Parkinsonism & Related Disorders

BackgroundParkinsons disease (PD) is a progressive neurodegenerative disorder with complex pathophysiology. The potential of integrating biomarkers of neuronal injury, neuroinflammation, and modulators of Wnt signaling for PD diagnosis remains largely unexplored. ObjectiveThis study aimed to evaluate the diagnostic and clinical predictive value of a ten-biomarker serum panel encompassing markers of neuronal injury (NSE, UCHL1), neuroinflammation (GFAP, HMGB1), synaptic plasticity (BDNF), proteinopathy (-Synuclein, {beta}-Amyloid-42), and Wnt signaling (R-spondin-1, DKK1, Sclerostin), with a particular focus on chronic fatigue in PD. MethodsIn this case-control study, 90 PD patients and 45 healthy controls were enrolled. Serum biomarkers were quantified using ELISA. Clinical severity was assessed using the Movement Disorder Society-Unified Parkinsons Disease Rating Scale (MDS-UPDRS) and Fibro-Fatigue (FF) scales. Binary logistic regression and multiple linear regression analyses were used to evaluate the diagnostic and predictive value of biomarkers for PD diagnosis, psychiatric and motoric scores, and an FF score reflecting chronic fatigue syndrome (CFS) severity. ResultsA model incorporating NSE, DKK1, and {beta}-Amyloid-42 effectively discriminated PD patients from controls, yielding an area under the curve (AUC) of 0.932 and an overall accuracy of 83.0%. NSE and DKK1 emerged as the main predictors of overall disease severity, motor symptoms, and CFS severity. Regression analyses indicated that 41.3% of the variance in the FF score was explained by increased NSE, DKK1, {beta}-amyloid, and UCHL1, while 42.9% of the variance in psychiatric symptoms was explained by increased NSE, DKK1, and {beta}-amyloid. Increased GFAP levels were significantly associated with motor dysfunction. ConclusionThe combined presence of neuronal injury, Wnt signaling dysregulation, and amyloid pathology may represent a key pathophysiological component underlying PD, CFS-like fatigue, and psychiatric symptoms in PD. Targeting neuronal injury and Wnt signaling pathways may offer novel therapeutic strategies for managing fatigue and psychiatric manifestations in PD.

Micrographia, characterized by abnormally small handwriting, is a common motor symptom in Parkinsons disease (PD), and has been classified into consistent micrographia (CM) and progressive micrographia (PM), which may reflect different underlying mechanisms. However, the relative contributions of motor execution and sensorimotor processing to these subtypes remain unclear. In this study, forty-five people with Parkinsons disease (PwP) and twenty age-matched healthy controls (HCs) completed a handwriting task and a control detection task (CDT) assessing the ability to distinguish self-generated from externally generated movements. PwP were classified based on handwriting metrics as showing no micrographia, CM, and/or PM. CDT accuracy was significantly lower in PwP than in HCs (p < 0.01) and was particularly reduced in PwP with PM (p < 0.01). These findings indicate that PM is associated with impaired motor awareness, suggesting altered sensorimotor integration as a characteristic feature of this subtype.

BackgroundParkinsons disease (PD) is a progressive chronic neurodegenerative disease. The PARK2 gene encoding the Parkin protein accounts for approximately half of early-onset autosomal recessive PD cases in humans. ObjectiveThe aim of this work was to study the effect of the PARK2 gene knockout in mice on the dynamics of behavioral and biochemical parameters of PD. MethodsThe study was performed on C57BL/6-line mice aged from 4 months to 1.5 years: wild type (park2 +/+), heterozygotes (park2 +/-) and homozygotes (park2 -/-) knocked out by the PARK2 using CRISPR-Cas9. The open field test, the Porsolt forced swimming test, the grid-walk test, the beam-walking test, the elevated plus maze test, the accelerating rotarod test were used to assess the behavioral phenotype. Measurement of the concentration of bioamines and their metabolites by HPLC and evaluation of the amount of tyrosine hydroxylase, BDNF and GDNF by Western Blot were used to study the biochemical signs of PD. ResultsPark2 -/- mice begin to show signs of decreased motor activity no earlier than at 4 months of life. At 12 months of life, it was shown only a decrease in the level of the mature isoform of GDNF and an increase in the number of immature isoforms in the frontal cortex and striatum were revealed. ConclusionThe data obtained indicates a different age dynamic of the condition of mice associated with the PARK2 knockout. However, no pronounced specific manifestations of PD in human were found in park2 -/- mice.

BackgroundThe Montreal Cognitive Assessment (MoCA) is a recommended brief screening tool to detect cognitive impairment in people with Parkinsons disease (PD). ObjectiveTo compare English and Bengali MoCA performance in Bangladeshi individuals with PD in East London. MethodsThis cross-sectional study involved participants completing both English and Bengali MoCA. Analyses included ANCOVA, paired and unpaired t-tests, and Bland-Altman methods in full and age-matched samples. ResultsFifty PD participants and 22 healthy controls (HC) were included in the full analysis. Both groups scored higher on Bengali than English MoCA (mean difference [~]4 points, p<0.001). Age-matched analyses (n= 29 PD and 22 HC) detected PD-control differences with the Bengali but not English version (p=0.02). Bengali scores aligned more closely with multidisciplinary assessments, though mean scores remained below normative cut-offs. ConclusionBengali MoCA improves detection of cognitive differences over English but still overestimates impairment, supporting the need for culturally adapted tools and population-specific cut-offs.

BackgroundVariants in GBA1 are important genetic risk factors for synucleinopathies, including Parkinsons disease (PD). While several GBA1 variants are established risk or severity modifiers, the role of the p.E427K variant remains unclear. ObjectiveTo determine whether the GBA1 p.E427K variant is associated with risk of synucleinopathies. MethodsWe performed a meta-analysis of case-control studies reporting the frequency of GBA1 p.E427K (p.E388K) in PD and related synucleinopathies. Data were obtained from published studies, open-access resources, and large cohorts, including in-house datasets. Odds ratios (ORs) were calculated for each cohort and pooled using a random-effects model. ResultsAcross 67,484 patients and 124,079 controls, GBA1 p.E427K was associated with increased disease risk (pooled OR = 1.87, 95% CI 1.28-2.72, P = 0.001). Enzymatic data showed reduced glucocerebrosidase activity in carriers. ConclusionsThe GBA1 p.E427K variant is a risk factor for synucleinopathies and should be considered in genetic studies and clinical trials.

BackgroundSevere putamen dopamine depletion in Parkinson disease (PD) has been attributed to nigrostriatal denervation; however, there are also functional abnormalities in extant terminals (the "sick-but-not-dead" phenomenon). Rates of intra-neuronal processes of synthesis, storage, and metabolism of dopamine complexly influence releasable dopamine stores but have not yet been systematically estimated. MethodsPost-mortem empirical data were available about putamen tissue contents of 7 reactants, including the autotoxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL). We constructed kinetic models depicting reactions related to putamen dopamine content, the simplest model consisting of 7 reactions and the most complete model 18 reactions among 10 intra-neuronal reactants. We used the post-mortem data, in vivo results of 18F-DOPA positron emission tomography (PET), and the models to estimate rates of the intra-neuronal processes and rank their contributions to control-PD differences. ResultsThere was about a 98% decrease in putamen tissue dopamine in PD. The concentration ratio of DOPAL/DA was about 9 times control. Applying the simplest kinetic model, vesicular sequestration was estimated to be decreased by 98.5% (0.073 vs. 4.91 nmol/min). About 3-fold greater in vivo "washout" of putamen 18F-DOPA-derived radioactivity compared to controls also indicated attenuated vesicular storage in PD. According to the complete model, control-PD differences in intra-neuronal reaction rates were, in descending order, vesicular uptake {approx} vesicular leakage > exocytotic release {approx} neuronal reuptake > L-aromatic-amino-acid decarboxylase activity {approx} tyrosine hydroxylase activity > other reactions. DiscussionEmpirical post-mortem and in vivo data and application of kinetic models provide convergent quantitative evidence for a substantial vesicular storage defect in residual dopaminergic terminals in PD, a potential target for disease-modifying treatment or prevention strategies. Trial RegistrationNone BRIEF SUMMARYWe estimated rates of reactions involved with synthesis, storage, release, reuptake, and metabolism of dopamine in the putamen in Parkinson disease and found that the main intra-neuronal functional abnormality separating Parkinson disease from controls was attenuated vesicular sequestration, implicating decreased vesicular uptake via the vesicular monoamine transporter and increased vesicular leakiness as key determinants of putamen dopamine deficiency in PD.

BackgroundPatients with Parkinsons disease (PD) almost inevitably experience cognitive impairments. These deficits have been linked to low frequency "theta" cortical activity [~]4 Hz, previously associated with cognitive control. ObjectiveOur study investigated effects of 4 Hz subthalamic nucleus (STN) deep brain stimulation (DBS) on cognitive performance in PD patients with cognitive impairments. MethodsWe recruited 17 PD participants with (n=10) and without (n=7) cognitive impairment. In these patients, we compared motor and cognitive performance during 4 Hz STN DBS, typical DBS for motor symptoms of PD ([~]130Hz) and DBS OFF. Motor performance was tested by Part III of the Movement Disorders Society Unified Parkinsons Disease Rating Scale (MDS-UPDRS-III). Cognitive performance was tested during performance of the Multi-Source Interference Task (MSIT), which requires conflict resolution to respond accurately. ResultsMotor function improved with 4 Hz STN DBS and further improved with [~]130 Hz STN DBS. Compared to DBS OFF, reaction times were decreased during 4 Hz STN DBS and were further decreased at [~]130 Hz. Strikingly, 4 Hz DBS alone improved accuracy compared to both DBS OFF and compared to [~]130 Hz STN DBS. ConclusionsThese data suggest that theta-frequency 4 Hz STN stimulation is effective in PD patients with cognitive impairments. Our findings will help guide new therapies targeted at improving cognitive dysfunction in PD and could broaden applications for low-frequency brain stimulation.

ObjectiveIn Parkinsons disease (PD), gait-related digital mobility outcomes (DMOs) show promise for monitoring mobility decline, but convergent validity remains limited. To improve convergent validity, demonstrating convergence with motor severity scales and PD-specific neural mechanisms underlying mobility has been proposed. However, severity scales capture both PD-specific and non-specific factors. Requiring mechanistic evidence may favor DMOs that converge with underlying mechanisms, while those converging only with severity scales may be overlooked despite capturing broader mobility dimensions. Here, we asked whether PD-specific neural mechanisms underlying mobility enhanced the convergence of DMOs with motor severity scales - so that integrating mechanistic evidence in validation could improve (and not impede) convergent validity. MethodPrincipal component analysis was applied to task-based functional neuroimaging data to identify a measure associated with PD motor network dysfunction. An optimization problem was then formulated in which deep learning examined the convergence of a signal-based DMO with motor severity in laboratory and real-world contexts, and Tracing Gradient Descent assessed the influence of the identified measure on DMO-severity convergence. ResultsGreater PD motor network dysfunction was associated with reduced Attractor Complexity Index (ACI) values ({rho}=-0.54). Strong DMO-severity convergence was found across contexts ({rho}=|0.81-0.82|). Reduced ACI (i.e., greater PD motor network dysfunction) markedly enhanced DMO-severity convergence across contexts (rrb=|0.63-0.29|). ConclusionPD-specific neural mechanisms underlying mobility enhanced the convergence of a DMO with severity scales. SignificanceIntegrating mechanistic validation into DMO validation could improve convergent (and construct) validity, a prerequisite for regulatory approval and adoption in clinical trials and practice.

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.

BackgroundProgressive supranuclear palsy (PSP) is a rare and devastating tauopathy with limited global data. Given Indias large population, genetic diversity, and clinical heterogeneity, large multicenter datasets are crucial to enrich global understanding of PSP. ObjectiveTo characterize the demographic, clinical, and phenotypic profiles of a large multicenter Indian PSP cohort. MethodsSubjects fulfilling MDS-PSP criteria were prospectively recruited across movement disorders centers (2021-2025). Standardized demographic and clinical data were collected. ResultsA total of 1,035 subjects were enrolled (M:F = 709:326), with a median age of 65 years and a mean onset age of 62.2{+/-}7.9 years. Regional distribution reflected pan-Indian recruitment (South 35%, North 26%, West 21%, East 18%). PSP-Richardsons syndrome was most common (41%), followed by PSP-Parkinsonism (18%) and PSP-CBS (11%); rarer phenotypes included PSP-PI (7%), PSP-F (7%), PSP-PGF (5%), PSP-OM (2%), PSP-SL (1%), and PSP-C (1%). Falls occurred earliest in PSP-PGF (13.7 months) and PSP-SL (16.3 months), while PSP-P showed delayed disability (falls at 31 months). Cognitive onset was prominent in PSP-F (21%) and PSP-SL (57%). Levodopa was prescribed to 893 patients; 186 (21%) reported >25% subjective benefit, and 358 (40%) reported [&le;]25% benefit. Amantadine was used in 351 (34%) patients, with improvement in 177. ConclusionThis largest systematically profiled PSP cohort highlights both shared and distinctive features: high frequency of non-RS variants, aggressive course in PSP-RS/SL, better survival in PSP-P, and limited pharmacological benefit. These findings establish a foundation for longitudinal and genetic studies in diverse populations.

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

Braak and others have proposed that Lewy body pathology LBP in Parkinson disease PD may arise not only in the brain but alternatively from an initial site in the gastrointestinal GI tract with subsequent passage to the central nervous system CNS through the vagus nerve or other routes. We tested this hypothesis by using both immunohistochemistry IHC and RT QuIC a form of alpha synuclein seed amplification assay SAA to detect alpha synuclein LBP in samples from selected brain regions and 10 GI tract sites taken from autopsies of 50 PD subjects and 128 elderly subjects without parkinsonism or dementia including 34 with IHC identified CNS incidental Lewy body disease ILBD and 94 with no Lewy body IHC pathology detected NLB. A positive SAA or IHC result was restricted to the GI tract in only 2 subjects while LBP by either SAA or IHC was restricted to the brain in 11 subjects. To fairly compare GI only with brain only synucleinopathy however we would have to do SAA on brain samples from all ILBD and NLB cases in at least 4 critical brain regions olfactory bulb medulla pons and amygdala. Further SAA of brain regions is estimated based on the proportional results to date to potentially identify 21 additional brain only LBP subjects total of 32 if it were done on all of the NLB subjects. From this brain only LBP is estimated to be 16 times more common than GI only LBP. To assess the clinical impact of SAA positive GI sites we found that the number of positive sites per subject is significantly correlated with UPDRS motor score and SCOPA AUT GI related scores including those for salivation straining constipation and bowel movement.

Freezing of gait (FOG) in Parkinsons disease (PD) involves impaired integration of posture and locomotion with altered body-segment coordination. We measured coordination using gait kinematics during walking in 16 PD patients with FOG, preoperatively with and without dopaminergic medication (OFF/ON-DOPA), and postoperatively with and without subthalamic deep brain stimulation (OFF/ON-DBS). Body-segment coordination was modeled from acceleration-based intersegmental correlations across trunk, pelvis, and limbs. We tested whether coordination metrics predict individual postoperative FOG severity using LASSO regression with nested cross-validation, including preoperative demographics, clinical scores, gait and coordination metrics. Preoperatively, DOPA decreased trunk-pelvis-upper-limb coordination but increased crossed upper-lower-limbs coupling; while STN-DBS selectively increased inter-upper-limb coordination, with DOPA- and STN-DBS-induced changes being correlated. Whole-body coordination predicted individual postoperative FOG severity, with the most important couplings being the trunk-pelvis and pelvis-lower-limb. Body-segment coordination captures clinically relevant gait metrics in PD, highlighting coordination as a potential biomarker for patient stratification and treatment response.

Transcranial temporal interference stimulation (tTIS) is a non-invasive method designed to target deep brain regions, such as the basal ganglia, without affecting overlying cortical areas. This study investigated intermittent theta-burst (iTBS) tTIS effects on symptom severity in Parkinsons disease (PD) and motor learning behavior, a condition associated with - among others - basal ganglia dysfunction. We hypothesized that iTBS-tTIS applied to the right putamen would alleviate PD symptoms and improve motor learning expressed by the contra-lateral hand. This randomized, double-blinded, crossover trial included 19 PD patients (mean age 64 years, 14 males) and 19 age- and sex-matched healthy controls (mean age 68.6 years). Structural MRI data were obtained for each participant, and individualized electric field simulations were performed to predict field strength in the right putamen. The motor part of the Movement Disorder Societys Unified Parkinsons Disease Rating Scale (MDS-UPDRS III) served as a primary outcome parameter, an alternating finger tapping task (aFTT) and Motor learning assessed through a sequential finger-tapping tasks (sFTT) were secondary outcome parameters. ITBS-tTIS significantly reduced MDS-UPDRS motor scores in PD patients and the stimulation induced changes in motor performance correlated with the electric field strength in the targeted putamen region. No significant effects were found for motor performance or motor learning in either group. These findings indicate that iTBS-tTIS in general holds potential as a non-invasive approach for deep brain stimulation in PD.

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.

BackgroundParkinsons disease (PD) is a neurodegenerative disorder for which there is currently no cure or reliable biomarker for early detection or for evaluating the effectiveness of potential treatments. PD pathology is driven by misfolding and subsequent accumulation of alpha-synuclein (Syn) protein into pathological aggregates within neurons and glial cells. Seed amplification assay (SAA) is a highly sensitive and specific diagnostic tool developed to detect pathological Syn species in the cerebrospinal fluid (CSF) of PD patients. However, Syn aggregates are present in multiple tissues and biosamples, including stools. In this study, we aimed to investigate the potential diagnostic value of SAA using stool samples from PD patients and healthy controls (HC). MethodsStool samples from PD patients (n=45) and healthy controls (n=35) were analysed for the presence of Syn species using slot blot assays with a panel of six Syn antibodies, and ELISA assays. Samples were subjected to SAA, and the end-point products (SAA EP) were characterised using transmission electron microscopy (TEM). Extracellular vesicles (EVs) were isolated from the subset of samples (n=5 per group) using size exclusion chromatography and characterized by TEM. The seeding activity of isolated EVs was evaluated using SAA, followed by TEM analysis of SAA EP. ResultsProtein extracts from both PD and HC stool samples revealed pathological Syn species in the slot blot assay using the phosphorylated Syn antibody, pS129 and conformation-specific antibodies, MJFR-14 and 5G4. ELISA showed significantly elevated total Syn levels in PD samples compared to HC, although no differences in aggregated Syn levels were detected. In stool protein extracts, SAA demonstrated 55.6% sensitivity and 60% specificity. When applied to stool-derived EVs from PD patients and controls, sensitivity increased to 100%, while specificity remained at 60%. Notably, SAA applied to stool-derived EVs pre-incubated with recombinant monomeric Syn achieved 100% sensitivity and 100% specificity. ConclusionThese findings suggest that SAA applied to EVs isolated from stool samples, particularly after pre-incubation with recombinant monomeric Syn, may serve as a valuable, non-invasive screening tool for the diagnosis of PD.

BackgroundLRRK2-Parkinsons disease (LRRK2-PD) is biologically heterogeneous with approximately 30% lacking aggregated alpha synuclein (Syn) in cerebrospinal fluid by seed amplification assay (SAA). Prior work has suggested slower progression in LRRK2-PD compared to sporadic PD (sPD). ObjectiveWe aimed to assess how LRRK2-PD with Syn aggregates on SAA (S+ LRRK2-PD) compares to S+ sPD. MethodsData from the Parkinsons Progression Markers Initiative were used to compare S+ LRRK2-PD and S+ sPD cohorts propensity score-matched on age, disease duration, sex and levodopa equivalent dose (N = 79 per cohort). Baseline clinical and biological features and 4-year longitudinal features were assessed. ResultsAt baseline, S+ LRRK2-PD participants had lower motor scores and dopaminergic deficit. Among measures showing within group progression, longitudinal trajectories did not differ significantly between groups. ConclusionsLongitudinal clinical progression of S+ LRRK2-PD and sPD in the PPMI study is similar despite differences in baseline features.

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; [&le;] 4y; [&ge;] 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.

Background: Visual dysfunction is a common but underrecognized contributor to disability in Parkinsons disease (PD), particularly deficits in binocular vision and vergence that impair reading, near work, and quality of life. The relationship between objective oculomotor abnormalities and patient-reported visual disability remains incompletely understood. Methods: We studied 25 individuals with PD and 11 age-matched controls who completed the National Eye Institute Visual Function Questionnaire 25 (VFQ25) and the Convergence Insufficiency Symptom Survey (CISS). Participants underwent comprehensive clinical ophthalmologic assessment and high resolution binocular eye tracking to quantify vergence latency, gain, fixation dynamics, and drift variability. Associations between objective measures and patient reported outcomes were examined, and predictive models were developed using clinic-only and combined clinical plus eye tracking approaches. Results: Compared with controls, PD participants demonstrated significantly worse VFQ25 composite scores and higher CISS scores, driven primarily by impairments in near activities and mental health. Clinically, PD was characterized by convergence insufficiency rather than generalized visual loss. Objective eye tracking revealed delayed vergence initiation, reduced gain, and increased instability. In PD, both clinical convergence measures (notably nearpoint convergence) and dynamic eye tracking metrics strongly correlated with VFQ25 and CISS scores, whereas such relationships were absent in controls. Predictive models showed limited performance using clinic measures alone, but improved with inclusion of eye racking variables. Conclusions: Visual disability in PD is tightly linked to convergence insufficiency and dynamic oculomotor instability. Simple clinical measures such as nearpoint convergence, augmented by eye tracking when available, provide meaningful insight into patient reported visual quality of life.