TY - JOUR
T1 - Synaptic biomarkers in the cerebrospinal fluid associate differentially with classical neuronal biomarkers in patients with Alzheimer’s disease and frontotemporal dementia
AU - Das, Shreyasee
AU - Goossens, Julie
AU - Jacobs, Dirk
AU - Dewit, Nele
AU - Pijnenburg, Yolande A. L.
AU - in ‘t Veld, Sjors G. J. G.
AU - Teunissen, Charlotte E.
AU - Vanmechelen, Eugeen
N1 - Funding Information: S.D., J.G., and D.J. are employees of ADx NeuroSciences, Gent, Belgium. S.D. is also enrolled as a Ph.D. candidate at the Amsterdam University Medical Centre, Amsterdam, Netherlands. E.V.M. is the co-founder of ADx NeuroSciences. C.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 no competing interests. Funding Information: The research discussed herein has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement number 860197. Part of the data used in this article has been collected as a part of the 18HLT09 NeuroMET2 project which received funding from the EMPIR program co-financed by the Participating States and from the European Union’s Horizon 2020 research and innovation program. Funding Information: Clinical CSF samples were transferred from the Amsterdam Dementia Cohort Biobank located at the Amsterdam University Medical Centre, Amsterdam, The Netherlands, to the ADx Biobank located at ADx NeuroSciences, Gent, Belgium, following a contract established between the two involved parties (contract number BBI2021-002). The human whole-brain extracts and human synaptosome extracts were graciously provided by Dr. Alberto Lléo and Dr. Olivia Belbin from the Hospital de la Santa Creu I Sant Pau, Barcelona, Spain. The authors would like to thank Dr. Olivia Belbin and Charlotte De Rocker for their critical review of the manuscript. Publisher Copyright: © 2023, The Author(s).
PY - 2023/12/1
Y1 - 2023/12/1
N2 - Background: Loss of synaptic functionality has been recently identified as an early-stage indicator of neurological diseases. Consequently, monitoring changes in synaptic protein levels may be relevant for observing disease evolution or treatment responses in patients. Here, we have studied the relationship between fluid biomarkers of neurodegeneration and synaptic dysfunction in patients with Alzheimer’s disease (AD), frontotemporal dementia (FTD), and subjective cognitive decline (SCD). Methods: The exploratory cohort consisted of cerebrospinal fluid (CSF) samples (n = 60) from patients diagnosed with AD (n = 20), FTD (n = 20), and SCD (n = 20) from the Amsterdam Dementia Cohort. We developed two novel immunoassays for the synaptic proteins synaptosomal-associated protein-25 (SNAP25) and vesicle-associated membrane protein-2 (VAMP2). We measured the levels of these biomarkers in CSF, in addition to neuronal pentraxin-2 (NPTX2), glutamate ionotropic receptor-4 (GluR4), and neurogranin (Ng) for this cohort. All in-house immunoassays were validated and analytically qualified prior to clinical application. CSF neurogranin (Ng) was measured using a commercially available ELISA. Results: This pilot study indicated that SNAP25, VAMP2, and Ng may not be specific biomarkers for AD as their levels were significantly elevated in patients with both AD and FTD compared to SCD. Moreover, the strength of the correlations between synaptic proteins was lower in the AD and FTD clinical groups compared to SCD. SNAP25, VAMP2, and Ng correlated strongly with each other as well as with total Tau (Tau) and phosphorylated Tau (PTau) in all three clinical groups. However, this correlation was weakened or absent with NPTX2 and GluR4. None of the synaptic proteins correlated to neurofilament light (NfL) in any clinical group. Conclusion: The correlation of the synaptic biomarkers with CSF Tau and PTau but the lack thereof with NfL implies that distinct pathological pathways may be involved in synaptic versus axonal degeneration. Our results reflect the diversity of synaptic pathology in neurodegenerative dementias.
AB - Background: Loss of synaptic functionality has been recently identified as an early-stage indicator of neurological diseases. Consequently, monitoring changes in synaptic protein levels may be relevant for observing disease evolution or treatment responses in patients. Here, we have studied the relationship between fluid biomarkers of neurodegeneration and synaptic dysfunction in patients with Alzheimer’s disease (AD), frontotemporal dementia (FTD), and subjective cognitive decline (SCD). Methods: The exploratory cohort consisted of cerebrospinal fluid (CSF) samples (n = 60) from patients diagnosed with AD (n = 20), FTD (n = 20), and SCD (n = 20) from the Amsterdam Dementia Cohort. We developed two novel immunoassays for the synaptic proteins synaptosomal-associated protein-25 (SNAP25) and vesicle-associated membrane protein-2 (VAMP2). We measured the levels of these biomarkers in CSF, in addition to neuronal pentraxin-2 (NPTX2), glutamate ionotropic receptor-4 (GluR4), and neurogranin (Ng) for this cohort. All in-house immunoassays were validated and analytically qualified prior to clinical application. CSF neurogranin (Ng) was measured using a commercially available ELISA. Results: This pilot study indicated that SNAP25, VAMP2, and Ng may not be specific biomarkers for AD as their levels were significantly elevated in patients with both AD and FTD compared to SCD. Moreover, the strength of the correlations between synaptic proteins was lower in the AD and FTD clinical groups compared to SCD. SNAP25, VAMP2, and Ng correlated strongly with each other as well as with total Tau (Tau) and phosphorylated Tau (PTau) in all three clinical groups. However, this correlation was weakened or absent with NPTX2 and GluR4. None of the synaptic proteins correlated to neurofilament light (NfL) in any clinical group. Conclusion: The correlation of the synaptic biomarkers with CSF Tau and PTau but the lack thereof with NfL implies that distinct pathological pathways may be involved in synaptic versus axonal degeneration. Our results reflect the diversity of synaptic pathology in neurodegenerative dementias.
KW - Alzheimer’s disease
KW - Biomarkers
KW - Dementia
KW - Frontotemporal dementia
KW - Immunoassay
KW - Synapse
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85150963589&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/36964594
U2 - https://doi.org/10.1186/s13195-023-01212-x
DO - https://doi.org/10.1186/s13195-023-01212-x
M3 - Article
C2 - 36964594
SN - 1758-9193
VL - 15
JO - Alzheimer's Research and Therapy
JF - Alzheimer's Research and Therapy
IS - 1
M1 - 62
ER -