title: Reduced CSF p-Tau181 to Tau ratio is a biomarker for FTLD-TDP.
abstract: OBJECTIVE
  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).
  
  
  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.
  
  
  CONCLUSIONS
  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.
  
  
  METHODS
  This study provides Class II evidence that the CSF p/t-Tau ratio distinguishes FTLD-TDP from FTLD-Tau.
authors.affiliation: From the Department of Neurology (W.T.H., K.W., J.G., J.J.L., C.H., M.S., A.I.L.), Center for Neurodegenerative Diseases Research (W.T.H., K.W., J.G., J.J.L., C.H., A.I.L.), Alzheimer's Disease Research Center (W.T.H., J.G., J.J.L., C.H., A.I.L.), Emory University School of Medicine, Atlanta, GA; and Departments of Neurology (M.G.) and Laboratory Medicine and Pathology (V.V.D., J.Q.T.), University of Pennsylvania, Philadelphia.
authors.forename: William T
authors.initials: WT
authors.lastname: Hu
authors.forename: Kelly
authors.initials: K
authors.lastname: Watts
authors.forename: Murray
authors.initials: M
authors.lastname: Grossman
authors.forename: Jonathan
authors.initials: J
authors.lastname: Glass
authors.forename: James J
authors.initials: JJ
authors.lastname: Lah
authors.forename: Chadwick
authors.initials: C
authors.lastname: Hales
authors.forename: Matthew
authors.initials: M
authors.lastname: Shelnutt
authors.forename: Vivianna
authors.initials: V
authors.lastname: Van Deerlin
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Allan I
authors.initials: AI
authors.lastname: Levey
mesh_terms: D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D015415:Biomarkers / Q000134:cerebrospinal fluid; D000073885:C9orf72 Protein; D016009:Chi-Square Distribution; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000134:cerebrospinal fluid* / Q000235:genetics; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000134:cerebrospinal fluid* / Q000175:diagnosis / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D053759:Interleukin-23 / Q000134:cerebrospinal fluid; D008297:Male; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D010766:Phosphorylation; D000077153:Progranulins; D011506:Proteins / Q000235:genetics; D012680:Sensitivity and Specificity; D013912:Threonine / Q000378:metabolism*; D016875:tau Proteins / Q000134:cerebrospinal fluid*
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D053759:Interleukin-23; D010446:Peptide Fragments; D000077153:Progranulins; D011506:Proteins; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D013912:Threonine