Movement Disorders

Introduction: GCH1 has been implicated in Parkinson's disease (PD), but its risks variants and associations are not well defined. Objectives: To investigate the clinical relevance and PD risk associated with the GCH1 p.Ser80Asn variant. Methods: We first identified a segregating GCH1 p.Ser80Asn variant in a Malaysian Chinese PD family via whole genome sequencing (WGS). We assessed its risk association using multi-ancestry WGS data from the Global Parkinson's Genetics Program (GP2) (n=22,372PD vs n=8,826Controls) and meta-analysis of East Asian (EAS) cohorts (n=4,712PD vs 38,733Controls). Clinico-demographic details of affected variant carriers were collated. Results: The GCH1 p.Ser80Asn variant was enriched in GP2 EAS PD populations (n=9/2,757; 0.33%) but not detected in other ancestries. Meta-analysis revealed increased PD risk in EAS populations (odds ratio:5.1; 95%CI:2.3-10.7; p=2.89x10-5). Affected carriers (mean age at onset:56.3+-12.5 years) had additional occurrence of dystonia, while dementia was rare. Conclusions: The GCH1 p.Ser80Asn variant is a rare, EAS-enriched risk variant for PD.

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and clinical exome sequencing (CES) data from the Global Parkinson Genetics Program (GP2) were analyzed together with unpublished and published GCH1-associated PD patients.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.

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: 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.

Introduction: Variants in the polymerase gamma (POLG) gene are associated with a wide range of mitochondrial disorders. Emerging evidence suggests a potential link between POLG variants and Parkinson's disease (PD); yet, results remain inconclusive. Objectives: To investigate the genetic spectrum and prevalence of POLG variants in PD across diverse ancestries. Methods: We leveraged multi-ancestry genetic data from the Global Parkinson's Genetics Program (GP2), including genotyping data from 98,589 and short-read sequencing data from 36,022 individuals. We performed a POLG rare variant screen, case-control association, and gene-level burden analyses. Results: Five PD cases carried potentially biallelic rare pathogenic/likely pathogenic POLG variants. Additionally, 228 individuals (<1%; 161 PD cases, 28 individuals with other neurological disorders, and 39 controls) carried 34 distinct rare pathogenic/likely pathogenic heterozygous variants, with no significant frequency differences between cases and controls, except for the p.Ala467Thr variant in the European population. The co-inherited pathogenic variants p.Thr251Ile and p.Pro587Leu were present in <1% of both cases and controls, with no significant group differences. Burden and variant-level association analyses showed no association between rare POLG variant burden or common POLG variant enrichment and PD. Conclusions: POLG variants are overall rare in PD. The identification of rare pathogenic variants among PD cases suggests that POLG-related mitochondrial dysfunction may contribute to PD in isolated instances, particularly under recessive inheritance. Our findings support a role for POLG variants in select cases and underscore the need for larger-scale sequencing and functional studies.

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: The cystine/glutamate antiporter encoded by SLC7A11 maintains cellular redox balances and lysosomal pH. Recent molecular evidence suggested that SLC7A11 may be involved in Parkinson's disease (PD). However, the genetic contribution of SLC7A11 to PD susceptibility remains unclear. Methods: We analysed whole-genome sequencing data from the Accelerating Medicines Partnership-Parkinson's Disease (AMP-PD) and United Kingdom Biobank (UKBB) cohorts, comprising of 5,5375 cases and 35,002 controls. Rare variant burden analyses were performed using SKAT-O and MetaSKAT. Common-variant associations with PD risk and glucocerebrosidase (GCase) enzyme activity were assessed with regional linkage disequilibrium plots using previous GWAS summary statistics. Gene expression effects were examined through brain-specific expression quantitative trait loci (eQTL) data from GTEx v7. Colocalization analyses and regional association plots were generated to visualize and compare GWAS and eQTL signals across the SLC7A11 locus. Results: No rare or common SLC7A11 variants were associated with PD or GCase activity, including variants that had strong effects on SLC7A11 expression in relevant brain regions. Discussion: These findings suggest that genetic variation in SLC7A11 or its expression are unlikely to have a major role in PD susceptibility.

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

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

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.

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

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

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

Background: Degeneration in the cholinergic nucleus basalis of Meynert (nbM) is thought to contribute to early cognitive deficits in Parkinson's disease (PD). However, it is unknown whether this relationship is confounded by the parallel degeneration of the substantia nigra (SN) and the locus coeruleus (LC), and whether this relationship is unique to PD. Methods: We conducted a cross-sectional analysis in 112 PD patients (disease duration <10 years) and 46 controls who underwent standard neuropsychological testing, diffusion-weighted and neuromelanin magnetic resonance imaging. Mean diffusivity (MD) of the nbM and neuromelanin signal of the SN and LC were used as proxy measures of neurodegeneration. Results: nbM MD did not differ between PD patients and controls ({beta}=0.05, 95% CI [-0.27, 0.37], p=.771), a finding that was replicated using other MRI metrics. Higher nbM MD in PD patients was associated with worse executive function ({beta}=-0.22, 95% CI [-0.39, -0.05], pFDR=.027), controlling for degeneration in the SN and LC. An association with attention did not survive multiple comparisons correction ({beta}=-0.22, 95% CI [-0.41, -0.02], pFDR=.112), and there was no association with memory ({beta}=0.08, 95% CI [-0.15, 0.30], pFDR=.572). When considering both groups jointly, the relationship between increased nbM MD and worse executive function was stronger in PD than controls ({beta}nbM*Group=-0.30, 95% CI [-0.54, -0.06], pFDR=.036). Conclusion: Our findings suggest that in early-stage PD, nbM microstructural changes may account for unique variance in executive dysfunction in PD, independent of the effects of LC degeneration, and with a stronger association in PD than controls.

Expanded short tandem repeats contribute to a broad spectrum of neurodegenerative diseases, yet their roles in Parkinson's disease (PD) and parkinsonism remain incompletely characterized, especially across diverse ancestries. We analyzed short-read whole-genome (WGS) and clinical exome sequencing (CES) data from 38,365 individuals (28,861 WGS; 9,504 CES), encompassing 23,242 patients with PD, 4,729 patients with atypical parkinsonism and 10,394 healthy controls from 11 genetic ancestries. To determine carrier frequencies and characterize repeat structures across diverse ancestries, we genotyped 12 established pathogenic loci where normal, intermediate, and pathogenic alleles can be reliably differentiated using short-read sequencing data. Additionally, we conducted threshold-based associations to determine the minimum threshold associated with increased PD risk in 15,995 individuals (8,591 PD, 7,404 controls) of European ancestry. Pathogenic repeat expansions were detected in 62 patients (56 PD and 6 atypical parkinsonism) and 5 controls across seven loci (AR, ATXN1, ATXN2, ATXN3, CACNA1A, HTT and THAP11), spanning seven ancestries. Among these, ATXN2 expansions were the most frequently observed in PD and were present in African, East Asian, European and Middle Eastern ancestries. Additionally, intermediate ATXN2 repeat expansions exhibited a strong, length-dependent association with PD risk in the European population, with individuals with [&ge;]32 repeats having a more than four-fold increased risk (odds ratio 4.25, 95% confidence interval 1.80-12.05). Overall, >92% of expanded alleles harbor CAA interruptions within the CAG tract. Pathogenic expansions at other loci, such as ATXN3 and THAP11, showed more ancestry-specific distributions. Clinically, individuals with pathogenic ATXN2 and ATXN3 expansions most often presented with typical PD features but frequently showed earlier disease onset and a strong family history of PD. This large-scale, multi-ancestry study comprehensively maps the genetic landscape of pathogenic and intermediate repeat expansions in PD. Our findings confirm a length- and structure-dependent risk association for ATXN2 with PD in the European population, and highlight the pleiotropic effects of repeat expansions across the parkinsonian spectrum.

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.

We report here, based on Parkinson's Progression Markers Initiative (PPMI) data, on the Cerebrospinal Fluid (CSF) profile of a group of 12 Parkinson's Disease (PD) subjects with the prototypical p.A53T SNCA mutation, comparing them to 36 matched Healthy Controls (HCs) and 36 idiopathic PD (iPD) cases. We furthermore assessed the CSF profile of 7 asymptomatic carriers of this mutation. There was no significant difference between the 3 groups of A53T-PD, HC and iPD in total alpha synuclein (a-syn) levels, beta-amyloid 1-42, total-Tau and p-Tau, although A53T-PD subjects tended to have slightly lower beta-amyloid 1-42, total-Tau and especially total a-syn levels. All A53T-PD cases had a positive CSF a-syn Seeding Amplification Assay (SAA). Four out of 7 asymptomatic carriers also had a positive SAA, in 3 without motor symptoms or signs and absence of clear prodromal manifestations. Conversion to motoric manifestations has occurred in one out of these 3 subjects, 8 years after SAA positivity, while one other subject only has hyposmia 8 years later. Overall, these results indicate that at least in early stages of PD, CSF Alzheimer's Disease profiles are not significantly different in A53T-PD compared to HCs or iPD, while the CSF a-syn SAA is universally positive in this group. Furthermore, the assay may be positive in asymptomatic carriers at a time with no prodromal manifestations and many years before motor disease onset, opening a window into very early stages of disease pathobiology and opportunities for early therapeutic intervention.

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