Acta Neuropathologica

, Volume 119, Issue 6, pp 669–678

Novel CSF biomarkers for Alzheimer’s disease and mild cognitive impairment

  • William T. Hu
  • Alice Chen-Plotkin
  • Steven E. Arnold
  • Murray Grossman
  • Christopher M. Clark
  • Leslie M. Shaw
  • Eve Pickering
  • Max Kuhn
  • Yu Chen
  • Leo McCluskey
  • Lauren Elman
  • Jason Karlawish
  • Howard I. Hurtig
  • Andrew Siderowf
  • Virginia M.-Y. Lee
  • Holly Soares
  • John Q. Trojanowski
Original Paper

DOI: 10.1007/s00401-010-0667-0

Cite this article as:
Hu, W.T., Chen-Plotkin, A., Arnold, S.E. et al. Acta Neuropathol (2010) 119: 669. doi:10.1007/s00401-010-0667-0

Abstract

Altered levels of cerebrospinal fluid (CSF) peptides related to Alzheimer’s disease (AD) are associated with pathologic AD diagnosis, although cognitively normal subjects can also have abnormal levels of these AD biomarkers. To identify novel CSF biomarkers that distinguish pathologically confirmed AD from cognitively normal subjects and patients with other neurodegenerative disorders, we collected antemortem CSF samples from 66 AD patients and 25 patients with other neurodegenerative dementias followed longitudinally to neuropathologic confirmation, plus CSF from 33 cognitively normal subjects. We measured levels of 151 novel analytes via a targeted multiplex panel enriched in cytokines, chemokines and growth factors, as well as established AD CSF biomarkers (levels of Aβ42, tau and p-tau181). Two categories of biomarkers were identified: (1) analytes that specifically distinguished AD (especially CSF Aβ42 levels) from cognitively normal subjects and other disorders; and (2) analytes altered in multiple diseases (NrCAM, PDGF, C3, IL-1α), but not in cognitively normal subjects. A multi-prong analytical approach showed AD patients were best distinguished from non-AD cases (including cognitively normal subjects and patients with other neurodegenerative disorders) by a combination of traditional AD biomarkers and novel multiplex biomarkers. Six novel biomarkers (C3, CgA, IL-1α, I-309, NrCAM and VEGF) were correlated with the severity of cognitive impairment at CSF collection, and altered levels of IL-1α and TECK associated with subsequent cognitive decline in 38 longitudinally followed subjects with mild cognitive impairment. In summary, our targeted proteomic screen revealed novel CSF biomarkers that can improve the distinction between AD and non-AD cases by established biomarkers alone.

Keywords

Amyloid betaAbeta42DiagnosisIL-1αMCINrCAMPDGFResistinTECKTDP-43Tau

Supplementary material

401_2010_667_MOESM1_ESM.doc (56 kb)
Supplementary material (DOC 56.0 kb)

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • William T. Hu
    • 1
    • 2
    • 8
  • Alice Chen-Plotkin
    • 1
    • 2
  • Steven E. Arnold
    • 3
  • Murray Grossman
    • 1
  • Christopher M. Clark
    • 1
  • Leslie M. Shaw
    • 4
  • Eve Pickering
    • 7
  • Max Kuhn
    • 7
  • Yu Chen
    • 7
  • Leo McCluskey
    • 1
  • Lauren Elman
    • 1
  • Jason Karlawish
    • 6
  • Howard I. Hurtig
    • 1
  • Andrew Siderowf
    • 1
  • Virginia M.-Y. Lee
    • 2
    • 4
    • 5
  • Holly Soares
    • 7
  • John Q. Trojanowski
    • 2
    • 4
    • 5
  1. 1.Department of NeurologyUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  2. 2.Center for Neurodegenerative Disease ResearchUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  3. 3.Department of PsychiatryUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  4. 4.Department of Pathology and Laboratory MedicineUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  5. 5.Institute on AgingUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  6. 6.Department of MedicineUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  7. 7.Pfizer Global Research and DevelopmentGrotonUSA
  8. 8.Department of NeurologyEmory University School of MedicineAtlantaUSA