npj Parkinson's Disease

Progress toward disease-modifying Parkinsons disease (PD) therapies is hindered by limited understanding of pathogenic drivers and lack of therapies that restore the damaged dopaminergic (DA) neurons driving motor deficits. We investigated the role of the bone morphogenetic protein (BMP) pathway in PD using common and rare genetic variants across large-scale datasets. Single-variant analyses identified nominal associations with PD risk and onset age. A BMP polygenic risk score (PRS) was significantly associated with PD risk (OR = 1.21, empirical P = 1.0 x 10-), a result replicated in proxy-case analyses (OR = 1.14, empirical P = 1.0 x 10-) and remained significant after sensitivity testing. To test the results functional relevance, we genetically and pharmacologically inhibited BMP signaling in mice, which induced motor deficits and PD-like neuropathology. In a -synuclein preformed fibril (PFF) mouse model, BMP5 and BMP7 (BMP5/7) demonstrated neuroprotective effects when administered concurrently with -synuclein PFFs. Importantly, when delivered after PFFs-induced motor symptoms onset, BMP5/7 demonstrated neurorestorative effects, ameliorating both motor impairments and neuropathology. These findings provide first evidence that BMP signaling variations contribute to polygenic PD risk, identify a physiological role for this pathway in safeguarding against PD-related pathology, and demonstrate BMPs therapeutic potential for disease modification.

Background. L-Dopa remains the primary treatment for Parkinson's disease (PD), but chronic administration frequently leads to L-Dopa-induced dyskinesia (LID). While D1 and D2 medium spiny neuron (MSN) specific structural changes on the spine level have been observed in the striatum of PD and LID, studying microglia mediated synapse loss has not been done to date. Methods. Here we generated novel reporter mice by crossing floxed PSD95c(mCherry/eGFP) mice with D1-Cre and D2-Cre lines, producing D1-PSD95-EGFP and D2-PSD95-EGFP strains for MSN-specific synapse visualization. Using the 6-OHDA mouse model of PD and LID we assessed microglia mediated MSN subtype specific synapse loss in these mice while PLX3397 was used to investigate effects of microglia depletion and repopulation on LID development and synapse loss. Results. Both D1- and D2-MSNs exhibited significant PSD95 synapse loss in PD, with D1-MSN loss further exacerbated in LID. Microglia displayed increased phagocytic activity and accumulated PSD95 material within lysosomes, particularly in LID. PLX3397-mediated microglial depletion reduced LID severity and preserved D1-MSN synapses. A depletion and repopulation paradigm attenuated LID severity, preserved D1-MSN synapses, and reduced synaptic material within microglia. Conclusions. Microglia-mediated synapse loss in MSN subtypes contributes to PD and LID pathogenesis. Pharmacological microglial depletion and repopulation mitigate synapse loss and dyskinesia, highlighting microglial turnover as a promising therapeutic strategy for LID.

BackgroundBiallelic loss-of-function mutations in PRKN gene (encoding Parkin protein) cause early-onset Parkinsons disease (EOPD). Parkin is a crucial component of PINK1-Parkin pathway, which marks damaged mitochondria for degradation via mitophagy. Without functional Parkin, damaged mitochondria accumulate, causing oxidative stress and neurodegeneration. ObjectiveInvestigate Parkin gene replacement via AAV gene therapy as a potential treatment for Parkin-dependent EOPD. MethodsWe initially validated phosphorylated ubiquitin Ser65 (pUbSer65) as an indicator of Parkin-mediated mitophagy initiation. We evaluated AAV-mediated PRKN replacement (hereafter, AAV-Parkin) in a Parkin knockout neuroblastoma cell line (SH-SY5Y cells) and feasibility of delivery in mouse and rat models. ResultsOur research showed pUbSer65 signal was reduced in Parkin-KO SH-SY5Y cells when compared to wild-type cells after mitochondrial stress, indicating deficiency in initiation of mitophagy. AAV-mediated human PRKN gene replacement successfully restored these pUbSer65 levels in knockout cells. We saw restoration in patient-derived fibroblasts following AAV-Parkin overexpression. We developed a translatable gene therapy approach using rodents. We demonstrated the feasibility of delivering AAV-Parkin directly into the substantia nigra (SN) of wild-type rats. Using an AAV1 capsid with Ef1a promoter, we achieved dose-dependent Parkin expression and identified a well-tolerated dose. We also evaluated multiple promoters in a proprietary Spark100 capsid, finding Ef1a and Synapsin1 (Syn1) were most effective for transducing dopaminergic neurons in the SN of mice without causing adverse effects. These findings established a well-tolerated vector dose and an optimal capsid-promoter combination. ConclusionsOur results support the potential of AAV-Parkin gene therapy as a disease-modifying approach for Parkin-deficient EOPD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/737487v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@16dd13corg.highwire.dtl.DTLVardef@c3dfcdorg.highwire.dtl.DTLVardef@19a310dorg.highwire.dtl.DTLVardef@a66f2_HPS_FORMAT_FIGEXP M_FIG C_FIG

Despite major progress in genomic risk loci identification, biological mechanisms underlying Parkinson's disease (PD) remain incompletely understood and the informativity of polygenic score (PGS)-based prediction remains modest. Polytranscriptomic scores (PTS) - the sum of an individual's observed gene expression weighted by transcriptome-wide association z-scores - combine the stability of genetics with the dynamic biology of gene expression and have the potential to identify associations not captured by genetics alone. We present the first large-scale cross-trait and multi-PTS analysis of PD, calculating ~550 PTS for 100 phenotypes using whole-blood RNA-seq data from three independent clinical cohorts in the Accelerating Medicines Partnership Parkinson's Disease programme (AMP-PD) (N = 2,741; NCASES = 1,644). We identify 26 Bonferroni significant cross-trait PTS associations with PD (p<9x10-5) involving 18 phenotypes and 11 trait categories, including neurodegenerative diseases, respiratory function, sleep and cardiovascular traits. Only one of these associations was observed using corresponding PGS, highlighting the added value of integrating directly measured transcriptomic data. Combining multiple PTS within machine learning multi-PTS models improved prediction of PD case/control status beyond age, sex and PD-PGS in external validation, with a sparse model including an additional seven PTS achieving an AUC of 0.74 [0.70-0.78], representing a 0.09-point improvement. These findings reveal transcriptomic overlap between PD and a range of clinically relevant traits, providing novel insights into disease biology with potential to improve disease prediction.

Background: Neurodegenerative diseases including Parkinson's disease (PD) are increasingly associated with dysfunction in both central and peripheral immune systems. Pathogenic mutations in leucine-rich repeat kinase 2 (LRRK2) represent a major cause of familial PD, while common polymorphisms are associated with inflammatory diseases. Methods: Here, using immunophenotyping flow cytometry and quantitative PCR (qPCR), we compared immune cell populations and function across both the central and peripheral immune systems in C57BL/6J wild type (WT), Lrrk2 p.G2019S knock-in (GKI) and Lrrk2 knock-out (LKO) models in basal and ex vivo immune-stimulated conditions. Results: With a focus on T cell biology, compared to their WT counterparts at baseline, GKI mice exhibit higher populations of Cd8+ and TH17 T cell subsets in the brain, whereas LKO mice exhibited unique central memory (TCM), follicular helper (TFH), and TH2 lineages. In the periphery, GKI mice demonstrated higher TH1, TH2, and TH17 subset expansions, whereas peripheral alterations in LKO are largely restricted to TH17 subsets. Within mutant genotypes, a striking discrepancy was observed between baseline gene expression and the translated proteins encoded, that reveals a fundamental loss of basal immune homeostasis. This phenomenon was further exposed following an acute (6-hour) ex vivo lipopolysaccharide (LPS) immune challenge. Following stimulation, GKI immune cells had reduced transcription, alongside stalled translation, for almost all effector molecules examined, while LKO immune cells had fewer transcriptional changes compared to wild type. Overall, both mutant lines had stalled or flatline effector molecule production after immune stimulation, suggesting a profound loss of functional responsiveness. This hypothesis was supported by a significant increase in surface protein of the inhibitory receptor Pd-1 on regulatory T cells (TREG) and TH1/TH2 Cd4+ T cell subsets in GKI mice. LKO immune landscapes trended toward similar exhaustion patterns, albeit less evident. Conclusions: These data suggest that bidirectional disruptions to normal Lrrk2 function break immune homeostasis. Immune cell function should be carefully considered when targeting LRRK2 kinase activity in patients with PD.

BackgroundParkinsons disease (PD) is increasingly recognized as a multisystem neurodegenerative disorder in which gastrointestinal dysfunction, microbial ecology, immune signaling, and nigrostriatal vulnerability intersect. Microbiome studies have identified PD-associated gut microbial alterations, but translating these observations into host-relevant biological axes requires integration across microbial functions, metabolites, host genes, and brain-region transcriptomic context. MethodsMiNi-PD was developed as a lightweight, fully in silico, table-level prioritization workflow integrating processed PD microbiome features, curated microbe-metabolite-host-gene associations from gutMGene v2.0, and processed substantia nigra and putamen transcriptomic support from GSE136666. The framework ranks microbe-metabolite-host-gene axes using exact-curated metabolite-mediated evidence, brain-region support, and a normalized Nigrostriatal Gut-Brain Convergence Score (NGBCS). ResultsStrict evidence filtering retained 639 primary exact-curated metabolite-mediated axes. Of these, 12 had FDR-level brain transcriptomic support and 65 had nominal-or-stronger support. IL1B emerged as the principal FDR-level host-gene convergence point. SCFA-linked metabolites dominated the primary exact-curated set, including 387 butyrate axes and 5 3-indolepropionic-acid axes. The FDR-supported axes reached the maximum NGBCS value of 5.0, while the top nominally supported axes reached the high-priority NGBCS value of 4.5. ConclusionMiNi-PD identifies a focused SCFA-linked gut-brain signature in PD, highlighting butyrate- and 3-indolepropionic-acid-associated links to IL1B as a biologically meaningful substantia nigra-supported inflammatory axis. The NGBCS framework provides an accessible and interpretable route for prioritizing metabolite-mediated gut-brain mechanisms for downstream validation.

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.

Estimating Parkinson's disease (PD) risk years before diagnosis remains an unmet need. We applied a validated machine learning classifier for REM sleep behavior disorder (RBD) detection to 7-day wrist accelerometry data in 87,975 UK Biobank participants followed for 10 years. Participants in the highest RBD risk stratum (>99th percentile) had an approximately fivefold increased hazard of incident PD compared with the lowest-risk group (0-90th percentile), with a dose-dependent relationship across the full score distribution. Among non-converters, higher RBD risk was associated with baseline cognitive deficits and longitudinal enrichment of autonomic and psychiatric prodromal features. The association with incident PD remained independent of PD polygenic risk score, while RBD score and genetic risk were synergistic. The combined high-risk group achieved a positive likelihood ratio of 7.91, approximately threefold higher than questionnaire-based RBD screening. These findings support wrist accelerometry as a scalable approach for prodromal PD risk enrichment in population screening.

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

Parkinsons disease (PD) and multiple system atrophy (MSA) are alpha-synucleinopathies with overlapping clinical phenotypes but distinct cellular pathological hallmarks. Whether these disorders share upstream molecular changes beyond alpha-synuclein aggregation remains unresolved. Here, we generated induced pluripotent stem cell (iPSC)-derived midbrain spheroids containing dopaminergic neurons from individuals with monogenic PD, idiopathic PD, MSA, and controls, and applied integrated proteomics, metabolomics, and phosphoproteomics to define disease-associated biochemical programs and their regulatory architecture. Despite their distinct etiologies, PD and MSA spheroids displayed highly concordant molecular remodeling, with cellular metabolism emerging as the dominant shared disturbance. Network analyses identified coordinated changes in central carbon metabolism, oxidative phosphorylation, branched-chain amino acid catabolism, pantothenate/CoA metabolism, and lipid remodeling, coupled to phosphorylation-driven rewiring of MAPK, mTOR, AMPK, PKA/PKC, and second-messenger kinase programs. Importantly, these metabolic and signaling axes were also prominent in postmortem substantia nigra from PD and MSA donors, supporting conservation between patient-derived models and postmortem brain tissue. Together, these data identify metabolic dysregulation as a unifying molecular feature across PD and MSA and suggesting phosphorylation-linked metabolic control nodes as candidate entry points for therapeutic intervention. HighlightsO_LIPD and MSA exhibit molecular programs that extend beyond alpha-synuclein pathology. C_LIO_LIProteomics identifies metabolism as the dominant shared disease axis across PD and MSA. C_LIO_LIMetabolomics resolves a coupled glucose-TCA-BCAA-CoA-lipid remodeling program in PD and MSA. C_LIO_LIPhosphorylation-centered kinase networks link signaling rewiring to metabolic bottlenecks. C_LIO_LIShared metabolic features are conserved between patient iPSC-derived midbrain spheroids and substantia nigra. C_LI Graphic abstract (generated using BioRender) O_FIG O_LINKSMALLFIG WIDTH=191 HEIGHT=200 SRC="FIGDIR/small/731777v1_ufig1.gif" ALT="Figure 1"> View larger version (77K): org.highwire.dtl.DTLVardef@1748e51org.highwire.dtl.DTLVardef@12b8f91org.highwire.dtl.DTLVardef@de8893org.highwire.dtl.DTLVardef@1d89ea1_HPS_FORMAT_FIGEXP M_FIG C_FIG

Human endogenous retroviruses (HERVs) are mobile genetic sequences derived from ancient retroviral infections. While typically silenced, their reactivation has been implicated in gene dysregulation, aging, and immune-related transcriptional pathogenesis of some neurodegenerative diseases. Parkinson's disease (PD) is the second most common neurodegenerative disorder, yet its etiology and HERV reactivation remain poorly understood. This study investigates locus-specific HERV expression in early-stage PD, including genetic and non-genetic cases (all PD), idiopathic PD without a known genetic cause (iPD), and PD driven by leucine-rich repeat kinase 2 mutations (LRRK2 PD). We analyzed RNA-seq whole-blood samples from 492 individuals (358 all PD, 256 were iPD, 63 LRRK2 PD, and 134 healthy controls (HC)). We identified 20 significantly dysregulated HERV loci in all PD versus HC. Five HERV loci were shared with iPD analysis, and one HERV locus was shared with LRRK2 PD. Notably, these shared loci included HERV-H and ERVLE elements, indicating robust disease-associated retroviral signals independent of disease subtype. We found that genes proximal to these HERVs revealed pathways implicated in PD pathogenesis. Immune cell deconvolution showed increased neutrophil abundance and decreased resting CD4+ memory T cells proportions across the PD cohorts when compared to HC, consistent with neutrophil-lymphocyte ratio observed in previous peripheral immunity studies. Transcriptomic HERV alterations are present in whole blood across PD populations and are associated with dysregulation of fundamental cellular pathways and peripheral immune remodeling. Our findings motivate experimental validation of locus-specific HERV expression as a candidate blood-based signature with potential to inform PD neuroinflammatory and neurodegenerative processes.

Parkinson disease (PD) affects more than 1.1 million individuals in the United States and around 12 million worldwide. Although Genome Wide Association Studies (GWAS) have substantially advanced our understanding of PD genetic architecture, the regulatory mechanisms linking PD risk loci to disease-relevant gene expression remain incompletely characterized, limiting our ability to infer disease mechanisms from genetic associations. Here, we integrated disease-state parietal cortex transcriptomics with the International Parkinsons Disease Genomics Consortium (iPDGC) locus prioritization to refine PD gene nomination and identify biologically plausible candidates missed by GWAS-only approaches. Using bulk RNA-seq from 99 neuropathologically confirmed PD cases and 30 neuropathologically confirmed controls, we prioritized candidate genes across 78 loci and classified them according to concordance between genetic evidence and differential expression in diseased cortices. This integrative approach recovered candidate genes not captured by external GWAS-based prioritization methods and highlighted synaptic, lysosomal, and proteostasis pathways as major components of PD risk biology. Network and transcription factor analyses further suggested coordinated regulation of these genes, with STAT3 emerging as a putative upstream glial regulator. Together, these findings suggest that integrating disease-state transcriptomics with genetic prioritization can refine PD risk-gene nomination and uncover regulatory programs that may be missed by GWAS alone.

Background: Lysosomal dysfunction plays a crucial role in the pathogenesis of Parkinson's disease (PD), particularly among GBA1 mutation carriers. Beyond GBA1, genes such as TMEM175, SCARB2, and CTSB identified in genome-wide association studies (GWAS) are also implicated in lysosomal pathways contributing to PD risk, although their functional effects in patients remain unclear. Proteins encoded by these lysosome-related genes have been explored as potential therapeutic targets in experimental models. Biomarker profiles, including clinical measures, alpha-synuclein seeding activity, lysosomal proteins, and sphingolipids, may facilitate patient stratification and support therapeutic monitoring in future clinical trials. Aim: The aim of this study is to investigate the impact of genetic variants of three lysosomal-related genes (TMEM175, SCARB2, and CTSB) on biomarker profiles in PD with and without GBA1 variants. Cross-sectional data from two German cohorts: the Tuebingen Parkinson Cohort (TUEPAC) and the DESCRIBE PD cohort of the German Center for Neurodegenerative Diseases were used as explorative cohorts, and data from Accelerating Medicines Partnership Parkinson's Disease (AMP-PD) were used as a validation cohort. The ultimate goal is to provide new data for patient stratification based on genetics, which might serve as a readout for target engagement and treatment efficiency assessment. Methods: Three cohorts were analyzed: TUEPAC, DESCRIBE PD, and AMP-PD. TUEPAC and DESCRIBE PD were combined into a single German discovery cohort (TUEPAC-DESCRIBE-PD), while AMP-PD served as an independent validation cohort. Within each cohort, for subgroup analyses, PD patients were classified as the overall PD cohort (PDall), and further stratified by GBA1 mutation status into PD patients without GBA1 mutations (PDGBA1_wildtype), and PD patients carrying GBA1 mutations (PDGBA1). We evaluated cognitive and motor function, as well as depression using the Montreal Cognitive Assessment (MoCA), Unified Parkinson Disease Rating Scale-part III (UPDRS III), and Beck Depression Inventory-II(BDI-II) scales. Analyzed biomarkers included CSF -syn seeding activity using seed amplification assay (SAA), CSF lysosomal protein levels of lysosomal integral membrane protein 2 (LIMP2), also known as SCARB2, cathepsin B (CTSB) and lysosome-associated membrane protein 2 (LAMP2), blood-based enzyme activity of the lysosomal glucocerebrosidase (GCase), and CSF sphingolipid profiles. PD patients carrying risk alleles in TMEM175, SCARB2, and CTSB were compared to non-carriers. Results: Genotype-phenotype correlation analysis in TUEPAC-DESCRIBE-PD and AMP-PD revealed: (1) In PDall, the TMEM175 p.M393T risk variant was nominally associated with decreased cognitive function when adjusted for GBA1 mutation status in TUEPAC-DESCRIBE-PD; this association could not be replicated, although a similar trend was observed in the slightly smaller, but multicentric AMP-PD cohort; TMEM175 p.M393T was not significantly associated with BDI-II or UPDRS-III scores in either cohort. (2) In PDGBA1_wildtype, GCase activity was significantly lower in PD patients with SCARB2 rs6812193 risk allele in TUEPAC-DESCRIBE-PD, while a similar but non-significant trend was observed in AMP-PD; (3) In PDall, CSF levels of CTSB were nominally lower in carriers of CTSB rs1293298 risk allele compared to carriers of CTSB rs1293298 protective allele in TUEPAC-DESCRIBE-PD; in PDGBA1_wildtype, LAMP2 was significantly lower in carriers of CTSB rs1293298 risk allele compared to carriers of CTSB rs1293298 protective allele in TUEPAC-DESCRIBE-PD; (4) In PDall, TMEM175 p.M393T risk allele was nominally associated with altered sphingolipid profiles across both TUEPAC-DESCRIBE-PD and AMP-PD cohorts. Conclusion: These findings demonstrate that genetic variants in lysosomal-related genes (TMEM175, SCARB2, and CTSB) have a functional impact on biomarker profiles in PD patients. Integrating genetic characterization with biochemical profiling provides a framework for patient stratification and may serve as a translational strategy to monitor target engagement and evaluate treatment efficacy in future clinical trials.

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

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.

Parkinsons disease (PD) affects an estimated 6.4 million men and 5.3 million women worldwide, and still lacks a validated peripheral biomarker. Brain tissue is inaccessible in living patients, making peripheral blood an attractive alternative, but existing studies have profiled immune cells almost exclusively as static, resting-state snapshots that cannot reveal how those cells function under challenge. A longitudinal design, following patients over time, or applying a controlled stimulus to reveal functional differences invisible at rest, offers a more sensitive window onto disease-associated dysfunction, and sex, despite differential PD incidence and progression, is rarely treated as a primary variable. Here, using ex vivo PMA/ionomycin stimulation as a controlled functional challenge, we profiled 195k PBMCs from 84 samples of 14 PD patients and 14 controls by single-cell RNA sequencing across an activation time course (0h, 2h, 4h), stratified by sex throughout. Sex explained more transcriptional variance than disease status, and male and female PD patients showed largely divergent responses at rest that converged, by peak activation, on a discrete CD8+ effector memory T cell subpopulation (Tem-CD8). This subpopulation showed an exhaustion-consistent programme, coinciding with a failure to resolve AP-1 induction and a reduction in inferred intercellular communication. The PD peripheral immune phenotype is therefore better characterised as a activation-dependent response than a fixed resting-state signature, identifying Tem-CD8 exhaustion as a disease-associated, sex-convergent candidate for further study.

Importance: Dementia is a common and disabling complication of Parkinson's disease (PD). Blood-based biomarkers that identify individuals at higher risk of future dementia could improve prognostication and trial stratification. Objective: To determine whether blood-based proteins are associated with future risk of dementia in PD. Design, Setting, and Participants: Prospective longitudinal cohort study with discovery and replication analyses in the Oxford Parkinson's Disease Centre (OPDC) Discovery cohort and the Parkinson's Progression Markers Initiative (PPMI). A total of 1,335 participants with PD and 431 healthy controls, with serum, plasma, or cerebrospinal fluid proteomic data and follow-up of up to 12 years, were included. Main Outcomes and Measures: Incident dementia, defined using a composite of MoCA scores, MDS-UPDRS items, and clinician diagnosis. Associations between baseline protein levels and time to dementia were evaluated. Results: Among 1,335 participants with PD, 168 developed incident dementia across cohorts (OPDC Discovery [serum], n = 108; PPMI Project 293 [plasma], n = 23; PPMI Project 181 [CSF], n = 37). In the OPDC cohort, GFAP was the only protein (of 5,408 tested) significantly associated with incident dementia (HR = 2.43; 95% CI: 1.79-3.30; p-adjust =1.35 x 10-4). Higher GFAP tertiles were associated with greater cumulative dementia incidence. Findings were replicated in the PPMI plasma project (HR = 2.42; 95% CI: 1.12-5.22; p = 0.024) but not in the CSF project (HR = 0.96; 95% CI: 0.66-1.39; p = 0.82). Higher baseline GFAP was significantly associated with lower baseline cognitive performance and greater longitudinal cognitive decline but no significant association with motor progression. In both cohorts, GFAP levels increased over time but showed no group-level differences. Conclusions and Relevance: Circulating GFAP is a robust and reproducible predictor of future dementia in PD, detectable early in the disease course. While the lack of differential longitudinal trajectories between PD patients with and without dementia suggests that GFAP does not act as a dynamic marker of cognitive decline, its relative stability supports its role as an early indicator of underlying biological vulnerability or subclinical pathology. These findings support serum GFAP as a promising, accessible biomarker for early dementia risk stratification.

Dopamine replacement therapy (DRT) alleviates motor symptoms in Parkinson's disease (PD) but can trigger hallucinations in a subset of patients, yet the neural basis of this selective vulnerability is unknown. Hallucinations are among the most disabling non-motor symptoms of PD, linked to social isolation, dementia and institutionalization. Using a validated robotic paradigm to induce and quantify hallucinations in real-time, combined with resting-state fMRI in a crossover On/Off DRT design, we studied patients with PD with (PD-H) and without (PD-nH) hallucinations. DRT selectively amplified sensitivity to robot-induced hallucinations in patients with pre-existing hallucinatory phenotype (PD-H, but not PD-nH) and was accompanied by cortico-striatal and large-scale network hyperconnectivity. Rather than supporting a uniform hallucinogenic effect of dopamine in PD, these findings indicate that DRT interacts with an intrinsic neural vulnerability that varies in patients. Prospective studies will establish whether this pharmacological-behavioural signature identifies patients at risk before clinical hallucinations emerge.

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.

Objective and scalable approaches for detecting subtle motor impairment in isolated REM sleep behavior disorder (iRBD), a prodromal stage of Parkinson's disease, remain limited. We investigated whether markerless motion capture from single RGB-camera videos can identify gait abnormalities in people living with iRBD and provide interpretable digital biomarkers. We retrospectively analyzed 93 standardized walking videos from three clinical sites. Human pose estimation extracted 12 body markers and 14 kinematic time series. Thirty-five machine learning approaches classified healthy controls (HC) and people with iRBD. The Movement Disorder Society Unified Parkinson's Disease Rating Scale Part 3 (MDS-UPDRS III) served as the clinical baseline. The best-performing model (tsfresh+XGBoost) achieved an AUROC of 0.739, significantly outperforming the MDS-UPDRS III sum score when trained on data from all three sites. Harmonized multi-site training improved performance. SHAP identified hip-related temporal features as key contributors, which differed between groups and showed stronger associations with regional dopaminergic deficits than clinical scores. Single-camera gait analysis may provide scalable digital biomarkers for low-cost screening and monitoring of prodromal PD.