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.

10 October, 2016

Pannee J1, Portelius E2, Minthon L3,4, Gobom J2, Andreasson U2, Zetterberg H2,5, Hansson O3,4, Blennow K2J Neurochem. 2016 Aug 31. doi: 10.1111/jnc.13838. [Epub ahead of print]

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 CSF1-42 /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 (18 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 18 F-flutemetamol PET. Comparing CSF1-42 concentrations with 18 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 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 CSF1-42 /Aβ1-40 and Aβ1-42 /Aβ1-38 ratios using the described MS method are strongly associated with cortical Aβ fibrils measured by 18 F-flutemetamol PET. The aim of this study was to cross-validate the Reference Measurement Procedure for amyloid β 1-42 (Aβ1-42) as well as the Aβ1-42/Aβ1-40 and Aβ1-42/Aβ1-38 ratios in cerebrospinal fluid (CSF), measured by mass spectrometry (MS), with the cortical level of Aβ fibrils as measured by positron emission tomography (PET). Our findings show that the CSF Aβ1-42/Aβ1-40 and Aβ1-42/Aβ1-38 ratios using the described MS method are strongly associated with the level of cortical Aβ fibrils, and that the ratios of Aβ1-42/Aβ1-40 (or Aβ1-42/Aβ1-38) is superior to using Aβ1-42 alone.

© 2016 International Society for Neurochemistry.

KEYWORDS:

Alzheimer’s disease; amyloid beta-peptides; cerebrospinal fluid; mass spectrometry; positron-emission tomography