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Ann Clin Transl Neurol. 2019 Mar 7;6(4):698-707. doi: 10.1002/acn3.745. eCollection 2019 Apr.

Novel CSF biomarkers in genetic frontotemporal dementia identified by proteomics.

Author information

1
Department of Neurology Erasmus Medical Center PO Box 2040 3015 GD Rotterdam The Netherlands.
2
Laboratory of Neuro-oncology Clinical and Cancer Proteomics Department of Neurology Erasmus Medical Center PO Box 2040 3000 CA Rotterdam The Netherlands.
3
Department of Internal Medicine Erasmus Medical Center PO Box 2040 3015 GD Rotterdam The Netherlands.
4
Alzheimer's Disease and Other Cognitive Disorders Unit Department of Neurology Hospital Clínic Institut d'Investigació Biomèdica August Pi i Sunyer Villarroel, 170 08036 Barcelona Spain.
5
Division of Neurogeriatrics Department NVS Karolinska Institutet Center for Alzheimer Research Visionsgatan 4 171 64 Solna Stockholm Sweden.
6
Unit for Hereditary Dementias Theme Aging Karolinska University Hospital-Solna 171 64 Stockholm Sweden.
7
Department of Neurology Penn Frontotemporal Degeneration Center University of Pennsylvania Perelman School of Medicine Philadelphia Pennsylvania.
8
Alzheimer Center and Department of Neurology Neuroscience Campus Amsterdam VU University Medical Center PO Box 7057 1007 MB Amsterdam The Netherlands.
9
Clinique Interdisciplinaire de Mémoire (CIME) CHU de Québec Département des Sciences Neurologiques Université Laval Québec Québec Canada.
10
Molecular Markers Laboratory IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli via Pilastroni 4 Brescia 25125 Italy.
11
MAC Memory Clinic IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli via Pilastroni 4 Brescia 25125 Italy.

Abstract

Objective:

To identify novel CSF biomarkers in GRN-associated frontotemporal dementia (FTD) by proteomics using mass spectrometry (MS).

Methods:

Unbiased MS was applied to CSF samples from 19 presymptomatic and 9 symptomatic GRN mutation carriers and 24 noncarriers. Protein abundances were compared between these groups. Proteins were then selected for validation if identified by ≥4 peptides and if fold change was ≤0.5 or ≥2.0. Validation and absolute quantification by parallel reaction monitoring (PRM), a high-resolution targeted MS method, was performed on an international cohort (n = 210) of presymptomatic and symptomatic GRN, C9orf72 and MAPT mutation carriers.

Results:

Unbiased MS revealed 20 differentially abundant proteins between symptomatic mutation carriers and noncarriers and nine between symptomatic and presymptomatic carriers. Seven of these proteins fulfilled our criteria for validation. PRM analyses revealed that symptomatic GRN mutation carriers had significantly lower levels of neuronal pentraxin receptor (NPTXR), receptor-type tyrosine-protein phosphatase N2 (PTPRN2), neurosecretory protein VGF, chromogranin-A (CHGA), and V-set and transmembrane domain-containing protein 2B (VSTM2B) than presymptomatic carriers and noncarriers. Symptomatic C9orf72 mutation carriers had lower levels of NPTXR, PTPRN2, CHGA, and VSTM2B than noncarriers, while symptomatic MAPT mutation carriers had lower levels of NPTXR and CHGA than noncarriers.

Interpretation:

We identified and validated five novel CSF biomarkers in GRN-associated FTD. Our results show that synaptic, secretory vesicle, and inflammatory proteins are dysregulated in the symptomatic stage and may provide new insights into the pathophysiology of genetic FTD. Further validation is needed to investigate their clinical applicability as diagnostic or monitoring biomarkers.

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