Journal of Parkinson’s Disease

Background: Cognitive impairment in Parkinson disease (PD) significantly affects patients ability to perform instrumental activities of daily living (IADLs). However, neuropsychiatric symptoms, which are highly prevalent in PD, may also contribute to functional impairments. In this study, we investigated the independent contributions of cognitive and neuropsychiatric symptoms to functional impairments and tested whether mood mediates cognition-function associations. Methods: We examined 104 patients from the Quebec Parkinson Network and replicated analyses in a sample of 144 patients from an independent online cohort. Participants completed the Penn Parkinsons Daily Activities Questionnaire (PDAQ), a validated patient-reported measure designed to capture cognition-dependent IADLs, standard cognitive tests (executive function, attention, working memory), and neuropsychiatric questionnaires (apathy, depression, impulsivity, and anhedonia). Regression models tested the independent and combined effects of cognition and neuropsychiatric symptoms on PDAQ; mediation analyses explored mechanistic pathways. Results: Both cognitive performance and neuropsychiatric symptoms were independently associated with PDAQ scores and the proportion of variance explained by neuropsychiatric symptoms was comparable to that explained by cognitive performance. Furthermore, depression and impulsivity partially confounded the relationship between cognitive performance and PDAQ and impulsivity partially mediated this relationship. The independent associations between neuropsychiatric symptoms and PDAQ were replicated in the replication sample. Conclusion: These results indicate that impairments in cognitive IADLs reflect contributions of both cognition and neuropsychiatric changes and suggest that trials using measures of IADLs as an outcome measure should also carefully assess and control for neuropsychiatric symptoms.

Background. Nigrostriatal dopaminergic dysfunction, a biological anchor of Parkinson's disease (PD), is routinely assessed using single-photon emission computed tomography of the dopamine transporter (DaT-SPECT). Dopa decarboxylase (DDC) in cerebrospinal fluid (CSF) is a promising biomarker of dopaminergic dysfunction, but its association with DaT-SPECT has to be demonstrated. Objectives. To investigate the association of CSF DDC with DaT-SPECT. Methods. We first analysed proteomic and DaT-SPECT data from the Parkinson's Progression Markers Initiative (PPMI), including PD (n=891), prodromal PD (n=867) and healthy controls (n=161). We then verified this association in a single-center clinical cohort (UNIPG), including PD/Dementia with Lewy Bodies (DLB) (n=78), atypical parkinsonisms (AP, n=11), other neurodegenerative diseases (OND, n=25) and controls (CTRL, n=40). Here, CSF DDC was measured by a novel fully automated quantitative immunoassay. Results. In PPMI, among 129 proteins assessed, DDC showed the strongest association with DaT-SPECT ({beta} = -0.132, FDR = 6.92 x 10-33). Across PPMI and UNIPG cohorts, DDC correlated with striatal binding ratio (SBR) ({rho} = -0.377, P < 0.001; {rho} = -0.466, P < 0.001, respectively) and accurately discriminated positive from negative scans (AUC 0.811, 95% CI 0.762-0.859; AUC 0.870, 95% CI 0.777-0.963, respectively). In PPMI prodromal cases, higher DDC predicted faster motor progression. In UNIPG, DDC distinguished PD/DLB and AP from OND and CTRL groups (AUC 0.830, 95% CI 0.764-0.896), independently of dopaminergic treatment. Conclusion. CSF DDC reflects nigrostriatal dopaminergic dysfunction, representing a potential quantitative biochemical alternative to DaT-SPECT that might be readily implemented via automated immunoassays.

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

Background: Peripheral inflammation has been implicated in the pathophysiology of Parkinson's disease (PD), but its relationship with autonomic dysfunction remains unclear. Objectives: To explore the association between peripheral inflammation, assessed by the neutrophil-to-lymphocyte ratio (NLR), and autonomic function in patients with PD. Methods: We retrospectively analyzed 97 patients with PD who underwent 123I-metaiodobenzylguanidine (MIBG) cardiac scintigraphy and differential blood cell counts. Associations of NLR with early and delayed heart-to-mediastinum (H/M) ratios, washout ratio, and the coefficient of variation of R-R intervals (CVRR) were assessed using Spearman's rank correlation and multivariable linear regression adjusted for age, sex, and disease duration. Results: No significant univariable correlations were observed between NLR and the autonomic measures. In multivariable analysis, higher NLR was associated with a lower early H/M ratio (B = -0.802, 95% CI -1.598 to -0.005, P = 0.049), whereas no significant associations were observed with the delayed H/M ratio, washout ratio, or CVRR. Sensitivity analyses showed a generally consistent direction of association, although the effect estimate was attenuated after exclusion of two influential observations and statistical significance was not consistently retained. Conclusions: Higher NLR was associated with lower early cardiac MIBG uptake after adjustment for age, sex, and disease duration in patients with PD. This exploratory finding raises the possibility of an association between systemic inflammation and sympathetic dysfunction in PD and requires confirmation in larger prospective studies.

Peripheral inflammation in Parkinson's disease (PD) remains poorly characterised among carriers of Asian-prevalent LRRK2 G2385R and R1628P variants. We investigated plasma immunoinflammatory markers (i.e., IL-6, TNF-, CCL2, CX3CL1, CCL5, and VCAM-1) via multiplex immunoassay in 240 participants: PD-G2385R (n=53), PD-R1628P (n=58), PD-G2385R+R1628P (n=5), idiopathic PD (iPD; n=62), and controls (n=62), and their clinicobiological correlates including monocyte LRRK2 kinase activity (pRab10Thr73). Compared with iPD and/or controls, TNF-, CCL2, CX3CL1, and CCL5 were lower in PD-G2385R, while IL-6, TNF-, CCL2, and CCL5 were lower in PD-R1628P. Higher LRRK2 kinase activity correlated with lower TNF-. CX3CL1 correlated with greater motor severity in iPD but less disability in both variant groups. CCL5 correlated with less motor complications in PD-G2385R, while IL-6 and VCAM-1 correlated with worse disability and/or cognition in PD-R1628P. These findings suggest that immunoinflammatory profiles and their clinical relevance in PD differ by genotype, with implications for stratification in future immunomodulatory trials.

In Parkinson's disease (PD), early phase clinical trials of disease-modifying agents generally use the MDS-UPDRS Part III as the primary outcome measure of motor function, which typically requires a large sample and/or a long (12-18 months) treatment duration, even if a substantial treatment effect is assumed. This is due to the rather slow rate of early PD progression relative to the variability of the MDS-UPDRS Part III assessments. Using placebo-arm data from four recent large Phase 2 trials of early-stage PD (SPARK, PASADENA, PADOVA and LUMA), the sample size needed to detect a range of assumed treatment effects on MDS-UPDRS Part III progression was estimated. The trial sample size estimates obtained for MDS-UPDRS Part III and for smartphone-based sensor-derived motor functional composite (MFC) endpoints were compared using an approach based on relative responsiveness to disease progression. The calculations were also implemented in an interactive, publicly accessible application. Powering a one-year trial using the MFC1 endpoint, derived from three active assessments (6-minute walk, U-turn and Hand Pronation-Supination), or the MFC2, which adds 60-Second Typing, was projected to reduce the required sample size by more than half relative to the MDS-UPDRS Part III, assuming equivalent proportional treatment effects.

Background Sporadic Parkinson disease (PD) lacks a molecular taxonomy that stratifies patients by dominant molecular drivers, limiting enrollment for disease-modifying trials, especially anti-inflammatory agents targeting NLRP3/NF-{kappa}B. Methods We developed ORIGIN-PD, an interpretable whole-blood transcriptomic classifier comprising 34 gene-level features and a composite low-expression score, with gene-level contributions organized into eight prespecified functional modules: midbrain dopaminergic (mDA) neuron identity/development, pathway-related, oxidative/mitochondrial, proteostasis, inflammation/ immunity, microglia, ncRNA, and other. Using LASSO regression on stringently quality-controlled whole-blood RNA-seq data from the Parkinson Progression Markers Initiative (PPMI) (Training Set: 204 PD and 92 controls; Locked Test Set: 51 PD and 23 controls), we assigned each patient a module-contribution profile. Module dominance was defined as >30% of total score. Results ORIGIN-PD discriminated PD from controls with high accuracy (Locked Test Set AUC 0.944, sensitivity 0.843, specificity 0.913). Among 255 sporadic PD patients, 49.4% exhibited a dominant module-contribution pattern, most frequently mDA neuron identity/development (22.0%), followed by pathway-related (11.8%), microglia/glial (7.5%), and inflammation/immunity (3.5%). Among the 50.6% with multi-module contributions, mDA neuron identity/development ranked in the top three in 62.8% of patients versus 35.7% for inflammation/immunity, indicating broader involvement of mDA neuron identity genes than inflammatory genes. The model showed high specificity against Alzheimer disease, ALS, and inflammatory controls. Conclusions ORIGIN-PD enables rational enrichment for NLRP3/NF-{kappa}B inhibitor trials by identifying patients with inflammatory involvement. In addition, the predominant contribution of the mDA neuron identity/development module, centred on WNT1, MSX1, NPM1, and LMX1B, identifies a larger patient subgroup with altered expression of mDA neuron identity module genes, suggesting that ORIGIN-PD may also be useful for patient enrichment in future trials of Wnt/{beta}-catenin pathway agonists. This dual-purpose framework provides a transparent, interpretable basis for pathogenic subtyping and precision enrichment in sporadic PD, with the aim of guiding disease-modifying therapy.

Background: Wearable sensing and machine learning can support objective assessment of Parkinson's disease (PD), but performance depends on sensor placement, modality, and analysis, and studies often target selected motor tasks, whereas clinical assessment integrates multiple standardized movements. How discriminative information is distributed across tasks and modalities remains unclear, limiting comparability and translation. Objectives: To quantify standardized Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III) tasks across complementary modalities, determine task- and modality-specific contributions to discrimination, and identify complementary, stable candidate digital biomarkers. Methods: Thirty-one participants with PD (Hoehn and Yahr stages I-III) and 30 age- and sex-matched healthy controls performed seven MDS-UPDRS III tasks (items 3.4-3.8, 3.10, 3.15). Unilateral surface electromyography from task-specific muscles and full-body inertial motion capture were acquired, which drove subject-specific musculoskeletal simulations. A leakage-free classification pipeline (in-fold feature selection, repeated cross-validation, permutation testing) was applied by task and modality, followed by sparse task fusion and stability-based biomarker selection. Results: Discrimination was concentrated in four upper-limb tasks, with pronation-supination (3.6) performing best (ROC-AUC 0.94; balanced accuracy 0.92). Multitask multimodal fusion maintained discrimination (ROC-AUC 0.93; balanced accuracy 0.92; sensitivity 0.87; specificity 0.97), retaining finger tapping (3.4), hand movements (3.5), pronation-supination (3.6), and postural tremor (3.15). Eighteen stable candidate biomarkers captured complementary alterations in movement execution, muscle activation, coordination, tremor, and proximal stabilization. Conclusions: In this cohort, discriminative information converged on a four-task upper-limb assessment and a physiologically interpretable multimodal biomarker profile. These findings support shorter, clinically anchored digital motor assessment, pending independent clinical validation.

Background: Parkinson's disease is a progressive neurodegenerative condition, often associated with motor complications, neuropsychiatric symptoms, and increased care costs in advanced stages. Neuromodulation, especially deep brain stimulation, represents a therapeutic alternative for selected patients. Objective: To characterize the clinical, epidemiological, therapeutic, and economic profile of patients with Parkinson's disease followed at a tertiary center and to estimate the proportion of individuals eligible for neuromodulation. Methods: A cross-sectional descriptive study included 4,060 patients with idiopathic Parkinson disease followed from January 2022 to December 2025. Demographic data, clinical characteristics, functional scales, therapeutic regimen, eligibility criteria for neuromodulation, and cost-effectiveness estimates were analyzed. Comparisons with data from the literature were performed using appropriate statistical tests, considering a significance of p<0.05. Results: The sample was predominantly male, with a median age of 69 years, and a median time of evolution of 8 years. Motor complications occurred in 58.4% of the patients, a frequency higher than that described in general populations. In all, 893 patients were considered eligible for neuromodulation, corresponding to 22.0% of the sample. The economic analysis estimated a reduction in annual costs after neuromodulation, with an average saving of R$ 8,247 per patient/year and an incremental cost-effectiveness ratio of R$ 46,505 per QALY. Conclusion: The study population presented a clinical profile compatible with advanced Parkinson's disease, a high frequency of motor complications and a significant proportion of patients potentially eligible for neuromodulation. The data suggest a possible clinical and economic benefit of the structured incorporation of this therapeutic strategy.

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

Parkinsons disease (PD) exhibits considerable variability in symptom onset, severity, and clinical trajectories, making prediction of individual disease progression a complex challenge. Leveraging large multimodal datasets from two independent cohorts of early PD patients, we examined predictive features for progression to mild cognitive impairment (MCI) and postural instability (PI) using Explainable Boosting Machines (EBM) - an interpretable machine learning (ML) approach. We found comparable predictive performances of EBM models using a minimal clinico-demographic dataset compared to an extended multimodal dataset including volumetric brain imaging and fluid biomarkers. Baseline age and Montreal Cognitive Assessment total score were identified as most important predictive features for both MCI and PI using the minimal dataset, while additional motor, cognitive and imaging features were identified using the extended dataset. Our study highlights the potential of ML predictions of cognitive and motor endpoints of PD progression at the individual level bringing personalized clinical decision-making within reach.

Background: Huntington's disease (HD) is an inherited neurodegenerative disorder primarily associated with motor and psychiatric manifestations. No disease-modifying treatment currently exists, with vesicular monoamine transporter type-2 inhibitors (VMAT2i's) being the only FDA-approved therapy for motor features in HD. Previous studies evaluated the antichorea effects of VMAT2i's but did not address its effects on non-choreiform features. Objectives: This study aimed to characterize the effect of VMAT2i's on hyperkinetic, hypokinetic and total hypokinetic subscores of the UHDRS motor assessment in patients with motor-manifest HD from the Enroll-HD research platform. Methods: Data from 622 participants were analyzed. Linear mixed effects models were constructed to compare the rates of change of choreiform and non-choreiform motor scores before and after the initiation of a VMAT2i. We calculated and plotted the direction, magnitude and significance of VMAT2i administration on the rates of change of motor subscores. A similar analysis was performed investigating the effect of antipsychotic medications on motor subscales in HD. Results: VMAT2i's reversed progression of hyperkinesis but significantly increased the rates of change in the hypokinetic and total hypokinetic subscores. Antipsychotics also displayed efficacy in reversing progression of chorea but did not significantly influence progression of hypokinesis. Conclusions: The initiation of VMAT2i's was associated with an improvement in hyperkinesis but was associated with worsening of other motor features of HD. Hypokinesis increases progressively in HD and is correlated with functional impairment and global decline. Therefore, the use of VMAT2i's to treat motor features in HD should be a nuanced decision, considering its multipronged impact.

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

Gait impairments are a major contributor to disability in patients with Parkinson's disease despite dopaminergic and neuromodulation therapies. External cues (e.g., visual targets, rhythmic auditory sounds) are commonly used to improve gait quality and reduce freezing of gait (FOG), yet their effectiveness varies across patients and contexts. Improved understanding of the neural mechanisms of cueing benefits is essential to personalize rehabilitation strategies and improve outcomes. We use mobile electroencephalography (EEG) to test the hypothesis that cues improve gait through engagement of voluntary motor control mechanisms to compensate for impaired gait automaticity. In addition, we investigate whether this mechanism is related to cueing benefits or freezing status. Eighteen PD patients with a history of freezing (PD-F), 21 patients without freezing (PD-NF) and 19 age-matched healthy controls (HC) walked overground under three conditions: normal walking, synchronizing to auditory cues, and stepping over visual cues. Stride-locked beta band (13-30 Hz) power dynamics in sensorimotor cortex were used to measure cortical control of stepping. Spatiotemporal gait parameters improved with cues in all groups. However, PD-F had smaller cue-related gains in speed and stride length when compared with PD-NF for both cue types, and did not improve gait speed with visual cues. EEG revealed greater contralateral sensorimotor cortex swing-phase beta suppression in PD-F than PD-NF patients, with visual cues eliciting the most robust response. In contrast, beta suppression with cues was less pronounced in PD-NF and HC, despite greater behavioral gains. In addition, engagement of sensorimotor cortex during visual cueing was associated with divergent gait effects across PD subgroups: In PD-NF greater beta suppression was associated with less gait improvement, whereas in PD-F the opposite was observed. These findings suggest distinct sensorimotor control mechanisms for cue utilization in PD-F and PD-NF, and indicate that engagement of voluntary motor control circuits may underlie cueing benefits primarily in PD-F.

Eye behavior disruption is reported in Parkinson's disease (PD), but its correlation with disease severity has not been well examined. Here, in a nonhuman primate model of PD, we show that spontaneous eye behavior is impaired in parkinsonism and correlates with clinical rating scores and subthalamic beta oscillatory activity. These findings suggest that spontaneous eye behavior could serve as an objective, non-invasive biomarker of parkinsonian severity.

Digital health technology (DHT) enables to detect and quantify charateristics motor dysfunction in Parkinsons disease (PD). However, the understanding of the relationship between dopaminergic nigrostriatal denervation and quantitative composite digital motor scores (DMS) captured by DHT remains largely limited to date. In this hybrid PET-MRI study, we used simultaneously acquired PET with 11C-d-threo-methylphenidate (11C-dMP-PET) - a tracer of presynaptic dopamine transporters - and resting-state-fMRI (rs-fMRI) to investigate this relationship and to explore associated neural network correlates in PD. Seventeen PD patients and 39 healthy controls underwent 11C-dMP-PET and rs-fMRI. Quantitative composite DMS for arm swing, gait and balance were calculated using DHT-derived parameters. Voxel-based correlation analysis of 11C-dMP-PET binding potential (BPND) was performed for each DMS and resulting clusters were used for seed-based functional connectivity analyses. We found that DMS of arm swing, gait and balance exhibit differential striatal representations associated with dopaminergic denervation as assessed by 11C-dMP-PET. Specifically, lower BPND correlated with more pathologic arm swing DMS in the central putamen and higher balance DMS in the right caudate, whereas the most robust correlation was observed for lower BPND with more pathologic gait DMS in the right caudate and anteromedial putamen. Seed-based functional connectivity analysis revealed lower functional connectivity in a frontostriatal network encompassing the basal ganglia and medial frontal regions associated to pathological gait DMS in PD. Taken together, our study demonstrates striatal representations of key domains of PD motor dysfunction captured by DHT. Highlighting the complex interplay of gait motor control, we show that gait dysfunction is associated with dopaminergic denervation in the anteromedial executive subregion of the striatum and frontostriatal connectivity changes in regions involved in planning and initiation of movement sequences. Therefore, our study provides first preliminary insights into the relationship of dopaminergic degeneration and DMS encouraging further investigation in larger cohorts and longitudinal studies to construct and validate digital motor biomarkers obtained from DHT as outcome measures in clinical trials in PD.

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

Healthy embryonic neurons grafted into the putamen of Parkinson's disease (PD) patients start to develop Lewy pathology 10 years after transplantation. It remains unclear whether this pathology is initiated by the spread of host-derived -synuclein (syn) aggregates which seed aggregation in the grafted cells or arises independently from a hostile PD environment (e.g., chronic inflammation). To distinguish these possibilities, we identified syn seeding sites in the human brain using a multiplex in situ seed immunodetection (isSID) assay. In PD and dementia with Lewy bodies (DLB), isSID labeled a subset of Lewy pathology (LP) as puncta along neurites and within inclusions. In multiple system atrophy (MSA), isSID labeled Papp-Lantos bodies and microglia. In progressive supranuclear palsy (PSP), isSID labeled tufted astrocytes. isSID labeled neuromelanin in the substantia nigra independent of diagnosis. In 16- and 27-year intraputamenal neuronal grafts, isSID labeled within and proximal to Lewy pathology, as well as outside the grafted tissue. Younger grafts (18 months and 4 years) lacked Lewy pathology. In the 18-month graft, isSID labeled grafted neurons; at 4 years, isSID was confined to amorphous deposits in the graft and was absent from tyrosine hydroxylase-positive grafted neurons. In conclusion, syn seeding is detectable in grafted neurons before and during LP formation. Because seeding accompanies melanization, but is not explained by melanization alone, these findings support host-derived seeds as a contributor to graft pathology.

Importance: Blood biomarkers for Alzheimer disease(AD), Parkinson disease(PD), and amyotrophic lateral sclerosis(ALS) are typically developed as disease-specific single-analyte tests. Whether one shared plasma panel can support disease-selective classification remains unclear. Objective: To test whether the Olink Target 48 Neurodegeneration plasma panel, analyzed with disease-specific Elastic Net models, can discriminate AD, PD, and ALS in a heterogeneous neurological cohort. Design, Setting, and Participants: Single-center diagnostic cohort study at Keio University Hospital, Tokyo, Japan. After quality control and one consent withdrawal, 302 participants were analyzed(healthy controls n = 62; AD continuum n = 93; PD n = 39; ALS n = 27; other neurological disorders n = 81) and allocated by diagnosis-stratified sampling into a discovery training set(n = 211) and a locked hold-out test set(n = 91). Exposures: Plasma normalized protein expression from 42 assays retained after protein quality control. Plasma DOPA decarboxylase was excluded a priori from all classifiers because blood levels primarily reflect dopaminergic treatment exposure. Main Outcomes and Measures: Hold-out receiver operating characteristic area under the curve(AUC). Sensitivity and specificity at a training-set Youden threshold locked for Test. Results: Hold-out AUCs were 0.974(95% CI, 0.942-0.995) for AD, 0.926(0.820-1.000) for PD, and 0.995(0.980-1.000) for ALS. At locked Youden cutoffs, sensitivity was 0.929 (95% CI, 0.765-0.991) and specificity was 0.921 (95% CI, 0.824-0.974) for AD, 0.833 (95% CI, 0.516-0.979) and 0.975 (95% CI, 0.912-0.997) for PD, and 1.000 (95% CI, 0.631-1.000) and 0.940 (95% CI, 0.865-0.980) for ALS. Conclusions and Relevance: A single plasma neurodegeneration panel supported disease-selective classification of AD, PD, and ALS in internal validation. Multicenter external validation is needed before clinical application.

Experimental models of Parkinson's disease (PD) traditionally involve direct perturbations of the functioning of dopamine (DA) neurons. However, PD is increasingly recognized as multifactorial in origin and involving both cell-autonomous vulnerability factors and non-cell-autonomous triggers including inflammatory signals deriving from bacterial or viral infections. Notably, genes associated with early-onset familial PD as PRKN (Parkin) and PINK1, are ubiquitously expressed and have been implicated in immune regulation, further supporting a role for inflammation in disease etiology. In the present study, we tested the hypothesis that alternate Polyinosinic:polycytidylic acid (Poly(I:C)), mimicking viral infection, and lipopolysaccharides (LPS), mimicking bacterial infection, may induce sufficient brain inflammation to impair the DA system in Parkin-deficient mice and recapitulate some of the systemic features of PD. We developed a protocol with alternating Poly(I:C) and LPS, inducing acute peripheral inflammation in both genotypes, with consistent body weight loss and an increase of fecal lipocalin-2. Modest levels of neuroinflammation were present six months after the treatment, with higher levels of the microglial marker Iba1 in the dorsal striatum and reduced levels of the astrocyte marker GFAP in the mesencephalon, potentially indicating reduced neuronal support in the longer term. Finally, we find that this alternating Poly(I:C)/LPS treatment does not induce dopaminergic denervation or motor dysfunctions, even in Parkin KO mice. Taken together, our findings suggest that repeated short-term exposure to pathogen-derived signals is insufficient to induce DA system impairment in young adult Parkin deficient mice. Instead, induction of PD-like pathology may require a convergence of factors, including a prolonged or recurrent inflammatory burden, aging, genetic susceptibility, and potentially additional environmental or cellular stressors, that together create a pathogenic "perfect storm". Thus, in its current form, the paradigm developed in the present study should not be regarded as a fully representative model of PD. Rather, it provides proof of concept that temporally alternating inflammatory stimuli can shape non-motor symptom-like phenotypes and underscores the need for future animal model research to incorporate interacting risk factors, disease duration, and age-dependent vulnerability.