Background Synaptosomal-associated protein 25 (SNAP-25) in cerebrospinal fluid (CSF) is an emerging synaptic biomarker for the early diagnosis of Alzheimer’s disease (AD). However, comprehensive studies investigating the marker in Creutzfeldt-Jakob disease (CJD) and in the differential diagnosis of neurodegenerative diseases are still lacking.
Methods We developed a novel, sensitive ELISA for the measurement of SNAP-25 in CSF. In total, we analysed 316 patients from 6 diagnostic groups comprising patients with AD (n=96), CJD (n=55), Parkinson’s disease spectrum (n=41), frontotemporal lobar degeneration (n=25) and amyotrophic lateral sclerosis (n=24) and non-neurodegenerative control patients (n=75). Using receiver operating characteristic curve analysis, we analysed the differential diagnostic potential and compared the results with core AD biomarkers.
Results SNAP-25 CSF concentrations were elevated in AD and CJD (p<0.0001) but not in the other neurodegenerative diseases. Increased levels were observed already at early AD and CJD stages (p<0.0001). In CJD, SNAP-25 levels correlated negatively with survival time (r=−0.33 (95% CI −0.57 to −0.04, p=0.02). For the discrimination of AD from all other diseases except CJD, we observed a good diagnostic performance for CSF SNAP-25 (area under the curve (AUC) 0.85) which was further improved by applying the ratio with CSF amyloid-β 1–42 (AUC 0.95). For CJD, we could demonstrate a strong differential diagnostic potential against all other groups including AD (AUC 0.97).
Conclusion Using the novel established CSF SNAP-25 ELISA, we here demonstrate the applicability of SNAP-25 as an early synaptic biomarker for both AD and CJD with a possible prognostic value in patients with CJD.
- Creutzfeldt-Jakob disease
- Alzheimer's disease
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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Contributors All authors made substantial contributions to conception and design, and/or acquisition of data, and/or analysis and interpretation of data. All authors gave final approval of the version to be submitted and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Conception and design of the study: SHa, PS, MO; sample collection and data management: SHa, PS, SHe, SA-S, JL, AG, CAFVA, ACL, MO; study management and coordination: SHa, PS, MO; statistical methods and analysis: SHa, PS, MO; interpretation of results: SHa, PS, SHe, PO, SAR, CAFVA, ACL, MO; manuscript writing (first draft): SHa, MO; critical revision of the manuscript: SHa, PS, SHe, PO, SAR, SA-S, JL, CAFVA, AG, ACL, MO. MO acts as guarantor.
Funding This study was supported by intramural funding from the University of Ulm (Bausteinprogramm), the EU Joint Programme-Neurodegenerative Diseases networks GenfiProx (01ED2008A), the German Federal Ministry of Education and Research (FTLDc 01GI1007A), the EU (Moodmarker) programme (01EW2008), the German Research Foundation/DFG (SFB1279), the foundation of the state Baden-Württemberg (D.3830), Boehringer Ingelheim Ulm University BioCenter (D.5009) and the Thierry Latran Foundation (D.2468).
Competing interests SHa, PS, SHe, PO, SAR, SA-S, JL, CAFVA, AG and ACL report no competing interests. MO gave scientific advice for Fujirebio, Roche, Biogen and Axon.
Provenance and peer review Not commissioned; externally peer reviewed.