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. 2024 Feb 14;16(1):34.
doi: 10.1186/s13195-024-01409-8.

The use of synaptic biomarkers in cerebrospinal fluid to differentiate behavioral variant of frontotemporal dementia from primary psychiatric disorders and Alzheimer's disease

Shreyasee Das  1   2 , Marie-Paule E van Engelen  3   4 , Julie Goossens  2 , Dirk Jacobs  2 , Bram Bongers  1 , Jay L P Fieldhouse  3   4 , Yolande A L Pijnenburg  3   4 , Charlotte E Teunissen  1   3   4 , Eugeen Vanmechelen  2 , Inge M W Verberk  5   6   7
Affiliations

The use of synaptic biomarkers in cerebrospinal fluid to differentiate behavioral variant of frontotemporal dementia from primary psychiatric disorders and Alzheimer's disease

Shreyasee Das et al. Alzheimers Res Ther. .

Abstract

Background: Lack of early molecular biomarkers in sporadic behavioral variants of frontotemporal dementia (bvFTD) and its clinical overlap with primary psychiatric disorders (PPD) hampers its diagnostic distinction. Synaptic dysfunction is an early feature in bvFTD and identification of specific biomarkers might improve its diagnostic accuracy. Our goal was to understand the differential diagnostic potential of cerebrospinal fluid (CSF) synaptic biomarkers in bvFTD versus PPD and their specificity towards bvFTD compared with Alzheimer's disease (AD) and controls. Additionally, we explored the association of CSF synaptic biomarkers with social cognition, cognitive performance, and disease severity in these clinical groups.

Methods: Participants with probable bvFTD (n = 57), PPD (n = 71), AD (n = 60), and cognitively normal controls (n = 39) with available CSF, cognitive tests, and disease severity as frontotemporal lobar degeneration-modified clinical dementia rating scale (FTLD-CDR) were included. In a subset of bvFTD and PPD cases, Ekman 60 faces test scores for social cognition were available. CSF synaptosomal-associated protein 25 (SNAP25), neurogranin (Ng), neuronal pentraxin 2 (NPTX2), and glutamate receptor 4 (GluR4) were measured, along with neurofilament light (NfL), and compared between groups using analysis of covariance (ANCOVA) and logistic regression. Diagnostic accuracy was assessed using ROC analyses, and biomarker panels were selected using Wald's backward selection. Correlations with cognitive measures were performed using Pearson's partial correlation analysis.

Results: NPTX2 concentrations were lower in the bvFTD group compared with PPD (p < 0.001) and controls (p = 0.003) but not compared with AD. Concentrations of SNAP25 (p < 0.001) and Ng (p < 0.001) were elevated in patients with AD versus those with bvFTD and controls. The modeled panel for differential diagnosis of bvFTD versus PPD consisted of NfL and NPTX2 (AUC = 0.96, CI: 0.93-0.99, p < 0.001). In bvFTD versus AD, the modeled panel consisted of NfL, SNAP25, Ng, and GluR4 (AUC = 0.86, CI: 0.79-0.92, p < 0.001). In bvFTD, lower NPTX2 (Pearson's r = 0.29, p = 0.036) and GluR4 (Pearson's r = 0.34, p = 0.014) concentrations were weakly associated with worse performance of total cognitive score. Lower GluR4 concentrations were also associated with worse MMSE scores (Pearson's r = 0.41, p = 0.002) as well as with worse executive functioning (Pearson's r = 0.36, p = 0.011) in bvFTD. There were no associations between synaptic markers and social cognition or disease severity in bvFTD.

Conclusion: Our findings of involvement of NTPX2 in bvFTD but not PPD contribute towards better understanding of bvFTD disease pathology.

Keywords: Differential diagnosis; Frontotemporal dementia; Primary psychiatric disorders; Synaptic biomarkers.

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Conflict of interest statement

S.D., and J.G., are employees of ADx NeuroSciences, Gent, Belgium. E.V. is the co-founder of ADx NeuroSciences. D.J. is a former employee of ADx NeuroSciences, Gent, Belgium, and is recently retired. C.E.T. has a collaboration contract with ADx NeuroSciences, Quanterix, and Eli Lilly, and has performed contract research or received grants from AC-Immune, Axon Neurosciences, Bioconnect, Bioorchestra, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Grifols, Novo Nordisk, PeopleBio, Roche, Toyama, and Vivoryon. She serves on editorial boards of Medidact Neurologie/Springer, Alzheimer Research and Therapy, Neurology: Neuroimmunology & Neuroinflammation, and is the editor of a Neuromethods book Springer. All the other authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Concentrations of candidate CSF biomarkers across the diagnostic groups. Analysis of covariance (ANCOVA) models corrected for age, sex, and psychotropic medication use with post hoc pairwise comparisons were used to determine the log10 transformed biomarker differences between the clinical groups, with Bonferroni’s multiple comparison correction. A SNAP25. B Ng. C NPTX2. D GluR4. E NfL. SNAP25, synaptosomal-associated protein 25; Ng, neurogranin; NPTX2, neuronal pentraxin 2; GluR4, glutamate receptor 4; NfL, neurofilament light. bvFTD, behavioral frontotemporal dementia; PPD, primary psychiatric disorders; AD, Alzheimer’s disease. *p < 0.05, **p < 0.01, ***p < 0.001
Fig. 2
Fig. 2
ROC curves showing the differentiation accuracy between the diagnostic groups of biomarkers in CSF. A bvFTD versus PPD, Panel-NfL, NPTX2. B bvFTD versus AD, Panel-NfL, SNAP25, Ng, GluR4. AUCs are shown for biomarkers alone. bvFTD, behavioral variant frontotemporal dementia, PPD, primary psychiatric disorders; AD, Alzheimer’s disease; AUC, area under curve; ROC, receiver operating characteristics; NfL, neurofilament; SNAP25, synaptosomal-associated protein 25; Ng, neurogranin; NPTX2, neuronal pentraxin 2; GluR4, glutamate receptor 4
Fig. 3
Fig. 3
Correlation matrix of the fluid biomarkers to cognitive test performance and social test scores in patients with bvFTD, PPD, AD, and controls. The associations are shown as Pearson’s partial correlations, controlling for age. bvFTD, behavioral variant frontotemporal dementia; PPD, primary psychiatric disorders; AD, Alzheimer’s disease; NfL, neurofilament light; SNAP25, synaptosomal-associated protein 25; Ng, neurogranin; NPTX2, neuronal pentraxin 2; GluR4, glutamate receptor 4; MMSE, mini-mental state examination; FTLD-CDR, frontotemporal lobe dementia-cognitive dementia rating. *p < 0.05, **p < 0.01, ***p < 0.001
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