Journal of Parkinson's Disease

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

Background: Historically, OFF burden in Parkinsons disease has been primarily attributed to motor features. Recent studies highlight that non motor symptoms, and the predictability of OFF episodes also drive functional impairment, yet they are rarely measured in clinical practice. Objective: To identify which clinical features are most closely associated with OFF time and OFF impact, and to quantify the added explanatory value of temporal predictability, non-motor, and behavioural domains beyond a core motor model. Methods: We analysed 1,252 OFF only visits from 430 PPMI participants. Outcomes were MDS UPDRS IV 4.3 (OFF time) and 4.4 (OFF impact). Linear mixed effects models with a participant random intercept were fitted. The core motor model included OFF state motor severity, freezing, tremor, levodopa responsiveness, and dyskinesia, plus covariates. Predictability (IV; 4.5), non motor (mood, fatigue/sleep, autonomic/GI), and behavioural (impulse control behaviours) domains were then added to assess added influence beyond motor. Analyses were stratified by time since diagnosis (Pooled; [≤] 4y; [≥] 6y). Results: Clinical features explained more variance in OFF impact than OFF time (25.9% vs 8.1%). OFF time was primarily linked to OFF state motor severity/freezing, with levodopa responsiveness important early. For OFF impact, predictability produced the largest increment in marginal R squared beyond the core motor model (pooled and Late). Within the core motor model, tremor was the largest contributor to OFF impact. Conclusions: Predictability is a prominent correlate of OFF impact. Asking about predictability may help tailor therapy, from timing optimisation to on demand rescue for unpredictable episodes.

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

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

Background: Most trials of Parkinson's disease (PD) measure progression over a short to medium time-period using continuous rating scales that may be hard to interpret and less meaningful for patients. There is a lack of evidence connecting changes in these scales to changes in outcomes important to patients. Objectives: We present causal modelling to translate the causal, short-term disease-modifying treatment effects on functional rating scales to the 10-year risk of serious clinical progression milestones. Methods: We selected four important clinical milestones of disease progression from the Oxford Parkinson's Disease Centre "Discovery" cohort: dementia, any falls, frequent falls, and mortality. We proposed a causal framework for our research objectives so we could model the potential impact of a 30% reduction in disease progression slopes ("treatment effect") using the summation of parts I and II of the Movement Disorders Society Unified Parkinson's Disease Rating Scale (UPDRS12). This outcome was regressed on time to milestone using flexible parametric survival models. Marginal predictions of survival and survival difference at year 10 were then calculated for the Discovery cohort, and a counterfactual cohort applying the treatment effect to estimate the relative and absolute reductions for the four clinical milestones. Results: The model increase in risk for each unit change in the UPDRS12 were as follows: dementia hazard ratio (HR)=1.52 (95% Confidence Interval (CI) 1.36-1.70), any falls HR=1.37 (95% CI 1.29-1.46), frequent falls HR=1.68 (95% CI 1.49-1.89), mortality=1.29 (95% CI 1.17-1.42). These models led to marginal predictions of absolute reductions, when the progression was reduced by 30%, between 4.0% (mortality) and 7.5% (frequent falls) at 10 years follow up. Conclusions: We have demonstrated how a treatment effect in a trial specified in terms of a progression change of a rating scale can be contextualised into a long-term reduction in the probability of clinically relevant milestones. Whilst we have used PD as our exemplar, we believe this methodological approach is generalisable to other chronic progressive diseases where trials are often limited to a relatively short follow-up period and use some scalar measure of progression, but significant clinical milestones usually take longer to be observed. Keywords: Clinical trials; disease modifying therapies; causal estimation; prediction models

Studies reporting alpha-synuclein seed amplification assay (aSyn-SAA) results are often cross-sectional. Here we investigated the intra-individual consistency of aSyn-SAA results over time from participants in the Parkinson's Progression Marker Initiative (PPMI). A total of 1238 participants had >1 CSF aSyn-SAA result for analysis (Parkinson's disease [PD]=633, prodromal =563, healthy control [HC]=42) which were collected over a median (min, max) of 2.0 (0.4, 11.4) years. Emphasis was placed on evaluating consistency in less common results such as aSyn-SAA- PD participants, aSyn-SAA+ HC and conversion rates from aSyn-SAA negative to positive results prodromal participants. Of aSyn-SAA+ PD participants, 96% (474/493, 95%CI 94-98%) remained positive in subsequent samples, and 92% (116/126, 95%CI 86-96%) of aSyn-SAA- PD participants remained negative. 99% (303/307, 95%CI 97-99%) of aSyn-SAA+ prodromal participants remained positive, and 95% (234/247, 95%CI 91-97%) of aSyn-SAA- prodromal participants remained negative. 89% (16/18, 95%CI 67-97%) of aSyn-SAA+ HC participants remained positive, and 87% (20/23, 95%CI 68-95%) of aSyn-SAA- HC participants remained negative. These results confirm a high consistency of aSyn-SAA results over time, even in less expected results.

Adeno-associated viral (AAV)-mediated overexpression of human wildtype -synuclein (-syn) in the substantia nigra (SN) is a widely used approach to model Parkinsons disease (PD) in rodents. However, variability in the ability of AAV-based systems to induce nigrostriatal pathology and motor deficits has limited reproducibility across studies, especially in mice. Here, we systematically optimized key vector features - AAV serotype, promoter, viral titer - to establish a highly efficient and reliable mouse model of PD. We compared the tropism and expression efficiency of mixed AAV2/1 and AAV2/rh10 serotypes combined with three promoters - CMV enhancer/chicken {beta}-actin (CBA), human Synapsin (hSYN), and rat Tyrosine Hydroxylase (TH) - to drive human -syn gene (SNCA) expression in nigral dopaminergic neurons. The AAV.TH.SNCA vector, delivered at an optimized titer, achieved selective and sustained -syn overexpression in nigral neurons, resulting in nigro-striatal neurochemical changes and progressive motor deficits preceding overt neuronal loss. Fine tuning -syn expression proved critical for detecting early disease processes: lower AAV.TH.SNCA titer induced early pathological signatures, including -syn hyperphosphorylation and neuroinflammation, whereas higher titers produced robust nigrostriatal degeneration not achieved with other promoter constructs. Notably, we demonstrate that motor and neurochemical impairments can occur prior to dopaminergic cell death, implicating microglial activation and -syn pathology as primary drivers of dysfunction. This observation is consistent with human genetic evidence showing that triplication of the wild-type SNCA gene alone can cause Parkinsonian pathology, highlighting that our model enables the use of a single experimental reagent to investigate the molecular, cellular, and behavioral consequences of controlled increases in -syn expression. This novel AAV.TH.SNCA model provides a powerful and versatile platform for investigating mechanisms of a -syn-mediated neurotoxicity and for evaluating disease modifying interventions targeting early, pre-degenerative stages of PD. HighlightsO_LITitrated -syn expression uncouples early dysfunction from dopaminergic neuron loss C_LIO_LIAAV2/rh10-TH-SNCA model captures prodromal and degenerative PD stages C_LIO_LIMotor deficits arise from -syn pathology and nigral molecular changes before neurodegeneration. C_LI

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

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

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

Deciding whether and how to act depends on a trade-off between the effort required to execute a given action and the potential reward for completing it. Impairments in this effort-reward trade-off have been proposed to underlie reduced movement vigor, or bradykinesia, in Parkinsons disease (PD). However, several mechanisms could alter the effort-reward trade-off in PD, each with unique implications for understanding and treating bradykinesia. Therefore, we individually examined whether people with PD (both on and off dopamine medication) demonstrated reduced sensitivity to reward value, increased perception of effort, or a biased mapping between effort and reward, compared to age- and sex-matched neurotypical controls. We found that people with PD exhibited increased effort perception and, surprisingly, no reduced sensitivity to reward value or a biased mapping between effort and reward. These findings suggest that effort perception could be an important factor driving bradykinesia in PD.

Non-motor symptoms in Parkinsons disease (PD) may be influenced by the 4{beta}2* subtype of nicotinic acetylcholine receptors (nAChR) present in the hippocampus and subiculum. To continue efforts in PET diagnostics for PD, autoradiographic [18F]nifene binding to 4{beta}2* nAChR was quantitively assessed in the hippocampus-subiculum (HP-SUB) of PD (n = 27; 14 males, 13 females) and cognitively normal (CN) (n = 32; 16 males, 16 females) cases. Anti-ubiquitin for Lewy body and anti--synuclein immunostaining on adjacent slices were analyzed in QuPath and [18F]nifene binding was quantified in OptiQuant. Subiculum had greater [18F]nifene binding (51% to 85%) compared to HP in all subjects. Significantly higher [18F]nifene binding (>250%) was seen in PD SUB and PD HP compared to CN in both males and females. The grey matter (GM) to white matter (WM) ratio in PD=3.53 while CN=1.33, a >150% increase in PD. Binding of [18F]nifene to GM and WM individually was >250% greater in PD compared to CN. Male CN exhibited an increase while and male PD exhibited a significant decrease in [18F]nifene binding with aging, while females did not exhibit significant differences. In summary, 4{beta}2* nAChR measured by [18F]nifene is significantly upregulated in the PD HP and SUB. This increased [18F]nifene binding may be of diagnostic value using PET imaging.

Background-Synuclein (-Syn) plays a central role in Parkinsons disease (PD). Under pathological conditions, -Syn aggregates into toxic oligomers and fibrils that act as damage-associated molecular patterns (DAMPs), stimulating microglial reactivity. This -Syn-microglia axis creates a self-perpetuating cycle of neuroinflammation and neurodegeneration, accelerating dopaminergic neuron loss in the substantia nigra pars compacta (SNpc) and contributing to motor deficits. Moreover, -Syn pathology spreads through the brain, disrupting synaptic plasticity in cognitive regions like the cortex and hippocampus, leading to early cognitive decline. Thus, targeting -Syn aggregation and its inflammatory consequences presents a promising dual-hit therapeutic strategy for PD. MethodsThis study investigates the therapeutic potential of 3-monothiopomalidomide (3MP), a novel thalidomide derivative designed to reduce neuroinflammation with a potentially better safety profile than Pomalidomide (POM). The neuroprotective and anti-inflammatory effects of 3MP were evaluated in rat primary mesencephalic mixed neuron-microglia cultures exposed to human -Syn oligomers (H-SynOs). Anti-aggregation activity was assessed via Thioflavin T (ThT) assays and Thioflavin S (ThS) staining in SH-SY5Y cells. Finally, the anti-aggregation, anti-inflammatory, and neuroprotective effects of 3MP were evaluated in vivo in a rat model of PD induced by intracerebral infusion of H-SynOs. ResultsIn primary cell cultures, 3MP dose-dependently reduced -Syn-induced neuronal death and microglial inflammatory responses. It also significantly inhibited -Syn aggregation in vitro in the ThT assay and in SH-SY5Y cells exposed to -Syn protofibrils, outperforming POM. When chronically administered in vivo, 3MP preserved dopaminergic neurons within the SNpc and yielded functional benefits on motor and cognitive readouts. Notably, 3MP markedly attenuated -Syn aggregates induced by the H-SynOs infusion in the SNpc more efficiently than POM, as shown by reduced intraneuronal staining for pSer129--Syn+ and reduced pSer129-Syn in both cytoplasmic and phagolysosomal compartments of microglia. In addition, mesencephalic and cortical inflammatory microgliosis that followed to intranigral H-SynOs-infusion, were significantly dampened by 3MP. ConclusionsOverall, 3MP emerges as a dual-action drug candidate capable of modulating neuroinflammation and -Syn aggregation and thereby disrupting the -Syn-driven inflammatory cycle. Its neuroprotective effects and favourable safety profile support its potential as a disease-modifying therapy for PD, with promising implications for clinical translation.

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

BackgroundFilamentation induced by cAMP domain-containing protein (FICD) is an endoplasmic reticulum (ER)-resident adenylyltransferase that catalyzes protein AMPylation, a post-translational modification. Although FICD-mediated AMPylation has been linked to the fine-tuning of proteostasis and neuronal integrity, its role in neurodegenerative diseases characterized by protein dyshomeostasis remains unclear. Parkinsons disease (PD) is defined by dopaminergic neurodegeneration and aggregation of -synuclein (aSyn) as a consequence of impaired protein homeostasis. We therefore investigated whether dysregulated FICD-mediated AMPylation contributes to PD pathogenesis. MethodsWe combined analyses of human post-mortem PD brain tissue with complementary models, including midbrain dopaminergic neurons derived from human induced pluripotent stem cells (hiPSCs) of a PD patient carrying an SNCA gene duplication and its isogenic gene dosage-corrected control line, transgenic mouse models of synucleinopathy, and an aSyn-overexpressing H4 neuroglioma cell model. Genetic and pharmacological modulation of FICD activity was integrated with multi-proteomic approaches, including chemical proteomics-based AMPylation profiling, stable isotope labelling with amino acids in cell culture-based global protein turnover analysis, and whole-proteome profiling to identify AMPylation-associated molecular pathways. ResultsFICD was preferentially expressed in dopaminergic neurons and was upregulated in SNCA duplication PD patient-derived neurons, as well as in the basal ganglia of PD post-mortem brains and synucleinopathy mice. Despite this overall increase, the proportion of FICD-expressing dopaminergic neurons was reduced under PD conditions, suggesting selective vulnerability of dopaminergic neurons to FICD. Mechanistically, FICD selectively AMPylated lysosomal proteins, thereby linking AMPylation to the regulation of degradative pathways. Moreover, hyperactivation of FICD-induced AMPylation triggered ER stress, impaired lysosomal function, reduced protein turnover, and ultimately promoted aSyn aggregation and apoptotic cell death. Importantly, pharmacological inhibition of AMPylation reversed aSyn pathology and neurite degeneration in PD patient-derived neurons. ConclusionsWe identify the pathological relevance of FICD-mediated AMPylation in PD-related neurodegeneration and its contribution to aSyn aggregation through a bidirectional interplay with aSyn pathology. Our findings support FICD-mediated AMPylation as a defining molecular switch regulating intracellular protein homeostasis in PD and highlight the FICD-AMPylation pathway as a potential therapeutic target for restoring aSyn pathology and mitigating disease progression.

Although a differential vulnerability of dopaminergic neurons to degeneration based on their specific location within the dorsal and ventral tiers of the substantia nigra pars compacta (SNcD and SNcV, respectively) has long been postulated, the underlying mechanisms sustaining these tier-specific differences remain poorly understood. Here, upon inducing a viral-mediated enhancement of neuromelanin (NMel) accumulation within dopaminergic neurons in non-human primates, the distribution of Lewy body-like inclusions (LBs) was analyzed within identified SNcD and SNcV neurons, together with their intracellular NMel levels. Results showed that the vast majority of intracytoplasmic inclusions were found in SNcV neurons, and indeed correlated to higher pigmentation levels. By contrast, only very few LBs were found in calbindin-positive neurons of the SNcD, which in parallel exhibited very low levels of NMel accumulation. These results postulate an additive effect made of a tier-specific location of LB burden together with high pigmentation levels as synergistic drivers sustaining the preferential vulnerability of SNcV dopaminergic neurons. Moreover, the evidence obtained here supported that NMel accumulation beyond a given threshold triggers the aggregation of endogenous -Syn in the form of LBs; therefore, approaches intended to reduce pigmentation levels in SNcV neurons would likely induce a neuroprotective effect by preventing the subsequent aggregation of -Syn.

Background. Parkinson's disease (PD) diagnosis remains delayed and suboptimally accurate, largely due to clinical overlap with atypical parkinsonian syndromes and the lack of reliable biomarkers. Here, we evaluated the performance of a previously patented 6-metabolites blood biomarker (6M-BB) for the differential diagnosis of PD and its translation to clinical IVDr NMR platform. Methods. Patient serum samples from de novo PD (n=30), multiple system atrophy (MSA, n=30), progressive supranuclear palsy (PSP, n=30), Alzheimer's disease (AD, n=33), and healthy individuals (n=29), were profiled by 1H NMR and classified using the 6M-BB. For clinical use, we rebuilt the model on absolute concentrations acquired on a Bruker Avance IVDr 600 MHz system. Results. The 6M-BB validation yielded 0.902 AUC and 87.9% accuracy for PD vs. HC (sensitivity 86.7%, specificity 89.3%), with an overall accuracy of 82.6% across all groups. The IVDr-based refit achieved 0.878 AUC (overall accuracy 77%). Adding VLDL-5 free cholesterol (V5FC) and citrate markedly improved performance to 0.959 AUC, with 94.9% accuracy for PD vs. HC (sensitivity 96.7%, specificity 93.1%) and 84.9% when MSA/PSP were included. Conclusion. The externally validated 6M-BB has demonstrated its robustness for the differential diagnosis of PD compared to other parkinsonian syndromes at de novo stage. Its successful transfer to a fully automated, standardized IVDr machine, with gains from V5FC and citrate, supports the feasibility and promising potential for clinical implementation, justifying future prospective multicenter studies.

Parkin, an E3 ubiquitin ligase encoded by PARK2, plays a key role in both hereditary and sporadic Parkinsons disease (PD), yet there are no therapies currently available that can target this important pathway. Here, we show that Parkin is critical for successful neuronal differentiation and survival, and we develop small-molecule Parkin agonists that can protect dopaminergic neurons. Upon differentiation of neural progenitor cells, loss of Parkin results in a reduced capacity to maintain neuronal cell state, dopaminergic neuronal phenotypes, and stress resistance. Moreover, Parkin loss disrupted cell morphology and the stability of neurites. Transcriptional and single-cell analyses reveal that Parkin controls critical pathways regulating stem-like cell transitions and is needed for stable neuronal maturation. We also examined the effects of FB231, a small molecule enhancer of Parkin E3 ligase activity, in models of PD. FB231 reduced pathological -synuclein and enhanced cell survival in human iPSC-derived dopaminergic neurons treated with -synuclein preformed fibrils. Furthermore, FB231 attenuated -synuclein pathology and dopaminergic neurodegeneration in a gut -synuclein murine model of PD. Our findings support that Parkin plays a crucial role in maintaining neuronal homeostasis and that pharmacologic activation of Parkin may be a promising strategy to attenuate neurodegeneration in PD.

Background: Peri-lead edema (PLE) occurs in up to 15% of Deep Brain Stimulation (DBS) cases, can cause morbidity, and its etiology remains unknown. We hypothesized that PLE represents a secondary brain injury modulated by hypoxemia, and that patients with obstructive sleep apnea (OSA) are at elevated risk. Methods: We conducted a retrospective case-control study of 121 Parkinson's disease (PD) patients undergoing DBS at a single center (2019-2024). PLE severity was quantified by CT volumetric segmentation and Hounsfield unit (HU) measures. Perioperative SpO2 and PaO2 were recorded. Polysomnography (PSG) was available in 26 patients; and the REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) was administered retrospectively. Results: Symptomatic PLE occurred in 12 patients (9.9%), with onset at 3.5 (2-9) days postoperatively. PLE patients had higher body mass index (p = 0.022) and higher OSA prevalence (75% vs. 30%; p = 0.002). Perioperative SpO2 was lower in the PLE group in both the operating room and post-anesthesia care unit (PACU; p < 0.05); PaO2 was lower in the PACU (p = 0.037). In the PSG subgroup, REM Sleep Behavior Disorder (RBD) incidence was lower in PLE patients (20% vs. 60%; unadjusted p = 0.048), and PLE severity correlated significantly with sleep-related hypoxemia and respiratory indices. RBDSQ scores were positively associated with edema density (normalized HU: rho = 0.86, p = 0.024). Conclusions: OSA and perioperative hypoxemia are associated with symptomatic PLE following DBS, while RBD appears protective. Preoperative sleep evaluation and optimized perioperative airway management warrant prospective investigation as PLE prevention strategies.

In the Global Parkinson's Genetics Program (GP2) we aim to advance precision medicine by integrating large-scale clinico-genetic data from diverse populations worldwide. We investigated potentially trial-eligible carriers of pathogenic and high-risk GBA1 and LRRK2 variants and conducted a global precision-medicine survey across GP2 sites. Among 65,509 individuals with Parkinson's disease, we identified 9,019 (13.8%) potentially trial-eligible genetic variant carriers, including 6,789 GBA1, 2,084 LRRK2, and 146 dual GBA1-LRRK2 carriers. Individuals were distributed across multiple global regions, many of which currently lack active gene-targeted trials, highlighting a global disparity between relevant variant carriers and the availability of disease modifying treatment trials. GP2's unified framework supports equitable recruitment for gene-targeted therapeutic studies and helps address critical gaps in Parkinson's disease genetics and future therapeutic development.