Journal of Parkinson’s Disease

Background. Cognitive impairment in Parkinson's disease (PD) is highly prevalent and heterogeneous. Assessing multiple cognitive domains is challenging and risks redundancy. This study evaluated whether a discriminant analysis approach could optimize the selection of specific tasks and measures for identifying attention and memory deficits in PD. Methods. Thirty PD patients and 25 cognitively unimpaired (CU) controls completed four experimental tasks: two assessing attention (flanker and spatial Stroop), one for recognition memory, one for working memory (n-back). Following group-level difference analyses, a discriminant analysis was performed to identify which tasks, and performance metrics possessed the highest sensitivity for distinguishing PD patients from CU individuals. Results. At the group level, PD patients exhibited significantly worse conflict costs in both attention tasks and lower sensitivity scores (d') in the recognition memory task compared to CU controls. The discriminant analysis revealed that time-based measures from the spatial Stroop task and the sensitivity score from the recognition memory task provided the highest discriminating power to differentiate between the two groups. Conclusion. These findings suggest that cognitive deficits in PD can be identified with high diagnostic accuracy using a targeted subset of metrics, eliminating the need for extensive and redundant neuropsychological testing batteries for attention and memory, without needing an extensive number of cognitive tasks for attention and memory.

Background: Freezing of gait (FOG) is a disabling and often underrecognized feature of Parkinsons disease (PD). Objective gait analysis may improve characterization of this motor symptom. Objective: To compare quantitative 3D gait parameters in PD with FOG (PDF) and PD without FOG (PDNF) in a routine clinical cohort. Methods: We retrospectively analyzed a sequential sample of 180 patients with PD referred for motion analysis between 2020 and 2024. All patients underwent 3D motion capture in the off-medication state. Eighteen gait outcomes spanning pace, rhythm, postural control, variability, and asymmetry domains were derived from steady-state walking tasks. FOG status was determined using physician documentation and Movement Disorder Society Unified Parkinsons Disease Rating Scale (MDS-UPDRS) items. Group differences between PDF (n=99) and PDNF (n=81) were evaluated using independent samples t-tests, with outcomes adjusted for disease duration and corrected for multiple comparisons. A secondary analysis among PDF compared those in Hoehn and Yahr (H&Y) stage [≥]III to those in H&Y [≤]II. Results: PDF had longer disease duration, higher OFF MDS-UPDRS III scores, and higher Hoehn and Yahr stage than PDNF but were similar in age and sex. After adjusting for disease duration and multiplicity, PDF demonstrated reduced step length, stride length, and forward velocity, and greater cadence variability, while most postural control, and asymmetry measures were comparable between groups. Among PDF, advanced H&Y stage was associated with impaired pace and rhythm, similar to previous reports among PD in general. Conclusion: In this large, sequential, clinically referred cohort, FOG was associated with more advanced PD and specific impairments in pace and gait variability. These findings support comprehensive 3D gait analysis as an objective tool to better delineate FOG-related gait abnormalities and identify features that may predict FOG, informing targeted interventions.

Importance: Dementia is a common and disabling complication of Parkinson's disease (PD). Blood-based biomarkers that identify individuals at higher risk of future dementia could improve prognostication and trial stratification. Objective: To determine whether blood-based proteins are associated with future risk of dementia in PD. Design, Setting, and Participants: Prospective longitudinal cohort study with discovery and replication analyses in the Oxford Parkinson's Disease Centre (OPDC) Discovery cohort and the Parkinson's Progression Markers Initiative (PPMI). A total of 1,335 participants with PD and 431 healthy controls, with serum, plasma, or cerebrospinal fluid proteomic data and follow-up of up to 12 years, were included. Main Outcomes and Measures: Incident dementia, defined using a composite of MoCA scores, MDS-UPDRS items, and clinician diagnosis. Associations between baseline protein levels and time to dementia were evaluated. Results: Among 1,335 participants with PD, 168 developed incident dementia across cohorts (OPDC Discovery [serum], n = 108; PPMI Project 293 [plasma], n = 23; PPMI Project 181 [CSF], n = 37). In the OPDC cohort, GFAP was the only protein (of 5,408 tested) significantly associated with incident dementia (HR = 2.43; 95% CI: 1.79-3.30; p-adjust =1.35 x 10-4). Higher GFAP tertiles were associated with greater cumulative dementia incidence. Findings were replicated in the PPMI plasma project (HR = 2.42; 95% CI: 1.12-5.22; p = 0.024) but not in the CSF project (HR = 0.96; 95% CI: 0.66-1.39; p = 0.82). Higher baseline GFAP was significantly associated with lower baseline cognitive performance and greater longitudinal cognitive decline but no significant association with motor progression. In both cohorts, GFAP levels increased over time but showed no group-level differences. Conclusions and Relevance: Circulating GFAP is a robust and reproducible predictor of future dementia in PD, detectable early in the disease course. While the lack of differential longitudinal trajectories between PD patients with and without dementia suggests that GFAP does not act as a dynamic marker of cognitive decline, its relative stability supports its role as an early indicator of underlying biological vulnerability or subclinical pathology. These findings support serum GFAP as a promising, accessible biomarker for early dementia risk stratification.

Background: Parkinsons disease (PD) has a prolonged prodromal phase, but minimally invasive molecular biomarkers distinguishing manifest PD from prodromal synucleinopathy remain insufficiently characterized. Isolated REM sleep behavior disorder (iRBD) represents a high-risk prodromal condition and provides an opportunity to investigate early blood-based transcriptional alterations. Objective: To identify peripheral blood transcriptomic signatures distinguishing healthy controls (HC), individuals with iRBD, and patients with PD, and to explore whether longitudinal iRBD samples exhibit movement toward a PD-like transcriptional state. Methods: Peripheral blood RNA-seq data were analyzed using harmonized metadata, DESeq2 differential-expression analysis, internally validated machine-learning models, PD-like projection, and integrated biomarker-panel prioritization. Independent baseline samples were used for cross-sectional differential-expression and machine-learning analyses. iRBD follow-up and post-conversion observations were excluded from baseline model development and reserved for exploratory longitudinal analyses. Results: Baseline analyses included 71 independent samples: 20 HC, 31 iRBD, and 20 PD. An additional 19 iRBD follow-up observations, including three post-conversion observations, were available for exploratory analyses. Differential-expression analysis identified 170 FDR-significant genes in PD versus HC and 85 in PD versus iRBD, compared with one FDR-significant gene in iRBD versus HC. Internal machine-learning validation showed stronger discrimination of manifest PD, with a best ROC-AUC of 0.883 for HC versus PD and 0.889 for iRBD versus PD. Discrimination between HC and iRBD was weak, with a best ROC-AUC of 0.584. PD-like projection scores were lowest in HC, highest in PD, and heterogeneous among baseline iRBD samples. Follow-up iRBD samples showed an exploratory upward shift in the mean PD-like projection score. Integrated prioritization produced a 24-gene PD candidate panel and a 24-gene exploratory iRBD panel, with genes in each panel supported by machine-learning feature-stability evidence and differential expression analysis. Conclusions: Manifest PD was associated with a distinct peripheral blood transcriptional signature, whereas iRBD-associated alterations were substantially weaker and more heterogeneous. The prioritized panels represent candidates for independent technical and external validation and should not yet be interpreted as clinically validated diagnostic or prognostic tests.

Background: Lysosomal dysfunction plays a crucial role in the pathogenesis of Parkinson's disease (PD), particularly among GBA1 mutation carriers. Beyond GBA1, genes such as TMEM175, SCARB2, and CTSB identified in genome-wide association studies (GWAS) are also implicated in lysosomal pathways contributing to PD risk, although their functional effects in patients remain unclear. Proteins encoded by these lysosome-related genes have been explored as potential therapeutic targets in experimental models. Biomarker profiles, including clinical measures, alpha-synuclein seeding activity, lysosomal proteins, and sphingolipids, may facilitate patient stratification and support therapeutic monitoring in future clinical trials. Aim: The aim of this study is to investigate the impact of genetic variants of three lysosomal-related genes (TMEM175, SCARB2, and CTSB) on biomarker profiles in PD with and without GBA1 variants. Cross-sectional data from two German cohorts: the Tuebingen Parkinson Cohort (TUEPAC) and the DESCRIBE PD cohort of the German Center for Neurodegenerative Diseases were used as explorative cohorts, and data from Accelerating Medicines Partnership Parkinson's Disease (AMP-PD) were used as a validation cohort. The ultimate goal is to provide new data for patient stratification based on genetics, which might serve as a readout for target engagement and treatment efficiency assessment. Methods: Three cohorts were analyzed: TUEPAC, DESCRIBE PD, and AMP-PD. TUEPAC and DESCRIBE PD were combined into a single German discovery cohort (TUEPAC-DESCRIBE-PD), while AMP-PD served as an independent validation cohort. Within each cohort, for subgroup analyses, PD patients were classified as the overall PD cohort (PDall), and further stratified by GBA1 mutation status into PD patients without GBA1 mutations (PDGBA1_wildtype), and PD patients carrying GBA1 mutations (PDGBA1). We evaluated cognitive and motor function, as well as depression using the Montreal Cognitive Assessment (MoCA), Unified Parkinson Disease Rating Scale-part III (UPDRS III), and Beck Depression Inventory-II(BDI-II) scales. Analyzed biomarkers included CSF -syn seeding activity using seed amplification assay (SAA), CSF lysosomal protein levels of lysosomal integral membrane protein 2 (LIMP2), also known as SCARB2, cathepsin B (CTSB) and lysosome-associated membrane protein 2 (LAMP2), blood-based enzyme activity of the lysosomal glucocerebrosidase (GCase), and CSF sphingolipid profiles. PD patients carrying risk alleles in TMEM175, SCARB2, and CTSB were compared to non-carriers. Results: Genotype-phenotype correlation analysis in TUEPAC-DESCRIBE-PD and AMP-PD revealed: (1) In PDall, the TMEM175 p.M393T risk variant was nominally associated with decreased cognitive function when adjusted for GBA1 mutation status in TUEPAC-DESCRIBE-PD; this association could not be replicated, although a similar trend was observed in the slightly smaller, but multicentric AMP-PD cohort; TMEM175 p.M393T was not significantly associated with BDI-II or UPDRS-III scores in either cohort. (2) In PDGBA1_wildtype, GCase activity was significantly lower in PD patients with SCARB2 rs6812193 risk allele in TUEPAC-DESCRIBE-PD, while a similar but non-significant trend was observed in AMP-PD; (3) In PDall, CSF levels of CTSB were nominally lower in carriers of CTSB rs1293298 risk allele compared to carriers of CTSB rs1293298 protective allele in TUEPAC-DESCRIBE-PD; in PDGBA1_wildtype, LAMP2 was significantly lower in carriers of CTSB rs1293298 risk allele compared to carriers of CTSB rs1293298 protective allele in TUEPAC-DESCRIBE-PD; (4) In PDall, TMEM175 p.M393T risk allele was nominally associated with altered sphingolipid profiles across both TUEPAC-DESCRIBE-PD and AMP-PD cohorts. Conclusion: These findings demonstrate that genetic variants in lysosomal-related genes (TMEM175, SCARB2, and CTSB) have a functional impact on biomarker profiles in PD patients. Integrating genetic characterization with biochemical profiling provides a framework for patient stratification and may serve as a translational strategy to monitor target engagement and evaluate treatment efficacy in future clinical trials.

Background: Motor complications, such as motor fluctuations and Levodopa-induced dyskinesias (LID), significantly impair quality of life in persons with Parkinson's disease (PD) on long-term Levodopa treatment. Predicting their onset is crucial for tailored patient care. Objectives: To develop and evaluate machine learning (ML) models to forecast the onset of new motor fluctuations and LID in PD patients within three years from baseline assessment, and to assess how training cohort composition influences performance. Methods: A comprehensive ML workflow with repeated Nested Grid Search Cross-Validation was applied to real-world clinical data from a multicentric cohort of 247 PD patients. ML models were rigorously evaluated on the clinically relevant subgroup free of motor complications at baseline. SHAP analysis provided model explainability. Results: Models achieved moderate predictive power for both LID (SVC: MCC 0.28 {+/-} 0.14) and motor fluctuations (Voting MCC = 0.32 {+/-} 0.18). For LID prediction, the strongest predictors were the Levodopa Equivalent Daily Dose (LEDD), baseline motor fluctuations, and duration of Levodopa therapy, with risk increasing significantly above a LEDD threshold of 300-400 mg. A critical ablation study revealed that excluding patients with pre-existing complications caused a collapse in model sensitivity, highlighting their essential role in defining the upper bound of predicted risk. Conclusions: The model-based risk assessment is consistent with established clinical factors. Inclusion of the full spectrum of disease severity, including patients with pre-existing motor complications, in the training set is essential for achieving a robust probabilistic risk scale and reliable model calibration for new-onset prediction.

Abstract Background. Parkinson's disease (PD) is a progressive neurodegenerative disorder of increasing prevalence, with diagnostic accuracy of approximately 26% in early symptomatic patients. There is a need for accurate, non-invasive biomarkers to aid in disease diagnosis. Methods. This proof-of-concept study enrolled 90 participants (PD n = 30, other movement disorders [OM] n = 30, healthy controls [HC] n = 30) at a single institution. Participants completed two 10-minute eye-tracking sessions using the SaccadeDX 250 Hz binocular system. A two-level cascade classifier was fitted using elastic-net feature selection followed by logistic regression on the selected features, validated by 10-fold cross-validation. The cascade distinguished HC from movement disorders (Level 1) and PD from OM (Level 2), with the objective of establishing clinical validity that an eye-tracking signal correlates reliably with PD diagnosis. Results. Level 1 achieved an area under the curve (AUC) of 0.818 (95% CI: 0.71, 0.91), with a sensitivity of 83% and specificity of 63%. Level 2 achieved an AUC of 0.670 (95% CI: 0.52, 0.80), with a sensitivity of 68% and specificity of 63%. End-to-end PD detection achieved an AUC of 0.866 and an accuracy of 83.5%, meeting the prospectively specified accuracy threshold and the proof-of-concept AUC benchmark. Five adverse events were recorded (three cases of dizziness, one of nausea, and one of dry eyes); one participant withdrew from the study. Conclusions. Clinical validity is established: a reproducible eye-tracking signal for PD is detectable using a two-level cascade classifier. A multi-center confirmatory study is warranted before assessment of clinical utility.

Purpose: The purpose of this study was to identify subgroups of talkers with Parkinsons disease (PD) with shared tongue, lip, and jaw articulatory amplitude behaviors. The study also sought to identify demographic and clinical features that can distinguish the identified kinematic subgroups. Methods: 53 talkers with PD and 54 controls participated. Articulatory amplitudes of the tongue, lip, and jaw were measured during a paragraph reading task using three-dimensional electromagnetic articulography. Amplitude performance profiles of the tongue, lip, and jaw were established for each talker with PD by referencing their performance to that of controls. These profiles were submitted to a hierarchical cluster analysis to identify kinematic-based subgroups. Amplitude performances were compared across subgroups to determine between-group patterns. Demographic and clinical features (e.g., age, sex, disease duration, selected perceptual speech characteristics, dysarthria severity) were compared across the identified kinematic subgroups. Results: Four main kinematic subgroups with differing amplitude performance profiles were identified. One subgroup exhibited normal to mildly exaggerated or mildly reduced amplitudes and was labeled preclinical subgroup (n = 16). Three subgroups exhibited pronounced amplitude reductions of either the tongue (n = 10), the tongue and lips (n = 12), or the tongue, lips, and jaw (n = 10). In addition, there were five talkers with PD whose performance profiles did not align with the identified four subgroups. Their performance was characterized by either pronounced amplitude exaggerations or mildly reduced jaw and lip amplitudes and exaggerated tongue amplitudes. None of the demographic or clinical features differed significantly between the main four subgroups. Conclusion: Findings suggest that the extent to which hypokinesia manifests within the articulatory subsystem can vary in talkers with PD. Longitudinal studies are needed to determine if these subgroups represent different stages of disease progression or distinctly different manifestations of the disease within the articulatory subsystem.

INTRODUCTION: Parkinson's disease (PD) presents with motor and non-motor symptoms, including dementia, but the severity and rate of cognitive decline are heterogeneous and difficult to predict clinically. METHODS: We quantified baseline serum proteins with the high-throughput SomaScan(R) assay in 834 PD individuals and performed Cox regression to identify proteins associated with subsequent development of dementia. Candidate biomarker proteins were replicated in 371 individuals from an independent cohort and meta-analysed. RESULTS: Protein targets significantly associated with progression to dementia were predominantly involved in synaptic plasticity, protein degradation/lysosomal function and extracellular matrix organisation. Mendelian Randomisation further revealed that changes in the Nogo receptor RTN4R may be causally associated with the development of Lewy body dementia. DISCUSSION: We identified several proteins predicting progression to dementia in PD, indicating changes in blood proteome that precede the development of clinical symptoms by several years, providing a window of opportunity to identify at-risk individuals early on.

Introduction: Parkinson's disease is a neurodegenerative disease affecting motor and cognitive function that has a major impact on society. Epidemiological evidence has suggested that the incidence of PD may be increasing; however, the underlying etiology is unclear. Here, we investigated the role of increasingly used antipsychotics in the diagnosis of PD. Methods: We harnessed Merative Marketscan insurance claims databases to conduct a case-control study of 65,275 new cases of PD and 652,364 age-, sex-, and time-matched controls. We estimated associations between exposure and duration of use for antipsychotics adjusted for important confounders using fixed effects logistic regression. We performed sensitivity analyses stratified by the level of D2 receptor inhibition to assess dose-response relationships; a lagged exposure analysis to address confounding by indication; analysis assessing exposure of other psychiatric medications without significant D2 inhibition (bupropion, trazodone, and Z-drugs); analysis assessing exposure of non-psychiatric medications with significant (metoclopramide) or no D2 inhibition (ondansetron). Results: We found cases with PD had elevated odds of antipsychotic exposure. Longer durations of exposure and greater affinity for the D2 receptor were associated with greater associations with PD. There was a dose-response relationship between D2 inhibition activity and increased odds of PD for a similar duration of exposure. There was a dose response relationship between duration of metoclopramide and the odds of PD; however, there was no such relationship between the non-D2 inhibiting control medications. The association between exposure to an antipsychotic and increased odds of PD was present even when the first exposure was 10 years prior to the PD diagnosis date. Conclusion: If these results are causal, antipsychotic use may explain up to 2.4% of all cases of PD. Given the increasing rate of use of these medications, and the concurrent increasing age-adjusted incidence of PD, there is an urgent need for further investigation into this association and greater awareness of the potential risks of these medications in older adults.

Background: Subthalamic nucleus deep brain stimulation (STN-DBS) improves levodopa-induced motor complications and cardinal motor symptoms of Parkinson's disease (PD), but stimulation frequency may differentially shape outcomes. This is evident for axial and gait symptoms, which may respond differently to lower-frequency stimulation. Whether frequency-dependent effects extend to cognition remains unclear. Objective: To investigate the cognitive effects of DBS at distinct frequencies in PD. Methods: We conducted a systematic review and meta-analysis (PROSPERO - CRD42024618253). PubMed, Web of Science, and EMBASE were searched for studies assessing cognitive outcomes under different stimulation frequencies. Eight cognitive domains were defined: verbal fluency, cognitive flexibility, executive control, working memory, attention, processing speed, episodic memory, and time processing. Multilevel random-effects meta-analyses were performed, with effect sizes expressed as Hedges' g. Results: Forty-three studies met the inclusion criteria, the majority (n = 31) involving STN-DBS. Twenty-one STN-DBS studies, including 355 patients, were included in the meta-analysis. Compared with HFS ([≥] 130 Hz), lower frequencies (4-80 Hz) were associated with better verbal fluency (g = 0.27) and cognitive flexibility (g = 0.38), with consistent effects across sensitivity and leave-one-out analyses. Accuracy-based executive control measures also favored lower-frequency stimulation. OFF-stimulation comparisons showed a concordant pattern. Evidence for other targets (PPN and NBM) was limited. Conclusions: Lower-frequency STN-DBS was associated with modest benefits in specific cognitive domains compared with HFS. These findings highlight the need for future research to determine how frequency interacts with stimulation location and symptom-specific networks to shape cognitive and cognitive-motor outcomes in PD.

Background The global burden of Parkinson's disease (PD) has increased substantially over recent decades, driven by population ageing and rising age-standardized prevalence. In Africa, accurate estimates remain limited due to a lack of recent, methodologically robust population-based studies. Objectives To determine the current age-standardized and sex-specific prevalence rates of PD in Nigeria. Methods We conducted a 2-stage, cross-sectional population-based door-to-door survey among adults aged [≥]18 years in two densely populated urban local government areas in Lagos State, Nigeria, between April 1, 2024 and January 31, 2025. The first stage involved a household census and screening for parkinsonism using a standardized screening tool. The second stage consisted of in-person clinical assessment and diagnostic confirmation by physicians using established clinical diagnostic criteria. Crude and age-standardized prevalence rates (to the World Health Organization World Standard and European Standard Populations) were calculated. Results 31,009 individuals (52.7% female) from 13,222 households were surveyed, and 70 persons were diagnosed with PD. The crude prevalence ratio was 225.7 per 100,000, with higher prevalence in males (53/14658, 361.6) than females (17/16,351, 104.0). The age-standardized prevalence rate (95% confidence interval) was 193 per 100,000 (150 -- 245) (females: 86 (50 -- 137); males: 277 (207 -- 362)), and increased with advancing age. The diagnostic gap (previously undiagnosed) was 60.0% (42/70). Treatment gap (never treated) was 44/70 (62.9%). Conclusions The age-standardized prevalence of PD is higher than previously reported in sub-Saharan Africa. These findings provide contemporary data to inform updated estimates of disease burden and support health systems planning.

Background. L-Dopa remains the primary treatment for Parkinson's disease (PD), but chronic administration frequently leads to L-Dopa-induced dyskinesia (LID). While D1 and D2 medium spiny neuron (MSN) specific structural changes on the spine level have been observed in the striatum of PD and LID, studying microglia mediated synapse loss has not been done to date. Methods. Here we generated novel reporter mice by crossing floxed PSD95c(mCherry/eGFP) mice with D1-Cre and D2-Cre lines, producing D1-PSD95-EGFP and D2-PSD95-EGFP strains for MSN-specific synapse visualization. Using the 6-OHDA mouse model of PD and LID we assessed microglia mediated MSN subtype specific synapse loss in these mice while PLX3397 was used to investigate effects of microglia depletion and repopulation on LID development and synapse loss. Results. Both D1- and D2-MSNs exhibited significant PSD95 synapse loss in PD, with D1-MSN loss further exacerbated in LID. Microglia displayed increased phagocytic activity and accumulated PSD95 material within lysosomes, particularly in LID. PLX3397-mediated microglial depletion reduced LID severity and preserved D1-MSN synapses. A depletion and repopulation paradigm attenuated LID severity, preserved D1-MSN synapses, and reduced synaptic material within microglia. Conclusions. Microglia-mediated synapse loss in MSN subtypes contributes to PD and LID pathogenesis. Pharmacological microglial depletion and repopulation mitigate synapse loss and dyskinesia, highlighting microglial turnover as a promising therapeutic strategy for LID.

Background: Motor disturbances are common in neurologic and neurodegenerative syndromes. A standard motor speed and dexterity measure is the finger tapping test (FTT). The FTT has traditionally been administered in clinic using a mechanical FTT, limiting accessibility and early motor change quantification. This study assessed the validity of a smartphone app-based FTT, which may expand access and enable more frequent testing. Methods: The cohort was diagnostically diverse, including participants with frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal syndrome, primary progressive aphasia, multiple sclerosis, and clinically unimpaired controls. Participants completed a 20-second ALLFTD Mobile App (mApp)-FTT with each hand. Tapping speed metrics were extracted. Participants completed the gold-standard mechanical FTT, a neurologist-administered finger tapping exam, the PSP Rating Scale (PSPRS) and the Unified Parkinson`s Disease Rating Scale (UPDRS). Correlations assessed mApp-FTT and mechanical FTT relationships; regressions evaluated associations with neurologist-rated finger tapping impairment, PSPRS and UPDRS, adjusting for age and sex. Results: The mApp-FTT showed moderate-to-strong correlations with the mechanical FTT (dominant: r=0.63, p<0.001; non-dominant: r=0.55, p<0.001). Taps per second were associated with PSPRS motor severity (dominant hand: std. {beta}=-0.59, 95% CI [-0.91, -0.27], p<0.001) and the UPDRS (dominant hand: std. {beta}=-0.41, 95% CI [-0.82, 0.00], p=0.049). Flight time was modestly associated with neurologist-rated finger tapping impairment (dominant hand: std. {beta}=0.15, 95% CI [0.00, 0.29], p=0.044). Conclusion: These findings support mApp-FTT validity as a measure of motor function across neurodegenerative conditions. Validation in longitudinal and unsupervised remote settings is warranted to understand scalability and evaluate change over time.

Abstract Background: Parkinson's disease (PD) genetics has been predominantly studied in Western European and North American populations, leaving Central Europe underrepresented. We aimed to characterise the genetic architecture of PD in the V4 countries (Slovakia, Czech Republic, Hungary, and Poland). Methods: The CEGEMOD study combined a systematic review of published PD genetic studies from the V4 region with prospective genetic screening of 1373 patients. All participants underwent genotyping array screening, while genetically unresolved patients with early-onset or familial PD underwent whole-exome sequencing analysis. Variants were interpreted using current clinical standards and validated using Sanger sequencing. Results: The systematic review identified 48 eligible studies reporting pathogenic or risk variants in PD patients from the V4 countries. In the prospective cohort, pathogenic, likely pathogenic, or established risk variants were identified in 157/1373 patients (11.4%). GBA1 variants accounted for the majority of findings, mostly driven by the two GBA1:p.(Thr408Met) and p.(Glu365Lys) mild common risk variants, followed by LRRK2, PRKN, POLG, PLA2G6, and ATP1A3. Whole-exome sequencing provided an additional 5% diagnostic yield in genetically unresolved high-risk patients. Our findings also demonstrate substantial disparities in genetic research across Central Europe. Conclusions: This study provides the largest genetic characterisation of PD in Central Europe to date. The CEGEMOD study expands knowledge of the regional genetic landscape, supports the implementation of genetic testing in clinical practice, and establishes an important resource for future precision medicine and collaborative PD genetics research.

Background: Hallucinations, ranging from minor (MH) to structured, are a common non-motor symptom in Parkinson's disease (PD). Structured hallucinations have been associated with altered functional connectivity (FC) between dorsal/ventral attention (DAN, VAN) and default mode (DMN) networks. As structured hallucinations are linked to rapid cognitive decline and MH are often viewed as their precursor, it is imperative to understand the neural basis of MH, and its relationship with cognitive alterations. Objectives: We aimed to identify a whole-brain FC pattern associated with MH and alterations in attention-executive functioning in PD, leveraging a robotic procedure inducing presence hallucinations (riPH) experimentally, to which patients with hallucinations previously showed increased sensitivity. Methods: Non-demented PD patients (N = 53) were categorized into three subgroups based on their hallucination symptoms: no hallucinations (nH; n = 19), MH (n = 18), and structured hallucinations, with or without MH (SMH; n = 16). We combined results from the riPH procedure and neuropsychological tests and applied multivariate methods capturing their shared variance in resting-state fMRI data across the three subgroups. Results: We identified a distributed FC pattern more strongly expressed in patients with hallucinations (MH, SMH), and equally so across both groups, significantly associated with alterations in attention-executive functions and differences in riPH sensitivity. The pattern was primarily driven by FC between subcortical areas and visual network, DAN and DMN, and within-cerebellar and within-subcortical FC. Conclusions: Our results highlight the role of subcortical-cortical connectivity in PD hallucinations, associated with cognitive alterations and already present in less advanced MH patients.

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is hypothesized to improve motor symptoms in Parkinson's disease (PD) by suppressing pathologically elevated beta activity and promoting "prokinetic" gamma activity in the cortico-basal ganglia-thalamo-cortical loop. Advances in bidirectional DBS devices have revealed that stimulation can modify gamma oscillations via subharmonic entrainment, though entrainment's therapeutic role remains unclear. Objectives: To identify stimulation parameters that entrain motor cortical and STN gamma oscillations in PD at rest and during movement, and examine their association with motor function. Methods: Sensorimotor cortex and STN field potentials were collected using a bidirectional DBS system in four subjects with PD over a range of stimulation amplitudes and frequencies. Entrainment amplitude at half the stimulation frequency was quantified at rest and during a finger-tapping task in the ON-medication state. The presence or absence of entrainment was studied as a physiomarker of motor symptom severity. Results: The amplitude of stimulation-entrained gamma oscillations was non-linearly related to stimulation intensity and frequency and varied by stimulation contact choice. Entrainment amplitude was highest in precentral gyrus and increased with movement. In the ON-medication state, precentral gyrus gamma entrainment was associated with reduced bradykinesia, dyskinesia, and dystonia. Subthalamic gamma entrainment predicted improved dystonia but was a less significant marker for motor benefit than cortical entrainment. Conclusions: Stimulation-entrained gamma oscillations in the motor network are a physiomarker for optimal DBS response in PD, and could have a role in physiology-guided DBS programming, complementing existing strategies based on suppression of basal ganglia beta activity.

Background: LRRK2 variants are major contributors to Parkinsons disease (PD). Many pathogenic variants increase kinase activity, underscoring the value of functional assays in nominating therapeutic targets and kinase inhibitors as potential disease-modifying therapies. Objective: To develop an interactive resource that provides functional context and ancestry-specific variant frequencies. Methods: Genotyping and short-read sequencing data were analyzed for 101,678 individuals (61,709 PD, 39,969 controls) from the Global Parkinsons Genetics Program (GP2) and integrated with clinical and in-vitro biochemical kinase activity information. Results: The LRRK2 Browser (http://gp2.org/lrrk2browser) displays ancestry-specific genetic data for 19,596 LRRK2 variants (968 exonic, 14 disease-associated) across 11 populations, and functional data for 171 variants. Clinical annotations include age, age at onset, and family history of PD. Discussion: The publicly available LRRK2 Browser represents an open-access, multi-ancestry resource to support LRRK2 variant interpretation. It aims to enhance the translational potential of genetic and functional data for precision medicine and the implementation of gene-targeted therapies in diverse populations.

Estimating Parkinson's disease (PD) risk years before diagnosis remains an unmet need. We applied a validated machine learning classifier for REM sleep behavior disorder (RBD) detection to 7-day wrist accelerometry data in 87,975 UK Biobank participants followed for 10 years. Participants in the highest RBD risk stratum (>99th percentile) had an approximately fivefold increased hazard of incident PD compared with the lowest-risk group (0-90th percentile), with a dose-dependent relationship across the full score distribution. Among non-converters, higher RBD risk was associated with baseline cognitive deficits and longitudinal enrichment of autonomic and psychiatric prodromal features. The association with incident PD remained independent of PD polygenic risk score, while RBD score and genetic risk were synergistic. The combined high-risk group achieved a positive likelihood ratio of 7.91, approximately threefold higher than questionnaire-based RBD screening. These findings support wrist accelerometry as a scalable approach for prodromal PD risk enrichment in population screening.

Parkinsons disease (PD) is characterised by progressive dopaminergic neurodegeneration in the substantia nigra, leading to debilitating motor dysfunction. Current treatments remain largely symptomatic, highlighting the need for disease-modifying therapies. {beta}1 integrin, implicated in neuroinflammation and trophic signalling, represents a candidate therapeutic target. We investigated whether allosteric {beta}1 integrin modulation could attenuate motor asymmetry in the unilateral 6-hydroxydopamine (6-OHDA) mouse model of PD. Adult male C57BL/6 mice received intracerebral 6-OHDA into the substantia nigra. The anti-{beta}1 integrin antibody JB1a (50 {micro}g) was administered prophylactically (3 days pre-lesion) or therapeutically (3 or 7 days post-lesion). Motor asymmetry was assessed through spontaneous circling (5 min) and apomorphine-induced (0.5 mg/kg s.c.) circling (30 min). 6-OHDA induced dose-dependent contralateral circling, confirming nigrostriatal lesion. Pre-treatment with JB1a (3 days before 6-OHDA) reduced apomorphine-induced circling, although this did not reach statistical significance (28.5 {+/-} 12.8, n = 4 versus 38.6 {+/-} 7.5, n = 8; p>0.05). Post-treatment at 3 days post-lesion produced no statistically significant change in either spontaneous or apomorphine-induced circling (p>0.05). Post-treatment at 7 days post-lesion reduced apomorphine-induced circling by approximately 50%, with values returning to those of sham-operated controls (n =8-9; p<0.01). These findings, obtained in a murine 6-OHDA model, indicate that allosteric {beta}1 integrin modulation attenuates lesion-induced motor asymmetry with apparent temporal specificity. As apomorphine-induced rotation reflects post-synaptic dopamine receptor supersensitivity rather than direct neuronal preservation, and as histological confirmation of dopaminergic integrity was not obtainable in this study, the present data should be interpreted as proof-of-concept behavioural evidence requiring further mechanistic and translational validation in models incorporating -synuclein pathology. The findings are not directly generalizable to human Parkinsons disease. The histological confirmation of lesion extent was not available and as such the behavioural findings are correspondingly interpreted as a proof-of-concept observation requiring histological replication.