Cerebrospinal fluid biomarkers measured by Elecsys assays compared to amyloid imaging

Abstract

Introduction: Levels of amyloid β peptide 42 (Aβ42), total tau, and phosphorylated tau-181 are well-established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease, but variability in manual plate-based assays has limited their use. We examined the relationship between CSF biomarkers, as measured by a novel automated immunoassay platform, and amyloid positron emission tomography.

Methods: CSF samples from 200 individuals underwent separate analysis for Aβ42, total tau, and phosphorylated tau-181 with automated Roche Elecsys assays. Aβ40 was measured with a commercial plate-based assay. Positron emission tomography with Pittsburgh Compound B was performed less than 1 year from CSF collection.

Results: Ratios of CSF biomarkers (total tau/Aβ42, phosphorylated tau-181/Aβ42, and Aβ42/Aβ40) best discriminated Pittsburgh Compound B-positive from Pittsburgh Compound B-negative individuals.

Discussion: CSF biomarkers and amyloid positron emission tomography reflect different aspects of Alzheimer's disease brain pathology, and therefore, less-than-perfect correspondence is expected. Automated assays are likely to increase the utility of CSF biomarkers.

Keywords: Alzheimer's disease; Amyloid; Biomarker; Cerebrospinal fluid; Cutoff.

Fig. 1. Single CSF analyte values compared to PIB binding

PIB binding was negatively correlated with CSF Aβ42 (A) and positively correlated with CSF Aβ40 (B), tTau (C) and pTau (D). Each point represents the analyte value and PIB mean cortical SUVR for one individual. The horizontal red dashed lines represent the cut-off values that best distinguish between PIB-positive and PIB-negative individuals. The horizontal grey dotted line represents the upper limit of quantitation for Aβ42 (A). For the upper panels, the vertical red dashed lines represent the established cut-off value for PIB positivity (SUVR>1.42). The Spearman correlation coefficient (r) with 95% confidence intervals is indicated. For the lower panels, individuals were dichotomized into PIB negative (SUVR≤1.42) and PIB positive (SUVR>1.42) groups. The lower panels indicate the cut-off values and associated positive percent agreement (PPA), negative percent agreement (NPA) and overall percent agreement (OPA) for each CSF analyte with PIB binding.

Fig. 2. CSF ratios compared to PIB binding

PIB binding is positively correlated with CSF tTau/Aβ42 (A), pTau/Aβ42 (B), and Aβ42/Aβ40 (C). Each point represents the ratio of analytes and PIB mean cortical SUVR for one individual. The horizontal red dashed lines represent the cut-off values that best distinguish between PIB-positive and PIB-negative individuals. For the upper panels, the vertical red dashed lines represent the established cut-off value for PIB positivity (SUVR>1.42). The Spearman correlation coefficient (r) with 95% confidence intervals is indicated. For the lower panels, individuals were dichotomized into PIB negative (SUVR≤1.42) and PIB-positive (SUVR>1.42) groups. The lower panels indicate the cut-off values and associated positive percent agreement (PPA), negative percent agreement (NPA) and overall percent agreement (OPA) for each CSF analyte with PIB binding.

Fig. 3. Receiver Operator Characteristic (ROC) curves for CSF biomarkers compared to PIB binding

For ROC analysis, individuals were dichotomized into PIB-negative (SUVR≤1.42) and PIB-positive (SUVR>1.42) groups. For each CSF biomarker measure, the table indicates the cut-off values and associated positive percent agreement (PPA), negative percent agreement (NPA) and area under the ROC curve (AUC) for the measure compared to PIB status. 95% confidence intervals are included in parentheses.

Fig. 4. Concordance of CSF ratios and PIB binding

The status (positive or negative according to CSF ratios or PIB binding) was evaluated in scatterplots of CSF tTau versus Aβ42 (A), pTau versus Aβ42 (B), and Aβ40 versus Aβ42 (C). Each point represents CSF biomarkers in one individual. Solid points have a positive biomarker status (as defined in the plot titles) and open points have a negative status. The horizontal red dashed lines represent the cut-off values for CSF tTau (A), pTau (B) and Aβ40 (C). The vertical red dashed lines represent the cut-off value for Aβ42. The vertical grey dotted lines represent the upper limit of quantitation for Aβ42. The sloped solid red lines represent the cut-off values for tTau/Aβ42 (A), pTau/Aβ42 (B), and Aβ40/Aβ42 (C).