title: Novel diagnostic cerebrospinal fluid biomarkers for pathologic subtypes of frontotemporal dementia identified by proteomics.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Teunissen
authors.affiliation: Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Naura
authors.initials: N
authors.lastname: Elias
authors.affiliation: Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Marleen J A
authors.initials: MJ
authors.lastname: Koel-Simmelink
authors.affiliation: Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Sisi
authors.initials: S
authors.lastname: Durieux-Lu
authors.affiliation: Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Arjan
authors.initials: A
authors.lastname: Malekzadeh
authors.affiliation: OncoProteomics Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Thang V
authors.initials: TV
authors.lastname: Pham
authors.affiliation: OncoProteomics Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Sander R
authors.initials: SR
authors.lastname: Piersma
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Beccari
authors.affiliation: Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Lieke H H
authors.initials: LH
authors.lastname: Meeter
authors.affiliation: Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands; Alzheimer Center & Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Elise G P
authors.initials: EG
authors.lastname: Dopper
authors.affiliation: Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands; Alzheimer Center & Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: John C
authors.initials: JC
authors.lastname: van Swieten
authors.affiliation: OncoProteomics Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Connie R
authors.initials: CR
authors.lastname: Jimenez
authors.affiliation: Alzheimer Center & Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Yolande A L
authors.initials: YA
authors.lastname: Pijnenburg
keywords: Biomarkers; Cerebrospinal fluid; Differential diagnosis; Frontotemporal dementia; Pathology; Proteomics; TDP-43; Tau