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. (c) 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Background Accumulating evidence indicates that habitual diet, including plant-based dietary patterns, is associated with neurodegenerative alpha-synucleinopathy risk. However, the role of diet and its correlation with the gut microbiome in prodromal alpha-synucleinopathy, specifically among patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD), remains unclear. Objective To evaluate dietary patterns, their interplay with gut microbial dysbiosis, and longitudinal effects on neurodegenerative progression in iRBD patients. Methods We recruited 287 iRBD patients and 208 age-and sex-matched controls. Plant-based diet indices (PDIs) were derived from food frequency questionnaires. Shotgun metagenomic sequencing was performed in 456 subjects for diet-microbiome analyses. After a median follow-up of 4.2 years, 45 (15.7%) iRBD patients converted to alpha-synucleinopathies. Cox proportional hazards models assessed the associations between diet and neurodegenerative outcomes. Results We found that iRBD patients exhibited lower healthful PDIs (adjusted odds ratio [aOR] 95% confidence interval [95% CI]: 0.48 [0.29-0.80], P = 0.005) but higher consumption of unhealthful plant-based foods (refined grains, sweets, and sweeteners). Diet-microbiome interaction analysis identified dietary associations for 84.3% of iRBD-related gut microbes, including co-occurrence between healthful PDI and Clostridium sp. AF20-17LB. Longitudinally, four dietary factors and five iRBD-related microbes were associated with neurodegenerative outcomes; specifically, higher coffee consumption was linked to a lower risk of progression to alpha-synucleinopathy (aHR [95% CI]: 0.30 [0.11-0.78], P = 0.01). Furthermore, mediation analyses indicated that the iRBD-enriched species Ruthenibacterium lactatiformans mediated the association between unhealthful PDI and dementia-first conversion. Conclusions Habitual diet in iRBD is associated with gut microbiome dysbiosis and predicts neurodegenerative progression. These findings highlight diet-microbiome interactions as modifiable targets for intervention in prodromal alpha-synucleinopathy.
Background Progressive supranuclear palsy (PSP) is a devastating 4-repeat tauopathy with no approved disease-modifying treatments. Recent evidence showed increased transforming growth factor-beta (TGF-beta) levels in PSP patient-derived ventral midbrain organoids (vMOs) and serum neuronally derived exosomes.Objective This study investigated whether TGF-beta pharmacological inhibition could mitigate PSP pathology in vMOs.Methods Ninety-six vMOs were generated from induced pluripotent stem cells from two PSP-Richardson's syndrome patients and two healthy control donors (HCs). From day 60 to day 90, PSP organoids were (1) exposed to TGF-beta receptor I inhibitor (SB431542); (2) exposed to recombinant TGF-beta 1, TGF-beta 2, and TGF-beta 3; or (3) untreated. At day 90, several tau species were assessed by immunoblotting; neurodegeneration was evaluated through TUNEL assay and immunofluorescence (tyrosine hydroxylase [TH], neurofilament light chain [NfL]); astrocytic activation (glial fibrillary acidic protein [GFAP]) marker was evaluated by immunofluorescence, and histopathological hallmarks were evaluated by immunohistochemistry. An HC-derived organoid subgroup was exposed to the treatment conditions to assess potential toxicity.Results At day 90, untreated PSP-derived vMOs exhibited increased phosphorylated tau levels (Ser396, Thr181, Ser202/Ser205 [AT8]) compared with HC-derived vMOs, dopaminergic neuron loss (reduced TH, increased NfL), and astrocytic reactivity (increased GFAP), along with PSP characteristic tau deposition. Tau hyperphosphorylation, neurodegeneration, and astrocytic reactivity were all markedly reduced in PSP-derived vMOs treated with TGF-beta receptor I inhibitor. Conversely, exposure to TGF-beta exacerbated these features. No toxic effects were observed in HC vMOs exposed to treatment conditions.Conclusions Pharmacological inhibition of TGF-beta signaling prevented key PSP molecular alterations in patient-derived organoids. These findings support further research and pave the way for future investigation of TGF-beta-targeting strategies in clinical trials in patients with PSP. (c) 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Background Remote assessment of ataxia is increasingly important for patient-centered care and clinical research. SARAhome, a validated video-based adaptation of the Scale for the Assessment and Rating of Ataxia (SARA), enables self-administration of key motor tasks at home.Objective The aim was to evaluate the correlation of pose-derived gait and stance endpoints from SARAhome videos with clinician-rated severity.Methods In a multisite observational study, participants recorded SARAhome tasks on consumer mobile devices via the Atom5TM app. Clinicians rated videos using standardized criteria, blinded to automated outputs. Kinematic measures were extracted via pose estimation and aggregated to video-level features. Videos were aggregated per participant before correlation using Spearman's rho and Kendall's tau, with 95% cluster-bootstrap confidence intervals.Results We analyzed 5418 gait and stance videos from 58 participants across 4 sites (gait n = 2205, stance n = 3213). Score distribution was skewed toward lower severity. For gait, clearance variability (rho = 0.52 [0.37-0.64]) and median-normalized base of support (rho = 0.51 [0.35-0.66]) correlated most strongly with item ratings, followed by shoulder sway root mean square (rho = 0.43 [0.24-0.60]). Adjusted foot clearance (worse limb) correlated negatively (rho = -0.35 [-0.52 to -0.15]). For stance, anteroposterior sway (rho = 0.51 [0.36-0.65]), leg alignment variability (rho = 0.51 [0.36-0.65]), and composite sway (rho = 0.48 [0.32-0.62]) were most associated with severity. Base of support widened monotonically with severity and was the most reliable gait feature (intraclass correlation coefficient [ICC] = 0.88).Conclusions Pose-derived digital endpoints from home-captured SARAhome videos show robust, clinically interpretable correlation with severity, supporting scalable remote phenotyping. Findings motivate longitudinal validation toward clinical and regulatory utility.
Background VPS13A disease is a very rare neurodegenerative disorder caused by mutations in the VPS13A gene. Its prevalence appears to be relatively high in Puerto Ricans, although limited genetic information has been available. Objectives To describe the genetics of VPS13A disease (chorea-acanthocytosis) in Puerto Rico. Methods Data were obtained from Puerto Rican patients with genetically confirmed VPS13A disease. Results Eighteen cases were identified, all carrying at least one of four mutations, c.1400_1401del, c.3556_3557dup, c.3889C > T, and c.2825-253_2905-374del (exon_27-deletion); six additional single variants were detected. Seizures were the presenting symptom in 53% of patients. Conclusion The presence of these probable founder mutations could explain the apparently increased prevalence in Puerto Rico; half of the described variants are newly described mutations and half have been previously reported. Enhanced clinical awareness of the spectrum of presenting symptoms and diagnostic clues, and improved access to genetic testing are essential for timely diagnosis in this population.
