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. 2020 Mar 31;12(1):36.
doi: 10.1186/s13195-020-00595-5.

Elecsys CSF biomarker immunoassays demonstrate concordance with amyloid-PET imaging

James D Doecke  1   2 , Larry Ward  3 , Samantha C Burnham  4 , Victor L Villemagne  5   6 , Qiao-Xin Li  5 , Steven Collins  5   7 , Christopher J Fowler  5 , Ekaterina Manuilova  8 , Monika Widmann  9 , Stephanie R Rainey-Smith  10 , Ralph N Martins  11   12 , Colin L Masters  5 ; AIBL Research Group
Affiliations

Elecsys CSF biomarker immunoassays demonstrate concordance with amyloid-PET imaging

James D Doecke et al. Alzheimers Res Ther. .

Abstract

Background: β-amyloid (Aβ) positron emission tomography (PET) imaging is currently the only Food and Drug Administration-approved method to support clinical diagnosis of Alzheimer's disease (AD). However, numerous research studies support the use of cerebrospinal fluid (CSF) biomarkers, as a cost-efficient, quick and equally valid method to define AD pathology.

Methods: Using automated Elecsys® assays (Roche Diagnostics) for Aβ (1-42) (Aβ42), Aβ (1-40) (Aβ40), total tau (tTau) and phosphorylated tau (181P) (pTau), we examined CSF samples from 202 participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing cohort, to demonstrate the concordance with pathological AD via PET imaging.

Results: Ratios Aβ42/Aβ40, tTau/Aβ42 and pTau/Aβ42 had higher receiver operator characteristic-area under the curve (all 0.94), and greater concordance with Aβ-PET (overall percentage agreement ~ 90%), compared with individual biomarkers.

Conclusion: Strong concordance between CSF biomarkers and Aβ-PET status was observed overall, including for cognitively normal participants, further strengthening the association between these markers of AD neuropathological burden for both developmental research studies and for use in clinical trials.

Keywords: Alzheimer’s disease; Beta-amyloid; Cerebrospinal fluid; Concordance PET; Tau.

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Conflict of interest statement

JDD, LW, SCB, QXL, SC, CJF, SRRS, RNM and CLM declare that they have no competing interests. EM and MW are employees of Roche Diagnostics GmbH. VLV reports speaker honoraria from GE Healthcare, Piramal Imaging and Avid Radiopharmaceuticals, and consulting fees from Lundbeck, AbbVie, Shanghai Green Valley Co and Hoffmann La Roche, all outside the scope of the submitted work.

Figures

Fig. 1
Fig. 1
Box and whisker plots of CSF biomarkers by Aβ-PET status and clinical classification. a Aβ42, b Aβ42/Aβ40 ratio, c tTau, d tTau/Aβ42 ratio, e pTau and f pTau/Aβ42 ratio. Dashed lines represent threshold values for each CSF biomarker as calculated via ROC analyses. Abbreviations: Aβ, β-amyloid; Aβ42, β-amyloid (1–42); Aβ42/Aβ40, β-amyloid (1–42)/β-amyloid (1–40) ratio; AD, Alzheimer’s disease; CSF, cerebrospinal fluid; HC, healthy controls; MCI, mild cognitive impairment; PET, positron emission tomography; pTau, phosphorylated tau (181P); pTau/Aβ42, phosphorylated tau (181P)/β-amyloid (1–42) ratio; ROC, receiver operating characteristic; tTau, total tau; tTau/Aβ42, total tau/β-amyloid (1–42) ratio
Fig. 2
Fig. 2
ROC curves of a individual CSF biomarkers and b biomarker ratios to predict Aβ-PET status. AUC statistics are presented for each biomarker. Abbreviations: Aβ, β-amyloid; Aβ42, β-amyloid (1–42); Aβ42/Aβ40, β-amyloid (1–42)/β-amyloid (1–40) ratio; AUC, area under the curve; CSF, cerebrospinal fluid; PET, positron emission tomography; pTau, phosphorylated tau (181P); pTau/Aβ42, phosphorylated tau (181P)/β-amyloid (1–42) ratio; tTau, total tau; tTau/Aβ42, total tau/β-amyloid (1–42) ratio
Fig. 3
Fig. 3
CSF biomarkers versus NAV/PiB SUVR for a Aβ42, threshold: 1054, b Aβ42/Aβ40 ratio, threshold: 64.0 (× 0.001) and c pTau/Aβ42 ratio,threshold: 0.018. Solid lines in plots a and b represent the non-linear relationship between CSF biomarkers and NAV/PiB SUVR. The solid line in plot c represents the linear relationship between NAV/PiB SUVR and pTau/Aβ42. Grey shaded areas represent the 95% CI around the solid line. Grey dashed lines represent thresholds for SUVR (vertical) and CSF (horizontal) biomarkers. Red symbols represent Aβ-PET+; blue symbols represent Aβ-PET–; circles represent CN participants; triangles represent participants with MCI; squares represent participants with AD. Abbreviations: Aβ, β-amyloid; Aβ42, β-amyloid (1–42); Aβ42/Aβ40, β-amyloid (1–42)/β-amyloid (1–40) ratio; AD, Alzheimer’s disease; CI, confidence interval; CN, cognitively normal; CSF, cerebrospinal fluid; MCI, mild cognitive impairment; NAV, 18F-NAV4694; PET, positron emission tomography; PiB, 11C-Pittsburgh compound B; pTau/Aβ42, phosphorylated tau (181P)/β-amyloid (1–42) ratio; SUVR, standardised uptake value ratio
Fig. 4
Fig. 4
CSF biomarker relationships for a tTau versus Aβ42 and b pTau versus Aβ42. Diagonal lines represent the split between the two clusters. Horizontal and vertical lines represent the cut-offs. Red symbols represent Aβ-PET+; blue symbols represent Aβ-PET–; circles represent cognitively normal participants; triangles represent participants with MCI; squares represent participants with AD. Abbreviations: Aβ, β-amyloid; Aβ42, β-amyloid (1–42); AD, Alzheimer’s disease; CSF, cerebrospinal fluid; MCI, mild cognitive impairment; PET, positron emission tomography; pTau, phosphorylated tau (181P); tTau, total tau
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