Acta Neuropathologica

, Volume 124, Issue 1, pp 23–35

CSF biomarkers cutoffs: the importance of coincident neuropathological diseases

  • Jon B. Toledo
  • Johannes Brettschneider
  • Murray Grossman
  • Steven E. Arnold
  • William T. Hu
  • Sharon X. Xie
  • Virginia M.-Y. Lee
  • Leslie M. Shaw
  • John Q. Trojanowski
Original Paper

DOI: 10.1007/s00401-012-0983-7

Cite this article as:
Toledo, J.B., Brettschneider, J., Grossman, M. et al. Acta Neuropathol (2012) 124: 23. doi:10.1007/s00401-012-0983-7

Abstract

The effects of applying clinical versus neuropathological diagnosis and the inclusion of cases with coincident neuropathological diagnoses have not been assessed specifically when studying cerebrospinal fluid (CSF) biomarker classification cutoffs for patients with neurodegenerative diseases that cause dementia. Thus, 142 neuropathologically diagnosed neurodegenerative dementia patients [71 Alzheimer’s disease (AD), 29 frontotemporal lobar degeneration (FTLD), 3 amyotrophic lateral sclerosis, 7 dementia with Lewy bodies, 32 of which cases also had coincident diagnoses] were studied. 96 % had enzyme-linked immunosorbant assay (ELISA) CSF data and 77 % had Luminex CSF data, with 43 and 46 controls for comparison, respectively. Aβ42, total, and phosphorylated tau181 were measured. Clinical and neuropathological diagnoses showed an 81.4 % overall agreement. Both assays showed high sensitivity and specificity to classify AD subjects against FTLD subjects and controls, and moderate sensitivity and specificity for classifying FTLD subjects against controls. However, among the cases with neuropathological diagnoses of AD plus another pathology (26.8 % of the sample), 69.4 % (ELISA) and 96.4 % (Luminex) were classified as AD according to their biomarker profiles. Use of clinical diagnosis instead of neuropathological diagnosis led to a 14–17 % underestimation of the biomarker accuracy. These results show that while CSF Aβ and tau assays are useful for diagnosis of AD and neurodegenerative diseases even at MCI stages, CSF diagnostic analyte panels that establish a positive diagnosis of Lewy body disease and FTLD are also needed, and must be established based on neuropathological rather than clinical diagnoses.

Keywords

BiomarkerCerebrospinal fluidAlzheimer’s diseaseFrontotemporal lobar degenerationAmyloid betaTau

Supplementary material

401_2012_983_MOESM1_ESM.docx (169 kb)
Supplementary material 1 (DOCX 168 kb)

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Jon B. Toledo
    • 1
  • Johannes Brettschneider
    • 1
  • Murray Grossman
    • 2
  • Steven E. Arnold
    • 3
  • William T. Hu
    • 4
  • Sharon X. Xie
    • 5
  • Virginia M.-Y. Lee
    • 1
  • Leslie M. Shaw
    • 1
  • John Q. Trojanowski
    • 1
  1. 1.Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, CNDRUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  2. 2.Department of NeurologyUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  3. 3.Department of PsychiatryUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  4. 4.Department of Neurology, Center for Neurodegenerative DiseasesEmory UniversityAtlantaUSA
  5. 5.Department of Biostatistics and EpidemiologyUniversity of Pennsylvania School of MedicinePhiladelphiaUSA