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

• Type of Material: Article
• Authors: William Hu, Emory University; Kelly Watts, Emory University; Murray Grossman, Emory University; Jonathan D Glass, Emory University; James J Lah, Emory University; Chadwick Hales, Emory University; Matthew Shelnutt, Emory University; Vivianna Van Deerlin, Emory University; John Q. Trojanowski, Emory University; Allan I Levey, Emory University
• Language: English
• Date: 2013-11-26
• Publisher: American Academy of Neurology (AAN)
• Publication Version: Final Published Version
• Copyright Statement: © 2013 American Academy of Neurology
• Final Published Version (URL): http://dx.doi.org/10.1212/01.wnl.0000436625.63650.27
• Title of Journal or Parent Work: Neurology
• ISSN: 0028-3878
• Volume: 81
• Issue: 22
• Start Page: 1945
• End Page: 1952
• Grant/Funding Information: Drs. Hu, Grossman, and Trojanowski have a patent pending on reduced p/t-Tau ratio as a biomarker for FTLD-TDP.; Supported by the Viretta Brady Discovery Fund (Emory University), the Alzheimer's Drug Discovery Foundation/the Association for Frontotemporal Degeneration, and the NIH (AG-25688, AG-10124, AG-17586, and NS-44266).
• Keywords: DIAGNOSTIC-CRITERIA; FRONTOTEMPORAL LOBAR DEGENERATION; Neurosciences & Neurology; Clinical Neurology; MUTATIONS; Life Sciences & Biomedicine; EXPRESSION; DEMENTIA; Science & Technology; CLINICOPATHOLOGICAL CORRELATIONS; PROGRANULIN; HUMAN CEREBROSPINAL-FLUID; PROGRESSIVE SUPRANUCLEAR PALSY; ALZHEIMERS-DISEASE
• Research Categories: Health Sciences, Pathology; Health Sciences, General; Psychology, Behavioral

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. © 2013 American Academy of Neurology.