Accuracy of Brain Amyloid Detection in Clinical Practice Using Cerebrospinal Fluid β-Amyloid 42
Authors: Sebastian Palmqvist, Henrik Zetterberg, Kaj Blennow, Susanna Vestberg, Ulf Andreasson, David J. Brooks, Rikard Owenius, Douglas Hägerström, Per Wollmer, Lennart Minthon, Oskar Hansson
Journal: JAMA Neurology (2014)

<h3>Importance</h3> Before adding cerebrospinal fluid (CSF) biomarkers to the diagnostic workup of Alzheimer disease, it needs to be determined whether CSF biomarkers analyzed in routine clinical practice can reliably predict cortical β-amyloid (Aβ) deposition. <h3>Objectives</h3> To study whether CSF biomarkers, analyzed consecutively in routine clinical practice during 2 years, can predict cortical Aβ deposition and to establish a threshold for Aβ42 abnormality. <h3>Design, Setting, and Participants</h3> This cross-sectional study (The Swedish BioFINDER [Biomarkers For Identifying Neurodegenerative Disorders Early and Reliably] Study) was conducted at 3 memory clinics. It involved consecutively referred, nondemented patients with mild cognitive symptoms (original cohort, n = 118; validation cohort, n = 38). <h3>Exposures</h3> Amyloid positron emission tomography imaging with<sup>18</sup>F-flutemetamol. <h3>Main Outcomes and Measures</h3> Analyses of CSF Aβ42, total tau, and phosphorylated tau using an enzyme-linked immunosorbent assay (INNOTEST) in clinical samples. <h3>Results</h3> The agreement between Aβ classification with CSF Aβ42 and<sup>18</sup>F-flutemetamol positron emission tomography was very high (κ = 0.85). Of all the cases, 92% were classified identically using an Aβ42 cutoff of 647 pg/mL or less. Cerebrospinal fluid Aβ42 predicted abnormal cortical Aβ deposition accurately (odds ratio, 165; 95% CI, 39-693; area under the receiver operating characteristic curve, 0.94; 95% CI, 0.88-0.97). The association was independent of age, sex,<i>APOE</i>(apolipoprotein E) genotype, hippocampal volume, memory, and global cognition (adjusted odds ratio, 169; 95% CI, 25-1143). Using ratios of CSF Aβ42:tau or Aβ42:phosphorylated tau did not improve the prediction of Aβ deposition. Cerebrospinal fluid Aβ42 correlated significantly with Aβ deposition in all cortical regions. The highest correlations were in regions with high<sup>18</sup>F-flutemetamol retention (eg, posterior cingulum and precuneus,<i>r</i> = −0.72).<sup>18</sup>F-flutemetamol retention, but not CSF Aβ42, correlated significantly with global cognition (<i>r</i> = −0.32), memory function (<i>r</i> = −0.28), and hippocampal volume (<i>r</i> = −0.36) among those with abnormal Aβ deposition. Finally, the CSF Aβ42 cutoff derived from the original cohort (≤647 pg/mL) had an equally high agreement (95%; κ = 0.89) with<sup>18</sup>F-flutemetamol positron emission tomography in the validation cohort. <h3>Conclusions and Relevance</h3> Cerebrospinal fluid Aβ42 analyzed consecutively in routine clinical practice at an accredited laboratory can be used with high accuracy to determine whether a patient has normal or increased cortical Aβ deposition and so can be valuable for the early diagnosis of Alzheimer disease. Abnormal<sup>18</sup>F-flutemetamol retention levels correlate with disease stage in patients with mild cognitive symptoms, but this is not the case for CSF Aβ42 measurements.