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Reduced CSF p-Tau 181 to Tau ratio is a biomarker for FTLD-TDP

2013; Lippincott Williams & Wilkins; Volume: 81; Issue: 22 Linguagem: Inglês

10.1212/01.wnl.0000436625.63650.27

1526-632X

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

Alzheimer's disease research and treatments

To validate the ability of candidate CSF biomarkers to distinguish between the 2 main 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).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.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.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.This study provides Class II evidence that the CSF p/t-Tau ratio distinguishes FTLD-TDP from FTLD-Tau.