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Reference measurement procedure for CSF amyloid beta (Aβ)1–42 and the CSF Aβ1–42/Aβ1–40 ratio – a cross-validation study against amyloid PET

Pannee, Josef; Portelius, Erik; Minthon, Lennart LU ; Gobom, Johan; Andreasson, Ulf; Zetterberg, Henrik LU ; Hansson, Oskar LU and Blennow, Kaj LU (2016) In Journal of Neurochemistry 139(4). p.651-658
Abstract

A clinical diagnosis of Alzheimer's disease is currently made on the basis of results from cognitive tests in combination with medical history and general clinical evaluation, but the peptide amyloid-beta (Aβ) in cerebrospinal fluid (CSF) is increasingly used as a biomarker for amyloid pathology in clinical trials and in recently proposed revised clinical criteria for Alzheimer's disease. Recent analytical developments have resulted in mass spectrometry (MS) reference measurement procedures for absolute quantification of Aβ1–42 in CSF. The CSF Aβ1–42/Aβ1–40 ratio has been suggested to improve the detection of cerebral amyloid deposition, by compensating for inter-individual variations in total Aβ... (More)

A clinical diagnosis of Alzheimer's disease is currently made on the basis of results from cognitive tests in combination with medical history and general clinical evaluation, but the peptide amyloid-beta (Aβ) in cerebrospinal fluid (CSF) is increasingly used as a biomarker for amyloid pathology in clinical trials and in recently proposed revised clinical criteria for Alzheimer's disease. Recent analytical developments have resulted in mass spectrometry (MS) reference measurement procedures for absolute quantification of Aβ1–42 in CSF. The CSF Aβ1–42/Aβ1–40 ratio has been suggested to improve the detection of cerebral amyloid deposition, by compensating for inter-individual variations in total Aβ production. Our aim was to cross-validate the reference measurement procedure as well as the Aβ1–42/Aβ1–40 and Aβ1–42/Aβ1–38 ratios in CSF, measured by high-resolution MS, with the cortical level of Aβ fibrils as measured by amyloid (18F-flutemetamol) positron emission tomography (PET). We included 100 non-demented patients with cognitive symptoms from the Swedish BioFINDER study, all of whom had undergone both lumbar puncture and 18F-flutemetamol PET. Comparing CSF Aβ1–42 concentrations with 18F-flutemetamol PET showed high concordance with an area under the receiver operating characteristic curve of 0.85 and a sensitivity and specificity of 82% and 81%, respectively. The ratio of Aβ1–42/Aβ1–40 or Aβ1–42/Aβ1–38 significantly improved concordance with an area under the receiver operating characteristic curve of 0.95 and a sensitivity and specificity of 96% and 91%, respectively. These results show that the CSF Aβ1–42/Aβ1–40 and Aβ1–42/Aβ1–38 ratios using the described MS method are strongly associated with cortical Aβ fibrils measured by 18F-flutemetamol PET. (Figure presented.).

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer's disease, amyloid beta-peptides, cerebrospinal fluid, mass spectrometry, positron-emission tomography
in
Journal of Neurochemistry
volume
139
issue
4
pages
8 pages
publisher
Wiley-Blackwell
external identifiers
  • scopus:84990037151
  • wos:000387842800012
ISSN
0022-3042
DOI
10.1111/jnc.13838
language
English
LU publication?
yes
id
7f8c53f6-005e-4015-a115-4ef76ee155ff
date added to LUP
2016-12-05 12:03:50
date last changed
2017-09-18 11:30:11
@article{7f8c53f6-005e-4015-a115-4ef76ee155ff,
  abstract     = {<p>A clinical diagnosis of Alzheimer's disease is currently made on the basis of results from cognitive tests in combination with medical history and general clinical evaluation, but the peptide amyloid-beta (Aβ) in cerebrospinal fluid (CSF) is increasingly used as a biomarker for amyloid pathology in clinical trials and in recently proposed revised clinical criteria for Alzheimer's disease. Recent analytical developments have resulted in mass spectrometry (MS) reference measurement procedures for absolute quantification of Aβ<sub>1–42</sub> in CSF. The CSF Aβ<sub>1–42</sub>/Aβ<sub>1–40</sub> ratio has been suggested to improve the detection of cerebral amyloid deposition, by compensating for inter-individual variations in total Aβ production. Our aim was to cross-validate the reference measurement procedure as well as the Aβ<sub>1–42</sub>/Aβ<sub>1–40</sub> and Aβ<sub>1–42</sub>/Aβ<sub>1–38</sub> ratios in CSF, measured by high-resolution MS, with the cortical level of Aβ fibrils as measured by amyloid (<sup>18</sup>F-flutemetamol) positron emission tomography (PET). We included 100 non-demented patients with cognitive symptoms from the Swedish BioFINDER study, all of whom had undergone both lumbar puncture and <sup>18</sup>F-flutemetamol PET. Comparing CSF Aβ<sub>1–42</sub> concentrations with <sup>18</sup>F-flutemetamol PET showed high concordance with an area under the receiver operating characteristic curve of 0.85 and a sensitivity and specificity of 82% and 81%, respectively. The ratio of Aβ<sub>1–42</sub>/Aβ<sub>1–40</sub> or Aβ<sub>1–42</sub>/Aβ<sub>1–38</sub> significantly improved concordance with an area under the receiver operating characteristic curve of 0.95 and a sensitivity and specificity of 96% and 91%, respectively. These results show that the CSF Aβ<sub>1–42</sub>/Aβ<sub>1–40</sub> and Aβ<sub>1–42</sub>/Aβ<sub>1–38</sub> ratios using the described MS method are strongly associated with cortical Aβ fibrils measured by <sup>18</sup>F-flutemetamol PET. (Figure presented.).</p>},
  author       = {Pannee, Josef and Portelius, Erik and Minthon, Lennart and Gobom, Johan and Andreasson, Ulf and Zetterberg, Henrik and Hansson, Oskar and Blennow, Kaj},
  issn         = {0022-3042},
  keyword      = {Alzheimer's disease,amyloid beta-peptides,cerebrospinal fluid,mass spectrometry,positron-emission tomography},
  language     = {eng},
  month        = {11},
  number       = {4},
  pages        = {651--658},
  publisher    = {Wiley-Blackwell},
  series       = {Journal of Neurochemistry},
  title        = {Reference measurement procedure for CSF amyloid beta (Aβ)<sub>1–42</sub> and the CSF Aβ<sub>1–42</sub>/Aβ<sub>1–40</sub> ratio – a cross-validation study against amyloid PET},
  url          = {http://dx.doi.org/10.1111/jnc.13838},
  volume       = {139},
  year         = {2016},
}