Volume 19, Issue S14 e078154
BIOMARKERS
Free Access

CSF proteome profiling identifies novel biomarkers for Frontotemporal Dementia and its pathological subtypes

Yanaika S. Hok-A-Hin

Corresponding Author

Yanaika S. Hok-A-Hin

Neurochemistry Laboratory, Department of Clinical Chemistry, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands

Correspondece

Yanaika S. Hok-A-Hin, Neurochemistry Laboratory, Department of Clinical Chemistry, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands.

Email: [email protected]

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Lisa Vermunt

Lisa Vermunt

Neurochemistry Laboratory, Amsterdam UMC, Amsterdam, Netherlands

Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, Netherlands

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Carel F.W. Peeters

Carel F.W. Peeters

Mathematical & Statistical Methods group – Biometris, Wageningen University & Research, Wageningen, Netherlands

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Emma L. van der Ende

Emma L. van der Ende

Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam University Medical Centers, Location VUmc, Amsterdam, Netherlands

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Sterre C.M. de Boer

Sterre C.M. de Boer

Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Noord-Holland, Netherlands

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Lieke H. Meeter

Lieke H. Meeter

Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands

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John C. van Swieten

John C. van Swieten

Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands

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William T. Hu

William T. Hu

Emory University, Atlanta, GA, USA

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Alberto Lleó

Alberto Lleó

Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

Center of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain

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Daniel Alcolea

Daniel Alcolea

Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

Center for Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain

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Sebastiaan Engelborghs

Sebastiaan Engelborghs

Vrije Universiteit Brussel, Center for Neurosciences (C4N), Neuroprotection and Neuromodulation Research Group (NEUR), Brussels, Belgium

Universitair Ziekenhuis Brussel, Brussels, Belgium

Reference Center for Biological Markers of Dementia (BIODEM), Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium

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Anne Sieben

Anne Sieben

Lab of neuropathology, Neurobiobank, Institute Born-Bunge, Antwerp University, Edegem, Belgium

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Alice Chen-Plotkin

Alice Chen-Plotkin

Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

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David J. Irwin

David J. Irwin

Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

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Wiesje M. van der Flier

Wiesje M. van der Flier

Epidemiology and Biostatistics, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands

Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands

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Yolande A.L. Pijnenburg

Yolande A.L. Pijnenburg

Amsterdam Neuroscience, Amsterdam UMC, Amsterdam, Netherlands

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Charlotte E. Teunissen

Charlotte E. Teunissen

Neurochemistry Laboratory, Department of Clinical Chemistry, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, Netherlands

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Marta del Campo

Marta del Campo

Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam University Medical Centers, Location VUmc, Amsterdam, Netherlands

Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Spain

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain

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First published: 25 December 2023

Abstract

Background

Frontotemporal dementia (FTD) is caused by frontotemporal lobar degeneration (FTLD) and the most common forms are characterized by either tau (FTLD-Tau) or TDP43 (FTLD-TDP) brain aggregates. However, FTD-specific fluid biomarkers are lacking. Furthermore, the pathological subtypes are not distinct in their presentation, hampering accurate subtyping at clinical diagnosis. Therefore, there is a strong need to identify fluid biomarkers that could aid in FTD diagnosis and to discriminate the pathological subtypes.

Method

We employed an antibody-based proteomic technology to analyze >600 proteins in a large multicenter cohort including cerebrospinal fluid (CSF) samples from FTD (n = 189), AD (n = 235) and cognitively unimpaired individuals (n = 196). For a subset of cases the underlying neuropathology was known or could be predicted (FTLD-Tau = 85 and FTLD-TDP = 57). Differences in protein expression profiles were analyzed by nested linear models. Penalized generalized linear modeling was used to identify classification protein panels. Protein panels were then validated in independent clinical cohorts (cohort 1: n = 157; cohort 2: n = 165) and a neuropathology cohort (n = 100) using customized assays.

Result

We observed 65 differentially regulated proteins in FTD versus controls and AD patients, associated with axonogenesis, synapse assembly, or locomotory behavior pathways. We identified panels of 14 and 13 proteins that could discriminate FTD from controls (AUC = 0.96, 95%CI:0.91-0.99) and AD patients (AUC = 0.91, 95%CI:0.85-0.96), respectively. Most of these proteins (21 out of 27) were translated into customized panels, which discriminated between groups with high accuracy for all three cohorts (FTDvsCon: AUCs > 0.96, FTDvsAD: AUCs > 0.88). When comparing the FTLD-Tau and FTLD-TDP subtypes, we observed that 86 proteins were increased in FTLD-Tau, and associated with developmental and cellular processes and locomotion pathways. A panel of 8 proteins could discriminate between the pathological subtypes (AUC = 0.82, 95%CI:0.66-0.95), which was however not stable during cross-validation.

Conclusion

We identified and validated CSF panels to discriminate FTD from controls and AD with high accuracy. The identification of a biomarker panel to discriminate between the FTLD pathological subtypes likely requires larger and more homogeneous groups. The panels developed within this study might be useful for diagnosis and trial inclusion of FTD patients.