CSF NPTX2 reflects α-synuclein pathology and predicts disease progression in Parkinson’s disease

CSF NPTX2 reflects α-synuclein pathology and predicts disease progression in Parkinson’s disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article CSF NPTX2 reflects α-synuclein pathology and predicts disease progression in Parkinson’s disease Ziyi Chen, Dan Song, Yu Ai, Mingzhu Yin, Yang Li, Xiaohan Zhou, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8386534/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by α-synuclein aggregation and dopaminergic neuronal loss. Neuronal pentraxin II (NPTX2), a synaptic plasticity-related protein implicated in several neurodegenerative diseases, has remained largely unexplored in PD. Here, we investigated whether CSF NPTX2 reflects α-synuclein pathology and predicts disease progression in PD. 528 PD patients and 178 healthy controls were recruited from the Parkinson’s Progression Markers Initiative cohort, with follow-up data spanning up to 14 years. We assessed cross-sectional or longitudinal associations between baseline CSF NPTX2 and a range of measures, including α-synuclein seed amplification assay kinetics parameters, dopamine transporter uptake, brain structure, motor and cognitive function, using multivariate linear regression and linear mixed model. Cox regression assessed risks of disease progression. The main results were validated in an external cohort from Fox Investigation for New Discovery of Biomarkers in Parkinson’s Disease. Compared with healthy controls, CSF NPTX2 levels were significantly reduced in PD patients ( P < 0.001), with consistent findings observed in external cohort. Higher baseline CSF NPTX2 levels were associated with delayed α-synuclein seed amplification assay kinetics, including longer time to threshold (β = 4.09, P = 0.017) and longer time to 50% maximal fluorescence (β = 3.72, P = 0.019), as well as higher dopamine transporter activity across all striatal subregions (all P < 0.01). Over a 14-year period, higher baseline NPTX2 was associated with a reduced risk of disease progression in Cox regression, including advanced motor disability (Hoehn-Yahr stage ≥ 4; HR = 0.334, P = 0.001) and dementia conversion (HR = 0.592, P = 0.009), and also predicted slower longitudinal worsening of UPDRS III and MoCA scores in linear mixed-effects models. Mediation analysis indicated that putamen volume and DAT activity jointly mediated the relationship between NPTX2 and UPDRS III scores. Together, these findings identify CSF NPTX2 as a biomarker that reflects α-synuclein pathology, dopaminergic neurodegeneration, and predicts disease progression in PD, highlighting its potential as a predictive and therapeutic target. Parkinson’s disease Neuronal pentraxin II α-synuclein pathology seed amplification assay biomarker dementia Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Parkinson’s disease (PD) is a progressive neurodegenerative disorder defined by the abnormal aggregation of α-synuclein (α-syn) and the selective loss of dopaminergic neurons in the substantia nigra1.[ 1 – 3 ] These pathological hallmarks underlie the cardinal clinical symptoms of PD, yet the mechanisms that govern the marked heterogeneity in disease progression remain poorly understood.[ 4 , 5 ] Disease trajectories vary widely among individuals, ranging from indolent to rapidly disabling forms, posing major challenges for prognosis and for the development of disease-modifying therapies. Accordingly, there is an urgent need for biomarkers that not only reflect core pathology but also capture the biological determinants of progression. Neuronal pentraxin II (NPTX2), a synaptic protein crucial for excitatory synapse homeostasis and plasticity, has been implicated in multiple neurodegenerative disorders.[ 6 , 7 ] Dysregulation of NPTX2 has been implicated in synaptic loss, cognitive decline, and TDP-43 pathology in Alzheimer’s disease (AD),[ 8 – 10 ] frontotemporal dementia (FTLD),[ 11 , 12 ] and dementia with Lewy bodies (DLB).[ 13 , 14 ] Intriguingly, its expression in PD presents a paradox: while NPTX2 is upregulated within the substantia nigra, suggesting a compensatory or pathological response, its levels are markedly reduced in the cerebrospinal fluid (CSF).[ 15 – 17 ] This tissue-fluid discrepancy points to a complex and uncharacterized biological mechanism linking NPTX2 to synaptic integrity and α-syn pathology. However, whether CSF NPTX2 reflects α-syn pathology, dopaminergic degeneration, and clinical progression in PD remains unknown. Based on this, we hypothesized that NPTX2 may reflect α-synuclein pathology, dopaminergic neurodegeneration, and predict the disease progression of PD. To validate this hypothesis, we utilized a large prospective cohort from the Parkinson’s Progression Markers Initiative cohort (PPMI). By integrating clinical assessments, neuroimaging, CSF biomarkers, and α-syn seed amplification assay (SAA) kinetic parameters, we systematically investigated CSF NPTX2 as a reflector of PD pathology and a predictor of its progression. Concurrently, parallel analyses of NPTX1 and NPTXR were performed, confirming the unique role of NPTX2. In addition, primary findings were validated in an independent external Fox Investigation for New Discovery of Biomarkers in Parkinson’s Disease (BioFIND) cohort. Our findings establish CSF NPTX2 as a biomarker that reflects α-synuclein pathology, dopaminergic neurodegeneration, and predicts disease progression in PD, highlighting its potential as a predictive and therapeutic target. Materials and methods Study participants Research data were downloaded from the Parkinson's Progression Markers Initiative (PPMI) repository.[ 18 ] ( http://www.ppmi-info.org ) The PPMI is a continuing, prospective, longitudinal, observational, and multinational multi-center research program designed to detect biomarkers for PD.[ 18 ] The PPMI investigation was sanctioned by the ethics review board of all collaborating establishments; furthermore, all subjects provided their signature on a written informed consent document prior to enrollment. PD subjects were recruited based on the inclusion criteria: individuals must be 30 years or older at diagnosis; have bradykinesia combined with resting tremor, rigidity, or only asymmetric resting tremor or bradykinesia; Hoehn-Yahr stage ≤ 2; and be free of dementia at baseline (MoCA ≥ 22). To prevent misdiagnosis, the researchers reviewed the diagnosis longitudinally. Patients diagnosed with conditions other than primary PD were excluded from the follow-up. In addition, our investigation mandated that all subjects possess baseline CSF neuronal pentraxins (NPTXs) data. NPTXs consist of NPTX1, NPTX2 and their receptor NPTXR. All enrolled participants were evaluated periodically to acquire clinical information and partake in CSF biomarker investigations. (Supplementary Table 1) shows the clinical and biomarker information of recruited PD patients during follow-up. Longitudinal follow-up included five yearly assessments of CSF biomarker, fourteen yearly clinical evaluations and five yearly of DAT-SPECT assessments subsequent to the initial lumbar puncture. Healthy controls (HCs) were individuals without neurologic disorders, signs, or symptoms and not undergoing treatment with specified medications such as dopamine receptor antagonists. Clinical assessment measures Motor function was assessed at baseline and then yearly with Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), with subscores divided into tremor (the sum of items 3.15 to 3.18), bradykinesia (the sum of items 3.4 to 3.8 and 3.14), rigidity (the sum of item 3.3)and postural imbalance and gait difficulty (PIGD) scores (the sum of items 3.10 to 3.12).Motor assessments were made in the “off” (non-drug use) state. The motor subtype classification of PD patients was evaluated according to Stebbins et al .[ 19 ] Briefly, the ratio of the mean MDS-UPDRS tremor scores (11 items) to the mean MDS-UPDRS PIGD scores (5 items) was calculated for each patient. If the ratio was ≤ 0.90, patients were classified as a PIGD subtype, if the ratio was ≥ 1.15 as a TD subtype, and if the ratio was between 0.90 and 1.15 as an indeterminate subtype. Motor subtypes were evaluated repeatedly at the follow-up time points. Converters were grouped during follow-up according to TD/PIGD groupings at baseline. The study employed several cognitive assessment scales, including the Montreal Cognitive Assessment (MoCA) for global cognitive function, the Hopkins Verbal Learning Test (HVLT) for episodic memory, the Benton Judgment of Line Orientation (JoLO) for visuospatial abilities, the Letter Number Sequencing (LNS) for executive function/working memory, the Semantic Fluency Test (SFT) for language, and the Symbol Digit Modalities Test (SDMT) for processing speed/attention. The cognitive status of participants was classified according to the criteria used in previous studies.[ 20 ] Participants were categorized as having normal cognition (NC, MoCA > 26), mild cognitive impairment (MCI, 22 ≤ MoCA ≤ 26), or dementia (MoCA < 22). The disease progression of Parkinson's disease patients was evaluated using six clinically relevant domain milestones ("walking and balance"; "motor complications"; "cognition"; "autonomic dysfunction"; "functional dependence"; "activities of daily living") to reflect meaningful disability.[ 21 ] Milestones were intended to be severe enough to reflect meaningful disability. Measurement of CSF biomarkers The collection and processing of CSF biomarker were conducted in accordance with the PPMI biologics manual. Neuronal pentraxins (NPTX1, NPTX2, and NPTXR) data from cerebrospinal fluid of Parkinson Disease patients and healthy volunteers are measured using the SOMAscan platform. The data is controlled for quality to remove outlier samples, calibrators, buffer and non-human SOMAmers. The measured values are hybridization normalized, plate scaled, median normalized intra plate and calibrated at SomaLogic’s side, then log2 transformed, median normalized inter plates and batch corrected at plate level. CSF amyloid-β 42 (Aβ1–42), total tau (T-tau) and phosphorylated tau (P-tau) concentrations were quantified through an Elecsys® electrochemiluminescence immunoassay (ECLIA) using a completely automated cobas e 601 analyzer (Roche Diagnostics, Basel, Switzerland).[ 22 ] CSF α-synuclein(α-syn) concentration, neurofilament light (NFL), glial fibrillary acidic protein (GFAP), chitinase-3-like protein 1 (YKL-40), S100 protein(S100), soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and Interleukin-6 (IL-6) were quantified using Roche NeuroToolKit.[ 23 ] α-synuclein oligomers in CSF were detected by using seed amplification assay (SAA) (Amprion: project number 155). The time to threshold (TTT [hours]), the time to reach 50% of the maximum fluorescence (T50 [hours]), the maximum fluorescence (Fmax [RFU]), the slope [RFU/s], and the area under the curve (AUC, [%*s]) are kinetic parameters of SAA that correlate with the α-syn seed concentration. Genotyping Genomic DNA was extracted from the whole blood of PD subjects for processing and analysis. Apolipoprotein E (APOE) genotypes were detected by allele-specific oligonucleotide probes labeled with a fluorogenic reporter (TaqMan method).[ 23 ] Besides, individuals were also divided into two groups according to the ε4 allele, namely, APOE ε4 carriers (APOE ε4+) and non-APOE ε4 carriers (APOE ε4-). DAT imaging outcomes DAT single-photon emission CT was performed to measure the DAT density at baseline and the 1-year, 2-year and 4-year follow-up visits for patients with PD and at baseline only for controls according to the PPMI imaging technical operations manual.[ 24 ] In this study, we used the mean caudate DAT binding ratio (average of the ipsilateral and contralateral caudate binding ratios), mean putamen DAT binding ratio (average of the ipsilateral and contralateral putamen binding ratios) and mean striatum DAT binding ratio (average of the ipsilateral and contralateral striatum binding ratios). Association with brain structures T1weighted images underwent processing with Freesurfer software (FreeSurfer-v7.3.2).[ 25 , 26 ] This study utilized imaging-derived phenotypes (IDPs) consisting of the cortical surface area (SA) and cortical thickness (CTh) of 35 cortical regions (average of the bilateral cortical thickness and the cortical surface are) and the volume of 26 subcortical regions (average of the subcortical regions) defined by the Desikan-Killiany (DK) and ASEG atlases. BioFIND External Validation Cohort The Fox Investigation for New Discovery of Biomarkers in Parkinson’s Disease (BioFIND) ( http://biofind.loni.usc.edu ) is an observational, multi-center, cross-sectional study of moderate-to-advanced PD participants evaluated with standardized clinical and biospecimen acquisition protocols5. Enrolled PD participants met the United Kingdom PD Society Brain Bank (UKPDBB) clinical diagnostic criteria, modified to require all three classic motor signs of PD (tremor, bradykinesia, and rigidity) instead of just two signs. The duration of the disease in the enrolled subjects was 5–18 years since the onset of motor symptoms, and those who had undergone deep brain stimulation or ablative surgeries for PD were excluded. BioFIND inclusion was limited to 50–75 years of age at the onset of the disease (age 55 to 93 at the time of enrollment). The institutional review board of BioFIND approved the study protocol. Written informed consent was obtained from each study participant. This study utilised baseline assessment data from the BioFIND cohort, conducted during the “on” state following regular medication to reflect typical functional status under routine stable treatment. Ultimately, 109 Parkinson's disease patients and 84 healthy controls were included in the analysis. External snRNA-seq transcriptional validation To complement our CSF protein findings with transcriptional-level evidence, we incorporated data from a recently published single-nucleus RNA sequencing (snRNA-seq) study of substantia nigra dopaminergic (DA) neurons in PD. In that study, midbrain DA neuron nuclei were enriched using a fluorescence-activated nuclei sorting (FANS) protocol prior to snRNA-seq. The dataset comprised 22,048 DA neurons obtained from age- and postmortem-interval-matched participants, including 8 controls, 7 individuals with PD, and 3 with dementia with Lewy bodies (LBD). From the differential expression results reported across ten DA neuron subtypes, we extracted statistics related to NPTX2 for use in our analysis. Differential expression was performed using the MAST framework (linear mixed-effects model, two-sided test), providing model coefficients (Coef), confidence intervals (ci.hi / ci.lo), raw P values (Pr[> Chisq]), and Benjamini-Hochberg-adjusted false discovery rates (FDR). No further processing of the original single-cell dataset was undertaken. The publicly reported differential expression results were used directly as independent transcriptional evidence supporting our analyses. Statistical analysis Before analysis, all CSF protein levels were log2-transformed and then standardized to Z-scores based on the mean and standard deviation of the healthy control cohort. We divided PD patients into two groups as follows: The first quartile of NPTX2 values was defined as the low-level NPTX2 group, and the 2nd, 3rd, and 4th quartiles of NPTX2 were defined as the high-level NPTX2 group. Chi-square tests were used for qualitative variables, whilst continuous variables meeting the assumption of normality were analysed using Student's t-test. Multivariate linear regression models were used to assess the baseline correlation of NPTX2 with characteristics of PD, SAA kinetic parameters, CSF biomarkers, DAT binding ratio and brain structure. For the analysis of brain structural metrics, we additionally performed false discovery rate (FDR) correction. To investigate the longitudinal associations between NPTX2 levels and clinical outcomes, linear mixed models (LMMs) were applied, incorporating interactions between NPTX2 levels and time. For time-to-event outcomes, including motor progression and incident dementia, progression milestones and motor subtype conversion, Cox proportional hazards models were constructed with covariate adjustments. We evaluated models with continuous and binary variables. In addition, we employed restricted cubic splines (RCS) to fit Cox regression and linear regression models respectively, in order to explore potential non-linear relationships between NPTX2 and outcome variables. To further elucidate the functional pathways of NPTX2, we conducted three mediation analyses: CSF sTREM2 and YKL-40 between NPTX2 and T-tau/P-tau; the role of DAT activity between NPTX2 and MDS-UPDRS III scores; and brain structure between NPTX2 and MDS-UPDRS III scores. Finally, subgroup analyses were conducted by stratifying participants according to age, sex, APOE ε4 carrier status, Hoehn-Yahr stage and MoCA stage. The statistical analyses in this study were conducted via SPSS 25.0 and R software version 4.5.0. Unless otherwise specified, all regression analyses, LMMs and Cox proportional hazards models were adjusted for the following covariates: age, sex, apolipoprotein E ε4 status, LEDD, baseline Hoehn-Yahr stage and disease duration. Additionally, for cognitive aspects, models were further adjusted for baseline MoCA scores and education. When analysing brain structure, the model further adjusted for signal-to-noise ratio; for cortical surface area and subcortical volume, the model additionally adjusted for intracranial volume. Results with P < 0.05 were considered statistically significant. Results Study participants The PPMI cohort included 528 patients with Parkinson's disease (PD) and 178 healthy controls (HC). The average age at baseline for the PD cohort was 61.91 ± 9.60 years, with 63.26% being male. The mean disease duration was 2.60 ± 2.48 years, and the mean years of education were 15.54 ± 3.18 years. No significant differences were observed between groups in age, gender, education, or APOE ε4 carrier frequency (Table 1 ). Table 1 Baseline characters of PD patients and controls in PPMI cohort. Variables Healthy Control (n = 178) Patients with PD (n = 528) P- value Baseline NPTX2 level P- value Low (n = 132) High(n = 396) Demographics Age (y) 60.68 ± 11.56 61.91 ± 9.60 0.511 63.73 ± 8.78 60.89 ± 9.76 0.006 * Gender (F/M) 67/111 194/334 0.83 28/104 166/230 < 0.001 * Education (y) 15.99 ± 2.72 15.54 ± 3.18 0.235 15.63 ± 3.13 15.51 ± 3.20 0.528 Duration (y) / 2.60 ± 2.48 / 2.35 ± 1.87 2.69 ± 2.66 0.459 APOE ɛ4 (%) 25.28% 24.24% 0.781 31.81% 21.71% 0.019 * Motor assessments Hoehn-Yahr stage (1/2) / 210/318 / 48/84 162/234 0.355 UPDRS III 1.15 ± 2.14 21.27 ± 9.44 < 0.001 * 23.18 ± 9.86 20.63 ± 9.22 0.009 * Cognitive assessments MCI (%) / 34.09% / 44.70% 30.56% 0.003 * MoCA 28.20 ± 1.12 27.15 ± 2.07 < 0.001 * 26.70 ± 2.10 27.29 ± 2.05 0.003 * CSF NPTXs NPTX1(log2 RFU) 15.47 ± 0.37 15.43 ± 0.33 0.155 15.10 ± 0.33 15.55 ± 0.24 < 0.001 * NPTX2(log2 RFU) 11.88 ± 0.54 11.66 ± 0.51 < 0.001 * 11.00 ± 0.31 11.89 ± 0.34 < 0.001 * NPTXR (log2 RFU) 15.84 ± 0.32 15.84 ± 0.23 0.268 15.63 ± 0.25 15.92 ± 0.17 < 0.001 * α-synuclein Seed Amplification Assay TTT (hours) 81.58 ± 25.95 67.38 ± 13.76 0.006 * 65.04 ± 14.31 68.18 ± 13.50 0.003 * T50% (hours) 83.81 ± 26.86 72.66 ± 12.74 0.061 70.44 ± 13.61 73.43 ± 12.37 0.002 * DAT binding ratio Caudate 3.00 ± 0.63 1.95 ± 0.56 < 0.001 * 1.82 ± 0.55 2.00 ± 0.56 0.004 * Putamen 2.17 ± 0.55 0.81 ± 0.30 < 0.001 * 0.75 ± 0.26 0.83 ± 0.31 0.004 * Striatum 2.58 ± 0.57 1.38 ± 0.41 < 0.001 * 1.28 ± 0.38 1.42 ± 0.41 0.003 * Categorical variables are reported as numbers or percentages; continuous variables are reported as means ± standard deviations. Student's t-test was used for continuous variables and chi-square test was used for categorical variables. PD, Parkinson's Disease; DAT, dopamine transporter; Low, Low NPTX2 level (Q1); High, High NPTX2 level(Q2-Q4); APOE ɛ4, APOE ɛ4 carriers; MCI, mild cognitive impairment; UPDRS III, Movement Disorder Society Unified Parkinson's Disease Rating Scale III score; MoCA, the Montreal Cognitive Assessment; NPTX1, Neuronal pentraxin I; NPTX2, Neuronal pentraxin 2; NPTXR, Neuronal pentraxin Receptor; T50%, the time to 50% max fluorescence of α-synuclein SAA; TTT, the time to threshold of α-synuclein SAA; SAA, Seed Amplification Assay. * P < 0.05. In PD patients, CSF NPTX2 levels decline with increasing age, consistent across both continuous variables (β = -1.126, P = 0.011) and binary variables ( P = 0.004). Furthermore, NPTX2 levels were significantly reduced in males ( P < 0.001), APOE ε4 carriers ( P = 0.030), and patients with mild cognitive impairment (MCI) ( P = 0.044). However, NPTX2 showed no significant correlation with Hoehn-Yahr stage (Fig. 1 a, b, Supplementary Table 3). NPTX1 and NPTXR also exhibited age-related decline and lower levels in male patients, similarly independent of Hoehn-Yahr stage. Unlike NPTX2, however, no significant differences in NPTX1 or NPTXR were observed among APOE ε4 carriers; NPTX1 was significantly reduced in MCI patients ( P = 0.04) (Supplementary Table 3). This suggests potential functional specificity within the neuronal pentraxin protein family in PD. To further investigate the clinical significance of cerebrospinal fluid NPTX2, the first quartile of CSF NPTX2 in PD patients was designated as the low NPTX2 group, while the second, third, and fourth quartiles constituted the high NPTX2 group. Concurrently, the high NPTX2 group exhibited lower UPDRS-III scores ( P = 0.009) and rigidity scores ( P = 0.004), higher MoCA scores ( P = 0.003), and superior processing speed (SDMT) ( P = 0.001) and episodic memory (HVLT) (HVLT Total Recall, P = 0.004; HVLT Delayed Recall, P = 0.004; HVLT Recognition Discrimination, P = 0.001) (Fig. 1 c, d, Table 1 , Supplementary Tables 2, 4). Moreover, validation within the BioFIND cohort further demonstrated that CSF NPTX2 levels were negatively correlated with PIGD scores (β = -1.39, P = 0.049), whilst positively correlated with MoCA scores (β = 2.32, P = 0.015) (Supplementary Table 25). The relationship between CSF NPTX2 and α-synuclein pathology Compared with HCs, CSF NPTX2 levels were significantly reduced in PD patients ( P < 0.001) (Fig. 2 a, Table 1 ), a finding that was independently replicated in the BioFIND cohort ( P = 0.010) (Fig. 2 f, Supplementary Table 24). In contrast, no significant differences were observed for NPTX1 or NPTXR. This profile is distinct from the widespread reduction of Neuronal pentraxins (NPTXs) documented in AD, MSA, PSP, and FTD,[ 6 , 11 , 15 ] suggesting NPTX2 may possess unique characteristics in PD. Previous studies of the substantia nigra transcriptome, however, indicated significantly elevated NPTX2 expression levels in PD, which contradicts the findings of reduced protein levels in cerebrospinal fluid observed in this study. To further validate this phenomenon, we consulted recently published single-cell transcriptome data from the substantia nigra in PD. This revealed significantly upregulated NPTX2 expression across three dopaminergic neuronal subpopulations in PD patients (CALB1_CALCR, β = 0.414, P < 0.001; CALB1_GEM, β = 1.860, P < 0.001; CALB1_RBP4, β = 1.288, P < 0.001) (Supplementary Fig. 1, Supplementary Table 5). Notably, previous studies have demonstrated that NPTX2 colocalises with α-synuclein aggregates within Lewy bodies in PD substantia nigra.[ 17 ] In post-mortem brain tissue from ALS and FTD patients, NPTX2 misaccumulated has also been observed within neurons harbouring abnormal TDP-43.[ 12 ] Based on this, we propose a potential explanation (Fig. 2 b): under pathological stress, neurons may transkripionally upregulate NPTX2 to maintain synaptic function. However, due to α-synuclein aggregation and impaired secretion/clearance pathways, newly synthesised NPTX2 is sequestered into insoluble complexes or undergoes abnormal processing. This reduces the pool of soluble protein available for release into cerebrospinal fluid. Thus, the decline in CSF NPTX2 may reflect impairment of the available synaptic protein pool and neuronal integrity, rather than reduced transcription levels. This hypothesis requires further validation through tissue-CSF paired analysis, soluble/insoluble fractionation, and mass spectrometry identification in the same cases. Consistent with previous reports,[ 27 , 28 ] we observed reduced CSF total α-syn levels in individuals with PD( P < 0.001)(Supplementary Table 2), suggesting increased aggregated α-syn in the brain. CSF NPTX2 levels in PD patients showed a significant positive correlation with total α-synuclein levels (β = 1.133, P < 0.001). Based on the α-syn SAA, higher NPTX2 levels were significantly correlated with both the time to threshold (TTT [hours]) (β = 4.088, P = 0.017) and the time to reach 50% of the maximum fluorescence (T50 [hours]) (β = 3.716, P = 0.019) (Fig. 2 c, d, Supplementary Fig. 2, Supplementary Tables 6–7). These findings indicate a significant negative correlation between CSF NPTX2 levels and synaptic protein pathological burden, supporting our prior hypothesis that reduced NPTX2 reflects impaired synaptic function and abnormal pathological protein accumulation. Therefore, NPTX2 holds promise as a potential therapeutic target in PD. The relationship between CSF NPTX2 and the dopaminergic degeneration We further investigated the relationship between NPTX2 and dopaminergic neuronal damage. Cross-sectional analysis revealed that baseline CSF NPTX2 levels were independently and positively correlated with DAT binding in the caudate(β = 0.152, P = 0.008), putamen(β = 0.087, P = 0.005), and striatum(β = 0.119, P = 0.004) (Fig. 2 c, d, Supplementary Table 6), yet showed no significant association with the longitudinal rate of decline in DAT binding ratio(Supplementary Fig. 3, Supplementary Table 8). This suggests NPTX2 exerts its influence on dopamine function more prominently in the early disease stages, potentially serving as a core biomarker of pathogenesis. Furthermore, mediation analysis demonstrated that reduced DAT binding ratio mediated the effect of CSF NPTX2 on PD severity (MDS-UPDRS III scores) (Proportion striatum = 11.63%; Proportion putamen = 20.59%; Proportion caudate = 11.77%) (Fig. 2 e, Supplementary Table 9). However, NPTX1 and NPTXR showed no or only weak correlations with PD dopaminergic function. we observed that NPTXR was positively correlated with DAT binding ratio in the caudate (β = 0.075, P = 0.036) and striatum (β = 0.052, P = 0.045), whereas NPTX1 showed no significant association with dopaminergic function (Supplementary Table 6). In contrast, within Alzheimer's disease, NPTXs demonstrate widespread associations with pathological burden and neuronal dysfunction.[ 29 ] These discrepancies further suggest that NPTX2 may possess a specific association with dopaminergic function in PD, rather than functioning solely as a pan-marker of synaptic dysfunction. Baseline CSF NPTX2 predicts longitudinal progression of Parkinson's disease Our findings establish baseline CSF NPTX2 as a significant predictor of motor progression in Parkinson's disease, with a preferential association with axial symptoms. Linear mixed models revealed that while the association with the longitudinal rate of change in UPDRS-III total scores was not statistically significant (β = -0.209, P = 0.084), analysis of specific motor sub-scores demonstrated distinct, symptom-specific relationships. Specifically, NPTX2 negatively correlated with longitudinal rate of increase in rigidity scores (β = -0.348, P = 0.006) and PIGD scores (β = -0.098, P < 0.001), but it showed a positive correlation with the longitudinal rate of increase in tremor scores, with no significant association observed for bradykinesia (Fig. 3 a, b, Supplementary Table 10). Critically, these differential motor associations demonstrated remarkable consistency across subgroups, including sporadic and genetic forms (LRRK2/GBA) of PD, as well as strata defined by age, sex, and APOE ε4 status (Supplementary Table 11). Furthermore, in time-to-event analyses, elevated NPTX2 was associated with a substantially lower risk of reaching the advanced motor disability stage (Hoehn-Yahr stage 4; HR = 0.334, P = 0.001) (Fig. 3 d-e, Supplementary Table 12). Restricted cubic spline analysis confirmed a nonlinear, L-shaped association between NPTX2 and motor progression risk (P nonlinear = 0.008) (Fig. 3 g, Supplementary Table 13). To further investigate the clinical relevance of these differential associations, we assessed motor subtype conversion. A higher baseline NPTX2 level was associated with a significantly reduced risk of conversion from TD or indeterminate to PIGD subtype (OR = 0.761, P = 0.018), corresponding to a 23.9% risk reduction per unit of NPTX2 (Supplementary Fig. 4, Supplementary Tables 14–15). Cox regression analysis similarly confirmed that elevated NPTX2 levels significantly reduced the risk of transitioning to the PIGD subtype (HR = 0.595, P = 0.006) (Supplementary Table 16). Consistent with previous AD research findings, this study identified that the interaction term between NPTX2 and time positively correlated with global cognitive function (MoCA) (β = 0.133, P < 0.001) and across cognitive domains (including visuospatial abilities (JoLO), executive functioning/working memory (LNS), language (SFT), and processing speed/attention (SDMT) (all P < 0.05) (Fig. 3 a-c, Supplementary Table 10). Subgroup analyses further confirmed that the longitudinal relationship between NPTX2 and cognition exhibits broad consistency, particularly evident in sporadic Parkinson's disease, PD patients carrying LRRK2/GBA genes, and those with MCI (Supplementary Table 11). Meanwhile, Cox analysis indicated that elevated baseline NPTX2 levels reduced the risk of dementia conversion (HR = 0.592, P = 0.009) (Fig. 3 d-h, Supplementary Tables 12–13). This indicates that NPTX2 may also serve as a potential biomarker for cognitive function in Parkinson's disease. To comprehensively evaluate the predictive value of NPTX2 for disease progression, we conducted survival analyses based on milestone events across six functional domains. Elevated baseline CSF NPTX2 levels significantly reduced the risk of progression in walking and balance (HR = 0.490, P < 0.001), functional dependency (HR = 0.692, P = 0.018), cognitive (HR = 0.599, P = 0.002), autonomic dysfunction (HR = 0.618, P < 0.007) and activities of daily living (HR = 0.44, P < 0.001) (Fig. 4 a-e, Supplementary Fig. 5, Supplementary Tables 12–13). These findings collectively indicate that baseline CSF NPTX2 may serve as a favorable biomarker reflecting the overall progression of PD. To further elucidate the role specificity of different members of the neuronal Pentraxin family in PD, we concurrently analysed the relationship between CSF NPTX1 and NPTXR levels and disease progression. Results indicate that while both are associated with Parkinson's disease symptoms, their scope and intensity of action are more limited compared to NPTX2(Supplementary Fig. 6, Supplementary Tables 10, 12). The Relationship Between NPTX2 and Brain Structure Linear regression analysis revealed significant associations between CSF NPTX2 levels and structural alterations in multiple PD-related brain regions. Specifically, elevated NPTX2 levels positively correlated with increased putamen volume (Continuous, β = 0.135, FDR- adjusted P = 0.049) and significantly negatively correlated with choroid plexus volume (Continuous, β = -0.275, FDR- adjusted P < 0.001) (Fig. 4 f, Supplementary Fig. 7, Supplementary Tables 17–19). Further mediation analysis indicated that reduced putamen volume and increased choroid plexus volume mediated the effect of CSF NPTX2 on PD severity-related MDS-UPDRS III scores (Proportion putamen = 9.11%; Proportion choroid plexus = 16.62%) (Fig. 4 g, Supplementary Table 20). These findings suggest that it may jointly influence the severity of motor symptoms in PD through dysfunction in both the basal ganglia motor circuitry and regional glymphatic dysfunction localized to the basal ganglia. Association between Baseline CSF NPTX2 and Cerebrospinal Fluid Biomarkers Cross-sectional analysis demonstrated that elevated baseline CSF NPTX2 levels were positively associated with core pathological proteins in Alzheimer's disease, including CSF Aβ₁-₄₂ (β = 1.125, P < 0.001), T-tau (β = 0.986, P < 0.001), and P-tau (β = 0.842, P < 0.001), as well as with neuroinflammatory markers, specifically the microglial marker sTREM2 (β = 0.381, P = 0.003) and the astrocyte marker YKL-40 (β = 0.504, P < 0.001) (Fig. 5 a, Supplementary Fig. 8, Supplementary Table 4). Notably, restricted cubic spline analyses revealed significant nonlinear relationships for T-tau (P nonlinear = 0.002), P-tau (P nonlinear < 0.001), and IL-6 (P nonlinear = 0.032). (Fig. 5 b, Supplementary Table 21). Mediation analysis indicated that neuroinflammatory pathways may mediate the association between NPTX2 and tau pathology, with sTREM2 and YKL-40 exerting significant mediating effects in the relationships between NPTX2 and both T-tau (Proportion sTREM2 = 9.59%, Proportion YKL-40 = 18.79%) and P-tau (Proportion sTREM2 = 13.98%, Proportion YKL-40 = 25.38%) (Supplementary Fig. 9 and Supplementary Table 22). These findings suggest CSF NPTX2 may act as an upstream regulator of tau-associated neurodegeneration via the microglia-astrocyte signaling pathway. Consistent with previous studies, longitudinal analyses, revealed that higher baseline NPTX2 levels were significantly associated with slower longitudinal increases in T-tau (β = -0.031, P = 0.016) and P-tau (β = -0.030, P = 0.011) (Fig. 5 c-f, Supplementary Table 23). This marked discrepancy between cross-sectional and longitudinal correlations may reflect compensatory upregulation of NPTX2 in response to initial tau phosphorylation, neurofibrillary tangle formation and/or tau release to maintain synaptic integrity and network excitability. In contrast, no significant associations were observed between NPTX2 and the longitudinal trajectories of other injury or inflammatory markers, including GFAP, YKL-40, S100, and sTREM2(Fig. 5 c-f, Supplementary Table 23). Discussion This study, based on the large-scale prospective PPMI cohort and the cross-sectional BioFIND cohort, systematically investigated the pathophysiological significance of cerebrospinal fluid NPTX2 in Parkinson's disease and its predictive value for disease progression. Our findings indicate that CSF NPTX2 is closely associated with α-synuclein pathology, dopaminergic neuronal function, and disease progression, suggesting its significant potential as a prognostic biomarker and potential therapeutic target for PD. Concurrently, the complementary use of the early-stage PPMI cohort and the moderate-to-advanced stage BioFIND cohort enhances the robustness of our findings across the disease spectrum. We observed a marked reduction in NPTX2 levels exclusively within the cerebrospinal fluid of PD patients, contrasting sharply with the decline in NPTXs proteins previously noted in Alzheimer's disease and other neurodegenerative disorders.[ 6 , 7 , 11 , 15 ] Moreover, compared to NPTX1 or NPTXR, NPTX2 exhibits a more extensive and pronounced association with α-synuclein pathology and dopaminergic function, suggesting it may play a distinct pathophysiological role in Parkinson's disease. Interestingly, despite reduced NPTX2 protein levels in CSF, scRNA-seq results from external validation revealed upregulation of NPTX2 mRNA expression in dopaminergic neurons of PD patient. This paradoxical phenomenon suggests that under pathological conditions in PD, neurons may respond to synaptic dysfunction by upregulating NPTX2 transcription. However, due to abnormal aggregation of α-synuclein or disruption of protein secretion/clearance pathways, newly synthesised NPTX2 becomes trapped within insoluble aggregates, consequently reducing soluble NPTX2 levels in cerebrospinal fluid. Extensive research has demonstrated that oligomers or fibrils of α-synuclein cause vesicular transport defects, thereby impairing neurotransmitter release at synapses.[ 30 – 32 ] As a secreted protein, NPTX2 must be synthesised within the neuronal cell body before being transported via vesicular transport to the synaptic terminal and secreted into the synaptic cleft.[ 30 ] Should α-synuclein pathology disrupt this transport pathway, newly synthesised NPTX2 cannot be normally transported out and secreted, leading to its abnormal accumulation within the neuron. Immunohistochemical evidence has also demonstrated colocalisation of NPTX2 with Lewy bodies.[ 17 ] However, the precise molecular mechanisms through which NPTX2 influences α-synuclein aggregation and dopaminergic neuron survival are still unclear, necessitating further mechanistic exploration in cellular and animal models to validate its potential as a therapeutic target. Notably, such pathological alterations in NPTX2 are not unique to PD. In the FTLD-ALS spectrum disorders, studies indicate that TDP-43 may bind to the 3' UTR of NPTX2 and potentially affect its mRNA stability or transport, leading to abnormal accumulation of NPTX2 protein within neurons.[ 12 ] Concurrently, NPTX2 levels decrease in the cerebrospinal fluid of symptomatic hereditary FTLD cases and correlate with clinical severity.[ 11 ] However, in AD, where the core pathology involves β-amyloid and tau lesions, both NPTX2 mRNA and protein expression are downregulated in human neuronal cells,[ 32 ] and CSF NPTX2 levels decrease with worsening cognitive impairment, potentially reflecting overall synaptic loss. The absence of NPTX2 and its receptor NPTXR causes major GluA4 loss,[ 31 ] increased network hyperactivity and increased complement-mediated microglial engulfment of synapses,[ 33 ] highlighting its critical role in maintaining synaptic integrity. This suggests that NPTX2 may exert distinct functions across different pathological states of neurodegenerative diseases. This study demonstrates that baseline CSF NPTX2 levels exhibit significant prognostic value in PD. Consistent with study by Nilsson et al .,[ 15 ] Cox regression analysis indicates that elevated NPTX2 levels correlate with a reduced risk of disease progression, encompassing worsening motor symptoms, dementia conversion, and multiple functional domains including walking and balance, cognition, autonomic function, and activities of daily living. Furthermore, longitudinal modelling further revealed that patients with higher NPTX2 levels exhibited slower rates of cognitive decline and progression of specific motor symptoms, such as rigidity and PIGD. Concurrently, our findings indicate that CSF NPTX2 levels correlate positively with putamen volumes and DAT binding ratio. This phenomenon suggests that NPTX2 may preferentially regulate PIGD and rigidity by influencing cortico-basal ganglia circuits, exerting lesser effects on resting tremor-primarily mediated by brainstem/thalamocortical circuits-and potentially generating complex effects via distinct neurotransmitter systems (e.g. cholinergic pathways). Notably, the mediation analysis provides tentative evidence for the pathway ‘NPTX2 → brain structure/function → clinical symptom’. Our fingdings suggest that reduced putamen volume and diminished dopamine DAT activity mediate the effect of low NPTX2 levels on more severe motor impairment (MDS-UPDRS III score). This implies that NPTX2 may indirectly preserve the structural and functional integrity of basal ganglia motor circuits by maintaining synaptic plasticity and neuronal viability, thereby ameliorating motor symptoms. However, further research is required to confirm this hypothesis. Secondly, although statistical models indicate significant mediating effects of choroid plexus volume, this association warrants cautious interpretation given the choroid plexus's role as a critical interface between the cerebrospinal fluid-blood-brain barrier system and neuroinflammation. Our findings indicate that CSF NPTX2 levels exhibit extensive positive correlations with multiple neurodegenerative markers (Aβ₁-₄₂, T-tau, P-tau) and neuroinflammatory proteins (YKL-40, sTREM2, IL-6) at baseline. This is consistent with the findings of Zhang et al .[ 29 ] and Massa et al .[ 34 ], who reported strong correlations between NPTX2 and Aβ₁-₄₂, T-tau, and P-tau in AD. Longitudinal analysis further demonstrates that elevated baseline NPTX2 levels correlate with a subsequent slower rate of tau protein (T-tau, P-tau) accumulation. Consistent with this, Massa et al . found that in the mild cognitive impairment (MCI) stage, patients who progressed to dementia within two years exhibited higher cerebrospinal fluid NPTX2 levels than stable at follow-up and slower progression.[ 34 ] This suggests a compensatory synaptic response may exist in the early disease phase, accompanied by NPTX2 upregulation. However, this compensatory mechanism may become exhausted as pathological burden increases, a finding supported by another mass spectrometry study. This research demonstrated that elevated baseline NPTX2 in preclinical AD patients correlates with increased P-tau and T-tau levels, followed by an accelerated decline in NPTX2 levels, potentially reflecting progressive neuronal and synaptic loss.[ 10 ] Based on these findings, we hypothesized that NPTX2 is deeply involved in the dynamic processes of neurodegenerative diseases. Inevitably, our research has some limitations. Firstly, as the PPMI cohort did not collect longitudinal CSF NPTX2 samples, we could only assess the association between baseline levels and disease progression, unable to characterise its dynamic trajectory throughout the disease course. Consequently, it is crucial to further determine the trajectory of NPTX2 in PD progression and its prospective clinical significance as a longitudinal monitoring tool. Secondly, CSF NPTX2 concentrations likely reflect global brain expression and soluble protein turnover rather than specific regional changes in the substantia nigra alone. Thus, the relationship between CSF NPTX2 levels and its precise localisation, aggregation state, and functional status within brain tissue remains unclear and requires validation through post-mortem studies combining biochemical fractionation and immunohistochemistry. Thirdly, interpretations regarding the disease-stage-specific role of NPTX2 should be made cautiously. While we incorporated data from a mid-to-late-stage cohort for validation, the limited sample size and, more critically, the fact that CSF and brain tissue data originated from separate groups of individuals mean that our observed associations are indirect. This biological and temporal disconnect between peripheral biomarker levels and central molecular pathology in the substantia nigra underscores the need for future validation in cohorts with matched disease stages and, ideally, paired biospecimens from the same subjects. Fourthly, the PPMI cohort, though large and well-characterized, consists predominantly of individuals of European ancestry, which may limit the generalizability of our findings to other populations. Concurrently, the BioFIND cohort serving as the validation set exhibits limited sample size and lacks a systematic longitudinal design, primarily demonstrating cross-sectional differences in NPTX2 expression. Its longitudinal predictive efficacy necessitates replication in larger, prospectively designed independent cohorts. Finally, the longitudinal cohort exhibited certain data gaps, particularly during subsequent follow-up periods, potentially exerting a nuanced influence on our findings. Conclusions In conclusion, this study establishes CSF NPTX2 as a key biomarker that reflects α-synuclein pathology, dopaminergic neurodegeneration, and predicts disease progression in PD. These findings provide novel theoretical foundations for developing NPTX2-based disease-modifying therapies. Abbreviations PD Parkinson's Disease NPTXs Neuronal pentraxins NPTX1 Neuronal pentraxin I NPTX2 Neuronal pentraxin II NPTXR Neuronal pentraxin Receptor Low Low NPTX2 level (Q1) High High NPTX2 level(Q2-Q4) UPDRS III score Movement Disorder Society Unified Parkinson's Disease Rating Scale III score PIGD postural imbalance and gait difficulty H-Y stage Hoehn-Yahr stage MCI mild cognitive impairment MoCA Montreal Cognitive Assessment JoLO the Benton Judgment of Line Orientation LNS the Letter Number Sequencing SFT the Semantic Fluency Test SDMT Symbol Digit Modalities Test HVLT the Hopkins Verbal Learning Test TotRec HVLT Total Recall DelRec HVLT Delayed Recall Retent HVLT Retention RecDisc HVLT Recognition Discrimination Aβ 1-42 Amyloid-beta (1-42) T-tau total tau P-tau tau phosphorylated at the threonine181 position (p-tau181) GFAP Glial fibrillary acid protein YKL-40 Chitinase-3-like Protein 1 sTREM2 Soluble triggering receptor expressed on myeloid cells 2 S100 S100 calcium binding protein B IL-6 Interleukin 6 SAA Seed Amplification Assay. α-syn total a-syn amounts in CSF T50% the time to 50% max fluorescence of α-syn SAA TTT the time to threshold of α-syn SAA SLOPE the slope of α-syn SAA AUC the area under the curve of α-syn SAA Fmax the maximum fluorescence of α-syn SAA APOE APOE ɛ4 carriers Ess Epworth Sleepiness Scale Score Rem REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) total score Gds Geriatric Depression Scale Score Stai State-Trait Anxiety Index (STAI) Total Score Scopa SCOPA-AUT Total Score TD tremor dominant Ind indeterminate ADL Modified Schwab & England ADL Declarations Acknowledgements The authors express gratitude to all patients for their participation in the studies. Data comes from Parkinson’s Progression Markers Initiative (PPMI) and Fox Investigation for New Discovery of Biomarkers in Parkinson’s Disease (BioFIND). We thank all researchers for sharing data. Author contributions All authors contributed to the study conception and design. Z.C. and D.S. conceptualized and designed the study, and were primarily responsible for drafting, editing, and revising the manuscript. Y.A. and M.Y. contributed to data analysis and manuscript revision. Y.L., X.Z., and D.L. were involved in data collection. H.Z. contributed to the study design, data analysis, and manuscript revision. O.C. conceived and supervised the project. All authors reviewed and approved the final manuscript. Funding This work was supported by the National Natural Science Foundation of China (81871002, 81471334, 81100981), the Natural Science Foundation of Chongqing, China (CSTB2024NSCQ-MSX0757), the National Key Clinical Specialties Construction Program in China, and the China Postdoctoral Science Foundation (2025M782402). Data availability The data analysed in this study were sourced from the Parkinson's Progression Markers Initiative (PPMI, http://www.ppmi-info.org) and the Fox Investigation for New Discovery of Biomarkers (BioFIND, https://biofind.loni.usc.edu/) database. Researchers may access these datasets by submitting a data usage request via the respective official websites. Declarations Ethics approval and consent to participate The study analysed data from the publicly available Parkinson Progression Marker Initiative (PPMI) and the Fox Investigation for New Discovery of Biomarkers (BioFIND) datasets. Both the PPMI and BioFIND studies were approved by the institutional review boards of all participating sites, and informed consent was obtained from all participants prior to inclusion in the study. The study complies with ethical standards for research involving human participants, and the original study’s ethics committee approval and informed consent documentation apply to this analysis. Consent for publication Not applicable. This manuscript does not contain data from any individual person in any form (including details, images, or videos). Competing interests The authors report no competing interests. References Ye H, Robak LA, Yu M, Cykowski M, Shulman JM. Genetics and Pathogenesis of Parkinson’s Syndrome. Annu Rev Pathol Mech Dis. 2023;18:95–121. https://doi.org/10.1146/annurev-pathmechdis-031521-034145 . Tanner CM, Ostrem JL. Parkinson’s Disease. Ropper AH. editor N Engl J Med. 2024;391:442–52. https://doi.org/10.1056/NEJMra2401857 . O’Keeffe GW, Sullivan AM. 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Cerebrospinal fluid NPTX2 changes and relationship with regional brain metabolism metrics across mild cognitive impairment due to Alzheimer’s disease. J Neurol. 2024;271:1999–2009. https://doi.org/10.1007/s00415-023-12154-7 . Additional Declarations No competing interests reported. Supplementary Files SupplementaryFigures.pdf Supplementary Figures 1-9: Supplementary Figures.pdf Supplementarytables.xlsx Supplementary Tables 1-25: Supplementary Tables.xlsx Graphicalabstracts.jpg Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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1","display":"","copyAsset":false,"role":"figure","size":1643427,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eBaseline demographic and clinical characteristics of PD participants. a\u003c/strong\u003e Baseline CSF NPTX2 levels of patients with PD in different diagnostic groups. P values were assessed by Student’s t test between two groups. \u003csup\u003e*\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05, \u003csup\u003e**\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.01, \u003csup\u003e***\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001. \u003cstrong\u003eb\u003c/strong\u003e Scatterplot showing the correlation between CSF NPTX2 and Age. Estimate regression coefficients (β) and P values are shown. Model adjusted for age, sex, apolipoprotein E ε4 status, LEDD, baseline Hoehn-Yahr stage, and disease duration. \u003cstrong\u003ec, d\u003c/strong\u003e Boxplots showing the difference of MoCA scores (\u003cstrong\u003ec\u003c/strong\u003e) and MDS-UPDRS III scores(\u003cstrong\u003ed\u003c/strong\u003e) between Low NPTX2 levels and High NPTX2 levels. CSF, cerebrospinal fluid; NPTX2, Neuronal pentraxin II; PD, Parkinson's disease; NC, normal cognition; MCI, mild cognitive impairment, HY, Hoehn-Yahr stage, Low, Low NPTX2 level; High, High NPTX2 level; APOE, APOE ɛ4 carriers.\u003c/p\u003e","description":"","filename":"Fig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-8386534/v1/ea303979ab8d9e89350b447e.png"},{"id":99316366,"identity":"7be1c4e7-40d8-4bea-b907-676a5b71235d","added_by":"auto","created_at":"2025-12-31 16:28:20","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":6607961,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe baseline relationship between CSF NPTX2 and α-synuclein pathology, as well as the dopaminergic degeneration. a, f\u003c/strong\u003e Boxplot showing the CSF NPTX2 level between PD patients and Healthy Controls in PPMI cohort(\u003cstrong\u003ea\u003c/strong\u003e) and BioFIND cohort(\u003cstrong\u003ef\u003c/strong\u003e). Boxplots depict the median and 25th and 75th quartiles, whereas whiskers represent the full range. Statistical significance was determined with Student’s t test. \u003cstrong\u003eb\u003c/strong\u003eThe NPTX2 Paradox in Parkinson's Disease: Transcriptional upregulation revealed by scRNA-seq Versus CSF downregulation, mediated by α-synuclein pathology. \u003cstrong\u003ec \u003c/strong\u003eForest plots showing relationship between CSF NPTX2 level and α-synuclein (α-syn, αS-SAA T50%, αS-SAA TTT) and mean DAT binding ratio (Striatum, Putamen, Caudate), using linear regression models. Dots: Standardized β; Horizontal lines: Standardized 95% CI. \u003cstrong\u003ed\u003c/strong\u003e Using linear regression model with RCS to explore non-linear relationship between CSF NPTX2 level and α-synuclein as well as mean DAT binding ratio. \u003cstrong\u003ee\u003c/strong\u003e DAT binding ratio significantly mediated the association between CSF NPTX2 level and MDS-UPDRS III score while adjusting for covariates. α-syn, total α-synuclein amounts in CSF; αS-SAA, α-synuclein Seed Amplification Assay; T50%, the time to 50% max fluorescence of α-syn SAA;TTT, the time to threshold of α-syn SAA; Striatum, the mean striatum DAT binding ratio; Putamen, the mean putamen DAT binding ratio; Caudate, the mean caudate DAT binding ratio; RCS, restricted cubic splines; Covariates including age, sex, apolipoprotein E ε4 status, LEDD, baseline Hoehn-Yahr stage, and disease duration.\u003c/p\u003e","description":"","filename":"Fig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-8386534/v1/1af7a867e4937b56cba4b437.png"},{"id":99191148,"identity":"9f5d9ff5-1933-424d-85b2-2f0f70a9c717","added_by":"auto","created_at":"2025-12-30 00:54:15","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":4216163,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEffects of CSF NPTX2 on longitudinal motor and cognitive function in Parkinson’s disease. a-c\u003c/strong\u003e LMMs were used to examine effects of baseline CSF NPTX2 levels with follow-up time on longitudinal motor (\u003cstrong\u003ea\u003c/strong\u003e,\u003cstrong\u003e b\u003c/strong\u003e) and cognitive function (\u003cstrong\u003ea\u003c/strong\u003e,\u003cstrong\u003e c\u003c/strong\u003e). \u003cstrong\u003ed-f\u003c/strong\u003e Cox proportional hazards models provided evidence of associations between CSF NPTX2 levels and incident Hoehn-Yahr stage ≥ 4 (\u003cstrong\u003ed, e\u003c/strong\u003e) or dementia conversion (\u003cstrong\u003ed\u003c/strong\u003e, \u003cstrong\u003ef\u003c/strong\u003e). \u003cstrong\u003eg, h\u003c/strong\u003eUsing Cox regression model with RCS to explore non-linear relationship between CSF NPTX2 levels and Hoehn-Yahr stage ≥ 4 (\u003cstrong\u003eg\u003c/strong\u003e) or dementia risk(\u003cstrong\u003eh\u003c/strong\u003e). Model adjusted for age, sex, apolipoprotein E ε4 status, LEDD, baseline Hoehn-Yahr stage, and disease duration. In addition, in terms of cognition, the model also corrected Baseline MoCA score and education. LMM, linear mixed model; UPDRS III, Movement Disorder Society Unified Parkinson's Disease Rating Scale III; PIGD, postural imbalance and gait difficulty; MoCA, the Montreal Cognitive Assessment; dementia, MoCA \u0026lt; 22; H-Y stage, Hoehn-Yahr stage;RCS, restricted cubic splines. TotRec, HVLT Immediate/Total Recall t-score; DelRec, HVLT Delayed Recall t-score; Retent, HVLT Retention t-score; RecDisc, HVLT Discrimination Recognition Index t-score; JoLO, the Benton Judgment of Line Orientation, LNS, the Letter Number Sequencing; SFT, the Semantic Fluency Test; SDMT, Symbol Digit Modalities Test.\u003c/p\u003e","description":"","filename":"Fig.3.png","url":"https://assets-eu.researchsquare.com/files/rs-8386534/v1/c0853145ec4fda4f869bf48c.png"},{"id":99191161,"identity":"891b18ca-52b5-49ea-aff9-d39f9e809a49","added_by":"auto","created_at":"2025-12-30 00:54:16","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":6391688,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAssociation between CSF NPTX2 levels and the milestones of PD progression alongside brain structural alterations. a\u003c/strong\u003e Correlation between CSF NPTX2 levels and milestone events in Parkinson's disease progression. The hazard ratio (HR) and\u003cem\u003e P \u003c/em\u003evalues were assessed by Cox proportional hazard regression. \u003cstrong\u003eb-e\u003c/strong\u003e Cumulative probability risk of milestone progression in the follow-up among PD participants. Walking and balance(\u003cstrong\u003eb\u003c/strong\u003e), Autonomic dysfunction(\u003cstrong\u003ec\u003c/strong\u003e), Functional dependence(\u003cstrong\u003ed\u003c/strong\u003e), Activities of daily living(\u003cstrong\u003ee\u003c/strong\u003e). \u003cstrong\u003ef\u003c/strong\u003eHeatmap showing associations between CSF NPTXs and Brain subcortical volumes. \u003cem\u003eP\u003c/em\u003evalues were FDR-adjusted (*FDR-adjusted \u003cem\u003eP\u003c/em\u003e value \u0026lt; 0.05, ** FDR-adjusted \u003cem\u003eP\u003c/em\u003e value \u0026lt; 0.01, and *** FDR-adjusted \u003cem\u003eP\u003c/em\u003e value \u0026lt; 0.001). \u003cstrong\u003eg\u003c/strong\u003e Putamen volume and Choroid plexus volume significantly mediated the association between CSF NPTX2 level and MDS-UPDRS III score while adjusting for covariates. Path thickness indicates the strength of associations. Solid lines represent positive correlations and dashed lines represent negative correlations. The analyses were adjusted for age, sex, apolipoprotein E ε4 status, LEDD, baseline Hoehn-Yahr stage, and disease duration. Additionally, for cognitive aspects, models were further adjusted for baseline MoCA scores and education. When analysing brain subcortical volume, the model further adjusted for signal-to-noise ratio and intracranial volume. The disease progression of Parkinson's disease patients was evaluated using six clinically relevant domain milestones (\"walking and balance\"; \"motor complications\"; \"cognition\"; \"autonomic dysfunction\"; \"functional dependence\"; \"activities of daily living\") to reflect meaningful disability. Milestones were intended to be severe enough to reflect meaningful disability.\u003c/p\u003e","description":"","filename":"Fig.4.png","url":"https://assets-eu.researchsquare.com/files/rs-8386534/v1/7499a088c646e3d0e2f6fbc8.png"},{"id":99191169,"identity":"013283cf-2dcd-49cb-b096-b1948e4e0fb4","added_by":"auto","created_at":"2025-12-30 00:54:16","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":4100550,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAssociation between Baseline CSF NPTX2 and Cerebrospinal Fluid Biomarkers. a\u003c/strong\u003e Forest plot showing baseline relationship between CSF NPTX2 level and CSF biomarkers. \u003cstrong\u003eb\u003c/strong\u003e Using linear regression model with RCS to explore non-linear relationship between baseline CSF NPTX2 level and baseline CSF biomarkers. \u003cstrong\u003ec\u003c/strong\u003e Forest plot showing relationship between baseline CSF NPTX2 level and longitudinal CSF biomarkers. \u003cstrong\u003ed-f\u003c/strong\u003e LMMs were used to examine effects of baseline CSF NPTX2 levels with follow-up time on CSF longitudinal neurodegenerative markers. Aβ\u003csub\u003e1-42\u003c/sub\u003e(\u003cstrong\u003ed\u003c/strong\u003e), T-tau(\u003cstrong\u003ee\u003c/strong\u003e), P-tau(\u003cstrong\u003ef\u003c/strong\u003e). Covariates included age, sex, apolipoprotein E ε4 status, LEDD, baseline Hoehn-Yahr stage, disease duration, baseline MoCA scores and education. Aβ\u003csub\u003e1-42\u003c/sub\u003e, Amyloid-beta (1-42); T-tau, total tau; P-tau, tau phosphorylated at the threonine181 position (p-tau181); GFAP, Glial fibrillary acid protein; YKL-40, Chitinase-3-like Protein 1; sTREM2, Soluble triggering receptor expressed on myeloid cells 2; S100, S100 calcium binding protein B; IL-6, Interleukin 6; LMMs, linear mixed models.\u003c/p\u003e","description":"","filename":"Fig.5.png","url":"https://assets-eu.researchsquare.com/files/rs-8386534/v1/c4ef365d440addfc77225a50.png"},{"id":99791902,"identity":"2b7412b4-ae97-482e-a5b9-361ec70843d6","added_by":"auto","created_at":"2026-01-08 13:11:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":24616695,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8386534/v1/d0d4828b-f4e3-4cdf-a0a7-6174544958ac.pdf"},{"id":99191131,"identity":"275b244b-539a-45bd-b36e-06b91d0e4b7e","added_by":"auto","created_at":"2025-12-30 00:54:14","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1649579,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Figures 1-9: Supplementary Figures.pdf\u003c/p\u003e","description":"","filename":"SupplementaryFigures.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8386534/v1/c7b3ef328472348df0fec96e.pdf"},{"id":99317356,"identity":"d8fd0ce3-0103-42f0-955a-77933117001c","added_by":"auto","created_at":"2025-12-31 16:30:04","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":2999422,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Tables 1-25: Supplementary Tables.xlsx\u003c/p\u003e","description":"","filename":"Supplementarytables.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8386534/v1/8127bea6eb2ad968e04c4118.xlsx"},{"id":99315945,"identity":"72614015-6c2c-45b5-9eba-577d7638b488","added_by":"auto","created_at":"2025-12-31 16:27:29","extension":"jpg","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":224347,"visible":true,"origin":"","legend":"","description":"","filename":"Graphicalabstracts.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8386534/v1/9e56ff27022d2d34d67e39c4.jpg"}],"financialInterests":"No competing interests reported.","formattedTitle":"CSF NPTX2 reflects α-synuclein pathology and predicts disease progression in Parkinson’s disease","fulltext":[{"header":"Introduction","content":"\u003cp\u003eParkinson\u0026rsquo;s disease (PD) is a progressive neurodegenerative disorder defined by the abnormal aggregation of α-synuclein (α-syn) and the selective loss of dopaminergic neurons in the substantia nigra1.[\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] These pathological hallmarks underlie the cardinal clinical symptoms of PD, yet the mechanisms that govern the marked heterogeneity in disease progression remain poorly understood.[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] Disease trajectories vary widely among individuals, ranging from indolent to rapidly disabling forms, posing major challenges for prognosis and for the development of disease-modifying therapies. Accordingly, there is an urgent need for biomarkers that not only reflect core pathology but also capture the biological determinants of progression.\u003c/p\u003e \u003cp\u003eNeuronal pentraxin II (NPTX2), a synaptic protein crucial for excitatory synapse homeostasis and plasticity, has been implicated in multiple neurodegenerative disorders.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] Dysregulation of NPTX2 has been implicated in synaptic loss, cognitive decline, and TDP-43 pathology in Alzheimer\u0026rsquo;s disease (AD),[\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] frontotemporal dementia (FTLD),[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] and dementia with Lewy bodies (DLB).[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] Intriguingly, its expression in PD presents a paradox: while NPTX2 is upregulated within the substantia nigra, suggesting a compensatory or pathological response, its levels are markedly reduced in the cerebrospinal fluid (CSF).[\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] This tissue-fluid discrepancy points to a complex and uncharacterized biological mechanism linking NPTX2 to synaptic integrity and α-syn pathology. However, whether CSF NPTX2 reflects α-syn pathology, dopaminergic degeneration, and clinical progression in PD remains unknown.\u003c/p\u003e \u003cp\u003eBased on this, we hypothesized that NPTX2 may reflect α-synuclein pathology, dopaminergic neurodegeneration, and predict the disease progression of PD. To validate this hypothesis, we utilized a large prospective cohort from the Parkinson\u0026rsquo;s Progression Markers Initiative cohort (PPMI). By integrating clinical assessments, neuroimaging, CSF biomarkers, and α-syn seed amplification assay (SAA) kinetic parameters, we systematically investigated CSF NPTX2 as a reflector of PD pathology and a predictor of its progression. Concurrently, parallel analyses of NPTX1 and NPTXR were performed, confirming the unique role of NPTX2. In addition, primary findings were validated in an independent external Fox Investigation for New Discovery of Biomarkers in Parkinson\u0026rsquo;s Disease (BioFIND) cohort.\u003c/p\u003e \u003cp\u003eOur findings establish CSF NPTX2 as a biomarker that reflects α-synuclein pathology, dopaminergic neurodegeneration, and predicts disease progression in PD, highlighting its potential as a predictive and therapeutic target.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy participants\u003c/h2\u003e \u003cp\u003eResearch data were downloaded from the Parkinson's Progression Markers Initiative (PPMI) repository.[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.ppmi-info.org\u003c/span\u003e\u003cspan address=\"http://www.ppmi-info.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) The PPMI is a continuing, prospective, longitudinal, observational, and multinational multi-center research program designed to detect biomarkers for PD.[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] The PPMI investigation was sanctioned by the ethics review board of all collaborating establishments; furthermore, all subjects provided their signature on a written informed consent document prior to enrollment.\u003c/p\u003e \u003cp\u003ePD subjects were recruited based on the inclusion criteria: individuals must be 30 years or older at diagnosis; have bradykinesia combined with resting tremor, rigidity, or only asymmetric resting tremor or bradykinesia; Hoehn-Yahr stage\u0026thinsp;\u0026le;\u0026thinsp;2; and be free of dementia at baseline (MoCA\u0026thinsp;\u0026ge;\u0026thinsp;22). To prevent misdiagnosis, the researchers reviewed the diagnosis longitudinally. Patients diagnosed with conditions other than primary PD were excluded from the follow-up. In addition, our investigation mandated that all subjects possess baseline CSF neuronal pentraxins (NPTXs) data. NPTXs consist of NPTX1, NPTX2 and their receptor NPTXR. All enrolled participants were evaluated periodically to acquire clinical information and partake in CSF biomarker investigations. (Supplementary Table\u0026nbsp;1) shows the clinical and biomarker information of recruited PD patients during follow-up. Longitudinal follow-up included five yearly assessments of CSF biomarker, fourteen yearly clinical evaluations and five yearly of DAT-SPECT assessments subsequent to the initial lumbar puncture.\u003c/p\u003e \u003cp\u003eHealthy controls (HCs) were individuals without neurologic disorders, signs, or symptoms and not undergoing treatment with specified medications such as dopamine receptor antagonists.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eClinical assessment measures\u003c/h3\u003e\n\u003cp\u003eMotor function was assessed at baseline and then yearly with Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), with subscores divided into tremor (the sum of items 3.15 to 3.18), bradykinesia (the sum of items 3.4 to 3.8 and 3.14), rigidity (the sum of item 3.3)and postural imbalance and gait difficulty (PIGD) scores (the sum of items 3.10 to 3.12).Motor assessments were made in the \u0026ldquo;off\u0026rdquo; (non-drug use) state.\u003c/p\u003e \u003cp\u003eThe motor subtype classification of PD patients was evaluated according to Stebbins \u003cem\u003eet al\u003c/em\u003e.[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] Briefly, the ratio of the mean MDS-UPDRS tremor scores (11 items) to the mean MDS-UPDRS PIGD scores (5 items) was calculated for each patient. If the ratio was \u0026le;\u0026thinsp;0.90, patients were classified as a PIGD subtype, if the ratio was \u0026ge;\u0026thinsp;1.15 as a TD subtype, and if the ratio was between 0.90 and 1.15 as an indeterminate subtype. Motor subtypes were evaluated repeatedly at the follow-up time points. Converters were grouped during follow-up according to TD/PIGD groupings at baseline.\u003c/p\u003e \u003cp\u003eThe study employed several cognitive assessment scales, including the Montreal Cognitive Assessment (MoCA) for global cognitive function, the Hopkins Verbal Learning Test (HVLT) for episodic memory, the Benton Judgment of Line Orientation (JoLO) for visuospatial abilities, the Letter Number Sequencing (LNS) for executive function/working memory, the Semantic Fluency Test (SFT) for language, and the Symbol Digit Modalities Test (SDMT) for processing speed/attention. The cognitive status of participants was classified according to the criteria used in previous studies.[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] Participants were categorized as having normal cognition (NC, MoCA\u0026thinsp;\u0026gt;\u0026thinsp;26), mild cognitive impairment (MCI, 22\u0026thinsp;\u0026le;\u0026thinsp;MoCA\u0026thinsp;\u0026le;\u0026thinsp;26), or dementia (MoCA\u0026thinsp;\u0026lt;\u0026thinsp;22).\u003c/p\u003e \u003cp\u003eThe disease progression of Parkinson's disease patients was evaluated using six clinically relevant domain milestones (\"walking and balance\"; \"motor complications\"; \"cognition\"; \"autonomic dysfunction\"; \"functional dependence\"; \"activities of daily living\") to reflect meaningful disability.[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] Milestones were intended to be severe enough to reflect meaningful disability.\u003c/p\u003e\n\u003ch3\u003eMeasurement of CSF biomarkers\u003c/h3\u003e\n\u003cp\u003eThe collection and processing of CSF biomarker were conducted in accordance with the PPMI biologics manual. Neuronal pentraxins (NPTX1, NPTX2, and NPTXR) data from cerebrospinal fluid of Parkinson Disease patients and healthy volunteers are measured using the SOMAscan platform. The data is controlled for quality to remove outlier samples, calibrators, buffer and non-human SOMAmers. The measured values are hybridization normalized, plate scaled, median normalized intra plate and calibrated at SomaLogic\u0026rsquo;s side, then log2 transformed, median normalized inter plates and batch corrected at plate level.\u003c/p\u003e \u003cp\u003eCSF amyloid-β 42 (Aβ1\u0026ndash;42), total tau (T-tau) and phosphorylated tau (P-tau) concentrations were quantified through an Elecsys\u0026reg; electrochemiluminescence immunoassay (ECLIA) using a completely automated cobas e 601 analyzer (Roche Diagnostics, Basel, Switzerland).[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eCSF α-synuclein(α-syn) concentration, neurofilament light (NFL), glial fibrillary acidic protein (GFAP), chitinase-3-like protein 1 (YKL-40), S100 protein(S100), soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and Interleukin-6 (IL-6) were quantified using Roche NeuroToolKit.[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eα-synuclein oligomers in CSF were detected by using seed amplification assay (SAA) (Amprion: project number 155). The time to threshold (TTT [hours]), the time to reach 50% of the maximum fluorescence (T50 [hours]), the maximum fluorescence (Fmax [RFU]), the slope [RFU/s], and the area under the curve (AUC, [%*s]) are kinetic parameters of SAA that correlate with the α-syn seed concentration.\u003c/p\u003e\n\u003ch3\u003eGenotyping\u003c/h3\u003e\n\u003cp\u003eGenomic DNA was extracted from the whole blood of PD subjects for processing and analysis. Apolipoprotein E (APOE) genotypes were detected by allele-specific oligonucleotide probes labeled with a fluorogenic reporter (TaqMan method).[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] Besides, individuals were also divided into two groups according to the ε4 allele, namely, APOE ε4 carriers (APOE ε4+) and non-APOE ε4 carriers (APOE ε4-).\u003c/p\u003e\n\u003ch3\u003eDAT imaging outcomes\u003c/h3\u003e\n\u003cp\u003eDAT single-photon emission CT was performed to measure the DAT density at baseline and the 1-year, 2-year and 4-year follow-up visits for patients with PD and at baseline only for controls according to the PPMI imaging technical operations manual.[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] In this study, we used the mean caudate DAT binding ratio (average of the ipsilateral and contralateral caudate binding ratios), mean putamen DAT binding ratio (average of the ipsilateral and contralateral putamen binding ratios) and mean striatum DAT binding ratio (average of the ipsilateral and contralateral striatum binding ratios).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eAssociation with brain structures\u003c/h2\u003e \u003cp\u003eT1weighted images underwent processing with Freesurfer software (FreeSurfer-v7.3.2).[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] This study utilized imaging-derived phenotypes (IDPs) consisting of the cortical surface area (SA) and cortical thickness (CTh) of 35 cortical regions (average of the bilateral cortical thickness and the cortical surface are) and the volume of 26 subcortical regions (average of the subcortical regions) defined by the Desikan-Killiany (DK) and ASEG atlases.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eBioFIND External Validation Cohort\u003c/h3\u003e\n\u003cp\u003eThe Fox Investigation for New Discovery of Biomarkers in Parkinson\u0026rsquo;s Disease (BioFIND) (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://biofind.loni.usc.edu\u003c/span\u003e\u003cspan address=\"http://biofind.loni.usc.edu\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) is an observational, multi-center, cross-sectional study of moderate-to-advanced PD participants evaluated with standardized clinical and biospecimen acquisition protocols5. Enrolled PD participants met the United Kingdom PD Society Brain Bank (UKPDBB) clinical diagnostic criteria, modified to require all three classic motor signs of PD (tremor, bradykinesia, and rigidity) instead of just two signs. The duration of the disease in the enrolled subjects was 5\u0026ndash;18 years since the onset of motor symptoms, and those who had undergone deep brain stimulation or ablative surgeries for PD were excluded. BioFIND inclusion was limited to 50\u0026ndash;75 years of age at the onset of the disease (age 55 to 93 at the time of enrollment). The institutional review board of BioFIND approved the study protocol. Written informed consent was obtained from each study participant.\u003c/p\u003e \u003cp\u003eThis study utilised baseline assessment data from the BioFIND cohort, conducted during the \u0026ldquo;on\u0026rdquo; state following regular medication to reflect typical functional status under routine stable treatment. Ultimately, 109 Parkinson's disease patients and 84 healthy controls were included in the analysis.\u003c/p\u003e\n\u003ch3\u003eExternal snRNA-seq transcriptional validation\u003c/h3\u003e\n\u003cp\u003eTo complement our CSF protein findings with transcriptional-level evidence, we incorporated data from a recently published single-nucleus RNA sequencing (snRNA-seq) study of substantia nigra dopaminergic (DA) neurons in PD. In that study, midbrain DA neuron nuclei were enriched using a fluorescence-activated nuclei sorting (FANS) protocol prior to snRNA-seq.\u0026nbsp;The dataset comprised 22,048 DA neurons obtained from age- and postmortem-interval-matched participants, including 8 controls, 7 individuals with PD, and 3 with dementia with Lewy bodies (LBD). From the differential expression results reported across ten DA neuron subtypes, we extracted statistics related to NPTX2 for use in our analysis. Differential expression was performed using the MAST framework (linear mixed-effects model, two-sided test), providing model coefficients (Coef), confidence intervals (ci.hi / ci.lo), raw P values (Pr[\u0026gt;\u0026thinsp;Chisq]), and Benjamini-Hochberg-adjusted false discovery rates (FDR). No further processing of the original single-cell dataset was undertaken. The publicly reported differential expression results were used directly as independent transcriptional evidence supporting our analyses.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eBefore analysis, all CSF protein levels were log2-transformed and then standardized to Z-scores based on the mean and standard deviation of the healthy control cohort. We divided PD patients into two groups as follows: The first quartile of NPTX2 values was defined as the low-level NPTX2 group, and the 2nd, 3rd, and 4th quartiles of NPTX2 were defined as the high-level NPTX2 group.\u003c/p\u003e \u003cp\u003eChi-square tests were used for qualitative variables, whilst continuous variables meeting the assumption of normality were analysed using Student's t-test. Multivariate linear regression models were used to assess the baseline correlation of NPTX2 with characteristics of PD, SAA kinetic parameters, CSF biomarkers, DAT binding ratio and brain structure. For the analysis of brain structural metrics, we additionally performed false discovery rate (FDR) correction.\u003c/p\u003e \u003cp\u003eTo investigate the longitudinal associations between NPTX2 levels and clinical outcomes, linear mixed models (LMMs) were applied, incorporating interactions between NPTX2 levels and time. For time-to-event outcomes, including motor progression and incident dementia, progression milestones and motor subtype conversion, Cox proportional hazards models were constructed with covariate adjustments. We evaluated models with continuous and binary variables.\u003c/p\u003e \u003cp\u003eIn addition, we employed restricted cubic splines (RCS) to fit Cox regression and linear regression models respectively, in order to explore potential non-linear relationships between NPTX2 and outcome variables. To further elucidate the functional pathways of NPTX2, we conducted three mediation analyses: CSF sTREM2 and YKL-40 between NPTX2 and T-tau/P-tau; the role of DAT activity between NPTX2 and MDS-UPDRS III scores; and brain structure between NPTX2 and MDS-UPDRS III scores. Finally, subgroup analyses were conducted by stratifying participants according to age, sex, APOE ε4 carrier status, Hoehn-Yahr stage and MoCA stage.\u003c/p\u003e \u003cp\u003eThe statistical analyses in this study were conducted via SPSS 25.0 and R software version 4.5.0. Unless otherwise specified, all regression analyses, LMMs and Cox proportional hazards models were adjusted for the following covariates: age, sex, apolipoprotein E ε4 status, LEDD, baseline Hoehn-Yahr stage and disease duration. Additionally, for cognitive aspects, models were further adjusted for baseline MoCA scores and education. When analysing brain structure, the model further adjusted for signal-to-noise ratio; for cortical surface area and subcortical volume, the model additionally adjusted for intracranial volume. Results with \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eStudy participants\u003c/h2\u003e \u003cp\u003eThe PPMI cohort included 528 patients with Parkinson's disease (PD) and 178 healthy controls (HC). The average age at baseline for the PD cohort was 61.91\u0026thinsp;\u0026plusmn;\u0026thinsp;9.60 years, with 63.26% being male. The mean disease duration was 2.60\u0026thinsp;\u0026plusmn;\u0026thinsp;2.48 years, and the mean years of education were 15.54\u0026thinsp;\u0026plusmn;\u0026thinsp;3.18 years. No significant differences were observed between groups in age, gender, education, or APOE ε4 carrier frequency (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characters of PD patients and controls in PPMI cohort.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eHealthy Control\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;178)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePatients with PD\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;528)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003eP-\u003c/em\u003evalue\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eBaseline NPTX2 level\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003eP-\u003c/em\u003evalue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow (n\u0026thinsp;=\u0026thinsp;132)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHigh(n\u0026thinsp;=\u0026thinsp;396)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003eDemographics\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (y)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60.68\u0026thinsp;\u0026plusmn;\u0026thinsp;11.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61.91\u0026thinsp;\u0026plusmn;\u0026thinsp;9.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.511\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e63.73\u0026thinsp;\u0026plusmn;\u0026thinsp;8.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e60.89\u0026thinsp;\u0026plusmn;\u0026thinsp;9.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.006\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender (F/M)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67/111\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e194/334\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e28/104\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e166/230\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEducation (y)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.99\u0026thinsp;\u0026plusmn;\u0026thinsp;2.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.54\u0026thinsp;\u0026plusmn;\u0026thinsp;3.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.235\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15.63\u0026thinsp;\u0026plusmn;\u0026thinsp;3.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15.51\u0026thinsp;\u0026plusmn;\u0026thinsp;3.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.528\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration (y)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.60\u0026thinsp;\u0026plusmn;\u0026thinsp;2.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.35\u0026thinsp;\u0026plusmn;\u0026thinsp;1.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.69\u0026thinsp;\u0026plusmn;\u0026thinsp;2.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.459\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAPOE ɛ4 (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25.28%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.24%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.781\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31.81%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e21.71%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.019\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMotor assessments\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHoehn-Yahr stage (1/2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e210/318\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e48/84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e162/234\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.355\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUPDRS III\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.15\u0026thinsp;\u0026plusmn;\u0026thinsp;2.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.27\u0026thinsp;\u0026plusmn;\u0026thinsp;9.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e23.18\u0026thinsp;\u0026plusmn;\u0026thinsp;9.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e20.63\u0026thinsp;\u0026plusmn;\u0026thinsp;9.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.009\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCognitive assessments\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMCI (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34.09%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e44.70%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e30.56%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.003\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMoCA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28.20\u0026thinsp;\u0026plusmn;\u0026thinsp;1.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27.15\u0026thinsp;\u0026plusmn;\u0026thinsp;2.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e26.70\u0026thinsp;\u0026plusmn;\u0026thinsp;2.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e27.29\u0026thinsp;\u0026plusmn;\u0026thinsp;2.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.003\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCSF NPTXs\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNPTX1(log2 RFU)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.47\u0026thinsp;\u0026plusmn;\u0026thinsp;0.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.43\u0026thinsp;\u0026plusmn;\u0026thinsp;0.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.155\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15.10\u0026thinsp;\u0026plusmn;\u0026thinsp;0.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15.55\u0026thinsp;\u0026plusmn;\u0026thinsp;0.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNPTX2(log2 RFU)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.88\u0026thinsp;\u0026plusmn;\u0026thinsp;0.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.66\u0026thinsp;\u0026plusmn;\u0026thinsp;0.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11.89\u0026thinsp;\u0026plusmn;\u0026thinsp;0.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNPTXR (log2 RFU)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.84\u0026thinsp;\u0026plusmn;\u0026thinsp;0.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.84\u0026thinsp;\u0026plusmn;\u0026thinsp;0.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.268\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15.63\u0026thinsp;\u0026plusmn;\u0026thinsp;0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15.92\u0026thinsp;\u0026plusmn;\u0026thinsp;0.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eα-synuclein Seed Amplification Assay\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTTT (hours)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e81.58\u0026thinsp;\u0026plusmn;\u0026thinsp;25.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67.38\u0026thinsp;\u0026plusmn;\u0026thinsp;13.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.006\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e65.04\u0026thinsp;\u0026plusmn;\u0026thinsp;14.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e68.18\u0026thinsp;\u0026plusmn;\u0026thinsp;13.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.003\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT50% (hours)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83.81\u0026thinsp;\u0026plusmn;\u0026thinsp;26.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72.66\u0026thinsp;\u0026plusmn;\u0026thinsp;12.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.061\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e70.44\u0026thinsp;\u0026plusmn;\u0026thinsp;13.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e73.43\u0026thinsp;\u0026plusmn;\u0026thinsp;12.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.002\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDAT binding ratio\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCaudate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.95\u0026thinsp;\u0026plusmn;\u0026thinsp;0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.82\u0026thinsp;\u0026plusmn;\u0026thinsp;0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.004\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePutamen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.17\u0026thinsp;\u0026plusmn;\u0026thinsp;0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.81\u0026thinsp;\u0026plusmn;\u0026thinsp;0.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.75\u0026thinsp;\u0026plusmn;\u0026thinsp;0.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.83\u0026thinsp;\u0026plusmn;\u0026thinsp;0.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.004\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStriatum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.58\u0026thinsp;\u0026plusmn;\u0026thinsp;0.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.38\u0026thinsp;\u0026plusmn;\u0026thinsp;0.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.28\u0026thinsp;\u0026plusmn;\u0026thinsp;0.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.003\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eCategorical variables are reported as numbers or percentages; continuous variables are reported as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations. Student's t-test was used for continuous variables and chi-square test was used for categorical variables. PD, Parkinson's Disease; DAT, dopamine transporter; Low, Low NPTX2 level (Q1); High, High NPTX2 level(Q2-Q4); APOE ɛ4, APOE ɛ4 carriers; MCI, mild cognitive impairment; UPDRS III, Movement Disorder Society Unified Parkinson's Disease Rating Scale III score; MoCA, the Montreal Cognitive Assessment; NPTX1, Neuronal pentraxin I; NPTX2, Neuronal pentraxin 2; NPTXR, Neuronal pentraxin Receptor; T50%, the time to 50% max fluorescence of α-synuclein SAA; TTT, the time to threshold of α-synuclein SAA; SAA, Seed Amplification Assay. \u003csup\u003e*\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003cp\u003eIn PD patients, CSF NPTX2 levels decline with increasing age, consistent across both continuous variables (β = -1.126, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011) and binary variables (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004). Furthermore, NPTX2 levels were significantly reduced in males (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), APOE ε4 carriers (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.030), and patients with mild cognitive impairment (MCI) (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.044). However, NPTX2 showed no significant correlation with Hoehn-Yahr stage (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea, b, Supplementary Table\u0026nbsp;3). NPTX1 and NPTXR also exhibited age-related decline and lower levels in male patients, similarly independent of Hoehn-Yahr stage. Unlike NPTX2, however, no significant differences in NPTX1 or NPTXR were observed among APOE ε4 carriers; NPTX1 was significantly reduced in MCI patients (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04) (Supplementary Table\u0026nbsp;3). This suggests potential functional specificity within the neuronal pentraxin protein family in PD.\u003c/p\u003e \u003cp\u003eTo further investigate the clinical significance of cerebrospinal fluid NPTX2, the first quartile of CSF NPTX2 in PD patients was designated as the low NPTX2 group, while the second, third, and fourth quartiles constituted the high NPTX2 group. Concurrently, the high NPTX2 group exhibited lower UPDRS-III scores (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009) and rigidity scores (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004), higher MoCA scores (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003), and superior processing speed (SDMT) (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) and episodic memory (HVLT) (HVLT Total Recall, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004; HVLT Delayed Recall, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004; HVLT Recognition Discrimination, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec, d, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Supplementary Tables\u0026nbsp;2, 4). Moreover, validation within the BioFIND cohort further demonstrated that CSF NPTX2 levels were negatively correlated with PIGD scores (β = -1.39, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.049), whilst positively correlated with MoCA scores (β\u0026thinsp;=\u0026thinsp;2.32, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.015) (Supplementary Table\u0026nbsp;25).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eThe relationship between CSF NPTX2 and α-synuclein pathology\u003c/h2\u003e \u003cp\u003eCompared with HCs, CSF NPTX2 levels were significantly reduced in PD patients (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), a finding that was independently replicated in the BioFIND cohort (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.010) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ef, Supplementary Table\u0026nbsp;24). In contrast, no significant differences were observed for NPTX1 or NPTXR. This profile is distinct from the widespread reduction of Neuronal pentraxins (NPTXs) documented in AD, MSA, PSP, and FTD,[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] suggesting NPTX2 may possess unique characteristics in PD. Previous studies of the substantia nigra transcriptome, however, indicated significantly elevated \u003cem\u003eNPTX2\u003c/em\u003e expression levels in PD, which contradicts the findings of reduced protein levels in cerebrospinal fluid observed in this study. To further validate this phenomenon, we consulted recently published single-cell transcriptome data from the substantia nigra in PD. This revealed significantly upregulated \u003cem\u003eNPTX2\u003c/em\u003e expression across three dopaminergic neuronal subpopulations in PD patients (CALB1_CALCR, β\u0026thinsp;=\u0026thinsp;0.414, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; CALB1_GEM, β\u0026thinsp;=\u0026thinsp;1.860, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; CALB1_RBP4, β\u0026thinsp;=\u0026thinsp;1.288, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Supplementary Fig.\u0026nbsp;1, Supplementary Table\u0026nbsp;5). Notably, previous studies have demonstrated that NPTX2 colocalises with α-synuclein aggregates within Lewy bodies in PD substantia nigra.[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] In post-mortem brain tissue from ALS and FTD patients, NPTX2 misaccumulated has also been observed within neurons harbouring abnormal TDP-43.[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] Based on this, we propose a potential explanation (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb): under pathological stress, neurons may transkripionally upregulate NPTX2 to maintain synaptic function. However, due to α-synuclein aggregation and impaired secretion/clearance pathways, newly synthesised NPTX2 is sequestered into insoluble complexes or undergoes abnormal processing. This reduces the pool of soluble protein available for release into cerebrospinal fluid. Thus, the decline in CSF NPTX2 may reflect impairment of the available synaptic protein pool and neuronal integrity, rather than reduced transcription levels. This hypothesis requires further validation through tissue-CSF paired analysis, soluble/insoluble fractionation, and mass spectrometry identification in the same cases.\u003c/p\u003e \u003cp\u003eConsistent with previous reports,[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] we observed reduced CSF total α-syn levels in individuals with PD(\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001)(Supplementary Table\u0026nbsp;2), suggesting increased aggregated α-syn in the brain. CSF NPTX2 levels in PD patients showed a significant positive correlation with total α-synuclein levels (β\u0026thinsp;=\u0026thinsp;1.133, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Based on the α-syn SAA, higher NPTX2 levels were significantly correlated with both the time to threshold (TTT [hours]) (β\u0026thinsp;=\u0026thinsp;4.088, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.017) and the time to reach 50% of the maximum fluorescence (T50 [hours]) (β\u0026thinsp;=\u0026thinsp;3.716, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.019) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec, d, Supplementary Fig.\u0026nbsp;2, Supplementary Tables\u0026nbsp;6\u0026ndash;7). These findings indicate a significant negative correlation between CSF NPTX2 levels and synaptic protein pathological burden, supporting our prior hypothesis that reduced NPTX2 reflects impaired synaptic function and abnormal pathological protein accumulation. Therefore, NPTX2 holds promise as a potential therapeutic target in PD.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eThe relationship between CSF NPTX2 and the dopaminergic degeneration\u003c/h2\u003e \u003cp\u003eWe further investigated the relationship between NPTX2 and dopaminergic neuronal damage. Cross-sectional analysis revealed that baseline CSF NPTX2 levels were independently and positively correlated with DAT binding in the caudate(β\u0026thinsp;=\u0026thinsp;0.152, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008), putamen(β\u0026thinsp;=\u0026thinsp;0.087, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005), and striatum(β\u0026thinsp;=\u0026thinsp;0.119, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec, d, Supplementary Table\u0026nbsp;6), yet showed no significant association with the longitudinal rate of decline in DAT binding ratio(Supplementary Fig.\u0026nbsp;3, Supplementary Table\u0026nbsp;8). This suggests NPTX2 exerts its influence on dopamine function more prominently in the early disease stages, potentially serving as a core biomarker of pathogenesis. Furthermore, mediation analysis demonstrated that reduced DAT binding ratio mediated the effect of CSF NPTX2 on PD severity (MDS-UPDRS III scores) (Proportion striatum\u0026thinsp;=\u0026thinsp;11.63%; Proportion putamen\u0026thinsp;=\u0026thinsp;20.59%; Proportion caudate\u0026thinsp;=\u0026thinsp;11.77%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ee, Supplementary Table\u0026nbsp;9).\u003c/p\u003e \u003cp\u003eHowever, NPTX1 and NPTXR showed no or only weak correlations with PD dopaminergic function. we observed that NPTXR was positively correlated with DAT binding ratio in the caudate (β\u0026thinsp;=\u0026thinsp;0.075, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.036) and striatum (β\u0026thinsp;=\u0026thinsp;0.052, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.045), whereas NPTX1 showed no significant association with dopaminergic function (Supplementary Table\u0026nbsp;6). In contrast, within Alzheimer's disease, NPTXs demonstrate widespread associations with pathological burden and neuronal dysfunction.[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] These discrepancies further suggest that NPTX2 may possess a specific association with dopaminergic function in PD, rather than functioning solely as a pan-marker of synaptic dysfunction.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eBaseline CSF NPTX2 predicts longitudinal progression of Parkinson's disease\u003c/h2\u003e \u003cp\u003eOur findings establish baseline CSF NPTX2 as a significant predictor of motor progression in Parkinson's disease, with a preferential association with axial symptoms. Linear mixed models revealed that while the association with the longitudinal rate of change in UPDRS-III total scores was not statistically significant (β = -0.209, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.084), analysis of specific motor sub-scores demonstrated distinct, symptom-specific relationships. Specifically, NPTX2 negatively correlated with longitudinal rate of increase in rigidity scores (β = -0.348, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006) and PIGD scores (β = -0.098, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), but it showed a positive correlation with the longitudinal rate of increase in tremor scores, with no significant association observed for bradykinesia (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea, b, Supplementary Table\u0026nbsp;10). Critically, these differential motor associations demonstrated remarkable consistency across subgroups, including sporadic and genetic forms (LRRK2/GBA) of PD, as well as strata defined by age, sex, and APOE ε4 status (Supplementary Table\u0026nbsp;11).\u003c/p\u003e \u003cp\u003eFurthermore, in time-to-event analyses, elevated NPTX2 was associated with a substantially lower risk of reaching the advanced motor disability stage (Hoehn-Yahr stage 4; HR\u0026thinsp;=\u0026thinsp;0.334, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ed-e, Supplementary Table\u0026nbsp;12). Restricted cubic spline analysis confirmed a nonlinear, L-shaped association between NPTX2 and motor progression risk (P nonlinear\u0026thinsp;=\u0026thinsp;0.008) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eg, Supplementary Table\u0026nbsp;13). To further investigate the clinical relevance of these differential associations, we assessed motor subtype conversion. A higher baseline NPTX2 level was associated with a significantly reduced risk of conversion from TD or indeterminate to PIGD subtype (OR\u0026thinsp;=\u0026thinsp;0.761, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.018), corresponding to a 23.9% risk reduction per unit of NPTX2 (Supplementary Fig.\u0026nbsp;4, Supplementary Tables\u0026nbsp;14\u0026ndash;15). Cox regression analysis similarly confirmed that elevated NPTX2 levels significantly reduced the risk of transitioning to the PIGD subtype (HR\u0026thinsp;=\u0026thinsp;0.595, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006) (Supplementary Table\u0026nbsp;16).\u003c/p\u003e \u003cp\u003eConsistent with previous AD research findings, this study identified that the interaction term between NPTX2 and time positively correlated with global cognitive function (MoCA) (β\u0026thinsp;=\u0026thinsp;0.133, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and across cognitive domains (including visuospatial abilities (JoLO), executive functioning/working memory (LNS), language (SFT), and processing speed/attention (SDMT) (all \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea-c, Supplementary Table\u0026nbsp;10). Subgroup analyses further confirmed that the longitudinal relationship between NPTX2 and cognition exhibits broad consistency, particularly evident in sporadic Parkinson's disease, PD patients carrying LRRK2/GBA genes, and those with MCI (Supplementary Table\u0026nbsp;11). Meanwhile, Cox analysis indicated that elevated baseline NPTX2 levels reduced the risk of dementia conversion (HR\u0026thinsp;=\u0026thinsp;0.592, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ed-h, Supplementary Tables\u0026nbsp;12\u0026ndash;13). This indicates that NPTX2 may also serve as a potential biomarker for cognitive function in Parkinson's disease.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTo comprehensively evaluate the predictive value of NPTX2 for disease progression, we conducted survival analyses based on milestone events across six functional domains. Elevated baseline CSF NPTX2 levels significantly reduced the risk of progression in walking and balance (HR\u0026thinsp;=\u0026thinsp;0.490, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), functional dependency (HR\u0026thinsp;=\u0026thinsp;0.692, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.018), cognitive (HR\u0026thinsp;=\u0026thinsp;0.599, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002), autonomic dysfunction (HR\u0026thinsp;=\u0026thinsp;0.618, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.007) and activities of daily living (HR\u0026thinsp;=\u0026thinsp;0.44, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea-e, Supplementary Fig.\u0026nbsp;5, Supplementary Tables\u0026nbsp;12\u0026ndash;13). These findings collectively indicate that baseline CSF NPTX2 may serve as a favorable biomarker reflecting the overall progression of PD.\u003c/p\u003e \u003cp\u003eTo further elucidate the role specificity of different members of the neuronal Pentraxin family in PD, we concurrently analysed the relationship between CSF NPTX1 and NPTXR levels and disease progression. Results indicate that while both are associated with Parkinson's disease symptoms, their scope and intensity of action are more limited compared to NPTX2(Supplementary Fig.\u0026nbsp;6, Supplementary Tables\u0026nbsp;10, 12).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eThe Relationship Between NPTX2 and Brain Structure\u003c/h2\u003e \u003cp\u003eLinear regression analysis revealed significant associations between CSF NPTX2 levels and structural alterations in multiple PD-related brain regions. Specifically, elevated NPTX2 levels positively correlated with increased putamen volume (Continuous, β\u0026thinsp;=\u0026thinsp;0.135, FDR- adjusted \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.049) and significantly negatively correlated with choroid plexus volume (Continuous, β = -0.275, FDR- adjusted \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ef, Supplementary Fig.\u0026nbsp;7, Supplementary Tables\u0026nbsp;17\u0026ndash;19). Further mediation analysis indicated that reduced putamen volume and increased choroid plexus volume mediated the effect of CSF NPTX2 on PD severity-related MDS-UPDRS III scores (Proportion putamen\u0026thinsp;=\u0026thinsp;9.11%; Proportion choroid plexus\u0026thinsp;=\u0026thinsp;16.62%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eg, Supplementary Table\u0026nbsp;20). These findings suggest that it may jointly influence the severity of motor symptoms in PD through dysfunction in both the basal ganglia motor circuitry and regional glymphatic dysfunction localized to the basal ganglia.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eAssociation between Baseline CSF NPTX2 and Cerebrospinal Fluid Biomarkers\u003c/h2\u003e \u003cp\u003eCross-sectional analysis demonstrated that elevated baseline CSF NPTX2 levels were positively associated with core pathological proteins in Alzheimer's disease, including CSF Aβ₁-₄₂ (β\u0026thinsp;=\u0026thinsp;1.125, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), T-tau (β\u0026thinsp;=\u0026thinsp;0.986, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and P-tau (β\u0026thinsp;=\u0026thinsp;0.842, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), as well as with neuroinflammatory markers, specifically the microglial marker sTREM2 (β\u0026thinsp;=\u0026thinsp;0.381, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003) and the astrocyte marker YKL-40 (β\u0026thinsp;=\u0026thinsp;0.504, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ea, Supplementary Fig.\u0026nbsp;8, Supplementary Table\u0026nbsp;4). Notably, restricted cubic spline analyses revealed significant nonlinear relationships for T-tau (P nonlinear\u0026thinsp;=\u0026thinsp;0.002), P-tau (P nonlinear\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and IL-6 (P nonlinear\u0026thinsp;=\u0026thinsp;0.032). (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eb, Supplementary Table\u0026nbsp;21). Mediation analysis indicated that neuroinflammatory pathways may mediate the association between NPTX2 and tau pathology, with sTREM2 and YKL-40 exerting significant mediating effects in the relationships between NPTX2 and both T-tau (Proportion sTREM2\u0026thinsp;=\u0026thinsp;9.59%, Proportion YKL-40\u0026thinsp;=\u0026thinsp;18.79%) and P-tau (Proportion sTREM2\u0026thinsp;=\u0026thinsp;13.98%, Proportion YKL-40\u0026thinsp;=\u0026thinsp;25.38%) (Supplementary Fig.\u0026nbsp;9 and Supplementary Table\u0026nbsp;22). These findings suggest CSF NPTX2 may act as an upstream regulator of tau-associated neurodegeneration via the microglia-astrocyte signaling pathway.\u003c/p\u003e \u003cp\u003eConsistent with previous studies, longitudinal analyses, revealed that higher baseline NPTX2 levels were significantly associated with slower longitudinal increases in T-tau (β = -0.031, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016) and P-tau (β = -0.030, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ec-f, Supplementary Table\u0026nbsp;23). This marked discrepancy between cross-sectional and longitudinal correlations may reflect compensatory upregulation of NPTX2 in response to initial tau phosphorylation, neurofibrillary tangle formation and/or tau release to maintain synaptic integrity and network excitability. In contrast, no significant associations were observed between NPTX2 and the longitudinal trajectories of other injury or inflammatory markers, including GFAP, YKL-40, S100, and sTREM2(Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ec-f, Supplementary Table\u0026nbsp;23).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study, based on the large-scale prospective PPMI cohort and the cross-sectional BioFIND cohort, systematically investigated the pathophysiological significance of cerebrospinal fluid NPTX2 in Parkinson's disease and its predictive value for disease progression. Our findings indicate that CSF NPTX2 is closely associated with α-synuclein pathology, dopaminergic neuronal function, and disease progression, suggesting its significant potential as a prognostic biomarker and potential therapeutic target for PD. Concurrently, the complementary use of the early-stage PPMI cohort and the moderate-to-advanced stage BioFIND cohort enhances the robustness of our findings across the disease spectrum.\u003c/p\u003e \u003cp\u003eWe observed a marked reduction in NPTX2 levels exclusively within the cerebrospinal fluid of PD patients, contrasting sharply with the decline in NPTXs proteins previously noted in Alzheimer's disease and other neurodegenerative disorders.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] Moreover, compared to NPTX1 or NPTXR, NPTX2 exhibits a more extensive and pronounced association with α-synuclein pathology and dopaminergic function, suggesting it may play a distinct pathophysiological role in Parkinson's disease. Interestingly, despite reduced NPTX2 protein levels in CSF, scRNA-seq results from external validation revealed upregulation of NPTX2 mRNA expression in dopaminergic neurons of PD patient. This paradoxical phenomenon suggests that under pathological conditions in PD, neurons may respond to synaptic dysfunction by upregulating NPTX2 transcription. However, due to abnormal aggregation of α-synuclein or disruption of protein secretion/clearance pathways, newly synthesised NPTX2 becomes trapped within insoluble aggregates, consequently reducing soluble NPTX2 levels in cerebrospinal fluid. Extensive research has demonstrated that oligomers or fibrils of α-synuclein cause vesicular transport defects, thereby impairing neurotransmitter release at synapses.[\u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] As a secreted protein, NPTX2 must be synthesised within the neuronal cell body before being transported via vesicular transport to the synaptic terminal and secreted into the synaptic cleft.[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] Should α-synuclein pathology disrupt this transport pathway, newly synthesised NPTX2 cannot be normally transported out and secreted, leading to its abnormal accumulation within the neuron. Immunohistochemical evidence has also demonstrated colocalisation of NPTX2 with Lewy bodies.[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] However, the precise molecular mechanisms through which NPTX2 influences α-synuclein aggregation and dopaminergic neuron survival are still unclear, necessitating further mechanistic exploration in cellular and animal models to validate its potential as a therapeutic target.\u003c/p\u003e \u003cp\u003eNotably, such pathological alterations in NPTX2 are not unique to PD. In the FTLD-ALS spectrum disorders, studies indicate that TDP-43 may bind to the 3' UTR of NPTX2 and potentially affect its mRNA stability or transport, leading to abnormal accumulation of NPTX2 protein within neurons.[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] Concurrently, NPTX2 levels decrease in the cerebrospinal fluid of symptomatic hereditary FTLD cases and correlate with clinical severity.[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] However, in AD, where the core pathology involves β-amyloid and tau lesions, both NPTX2 mRNA and protein expression are downregulated in human neuronal cells,[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] and CSF NPTX2 levels decrease with worsening cognitive impairment, potentially reflecting overall synaptic loss. The absence of NPTX2 and its receptor NPTXR causes major GluA4 loss,[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] increased network hyperactivity and increased complement-mediated microglial engulfment of synapses,[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] highlighting its critical role in maintaining synaptic integrity. This suggests that NPTX2 may exert distinct functions across different pathological states of neurodegenerative diseases.\u003c/p\u003e \u003cp\u003eThis study demonstrates that baseline CSF NPTX2 levels exhibit significant prognostic value in PD. Consistent with study by Nilsson \u003cem\u003eet al\u003c/em\u003e.,[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] Cox regression analysis indicates that elevated NPTX2 levels correlate with a reduced risk of disease progression, encompassing worsening motor symptoms, dementia conversion, and multiple functional domains including walking and balance, cognition, autonomic function, and activities of daily living. Furthermore, longitudinal modelling further revealed that patients with higher NPTX2 levels exhibited slower rates of cognitive decline and progression of specific motor symptoms, such as rigidity and PIGD. Concurrently, our findings indicate that CSF NPTX2 levels correlate positively with putamen volumes and DAT binding ratio. This phenomenon suggests that NPTX2 may preferentially regulate PIGD and rigidity by influencing cortico-basal ganglia circuits, exerting lesser effects on resting tremor-primarily mediated by brainstem/thalamocortical circuits-and potentially generating complex effects via distinct neurotransmitter systems (e.g. cholinergic pathways). Notably, the mediation analysis provides tentative evidence for the pathway \u0026lsquo;NPTX2 \u0026rarr; brain structure/function \u0026rarr; clinical symptom\u0026rsquo;. Our fingdings suggest that reduced putamen volume and diminished dopamine DAT activity mediate the effect of low NPTX2 levels on more severe motor impairment (MDS-UPDRS III score). This implies that NPTX2 may indirectly preserve the structural and functional integrity of basal ganglia motor circuits by maintaining synaptic plasticity and neuronal viability, thereby ameliorating motor symptoms. However, further research is required to confirm this hypothesis. Secondly, although statistical models indicate significant mediating effects of choroid plexus volume, this association warrants cautious interpretation given the choroid plexus's role as a critical interface between the cerebrospinal fluid-blood-brain barrier system and neuroinflammation.\u003c/p\u003e \u003cp\u003eOur findings indicate that CSF NPTX2 levels exhibit extensive positive correlations with multiple neurodegenerative markers (Aβ₁-₄₂, T-tau, P-tau) and neuroinflammatory proteins (YKL-40, sTREM2, IL-6) at baseline. This is consistent with the findings of Zhang \u003cem\u003eet al\u003c/em\u003e.[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] and Massa \u003cem\u003eet al\u003c/em\u003e.[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], who reported strong correlations between NPTX2 and Aβ₁-₄₂, T-tau, and P-tau in AD. Longitudinal analysis further demonstrates that elevated baseline NPTX2 levels correlate with a subsequent slower rate of tau protein (T-tau, P-tau) accumulation. Consistent with this, Massa \u003cem\u003eet al\u003c/em\u003e. found that in the mild cognitive impairment (MCI) stage, patients who progressed to dementia within two years exhibited higher cerebrospinal fluid NPTX2 levels than stable at follow-up and slower progression.[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] This suggests a compensatory synaptic response may exist in the early disease phase, accompanied by NPTX2 upregulation. However, this compensatory mechanism may become exhausted as pathological burden increases, a finding supported by another mass spectrometry study. This research demonstrated that elevated baseline NPTX2 in preclinical AD patients correlates with increased P-tau and T-tau levels, followed by an accelerated decline in NPTX2 levels, potentially reflecting progressive neuronal and synaptic loss.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] Based on these findings, we hypothesized that NPTX2 is deeply involved in the dynamic processes of neurodegenerative diseases.\u003c/p\u003e \u003cp\u003eInevitably, our research has some limitations. Firstly, as the PPMI cohort did not collect longitudinal CSF NPTX2 samples, we could only assess the association between baseline levels and disease progression, unable to characterise its dynamic trajectory throughout the disease course. Consequently, it is crucial to further determine the trajectory of NPTX2 in PD progression and its prospective clinical significance as a longitudinal monitoring tool. Secondly, CSF NPTX2 concentrations likely reflect global brain expression and soluble protein turnover rather than specific regional changes in the substantia nigra alone. Thus, the relationship between CSF NPTX2 levels and its precise localisation, aggregation state, and functional status within brain tissue remains unclear and requires validation through post-mortem studies combining biochemical fractionation and immunohistochemistry. Thirdly, interpretations regarding the disease-stage-specific role of NPTX2 should be made cautiously. While we incorporated data from a mid-to-late-stage cohort for validation, the limited sample size and, more critically, the fact that CSF and brain tissue data originated from separate groups of individuals mean that our observed associations are indirect. This biological and temporal disconnect between peripheral biomarker levels and central molecular pathology in the substantia nigra underscores the need for future validation in cohorts with matched disease stages and, ideally, paired biospecimens from the same subjects. Fourthly, the PPMI cohort, though large and well-characterized, consists predominantly of individuals of European ancestry, which may limit the generalizability of our findings to other populations. Concurrently, the BioFIND cohort serving as the validation set exhibits limited sample size and lacks a systematic longitudinal design, primarily demonstrating cross-sectional differences in NPTX2 expression. Its longitudinal predictive efficacy necessitates replication in larger, prospectively designed independent cohorts. Finally, the longitudinal cohort exhibited certain data gaps, particularly during subsequent follow-up periods, potentially exerting a nuanced influence on our findings.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, this study establishes CSF NPTX2 as a key biomarker that reflects α-synuclein pathology, dopaminergic neurodegeneration, and predicts disease progression in PD. These findings provide novel theoretical foundations for developing NPTX2-based disease-modifying therapies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003ePD\u003c/strong\u003e Parkinson's Disease\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNPTXs\u003c/strong\u003e Neuronal pentraxins\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNPTX1\u003c/strong\u003e Neuronal pentraxin I\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNPTX2\u003c/strong\u003e Neuronal pentraxin II\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNPTXR\u003c/strong\u003e Neuronal pentraxin Receptor\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLow\u003c/strong\u003e Low NPTX2 level (Q1)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHigh\u003c/strong\u003e High NPTX2 level(Q2-Q4)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eUPDRS III score\u003c/strong\u003e Movement Disorder Society Unified Parkinson's Disease Rating Scale III score\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePIGD\u003c/strong\u003e postural imbalance and gait difficulty\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eH-Y stage\u003c/strong\u003e Hoehn-Yahr stage\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMCI\u003c/strong\u003e mild cognitive impairment\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMoCA\u003c/strong\u003e Montreal Cognitive Assessment\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eJoLO\u003c/strong\u003e the Benton Judgment of Line Orientation\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLNS\u003c/strong\u003e the Letter Number Sequencing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSFT\u003c/strong\u003e the Semantic Fluency Test\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSDMT\u003c/strong\u003e Symbol Digit Modalities Test\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHVLT\u003c/strong\u003e the Hopkins Verbal Learning Test\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTotRec\u003c/strong\u003e HVLT Total Recall\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDelRec\u003c/strong\u003e HVLT Delayed Recall\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRetent\u003c/strong\u003e HVLT Retention\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRecDisc\u003c/strong\u003e HVLT Recognition Discrimination\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAβ\u003csub\u003e1-42\u003c/sub\u003e\u003c/strong\u003e Amyloid-beta (1-42)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eT-tau\u003c/strong\u003e total tau\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eP-tau\u003c/strong\u003e tau phosphorylated at the threonine181 position (p-tau181)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGFAP\u003c/strong\u003e Glial fibrillary acid protein\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eYKL-40\u003c/strong\u003e Chitinase-3-like Protein 1\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003esTREM2\u003c/strong\u003e Soluble triggering receptor expressed on myeloid cells 2\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eS100\u003c/strong\u003e S100 calcium binding protein B\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIL-6\u003c/strong\u003e Interleukin 6\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSAA\u003c/strong\u003e Seed Amplification Assay.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eα-syn\u003c/strong\u003e total a-syn amounts in CSF\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eT50%\u003c/strong\u003e the time to 50% max fluorescence of α-syn SAA\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTTT\u003c/strong\u003e the time to threshold of α-syn SAA\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSLOPE\u003c/strong\u003e the slope of α-syn SAA\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUC\u003c/strong\u003e the area under the curve of α-syn SAA\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFmax\u003c/strong\u003e the maximum fluorescence of α-syn SAA\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAPOE\u003c/strong\u003e APOE ɛ4 carriers\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEss\u0026nbsp;\u003c/strong\u003eEpworth Sleepiness Scale Score\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRem\u003c/strong\u003e REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) total score\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGds\u0026nbsp;\u003c/strong\u003eGeriatric Depression Scale Score\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStai\u003c/strong\u003e State-Trait Anxiety Index (STAI) Total Score\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eScopa\u003c/strong\u003e SCOPA-AUT Total Score\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTD\u003c/strong\u003e tremor dominant\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInd\u0026nbsp;\u003c/strong\u003eindeterminate\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eADL\u0026nbsp;\u003c/strong\u003eModified Schwab \u0026amp; England ADL\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAcknowledgements\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors express gratitude to all patients for their participation in the studies. Data comes from Parkinson\u0026rsquo;s Progression Markers Initiative (PPMI) and\u0026nbsp;Fox Investigation for New Discovery of Biomarkers in Parkinson\u0026rsquo;s Disease\u0026nbsp;(BioFIND). We thank all researchers for sharing data.\u003c/p\u003e\n\u003cp\u003eAuthor contributions\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Z.C. and D.S. conceptualized and designed the study, and were primarily responsible for drafting, editing, and revising the manuscript. Y.A. and M.Y. contributed to data analysis and manuscript revision. Y.L., X.Z., and D.L. were involved in data collection. H.Z. contributed to the study design, data analysis, and manuscript revision. O.C. conceived and supervised the project. All authors reviewed and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eFunding\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Natural Science Foundation of China (81871002, 81471334, 81100981), the Natural Science Foundation of Chongqing, China (CSTB2024NSCQ-MSX0757), the National Key Clinical Specialties Construction Program in China, and the China Postdoctoral Science Foundation (2025M782402).\u003c/p\u003e\n\u003cp\u003eData availability\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe data analysed in this study were sourced from the Parkinson\u0026apos;s Progression Markers Initiative (PPMI, http://www.ppmi-info.org) and the Fox Investigation for New Discovery of Biomarkers (BioFIND, https://biofind.loni.usc.edu/) database. Researchers may access these datasets by submitting a data usage request via the respective official websites.\u003c/p\u003e\n\u003cp\u003eDeclarations\u003c/p\u003e\n\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThe study analysed data from the publicly available Parkinson Progression Marker Initiative (PPMI) and the Fox Investigation for New Discovery of Biomarkers (BioFIND) datasets. Both the PPMI and BioFIND studies were approved by the institutional review boards of all participating sites, and informed consent was obtained from all participants prior to inclusion in the study. The study complies with ethical standards for research involving human participants, and the original study\u0026rsquo;s ethics committee approval and informed consent documentation apply to this analysis.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eNot applicable. This manuscript does not contain data from any individual person in any form (including details, images, or videos).\u003c/p\u003e\n\u003cp\u003eCompeting interests\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors report no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eYe H, Robak LA, Yu M, Cykowski M, Shulman JM. Genetics and Pathogenesis of Parkinson\u0026rsquo;s Syndrome. Annu Rev Pathol Mech Dis. 2023;18:95\u0026ndash;121. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1146/annurev-pathmechdis-031521-034145\u003c/span\u003e\u003cspan address=\"10.1146/annurev-pathmechdis-031521-034145\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTanner CM, Ostrem JL. Parkinson\u0026rsquo;s Disease. 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Cerebrospinal fluid NPTX2 changes and relationship with regional brain metabolism metrics across mild cognitive impairment due to Alzheimer\u0026rsquo;s disease. J Neurol. 2024;271:1999\u0026ndash;2009. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00415-023-12154-7\u003c/span\u003e\u003cspan address=\"10.1007/s00415-023-12154-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Parkinson’s disease, Neuronal pentraxin II, α-synuclein pathology, seed amplification assay, biomarker, dementia","lastPublishedDoi":"10.21203/rs.3.rs-8386534/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8386534/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eParkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by α-synuclein aggregation and dopaminergic neuronal loss. Neuronal pentraxin II (NPTX2), a synaptic plasticity-related protein implicated in several neurodegenerative diseases, has remained largely unexplored in PD. Here, we investigated whether CSF NPTX2 reflects α-synuclein pathology and predicts disease progression in PD.\u003c/p\u003e\n\u003cp\u003e528 PD patients and 178 healthy controls were recruited from the Parkinson’s Progression Markers Initiative cohort, with follow-up data spanning up to 14 years. We assessed cross-sectional or longitudinal associations between baseline CSF NPTX2 and a range of measures, including α-synuclein seed amplification assay kinetics parameters, dopamine transporter uptake, brain structure, motor and cognitive function, using multivariate linear regression and linear mixed model. Cox regression assessed risks of disease progression. The main results were validated in an external cohort from Fox Investigation for New Discovery of Biomarkers in Parkinson’s Disease.\u003c/p\u003e\n\u003cp\u003eCompared with healthy controls, CSF NPTX2 levels were significantly reduced in PD patients (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001), with consistent findings observed in external cohort. Higher baseline CSF NPTX2 levels were associated with delayed α-synuclein seed amplification assay kinetics, including longer time to threshold (β = 4.09, \u003cem\u003eP\u003c/em\u003e = 0.017) and longer time to 50% maximal fluorescence (β = 3.72, \u003cem\u003eP\u003c/em\u003e = 0.019), as well as higher dopamine transporter activity across all striatal subregions (all \u003cem\u003eP\u003c/em\u003e\u0026lt; 0.01). Over a 14-year period, higher baseline NPTX2 was associated with a reduced risk of disease progression in Cox regression, including advanced motor disability (Hoehn-Yahr stage ≥ 4; HR = 0.334, \u003cem\u003eP\u003c/em\u003e = 0.001) and dementia conversion (HR = 0.592, \u003cem\u003eP\u003c/em\u003e = 0.009), and also predicted slower longitudinal worsening of UPDRS III and MoCA scores in linear mixed-effects models. Mediation analysis indicated that putamen volume and DAT activity jointly mediated the relationship between NPTX2 and UPDRS III scores.\u003c/p\u003e\n\u003cp\u003eTogether, these findings identify CSF NPTX2 as a biomarker that reflects α-synuclein pathology, dopaminergic neurodegeneration, and predicts disease progression in PD, highlighting its potential as a predictive and therapeutic target.\u003c/p\u003e","manuscriptTitle":"CSF NPTX2 reflects α-synuclein pathology and predicts disease progression in Parkinson’s disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-30 00:54:09","doi":"10.21203/rs.3.rs-8386534/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c6dda29c-4e98-4910-94a6-256ad491b019","owner":[],"postedDate":"December 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-05T22:08:45+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-30 00:54:09","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8386534","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8386534","identity":"rs-8386534","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}