Reference measurement procedure for CSF amyloid beta (Aβ)_1-42 and the CSF Aβ_1-42 /Aβ_1-40 ratio - a cross-validation study against amyloid PET

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_1-42 in CSF. The CSF Aβ_1-42 /Aβ_1-40 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 Aβ_1-42 /Aβ_1-40 and Aβ_1-42 /Aβ_1-38 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 CSF Aβ_1-42 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 Aβ_1-42 /Aβ_1-40 or Aβ_1-42 /Aβ_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 Aβ_1-42 /Aβ_1-40 and Aβ_1-42 /Aβ_1-38 ratios using the described MS method are strongly associated with cortical Aβ fibrils measured by ¹⁸ F-flutemetamol PET.