on the 2-second time windows preceding each event.

RESULTS

Transitions to freezing were characterized by increased local beta-band connectivity within right frontoparietal, middle-frontal, parietal-occipital, visual, and bilateral insula regions, alongside reduced connectivity between frontal and posterior areas in lower-frequency bands.

CONCLUSIONS

Increased local beta segregation and reduced fronto-posterior connectivity may reflect network alterations that precedes freezing episodes. Such patterns could help identify neurophysiological markers for predicting and potentially preventing FOG in PD. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Parkinson's disease (PD) risk and progression are influenced by a complex interplay of genetic, environmental, and internal factors. Environmental exposures have been understudied, primarily because of the associated complexity and inherent measurement challenges. The exposome framework, encompassing lifetime environmental exposures and biological responses, offers a way to better characterize these influences. The exposome embraces the "biography-to-biology" transition, encompassing general and specific external and internal exposures accumulating over the lifespan, and interacting with genetic factors. In other fields, machine learning has been applied to develop polyexposure scores to quantify cumulative environmental risks, although challenges remain in exposure measurement, latency, and disease heterogeneity. Advancing PD research requires refined exposome definitions, systematic data integration, validation, and collaboration to improve prediction, prevention, and personalized therapies. © 2026 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.

Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by motor symptoms that initially manifest unilaterally. Whilst some studies indicate that right-side onset is associated with greater symptom severity, others report no differences between right-side and left-side onset patients. The present meta-analysis was thus designed to reconcile inconsistencies in the literature and determine whether side of onset affects PD symptom severity. Following the PRISMA guidelines 1013 studies were initially identified in database and grey literature searches; following title and abstract, and full text, screening 34 studies met the stringent inclusion criteria (n = 2210). Results of the random-effects meta-analysis indicated no difference in symptom severity between PD patients with left-side (n = 1104) and right-side (n = 1106) onset. As such, the meta-analysis suggests that the side of onset should not be used to predict symptom trajectory or to formulate prognoses for PD patients. The current meta-analysis was the first to focus on the relationship between the side of onset and symptom severity in PD. However, the studies included were limited by the common exclusion of left-handed participants. Future research would benefit from exploring other factors that may influence symptom severity and disease progression in PD, such as asymmetric loss of nigrostriatal dopaminergic neurons.

BACKGROUND

Although genome-wide association studies (GWAS) have identified numerous common genetic risk variants for Parkinson's disease (PD), the underlying biological mechanisms remain largely unresolved.

OBJECTIVES

We aimed to identify circulating proteins causally associated with PD risk in European and East Asian populations and determine whether these associations are shared or ancestry-specific.

METHODS

We employed a two-sample Mendelian randomization (MR) approach, integrating large-scale proteomic and genetic data, with validation using summary-data-based MR (SMR). European analyses used UK Biobank Pharma Proteomics Project (UKB-PPP; n = 54,219; 2,392 proteins) and a large PD GWAS (37,688 cases, 18,618 proxy cases, 1.4 million controls). East Asian analyses combined Han Chinese and UKB-PPP data (n = 3,220; 229 proteins) with a PD GWAS (6,724 cases, 24,851 controls). False discovery rate (FDR) < 0.05 determined significance. Sensitivity analyses addressed instrument heterogeneity, pleiotropy, and sample overlap.

RESULTS

MR analyses identified 21 proteins causally associated with PD in Europeans and 8 in East Asians, all directionally concordant in SMR validation. Notably, BST1 emerged as a shared causal protein, increasing PD risk in both Europeans (odds ratio [OR] = 1.04, 95% confidence interval [CI]: 1.02-1.06) and East Asians (OR = 1.18, 95% CI: 1.10-1.27), remaining robust after excluding UK Biobank participants. Several ancestry-specific proteins were detected, including TXNDC15 in Europeans and PM20D1 in East Asians, both targets of existing or investigational drugs.

CONCLUSIONS

This cross-ancestry proteogenomic analysis reveals shared and ancestry-specific proteomic signatures causally linked to PD, underscoring the importance of using ancestry-aware analytical frameworks to discover robust biomarkers and novel therapeutic targets. © 2026 International Parkinson and Movement Disorder Society.

Parkinson's disease is one of the fastest-growing neurodegenerative disorders, with no effective treatments to modify its progression. Microglial-driven neuroinflammation, mediated by NOD-leucine rich repeat and pyrin containing protein 3 (NLRP3) inflammasome activation, plays a key role in disease onset and progression. The NLRP3 inflammasome is upregulated in microglia from Parkinson's disease patients and activated by oxidative stress and α-synuclein aggregates, triggering the release of pro-inflammatory mediators that contribute to neuroinflammation and neuronal death. MCC950, the first described specific NLRP3 inhibitor, has shown promise in Parkinson's disease models but is limited by suboptimal pharmacokinetics and safety, hindering its clinical development. Here, we developed a novel NLRP3 inflammasome inhibitor, MCC7840 (also known as Inzomelid or Emlenoflast), and utilized clinically relevant PET-MRI imaging biomarkers to assess its therapeutic efficacy in preclinical models of Parkinson's disease. MCC7840 inhibited NLRP3 in human and mouse microglia with nanomolar potency, while demonstrating improved systemic exposure, half-life, brain permeability and bioavailability compared with MCC950. In a murine NLRP3 gain-of-function model of Muckle-Wells syndrome, MCC7840 effectively inhibited mortality and demonstrated superior potency compared with MCC950. Chronic oral administration of MCC7840 protected against neuroinflammation, motor deficits and dopamine loss in both 6-hydroxydopamine and preformed α-synuclein fibril mouse models of Parkinson's disease. Radiotracer imaging of multiple PET markers in the same mouse revealed that MCC7840 attenuated neuroinflammation (translocator protein ligand; 18F-DPA-714), preserved dopamine uptake (fluorodopa; 18F-FDOPA), mitigated dopamine transporter (DAT) loss (DAT ligand; 18F-FBCTT) and reduced blood-brain barrier leakage (gadolinium contrast MRI). Notably, MCC7840 was effective in a slowly progressing 12-month α-synuclein model, even when administered after symptom onset, 4 months post-α-synuclein injection. These findings highlight the utility of PET/MRI as a non-invasive tool to evaluate drug efficacy and support MCC7840, and other brain-penetrant NLRP3 inhibitors, as promising disease-modifying therapies for Parkinson's disease, warranting future clinical investigation.

OBJECTIVE

To investigate evidence for group-based interventions compared with individual-based interventions for sensorimotor rehabilitation in adults with neurologic conditions.

DATA SOURCES

Medline, Embase, Emcare, and PsychINFO were searched from inception to July 2024.

STUDY SELECTION

Randomized controlled trials that compared group versus individual delivery of the same type of sensorimotor rehabilitation for adults with neurologic conditions were included.

DATA EXTRACTION

Two reviewers independently screened, assessed methodological quality, and extracted data. Study characteristics, participant details, intervention/control characteristics, and clinical outcomes were extracted.

DATA SYNTHESIS

Ten trials were included in the review. Participant groups included people with Parkinson disease (2 trials), multiple sclerosis (1 trial), and stroke (7 trials). Meta-analyses found significant effects in favor of group interventions for 6-minute walk test distance (mean difference, 36.18m; 95% CI, 14.58-57.77; P=.001), and gait speed (mean difference, 0.2m/s; 95% CI, 0.13-0.27; P<.0001). No difference was found for other clinical measures.

CONCLUSIONS

Group-based rehabilitation appears to deliver improved ambulation speed and distance in people with neurologic conditions. Further research is required to understand whether group-based rehabilitation has additional benefits for motivation and social support. Delivery of rehabilitation in a group appears worthy of consideration in clinical settings.

BACKGROUND

Peripheral disease mechanisms such as immune dysregulation may contribute to Parkinson's disease (PD). To investigate interactions between common PD mutations and immune responses to environmental pathogens, we studied responses to Pseudomonas aeruginosa (P. aeruginosa) in peripheral blood mononuclear cells (PBMCs) from PD patients with leucine-rich repeat kinase 2 (LRRK2) mutations, GBA1 mutations, and idiopathic disease (iPD) relative to neurologically healthy controls (NHC).

OBJECTIVES

The goal was to test the hypothesis that LRRK2 and GBA modify the human peripheral immune response to bacteria, specifically P. aeruginosa, based on prior animal studies involving Lrrk2 mutations and microbial pathogens.

METHODS

PBMCs from LRRK2-PD, GBA-PD, and iPD patients plus age- and sex-matched controls were treated ex vivo with live P. aeruginosa and pharmacological agents that block LRRK2 kinase activity (MLi-2) or enhance glucocerebrosidase (GCase) activation (NCGC00188758) to measure enzymatic activities and cytokine release.

RESULTS

GBA-PD PBMCs exhibited increased P. aeruginosa-dependent secretion of specific inflammatory cytokines including interleukin-1β. Antigen presentation was increased in LRRK2-PD nonclassical monocytes treated with the GCase activator. Levels of pRab10, a proxy for LRRK2 kinase activity, were increased in GBA-PD classical monocytes relative to NHC and iPD. GCase activator treatment increased pRab10 expression in LRRK2-PD intermediate monocytes. GBA-PD and individual treatments with MLi-2 or GCase activator were associated with reduced P. aeruginosa-dependent LRRK2 protein levels in PBMC subsets.

CONCLUSIONS

This work demonstrates that PD-linked mutations in LRRK2 and GBA1 converge on peripheral blood immune cell dysregulation, as evinced by the ability of LRRK2 inhibitors and GCase activators to modulate the ex vivo immune response to bacterial exposure. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BACKGROUND

Variants in the GBA1 gene can increase the risk of Parkinson's disease (PD) by reducing glucocerebrosidase (GCase) activity, disrupting lysosomal and mitochondrial function, and increasing alpha-synuclein aggregation. The molecule GT-02287 prevents misfolding of GCase and ameliorates downstream pathway abnormalities.

OBJECTIVES

To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of GT-02287.

METHODS

The safety, tolerability, and plasma pharmacokinetics of single and multiple oral doses were evaluated in 73 healthy volunteers, and GT-02287 levels in cerebrospinal fluid (CSF) and GCase activity in blood were measured.

RESULTS

All dose levels tested were safe and generally well-tolerated. No serious or severe adverse events occurred. The most common events were nausea and headache. Plasma and CSF exposures were within the projected therapeutic range, and GCase activity increased after GT-02287 administration.

CONCLUSIONS

GT-02287 was safe and well-tolerated in healthy volunteers. Plasma and CSF levels were consistent with levels in rodents that modulate PD biology. © 2025 International Parkinson and Movement Disorder Society.

Parkinson's disease is a progressive neurodegenerative disorder characterized by motor dysfunction, dopaminergic neuronal loss in the substantia nigra and abnormal accumulation of α-synuclein Lewy bodies. Research suggests that the cerebrovascular system plays a role in fluid dynamics, waste clearance and removal of abnormal proteins. Imaging studies show that this waste clearance system, known as the glymphatic system, is disrupted in Parkinson's disease, highlighting its involvement in the disease. This immunohistochemical human brain tissue study quantified changes in the cerebrovascular system (perivascular space, string vessels, pericytes, aquaporin-4 and astrocytes) in Parkinson's disease (n = 18) cases with variable disease durations (median = 14 years, range = 19 years) compared with age- and post-mortem-matched (P > 0.05) control cases (n = 7). Analysis was carried out in brain regions variably affected by cell loss (substantia nigra) and protein deposition (substantia nigra and medial temporal cortex). The occipital cortex was included because this region is not affected by cell loss or protein deposition. Group differences were analysed, and the relationship with protein deposition (Lewy body stage, amyloid score and neurofibrillary tangle score) was assessed. Although total astrocyte density did not change (P > 0.05), Parkinson's disease cases exhibited reduced aquaporin-4 in astrocytic endfeet and enlargement of the arteriolar and venular perivascular space. Significant changes in the capillary network were also observed, with increased presence of string vessels (P < 0.001) and pericyte loss (P < 0.001), changes likely to impact blood flow and its regulation. The increased presence of string vessels was significantly correlated with disease duration (P < 0.05), especially in the occipital cortex. The occipital cortex demonstrated the greatest decreases in pericytes (P < 0.001) and aquaporin-4 mislocalization (P < 0.05), and changes in pericyte density were also significant in the substantia nigra. In contrast, these changes were not significant in the medial temporal cortex despite protein deposition in this region. Although no Lewy pathology was detected in the occipital cortex, there was a positive relationship between Lewy body stage and perivascular space size (ρ = 0.6, P < 0.05). These findings reveal progressive, region-specific alterations in the cellular components of the glymphatic system and vascular integrity in Parkinson's disease. Notably, the correlation between increased presence of string vessels and disease duration, even in a region unaffected by protein deposition, suggests that vascular changes might play an important role in disease progression. These results emphasize the need for further investigation into the interplay between regional vascular changes and Parkinson's disease progression, which might offer new insights for therapeutic strategies.

BACKGROUND

Huntington's disease (HD) presents a unique clinical challenge with coexisting hyperkinetic and hypokinetic symptoms, yet the underlying neural oscillatory mechanisms remain poorly understood.

OBJECTIVE

The aim of this study was to characterize pathological pallidal neural activity in HD and identify biomarkers for therapeutic optimization.

METHODS

We investigated pallidal oscillatory patterns in 15 patients with HD undergoing deep brain stimulation, recording video-synchronized local field potentials during symptom fluctuations and comparing findings with patients with Parkinson's disease and dystonia.

RESULTS

HD exhibited distinct pallidal oscillatory signatures that differed from PD and dystonia. Theta power (2-8 Hz) increased during hyperkinetic states, whereas high beta power (20-30 Hz) elevated during hypokinetic states, both correlating significantly with clinical symptom severity. These patterns were not modulated by voluntary movement. Electrophysiological connectivity analysis integrated with neuroimaging analysis showed that globus pallidum externus-globus pallidus internus theta coherence correlated with indirect pathway structural connectivity, whereas pallidal high beta power associated with direct pathway functional connectivity, reflecting HD's dual circuit pathology. Spatial mapping localized theta oscillations to the posterior globus pallidus, with fibers projecting to motor cortical areas.

CONCLUSIONS

We establish an electrophysiological framework explaining HD's complex symptomatology through dual oscillatory signatures. These findings provide circuit-specific biomarkers for disease monitoring and anatomical targets for optimizing deep brain stimulation in patients with HD. © 2026 International Parkinson and Movement Disorder Society.

BACKGROUND/OBJECTIVE

Within-patient comparison of intravenous levodopa and subthalamic nucleus deep brain stimulation effects on neural oscillations and motor function in Parkinson's disease (PD).

METHODS

Twelve patients with advanced PD and bilaterally implanted subthalamic electrodes underwent five treatment conditions: medication off/stimulation off, placebo infusion, medication on/stimulation off, medication off/stimulation on, and medication on/stimulation on. For each condition, bilateral local field potentials were recorded, and motor function was evaluated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III.

RESULTS

Both levodopa and stimulation improved motor scores (p < 0.01) and reduced low β activity (13-20 Hz). High β activity (21-30 Hz) decreased only during stimulation (p < 0.01). Finely tuned γ (FTG) oscillations (60-90 Hz) appeared most often during combined therapy (68.2%), with peak frequencies entrained to half the stimulation frequency in 93.3% of electrodes, except under 180 Hz stimulation. During intravenous levodopa infusion, FTG emerged with a median latency of 14.3 minutes, frequently before peak plasma levels, and declined in frequency over time. Changes in FTG power correlated with motor improvement (p < 0.05), whereas placebo had no effect.

CONCLUSIONS

Levodopa and stimulation exert distinct but complementary effects on oscillatory activity. FTG, rather than β power alone, reflected therapeutic state and was associated with motor improvement without dyskinesia. These findings highlight FTG as a potential biomarker for adaptive stimulation systems in PD. © 2026 International Parkinson and Movement Disorder Society.

Elucidating the genetic contributions to Parkinson's disease aetiology across diverse ancestries is a critical priority for the development of targeted therapies in a global context. We conducted the largest sequencing characterization of potentially disease-causing, protein-altering and splicing mutations in 710 cases and 11 827 controls from genetically predicted African or African admixed ancestries. We explored copy number variants (CNVs) and runs of homozygosity in prioritized early onset and familial cases. Our study identified rare GBA1 coding variants to be the most frequent mutations among patients with Parkinson's disease, with a frequency of 4% in our case cohort. Of the 18 GBA1 variants identified, 10 were previously classified as pathogenic or likely pathogenic, four were novel and four were reported as of uncertain clinical significance. The most common known disease-associated GBA1 variants in the Ashkenazi Jewish and European populations, p.Asn409Ser, p.Leu483Pro, p.Thr408Met and p.Glu365Lys, were not identified among the screened Parkinson's disease cases of African and African admixed ancestry. Similarly, the European and Asian LRRK2 disease-causing mutational spectrum, including LRRK2 p.Gly2019Ser and p.Gly2385Arg genetic risk factors, did not appear to play a major role in Parkinson's disease aetiology among West African ancestry populations. However, we found three heterozygous novel missense LRRK2 variants of uncertain significance, with two (p.Glu268Ala and p.Arg1538Cys) displaying higher frequencies in the African ancestry population reference datasets. Structural variant analyses revealed the presence of PRKN CNVs with a frequency of 0.7% in African and African admixed cases, with 66% of CNVs detected being compound heterozygous or homozygous in early-onset cases, providing further insights into the genetic underpinnings in early-onset juvenile Parkinson's disease in these populations. Short tandem repeat analysis also identified ATXN3 CAG repeat expansions within the pathogenic range (CAGn > 45) in three patients with Parkinson's disease of African ancestry. Novel genetic variation among screened genes warrants further replication and functional prioritization to unravel their pathogenic potential. Here, we created the most comprehensive genetic catalogue of both known and novel coding and splicing variants potentially linked to Parkinson's disease aetiology in an underserved population and further conducted global and local ancestry analyses to further explore population-specific effects. Our study has the potential to guide the development of targeted therapies in the emerging era of precision medicine. By expanding genetics research to involve underrepresented populations, we hope that future Parkinson's disease treatments are not only effective but also inclusive, addressing the needs of diverse ancestral groups.

Animal models of the pathology of Parkinson's disease (PD) have provided most of the treatments to date, but the disease is restricted to human patients. In vitro models using human pluripotent stem cell (hPSC)-derived neural organoids have provided improved access to study PD aetiology. This study established a method to generate human striatal-midbrain assembloids (hSMAs) from hPSCs for modelling alpha-synuclein (α-syn) propagation and recapitulating basal ganglia circuits, including nigrostriatal and striatonigral pathways. Human striatal organoids and midbrain organoids were generated using a stepwise differentiation protocol from hPSCs, and both regionalized neural organoids were assembled to form hSMAs, mimicking some basal ganglia circuits. Both the nigrostriatal and striatonigral pathways were present, and the neurons, such as dopaminergic neurons and GABAergic neurons, were electrophysiologically active in the hSMAs. Development of hSMAs in the presence of increased α-syn from SNCA overexpression induced nigrostriatal system damage, which is typical of the disease. Using the α-syn-linker-mKO2 reporter and a bimolecular fluorescence complementation system, we demonstrated that fluorescent α-syn was retrogradely transported from the striatal area to dopaminergic neurons of the midbrain area and exhibited α-syn aggregates and Lewy body-like inclusions. Furthermore, phosphorylated and detergent-resistant α-syn aggregates, similar to the pathological form in human patients, accumulated in the midbrain area of hSMAs. Treatment with a protein aggregation inhibitor (Anle138b) and an autophagy inducer (rapamycin) reduced α-syn aggregation, indicating the potential of hSMAs for drug testing. This study established hSMAs as a novel platform for modelling PD, demonstrating α-syn propagation and associated neural pathologies. These assembloids offer significant potential for developing therapeutic strategies and understanding the mechanisms of PD progression.

There is considerable evidence linking alterations in gut microbiome composition with Parkinson's disease, leading to several recent randomized controlled faecal microbiota transplantation (FMT) trials in patients with Parkinson's disease targeting gut dysbiosis with the aim to modulate the gut-brain axis. Some FMT trials have observed motor and non-motor symptoms improvements in patients with Parkinson's disease, possibly through microbiota linked enhanced short-chain fatty acid or other metabolite effects and reduced systemic inflammation. While the findings are exciting and can potentially open a new treatment paradigm, crital questions on donor selection, the optimal screening and selection of the donor microbiome, delivery routes and the timing and frequency of transplantation need to be addressed. We suggest that future FMT trials should incorporate blood, metabolites, urine and functional neuroimaging biological markers and to control for dietary, lifestyle comorbidities, medication intake and/or other potential variables to ensure optimal evaluation of interactions between the gut microbes and brain outcomes prospectively over a longer time frame.

BACKGROUND AND OBJECTIVES

"Motor reserve" refers to the brain's dynamic resilience against dopaminergic degeneration in Parkinson disease (PD). However, its clinical significance remains unclear because of critical limitations, including the lack of data on its longitudinal trajectories. Using Parkinson's Progression Markers Initiative data with serial dopamine transporter (DAT) imaging from the drug-naive stage, we investigated its trajectories, determinants, and prognostic implications.

METHODS

This retrospective observational cohort study assessed motor reserve using 2 complementary approaches. The residual-based approach calculated deviations in Movement Disorders Society-sponsored Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part 3 scores from expected values derived from a linear regression model incorporating putamen DAT specific binding ratio (putamen SBR), age, sex, and disease duration. The interaction-based approach extended this model by introducing interaction terms between putamen SBR and each factor, analyzing the corresponding β coefficients. We examined motor reserve's cross-sectional associations with clinical parameters, its mediation effects, and its longitudinal trajectories-up to 4 years-based on DAT imaging data availability, while identifying factors influencing its changes. Finally, we assessed its impact on long-term prognosis using Cox proportional hazards and linear mixed-effects models (LMEMs).

RESULTS

We included 566 drug-naive patients with PD (median age 62.3 [interquartile range 56.3-69.6] years; 33.7% female). At baseline, regular physical activity was significantly associated with motor reserve in both approaches, with mediation analysis indicating that motor reserve largely mediated the effect of physical activity on motor symptom improvement. Longitudinally, adequate medication and sustained regular physical activity levels were strongly associated with a slower early-years decline in motor reserve. It is important to note that early-years average motor reserve, not the baseline value, was a strong predictor of long-term motor outcomes (Cox: Hoehn/Yahr stage 3, hazard ratio = 0.50, 95% CI 0.37-0.66; LMEMs: MDS-UPDRS Part 3 score, fixed-effects standardized interaction coefficient = -0.57, 95% CI -0.79 to -0.35). These findings were further validated through propensity score matching.

DISCUSSION

Maintaining motor reserve in the early years after diagnosis strongly predicts favorable long-term motor outcomes, with adequate treatment and regular physical activity-both modifiable factors-supporting this maintenance. Because our study includes early-stage, drug-naive PD, further research in later stages is warranted.

TRIAL REGISTRATION INFORMATION

ClinicalTrials.gov (NCT01141023). A link to the trial registry page is clinicaltrials.gov/ct2/show/NCT01141023.

BACKGROUND

The efficacy of pallidothalamic tract (PTT)-focused ultrasound (FUS) in the treatment of advanced Parkinson's disease (aPD) remains unclear.

OBJECTIVE

This study aimed to evaluate the safety and efficacy of PTT-FUS.

METHODS

Nine patients with aPD underwent PTT-FUS. Clinical assessments, including the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), were conducted at baseline and 3 months after the first procedure, with contralateral procedure and clinical evaluation up to 12 months later.

RESULTS

MDS-UPDRS Part III on/off medication scores improved from 26.1 ± 15.4/54.4 ± 16.7 at baseline to 11.9 ± 9.6/26.6 ± 15.9 at 3 months after the unilateral procedure. The Unified Dyskinesia Rating Scale score improved from 25.0 ± 18.9 to 3.6 ± 7.0. Because of ipsilateral and axial symptom improvement, treatment was terminated after the unilateral procedure in seven patients. Adverse events included permanent freezing in one patient.

CONCLUSIONS

Unilateral PTT-FUS improves wearing off and dyskinesia, with bilateral effects observed short term. © 2025 International Parkinson and Movement Disorder Society.

OBJECTIVES

To investigate trajectories of regional brain volume changes in multiple system atrophy (MSA) and their potential utility as surrogate markers of disease progression in the cerebellar subtype (MSA-C).

BACKGROUND

Reliable biomarkers for tracking disease progression in MSA are urgently needed. Although several studies have explored neuroimaging markers, imaging measures that are reliable and reproducible at the individual-level are lacking.

METHODS

Longitudinal three-dimensional (3D)-T1 images from multiple cohorts of 21 subjects with probable MSA-C, 19 with probable MSA-parkinsonian subtype (MSA-P), 113 with Parkinson's disease, and 227 healthy controls were processed using the FreeSurfer longitudinal pipeline. Extracted volumes were assessed for individual longitudinal trajectories, intra-individual variability, and pontine regional volume decline.

RESULTS

Pontine volumes showed lower intra-individual variability in measurements compared with other infratentorial brain regions. All probable MSA-C patients exhibited a decline in pontine volume, ranging from -3.6% to -16.8% per year (mean: -9.1%), falling more than two standard deviations below the mean of healthy controls. In MSA-C, the temporal dynamics of pontine volumes exhibited nonlinear changes, characterized by progressive atrophy in the earlier period of the disease, followed by a pre-plateau phase associated with advanced disability in the later period. Predictive modeling suggests that pontine atrophy may begin before symptom onset of MSA-C.

CONCLUSIONS

Pontine volume is a sensitive marker of disease progression, exhibiting a nonlinear decline with low intra-individual variability in measurements and greater volume loss in the earlier stages, reaching a pre-plateau phase in the later stages with advanced disability. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BACKGROUND

Previous studies have reported Parkinson's disease (PD) patients usually have changes in brain image-derived phenotypes (IDPs). However, the role of genetic factors in their association and biological mechanism remains unclear. We aimed to unveil genetic and biological links between brain IDPs and PD.

METHODS

Using genome-wide association study (GWAS) summary statistics and single-cell RNA sequencing (scRNA-seq) data, we performed a comprehensive analysis between 624 brain IDPs and PD. The genetic correlations and causality were examined by linkage disequilibrium score regression (LDSC), two-sample bidirectional Mendelian randomization (MR) and meta-analysis. Potential shared genes were identified using MAGMA and PLACO. Finally, pathway enrichment using FUMA and Metascape, and scRNA-seq analysis were performed to determine biological mechanisms and gene expression atlas across various cell types in brain tissue.

RESULTS

LDSC revealed that 50 brain IDPs were genetically correlated with PD (P -4). Additionally, we identified 56 unique pleiotropic genes, such as FAM13A, with notable enrichment in neuronal cells. Biological mechanism analysis revealed these genes were enriched in brain tissues and a variety of pathways such as negative regulation of neuron apoptotic processes.

CONCLUSION

We indicated the shared genetic architecture and biological mechanisms between brain IDPs and PD. These findings might provide insights on the therapeutic intervention and early prediction of PD at the brain imaging level.

Bilateral lesions of the basal ganglia using termocoagulation or radiation for improving tremor, bradykinesia, and rigidity in people with Parkinson's disease (PD) have been performed starting several decades ago, especially when levodopa and deep brain stimulation (DBS) surgery were not available. However, because of unclear additional benefit compared to unilateral lesion, and particularly to the evidence of increased adverse events occurrence, bilateral lesions were basically abandoned at the end of the 20th century. Therefore, bilateral DBS has become the standard procedure to treat PD. Magnetic resonance imaging-guided focused ultrasound (MRgFUS) is an emerging incisionless technique used to produce therapeutic brain ablation. The positive experiences of unilateral MRgFUS ablation for PD, along with the preliminary favorable outcomes of bilateral thalamic MRgFUS for essential tremor, raise the possibility to eventually reintroduce bilateral lesioning in the management of PD motor features. This possibility has so far only been tested in a few small studies. This article reviews the evidence of bilateral lesioning of the basal ganglia to treat PD, and elaborates on current gaps, controversies, and perspectives of the different available neurosurgical procedures and specifically of MRgFUS ablation. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

INTRODUCTION

Adjunctive therapies to treat OFF episodes resulting from long-term levodopa treatment in Parkinson disease (PD) are hampered by safety and tolerability issues. Istradefylline offers an alternative mechanism (adenosine A2A receptor antagonist) and therefore potentially improved tolerability.

METHODS

A systematic review of PD adjuncts published in 2011 was updated to include randomized controlled trials published from January 1, 2010-April 15, 2019. Pairwise meta-analyses were updated, and Bucher indirect comparisons were used to generate estimates of relative safety, presented as odds ratio (OR) and 95% confidence interval (CI) for comparators versus istradefylline.

RESULTS

Fifty-seven randomized controlled trials involving 11,517 patients were included in the meta-analysis. Relative to istradefylline, dopamine agonists and catechol-O-methyl transferase (COMT) inhibitors had statistically significant higher odds of dyskinesia and somnolence. Monoamine oxidase-B inhibitors had significantly higher odds of hypotension. Amantadine extended-release (ER) had statistically significant higher odds of hallucination, orthostatic hypotension, insomnia, and withdrawals due to adverse events. All interventions combined had significantly higher odds of dyskinesia versus istradefylline 20 mg and somnolence versus istradefylline 40 mg. Considering overall incidence of adverse events, COMT inhibitors and amantadine ER had statistically significant higher odds versus both istradefylline doses (COMT versus istradefylline 40 mg, OR: 1.33; 95% CI: 1.03, 1.75; versus istradefylline 20 mg, OR: 1.32; 95% CI: 1.01, 1.72; amantadine ER versus istradefylline 40 mg, OR: 3.45; 95% CI: 1.85, 6.25; versus istradefylline 20 mg, OR: 3.33; 95% CI: 1.82, 6.25).

CONCLUSION

Istradefylline was associated with a generally favorable safety profile relative to other adjunct medications in this study.

BACKGROUND

Freezing of gait is one of the most disturbing motor symptoms of Parkinson's disease (PD). However, the effective connectivity between key brain hubs that are associated with the pathophysiological mechanism of freezing of gait remains elusive.

OBJECTIVE

The aim of this study was to identify effective connectivity underlying freezing of gait.

METHODS

This study applied spectral dynamic causal modeling (DCM) of resting-state functional magnetic resonance imaging in dedicated regions of interest determined using a data-driven approach.

RESULTS

Abnormally increased functional connectivity between the bilateral dorsolateral prefrontal cortex (DLPFC) and the bilateral mesencephalic locomotor region (MLR) was identified in freezers compared with nonfreezers. Subsequently, spectral DCM analysis revealed that increased top-down excitatory effective connectivity from the left DLPFC to bilateral MLR and an independent self-inhibitory connectivity within the left DLPFC in freezers versus nonfreezers (>99% posterior probability) were inversely associated with the severity of freezing of gait. The lateralization of these effective connectivity patterns was not attributable to the initial dopaminergic deficit nor to structural changes in these regions.

CONCLUSIONS

We have identified novel effective connectivity and an independent self-inhibitory connectivity underlying freezing of gait. Our findings imply that modulating the effective connectivity between the left DLPFC and MLR through neurostimulation or other interventions could be a target for reducing freezing of gait in PD. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BACKGROUND

There remains high variability in clinical outcomes when the same magnetic resonance image-guided focused ultrasound (MRgFUS) thalamotomy target is used for both essential tremor (ET) and tremor-dominant Parkinson's disease (TDPD).

OBJECTIVE

Our goal is to refine the MRgFUS thalamotomy target for TDPD versus ET.

METHODS

We retrospectively performed voxel-wise efficacy and structural connectivity mapping using 3-12-month post-procedure hand tremor scores for a multicenter cohort of 32 TDPD patients and a previously published cohort of 79 ET patients, and 24-hour T1-weighted post-MRgFUS brain images. We validated our findings using Unified Parkinson's Disease Rating Scale part III scores for an independent cohort of nine TDPD patients.

RESULTS

The post-MRgFUS clinical improvements were 45.9% ± 35.9%, 55.5% ± 36%, and 46.1% ± 18.6% for ET, multicenter TDPD and validation TDPD cohorts, respectively. The TDPD and ET efficacy maps differed significantly (ppermute 2 = 0.64; P 2 = 0.53; P = 0.025-voxel analysis).

CONCLUSION

We demonstrated that the most effective MRgFUS thalamotomy target in TDPD is in the ventral intermediate nucleus/ventralis oralis posterior border region. This finding offers new insights into the thalamic regions instrumental in tremor control, with pivotal implications for improving treatment outcomes. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The clinical manifestation of Parkinson's disease exhibits significant heterogeneity in the prevalence of non-motor symptoms and the rate of progression of motor symptoms, suggesting that Parkinson's disease can be classified into distinct subtypes. In this study, we aimed to explore this heterogeneity by identifying a set of subtypes with distinct patterns of spatiotemporal trajectories of neurodegeneration. We applied Subtype and Stage Inference (SuStaIn), an unsupervised machine learning algorithm that combined disease progression modelling with clustering methods, to cortical and subcortical neurodegeneration visible on 3 T structural MRI of a large cross-sectional sample of 504 patients and 279 healthy controls. Serial longitudinal data were available for a subset of 178 patients at the 2-year follow-up and for 140 patients at the 4-year follow-up. In a subset of 210 patients, concomitant Alzheimer's disease pathology was assessed by evaluating amyloid-β concentrations in the CSF or via the amyloid-specific radiotracer 18F-flutemetamol with PET. The SuStaIn analysis revealed three distinct subtypes, each characterized by unique patterns of spatiotemporal evolution of brain atrophy: neocortical, limbic and brainstem. In the neocortical subtype, a reduction in brain volume occurred in the frontal and parietal cortices in the earliest disease stage and progressed across the entire neocortex during the early stage, although with relative sparing of the striatum, pallidum, accumbens area and brainstem. The limbic subtype represented comparative regional vulnerability, which was characterized by early volume loss in the amygdala, accumbens area, striatum and temporal cortex, subsequently spreading to the parietal and frontal cortices across disease stage. The brainstem subtype showed gradual rostral progression from the brainstem extending to the amygdala and hippocampus, followed by the temporal and other cortices. Longitudinal MRI data confirmed that 77.8% of participants at the 2-year follow-up and 84.0% at the 4-year follow-up were assigned to subtypes consistent with estimates from the cross-sectional data. This three-subtype model aligned with empirically proposed subtypes based on age at onset, because the neocortical subtype demonstrated characteristics similar to those found in the old-onset phenotype, including older onset and cognitive decline symptoms (P < 0.05). Moreover, the subtypes correspond to the three categories of the neuropathological consensus criteria for symptomatic patients with Lewy pathology, proposing neocortex-, limbic- and brainstem-predominant patterns as different subgroups of α-synuclein distributions. Among the subtypes, the prevalence of biomarker evidence of amyloid-β pathology was comparable. Upon validation, the subtype model might be applied to individual cases, potentially serving as a biomarker to track disease progression and predict temporal evolution.

BACKGROUND

Patient-rated motor symptoms (PRMS) and clinician-rated motor symptoms (CRMS) often differ in Parkinson's disease (PD).

OBJECTIVE

Our goal was to investigate the determinants and clinical implications of PRMS compared with CRMS in PD.

METHODS

This retrospective, observational cohort study analyzed the cross-sectional associations and longitudinal impacts of PRMS as assessed by the Movement Disorders Society-sponsored Unified PD Rating Scale (MDS-UPDRS) part 2, while controlling for CRMS measured by MDS-UPDRS part 3. Longitudinal analyses used Cox proportional hazards models and multiple linear mixed-effects random intercepts/slope models, adjusting for many clinical predictors. We conducted propensity score matching (PSM) to reinforce our analyses' robustness and surface-based morphometry to investigate neural correlates.

RESULTS

We enrolled 442 patients with early-stage PD. At baseline, regardless of CRMS, PRMS were associated with the severity of postural instability and gait disturbance (PIGD). Notably, PRMS independently and more accurately predicted faster long-term deterioration in motor function than CRMS (Hoehn and Yahr 4, adjusted hazard ratio per +1 point = 1.19 [95% confidence intervals, 1.08-1.32]), particularly in PIGD (PIGD subscore, β-interaction = 0.052 [95% confidence intervals, 0.018-0.086]). PSM confirmed these findings' robustness. Surface-based morphometry suggested that enhanced sensory processing was distinctively associated with PRMS.

CONCLUSIONS

In early-stage PD, PRMS weighed different aspects of symptoms and more effectively predicted motor deterioration compared to CRMS, with distinctive brain structural characteristics. The superior sensitivity of PRMS to subtle declines in drug-refractory symptoms like PIGD likely underlie our results, highlighting the importance of understanding the differential clinical implications of PRMS to prevent long-term motor deterioration. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

배경 및 목적

파킨슨병(PD)은 진행성 신경퇴행성 질환으로, 보행 장애가 흔하고 일상생활에 지장을 주는 대표적인 임상 특징입니다. 저희는 아직 약물 치료를 시작하지 않은 초발 파킨슨병(de novo PD)에서, 선조체 도파민 운반체(DAT) 가용성과 회백질(GM) 부피가 정량적 보행 장애에 미치는 독립적 기여와, 매개를 통한 기여를 규명하고자 했습니다.

방법

이 전향적 연구에서는 영국 브레인뱅크 임상 기준을 충족하는 초발 파킨슨병 환자와, 국소 신경학적 증상 및 파킨슨증이 없는 건강한 대조군(HC)을 원주세브란스기독병원에서 연속적으로 모집했습니다. 모든 참여자는 GAITRite 기반 보행 분석을 받았고, 환자군은 추가로 회백질 부피 측정을 위한 뇌 MRI, 선조체 DAT 가용성 측정을 위한 18F-FP-CIT PET, 그리고 운동·인지 평가를 받았습니다. 탐색적 보행 관련 상관분석 이후, 신경영상 생체지표가 보행 지표에 미치는 영향이 인지 기능이나 운동 증상 중증도에 의해 매개되는지를 인과매개분석(causal mediation analysis)으로 검증했습니다.

결과

초발 파킨슨병 환자 총 122명(평균 연령 69.66세, 여성 45.90%)과 건강한 대조군 177명(평균 연령 72.07세, 여성 51.41%)이 등록되었습니다. 대조군과 비교했을 때 파킨슨병 환자군은 보행 속도가 더 느렸고, 걸음 폭(step length)·활보장(stride length)이 더 짧았으며, 흔듦기(swing time)와 단일지지 시간(single-support time)이 감소하고, 양측지지 시간(double-support time)이 증가했으며, 여러 보행 영역에서 편차(변동성)도 더 컸습니다. 둘레계(limbic) 관련 회백질 부피는 걸음 폭·활보장 및 시간적 위상 구성과 관련이 있었고, 이 관련성은 전반적 인지 기능에 의해 상당 부분 매개되었습니다. 활보장에 대한 대표적 평균 인과매개효과(ACME, 95% 신뢰구간)는 다음과 같았습니다: 후측대상피질(posterior cingulate cortex) 1.9559(0.5606–4.2238), 해마(hippocampus) 3.6722(1.0707–8.2118), 시상(thalamus) 2.8794(0.0408–7.2535), 편도체(amygdala) 4.9696(1.8241–10.3405) — 매개 비율은 19%~50%였습니다. 조가비핵(putamen)의 DAT 가용성이 낮을수록 기립 시간(stance time)과 양측지지 시간의 변동성이 더 컸고, 반면 꼬리핵(caudate)의 DAT 가용성이 낮을수록 흔듦기와 단일지지 시간이 더 길어지고 위상 지표가 변화했습니다. 이러한 관련성은 서동증·경직 점수에 의해 유의하게 매개되지 않았으며, 직접효과(ADE, 95% 신뢰구간)가 유의하게 유지되었습니다: 꼬리핵–흔듦기 시간 −0.0237(−0.0428 ~ −0.0086), 조가비핵–양측지지 시간 변동성 −2.0249(−3.1445 ~ −0.8835).

논의

이 결과는 초발 파킨슨병 환자의 보행 조절에 "이중 경로" 모델이 작동함을 뒷받침합니다 — 선조체 도파민 신경의 손상은 보행 리듬에 직접 영향을 미치고, 둘레계의 위축은 직접적 경로와 인지 기능을 통한 매개 경로 양쪽으로 보행에 영향을 미칩니다. 다만 이번 연구는 약물 치료를 받지 않은 환자군만을 대상으로 했기 때문에, 전체 파킨슨병 환자군으로 일반화하는 데는 제한이 있을 수 있습니다.

Grounded in the conceptual framework of arts-based rehabilitation, this study systematically evaluated the effectiveness of arts-based interventions (ABIs) in alleviating motor and non-motor symptoms among individuals with Parkinson's disease (PD). A systematic review and meta-analysis were conducted following PRISMA and Cochrane guidelines by searching PubMed, Web of Science, Embase, and the Cochrane Library through October 2025. Thirty-four randomized controlled trials (RCTs) were included. Meta-analysis suggested that ABIs significantly improved motor symptoms, as indicated by reductions in UPDRS III scores (SMD = -0.58, 95% CI [-0.81, -0.35]) and improvements in functional mobility assessed by the TUG test (SMD = -0.22, 95% CI [-0.37, -0.07]). Additional benefits were observed in balance (Mini-BESTest, SMD = 0.41, 95% CI [0.10, 0.72]), walking endurance (6MWT, SMD = 0.41, 95% CI [0.11, 0.72]), and gait speed (SMD = 0.34, 95% CI [0.03, 0.65]). Non-motor outcomes also improved, including quality of life (PDQ-39, SMD = -0.29, 95% CI [-0.48, -0.10]) and fall self-efficacy (FES, SMD = -0.41, 95% CI [-0.67, -0.15]). Prediction intervals showed heterogeneous future effect ranges across outcomes. Subgroup analyses indicated that dance-and yoga-based interventions appeared to be associated with relatively consistent effects, whereas no statistically significant changes were observed in depressive symptoms (BDI) or cadence. These findings suggest that ABIs may offer a potentially safe and cost-effective complementary approach for reducing overall symptom burden in PD. Future large-scale, rigorously designed RCTs are warranted to further clarify long-term effects and underlying mechanisms.

BACKGROUND

Parkinson's disease (PD) is a neurodegenerative disorder accompanied by cognitive impairment, which increases a risk of dementia as the condition progresses. Although monoamine oxidase B (MAO-B) inhibitors, such as selegiline, rasagiline and safinamide, are used to treat motor symptoms in PD, their impacts on cognitive performance remain unclear.

OBJECTIVES

This study systematically evaluated and compared the impacts of MAO-B inhibitors on global cognitive performance and performance of individual cognitive domains in patients with PD.

METHODS

Databases were searched through PubMed/Medline, Embase, and Cochrane Library from the inception to May 30, 2025. Thirteen randomized controlled trials (RCTs) evaluating cognitive outcomes in patients with PD treated with selegiline, rasagiline or safinamide were included. Standardized mean differences (SMDs) for global cognition and five cognitive sub-domains were pooled, respectively, using random-effects models. Publication bias and methodological quality were also assessed.

RESULTS

13 RCTs met inclusion criteria. Network meta-analysis showed that only rasagiline significantly improved global cognition compared to placebo (SMD, 0.863; 95% CI, 0.064-1.663), whereas selegiline and safinamide did not show any statistical difference when compared to placebo. None of the MAO-B inhibitors demonstrated significant effects on specific cognitive sub-domains (ie, attention, executive function, memory, language, and visuospatial abilities).

CONCLUSIONS

Rasagiline may provide global cognitive benefits in PD, but MAO-B inhibitors, including rasagiline, generally did not demonstrate significant effects on individual cognitive domains. These findings suggest limited cognitive impacts of MAO-B inhibitors beyond managing the motor symptoms. Further large-scale, long-term studies using domain-specific cognitive assessments are warranted to clarify their roles in cognitive performance in patients with PD.

BACKGROUND AND OBJECTIVES

In Parkinson disease (PD), deafferentation of nigral dopaminergic neurons to the striatum leads to striatal dopamine depletion and impaired direct and indirect basal ganglia pathways, which in turn reduce thalamocortical excitation and ultimately lead to parkinsonism. Therefore, understanding the manifestation of motor deficits requires the evaluation of degree of striatal dopamine depletion and the related changes in striatal functional connectivity (FC) as the nigrostriatal system degenerates.

METHODS

In this cross-sectional study, we recruited 326 patients with PD and 29 patients with idiopathic REM sleep behavior disorder who underwent brain resting-state functional MRI, N-(3-[18F]fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane PET, and the Unified Parkinson's Disease Rating Scale assessment. A total of 40 healthy controls (HCs) were recruited to determine the extent of striatal dopamine depletion in patients with PD spectrum, and another 40 HCs were recruited to compare corticostriatal FC with that of the patient group. Using a sliding window method, we examined changes in FC with seed regions in the anterior and posterior caudate and putamen on both the more affected and less affected sides as the mean putaminal dopamine declined from 70% to 20%.

RESULTS

The more affected side of the posterior caudate showed elevated FC with the primary motor cortex and paracentral lobule, which was present before approximately 50% putaminal dopamine depletion, peaked around this depletion level, and disappeared when caudate dopamine was abnormally reduced. The more affected side of the posterior putamen showed reduced FC with the superior parietal cortex, precuneus, and cuneus when putaminal dopamine depletion reached approximately 50%, after which the motor symptoms deteriorated linearly.

DISCUSSION

In summary, our study demonstrated that the FC between the posterior caudate and primary motor cortex was elevated from the prodromal to early stages of PD, a period in which motor symptom progression remained relatively slow. The FC between the posterior putamen and motor cortex remained unchanged, while its connectivity with the posterior cortical regions declined from the onset of motor symptoms, coinciding with the accelerated progression of motor deterioration. Collectively, our study demonstrated that corticostriatal connectivity undergoes functional reorganization across the different stages of PD, which is associated with motor symptoms.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are promising candidates for Alzheimer's disease (AD) and Parkinson's disease (PD). However, their effects in non-diabetic populations, independent of metabolic confounding, remain unclear. We evaluated the effects of GLP-1RAs on cognition, clinical outcomes, biomarkers, and safety in non-diabetic individuals with PD, AD, and mild cognitive impairment. We assessed the clinical meaningfulness of these effects using minimal clinically important difference thresholds. Relevant studies were retrieved from PubMed, Embase, and Web of Science from inception to November 2025. A random-effects meta-analysis was applied to calculate standardized mean differences (SMDs), mean differences (MDs), and risk ratios with 95% confidence intervals (CIs). The protocol was registered in PROSPERO (CRD420261277032). Fourteen randomized controlled trials enrolling 1260 participants were included. GLP-1RAs showed a small statistically significant improvement in global cognition (SMD 0.14, 95% CI 0.01 to 0.27; I2 = 7%), supported by high-certainty evidence. Despite statistical significance, findings suggest only a trivial probability (1%) of a clinically important benefit. Conversely, GLP-1RAs were associated with poorer verbal fluency (SMD - 0.43, 95% CI - 0.79 to - 0.08; I2 = 0%), supported by high-certainty evidence. For clinical severity, function, depression, and PD-related outcomes, pooled estimates generally favored GLP-1RAs, but none reached statistical significance. A significant between-disease subgroup difference was observed for function. In the PD subgroup, GLP-1RAs significantly improved depression symptoms relative to control (MD - 2.09, 95% CI - 3.99 to - 0.20; I2 = 0%). Nevertheless, this magnitude of improvement remained below the threshold for clinically important benefit. Biomarker findings were inconsistent across trials. GLP-1RAs significantly reduced weight and were associated with poorer tolerability and increased gastrointestinal adverse events. Current evidence provides no convincing support for a clinically meaningful or disease-modifying effect of GLP-1RAs, and adverse effects may limit their clinical utility. Large-scale trials are needed to definitively weigh potential benefits against associated risks.

UNLABELLED

Objectives: This study aimed to assess the overall and cause-specific standardized mortality ratios (SMRs) in patients diagnosed with Parkinson's disease (PD).

METHODS

A systematic review was conducted, focusing on studies that evaluated SMRs for all-causes and specific causes in PD patients compared to the general population. Searches were performed extensively in Medline, Embase, and Cochrane databases to compile relevant literature. A meta-analysis was subsequently conducted to evaluate all-cause, sex-specific, region-specific, and cause-specific SMRs in individuals with PD.

RESULTS

Twenty-one studies including 26,114 PD patients and 10,247 deaths from 12 European, 4 Asian, 3 Oceanian, 1 North American, and 1 Middle Eastern country met the inclusion criteria. The overall SMR analysis revealed that PD patients exhibited a 1.617-fold higher risk of all-cause mortality compared to the general population (SMR 1.617, 95% confidence interval [CI] 1.295-2.020, p < 0.001). Region-specific analysis showed significant SMR increases across all regions. Sex-specific analysis indicated elevated SMRs for both women (SMR 1.702, 95% CI 1.426-2.033, p < 0.001) and men (SMR 1.588, 95% CI 1.365-1.848, p < 0.001). PD onset before 60 years of age was associated with a higher, albeit not statistically significant, SMR compared to onset after 60 (SMR 1.991, 95% CI 1.313-3.021 vs. SMR 1.589, 95% CI 1.109-2.277). Cause-specific analyses revealed significantly increased SMRs for pneumonia (SMR 3.414, 95% CI 2.227-5.234, p < 0.001), cerebrovascular accidents (CVAs) (SMR 1.484, 95% CI 1.048-2.102, p = 0.026), cardiovascular disease (SMR 1.449, 95% CI 1.156-1.816, p = 0.001), and suicide (SMR 2.049, 95% CI 1.383-3.035, p < 0.001), with no significant increase observed for cancer-related mortality.

CONCLUSION

These findings highlight the increased mortality risk in PD patients, particularly due to causes such as pneumonia and CVA. .

BACKGROUND AND OBJECTIVES

Smoking has been reported to be inversely associated with Parkinson disease (PD). However, the higher premature mortality among smokers may act as a competing risk, potentially confounding the inverse association. Because smoking behavior is dynamic, the long-term impact of changes among current smokers remains unclear. We investigated the association between longitudinal changes in smoking status and the risks of PD and all-cause mortality using a competing risk framework and an age-based time scale with left truncation.

METHODS

This large-scale retrospective cohort study included current smokers aged 40 years or older who participated in all 3 examination periods of the Korean National Health Screening. Based on longitudinal changes from the initial smoking status to 2 subsequent time points, participants were categorized into 4 groups: persistent smokers, recent quitters, sustained quitters, and relapsed smokers. Cumulative incidence functions for PD were estimated, with all-cause mortality as a competing event, and subdistribution hazard ratios (sHRs) with 95% CIs were obtained using Fine-Gray models.

RESULTS

Data were obtained from 410,489 eligible participants (mean age 51.7 ± 9.0 years; 93.5% male). During a median 9.1-year follow-up, persistent smokers exhibited the lowest risk of PD. Both recent quitters and sustained quitters had higher PD risk than persistent smokers (sHR 1.60 [1.41-1.82] and 1.61 [1.42-1.81]), whereas relapsed smokers did not differ from persistent smokers (sHR 1.05 [0.87-1.28]). For all-cause mortality, recent and sustained quitters had 3% and 17% lower risks, respectively, compared with persistent smokers, whereas relapsed smokers showed no significant difference.

DISCUSSION

The observed pattern of PD risk was suggested to be primarily associated with current smoking status rather than cumulative smoking exposure, as relapsed smokers and recent quitters, who had the same number of smoking time points, showed distinctly different risks. Furthermore, 1 time point (∼2 years) of short-term abstinence did not attenuate the protective association. Mortality was lowest in sustained quitters while recent quitters showed a marginal trend toward lower risk, supporting the benefit of early cessation. Interpretation should be cautious because smoking status was assessed at 3 time points, subsequent changes were unknown, and most participants were male.

Animal models of the pathology of Parkinson's disease (PD) have provided most of the treatments to date, but the disease is restricted to human patients. In vitro models using human pluripotent stem cell (hPSC)-derived neural organoids have provided improved access to study PD aetiology. This study established a method to generate human striatal-midbrain assembloids (hSMAs) from hPSCs for modelling alpha-synuclein (α-syn) propagation and recapitulating basal ganglia circuits, including nigrostriatal and striatonigral pathways. Human striatal organoids and midbrain organoids were generated using a stepwise differentiation protocol from hPSCs, and both regionalized neural organoids were assembled to form hSMAs, mimicking some basal ganglia circuits. Both the nigrostriatal and striatonigral pathways were present, and the neurons, such as dopaminergic neurons and GABAergic neurons, were electrophysiologically active in the hSMAs. Development of hSMAs in the presence of increased α-syn from SNCA overexpression induced nigrostriatal system damage, which is typical of the disease. Using the α-syn-linker-mKO2 reporter and a bimolecular fluorescence complementation system, we demonstrated that fluorescent α-syn was retrogradely transported from the striatal area to dopaminergic neurons of the midbrain area and exhibited α-syn aggregates and Lewy body-like inclusions. Furthermore, phosphorylated and detergent-resistant α-syn aggregates, similar to the pathological form in human patients, accumulated in the midbrain area of hSMAs. Treatment with a protein aggregation inhibitor (Anle138b) and an autophagy inducer (rapamycin) reduced α-syn aggregation, indicating the potential of hSMAs for drug testing. This study established hSMAs as a novel platform for modelling PD, demonstrating α-syn propagation and associated neural pathologies. These assembloids offer significant potential for developing therapeutic strategies and understanding the mechanisms of PD progression.

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.

BACKGROUND

Dystonia and Parkinson's disease (PD) exhibit clinical and genetic overlap, but the relevance of dystonia gene variants in PD remains unclear.

OBJECTIVE

The aim was to assess the frequency of dystonia-linked pathogenic variants in PD.

METHODS

We screened sequencing data from 15,684 individuals (8272 PD, 3200 atypical parkinsonism, and 4212 unaffected) from the Global Parkinson's Genetics Program (GP2) and Accelerating Medicines Partnership-Parkinson's Disease (AMP-PD) for variants in genes linked to isolated dystonia, dystonia-parkinsonism, and myoclonus-dystonia.

RESULTS

Pathogenic variants were identified only in PD patients. Forty-five PD individuals (0.54%) carried 26 distinct (likely) pathogenic variants in nine dystonia-linked genes, most frequently in GCH1, followed by VPS16.

CONCLUSION

Though rare, pathogenic variants in dystonia-linked genes are present in clinically and pathologically diagnosed PD. Our results reinforce GCH1 as a PD-relevant gene with clinical implications, whereas variants identified in other genes are rare and of uncertain relation to the PD phenotype. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Although growing evidence suggests that cholinergic basal forebrain degeneration is linked to cognitive impairment and axial motor symptoms in Lewy body disorders, the cholinergic contribution to their prodromal phase remains largely unknown. Herein, we aimed to address three important yet unresolved problems focusing on prodromal Lewy body disorders: (i) to examine whether and where basal forebrain degeneration begins; (ii) to determine how such alterations are related to other brain morphometric changes and monoaminergic deficits; and (iii) to investigate the extent to which basal forebrain atrophy contributes to the clinical picture. We included 93 patients with polysomnography-confirmed isolated REM sleep behaviour disorder (iRBD), 33 with de novo Parkinson's disease (PD) with a premorbid history of RBD (dnPDRBD) and 36 healthy controls. Participants underwent baseline assessments including volumetric MRI, 18F-N-3-fluoropropyl-2β-carboxymethoxy-3β-(4-iodophenyl)-nortropane PET scan, the Movement Disorders Society-Unified Parkinson's Disease Rating Scale and neuropsychological evaluations. Regional volumes of cholinergic nuclei 1, 2 and 3 (Ch1-3) and cholinergic nucleus 4 (Ch4) were extracted using probabilistic maps, and voxel-based and surface-based morphometric analyses were applied to identify basal forebrain atrophy-associated cortical and subcortical regions. Subgroups of patients with iRBD underwent repeated motor and cognitive assessments (38 and 34 patients for 2 and 4 years, respectively). Among the basal forebrain complex, Ch4 volumes, but not Ch1-3 volumes, were significantly reduced in patients with iRBD. This reduction was positively correlated with limbic regions, including the amygdala and cingulate cortex, and, to a lesser extent, with the neocortical regions, particularly the frontal and temporal cortices. With respect to clinical symptoms, both Ch1-3 and Ch4 volume reductions were modestly associated with severe axial motor symptoms. Additionally, Ch1-3 volume reduction was associated with higher incidence of dementia and faster progression of memory impairment, whereas Ch4 volume reduction was associated with faster progression of limb bradykinesia. Using a multimodal imaging approach, we found that iRBD patients who later converted to PD showed predominant monoaminergic deficits but variable cholinergic involvement, and these patterns were similar to those observed in the dnPDRBD group. Conversely, iRBD patients who later converted to dementia with Lewy bodies showed predominant cholinergic deficits but variable monoaminergic involvement. This comprehensive analysis provides important implications for understanding how cholinergic basal forebrain degeneration is associated with brain morphometric changes, clinical outcomes and monoaminergic degeneration during the prodromal phase of Lewy body disorders.

BACKGROUND

Resilience factors are crucial in the progression of neurodegenerative diseases. However, it remains unclear whether a genetic predisposition to cognitive reserve influences clinical heterogeneity in the prognosis of Parkinson's disease (PD).

OBJECTIVES

The aim is to evaluate the utility of polygenic scores (PGSs) for cognitive reserve proxies, including intelligence (INT), educational attainment (EA), and occupational attainment (OA), in predicting the clinical progression of PD.

METHODS

Genetic and clinical data for progression of PD (progression to Hoehn and Yahr stage ≥3, progression to a Montreal Cognitive Assessment score ≤24, and occurrence of psychosis) were obtained from the Accelerating Medicine Partnership Parkinson's Disease database. We conducted multivariate Cox regression analysis, adjusting for relevant covariates, including years of education, variants in APOE, GBA1, LRRK2, and other cognitive reserve-related PGSs.

RESULTS

All cognitive reserve-related PGSs significantly reduced the risk of cognitive decline, and EA-PGS (hazard ratio [HR], 0.550; 95% confidence interval [CI], 0.447-0.676; P < 0.001) remained significant after controlling for INT-PGS and OA-PGS. EA-PGS (HR, 0.805; 95% CI, 0.672-0.964; P = 0.019) was significantly associated with better motor prognosis after controlling for other PGSs. OA-PGS was linked to a decreased risk of developing psychosis in PD and remained significant after adjusting for others (HR, 0.784; 95% CI, 0.631-0.975; P = 0.029).

CONCLUSIONS

Genetic proxies of cognitive reserve are associated with a reduced risk of cognitive decline, motor progression, and development of psychosis in PD. These findings may enhance our understanding of individual differences in resilience in progression of PD. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BACKGROUND

We aimed to compare the acute and retention effects of motor training alone versus its combination with transcranial direct current stimulation (tDCS) on motor symptoms in Parkinson's disease (PD) patients.

METHOD

Two independent reviewers searched for randomized controlled trials that applied motor training with active tDCS versus sham tDCS with motor function as an outcome measure for patients with PD. Random-effects meta-analyses were conducted to calculate standardized mean differences between the effects of motor training with active tDCS versus sham tDCS on motor function. A total of 16 randomized controlled trials (344 PD patients) were eligible for meta-analysis, resulting in 75 motor function comparisons for data synthesis.

RESULTS

Motor training with active tDCS showed positive acute effects on overall motor function compared to motor training with sham tDCS, particularly improving step length and gait speed. Moderator variable analyses indicated that these acute effects persisted regardless of the number of sessions or the targeted brain regions for tDCS. Meta-regression analysis showed that a higher proportion of female participants and shorter PD duration were associated with greater acute effects. No positive retention effects of motor training with active tDCS on overall motor function were observed.

CONCLUSIONS

Our results suggest that combining motor training with tDCS improves motor function, particularly in gait-related parameters, in PD patients. However, these effects were not sustained over time, highlighting the temporary nature of the benefits. Sex differences may influence the acute effects of combined motor training and tDCS interventions.

BACKGROUND

Parkinson disease (PD) presents motor and nonmotor challenges that significantly affect quality of life. Telemedicine has emerged as a promising approach to deliver interventions, including exercise performed through remote equipment (e-Exercise), cognitive behavioral training sessions conducted remotely (e-Cognitive), and consultations conducted through remote devices (e-Visits), yet their comparative effectiveness remains unclear.

OBJECTIVE

This paper aimed to evaluate the effectiveness of telemedicine interventions on motor and nonmotor outcomes in PD and compare the efficacy of e-Exercise, e-Cognitive, and e-Visits.

METHODS

A systematic review and network meta-analysis were conducted by searching PubMed, MEDLINE, Embase, Cochrane CENTRAL, and Web of Science through November 2024. Randomized controlled trials comparing telemedicine interventions with usual care were included. Outcomes assessed included total motor symptoms, quality of life, cognitive function, depressive and anxiety symptoms, fear of falling, 6-minute walk test, walking velocity, balance ability, and timed up and go. Two investigators independently performed study selection, data extraction, and risk-of-bias assessment using the Cochrane risk of bias 2 tool. Data synthesis included (1) pairwise meta-analyses using random-effects models to calculate standardized mean differences (SMDs) and mean differences; and (2) Bayesian network meta-analysis integrating direct and indirect comparisons to rank intervention efficacy, with transitivity and inconsistency evaluated. Evidence quality was graded using GRADE (Grading of Recommendations, Assessment, Development and Evaluation), incorporating risk of bias, heterogeneity (I²>50% indicating substantial heterogeneity), precision, and publication bias (Egger test). Statistical heterogeneity was quantified by τ² and I².

RESULTS

A total of 23 studies involving 1330 participants were included. Pairwise meta-analyses demonstrated that telemedicine significantly improved total motor symptoms (SMD=-0.61, 95% CI -1.19 to -0.4), cognitive function (SMD=0.58, 95% CI 0.15-1.01), depressive symptoms (SMD=-0.46, 95% CI -0.88 to -0.04), anxiety symptoms (SMD=-0.57, 95% CI -1.10 to -0.03), fear of falling (SMD=-0.48, 95% CI -0.77 to -0.19), and 6-minute walk test performance (mean difference=18.98, 95% CI 16.06-21.90 meters). The network meta-analysis revealed that e-Exercise was most effective for improving total motor symptoms (SMD=-1.01, 95% credible interval [CrI] -1.96 to -0.05) and 6-minute walk test performance. e-Cognitive was most effective for enhancing quality of life (SMD=0.39, 95% CrI 0.06-0.73) and cognitive function (SMD=1.02, 95% CrI 0.38-1.66), and reducing depressive (SMD=-1.28, 95% CrI -1.61 to -0.96) and anxiety symptoms (SMD=-1.07, 95% CrI -1.40 to -0.75). e-Visits had a limited impact across outcomes. Evidence quality was moderate or high for motor symptoms, quality of life, and depression, but low or very low for other outcomes.

CONCLUSIONS

Telemedicine is effective for improving motor and nonmotor outcomes in PD. e-Exercise is optimal for motor function and physical performance, while e-Cognitive is most effective for psychological and cognitive challenges. These findings highlight the importance of tailoring telemedicine programs to address specific therapeutic needs in PD management.

TRIAL REGISTRATION

PROSPERO CRD42024628687; https://www.crd.york.ac.uk/PROSPERO/view/CRD42024628687.

INTRODUCTION

Although growing evidence suggests that aerobic exercise has beneficial effects on motor symptoms in patients with Parkinson's disease (PD), it remains unclear which specific aerobic exercise regimen optimizes improvement in these symptoms. This study aimed to investigate the difference in the effects of aerobic exercise on motor function in patients with PD according to exercise intervention protocols.

METHODS

Through 28 qualified studies with randomized controlled trials, we assessed motor function using either the Unified PD Rating Scale (UPDRS) III or Movement Disorder Society-UPDRS III as an outcome measure. We employed random effects meta-analysis models to obtain standardized mean differences and 95 % confidence intervals (CIs). Moderator variable analyses were conducted based on exercise type (aerobic exercise vs. aerobic-based combined exercise), duration (<60 min vs. ≥60 min per session), frequency (<four vs. ≥four sessions per week), period (<12 weeks vs. ≥12 weeks), and intensity (low-to-moderate vs. moderate-to-high).

RESULTS

Aerobic exercise interventions demonstrated significant improvements in overall motor function. Although all categories were significantly effective in improving motor function, aerobic-based combined exercise had a greater effect size on motor symptoms compared to aerobic exercise alone. Additionally, ≥60 min per session showed a significantly increased effect size compared to <60 min per session. The impact of aerobic exercise did not differ based on exercise frequency, period, or intensity.

CONCLUSIONS

Our observations suggest that aerobic-based combined exercise and exercise sessions lasting 60 min or longer may be associated with greater improvements in motor symptoms in patients with PD.