Abstract Background Impulse control disorders (ICDs) and related compulsive behaviors (CBs) are frequent non‐motor complications of Parkinson's disease (PD) with a probable genetic contribution. Objective To investigate whether genetic variants involved in reward and punishment processing are associated with impulsive–compulsive phenotypes in PD. Methods We analyzed a cross‐sectional Seville cohort (N = 449) and an independent Parkinson's Progression Markers Initiative (PPMI) cohort (N = 433) with longitudinally collected assessments. ICDs and CBs were assessed with the full QUIP (Questionnaire for Impulsive‐Compulsive Disorders in Parkinson’s Disease) in Seville and the short form (QUIP‐S) in PPMI. Dopaminergic exposure was quantified as levodopa‐ and dopamine agonist‐equivalent daily doses. A candidate‐variant panel selected through systematic review was evaluated using covariate‐adjusted case–control analyses with empirical P ‐values from 5000 permutations, followed by random‐effects meta‐analysis, exploratory genotype‐by‐treatment analyses, and in silico functional annotation. Results rs702859, a synonymous KCNJ6 variant, was associated with CBs in Seville (odds ratio [OR] 1.46; 95% confidence interval [CI] 1.02–2.09) and with ICDs in PPMI (OR 1.56; 95% CI 1.11–2.19). Meta‐analysis supported an association with ICDs (pooled OR 1.36; 95% CI 1.03–1.80). Exploratory analyses showed nominal interactions between rs702859 and dopamine agonist dose in Seville that were not reproduced in PPMI. rs702859 was in strong linkage disequilibrium with rs146589674, a KCNJ6 3′ untranslated region variant; expression, chromatin accessibility, and methylation quantitative trait loci (QTL) data linked risk alleles to reduced KCNJ6 expression. Conclusions KCNJ6 rs702859 showed convergent variant‐level associations across related impulsive–compulsive phenotypes in two independent cohorts, supporting further investigation of KCNJ6 ‐related pathways. Independent functional and clinical validation is required. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Abstract Background Cueing strategies are widely used to improve gait in Parkinson's disease (PD), but interindividual variability in cueing responsiveness remains poorly understood. Objectives The objective of the study was to identify determinants of internal and external cueing efficacy in persons with PD. Methods We performed a multicenter cohort study within the UNITE‐PD consortium, including 277 persons with PD and self‐reported gait impairment. Participants underwent motor, cognitive, and affective status assessments, followed by gait evaluations during uncued walking, external cueing (metronome), and internal cueing (silent counting). The dependent variable was cueing efficacy, expressed as change in stride time variability relative to uncued gait. Univariable and multivariable regression analyses, bootstrap resampling, and principal axis factoring were performed separately for internal and external cueing. Results Cueing efficacy for both external and internal cueing was greater in persons with higher uncued stride time variability. Bootstrap analyses showed inconsistent selection of individual clinical tests. Factor analysis identified motor and cognitive constructs associated with cueing efficacy for both cueing types, with affective status additionally contributing to internal cueing responsiveness. A significant three‐way interaction between stride time variability, motor performance, and cognitive performance was found for internal cueing responsiveness. Conclusions Cueing efficacy in PD is governed by uncued gait impairment at baseline and the interplay of motor, cognitive, and affective capacities, rather than by isolated clinical measures. These findings support the concept that cueing responsiveness depends on the availability and recruitment of strategy‐specific (sub‐)cerebral resources across motor, cognitive, and affective domains, where preserved capacity in one domain seems to offset limitations in another. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Abstract Background In the classical model of basal ganglia circuitry, striatal spiny projection neurons of the direct and indirect pathways (dSPNs, iSPNs) promote and suppress movement, respectively, and exhibit unbalanced activity levels during hypokinetic or hyperkinetic conditions. Most therapies for these conditions are thought to work by rebalancing the relative activity of dSPNs and iSPNs toward normal levels. However, the mechanism of amantadine, which uniquely improves both hypokinetic and hyperkinetic conditions, is poorly understood. Objective Our aim was to determine whether amantadine restores motor function by normalizing the balance of dSPN and iSPN activity or through a distinct mechanism. Methods We used dual‐color two‐photon Ca 2+ imaging in the 6‐hydroxydopamine (6‐OHDA) mouse model of Parkinson's disease to concurrently monitor dSPN and iSPN dynamics across healthy, hypokinetic (parkinsonian), and hyperkinetic (dyskinetic) conditions. Results We evaluated both dSPN/iSPN activity balance and action‐specific neural ensemble activity in the dorsolateral striatum. In hypokinetic conditions, levodopa rescued the dSPN/iSPN imbalance but failed to restore the disrupted activity of the locomotion‐specific ensemble. Conversely, amantadine improved locomotion‐specific ensemble activity without normalizing the dSPN/iSPN imbalance. In hyperkinetic conditions, forelimb dyskinesias were characterized by neural activity patterns distinct from those encoding locomotion. Amantadine selectively suppressed the resting activity of forelimb dyskinesia ensembles without affecting locomotion‐coding ensembles or restoring pathway balance. Conclusions Levodopa and amantadine may act through distinct mechanisms, with levodopa normalizing pathway balance and amantadine modulating action‐specific neural ensembles. These findings support the importance of action‐coding disruptions during hypokinetic and hyperkinetic conditions and suggest that correcting them can restore motor function. © 2026 International Parkinson and Movement Disorder Society.
Abstract Background Cognitive impairment is a prevalent and debilitating feature of Parkinson's disease (PD). Increasing evidence from postmortem and in vivo positron emission tomography imaging studies supports cholinergic dysfunction in PD. There is, however, little evidence regarding the influence of the structural integrity of cortical cholinergic pathways that emanate from the nucleus basalis of Meynert (NBM). Objectives To investigate the association between cognition and the structural integrity of medial and lateral cortical cholinergic projection pathways in PD. Methods Neuropsychological assessment, T1 imaging, and high angular resolution diffusion imaging (HARDI) were acquired from 108 participants with PD (41 female, mean age 71.3 years) and 41 control participants (22 female, mean age 70.6 years). Streamlines representing three cortical cholinergic pathways (one medial and two lateral) from the NBM were extracted from anatomically constrained tractography. Structural integrity was compared across controls and cognitive subgroups (PD with normal cognition [PD‐N], with mild cognitive impairment [PD‐MCI], and with dementia [PDD]) and using a continuous global measure of cognition. Results In PD, we found evidence that lower cognitive performance was associated with increased mean diffusivity across all pathways, especially the perisylvian component of the lateral pathway. In those individuals with dementia, increased free water fraction and decreased fractional anisotropy and fiber density and cross‐section was detected across all pathways. Conclusions Degeneration of the cortical cholinergic system is associated with cognitive decline in PD. Future work should determine whether pathway degeneration predicts future cognitive decline and dementia. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Abstract Background Recent studies have reported longitudinal brain atrophy in multiple system atrophy (MSA) in relatively small patient cohorts. Objective To compare longitudinal regional brain volume and clinical changes as endpoint measures for MSA clinical trials. Methods MSA patients with 1‐year longitudinal brain magnetic resonance imaging (MRI) were selected from the placebo arm of the M‐STAR Study (NCT03952806) and stratified into MSA‐cerebellar (MSA‐C) and MSA‐parkinsonism (MSA‐P) subtypes. A multisite healthy control (HC) cohort from international datasets was included for comparison. Baseline and longitudinal atrophy were assessed through automated MRI volumetry. Standardized longitudinal effect size values with 95% confidence intervals (CIs) and sample sizes required to detect treatment effect were estimated for 42 individual regional brain volumes, four combined volumetric indexes, nine clinical scales, and serum neurofilament light chain. Results The final study cohort included 129 MSA patients (76 MSA‐C, 53 MSA‐P) and 184 HC. The most atrophic structures at baseline were infratentorial regions in MSA‐C and putamen in MSA‐P. In both subtypes, infratentorial structures showed the largest longitudinal volume loss compared with HC. The annualized change of a cerebellum‐pons‐putamen volumetric index was the most powerful progression biomarker in MSA patients (effect size: −1.81 [95% CI: −2.14, −1.55]) and in both subtypes (MSA‐C: −2.04 [95% CI: −2.58, −1.68], MSA‐P: −1.55 [95% CI: −2.08, −1.22]), requiring the lowest sample size per arm (MSA, N = 55 to detect 30% treatment effect), and outperforming clinical measures (−59.6% patients required per arm). Conclusion These findings support longitudinal MRI‐derived regional atrophy rates as sensitive imaging endpoints to assess treatment efficacy in MSA clinical trials. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
