Parkinsonism & Related Disorders

Walking impairments in Parkinsons disease (PD), including reduced speed, cadence, and stride length, and increased variability, impair mobility and raise fall risk. Conventional treatments may fail to address these deficits, underscoring the need for complementary non-invasive alternatives. This study examined whether combining rhythmic auditory cueing with transcranial direct current stimulation (tDCS) over the supplementary motor area (SMA), a critical region for internally-generated movement, would enhance gait performance in PD. Thirty-three participants with PD and thirty-two healthy controls completed two sessions (anodal vs. sham tDCS) with gait assessed during stimulation, immediately after stimulation, and 15 minutes after stimulation under two auditory conditions: walking in silence and walking to music paced 10% faster than baseline cadence. Spatiotemporal, variability, and stability gait parameters were analyzed using linear mixed-effects models. Rhythmic auditory cueing significantly increased cadence and speed during, immediately after, and especially 15 minutes after stimulation, suggesting sustained effects of rhythmic entrainment. Anodal tDCS produced faster cadence, as well as lower stride time variability and stride width, particularly in individuals with PD. Although both music and anodal tDCS affected gait, no interaction was observed, indicating independent effects. Individuals with PD had greater gait variability overall, and adjusted temporal gait parameters less to music than healthy controls did. Anodal stimulation reduced walking variability in PD, reducing the group differences observed under sham conditions. These findings suggest that rhythmic cueing and SMA stimulation target complementary mechanisms, highlighting the promise of combined tDCS-music interventions for gait rehabilitation in PD.

Non-motor symptoms in Parkinsons disease (PD) may be influenced by the 4{beta}2* subtype of nicotinic acetylcholine receptors (nAChR) present in the hippocampus and subiculum. To continue efforts in PET diagnostics for PD, autoradiographic [18F]nifene binding to 4{beta}2* nAChR was quantitively assessed in the hippocampus-subiculum (HP-SUB) of PD (n = 27; 14 males, 13 females) and cognitively normal (CN) (n = 32; 16 males, 16 females) cases. Anti-ubiquitin for Lewy body and anti--synuclein immunostaining on adjacent slices were analyzed in QuPath and [18F]nifene binding was quantified in OptiQuant. Subiculum had greater [18F]nifene binding (51% to 85%) compared to HP in all subjects. Significantly higher [18F]nifene binding (>250%) was seen in PD SUB and PD HP compared to CN in both males and females. The grey matter (GM) to white matter (WM) ratio in PD=3.53 while CN=1.33, a >150% increase in PD. Binding of [18F]nifene to GM and WM individually was >250% greater in PD compared to CN. Male CN exhibited an increase while and male PD exhibited a significant decrease in [18F]nifene binding with aging, while females did not exhibit significant differences. In summary, 4{beta}2* nAChR measured by [18F]nifene is significantly upregulated in the PD HP and SUB. This increased [18F]nifene binding may be of diagnostic value using PET imaging.

Background: Most trials of Parkinson's disease (PD) measure progression over a short to medium time-period using continuous rating scales that may be hard to interpret and less meaningful for patients. There is a lack of evidence connecting changes in these scales to changes in outcomes important to patients. Objectives: We present causal modelling to translate the causal, short-term disease-modifying treatment effects on functional rating scales to the 10-year risk of serious clinical progression milestones. Methods: We selected four important clinical milestones of disease progression from the Oxford Parkinson's Disease Centre "Discovery" cohort: dementia, any falls, frequent falls, and mortality. We proposed a causal framework for our research objectives so we could model the potential impact of a 30% reduction in disease progression slopes ("treatment effect") using the summation of parts I and II of the Movement Disorders Society Unified Parkinson's Disease Rating Scale (UPDRS12). This outcome was regressed on time to milestone using flexible parametric survival models. Marginal predictions of survival and survival difference at year 10 were then calculated for the Discovery cohort, and a counterfactual cohort applying the treatment effect to estimate the relative and absolute reductions for the four clinical milestones. Results: The model increase in risk for each unit change in the UPDRS12 were as follows: dementia hazard ratio (HR)=1.52 (95% Confidence Interval (CI) 1.36-1.70), any falls HR=1.37 (95% CI 1.29-1.46), frequent falls HR=1.68 (95% CI 1.49-1.89), mortality=1.29 (95% CI 1.17-1.42). These models led to marginal predictions of absolute reductions, when the progression was reduced by 30%, between 4.0% (mortality) and 7.5% (frequent falls) at 10 years follow up. Conclusions: We have demonstrated how a treatment effect in a trial specified in terms of a progression change of a rating scale can be contextualised into a long-term reduction in the probability of clinically relevant milestones. Whilst we have used PD as our exemplar, we believe this methodological approach is generalisable to other chronic progressive diseases where trials are often limited to a relatively short follow-up period and use some scalar measure of progression, but significant clinical milestones usually take longer to be observed. Keywords: Clinical trials; disease modifying therapies; causal estimation; prediction models

Abstract/SummaryO_ST_ABSBackgroundC_ST_ABSCerebrospinal fluid (CSF) -synuclein seed amplification assay (SAA) has emerged as a diagnostic biomarker for Parkinsons disease (PD) and has been linked to differences in disease severity and progression. However, whether SAA status predicts responsiveness to levodopa remains unknown. We investigated the longitudinal association between SAA status, levodopa responsiveness, dopaminergic denervation, and motor complications in sporadic PD. MethodsIn this longitudinal analysis, PD participants from the Parkinsons Progression Markers Initiative (PPMI) cohort with CSF SAA testing who initiated levodopa treatment were included. SAA- and SAA+ patients were matched on sex, age, and disease duration at treatment initiation. Motor severity was assessed using MDS-UPDRS Part III, with proportional and absolute responsiveness derived from ON and OFF medication states. Motor complications were assessed using MDS-UPDRS Part IV, and dopaminergic dysfunction was quantified using caudate DAT-SPECT. Linear mixed-effects models examined longitudinal differences as a function of SAA status. FindingsIn this analysis, 40 SAA- patients were compared to 183 matched SAA+ patients. SAA+ patients showed a slower rate of ON-state motor progression than SAA- patients (0.87 vs 3.47 points/year; p = 0.01). Consistently, proportional levodopa responsiveness increased over time in SAA+ patients while declining in SAA- patients (p = 0.036). These differences were accompanied by lower caudate DAT binding at treatment initiation in SAA- patients (p = 0.002) and faster dopaminergic decline over time (p = 0.008). Although SAA+ patients had fewer motor complications at treatment initiation, their progression was similar. InterpretationCSF -synuclein SAA status is associated with divergent levodopa response in PD, with SAA+ patients showing sustained and progressively greater motor benefit, while SAA- patients show declining responsiveness. Faster dopaminergic denervation in SAA- patients may underlie this difference. SAA status captures clinically relevant heterogeneity that may inform patient stratification and therapeutic decision-making.

Background: Historically, OFF burden in Parkinsons disease has been primarily attributed to motor features. Recent studies highlight that non motor symptoms, and the predictability of OFF episodes also drive functional impairment, yet they are rarely measured in clinical practice. Objective: To identify which clinical features are most closely associated with OFF time and OFF impact, and to quantify the added explanatory value of temporal predictability, non-motor, and behavioural domains beyond a core motor model. Methods: We analysed 1,252 OFF only visits from 430 PPMI participants. Outcomes were MDS UPDRS IV 4.3 (OFF time) and 4.4 (OFF impact). Linear mixed effects models with a participant random intercept were fitted. The core motor model included OFF state motor severity, freezing, tremor, levodopa responsiveness, and dyskinesia, plus covariates. Predictability (IV; 4.5), non motor (mood, fatigue/sleep, autonomic/GI), and behavioural (impulse control behaviours) domains were then added to assess added influence beyond motor. Analyses were stratified by time since diagnosis (Pooled; [≤] 4y; [≥] 6y). Results: Clinical features explained more variance in OFF impact than OFF time (25.9% vs 8.1%). OFF time was primarily linked to OFF state motor severity/freezing, with levodopa responsiveness important early. For OFF impact, predictability produced the largest increment in marginal R squared beyond the core motor model (pooled and Late). Within the core motor model, tremor was the largest contributor to OFF impact. Conclusions: Predictability is a prominent correlate of OFF impact. Asking about predictability may help tailor therapy, from timing optimisation to on demand rescue for unpredictable episodes.

BackgroundBalance instability is a major contributor to disability and falls in people with Parkinsons disease (PwP) and is often insufficiently explained by motor impairment alone. Altered awareness of motor control has been suggested to contribute to sensorimotor dysfunction in PwP, but its relationship with balance performance is poorly understood. ObjectiveTo determine whether awareness of balance control, assessed using a control detection task (CDT), differs between healthy controls (HC) and PwP, and whether CDT performance is associated with balance-related measures. MethodsHealthy older adults (n=20) and PwP (n=22) performed a standing version of the CDT based on center-of-pressure (COP) control, using a force plate. CDT accuracy was used as the primary outcome measure. Static balance during quiet standing was assessed using the COP trajectory length and rectangular area. Dynamic standing balance was assessed using the Index of Postural Stability (IPS). Group differences were examined by independent-samples t-tests. Correlations between CDT accuracy and balance measures were analyzed. ResultsThe PwP group showed significantly lower CDT accuracy. Higher CDT accuracy was associated with better static balance in the HC group and the combined sample, and with higher IPS primarily in the PwP group. ConclusionsMotor awareness during postural tasks is altered in PwP and is associated with balance control. These findings suggest that balance instability in Parkinsons disease may involve altered balance-related action-outcome monitoring in addition to motor dysfunction.

BackgroundParkinsons disease (PD) is a prevalent neurodegenerative disorder characterized by progressive motor dysfunction and broad cellular impairment, including significant disruptions in lysosomal function, lipid metabolism, and intracellular trafficking. Glycosphingolipids (GSLs), critical for various cellular processes, depend on effective lysosomal degradation. Aberrant GSL metabolism has been linked to PD pathology, and glycoprotein non-metastatic melanoma protein B (GPNMB) has emerged as a biomarker associated with lysosomal dysfunction and lipid imbalance in PD. ObjectivesTo assess the relationship between GPNMB and GSL levels in cerebrospinal fluid (CSF) and plasma from PD patients and controls within the BioFIND cohort. We also investigated potential sex differences and associations with PD-related biomarkers such as -synuclein. MethodsGSL species and GPNMB protein levels were quantified using high-performance liquid chromatography (HPLC) and ELISA assays, respectively, in matched CSF and plasma samples from PD patients and controls. ResultsLevels of the paraglobosides GSL species, alpha-2,3SpG and pGb were significantly elevated in the plasma of PD patients compared to healthy controls, while levels of the ganglioside GD1a and the lacto-series GSL, Leb combined (GD1a + Leb), were significantly reduced in PD. GPNMB levels positively correlated with several GSL species in both plasma and CSF. Plasma GSLs and GPNMB concentrations were significantly higher in females compared to males, independent of PD diagnosis. CSF GPNMB correlated positively with age and -synuclein concentrations. InterpretationOur findings confirm that GSL metabolism is altered in PD. They also highlight significant sex-based biochemical variations in GSL and GPNMB levels, emphasizing the need for sex-specific analyses in PD biomarker research. The relationship between GSLs and GPNMB supports their potential as interconnected biomarkers of lipid pathology in PD.

Background-Synuclein (-Syn) plays a central role in Parkinsons disease (PD). Under pathological conditions, -Syn aggregates into toxic oligomers and fibrils that act as damage-associated molecular patterns (DAMPs), stimulating microglial reactivity. This -Syn-microglia axis creates a self-perpetuating cycle of neuroinflammation and neurodegeneration, accelerating dopaminergic neuron loss in the substantia nigra pars compacta (SNpc) and contributing to motor deficits. Moreover, -Syn pathology spreads through the brain, disrupting synaptic plasticity in cognitive regions like the cortex and hippocampus, leading to early cognitive decline. Thus, targeting -Syn aggregation and its inflammatory consequences presents a promising dual-hit therapeutic strategy for PD. MethodsThis study investigates the therapeutic potential of 3-monothiopomalidomide (3MP), a novel thalidomide derivative designed to reduce neuroinflammation with a potentially better safety profile than Pomalidomide (POM). The neuroprotective and anti-inflammatory effects of 3MP were evaluated in rat primary mesencephalic mixed neuron-microglia cultures exposed to human -Syn oligomers (H-SynOs). Anti-aggregation activity was assessed via Thioflavin T (ThT) assays and Thioflavin S (ThS) staining in SH-SY5Y cells. Finally, the anti-aggregation, anti-inflammatory, and neuroprotective effects of 3MP were evaluated in vivo in a rat model of PD induced by intracerebral infusion of H-SynOs. ResultsIn primary cell cultures, 3MP dose-dependently reduced -Syn-induced neuronal death and microglial inflammatory responses. It also significantly inhibited -Syn aggregation in vitro in the ThT assay and in SH-SY5Y cells exposed to -Syn protofibrils, outperforming POM. When chronically administered in vivo, 3MP preserved dopaminergic neurons within the SNpc and yielded functional benefits on motor and cognitive readouts. Notably, 3MP markedly attenuated -Syn aggregates induced by the H-SynOs infusion in the SNpc more efficiently than POM, as shown by reduced intraneuronal staining for pSer129--Syn+ and reduced pSer129-Syn in both cytoplasmic and phagolysosomal compartments of microglia. In addition, mesencephalic and cortical inflammatory microgliosis that followed to intranigral H-SynOs-infusion, were significantly dampened by 3MP. ConclusionsOverall, 3MP emerges as a dual-action drug candidate capable of modulating neuroinflammation and -Syn aggregation and thereby disrupting the -Syn-driven inflammatory cycle. Its neuroprotective effects and favourable safety profile support its potential as a disease-modifying therapy for PD, with promising implications for clinical translation.

Background. Parkinson's disease (PD) diagnosis remains delayed and suboptimally accurate, largely due to clinical overlap with atypical parkinsonian syndromes and the lack of reliable biomarkers. Here, we evaluated the performance of a previously patented 6-metabolites blood biomarker (6M-BB) for the differential diagnosis of PD and its translation to clinical IVDr NMR platform. Methods. Patient serum samples from de novo PD (n=30), multiple system atrophy (MSA, n=30), progressive supranuclear palsy (PSP, n=30), Alzheimer's disease (AD, n=33), and healthy individuals (n=29), were profiled by 1H NMR and classified using the 6M-BB. For clinical use, we rebuilt the model on absolute concentrations acquired on a Bruker Avance IVDr 600 MHz system. Results. The 6M-BB validation yielded 0.902 AUC and 87.9% accuracy for PD vs. HC (sensitivity 86.7%, specificity 89.3%), with an overall accuracy of 82.6% across all groups. The IVDr-based refit achieved 0.878 AUC (overall accuracy 77%). Adding VLDL-5 free cholesterol (V5FC) and citrate markedly improved performance to 0.959 AUC, with 94.9% accuracy for PD vs. HC (sensitivity 96.7%, specificity 93.1%) and 84.9% when MSA/PSP were included. Conclusion. The externally validated 6M-BB has demonstrated its robustness for the differential diagnosis of PD compared to other parkinsonian syndromes at de novo stage. Its successful transfer to a fully automated, standardized IVDr machine, with gains from V5FC and citrate, supports the feasibility and promising potential for clinical implementation, justifying future prospective multicenter studies.

BackgroundSubthalamic deep brain stimulation (STN-DBS) represents an established therapeutic intervention for advanced Parkinsons disease (PD), alleviating motor and non-motor symptoms. However, impulse control disorders (ICDs) present a complex challenge, with some patients experiencing postoperative improvements while others develop treatment induced impulsive-compulsive behaviours (ICB). The mechanisms determining these variable outcomes remain poorly understood, highlighting the need to predict postoperative ICB outcomes. MethodsThis prospective open-label study aimed to identify microstructural markers associated with postoperative changes in impulsive-compulsive behaviour following STN-DBS. Thirty-five patients underwent diffusion MRI and clinical evaluations preoperatively and six months postoperatively. A whole-brain voxel-wise analysis utilising diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) was conducted to explore associations between microstructural metrics and changes in the Questionnaire for Impulsive-Compulsive Disorders in Parkinsons Disease-Rating Scale (QUIP-RS). ResultsIntact microstructure in frontolimbic WM tracts, including the cingulum, insular cortex connections, and major association fibres, was associated with greater postoperative reductions in impulsive-compulsive symptoms. Conversely, intact microstructure in specific grey matter areas including paracingulate gyrus, insular cortex, and precentral gyrus were associated with lower reductions or increases in postoperative ICB. ConclusionThese findings demonstrate that preoperative microstructural integrity within frontolimbic circuits and executive control networks associates with susceptibility to treatment-emergent impulsive-compulsive behaviours following STN-DBS. The convergent evidence from multiple diffusion metrics suggests that diffusion MRI may serve as a valuable tool for identifying patients at risk for developing ICB, potentially enhancing preoperative counselling and enabling targeted behavioural monitoring strategies.

BackgroundThe X-linked muscle wasting disorder Duchenne muscular dystrophy (DMD) is a progressive and ultimately fatal disease caused by loss of function mutations in the dystrophin (DMD) gene. Upregulation of utrophin (UTRN), an embryonic homologue of dystrophin, has been proposed as a therapeutic option that could ameliorate disease. We previously generated a bioluminescent screen for utrophin-upregulating compounds using a mouse reporter of endogenous utrophin expression and discovered that inhibition of ERK1/2 and EZH2, increases utrophin expression in myoblasts. MethodologyHere we extend this analysis to show that treatment of human myoblasts with the ERK1/2 inhibitor LY3214996 and the EZH2 inhibitor GSK503, increases UTRN expression in primary and immortalised myoblasts derived from healthy volunteers and DMD patients. ResultsShort-term (24 hours) inhibition of ERK1/2 and EZH2 resulted in increased expression of utrophin in proliferating myoblasts. Surprisingly, in patient-derived samples, but not healthy controls, increased UTRN expression was sustained following drug removal and in vitro differentiation. Furthermore, dystrophin deficient myoblasts have altered expression of myogenic transcription factors MYOD1 and MYOG and proliferation marker Ki67, signalling an altered regenerative capacity of these cells, while ERK1/2 inhibition, alone or combined with EZH2i, reversed this transcriptional signature. ConclusionsTreatment with ERK1/2 and EZH2 inhibitors could offer a therapeutic option for DMD by increasing UTRN and MYOD1 expression. We propose that this may compensate for DMD loss and help restore productive muscle differentiation and regeneration.

BackgroundPhenoconversion to Parkinsons disease (PD) or dementia with Lewy bodies (DLB) currently relies on established clinical diagnostic criteria. Availability of in vivo biomarkers--CSF -synuclein seed amplification assay (CSFaSynSAA) and dopamine transporter (DAT) imaging--offer the opportunity to investigate congruency between clinical phenoconversion and biologically defined disease. MethodsWe analyzed Parkinso[n]s Progression Markers Initiative participants who phenoconverted to PD, DLB, multiple system atrophy (MSA), Alzheimers disease (AD) or other dementias from prodromal and non-manifesting genetic carrier (NMC) groups and controls. Site investigators determined phenoconversion based on established diagnostic criteria. All phenoconverters with [≥]1 annual follow-up visit, with available biomarkers and persistent clinically defined diagnosis at last observation were included. Neuronal alpha-Synuclein Disease Integrated Staging System (NSD-ISS) staging was applied. ResultsAmong 121 phenoconverters, 103 had evaluable CSFaSynSAA and DAT data and were included in analysis: 92 PD, 7 DLB, 2 MSA, 2 AD/other dementias. Phenoconversion annual rates varied widely across groups: iRBD 7.9%, hyposmia 4.2%, GBA1 0.3%, LRRK2 1.3%, LRRK2+GBA1 0.9%, and controls 0.5%. Median time from baseline to phenoconversion ranged from 13-14 months in iRBD and hyposmia to 36-85 months in NMCs. The expected biomarker profile (CSFaSynSAA+/DAT+) for clinically-diagnosed synucleinopathy occurred in 74 (71.8%) participants. Biological alignment (CSFaSynSAA+/DAT+) was present in 87% hyposmics and 72% iRBD phenoconverters. CSFaSynSAA negativity was high among LRRK2 phenoconverters (67%), who also were more likely to have a preserved sense of smell (83%). Phenoconversion occurred later than onset of functional impairment: 15/47 (31.9%) iRBDs and 7/38 (18.4%) hyposmics were already NSD-ISS stage [≥]4 at time of phenoconversion. ConclusionsClinical phenoconversion did not necessarily align with biological evidence of synucleinopathy or dopaminergic loss and can be delayed compared to onset of meaningful functional impairment. Longitudinal follow up on converters without biological evidence of PD is required to confirm conversion diagnosis and evaluate for a later occurrence of biomarker positivity.

Background: Peri-lead edema (PLE) occurs in up to 15% of Deep Brain Stimulation (DBS) cases, can cause morbidity, and its etiology remains unknown. We hypothesized that PLE represents a secondary brain injury modulated by hypoxemia, and that patients with obstructive sleep apnea (OSA) are at elevated risk. Methods: We conducted a retrospective case-control study of 121 Parkinson's disease (PD) patients undergoing DBS at a single center (2019-2024). PLE severity was quantified by CT volumetric segmentation and Hounsfield unit (HU) measures. Perioperative SpO2 and PaO2 were recorded. Polysomnography (PSG) was available in 26 patients; and the REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) was administered retrospectively. Results: Symptomatic PLE occurred in 12 patients (9.9%), with onset at 3.5 (2-9) days postoperatively. PLE patients had higher body mass index (p = 0.022) and higher OSA prevalence (75% vs. 30%; p = 0.002). Perioperative SpO2 was lower in the PLE group in both the operating room and post-anesthesia care unit (PACU; p < 0.05); PaO2 was lower in the PACU (p = 0.037). In the PSG subgroup, REM Sleep Behavior Disorder (RBD) incidence was lower in PLE patients (20% vs. 60%; unadjusted p = 0.048), and PLE severity correlated significantly with sleep-related hypoxemia and respiratory indices. RBDSQ scores were positively associated with edema density (normalized HU: rho = 0.86, p = 0.024). Conclusions: OSA and perioperative hypoxemia are associated with symptomatic PLE following DBS, while RBD appears protective. Preoperative sleep evaluation and optimized perioperative airway management warrant prospective investigation as PLE prevention strategies.

Studies reporting alpha-synuclein seed amplification assay (aSyn-SAA) results are often cross-sectional. Here we investigated the intra-individual consistency of aSyn-SAA results over time from participants in the Parkinson's Progression Marker Initiative (PPMI). A total of 1238 participants had >1 CSF aSyn-SAA result for analysis (Parkinson's disease [PD]=633, prodromal =563, healthy control [HC]=42) which were collected over a median (min, max) of 2.0 (0.4, 11.4) years. Emphasis was placed on evaluating consistency in less common results such as aSyn-SAA- PD participants, aSyn-SAA+ HC and conversion rates from aSyn-SAA negative to positive results prodromal participants. Of aSyn-SAA+ PD participants, 96% (474/493, 95%CI 94-98%) remained positive in subsequent samples, and 92% (116/126, 95%CI 86-96%) of aSyn-SAA- PD participants remained negative. 99% (303/307, 95%CI 97-99%) of aSyn-SAA+ prodromal participants remained positive, and 95% (234/247, 95%CI 91-97%) of aSyn-SAA- prodromal participants remained negative. 89% (16/18, 95%CI 67-97%) of aSyn-SAA+ HC participants remained positive, and 87% (20/23, 95%CI 68-95%) of aSyn-SAA- HC participants remained negative. These results confirm a high consistency of aSyn-SAA results over time, even in less expected results.

Deciding whether and how to act depends on a trade-off between the effort required to execute a given action and the potential reward for completing it. Impairments in this effort-reward trade-off have been proposed to underlie reduced movement vigor, or bradykinesia, in Parkinsons disease (PD). However, several mechanisms could alter the effort-reward trade-off in PD, each with unique implications for understanding and treating bradykinesia. Therefore, we individually examined whether people with PD (both on and off dopamine medication) demonstrated reduced sensitivity to reward value, increased perception of effort, or a biased mapping between effort and reward, compared to age- and sex-matched neurotypical controls. We found that people with PD exhibited increased effort perception and, surprisingly, no reduced sensitivity to reward value or a biased mapping between effort and reward. These findings suggest that effort perception could be an important factor driving bradykinesia in PD.

Background: Dystonia frequently co-exists with Parkinson's disease (PD), yet the extent of genetic overlap remains insufficiently explored. Objective: To examine whether rare variants in dystonia-related genes are associated with PD or early-onset PD (EOPD). Methods: We curated 44 dystonia-related genes using OMIM and the updated Movement Disorder Society report on hereditary dystonia. Whole-genome sequencing data from 5,315 PD patients, including 300 with EOPD, and 36,902 controls across the Accelerating Medicines Partnership-PD and UK Biobank cohorts were analyzed. For each gene, we evaluated rare variants (minor allele frequency <1%) in four pre-specified variant classes: exonic, nonsynonymous, CADD score [&ge;]20 and loss-of-function. For the rare variant burden analysis, SKAT-O was performed, followed by meta-analysis with MetaSKAT. Results: In analyses of all PD cases, several genes showed nominal associations in meta-analysis: SQSTM1 (Ploss-of-function = 5.52 x 10-3), AOPEP (Pexonic = 6.96 x 10-3; Pnonsynonymous = 0.017), KCNA4 (Pexonic = 0.017), SPR (Pexonic = 0.029), SLC30A10 (PCADD[&ge;]20 = 0.046), and ACTB (Pexonic = 0.047). However, none remained significant after multiple-testing correction. In exploratory EOPD analyses, five genes reached significance after multiple test correction (ATP5MC3, DNAJC12, KMT2B, TBC1D24, TMEM151A). These signals were driven by small numbers of variants and were not robust to leave-one-variant-out analyses. GCH1 was nominally significant in the meta-analysis of EOPD (Pnonsynonymous = 4.36 x 10-3, PFDR = 0.062). Conclusions: Rare variants in dystonia-related genes do not appear to make a major contribution to PD risk overall. Signals observed in the EOPD subset were based on small numbers of variant carriers and require replication in larger cohorts.

Background: Rett Syndrome (RTT) is a severe neurodevelopmental disorder affecting approximately 1 in 10,000 live female births worldwide. The Rett Syndrome Behaviour Questionnaire (RSBQ), remains one of the most widely used standardized behavioral assessment tools for RTT. However, the RSBQ was originally validated only in British English, limiting its applicability for Spanish-speaking caregivers and clinical centers across Latin America and Spain. Objective: The primary aim of this study was to develop and validate the comprehension of the Spanish translation of the RSBQ to ensure cultural and linguistic equivalence, enhance data reliability, and facilitate earlier, more accurate clinical assessments among Spanish-speaking RTT populations. Methods: Surveys were administered in two phases to Spanish-speaking caregivers between November 2023 and September 2025. Phase I consisted of 12 guided survey administrations with participants being able to ask clarifying questions and offer linguistic modifications of RSBQ questions. Phase II consisted of independent online administration of the refined Spanish RSBQ and a retest at least 7 days later. Participants were recruited through direct outreach and supported virtually during questionnaire completion. Results: Following data cleaning and quality control, a total of 51 caregivers successfully completed both surveys. The Spanish RSBQ demonstrated high caregiver comprehension and strong engagement across multiple Latin American countries, including Argentina, Mexico, and Peru. Responses were highly correlated between test and retest timepoints, and no question showed biased response distributions. A slight effect of response interval on test-retest correlation was observed, potentially indicating the impact of natural disease progression confounding retest evaluation for long (>80 day) intervals; however this effect did not impact the overall linguistic validation results as analysis of only <21 day test-retest responders confirmed the findings. Conclusions: This linguistic validation study represents the first formal step toward the clinical validation of the Spanish RSBQ, enabling broader inclusion of Spanish-speaking populations in RTT research. The collaborative, bilingual data collection strategy proved both feasible and effective, paving the way for multinational trials and expanding therapeutic accessibility through localized, patient-centered innovation.

Parkinsons disease (PD) is a progressive neurodegenerative disorder characterized by -Synuclein (-Syn) aggregation, dopaminergic neuronal loss, and chronic neuroinflammation. Chlorogenic acid (CA), a dietary polyphenol abundant in coffee, exhibits antioxidant and anti-inflammatory properties and has shown neuroprotective effects in acute toxin-based PD models. However, its efficacy in chronic, -Syn-driven PD models remains unclear. Here, we evaluated the therapeutic potential of CA using an -Syn-based in vitro system and a chronic -Syn overexpression mouse model that recapitulates key pathological features of human PD. In vitro, CA significantly improved cell viability, reduced -Syn aggregation, and attenuated H2O2-induced apoptosis in U118 and N2a cells. In contrast, chronic oral administration of CA (100 mg/kg for 16 weeks) in C57BL/6J mice (male and female) failed to improve motor behavior, attenuate -Syn pathology, preserve nigrostriatal dopaminergic neurons, or reduce oxidative stress-associated DNA double-strand breaks in vivo. Notably, CA elicited a modest reduction in microglial and astrocytic activation in female mice, highlighting a sex-dependent immunomodulatory response. Collectively, these findings reveal a clear dissociation between robust in vitro neuroprotection and limited in vivo efficacy in a chronic -Syn-driven PD mouse model, emphasizing the importance of incorporating progressive disease paradigms and sex as a biological variable in preclinical therapeutic evaluation.

Motor memory retention is impaired in Parkinson's disease (PD), affecting long-term rehabilitation outcomes. It appears that NREM sleep could be beneficial for consolidation processes in PD, and could be leveraged with non-invasive sleep interventions. This study examined the effect of auditory targeted memory reactivation (TMR) during NREM sleep on the retention of a motor sequence learning finger tapping task in 20 PD and 20 healthy older adults (HOA). TMR was applied during a 2-hour nap and its effect on motor retention was post-nap, after 24-hours and with a dual-task. The impact of TMR on sleep electrophysiology was also evaluated. Results showed no effect of TMR on motor retention or dual-tasking, with no difference between the groups. However, the TMR intervention did increase slow-wave density and decreased spindle density in both groups, and slow-wave amplitude during the presentation of the auditory cues was positively associated with performance in HOA. In conclusion, TMR applied during a 2 hour nap did not enhance motor retention, but the changes in sleep physiological features could be linked to a possible underlying effect on memory processing that warrants further investigation.

Background/ObjectivesThe quality and characteristics of approved medicines can vary substantially depending on manufacturing processes and standards within a given country. The aim of the study was to compare the available marketed brands of ademetionine tablets derived from various countries in order to identify potential differences between the different formulations. MethodsWe performed comprehensive analyses of the physical, chemical, and dissolution characteristics of different formulations of ademetionine tablets marketed in China, India, Russia, Ukraine, and Uzbekistan, using the originator formulation of Heptral(R) as the reference standard. The formulations were evaluated at initial analysis and after 3 months at 40{degrees}C/75% relative humidity. Clinical parameters such as ademetionine content, degradation products, S,S-isomer, and water content were assessed using HPLC, and a dissolution profile analysis performed in 2 hours of acid solution followed by 90 minutes in a buffer solution. ResultsThe Nusam (India) and Ximeixin (China) products were the two products most comparable to the Heptral products. Adenomak (Ukraine), the only food-grade product and only one with the tosylate salt showed the most significant quality variations compared to Heptral including dissolution failure as well as considerable variability between batches. ConclusionsThe study highlights the importance of using pharmaceutical-grade ademetionine products to maintain clinical efficacy and ensuring standards are maintained across global markets.