Synaptic biomarkers in the cerebrospinal fluid associate differentially with classical neuronal biomarkers in patients with Alzheimer’s disease and frontotemporal dementia

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

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.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13195-023-01212-x.

Related collections

Most cited references 28

Record: found
Abstract: found
Article: not found

G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences

Franz Faul, Edgar Erdfelder, Albert-Georg Lang … (2007)

G*Power (Erdfelder, Faul, & Buchner, 1996) was designed as a general stand-alone power analysis program for statistical tests commonly used in social and behavioral research. G*Power 3 is a major extension of, and improvement over, the previous versions. It runs on widely used computer platforms (i.e., Windows XP, Windows Vista, and Mac OS X 10.4) and covers many different statistical tests of the t, F, and chi2 test families. In addition, it includes power analyses for z tests and some exact tests. G*Power 3 provides improved effect size calculators and graphic options, supports both distribution-based and design-based input modes, and offers all types of power analyses in which users might be interested. Like its predecessors, G*Power 3 is free.

0 comments Cited 11599 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Biomarkers for Alzheimer's disease: current status and prospects for the future

K Blennow, H Zetterberg (2018)

Accumulating data from the clinical research support that the core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers amyloid-β (Aβ42), total tau (T-tau), and phosphorylated tau (P-tau) reflect key elements of AD pathophysiology. Importantly, a large number of clinical studies very consistently show that these biomarkers contribute with diagnostically relevant information, also in the early disease stages. Recent technical developments have made it possible to measure these biomarkers using fully automated assays with high precision and stability. Standardization efforts have given certified reference materials for CSF Aβ42, with the aim to harmonize results between assay formats that would allow for uniform global reference limits and cut-off values. These encouraging developments have led to that the core AD CSF biomarkers have a central position in the novel diagnostic criteria for the disease and in the recent National Institute on Aging and Alzheimer's Association biological definition of AD. Taken together, this progress will likely serve as the basis for a more general introduction of these diagnostic tests in clinical routine practice. However, the heterogeneity of pathology in late-onset AD calls for an expansion of the AD CSF biomarker toolbox with additional biomarkers reflecting additional aspects of AD pathophysiology. One promising candidate is the synaptic protein neurogranin that seems specific for AD and predicts future rate of cognitive deterioration. Further, recent studies bring hope for easily accessible and cost-effective screening tools in the early diagnostic evaluation of patients with cognitive problems (and suspected AD) in primary care. In this respect, technical developments with ultrasensitive immunoassays and novel mass spectrometry techniques give promise of biomarkers to monitor brain amyloidosis (the Aβ42/40 or APP669-711/Aβ42 ratios) and neurodegeneration (tau and neurofilament light proteins) in plasma samples, but future studies are warranted to validate these promising results further.

0 comments Cited 326 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: found

Is Open Access

Current state of Alzheimer’s fluid biomarkers

José Molinuevo, Scott Ayton, Richard Batrla … (2018)

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a complex and heterogeneous pathophysiology. The number of people living with AD is predicted to increase; however, there are no disease-modifying therapies currently available and none have been successful in late-stage clinical trials. Fluid biomarkers measured in cerebrospinal fluid (CSF) or blood hold promise for enabling more effective drug development and establishing a more personalized medicine approach for AD diagnosis and treatment. Biomarkers used in drug development programmes should be qualified for a specific context of use (COU). These COUs include, but are not limited to, subject/patient selection, assessment of disease state and/or prognosis, assessment of mechanism of action, dose optimization, drug response monitoring, efficacy maximization, and toxicity/adverse reactions identification and minimization. The core AD CSF biomarkers Aβ42, t-tau, and p-tau are recognized by research guidelines for their diagnostic utility and are being considered for qualification for subject selection in clinical trials. However, there is a need to better understand their potential for other COUs, as well as identify additional fluid biomarkers reflecting other aspects of AD pathophysiology. Several novel fluid biomarkers have been proposed, but their role in AD pathology and their use as AD biomarkers have yet to be validated. In this review, we summarize some of the pathological mechanisms implicated in the sporadic AD and highlight the data for several established and novel fluid biomarkers (including BACE1, TREM2, YKL-40, IP-10, neurogranin, SNAP-25, synaptotagmin, α-synuclein, TDP-43, ferritin, VILIP-1, and NF-L) associated with each mechanism. We discuss the potential COUs for each biomarker.

0 comments Cited 183 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Eugeen Vanmechelen: eugeen.vanmechelen@adxneurosciences.com

Journal

Journal ID (nlm-ta): Alzheimers Res Ther

Journal ID (iso-abbrev): Alzheimers Res Ther

Title: Alzheimer's Research & Therapy

Publisher: BioMed Central (London )

ISSN (Electronic): 1758-9193

Publication date (Electronic): 24 March 2023

Publication date PMC-release: 24 March 2023

Publication date Collection: 2023

Volume: 15

Electronic Location Identifier: 62

Affiliations

[1 ]ADxNeuroSciences NV, Zwijnaarde 94, 9052 Ghent, Belgium

[2 ]GRID grid.12380.38, ISNI 0000 0004 1754 9227, Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Program Neurodegeneration, Amsterdam UMC, , Vrije Universiteit Amsterdam, ; De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands

[3 ]Medpace, Technologielaan 11, 3001 Leuven, Belgium

Article

Publisher ID: 1212

DOI: 10.1186/s13195-023-01212-x

PMC ID: 10037899

PubMed ID: 36964594

SO-VID: 7e0f7d07-95b2-48f9-8b73-3449f3c4adf8

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 12 November 2022

Date accepted : 14 March 2023

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100010686, H2020 European Institute of Innovation and Technology;

Award ID: 860197

Award ID: 18HLT09

Award ID: 860197

Custom metadata

ScienceOpen disciplines: Neurology

Keywords: biomarkers,immunoassay,synapse,dementia,alzheimer’s disease,frontotemporal dementia

Data availability:

ScienceOpen disciplines: Neurology

Keywords: biomarkers, immunoassay, synapse, dementia, alzheimer’s disease, frontotemporal dementia

Comments

Comment on this article

scite_

Smart Citations

Citing PublicationsSupportingMentioningContrasting

View Citations

See how this article has been cited at scite.ai

scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.

Cited by 16

See all cited by

Most referenced authors 511

See all reference authors

Synaptic biomarkers in the cerebrospinal fluid associate differentially with classical neuronal biomarkers in patients with Alzheimer’s disease and frontotemporal dementia

Read this article at

Abstract

Background

Methods

Results

Conclusion

Supplementary Information

Related collections

Karger: Neurology and Neuroscience

Most cited references 28

G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences

Biomarkers for Alzheimer's disease: current status and prospects for the future

Current state of Alzheimer’s fluid biomarkers

Author and article information

Contributors

Journal

Affiliations

Article

History

Funding

Categories

Custom metadata

Comments

Comment on this article

Similar content 743

Cited by 16

Most referenced authors 511