Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study.
BACKGROUND
Abnormal hyperphosphorylation of the microtubule-associated protein tau and its incorporation into neurofibrillary tangles are major hallmarks of the pathogenesis of Alzheimer disease (AD). Different tau phosphoepitopes can be sensitively detected in cerebrospinal fluid (CSF).


OBJECTIVE
To compare the diagnostic accuracy of CSF concentrations of tau proteins phosphorylated at 3 pathophysiologically important epitopes (p-tau) to discriminate among patients with AD, nondemented control subjects, and patients with other dementias.


METHODS
Cross-sectional, bicenter, memory clinic-based studies.


METHODS
One hundred sixty-one patients with a clinical diagnosis of AD, frontotemporal dementia, dementia with Lewy bodies, or vascular dementia and 45 nondemented controls (N = 206).


METHODS
Levels of tau protein phosphorylated at threonine 231 (p-tau231), threonine 181 (p-tau181), and serine 199 (p-tau199). The CSF p-tau protein levels were measured using 3 different enzyme-linked immunosorbent assays.


RESULTS
The mean CSF levels of the studied p-tau proteins were significantly elevated in patients with AD compared with the other groups. Applied as single markers, p-tau231and p-tau181 reached specificity levels greater than 75% between AD and the combined non-AD group when sensitivity was set at 85% or greater. Statistical differences between the assay performances are presented. Particularly, discrimination between AD and dementia with Lewy bodies was maximized using p-tau181at a sensitivity of 94% and a specificity of 64%, and p-tau231 maximized group separation between AD and frontotemporal dementia with a sensitivity of 88% and a specificity of 92%. Combinations of the 3 markers did not add discriminative power compared with the application as single markers.


CONCLUSIONS
The p-tau proteins in CSF come closest to fulfilling the criteria of a biological marker of AD. There is a tendency for p-tau proteins to perform differently in the discrimination of primary dementia disorders from AD.
Hampel
Harald
H
Dementia Research Section and Memory Clinic, Alzheimer Memorial Center and Geriatric Psychiatry Branch, Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany. hampel@psy.med.uni-muenchen.de
Buerger
Katharina
K
Zinkowski
Raymond
R
Teipel
Stefan J
SJ
Goernitz
Alexander
A
Andreasen
Niels
N
Sjoegren
Magnus
M
DeBernardis
John
J
Kerkman
Daniel
D
Ishiguro
Koichi
K
Ohno
Hideto
H
Vanmechelen
Eugeen
E
Vanderstichele
Hugo
H
McCulloch
Cheryl
C
Moller
Hans-Jurgen
HJ
Davies
Peter
P
Blennow
Kaj
K
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000175:diagnosis*; D003430:Cross-Sectional Studies; D003704:Dementia / Q000134:cerebrospinal fluid / Q000175:diagnosis*; D015140:Dementia, Vascular / Q000134:cerebrospinal fluid / Q000175:diagnosis; D003937:Diagnosis, Differential; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000134:cerebrospinal fluid; D005260:Female; D006801:Humans; D020961:Lewy Body Disease / Q000134:cerebrospinal fluid / Q000175:diagnosis; D008297:Male; D008875:Middle Aged; D010755:Organophosphates / Q000134:cerebrospinal fluid*; D010766:Phosphorylation; D011237:Predictive Value of Tests; D012016:Reference Values; D016875:tau Proteins / Q000134:cerebrospinal fluid*
D000939:Epitopes; D010755:Organophosphates; D016875:tau Proteins