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Research paper
Elevated YKL-40 and low sAPPβ:YKL-40 ratio in antemortem cerebrospinal fluid of patients with pathologically confirmed FTLD
  1. Daniel Alcolea1,2,
  2. David J Irwin3,
  3. Ignacio Illán-Gala1,2,
  4. Laia Muñoz1,2,
  5. Jordi Clarimón1,2,
  6. Corey T McMillan3,
  7. Juan Fortea1,2,
  8. Rafael Blesa1,2,
  9. Edward B Lee4,
  10. John Q Trojanowski4,
  11. Murray Grossman3,
  12. Alberto Lleó1,2
  1. 1 Sant Pau Memory Unit, Department of Neurology, Institut d’Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
  2. 2 Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas, CIBERNED, Madrid, Spain
  3. 3 Penn FTD Center, Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
  4. 4 Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
  1. Correspondence to Dr Alberto Lleó, Department of Neurology, Hospital Sant Pau, Barcelona 08041, Spain; alleo{at}


Objectives The combination of high YKL-40 (a glial inflammatory marker) and low sAPPβ (a soluble β fragment of amyloid precursor protein) in cerebrospinal fluid (CSF) has been associated with frontotemporal lobar degeneration (FTLD) in clinical series. We investigate these biomarkers in a neuropathologically confirmed cohort of patients with FTLD.

Methods CSF samples were selected from the Penn FTD Center (University of Pennsylvania). Participants were followed to autopsy and had a neuropathological diagnosis of FTLD-Tau (n=24), transactive response DNA-binding protein with 43 kDa (FTLD-TDP) (n=25) or Alzheimer’s disease (AD, n=97). We compared levels of YKL-40 and sAPPβ between groups and with cognitively normal controls (n=77), and assessed their diagnostic utility using receiver operating characteristic curves. We also investigated the effect of AD copathology and the correlation between these CSF markers and tau burden at autopsy.

Results Both FTLD groups had lower levels of sAPPβ, higher levels of YKL-40 and lower sAPPβ:YKL-40 ratio in CSF compared with controls. The group of pure FTLD-Tau (without AD copathology) showed higher levels of YKL-40 than AD and than pure FTLD-TDP. YKL-40 levels correlated with pathological tau burden. The sAPPβ:YKL-40 ratio had an area under the curve (AUC) of 0.91 (95% CI 0.86 to 0.96) to distinguish subjects with FTLD from controls, but lower values to distinguish FTLD from AD (AUC 0.70; 95%  CI 0.61 to 0.79) and to discriminate FTLD-Tau from FTLD-TDP (AUC 0.67; 95%  CI 0.51 to 0.82).

Conclusions Our study provides pathological confirmation that the combination of low sAPPβ and high YKL-40 in CSF is associated with FTLD. These biomarkers could be useful in particular clinical settings when FTLD is suspected.

  • frontotemporal lobar degeneration
  • CSF biomarkers
  • sAPPβ
  • YKL-40
  • Tau
  • TDP-43

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  • Contributors DA and AL contributed to the design and concept of the study, analysis and interpretation of data, statistical analysis, and study supervision or coordination. DJI, JC, CTM, JF, EBL, JQT, MG and AL contributed to obtaining funding. All authors contributed to drafting and revising the manuscript for content and to acquisition of data and/or samples.

  • Funding This work was supported by CIBERNED and Instituto de Salud Carlos III (PI11/02425 and PI14/01126 to JF, PI13/01532 to RB, PI15/00026 to JC, and PI14/01561 to AL), jointly funded by Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea, 'Una manera de hacer Europa'. This work was also supported in part by Generalitat de Catalunya (2014SGR-0235), PERIS grants (SLT002/16/00408 and SLT006/17/125), and 'Marató TV3' grants 201412 10 to JF and 201426 10 to AL. II-G was supported by an i-PFIS grant (IF15/00060) from the Fondo de Investigación en Salud, Instituto de Salud Carlos III. This study was also supported by grants AG010124, AG032953, AG043503,NS088341, AG017586, NS053488, AG052943 and AG038490 from the National Institute of Health, and the Wyncote Foundation, Dana Foundation, BrightFocus Foundation, Penn Institute on Aging, Newhouse Foundation and Arking Family Foundation. The study sponsors had no role in the design of the study, in the collection, analysis and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

  • Competing interests None declared.

  • Ethics approval The Institutional Review Board at the University of Pennsylvania approved the study.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement To request any specific data, please contact the corresponding author (

  • Author note Statistical analyses were performed by Dr. Alcolea and Dr. Lleó.