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

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.