Journal of Parkinson's Disease

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.

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.

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.

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.

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: 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.

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: 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.

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.

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: 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.

LRRK2 is implicated in Parkinson's disease (PD) microbiome-gut-brain axis. We compared plasma lipopolysaccharide-binding protein (LBP) and soluble CD14 (sCD14), markers of gut permeability and endotoxin exposure, in PD patients with/without LRRK2 p.G2385R and/or p.R1628P, and controls, and examined their associations with systemic inflammation and clinical severity. Neither marker differed between groups. Across PD patients, LBP correlated with higher IL-6, TNF- and worse motor function, while sCD14 correlated with higher IL-6, CCL5 and worse constipation. These findings highlight the clinical relevance of endotoxin-related immune signaling in PD, without LRRK2 risk variant-specific associations and identify LBP as an emerging marker of inflammatory burden.

Parkinson's disease (PD) exhibits pronounced sex differences, yet the underlying genetic and molecular mechanisms remain poorly understood. We performed the largest-to-date meta-analysis of sex-stratified genome-wide association studies of PD followed by brain proteogenomics-based causal inference analyses. We nominated 10 candidate proteins that appear important to sex-biased PD risk, of which 2 female-biased, GALC and PSMG1, and 3 male-biased, ACTR1B, WDR41, and CD151, were most robustly prioritized. Together, our findings provide evidence for genetic sex differences in PD, prioritizing sex-biased proteins implicated in lysosomal regulation, neuroinflammation, lipid biology, and other PD-relevant mechanisms, and highlighting potential sex-informed therapeutic opportunities.

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.

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.

Introduction Parkinson's disease (PD) is a multifactorial disorder, affecting multiple neurotransmitter systems, including the cholinergic system. Cholinergic denervation is heterogeneous across patients and difficult to predict based on clinical presentation. In this study, we assessed the sensitivity of structural MRI (sMRI) and functional MRI (fMRI) to cholinergic degeneration related to PD and to cognitive functioning in PD. We compared our results to results from previously reported [18F]Fluoroethoxybenzovesamicol ([18F]FEOBV) PET imaging, which is considered the gold standard for cholinergic imaging. Methods 34 PD patients and 10 healthy controls underwent structural T1-weighted MRI. A subset of 14 patients and 9 controls also underwent resting-state fMRI. We extracted the bilateral volumes of the nucleus basalis of Meynert (NBM) from the sMRI images. Functional connectivity (FC) from the NBM to the cortex (NBM-FC) was determined using fMRI data. Principal component analysis (PCA) was applied to reduce the dimensionality of the NBM-FC images. We assessed performances for NBM-FC in distinguishing patients from controls using stepwise logistic regression. Similarly, NBM volume was used using logistic regression. Furthermore, the relation between these measures and cognitive function in several domains was investigated with (stepwise) linear regression. Leave-one-out cross validation (LOOCV) and bootstrapping was performed to assess robustness of the results. Results NBM-FC was well able to discriminate patients from controls with an AUC of 0.84 (95% CI: 0.62-1). NBM volume showed lower performance, but was still better than chance: AUC: 0.75 (95% CI: 0.57-0.93). Significant correlations were found between 1) cognition in the attentional domain and NBM-FC (r=0.63; p=.015) and 2) global cognition and NBM volume (r=0.55, p=.001). These results were inferior to those previously reported using [18F]FEOBV tracer uptake (see Chapter 6). Bootstrapping revealed that NBM volume of only the left hemisphere was stably related to PD diagnosis and global cognition in PD patients. We found that a lower NBM-FC in specific brain areas, including the fusiform gyrus, supramarginal gyrus and dorsolateral prefrontal cortex, was related to PD diagnosis. Bootstrapping revealed no stable NBM-FC pattern related to attention. Conclusion Although MRI results were slightly inferior to [18F]FEOBV PET data, MRI may provide a cheaper and more widely available alternative for cholinergic imaging. We recommend testing the utility of MRI as predictor and monitor of cholinergic treatment effect in a longitudinal study.

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.

Aggregation of -synuclein protein is a characteristic of Parkinsons disease pathology that relates to the degeneration of vulnerable dopaminergic neurons and motor symptoms of the disease. However, -synuclein pathology can contribute to neuronal dysfunction by disrupting several processes within the cell, including intracellular calcium balance, mitochondrial function, and synaptic function. Here, we use a preformed fibril (PFF) model of synucleinopathy to examine effects of striatal -synuclein seeding on dopamine neurons of the substantia nigra pars compacta (SNc). The SNc is heterogeneous and contains dopaminergic neurons with differential vulnerability to Parkinsons disease pathology. We found that intrastriatal injections of PFFs differentially affect these SNc neuron subtypes by increasing the excitability of resilient SNc neurons, while altering tonic firing patterns and T-type calcium currents in vulnerable SNc neurons. In addition, we performed comprehensive electrophysiological analyses and neural morphology reconstructions on SNc neurons from PFF and monomer injected mice. These findings provide insights to the selective vulnerability of SNc neuron subtypes and further our understanding of the role of -synuclein in Parkinsons disease progression and circuit dysfunction.

Pathogenic variants in leucine-rich repeat kinase 2 (LRRK2) 1 are among the most frequent monogenic causes of Parkinson's disease (PD) and act through a gain-of-function mechanism of increased kinase activity. LRRK2-targeted therapies are in clinical development, but interpretation of the rapidly expanding catalogue of rare LRRK2 variants remains a barrier to translation. Here, we present functionally annotated data on more than 350 LRRK2 variants using a standardized cellular assay with Rab10 phosphorylation as a readout of kinase activity and integrated these data with curated genetic and clinical annotations from the Movement Disorders Society Genetic Mutation Database (MDSGene). Variants differed in activation magnitude, ranging from modest increases (e.g., p.G2019S) to strongly activating substitutions such as p.Y1699C or p.L1795F. Activating variants occurred across the full length of LRRK2, although the largest effects clustered within the ROC-COR regulatory hub, where structural analysis identified subdomains forming an allosteric scaffold controlling kinase output. All known/established pathogenic variants showed increased activity, whereas benign and likely benign variants remained within the wild-type range. Functional effect sizes correlated with pathway activation in patient-derived immune cells, altogether providing a framework for ACMG-based variant interpretation in which kinase activation can support PS3 functional evidence for reclassification of variants.

Parkinson's disease (PD) is a progressive neurodegenerative disorder commonly accompanied by cognitive decline, yet the mechanisms linking disrupted brain homeostasis to progressive cognitive impairment remain unclear. Emerging evidence suggests that the choroid plexus (ChP) and the locus coeruleus (LC) are involved in cerebrospinal fluid dynamics and norepinephrine regulation, respectively, but their longitudinal alterations and interrelationships in PD have not been systematically examined. We conducted a two-year longitudinal study including 90 PD patients and 51 healthy controls (HCs) undergoing multimodal MRI. ChP volume (ChP-V) was derived from T1-weighted structural imaging, ChP blood flow (ChP-BF) was assessed using pseudo-continuous arterial spin labeling, and LC integrity was ascertained with the contrast-to-noise ratio of the LC (LC-CNR) in neuromelanin-sensitive MRI. Group differences, longitudinal alterations, and associations with neuropsychological performance were examined. Over two years, PD patients showed progressive increases in ChP-V (F = 12.45, p < 0.001), reductions in ChP-BF (F = 18.98, p < 0.001), and declines in LC-CNR (F = 16.80, p < 0.001). Baseline LC-CNR was already reduced in PD compared with HCs (t = 3.023, p = 0.003). The longitudinal changes were more pronounced in male patients. ChP-BF was positively correlated with LC-CNR at baseline (r = 0.293, p = 0.006). Moreover, reductions in ChP-BF and LC-CNR were associated with worsening cognitive performance. While LC dysfunction was evident early in the disease course, progressive ChP alterations, particularly in ChP perfusion, provided additional information on longitudinal disease progression, supporting their combined value and highlighting the importance of gender-specific longitudinal monitoring.