Movement Disorders

Background: Parkinson disease (PD) is a genetically complex neurodegenerative disorder, but most genetic discoveries have been derived from populations of European ancestry, limiting the understanding of ancestry-specific genetic risk. Methods: This GWAS included 5,825 East Asian participants (3,043 patients with PD and 2,782 controls). We then combined these results with data from two additional East Asian cohorts through meta-analysis, resulting in a total of 74,716 participants (15,603 patients with PD and 59,113 controls). To our knowledge, this represents the largest genetic study of PD in East Asian populations to date. Findings: We identified two novel loci that were associated with PD in East Asian cohorts and reached genome-wide significance in the cross-ancestry meta-analysis (>1.9 million subjects): TLE4 (lead variant rs10780320, Pmeta_combined = 2.853 x 10^-10) and HLA-V/HLA-G (lead variant rs11751333, Pmeta_combined = 1.031 x 10^-9). Integration of brain eQTL data identified an East Asian-specific intergenic variant at the LRRK2 locus (rs1388594) that was significantly associated with LRRK2 expression in the basal ganglia. This association was replicated across three independent East Asian cohorts (Pgp2_EAS = 8.71 x 10^-4, Psg_EAS = 1.13 x 10^-5, PTPMI_EAS = 4.86 x 10^-4) and reached genome-wide significance in the East Asian meta-analysis (Pmeta_EAS = 5.85 x 10^-10; OR = 1.10, 95% CI: 1.07-1.13). The variant was not associated with PD in populations of European ancestry (P = 0.08). Interpretation: These findings improve our understanding of the genetics of PD across ancestry groups and highlight the importance of including diverse populations in genetic studies to identify ancestry-specific risk variants.

Background: Pathogenic variants in GCH1 have been associated with Parkinson's disease (PD), but the clinical phenotype and longitudinal disease course of GCH1-associated PD remain incompletely characterized. Objectives: To characterize the genetic spectrum, clinical phenotype, and longitudinal progression of GCH1-associated PD across multiple populations. Methods: Whole-genome sequencing (WGS) and clinical exome sequencing (CES) data from the Global Parkinson Genetics Program (GP2) were analyzed together with unpublished and published GCH1-associated PD patients. Variant pathogenicity was classified according to ACMG criteria. Demographic, clinical, and longitudinal features were compared between GCH1 P/LP variant carriers and non-carrier PD patients; individuals with known pathogenic variants in PD-associated genes were excluded from both groups. Results: In the GP2 cohort (PD, n=22,825; controls, n=4,453), 16 pathogenic or likely pathogenic (P/LP) GCH1 variants were identified in 58 individuals, including 54 PD patients, one control, and three individuals with other neurodegenerative phenotypes (two with progressive supranuclear palsy and one with dementia with Lewy bodies). In the pooled-ancestry WGS analysis, GCH1 P/LP variants were enriched in PD patients versus controls (0.267% vs 0.023%; OR=11.854; 95% CI=1.620-86.699; p=0.0006). Variant frequencies in PD patients ranged from 0.121% to 0.714% across ancestries. In the CES cohort, P/LP variants were identified in 0.201% of PD patients. After integrating GP2 with additional unpublished and published datasets, 119 GCH1-associated PD patients were analyzed. Compared with noncarriers, carriers of P/LP GCH1 variants had an earlier age at onset (mean [SD], 53.7 [14.8] vs 59.2 [11.7] years; P < .001), lower levodopa equivalent daily dose requirements (mean [SD , 467.5 [331.7] vs 680.3 [466.4] mg/d; P < .001), and a higher frequency of a family history of Parkinson disease (47.6% vs 19.9%; P < .001). Adjusted Cox models showed significant delayed progression to motor fluctuations (HR=0.32, 95% CI=0.16-0.62) and levodopa-induced dyskinesias (HR=0.51, 95% CI=0.30-0.87). Conclusion: GCH1 pathogenic variants were associated with a clinically distinct phenotype characterized by earlier disease onset and slower progression of motor complications. These findings suggest that GCH1 genetic variants may serve as genetic biomarkers for patient stratification and prognosis in PD.

Objective: Impulse control disorders (ICDs) are clinically important nonmotor features of Parkinson's disease (PD). Tremor-dominant PD (TD-PD) has been associated with greater cerebello-thalamo-cortical involvement, whereas postural instability/gait difficulty-dominant PD (PIGD-PD) has been linked to more prominent basal ganglia and frontostriatal dysfunction. We therefore examined whether ICD symptoms differ by motor phenotypes. Methods: This cross-sectional study analyzed baseline data from the Parkinson's Precision Medicine Initiative (PPMI). Motor subtype classification was based on Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) criteria. ICD symptoms were assessed using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Current Short Form (QUIP-CS) and evaluated across multiple levels of analysis using the standard screening definition and normalized QUIP-CS scores analyzed categorically and continuously. Temporal-alignment, subgroup, multivariable, and Bayesian analyses were performed to assess the robustness of the primary findings. Results: We analyzed 305 participants (173 TD-PD, 132 PIGD-PD). Screening-defined ICD positivity was similar between subtypes (21.4% vs 21.2%, OR = 1.01, 95% CI 0.58-1.76, p = 0.970). Continuous and categorical normalized QUIP-CS scores likewise did not differ between groups (continuous score: 0.0338 vs 0.0384, p = 0.674; categorical score: 3.5% vs 4.5%, p = 0.632). Temporally aligned, subgroup, and multivariable sensitivity analyses consistently supported the primary finding, and Bayesian analysis provided moderate evidence supporting the null hypothesis (BF01 = 7.21). Conclusions: ICD symptoms do not differ between TD-PD and PIGD-PD motor subtypes in early PD. These findings suggest that motor subtype-associated differences in cerebellar involvement do not substantially influence ICD symptoms in early PD.

BackgroundThe relationship between essential tremor (ET) and Parkinsons disease (PD) remains controversial. Beyond viewing ET as a discrete risk factor for PD, recent frameworks propose that an ET phenotype may represent a clinical presentation of prodromal PD (pPD), consistent with the current reconceptualization of ET as a syndrome. Whether co-occurring subtle motor signs alter pPD probability in ET remains unknown. MethodsUsing the MDS research criteria, we calculated pPD probability in a large cohort of ET patients with and without subtle motor signs (rest tremor, hypomimia, isolated rigidity, reduced arm swing, altered repetitive movements, global slowing). Multivariable regression was used to identify independent predictors of pPD probability. ResultsAmong 599 ET patients (median disease duration: 12 years), only 6 (1.0%) met criteria for probable pPD. Although ET patients with subtle motor signs exhibited higher continuous pPD probability scores than those without, the frequency of possible or probable pPD did not differ significantly between groups. In multivariable regression, neither ET nor individual subtle motor signs, but hypomimia, were independent predictors of pPD probability, which was primarily driven by older age and male sex. ConclusionsLong-standing ET, whether isolated or accompanied by subtle motor signs, is not associated with pPD, with the possible exception of co-occurring hypomimia.

Background and Objectives: X-linked dystonia-parkinsonism (XDP) is a severe neurodegenerative movement disorder caused by a retrotransposon insertion with a polymorphic hexanucleotide repeat expansion in the TAF1 gene. While the disease predominantly affects males, female carriers may exhibit a variable phenotypic expression. Neurobiological alterations in asymptomatic female mutation carriers (fMC) remain largely unexplored. We aimed to investigate whether fMC exhibit neurodegenerative changes despite the absence of overt clinical manifestations and to assess their clinical, genetic, and longitudinal correlates using multimodal MRI. Methods: In this cross-sectional and longitudinal multimodal study, 103 female relatives of XDP patients underwent clinical, genetic, and MRI assessments. Forty-two were identified as fMC and 61 as healthy controls (HC). Structural T1-weighted MRI was analyzed using voxel-based morphometry and subcortical volumetry, while susceptibility-weighted imaging assessed iron deposition. Clinical evaluation included standardized motor and cognitive testing. Longitudinal follow-up MRI was available for a subset of participants (20 fMC, 13 HC). Results: fMC exhibited significant striatal atrophy compared to HC, with volume reductions in the caudate (-19.4%), putamen (-18.6%), and pallidum (-28.6%) (all p<0.001), despite the absence of overt movement disorders or cognitive deficits, accompanied by relative cerebellar hypertrophy. In fMC striatal volumes decreased with increasing age (putamen: rho=-0.382, p=0.012; caudate: rho=-0.631, p<0.001) and virtual time from genetically determined estimated age at onset (putamen: rho=-0.406, p=0.008; caudate: rho=-0.660, p<0.001). Susceptibility-weighted imaging revealed increased iron deposition in the caudate in fMC, which increased with greater local atrophy (rho=0.718, p<0.001). No significant longitudinal progression was detected over follow-up intervals of up to 25.5 months. Discussion: Asymptomatic female carriers of the XDP-associated TAF1 variant exhibit significant striatal neurodegeneration and iron accumulation, indicating a dominant-negative effect despite X-linked inheritance. Future longitudinal studies should focus on non-motor features and integrate genetic, imaging, and clinical markers to improve risk stratification and identify the subset of female carriers most likely to benefit from future disease-modifying therapies.

Background Scalable models for Parkinson's disease (PD) genetics in underrepresented populations are needed, as most studies have focused on individuals of European-ancestry, limiting generalisability across ancestral and environmental contexts. Kyrgyzstan has been largely absent from global PD research. Using Kyrgyzstan as a case study, we aimed to develop and evaluate a scalable PD genetics model integrating research and local capacity building. Methods We implemented a stepwise capacity-building framework within a multi-site prospective PD genetics cohort that included participants with PD and controls, with longitudinal follow-up. The framework integrated community engagement, workforce development, specialist clinical services, data governance, clinical phenotyping, biobanking, and genetic data generation. Participants were recruited through a university-affiliated movement disorders clinic and mobile outreach clinics, using a secure electronic data-capture system and Global Parkinson's Genetics Program (GP2)-aligned standards. Feasibility endpoints included recruitment, participation, assessment completeness, and genetic quality-control metrics. Findings Within 20 months, specialist clinical services and a PD registry with biobanking and secure data infrastructure were established, and 1240 participants were enrolled, representing multiple Central Asian ethnicities, including Kyrgyz, Uzbek, Uyghur, Tatar, Kalmyk, and Dungan, and the country's rural-urban distribution. High participation coincided with community engagement and recruitment through mobile clinics and community outreach. Interpretation Embedding capacity building within active research enabled rapid development of neurogenetic and specialist clinical infrastructure in a resource-limited setting. This programme provides a potentially transferable model for equitable inclusion of underrepresented populations in PD genetics and related neurogenetic research in low- and middle-income countries. Funding This project was supported by the Global Parkinson's Genetics Program (GP2; https://gp2.org). GP2 is funded by the Aligning Science Across Parkinson's (ASAP) initiative and implemented by The Michael J. Fox Foundation for Parkinson's Research (MJFF).

Background and Objectives: To test whether the positive correlation between rest tremor (RT) and ipsilateral striatal DAT binding reflects a tremor-specific ipsilateral mechanism or simply the globally better-preserved dopamine terminals in RT patients. Methods: We compared ipsilateral and contralateral correlations between striatal binding, rest tremor, bradykinesia and rigidity in two cross-sectional Parkinson disease cohorts from the Parkinson's Progression Markers Initiative (baseline, N=1055; follow-up, median 2.2 years, N=652). We tested whether correlations survived permutation testing that shuffled severity scores isolating severity-dependent effects from group-level effects and used out-of-sample prediction to compare how well binding predicted symptom presence versus severity. Results: Bradykinesia and rigidity showed large contralateral correlations, distinguishable from the permutation null in every comparison, and predicted both presence and severity. Rest tremor's ipsilateral correlation was not distinguishable from the null in most comparisons. Striatal binding, both ipsi or contralateral, predicted its presence (AUC 0.55-0.61) but not its severity (R2<0.002), in both cohorts. Conclusions: Our findings argue against a direct pathophysiologic link between tremor amplitude and ipsilateral dopaminergic function. More parsimoniously, the ipsilateral binding-RT correlation likely reflects a distinct degeneration pattern in patients with RT rather than a graded, dose-dependent circuit mechanism.

The genetics of Parkinsons disease (PD) in underrepresented populations remain poorly characterized, potentially overlooking population-specific contributions. We analyzed 461 Chilean PD cases from a movement disorders center. Pathogenic, likely pathogenic, or GBA1 risk variants were identified in 58 individuals (12.6%), mainly in LRRK2 (50%) and GBA1 (44.8%), while PRKN, SNCA, and SQSTM1 collectively represented 5.2%. All LRRK2 variants were p.G2019S, with an overall frequency of 6.3%, the highest reported in South America, and enrichment of Ashkenazi Jewish ancestry at this locus. These findings characterize the genetic landscape of PD in Chile and support its relevance for LRRK2-targeted studies.

Recent evidence suggests that TMEM106B expression is reduced in the brains of patients with Parkinson's disease (PD). However, an association between rare genetic variants in TMEM106B and PD risk has not been previously established. In this work, we investigated the association between rare TMEM106B variants and PD risk. We leveraged whole-genome sequencing data from 22,010 cases and 40,550 controls across diverse ancestries from the Global Parkinson's Genetics Program (GP2), the Accelerating Medicines Partnership in Parkinson's Disease (AMP-PD), and the UK Biobank (UKBB). A total of 4,581 unique rare variants were identified across all groups. No pathogenic or likely pathogenic variants according to ClinVar were observed in any cohort. We found no evidence that rare coding variants in TMEM106B were associated with PD risk, either individually or through cumulative burden. These findings suggest that rare variation in TMEM106B does not play a major role in PD susceptibility across the populations studied.

Background: GBA1 variants are common risk factors for Parkinson's disease (PD), yet the structural consequences of most variants remain uncharacterized. No centralized resource currently integrates the growing number of GCase structures, compounds, and PD-associated variants. Objectives: To develop an interactive tool mapping GBA1-PD missense variants onto GCase structures, alongside interactors and therapeutic compounds. Methods: We built GBAviewer, an R/Shiny web server integrating GBA1-PD Browser variants with crystal structures, cryo-EM complexes, AlphaFold3 models, and AlphaMissense scores. We also modelled a putative GCase-Saposin C-glucosylceramide ternary complex using AlphaFold3. Results: GBAviewer maps variants in 3D across the GCase active site, LIMP-2 and SapC surfaces, chaperone pockets, and dimerization interface. Our ternary model corroborates SapC binding to the GCase active site entrance, where several variants of unknown significance cluster. Conclusions: GBAviewer is a freely accessible platform for structural analysis of GBA1 variants, supporting mechanistic studies and therapeutic development. Available at: https://g-can.shinyapps.io/GBAviewer/

Background: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic risk factor for Parkinson's disease (PD). G2019S, the most common pathogenic variant, has been linked to milder motor symptoms, but the effects of other LRRK2 variants on disease trajectory remain incompletely characterized. R1441G, the second most common pathogenic variant, co-occurs with the PD risk variant M1646T on a shared haplotype. Whether this haplotype confers a distinct rate of motor progression has not been established. Methods: We analyzed up to 12 years of longitudinal data from 603 participants in the Parkinson's Progression Markers Initiative (PPMI) with PD and available whole-genome sequencing data: 394 sporadic PD, 169 G2019S carriers, 20 R1441G+M1646T carriers, and 20 M1646T carriers. Motor symptom progression (MDS-UPDRS III) was assessed using linear mixed-effects models with genotype-by-time interactions, adjusted for age at onset, disease duration at baseline, sex, race, baseline score, and levodopa equivalent daily dose. Results: R1441G+M1646T carriers exhibited 76% slower progression in OFF-state MDS-UPDRS III than sporadic PD (0.50 vs. 2.04 points/year; {beta}=-1.54 [95% CI: -2.48, -0.60]; p=0.001). G2019S carriers exhibited 26% slower progression (1.52 points/year; {beta}=-0.52 [-0.99, -0.06]; p=0.03). M1646T carriers did not differ from sporadic PD (p=0.60). Slower progression in R1441G+M1646T carriers was characterized by attenuated bradykinesia (64% slower; p=0.008), axial decline (76% slower; p=0.002), and a lack of orofacial symptom progression (p<0.001). R1441G+M1646T carriers also exhibited 55% slower self-reported motor decline (MDS-UPDRS II; p=0.04) Conclusions: R1441G+M1646T carriers exhibit substantially slower motor progression than sporadic PD while M1646T carriers do not.

Background An X-linked levodopa-responsive parkinsonism-epilepsy syndrome has been associated with PGK1, and the gene lies within the previously suspected PD locus PARK12. Objective To examine the association of common and rare PGK1 variants with PD. Methods We analyzed common and rare variants from Accelerated Medicines Partnership - Parkinsons Disease (AMP-PD) and UK Biobank (UKBB, total N=4,523 PD cases, 19,736 proxy cases, and 390,532 controls). To account for the X-linked location of PGK1, we used sex-stratified, combined regression models and optimized sequence Kernel association (SKAT-O) tests, followed by meta-analysis using MetaSKAT. Results We found no association between common or rare PGK1 variants and PD in sex-stratified or combined analyses, including after cross-cohort meta-analysis. Conclusion Although we did not find evidence supporting an association between PGK1 and PD, very rare pathogenic PGK1 variants may still contribute to syndromic parkinsonism. Future research could explore larger datasets to further examine this potential association.

Background Parkinson's disease (PD), the most common neurodegenerative movement disorder, is commonly thought of as an aging and sporadic disease; however, 5-14% of individuals experience disease onset before the age of 50 years (early-onset PD; EOPD) and about 20% have a positive family history. In the case of both EOPD and people with a family history of PD, evidence suggests higher rates of a disease-causing genetic contribution. Objectives Our goal was to perform a variant screening of seven PD-related genes and 21 genes associated with related parkinsonian disorders to identify pathogenic/likely pathogenic variants and variants of uncertain significance within EOPD and family-history-positive individuals within the Latin American Research Consortium on the Genetics of PD (LARGE-PD). Methods We performed short-read whole-genome sequencing on a subset of 263 individuals with EOPD and/or a familial history of PD who had no known pathogenic PD variant in genotyping data. Results Of the analyzed individuals, a monogenic burden in primary and secondary PD genes due to pathogenic or likely pathogenic variants for PD was observed in 4.7%, an additional 5.5% had pathogenic or likely pathogenic variants for Gaucher's disease, and 2.7% had known risk variants in GBA1. Conclusions By expanding the reported spectrum of disease-associated variants in a Latin American population, we identified previously unreported or underrepresented variants that would likely be missed by array-based or targeted screening approaches and contribute to the characterization of EOPD and familial PD in Latin America.

Objective: Genes within the lysosomal glycosphingolipid pathway, including GBA1 and GALC, are important genetic risk factors in Parkinson's disease (PD). We hypothesized that PD risk relates not only to individual enzyme effects but also to coordination between glucocerebrosidase (GCase) and galactosylceramidase (GalCase) activities, and examined how genetic variants influence their activity ratio. Methods: We studied 1,290 individuals from the Parkinson's Precision Medicine Initiative and Columbia University cohorts with genetic and dried-blood-spot enzymatic data. Genome-wide association analyses of the glucocerebrosidase/galactosylceramidase activity ratio were performed in the combined cohort, by sex, and per cohort, followed by meta-analysis. For lead variants, Pearson correlations between enzyme activities were compared across genotypes, and genotype-by-GCase interactions were tested. Results: The GALC locus was associated with glucocerebrosidase/galactosylceramidase activity ratio in the combined cohort (rs365448; beta=-1.90; P=5.91e-115), replicated across cohorts and meta-analysis (beta = -1.66, P=6.33e-191), and in linkage disequilibrium with the PD GWAS index variant rs979812. This association remained significant in both sexes. Correlation between glucocerebrosidase and galactosylceramidase activities differed by rs979812 genotype (TT r=0.33 versus GG r=0.13; P=0.01), with a significant genotype-by-GCase interaction (P=3.05e-5). Among 134 PD loci examined, ten showed nominal association with the ratio-GWAS, including GBA1, where risk-variant carriers showed a similar pattern, yet not statistically significant. Interpretation: GALC variants influence the balance between glucocerebrosidase and galactosylceramidase activity, and this relationship may differ by genotype at PD-associated variants. These findings suggest PD risk at lysosomal glycosphingolipid genes may partly reflect altered coordination between pathway enzymes rather than isolated single-enzyme effects, warranting functional validation.

Isolated rapid eye movement sleep behavior disorder (iRBD) is characterized by nigro-striatal deficits, comprising dopaminergic denervation of the striatum and loss of dopaminergic cells in the substantia nigra (SN), that may herald phenoconversion to clinically manifest synucleinopathy. While phenoconversion has repeatedly been shown to relate to pre-synaptic dopaminergic deficits in the striatum, potential involvement of loss of dopaminergic cells in the SN remain unclear. In addition, phenoconversion may independently relate to noradrenergic deficits, stemming from cell loss in the locus coeruleus/subcoeruleus (LC/LsC) complex. Fifty-six iRBD patients were included and clinically followed over an 11-years as part of the ICEBERG study. Putamen dopamine denervation was quantified using 123I-FP-CIT single-photon emission computed tomography. Cell loss in the SN and LC/LsC was quantified using neuromelanin-sensitive magnetic resonance imaging (MRI). SN cell loss was additionally characterized as free water, derived from diffusion-weighted MRI. The primary outcome was time to phenoconversion. Cox proportional hazards regression was used to investigate relationships between phenoconversion risk and imaging predictors, estimated as hazard ratios (HRs). Out of 56 patients, 24 (41%) converted to a clinically manifest synucleinopathy [PD=14 (58%), DLB=8 (33%), MSA=2 (8%)] over a maximum period of 11 years. We replicated the well-established finding that reduced putamen DaT confers an increased phenoconversion risk [HR (95%CI)=3.1 (1.7-5.5), P<0.001]. We extend on this by showing a similar relationship for SN neuromelanin [HR (95%CI)=2.5 [1.3-4.6], P=0.004], SN free water [HR (95%CI)=1.54 (1.06-2.24), P=0.025], and LC/LsC neuromelanin [HR (95%CI)=2.1 (1.2-3.7), P=0.011], demonstrating involvement of the broader nigro-striatal dopaminergic system along with potential involvement of noradrenergic neurotransmission. When adjusting for putamen DaT, the relationship between phenoconversion risk and SN neuromelanin was attenuated [P=0.16], suggesting partial overlap between the metrics. In contrast, when modelled together, SN neuromelanin [HR (95%CI)=2.8 (1.4-5.6), P=0.003] and LC/LsC neuromelanin [HR (95%CI)=2.3 (1.1-4.8), P=0.037] contributed to phenoconversion risk independently of each other, indicating a differential contribution of dopaminergic and noradrenergic neurotransmitter deficits to iRBD phenoconversion. We demonstrate that phenoconversion in iRBD relates similarly to dopaminergic denervation of the putamen and cell loss in the SN. This opens possibilities for using NM-MRI, which can simultaneously capture dopaminergic and noradrenergic deficits, as an alternative to nuclear imaging techniques when estimating phenoconversion risk in iRBD.

Background: Pseudo-orthostatic tremor (psOT) is a rare form of tremor of the lower body, triggered by standing, at frequencies lower than 13 Hz. It is believed to be secondary to other neurological disorders in a large proportion of cases. Surface electromyography (sEMG) can identify its core characteristics and differentiate it from other similar disorders such as primary orthostatic tremor (POT) and orthostatic myoclonus (OM). Objectives: Our study aims to illustrate the clinical and neurophysiological features as well as the outcomes and final diagnoses of patients with psOT in a retrospective two-centre cohort. Methods: We retrospectively examined the available clinical and neurophysiological records of 35 consecutive patients with a diagnosis of psOT in the 2022-2026 period. Data on demographics, clinical characteristics, sEMG findings, pharmacological treatments, ancillary investigations and patient reported outcomes were collected. Results: 35 patients with psOT were identified, of which 6 (17%) displayed features consistent with a functional neurological disorder (FND). Among the 29 patients with organic psOT, 21 (72.4%) fulfilled the diagnostic criteria for essential tremor (ET), while an identifiable neurological cause was established in four (13.8%). sEMG findings differed between functional and organic psOT, with the latter often displaying features consistent with weight-bearing hyperkinesias. Conclusions: Our retrospective study suggests that psOT is most often associated with ET, while an identifiable neurological cause was found in a relatively small proportion of patients. We also describe functional psOT as a previously unrecognized clinical presentation of FND.

Purpose Dynamic [11C]UCB-J PET can simultaneously provide information about synaptic density and relative perfusion in Parkinson's disease (PD). We investigated whether these complementary biomarkers could explain a higher percentage of motor symptom severity variation in PD and inform other PD-specific physiological alterations and symptomatology. Methods Binding potential (BPND) and relative perfusion (R1) images were derived 30 PD and 30 controls imaged with [11C]UCB-J PET. A spatial covariance analysis was used on R1 to derive PDRP-a known metabolic network alteration in PD. Linear models related PD-motor symptom severity to PDRP expression and nigral synaptic losses. Next, whole-brain cluster analyses identified physiological correlates for PD-tremor severity, a prominent motor symptom that does not correlate with dopaminergic losses. Lastly, inter-individual regional correlation alterations in PD were examined for both BPND and R1. Results PDRP was identified from R1, with higher expression in PD (p=1.7x10-5, Cohen's d=1.2), and its expression correlated with MDS-UPDRS III (r=0.57, p=0.0009). Combining PDRP expression scores with synaptic density in the substantia nigra explained 48% of the total variation in MDS-UPDRS Part III, twice as much as previously reported using nigral synaptic density alone. Two significant large clusters (pk<1x10-6) were identified in the occipital-parietal areas where R1 was negatively correlated with tremor severity (r ~ -0.65, p<0.001). Extensive correlation alterations were observed in synaptic density (prominently involving pallidum) and perfusion (prominently involving thalamus). Conclusions Combining synaptic and perfusion outcomes for [11C]UCB-J PET explains more physiological alterations associated with PD.

Background: Lysosomal dysfunction has been implicated in Parkinson's disease (PD) pathogenesis. However, lysosomal polygenic risk scores (lyso-PRS) have not been evaluated extensively in PD across populations. Objectives: (1) Evaluation of lyso-PRS (lyso-PRS) performance for PD risk across populations; (2) Comparison of lyso-PRS across idiopathic PD (iPD), GBA1-PD, non-manifesting GBA1 carriers (NMC), and healthy controls (HC) in the European population. (3) Assessment of the lyso-PRS association with clinical outcomes in the PD patients of European population. Methods: We analyzed Neurobooster array data from the Global Parkinson's Genetics Program (GP2) dataset, including 32,054 iPD cases and 18,188 healthy controls across ten ancestries. Results: (1) lyso-PRS performed best in Europeans (European-GP2 test cohort: AUC = 0.602, p = 2.02e-172; European-TUEPAC validation cohort: AUC = 0.632, p = 5.34e-20) and worse in other populations (AUC: 0.51-0.59, p<0.05). (2) In the European population, the lyso-PRS distinguished GBA1-PD from HC (AUC = 0.621, p = 7.83e-71) and from NMC (AUC = 0.621, p = 1.05e-18). (3) In the European-GP2 cohort, higher lyso-PRS was significantly associated with earlier age at onset ({beta}=-0.21, p=0.022) and higher Unified Parkinson's Disease Rating Scale (UPDRS) scores ({beta}=0.32-1.13, all p < 0.05). Conclusions lyso-PRS was associated with iPD and GBA1-PD status, with the strongest predictive performance in the European population, underscoring the need to improve accuracy in other ancestries. In the European population, the lyso-PRS showed associations with clinical features; however, not all findings were replicated in the validation cohort, highlighting the need for further investigation in large and diverse cohorts.

Background Parkinson disease (PD) is associated with increased sedentary time and reduced cardiorespiratory fitness, making exercise an important component of disease management. Although exercise improves cardiorespiratory fitness, individuals with PD vary substantially in their response to exercise. Sedentary time may contribute to this variability, yet whether sedentary time modifies the response to intervention and varying exercise intensities within an intervention is unknown. We examined whether sedentary time interacted with 6 months of moderate-intensity or high-intensity aerobic exercise on maximal oxygen consumption (VO2max) in individuals with PD. Methods This secondary analysis used data from the SPARX phase 2 randomized clinical trial including 128 de novo PD patients assigned to high- or moderate-intensity treadmill exercise, or usual care for 6 months. Interactions between randomized group and post-randomization 6-months average sedentary time were assessed for associations with 6-month change in VO2max by using linear regression models corresponding to Analysis of Covariance (ANCOVA) models with interaction. Results The interaction between exercise intensity and sedentary behavior on 6-month change in VO2max in the moderate-intensity group compared with usual care was not significant ({beta}: -1.78, 95% CI: -3.76 to 0.20, p-value: 0.08), although the sensitivity analysis restricted to complete cases showed a significant interaction where each 10% increase in 6-months average sedentary time was associated with a 2.51 mL/kg/min decrease in VO2max change in the moderate-intensity group compared with usual care ({beta}: -2.51, 95% CI: -4.53 to -0.48, p-value: 0.02). There was no significant interaction between exercise intensity and sedentary behavior on 6-month change in VO2max in the high-intensity group compared with usual care ({beta}: -1.46, 95% CI: -4.74 to 1.83, p-value: 0.38). The sensitivity analysis showed similar results. Conclusions These hypothesis-generating, preliminary findings suggest that sedentary time may modify the response to exercise among individuals participating in moderate-intensity aerobic exercise. Future adequately powered randomized controlled trials are needed to confirm these findings and determine whether sedentary behavior should be considered when prescribing exercise for individuals with PD.

Parkinsons disease (PD) arises through disruption of multiple interconnected cellular processes, but the genetic contributions to these processes may differ across ancestries. We investigated functional convergence among genes harboring pathogenic or likely pathogenic (P/LP) variants and variants of uncertain significance (VUS) in a multicenter Indian cohort recruited through the Genetics of Parkinsons Disease in India Young Onset Parkinsons Disease project (GOPI YOPD). The cohort included 668 participants (463 males 69.3%) with a mean age at motor onset of 39.4+/-8.8 years. P/LP variants and VUS identified through previously reported whole-exome or whole genome sequencing were retained as separate evidential categories. The P/LP-associated gene set comprised 11 unique genes and the VUS associated set comprised 40 unique genes. Separate STRING functional-enrichment analyses evaluated Gene Ontology Biological Process, Molecular Function and Cellular Component terms, KEGG pathways, WikiPathways and STRING local network clusters. Terms meeting a Benjamini Hochberg false discovery rate threshold of <0.05 were organized into eight non-mutually-exclusive ontology/pathway categories. Gene to pathway mappings were subsequently projected to individual participants to estimate pathway representation and examine clinical associations. At least one reportable P/LP variant or VUS was identified in 336/668 participants (50.3%): 35 had a P/LP variant alone, 282 had VUS alone and 19 had a P/LP variant together with VUS in one or more additional genes. The most frequently represented categories were mitochondrial organization (247/336, 73.5%), autophagy related processes (228/336, 67.9%) and regulation of synaptic vesicle transport (201/336, 59.8%). PRKN was the most frequent P/LP-associated gene, occurring in 29/54 P/LP carriers, followed by PLA2G6 and PINK1. Lysosomal transport was represented exclusively by VUS-associated genes, particularly GBA1, VPS13C and LRRK2. Among P/LP carriers, additional VUS in distinct genes were not associated with age at onset (P = 0.81) or family history (52.6% versus 31.4%; P = 0.15). No pathway phenotype association remained significant after correction for multiple testing. Genetic findings in this Indian cohort converged across an interconnected mitochondrial autophagic lysosomal vesicular network, with different contributions from P/LP-associated and VUS associated gene sets. This study provides the first pathway resolved South Asian genetic profile and a framework for comparative studies across populations.