Tau Rather than TDP-43 Proteins are Potential Cerebrospinal Fluid Biomarkers for Frontotemporal Lobar Degeneration Subtypes: A Pilot Study.
Frontotemporal dementia (FTD) is a heterogeneous disease both at the clinical, genetic, and pathobiological level. The underlying pathological spectrum (termed FTLD, frontotemporal lobar degeneration) is in most cases defined by accumulation of either tau (FTLD-tau) or TDP-43 proteins (FTLD-TDP). Biomarkers to differentiate these subtypes are not yet available, whereas these are essential requirements to study the natural course of disease and for homogeneous inclusion of patients in clinical studies.



To study if a combination of total (t-) and phosphorylated (p-)tau, and t-TDP-43 and p-TDP-43 proteins in cerebrospinal fluid (CSF) is suitable to discriminate FTLD-tau and FTLD-TDP subtypes.



We developed immunoassays for the quantification of t-TDP-43 and p-TDP-43 proteins and used commercially available assays for the quantification of t-tau and p-tau proteins. We quantified these proteins in ventricular CSF samples from neuropathologically defined FTLD-tau and FTLD-TDP cases to study the reflection of underlying brain pathology in CSF composition, and in lumbar CSF samples from FTLD-tau and FTLD-TDP patients to study the diagnostic potential of CSF biomarkers.



In ventricular CSF, t-TDP-43 and t-tau levels, when combined into one model, were significantly different between neuropathologically-defined FTLD-tau and FTLD-TDP cases. In a pilot study using lumbar CSF, the p-tau/t-tau ratio, but not t-TDP-43 levels, were significantly different between FTLD-TDP and FTLD-tau patients.



We conclude that with current available methods, CSF tau, rather than TDP-43 proteins, may have diagnostic value in the differentiation of FTLD patients with either tau or TDP-43 pathology.
Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
H Bea
HB
Kuiperij
Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
Alexandra A M
AA
Versleijen
Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
Marijke
M
Beenes
Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.|Present affiliation: Medisch Centrum Leeuwarden, Leeuwarden, The Netherlands.
Nicolaas A
NA
Verwey
Molecular Markers Lab, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
Luisa
L
Benussi
Molecular Markers Lab, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
Anna
A
Paterlini
Molecular Markers Lab, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
Giuliano
G
Binetti
Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
Charlotte E
CE
Teunissen
Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Radboud University Medical Center, Nijmegen, The Netherlands.
Joost
J
Raaphorst
Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Radboud University Medical Center, Nijmegen, The Netherlands.
Helenius J
HJ
Schelhaas
Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
Benno
B
Küsters
Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
Yolande A L
YA
Pijnenburg
Molecular Markers Lab, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
Roberta
R
Ghidoni
Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
Marcel M
MM
Verbeek
D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001921:Brain / Q000473:pathology; D004268:DNA-Binding Proteins / Q000134:cerebrospinal fluid*; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000134:cerebrospinal fluid* / Q000145:classification / Q000473:pathology; D006801:Humans; D007118:Immunoassay; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D016875:tau Proteins / Q000134:cerebrospinal fluid*
D015415:Biomarkers; D004268:DNA-Binding Proteins; C054369:MAPT protein, human; C000598624:TARDBP protein, human; D016875:tau Proteins
Biomarkers; TAR DNA-binding protein 43; cerebrospinal fluid; frontotemporal lobar degeneration; tau proteins