Accuracy of Brain Amyloid Detection in Clinical Practice Using Cerebrospinal Fluid β-Amyloid 42

Abstract

IMPORTANCE 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. OBJECTIVES 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. DESIGN, SETTING, AND PARTICIPANTS 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). EXPOSURES Amyloid positron emission tomography imaging with 18 F-flutemetamol. MAIN OUTCOMES AND MEASURES Analyses of CSF Aβ42, total tau, and phosphorylated tau using an enzyme-linked immunosorbent assay (INNOTEST) in clinical samples. RESULTS The agreement between Aβ classification with CSF Aβ42 and 18 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, APOE (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 18 F-flutemetamol retention (eg, posterior cingulum and precuneus, r = −0.72). 18 F-flutemetamol retention, but not CSF Aβ42, correlated significantly with global cognition (r = −0.32), memory function (r = −0.28), and hippocampal volume (r = −0.36) among those with abnormal Aβ deposition. Finally, the CSF Aβ42 cutoff derived from the original cohort (Յ647 pg/mL) had an equally high agreement (95%; κ = 0.89) with 18 F-flutemetamol positron emission tomography in the validation cohort. CONCLUSIONS AND RELEVANCE 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 18 F-flutemetamol retention levels correlate with disease stage in patients with mild cognitive symptoms, but this is not the case for CSF Aβ42 measurements.

Use of amyloid-PET to determine cutpoints for CSF markers: A multicenter study

“…The use of amyloid-PET positivity as a standard of truth overcomes this problem. A previous study 27 also found a higher CSF Ab 42 cutpoint based on amyloid-PET compared with routinely used cutpoints, although our cutpoint of 557 pg/mL was lower than in the previous study. It should be noted that the present study addressed data derived from 5 different laboratories, while in particular Ab 42 is sensitive to preanalytical and analytical factors with interlaboratory variability up to 28%.…”

Assessing the commutability of reference material formats for the harmonization of amyloid-β measurements

“…CSF Aβ42 levels correlate inversely with neuropathological measures of plaque density in Alzheimer brains [3,4] and show high concordance with amyloid positron emission tomography [5,6]. Routine clinical use of CSF Aβ42 is part of the diagnostic process in an increasing number of countries and may be used as a surrogate for neuropathology to either support or rule out a diagnosis of AD in memory-impaired individuals [4,[6][7][8]. Together with other markers, Aβ42 is included in both the IWG-2 and the NIA-AA research criteria for AD [9][10][11].…”

“…It is used to aid in early clinical diagnosis, for enrichment purposes in clinical trials, to monitor the effect of therapeutics and for research purposes [1,2]. CSF Aβ42 levels correlate inversely with neuropathological measures of plaque density in Alzheimer brains [3,4] and show high concordance with amyloid positron emission tomography [5,6]. Routine clinical use of CSF Aβ42 is part of the diagnostic process in an increasing number of countries and may be used as a surrogate for neuropathology to either support or rule out a diagnosis of AD in memory-impaired individuals [4,[6][7][8].…”

The Gothenburg MCI study: Design and distribution of Alzheimer’s disease and subcortical vascular disease diagnoses from baseline to 6-year follow-up

“…It is well recognized that to reliably use biomarkers for all of these purposes and also to be able to compare research findings across the community a lot of effort is being put into reducing measurement variability between different centers by investigating confounding factors. 49,62,63 There are some drawbacks of the study such as potential cohort effects, drop-outs, low number of cases that has developed specific dementia diseases, the presence of lacunes has not been rated in the diagnostic process, and that for practical reasons not all patients eligible for inclusion have been included in the study. Time constraints in the clinic may be a contributing factor to noninclusion.…”

“…The CSF biomarker analyses are performed by board-certified laboratory technicians using a standard laboratory quality control program to assure quality, as described previously. 49 The core biomarker levels are mainly evaluated by commercially available enzyme-linked immunosorbent assays (INNOTEST, Fujirebio, Gent, Belgium). 50,51,52 Internal quality controls, two or more internal control CSF samples (aliquots of pooled CSF), are analyzed each run, to minimize between-assay variability.…”