Reduced CSF p-Tau181 to Tau ratio is a biomarker for FTLD-TDP

William T. Hu, Kelly Watts, Murray Grossman, Jonathan Glass, James J. Lah, Chadwick Hales, Matthew Shelnutt, Vivianna Van Deerlin, John Q. Trojanowski, Allan I. Levey

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

Abstract

Objectives: To validate the ability of candidateCSF biomarkers to distinguish between the 2main forms of frontotemporal lobar degeneration (FTLD), FTLD with TAR DNA-binding protein 43 (TDP-43) inclusions (FTLD-TDP) and FTLD with Tau inclusions (FTLD-Tau). Methods: Antemortem CSF samples were collected from 30 patients with FTLD in a single-center validation cohort, and CSF levels of 5 putative FTLD-TDP biomarkers as well as levels of total Tau (t-Tau) and Tau phosphorylated at threonine 181 (p-Tau181) were measured using independent assays. Biomarkers most associated with FTLD-TDP were then tested in a separate 2-center validation cohort composed of subjects with FTLD-TDP, FTLD-Tau, Alzheimer disease (AD), and cognitively normal subjects. The sensitivity and specificity of FTLD-TDP biomarkers were determined. Results: In the first validation cohort, FTLD-TDP cases had decreased levels of p-Tau181 and interleukin-23, and increased Fas. Reduced ratio of p-Tau181 to t-Tau (p/t-Tau) was the strongest predictor of FTLD-TDP pathology. Analysis in the second validation cohort showed CSF p/t-Tau ratio ,0.37 to distinguish FTLD-TDP from FTLD-Tau, AD, and healthy seniors with 82% sensitivity and 82% specificity. Conclusion: A reduced CSF p/t-Tau ratio represents a reproducible, validated biomarker for FTLD-TDP with performance approaching well-established CSF AD biomarkers. Introducing this biomarker into research and the clinical arena can significantly increase the power of clinical trials targeting abnormal accumulations of TDP-43 or Tau, and select the appropriate patients for target-specific therapies. Classification of evidence: This study provides Class II evidence that the CSF p/t-Tau ratio distinguishes FTLD-TDP from FTLD-Tau.

Original languageEnglish (US)
Pages (from-to)1945-1952
Number of pages8
JournalNeurology
Volume81
Issue number22
DOIs
StatePublished - Nov 26 2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

Keywords

  • AD 5 Alzheimer disease
  • ALS 5 amyotrophic lateral sclerosis
  • AUC 5 area under the curve
  • Ab42 5 b-amyloid 1-42
  • CI 5 confidence interval
  • FTD 5 frontotemporal degeneration
  • FTLD 5 frontotemporal lobar degeneration
  • FTLD-TDP 5 frontotemporal lobar degeneration with TAR DNA-binding protein 43 (TDP-43) inclusions
  • FTLD-Tau 5 frontotemporal lobar degeneration with Tau inclusions
  • IL 5 interleukin
  • P-Tau181 5 Tau phosphorylated at threonine 181
  • PN 5 peripheral neuropathy
  • PSP 5 progressive supranuclear palsy
  • Penn 5 University of Pennsylvania
  • ROC 5 receiver operating characteristic
  • T-Tau 5 total Tau

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