NPTX2 Identified as Synaptic Biomarker Implicated in ALS Survival, Disease Progression

Koen Poesen, PhD

A recently published study found that serum neuronal pentraxin 2 (NPTX2) levels, quantified using the Lumipulse, are associated with shorter survival in amyotrophic lateral sclerosis (ALS). More notably, integrating NPTX2 into a survival prediction model with serum neurofilament light (NfL) improved the predictive performance compared with single biomarker models.¹

The findings, made by Koen Poesen, PhD, department chair of neurosciences at KU Leueven, and others, have significant implications, as there are already a limited number of biomarkers available to track ALS progression. In the conclusion section, the study authors noted that combining NPTX2 with biomarkers of neuroinflammation and neurodegeneration could enable more precise approaches for ALS prognosis, disease monitoring, and patient outcome evaluation.

In the study, 43 patients with ALS, 54 disease controls (DCs) and 16 healthy controls (HCs) had serum sample data collected for both NPTX2 and SNAP-25 levels, using Lumipulse and single molecule array platforms, respectively. NfL serum samples were quantified using a commercially available kit from Fujirebio.

All told, the study revealed that overall survival was significantly shorter in patients with elevated serum NPTX2 (median survival 17.7 months vs 37.5 months; P _log-rank = 0.009) or elevated NfL (median survival, 19.4 months vs 42.5 months; P _log-rank = 0.0008). In single biomarker Cox models, high NPTX2 (HR, 3.66; 95% CI, 1.41-9.50; P = .008) and high NfL (HR, 3.16; 95% CI, 1.21-8.25; P = .019) were significant survival predictors.

After classifying patients as either (1) both elevated NPTX2 and NfL, (2) either elevated NPTX2 or NfL, and (3) both low NPTX2 and NfL, results showed 3 significantly different survival profiles (1: 17.1 months; 2: 28.7 months; 3: 76.6 months; P log-rank <.0001). A notable finding revealed that combining NPTX2 with NfL improved the predictive performance compared with either marker alone (P = .03), yielding HRs of 3.39 (95% CI, 1.29-8.93) for elevated NPTX2 and 2.78 (95% CI, 1.08-7.12) for elevated NfL levels. For patients with both, the results yielded an HR of 9.90 (95% CI, 2.56-38.24).

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Regarding NPTX2 and NfL, the study authors wrote that, "This combination also refined patient stratification into distinct survival groups (short, intermediate and long survivors). Our findings suggest that using multibiomarker models that reflect distinct disease mechanisms enhances survival-based patient profiling, consistent with our earlier CSF findings in ALS. Hence, our study now demonstrates that a novel serum synaptic biomarker improves survival prediction alongside serum NfL in ALS."

Additional data showed an association between serum levels of NPTX2, NfL, and the ALS Functional Rating Scale-Revised (ALSFRS-R) slope (NPTX2: ß = 0.20; P = .030; NfL: ß = 0.27; P = .005), suggesting that serum NPTX2 could serve as a potential biomarker for tracking disease severity. This finding contrasted a previously completed mass-spectrometry study by Oh et al which reported no association between cerebrospinal fluid (CSF) NPTX2 levels and clinical disease status. That study, published in 2023, focused on CSF levels of NPTX2 instead, which were reportedly reduced in patients with ALS vs HC.²

The 2023 analysis identified 53 proteins that were different between patients with ALS (n = 20) and HCs (n = 20) after CSF fractionation. Subsequently, the identified proteins were examined using parallel reaction monitoring (PRM) MS methods on 61 unfractionated CSF samples comprising 30 patients with ALS and 31 HC individuals. All told, fifteen proteins (APOB, APP, CAMK2A, CHI3L1, CHIT1, CLSTN3, ERAP2, FSTL4, GPNMB, JCHAIN, L1CAM, SERPINA1, SERPINA3, UCHL1), including NPTX2, showed significant differences between ALS and the control.

REFERENCES
1. Alali S, Dubin J, Hobin F, et al. Serum neuronal pentraxin 2 levels are associated with shorter survival in amyotrophic lateral sclerosis. Neurol, Neurosurg, & Psych. Published online June 15, 2025. doi: 10.1136/jnnp-2025-336198
2. Oh S, Jang Y, Na CH. Discovery of Biomarkers for Amyotrophic Lateral Sclerosis from Human Cerebrospinal Fluid Using Mass-Spectrometry-Based Proteomics. Biomedicines. 2023;11(5):1250. doi: 10.3390/biomedicines11051250