Movement Disorders

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

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.

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.

BackgroundThe SLC25A46 gene encodes a mitochondrial carrier protein previously implicated in neuropathy and optic atrophy. Biallelic variants in SLC25A46 have been described in patients with Parkinsons disease (PD) with optic atrophy, but the evidence supporting a role in PD remains limited. ObjectiveTo assess whether SLC25A46 variants contribute to PD, REM sleep behavior disorder (RBD), or Dementia with Lewy Bodies (DLB). MethodsWe examined common variants using four representative PD genome-wide association studies (GWAS) and an RBD GWAS and applied Summary-data-based Mendelian Randomization (SMR) to evaluate whether genetically regulated expression of SLC25A46 shows a causal association with the risk of PD or RBD. Rare variant analyses were conducted in four cohorts of European descent: Accelerated Medicines Partnership: Parkinsons Disease (AMP-PD) PD (3,051 PD, 3,667 controls), UK Biobank (3,267 PD, 14,939 proxy, 54,800 controls), RBD (1,376 RBD, 2,580 controls), and AMP-PD DLB (2,605 DLB, 1,894 controls). Optimal Sequence Kernel Association test (SKAT-O) and meta-analysis were used to assess rare variants. ResultsNo associations were observed between SLC25A46 variants and PD, RBD, or DLB. SMR analyses revealed no evidence supporting a causal relationship between SLC25A46 expression and PD or RBD risk. Rare variant burden analyses did not identify significant associations after multiple-testing correction across cohorts or meta-analyses. ConclusionSLC25A46 variants showed no evidence of association, suggesting the gene does not play a major role in PD, RBD, or DLB risk.

BackgroundParkinsons disease (PD) is a multifactorial neurodegenerative disorder shaped by, amongst others, high-impact variants and common polygenic factors. The Personalized Parkinson Project (PPP) offers deep phenotyping and longitudinal follow-up of Dutch people with PD. Here, we characterize the genetic landscape and its interaction with lifestyle factors within PPP. MethodsWe utilized three complementary approaches in N=507 persons with PD: 1) short-read PD gene panel sequencing of eight PD genes, 2) genome-wide genotyping array, and 3) targeted long-read sequencing of the GBA1 gene. Additionally, we calculated the mitochondrial-function polygenic score (MGS). Associations between genetic factors, smoking status, and age at onset (AAO) were assessed using non-parametric tests, correlation analyses, and multiple regression models. ResultsGenetic screening of the participants revealed N=79 GBA1 ([~]15%), N=3 LRRK2, N=1 CHCHD2, N=1 SNCA variant carrier, and N=9 heterozygous PRKN/PINK1 variants. We also observed an interaction between MGS and smoking: MGS was associated with earlier AAO in non-smokers in persons with iPD (N=414, {beta}=-1.87, p=0.038). ConclusionOur findings corroborate previously reported frequencies of variants in PD-associated genes in European populations, and suggest a potential association between smoking and a mitochondrial dysfunction signature in PD. Thus, even in persons without rare variants (iPD subgroup), complex genetic contributions remained relevant. Our study supports future downstream stratification and personalized medicine approaches with high-impact variants and polygenic risk scores.

BackgroundDopa-responsive dystonia is caused by pathogenic variants in the GCH1 gene. Although its clinical features and reduced penetrance are known, in vivo metabolic and structural alterations in symptomatic (sMC) and asymptomatic mutation carriers (aMC) remain poorly understood. ObjectivesTo characterize volumetric and neurometabolic brain changes of GCH1 mutation carriers and explore their relationship with clinical severity. MethodsWe studied 20 sMC, 5 aMC, and 25 mutation-free healthy controls (HC) using volumetric MRI combined with 31phosphorus magnetic resonance spectroscopy imaging (31P-MRSI) of the basal ganglia and cerebellum. ANCOVA was used for group comparisons, and correlations were assessed with clinical symptom severity rating scales. ResultsVolumetric analyses revealed enlarged globus pallidus (+16.6%, p = 0.001) and putamen (+7.2%, p = 0.031) volumes in carriers and increased cerebellar gray matter in aMC (+8.0%, p = 0.050). NAD levels were significantly reduced in the basal ganglia of carriers (NAD/Pi: -14.7%, p = 0.046; NAD/ATP-: -15.5%, p = 0.018). In the cerebellum, aMC demonstrated elevated high-energy phosphate ratios ((ATP-+PCr)/Pi: +23.7%, p = 0.017; ATP-/Pi: +21.3%, p = 0.046; PCr/Pi: +25.2%, p = 0.009) compared with sMC and HC. Smaller cerebellar volumes correlated with greater dystonia severity (BFMDRS, {rho} = -0.475, p = 0.019) while lower basal ganglia NAD ratios correlated with higher MDS-UPDRS-III ({rho} = -0.472, p=0.041) and TWSTRS scores ({rho} = -0.477, p = 0.039). Conclusions31P-MRSI and volumetric MRI reveal region- and subgroup-specific metabolic and structural alterations in GCH1 mutation carriers, linking basal ganglia vulnerability and cerebellar adaptation to clinical severity.

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 characterized by the progressive degeneration of nigrostriatal dopaminergic neurons, yet the molecular mechanisms initiating this cascade remain elusive. Genetic linkage studies have implicated KCNJ15 (encoding the inwardly rectifying potassium channel Kir4.2) in familial PD. Specifically, a mutation identified in a four-generation PD family acts as a loss-of-function variant with dominant-negative effects. However, the neural function of Kir4.2 and its role in driving neurodegeneration have not been established. MethodsTo investigate the pathological consequences of Kir4.2 loss, we performed longitudinal profiling of behavior, neuropathology, and transcriptomics in newly generated Kcnj15 knockout (Kcnj15-/-) mice and age and sex-matched WT littermates at 6 and 12 months of age. Motor, anxiety-like, and cognitive phenotypes were assessed with the behavioral battery (open field, accelerating rotarod, elevated balance beam, DigiGait, and Barnes maze tests), while neuropathological integrity of PD-relevant brain areas was evaluated via immunohistochemistry. Furthermore, bulk RNA-sequencing was performed on striatal tissue to identify downstream molecular signatures associated with channel loss. ResultsKcnj15-/- mice exhibited a progressive "coordination-first" motor syndrome, where deficits in dynamic balance and fine motor control emerged prior to gross locomotor impairments. This motor phenotype was accompanied by dynamic alterations in anxiety-like behavior and impaired spatial memory consolidation, mirroring prodromal cognitive decline. Neuropathologically, Kir4.2 loss triggered selective neurodegeneration in the substantia nigra pars compacta (SNpc), sparing the ventral tegmental area (VTA). This pathology was characterized by robust microglial hyperactivation and neuronal/microglial phosphorylated -synuclein accumulation. As such, these changes were indicative of disrupted proteostasis and a pro-inflammatory feed-forward loop. Striatal transcriptomics revealed up-regulation of oligodendrocyte- and myelin-associated genes, suggesting remodeling of glial support networks. ConclusionThese findings identify Kir4.2 as a critical homeostatic regulator of nigrostriatal circuit function. Kir4.2 dysfunction links ionic instability to a triad of neuroinflammation, synucleinopathy, and myelin plasticity, positioning Kir4.2 as a novel susceptibility factor in PD neurodegenerative vulnerability.

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.

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.

ImportanceDementia is common in Parkinsons disease (PD), causing greater disability than other symptoms, but varies in timing. Although visual deficits are linked with PD dementia, how these interact with genetic factors to predict PD dementia has not been characterised. ObjectiveTo investigate whether visual deficits and genetic factors predict PD dementia. DesignLarge prospective longitudinal case-control study, mean follow-up 32.7 (SD=12.3) months. SettingCases were recruited between 2017-2020 at 35 UK PD clinics. ParticipantsPeople with PD without dementia at baseline were included. Main outcomes and measuresVisual function was measured using a web-based platform. The main outcome measure was global cognition, measured as the Montreal Cognitive Assessment (MoCA). Blood samples were collected for genetics. Results450 patients with PD were included. Mean age of PD patients was 71.7 (SD=7.8), 68% male. Mean baseline MoCA was 27.7 (SD=1.7). 263 patients with PD were classed as poor-vision based on baseline visual tests: mean age 74.4 (SD=6.8) compared to 69.7 (SD=7.5) with good-vision. Poor-vision PD patients had higher rates of progression to mild cognitive impairment (PD-MCI) (HR=2.34, CI=1.58-3.48, pFDR=0.00062, age- and sex-corrected). The combination of genetic factors together with vision influenced outcomes. In good-vision PD patients, high-risk GBA1 gene variants were linked with greater progression to PD-MCI (HR=4.61, CI=1.73-12.28, pFDR=0.0068). Polygenic Risk Score (PRS) for both PD and Alzheimers disease (AD) also modified cognitive survival when combined with vision status. High PD-PRS was associated with greater progression to PD-MCI in good-vision patients (HR=2.66, CI=1.21-5.81, pFDR=0.0381); and high AD-PRS with greater progression to PD-MCI in poor-vision PD patients (HR=1.91, CI=1.10-3.32, pFDR=0.04999). Combining high PD- and AD-PRS, compared to low PD- and AD-PRS in good-vision PD showed even higher progression to PD-MCI (HR=6.14, CI=1.36-27.83, pFDR=0.046). Simulations showed that adding visual and genetic stratification reduced sample size from n=705 to n=160 for clinical trials. Conclusions and relevancePoor vision in PD predicts progression to PD-MCI and dementia. This combines with the effects of genetic factors including GBA risk variants and PD- and AD-PRS. These findings can enable enrichment of clinical trials for patients at higher risk of PD dementia, for more efficient trial design for interventions to slow progression. Key pointsO_ST_ABSQuestionC_ST_ABSDo clinical factors, measured by performance on visual tests, and genetic factors help predict which patients are more likely to develop cognitive involvement in Parkinsons disease? FindingsThis prospective longitudinal study of 450 Parkinsons patients, based in Parkinsons clinics, with mean follow-up 32.7 months, found that Parkinsons patients with poor vision are more likely to develop cognitive impairment; and that genetic factors in combination with poor vision further predict poor prognostic groups for Parkinsons dementia. MeaningThese data could enable selection of Parkinsons patients at highest risk of dementia for clinical trials aimed at slowing Parkinsons dementia.

ObjectiveTo evaluate whether the presence of orthostatic hypotension (OH) impacts the association between white matter hyperintensity (WMH) volume and motor symptom burden in persons with Parkinsons disease (PWP). MethodsMotor symptom burden in PWP was quantified using the Movement Disorders Society Unified Parkinsons Disease Rating Scale (MDS-UPDRS) Part III. Total WMH volume was segmented based on high-resolution T1-weighted (T1W) and T2 Fluid Attenuated Inversion Recovery (FLAIR) images. Determination of whether individual participants qualified as having OH was based on orthostatic vital signs. All data were obtained from the Parkinsons Progression Markers initiative (PPMI) dataset. ResultsA total of 218 PWP (mean age, 64.84 {+/-} 9.51) and 50 control participants (mean age, 65.52 {+/-} 11.04) were included in the analyses. WMH volume did not differ significantly between the two groups. 15.1% of the participants in the PD group and only 4% of the control group qualified as having OH. Analysis of covariance determined that in PWP, the association between WMH volume and motor symptom burden was significantly different in participants with OH in comparison to those without OH (steeper in the former group). Follow-up analyses suggested that the effects were strongest for bradykinesia symptoms. Adjusting for disease and symptom duration did not alter results. ConclusionsThe presence of OH in PWP impacts the links between white matter lesion volume and motor symptom burden. These findings may provide a potential mechanism underlying the poorer disease prognosis among PWP with OH.

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.

BackgroundPrognosis and therapeutic management in Parkinsons disease remain challenging due to the diseases heterogeneous progression and symptom presentation and lack of reliable biomarkers to predict individual disease trajectories. ObjectiveTo determine whether baseline blood transcriptomes, analyzed through biologically defined pathway gene sets, contain signatures that distinguish distinct motor and non-motor progression trajectories in Parkinsons disease. MethodsUsing data from the Parkinsons Progression Markers Initiative cohort, we developed a pathway-based computational framework to derive individualized molecular severity scores from baseline blood transcriptomic profiles by integrating pathway-level gene expression with longitudinal clinical data. Severity indices for motor and non-motor features established domain-specific progression trajectories of sporadic Parkinsons disease. Machine learning models were trained to predict patient trajectory membership from baseline transcriptomics. Findings were validated in genetic subcohorts and externally in the Parkinsons Disease Biomarkers Program cohort. ResultsMolecular severity scores were associated with key clinical features. Analysis of score changes revealed two non-motor and two motor progression groups, each characterized by specific gene signatures (20 genes for non-motor; 121 for motor). From baseline transcriptomic data, we accurately predicted an individuals trajectory group (0.87 for motor progression). The framework demonstrated high generalizability across independent and genetic cohorts, producing clinically coherent profiles. ConclusionsOur analysis reveals that baseline blood transcriptomic profiles delineate motor and non-motor progression trajectories in sporadic Parkinsons disease. The results are consistent with prior findings and may contribute to the identification of novel biomarkers, thereby informing and potentially optimizing the design of clinical trials aimed at modifying disease progression.

ImportanceAccurate diagnosis of neurodegenerative movement disorders is challenging because of a lack of in vivo biomarkers, overlapping clinical features and a delay in the emergence of pathognomonic features. ObjectiveTo evaluate clinicopathological correlation, diagnostic accuracy, genetic association with pathology, and ancestry-related differences in a multi-ancestry brain bank cohort. DesignMulticentre retrospective autopsy cohort study on donors enrolled between 1985 - 2024. Setting11 academic brain banks in the UK, US and Australia ParticipantsBrain donors identified from participating brain banks with available brain tissue and a clinical diagnosis of Parkinsons disease, Parkinsons disease dementia, dementia with Lewy bodies, progressive supranuclear palsy, corticobasal syndrome, multiple system atrophy, or neurologically normal controls. ExposureGenetic variant carrier status and clinical diagnostic category. Main outcomeClinical diagnostic accuracy; Lewy body and Alzheimers disease pathology burden; survival; association with genetic variants and genetically inferred ancestry. ResultsWe studied 3,353 brain donors (1281 [38.2%] female, mean [SD] age at death, 76.8 [10.6] years). Misdiagnosis rates for movement disorders ranged approximately from 10% - 20%. Clinical diagnoses of dementia with parkinsonism (PDD/DLB) were more strongly associated with Lewy body pathology than Parkinsons disease without dementia (OR = 1{middle dot}96, 95% CI = 1{middle dot}30 - 3{middle dot}04, p = 7{middle dot}2e-04). Lewy pathology was identified in 4% of neurologically normal controls. Alzheimers disease co-pathology was present in 40% of cases with Lewy body disease. GBA1 variant carriers exhibited greater Lewy body burden compared with noncarriers (OR = 1{middle dot}94, 95% CI = 1{middle dot}24 - 3{middle dot}03, p = 0{middle dot}01) or LRRK2 carriers (OR = 7{middle dot}44, 95% CI = 2{middle dot}16 - 25{middle dot}64, p = 0{middle dot}01). Pathological diagnoses differed by ancestry, with South Asian donors more likely to have progressive supranuclear palsy pathology and Ashkenazi Jewish donors more likely to have Lewy body disease (p < 0.0001), independent of GBA1 and LRRK2 mutation status. Conclusion and RelevanceOur findings highlight the value of integrating genetic and pathological data to improve diagnostic accuracy. The high prevalence of Alzheimers disease co-pathology and ancestry-related differences in pathology point to the need for biologically informed diagnostic tools. These results support the integration of genetically and pathologically stratified approaches, correlating pathology with in vivo biomarkers, for future therapeutic trials. FundingMedical Research Council, Global Parkinsons Genetic Program/Aligning Science Across Parkinsons Key PointsO_ST_ABSQuestionC_ST_ABSHow do genetic variants and neuropathology influence clinical features and diagnostic accuracy in movement disorders? FindingsIn this multi-ancestry brain bank series including over 3000 individuals, clinical misdiagnosis was common. Dementia with parkinsonism was more strongly associated with Lewy body (LB) pathology than Parkinsons disease without dementia, and Alzheimers disease co-pathology was frequent. Genetic variation was associated with pathological differences. GBA1 carriers had greater LB burden, while LRRK2 pathogenic variant carriers had a lower LB burden and longer survival. Pathological diagnosis differed by ancestry. MeaningIntegrating genetics and neuropathology may improve diagnosis and support pathology-informed therapeutic trials.

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.

BackgroundOculomotor dysfunction is common in parkinsonian syndromes and ataxias, but its impact on patient-reported vision-related quality of life (VQoL) remains insufficiently understood. ObjectivesTo characterize VQoL across parkinsonian syndromes and ataxias and assess the functional significance of specific oculomotor abnormalities in spinocerebellar ataxias. MethodsParticipants were recruited at Massachusetts General Hospital (n=231): 104 with Parkinsons disease (PD), 10 with progressive supranuclear palsy (PSP), 56 with genetically defined ataxias (SCA2, SCA3, SCA6, SCA27B, CANVAS), and 61 healthy controls. VQoL was assessed using a 13-item subset of the Visual Activities Questionnaire targeting depth perception, visual acuity/spatial vision, and visual processing speed. Clinical severity was assessed with the Brief Ataxia Rating Scale and Modified International Cooperative Ataxia Rating Scale, and subjective symptoms with PROM-Ataxia. Group comparisons, correlations, and regression analyses were performed. ResultsAll disease groups reported significantly worse VQoL than controls, with the largest deficits in visual processing speed. PSP showed the greatest impairment across all domains, while PD was less affected. Individuals with SCA3 and SCA6 had significantly lower VQoL across all subcategories. In ataxias, VQoL correlated moderately with PROM-Ataxia and weakly with clinical oculomotor scores. Gaze-evoked nystagmus was the only oculomotor sign independently associated with reduced VQoL. ConclusionsParkinsonian syndromes and ataxias are associated with substantial VQoL impairment, particularly in visual processing speed. Gaze-evoked nystagmus is a key predictor of reduced VQoL in ataxias, highlighting the functional relevance of fixation instability. Patient-reported outcomes and oculomotor assessments are essential for capturing visual disability in clinical care and trials.

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

BackgroundHuntingtons disease (HD) causes progressive loss of function, cognition, and motor control, with no approved therapy yet shown to slow disease progression. In the PROOF-HD phase 3 trial, pridopidine did not meet the primary or key secondary outcomes in the overall population, but participants who remained off antidopaminergic medications (ADMs) showed benefits compared to placebo during the double-blind phase. Whether such benefits continue with longer duration treatment and how they compare with expected natural-history trajectories remains unknown. MethodsWe evaluated outcomes through Week 104 from baseline in participants who received continuous pridopidine (45 mg twice daily) and remained off-ADMs throughout the double-blind and open-label extension period (n=90). External comparators from ENROLL-HD and TRACK-HD were constructed using propensity-score weighting methods. Least-squares mean changes from baseline to Week 104 were estimated using mixed-effects models for repeated measures across outcomes. ResultsAt two-years, pridopidine treatment was associated with benefits versus propensity-score weighted natural-history comparators across multiple outcomes. Relative to ENROLL-HD, participants receiving pridopidine showed slowing of progression over 104 weeks, expressed as percent slowing across cUHDRS, TFC, SWR, SDMT, and TMS outcomes (39.5-88.3% slowing). Similar patterns were observed relative to TRACK-HD across the same measures (48.5 - 81.5% slowing), including quantitative motor performance assessed by Q-Motor FT-IOI (77.8% slowing). Exploratory analyses including participants receiving concomitant ADMs showed similar directional patterns as the primary analyses. ConclusionsIn a two-year follow-up, continuous pridopidine treatment in participants remaining off-ADMs was associated with slower clinical progression relative to expected natural-history trajectories. (Clinical Trials Identifier: NCT04556656)

BackgroundContinuous subcutaneous foslevodopa/foscarbidopa infusion (LDp/CDp-CSI) is an effective treatment for patients with Parkinsons disease (PD), but infusion-site nodules are a major cause of treatment discontinuation. Systemic inflammation can influence local skin tolerance; however, predictive biomarkers remain unidentified. ObjectiveTo evaluate the predictive value of the neutrophil-to-lymphocyte ratio (NLR) for clinically significant infusion-site nodules (PD-CSN) during LDp/CDp-CSI and to establish a clinical management framework to mitigate their development. MethodsWe prospectively followed 38 patients with PD initiating LDp/CDp-CSI for [&ge;]3 months. Baseline immunological data were collected before infusion. A subset of 30 patients was followed for an average of 11 months to identify factors associated with skin nodules at longer follow-up. Nodules were classified by blinded raters. Between-group comparisons, ANCOVA, ROC curve, and Kaplan-Meier analyses were performed. ResultsAt 3 months, 42% of patients were PD-CSN and showed higher baseline neutrophil counts (P=0.030) and NLR (P=0.007), with NLR remaining independently associated with nodule status (F=7.06, P=0.012). ROC analysis demonstrated acceptable discrimination (AUC=0.73, P=0.016). At last follow-up, lower baseline lymphocyte counts (P=0.002) and higher NLR (P=0.001) were observed in PD-CSN. High baseline NLR predicted earlier nodule onset (P=0.001). Despite frequent nodules, multidisciplinary team surveillance, including remote and in-person follow-up, limited treatment discontinuation to 5.3%. ConclusionsBaseline systemic inflammation, reflected by NLR, predicts both the onset and persistence of infusion-site nodules during LDp/CDp-CSI. NLR may serve as a clinically accessible biomarker for early risk stratification. Multidisciplinary surveillance facilitates timely nodule management and enhances treatment adherence.