BACKGROUND:Progression of substantia nigra pars compacta (SNc) iron content in early-stage Parkinson's patients (PD) is poorly understood. OBJECTIVE:To determine if nigral iron measured by quantitative susceptibility mapping (QSM) with zero-referencing can track disease progression in early-stage PD. METHODS:Thirty-four early-stage PD patients and 35 matched controls were recruited. Iron content in the SNc and related regions were obtained using QSM with zero-referencing at both baseline and 1-year follow-up, along with clinical metrics. RESULTS:Of seven clinic metrics and five regional iron measures, only Movement Disorder Society-Unified Parkinson's Disease Rating Scale-Part II (MDS-UPDRS-II) (P = 0.046) and SNc iron (P = 0.0025 for cerebrospinal fluid zero-referencing; P = 0.014 for whole-brain zero-referencing) showed significant changes in PD subjects in the 1-year epoch. The changes in SNc iron were also correlated with changes in MDS-UPDRS-II (P = 0.004). CONCLUSION:Nigral iron content measured by zero-referencing QSM can be used to track disease progression in early-stage PD over the 1-year epoch. © 2026 International Parkinson and Movement Disorder Society.
BACKGROUND:Bilateral pallidal deep brain stimulation (GPi-DBS) is effective for dystonia. Long-term evolution of therapeutic benefit and emergence of parkinsonism have not been systematically characterized. OBJECTIVES:To assess 15-year dystonia outcomes and characterize parkinsonism after bilateral GPi-DBS. METHODS:Dystonia severity and disability were evaluated at baseline,1, 3, and 15 years postoperatively with the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). Parkinsonism was assessed at last visit using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale-Part III and freezing of gait (FoG) questionnaire. RESULTS:Of 17 patients reassessed at 15 years, 41% maintained clinical benefit. Parkinsonism was observed in 94%, predominantly axial, with self-reported FoG in 67%. Higher baseline BFMDRS-Motor scores predicted last follow-up axial parkinsonism (R = 0.800, P < 0.001). CONCLUSIONS:Over 15 years, interindividual therapeutic benefit diverged while axial parkinsonism emerged in nearly all patients. These findings highlight the need for systematic long-term monitoring extending beyond dystonia control after GPi-DBS. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
BACKGROUND:Florzolotau (18F) positron emission tomography (florzolotau PET) enables high-contrast in vivo detection of four-repeat tau pathology in progressive supranuclear palsy (PSP), but whether longitudinal tau imaging reflects disease progression remains unclear. OBJECTIVES:To explore longitudinal tau accumulation using florzolotau PET and evaluate its association with clinical progression in PSP. METHODS:Twenty-six patients with PSP (18 Richardson's syndrome [PSP-RS], 8 non-RS) and 10 age- and sex-matched healthy controls (HCs) underwent florzolotau PET, magnetic resonance imaging, and clinical assessments at baseline and after 1 year. Regional standardized uptake value ratios (SUVRs) were extracted across 57 regions of interest. Partial least squares (PLS) multivariate analyses revealed regions with elevated baseline SUVR and longitudinal increase (ΔSUVR) in PSP relative to HCs, alongside regions where ΔSUVR was associated with changes in PSP Rating Scale scores. RESULTS:At baseline, tau deposition was most prominent in the globus pallidus (GP) and midbrain in patients with PSP. Longitudinal tau increases were observed in the GP, frontoparietal cortex, and cerebellar white matter, and minimal progression was observed in the midbrain. GP tau accumulation exhibited the strongest association with clinical progression in the PLS model among PSP-RS and a univariate correlation (Spearman's ρ = 0.688, P = 0.002). CONCLUSIONS:This study provides in vivo evidence of the spatiotemporal progression of tau pathology in PSP. In the GP, tau accumulation emerges early and continues to increase with clinical deterioration. These findings support the utility of florzolotau PET for monitoring disease progression and as a biological outcome measure in tau-targeted therapeutic trials. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
BACKGROUND:Understanding the heterogeneity of Parkinson's disease (PD) is essential to guide patient care, prognosis, and treatment. OBJECTIVE:We used 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET), 18F-N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane (18F-FP-CIT) PET, and Subtype and Stage Inference (SuStaIn) algorithm to define subtypes in drug-naive patients with PD. METHODS:A total of 147 de novo PD patients and 38 healthy individuals who underwent 18F-FDG PET, 18F-FP-CIT, and brain magnetic resonance imaging were enrolled. The SuStaIn algorithm was employed to identify FP-CIT- and FDG-based subtypes. Motor and nonmotor features were compared between them. Correlations were analyzed to assess the associations between the progression stage and motor or cognitive scores within each subtype. RESULTS:Two distinct subtypes were identified: subtype 1 (fronto-striatal hypometabolic) and subtype 2 (mixed hypermetabolic-posterior hypometabolic). In subtype 1, striatal dopamine transporter (DAT) loss was accompanied by decreases in frontal and caudate metabolism at earlier stages, whereas hypometabolism in the posterior cortical and limbic regions appeared at later stages. In subtype 2, striatal DAT deficit and hypermetabolism of the putamen, medial temporal, and anterior cingulate cortices and lateral occipital hypometabolism appeared in the early stages. This metabolic reduction subsequently involved parieto-temporal, frontal, and limbic regions. Motor deficits were comparable between the subtypes. Those with subtype 2 exhibited poorer cognitive and olfactory performance, higher anxiety scores, higher Rapid Eye Movement Behavior Disorder Screening Questionnaire scores, and lower putaminal DAT availability and asymmetry than in subtype 1. The stage correlated with cognitive decline only in subtype 2, with a marginally significant stage-by-group interaction. CONCLUSIONS:De novo PD can be classified into two distinct metabolic subtypes: fronto-striatal hypometabolic and mixed hypermetabolic-posterior hypometabolic, with nonmotor manifestations being more severe in the latter. © 2026 International Parkinson and Movement Disorder Society.
INTRODUCTION:Network attack tolerance (NAT) measures the brain's ability to sustain information flow despite the loss of critical brain regions. In Parkinson's disease (PD), NAT has been linked to cognitive and motor function. However, it remains unclear how dopaminergic degeneration shapes NAT, and whether it relates to motor symptom progression. OBJECTIVE:To examine dopamine deficiency-related changes in NAT across the early PD disease continuum and its association with longitudinal motor outcomes. METHODS:We used cross-sectional resting-state functional magnetic resonance imaging of 28 healthy controls, 60 prodromal, and 94 clinical PD patients to create graph-theoretical networks. NAT was assessed at the global and subnetwork levels by calculating the global efficiency upon iterative node removal at different network densities. Using linear mixed-effects models, we assessed how putaminal dopamine transporter (DaT) binding or disease status affected NAT, controlling for network density, age, sex, and education. Baseline somatomotor (SMN) NAT was examined as a predictor of motor symptom progression in 145 patients. RESULTS:Lower putaminal DaT signal was associated with higher SMN NAT across groups. PD patients exhibited elevated SMN NAT relative to controls. Neither global nor other subnetworks showed effects. While the effect of baseline SMN NAT on motor progression was not significant, an exploratory analysis (Johnson-Neyman) suggested that higher SMN NAT may associate with slower motor decline across most of the observed NAT range. CONCLUSIONS:Dopaminergic depletion is associated with a targeted SMN reorganization, potentially maintaining network information flow despite progressive hub loss. Whether this reorganization represents compensation or a consequence of progressive pathology requires further longitudinal assessment. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
BACKGROUND:Mutations in the glucocerebrosidase 1 (GBA1) and leucine-rich repeat kinase 2 (LRRK2) genes are associated with Parkinson's disease (PD) phenotype. OBJECTIVE:To asses the contribution of genetic status to long-term survival of patients with PD. METHODS:A total of 2039 PD patients with Ashkenazi ancestry were genotyped for mutations in the GBA1 and LRRK2 genes between 2005 and 2025 at Tel-Aviv Medical Center. National death registries were studied to identify date of death. The primary endpoint was defined as overall survival. Regression analysis was performed to assess the risk for each group. Separate analysis comparing early-onset PD (EOPD, age of onset <50) to late-onset PD (LOPD) was also conducted. RESULTS:Mortality hazard ratios (HRs) were increased for GBA1-PD (1.52; 95% confidence interval [CI]: 1.27-1.81) and reduced for LRRK2-PD (0.76; 95% CI: 0.59-0.96) compared to idiopathic PD (iPD). Median survival for all groups was lower than expected, ranging from 18 to 20 years from onset. Women were associated with lower mortality HR = 0.69 (95% CI: 0.60-0.79). EOPD patients had increased overall disease duration compared to LOPD, with lower survival and age at death (67.8 ± 9.3 vs. 80.2 ± 7.3), consistent across genetic subgroups. CONCLUSIONS:PD is associated with reduced longevity compared to population norms. LRRK2-PD has reduced mortality, and GBA1-PD has increased mortality compared to iPD. EOPD is associated with longer disease duration and lower overall life expectancy compared to patients with LOPD. These findings can assist in discussing prognosis with patients and demonstrate the need for research directed at these subgroups to identify factors and interventions to help personalize patient care. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
BACKGROUND:Despite increasing numbers of women practising neurosciences, gender disparities persist in academic authorship. Focused evaluation of authorship patterns within movement disorders remains limited. OBJECTIVE:To examine trends in women authorship across movement disorders publications in high-impact neurology journals and movement disorders-specific journals across a decade. METHODS:We conducted a cross-sectional bibliometric analysis of movement disorder-related articles published in 2014 and 2024 in 20 neurology journals with the highest impact factor and two flagship movement disorders journals related to the International Parkinson and Movement Disorders Society. Women authorship proportions were calculated overall and by article type. First-to-senior authorship representation ratios were examined, and associations with journal impact factors were explored. RESULTS:A total of 919 articles (9431 authors) were analyzed in 2024 and 755 articles (5801 authors) in 2014. Overall women authorship was 41.1% in 2024 compared with 38% in 2014 and senior (last) women authorship was 37% (2024) and 36% (2014). In 2024, women accounted for 43% of first and 31% of senior authors in Movement Disorders, compared with 41% and 27%, respectively, in 2014. A representation gap from first-to-senior authorship persisted across most journals. No clear association was observed between journal impact factor and women authorship. CONCLUSIONS:Over the past decade, women's representation in movement disorders publishing improved at first authorship levels but remained stagnant at low levels in senior authorship roles. Persistent lacuna between first and senior women authorship is an underexplored gap that may reflect a combination of structural barriers, cohort effects, and life-course factors. © 2026 International Parkinson and Movement Disorder Society.
BACKGROUND:Deep-learning models are capable of predicting age from retinal scans and the difference between this and chronological age, retinal age gap, has been shown to be significantly associated with risk of mortality, cardiovascular diseases, and kidney failure. OBJECTIVE:Our aim was to investigate the association between Parkinson's disease (PD) and retinal age gap in a large, real-world population. METHODS:The deep-learning model was trained and validated using 19,200 fundus images from 11,052 participants in the UK Biobank study. This cross-sectional analysis used data from the AlzEye study, a retrospective cohort of 154,830 patients aged 40 years and older. Retinal age gap was calculated as the difference between the retina-predicted age by the model and chronological age. Adjusted linear mixed-effects models were used to assess the association between PD and retinal age gap. RESULTS:A total of 776 individuals with PD (mean [standard deviation] age, 69.6 [8.9] years; 42.9% female) and 93,944 without PD (mean age, 57.6 [13.7] years; 51.6% female) were included. After adjusting for confounders, retinal age gap was significantly greater in those with PD (β, 5.92, 95% confidence interval: 5.33-6.51; P < 0.001). Stratified analyses showed a larger retinal age gap across all age deciles ≥50 years. Within the PD group, males and individuals with diabetes had greater retinal age gaps than females and individuals without diabetes. CONCLUSIONS:Individuals with PD aged ≥50 years demonstrate older retinal age relative to chronological age. Retinal age gap may serve as a biomarker of accelerated aging in PD. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
BACKGROUND:Preclinical and human brain postmortem studies indicate that progressive supranuclear palsy (PSP) is associated with increased expression of the retrotransposon Long Interspersed Nuclear Element-1 (L1Hs). L1Hs activity initiates an innate immune response that leads to neuroinflammation and neurodegeneration, which can be attenuated by inhibiting the L1Hs-encoded reverse transcriptase. TPN-101 is a potent inhibitor of the L1Hs reverse transcriptase. OBJECTIVE:The objective of this study was to assess the safety, pharmacokinetics, and biomarker and clinical effects of TPN-101 in patients with PSP. METHODS:A double-blind, placebo-controlled, parallel-group study randomly assigned patients with probable PSP to receive TPN-101 100, 200, or 400 mg, or placebo daily for 24 weeks. Following the double-blind period, all patients received open-label TPN-101 400 mg daily for 24 weeks. The primary outcome was the incidence and severity of treatment-emergent adverse events. Biomarker, clinical, and TPN-101 pharmacokinetic assessments were conducted throughout the study. RESULTS:Forty-two patients were randomly assigned to TPN-101 100 mg (N = 11), 200 mg (N = 10), 400 mg (N = 11), or placebo (N = 10). TPN-101 was well tolerated, with no notable safety differences between any drug dose and placebo. Greater reductions in cerebrospinal fluid levels of neurofilament light chain with increasing dose were seen in patients taking TPN-101 during the double-blind period, compared with an increase in the placebo arm. There were no differences among the treatments on the Progressive Supranuclear Palsy Rating Scale during the double-blind period. CONCLUSIONS:The safety, pharmacokinetics, and reductions in biomarkers of neuroinflammation and neurodegeneration warrant future trials powered to detect clinical effects of TPN-101 in PSP. © 2026 International Parkinson and Movement Disorder Society.
In celebration of the 40-year legacy of Movement Disorders Journal (MDJ), this historical reflection traces the evolution of epidemiological research in movement disorders through the lens of papers published in MDJ from 1986 through 2025. Over four decades, the discipline has transformed from clinic-based descriptive observations into population-based methodologies, with both genetic and environmental factors taken into consideration. The initial decade (1986-1995) established foundational measures of movement disorders and identified key environmental risks. These clinic-based studies expanded during the second decade (1996-2005) into door-to-door community prevalence studies and health services research utilizing administrative databases. The third decade (2006-2015) marked a paradigm shift driven by genetic epidemiology (particularly the mapping of global LRRK2 variants), gene-environment interactions, and the characterization of prodromal biomarkers. The modern era (2016-2025) has embraced race-ethnicity diversity, pharmacoepidemiology, and advanced causal inference methods to control for time-varying factors. Together, these epidemiological works in MDJ chart a historical trajectory toward precision medicine, delivering the infrastructure to define at-risk populations and deploy trial-ready cohorts for disease-modification trials. © 2026 International Parkinson and Movement Disorder Society.
BACKGROUND:The long-latency reflex (LLR), particularly LLR II elicited by peripheral stimulation, is considered a transcortical reflex and may reflect cortical-subcortical excitability. Its relevance as a biomarker for subthalamic nucleus deep brain stimulation (STN-DBS) optimization in Parkinson's disease remains unclear. OBJECTIVE:To examine whether LLR II responses are modulated by STN-DBS stimulation parameters and dopaminergic medication, and to explore the potential mechanisms underlying STN-DBS-related motor improvement. METHODS:Thirteen Parkinson's disease patients with STN-DBS underwent median nerve stimulation to assess LLR II, quantified as the peak abductor pollicis brevis electromyography (EMG) response at 50-70 ms, normalized to prestimulus baseline EMG, across different stimulation intensities, contacts, and frequency conditions, including 60 Hz, 130 Hz, and an energy-matched condition. A single DBS pulse was also paired with the cortical N20 response at N20 - 2 ms (T1) or N20 + 10 ms (T2) to assess timing-dependent effects. Sixteen Parkinson's disease patients without DBS were tested in medication-on and -off states. Motor severity was assessed using tested-side Unified Parkinson's Rating Scale Part III (UPDRS III) subscores. RESULTS:LLR II ratio was higher at 70% and 100% of clinical stimulation intensity than during DBS-off (P = 0.0029 and P = 0.042, respectively). LLR II was higher at the most effective than at the least-effective contact (P = 0.042). The clinically most-effective frequency showed higher LLR II than DBS-off and the least-effective frequency (both P = 0.048). In the single-pulse DBS experiment, LLR II increased only at T2 compared to DBS-off (P = 0.047). No medication-state difference was observed. CONCLUSIONS:LLR II was modulated by clinically effective STN-DBS parameters but was insensitive to dopaminergic medication, supporting its utility as a biomarker of DBS-related sensorimotor circuit modulation, potentially involving the hyperdirect pathway. © 2026 International Parkinson and Movement Disorder Society.
Apathy is one of the most prevalent and disabling non-motor symptoms in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), collectively referred to as Lewy body disorders (LBDs). It is associated with reduced quality of life, accelerated cognitive decline, increased caregiver burden, and poorer functional outcomes, yet remains underrecognized and undertreated. A Working Group of the International Parkinson and Movement Disorder Society's Non-Motor Symptoms Study Group conducted a comprehensive review of the literature and developed a position paper through iterative expert discussion and critical appraisal of available data. This review aims to provide a structured, expert-informed synthesis of the current evidence on the clinical features, neurobiology, assessment, and management of apathy in LBDs and to define priorities for future research and clinical trials. Apathy in LBDs is a multidimensional syndrome encompassing reward insensitivity, negative affect, executive dysfunction, and auto-activation deficits. Converging evidence implicates dysfunction within distributed frontal-striatal-limbic networks and multi-neurotransmitter systems, including dopaminergic, serotonergic, noradrenergic, and cholinergic pathways. Although several pharmacological and nonpharmacological interventions have been explored, few randomized controlled trials have specifically targeted apathy, and no treatment can currently be considered definitively efficacious. Methodological heterogeneity, inadequate phenotyping, and inconsistent outcome measures have limited therapeutic progress. Apathy should be recognized as a primary clinical and research priority in LBDs. Future adequately powered, mechanistically informed trials using standardized diagnostic criteria and validated outcome measures are urgently needed to advance treatment development. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
BACKGROUND:Combined effects of multiple risk factors on incident late-onset Parkinson's disease (PD; LOPD) remain poorly characterized. OBJECTIVE:The objective of this study was to quantify the impact of joint risk exposures and estimate the contribution of potentially modifiable factors to incident LOPD risk. METHODS:In this prospective cohort study, 311,261 UK Biobank participants aged ≥50 years and free of PD at baseline were followed for up to 15 years. During follow-up, 2769 individuals developed incident LOPD. Multivariable Cox proportional hazards models estimated hazard ratios (HRs) for 65 candidate risk factors. Combinations of two (pairs) or three (triplets) risk factors were evaluated for additive interaction. Population-attributable fractions (PAFs) were estimated for potentially modifiable risk factors. RESULTS:Eighteen risk factors (mean HR, 1.43) were independently associated with incident LOPD and subsequently evaluated as joint exposures. Thirteen pairs (mean HR, 2.00) and 14 triplets (mean HR, 4.21) demonstrated significant positive additive interaction and larger effect sizes than individual factors alone. A limited set of modifiable factors-loneliness, low handgrip strength, epilepsy, hearing loss, and diabetes-within the highest-risk pairs (HR range, 2.55-2.93) and triplets (HR range, 5.28-12.24) emerged as major contributors to elevated LOPD risk. Removing modifiable exposures from additive pairs and triplets was associated with reduction in mean HRs of 30% and 49%, respectively (P = 0.001). At the population level, removal of modifiable risk factors accounted for an estimated 34.4% reduction in LOPD incidence. CONCLUSIONS:Integrating traditional single-factor approaches with high-risk additive joint exposure profiles may improve risk stratification and inform targeted prevention strategies for incident PD. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
