Novel diagnostic cerebrospinal fluid biomarkers for pathologic subtypes of frontotemporal dementia identified by proteomics

Charlotte E. Teunissen, Naura Elias, Marleen J A Koel-Simmelink, Sisi Durieux-Lu, Arjan Malekzadeh, Thang V. Pham, Sander R. Piersma, Tommaso Beccari, Lieke H H Meeter, Elise G P Dopper, John C. van Swieten, Connie R. Jimenez, Yolande A L Pijnenburg

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Introduction: Reliable cerebrospinal fluid (CSF) biomarkers enabling identification of frontotemporal dementia (FTD) and its pathologic subtypes are lacking. Methods: Unbiased high-resolution mass spectrometry-based proteomics was applied on CSF of FTD patients with TAR DNA-binding protein 43 (TDP-43, FTD-TDP, n = 12) or tau pathology (FTD-tau, n = 8), and individuals with subjective memory complaints (SMC, n = 10). Validation was performed by applying enzyme-linked immunosorbent assay (ELISA) or enzymatic assays, when available, in a larger cohort (FTLD-TDP, n = 21, FTLD-tau, n = 10, SMC, n = 23) and in Alzheimer's disease (n = 20), dementia with Lewy bodies (DLB, n = 20), and vascular dementia (VaD, n = 18). Results: Of 1914 identified CSF proteins, 56 proteins were differentially regulated (fold change >1.2, P <.05) between the different patient groups: either between the two pathologic subtypes (10 proteins), or between at least one of these FTD subtypes and SMC (47 proteins). We confirmed the differential expression of YKL-40 by ELISA in a partly independent cohort. Furthermore, enzyme activity of catalase was decreased in FTD subtypes compared with SMC. Further validation in a larger cohort showed that the level of YKL-40 was twofold increased in both FTD pathologic subtypes compared with SMC and that the levels in FTLD-tau were higher compared to Alzheimer's dementia (AD), DLB, and VaD patients. Clinical validation furthermore showed that the catalase enzyme activity was decreased in the FTD subtypes compared to SMC, AD and DLB. Discussion: We identified promising CSF biomarkers for both FTD differential diagnosis and pathologic subtyping. YKL-40 and catalase enzyme activity should be validated further in similar pathology defined patient cohorts for their use for FTD diagnosis or treatment development.

Original languageEnglish
Pages (from-to)86-94
Number of pages9
JournalAlzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
Volume2
DOIs
Publication statusPublished - 2016

Cite this

@article{13d2f70eedbb4fe7bc079100626714b3,
title = "Novel diagnostic cerebrospinal fluid biomarkers for pathologic subtypes of frontotemporal dementia identified by proteomics",
abstract = "Introduction: Reliable cerebrospinal fluid (CSF) biomarkers enabling identification of frontotemporal dementia (FTD) and its pathologic subtypes are lacking. Methods: Unbiased high-resolution mass spectrometry-based proteomics was applied on CSF of FTD patients with TAR DNA-binding protein 43 (TDP-43, FTD-TDP, n = 12) or tau pathology (FTD-tau, n = 8), and individuals with subjective memory complaints (SMC, n = 10). Validation was performed by applying enzyme-linked immunosorbent assay (ELISA) or enzymatic assays, when available, in a larger cohort (FTLD-TDP, n = 21, FTLD-tau, n = 10, SMC, n = 23) and in Alzheimer's disease (n = 20), dementia with Lewy bodies (DLB, n = 20), and vascular dementia (VaD, n = 18). Results: Of 1914 identified CSF proteins, 56 proteins were differentially regulated (fold change >1.2, P <.05) between the different patient groups: either between the two pathologic subtypes (10 proteins), or between at least one of these FTD subtypes and SMC (47 proteins). We confirmed the differential expression of YKL-40 by ELISA in a partly independent cohort. Furthermore, enzyme activity of catalase was decreased in FTD subtypes compared with SMC. Further validation in a larger cohort showed that the level of YKL-40 was twofold increased in both FTD pathologic subtypes compared with SMC and that the levels in FTLD-tau were higher compared to Alzheimer's dementia (AD), DLB, and VaD patients. Clinical validation furthermore showed that the catalase enzyme activity was decreased in the FTD subtypes compared to SMC, AD and DLB. Discussion: We identified promising CSF biomarkers for both FTD differential diagnosis and pathologic subtyping. YKL-40 and catalase enzyme activity should be validated further in similar pathology defined patient cohorts for their use for FTD diagnosis or treatment development.",
keywords = "Biomarkers, Cerebrospinal fluid, Differential diagnosis, Frontotemporal dementia, Pathology, Proteomics, Tau, TDP-43",
author = "Teunissen, {Charlotte E.} and Naura Elias and Koel-Simmelink, {Marleen J A} and Sisi Durieux-Lu and Arjan Malekzadeh and Pham, {Thang V.} and Piersma, {Sander R.} and Tommaso Beccari and Meeter, {Lieke H H} and Dopper, {Elise G P} and {van Swieten}, {John C.} and Jimenez, {Connie R.} and Pijnenburg, {Yolande A L}",
year = "2016",
doi = "10.1016/j.dadm.2015.12.004",
language = "English",
volume = "2",
pages = "86--94",
journal = "Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring",
issn = "2352-8729",
publisher = "Elsevier BV",

}

TY - JOUR

T1 - Novel diagnostic cerebrospinal fluid biomarkers for pathologic subtypes of frontotemporal dementia identified by proteomics

AU - Teunissen, Charlotte E.

AU - Elias, Naura

AU - Koel-Simmelink, Marleen J A

AU - Durieux-Lu, Sisi

AU - Malekzadeh, Arjan

AU - Pham, Thang V.

AU - Piersma, Sander R.

AU - Beccari, Tommaso

AU - Meeter, Lieke H H

AU - Dopper, Elise G P

AU - van Swieten, John C.

AU - Jimenez, Connie R.

AU - Pijnenburg, Yolande A L

PY - 2016

Y1 - 2016

N2 - Introduction: Reliable cerebrospinal fluid (CSF) biomarkers enabling identification of frontotemporal dementia (FTD) and its pathologic subtypes are lacking. Methods: Unbiased high-resolution mass spectrometry-based proteomics was applied on CSF of FTD patients with TAR DNA-binding protein 43 (TDP-43, FTD-TDP, n = 12) or tau pathology (FTD-tau, n = 8), and individuals with subjective memory complaints (SMC, n = 10). Validation was performed by applying enzyme-linked immunosorbent assay (ELISA) or enzymatic assays, when available, in a larger cohort (FTLD-TDP, n = 21, FTLD-tau, n = 10, SMC, n = 23) and in Alzheimer's disease (n = 20), dementia with Lewy bodies (DLB, n = 20), and vascular dementia (VaD, n = 18). Results: Of 1914 identified CSF proteins, 56 proteins were differentially regulated (fold change >1.2, P <.05) between the different patient groups: either between the two pathologic subtypes (10 proteins), or between at least one of these FTD subtypes and SMC (47 proteins). We confirmed the differential expression of YKL-40 by ELISA in a partly independent cohort. Furthermore, enzyme activity of catalase was decreased in FTD subtypes compared with SMC. Further validation in a larger cohort showed that the level of YKL-40 was twofold increased in both FTD pathologic subtypes compared with SMC and that the levels in FTLD-tau were higher compared to Alzheimer's dementia (AD), DLB, and VaD patients. Clinical validation furthermore showed that the catalase enzyme activity was decreased in the FTD subtypes compared to SMC, AD and DLB. Discussion: We identified promising CSF biomarkers for both FTD differential diagnosis and pathologic subtyping. YKL-40 and catalase enzyme activity should be validated further in similar pathology defined patient cohorts for their use for FTD diagnosis or treatment development.

AB - Introduction: Reliable cerebrospinal fluid (CSF) biomarkers enabling identification of frontotemporal dementia (FTD) and its pathologic subtypes are lacking. Methods: Unbiased high-resolution mass spectrometry-based proteomics was applied on CSF of FTD patients with TAR DNA-binding protein 43 (TDP-43, FTD-TDP, n = 12) or tau pathology (FTD-tau, n = 8), and individuals with subjective memory complaints (SMC, n = 10). Validation was performed by applying enzyme-linked immunosorbent assay (ELISA) or enzymatic assays, when available, in a larger cohort (FTLD-TDP, n = 21, FTLD-tau, n = 10, SMC, n = 23) and in Alzheimer's disease (n = 20), dementia with Lewy bodies (DLB, n = 20), and vascular dementia (VaD, n = 18). Results: Of 1914 identified CSF proteins, 56 proteins were differentially regulated (fold change >1.2, P <.05) between the different patient groups: either between the two pathologic subtypes (10 proteins), or between at least one of these FTD subtypes and SMC (47 proteins). We confirmed the differential expression of YKL-40 by ELISA in a partly independent cohort. Furthermore, enzyme activity of catalase was decreased in FTD subtypes compared with SMC. Further validation in a larger cohort showed that the level of YKL-40 was twofold increased in both FTD pathologic subtypes compared with SMC and that the levels in FTLD-tau were higher compared to Alzheimer's dementia (AD), DLB, and VaD patients. Clinical validation furthermore showed that the catalase enzyme activity was decreased in the FTD subtypes compared to SMC, AD and DLB. Discussion: We identified promising CSF biomarkers for both FTD differential diagnosis and pathologic subtyping. YKL-40 and catalase enzyme activity should be validated further in similar pathology defined patient cohorts for their use for FTD diagnosis or treatment development.

KW - Biomarkers

KW - Cerebrospinal fluid

KW - Differential diagnosis

KW - Frontotemporal dementia

KW - Pathology

KW - Proteomics

KW - Tau

KW - TDP-43

UR - http://www.scopus.com/inward/record.url?scp=84964467690&partnerID=8YFLogxK

U2 - 10.1016/j.dadm.2015.12.004

DO - 10.1016/j.dadm.2015.12.004

M3 - Article

VL - 2

SP - 86

EP - 94

JO - Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring

JF - Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring

SN - 2352-8729

ER -