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

摘要

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 (A) 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 A beta(1-42) in CSF. The CSF A beta(1-42)/A beta(1-40) ratio has been suggested to improve the detection of cerebral amyloid deposition, by compensating for inter-individual variations in total A production. Our aim was to cross-validate the reference measurement procedure as well as the A beta(1-42)/A beta(1-40) and A beta(1-42)/A beta(1-38) ratios in CSF, measured by high-resolution MS, with the cortical level of A fibrils as measured by amyloid (F-18-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 F-18-flutemetamol PET. Comparing CSF A beta(1-42) concentrations with F-18-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 A beta(1-42)/A beta(1-40) or A beta(1-42)/A beta(1-38) 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 A(1-42)/A beta(1-40) and A beta(1-42)/A beta(1-38) ratios using the described MS method are strongly associated with cortical A fibrils measured by F-18-flutemetamol PET.