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Cited by 809Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsCerebrospinal fluid and hydrocephalus

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CSF biomarkers of Alzheimer's disease concord with amyloid‐β PET and predict clinical progression: A study of fully automated immunoassays in BioFINDER and ADNI cohorts

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Hansson, Oskar, Seibyl, John, Stomrud, Erik, Zetterberg, Henrik, Trojanowski, John Q., Bittner, Tobias, Lifke, Valeria, Corradini, Veronika, Eichenlaub, Udo, Batrla, Richard, Buck, Katharina, Zink, Katharina, Rabe, Christina, Blennow, Kaj, Shaw, Leslie M., for the Swedish BioFINDER study group, Alzheimer's Disease Neuroimaging Initiative·2018·Alzheimer's & Dementia
DOI 10.1016/j.jalz.2018.01.010PMC PMC6119541
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Abstract

Introduction: We studied whether fully automated Elecsys cerebrospinal fluid (CSF) immunoassay results were concordant with positron emission tomography (PET) and predicted clinical progression, even with cutoffs established in an independent cohort. Methods: Cutoffs for Elecsys amyloid‐β 1–42 (Aβ), total tau/Aβ(1–42), and phosphorylated tau/Aβ(1–42) were defined against [18 F]flutemetamol PET in Swedish BioFINDER (n = 277) and validated against [18 F]florbetapir PET in Alzheimer's Disease Neuroimaging Initiative (n = 646). Clinical progression in patients with mild cognitive impairment (n = 619) was studied. Results: CSF total tau/Aβ(1–42) and phosphorylated tau/Aβ(1–42) ratios were highly concordant with PET classification in BioFINDER (overall percent agreement: 90%; area under the curve: 94%). The CSF biomarker statuses established by predefined cutoffs were highly concordant with PET classification in Alzheimer's Disease Neuroimaging Initiative (overall percent agreement: 89%–90%; area under the curves: 96%) and predicted greater 2‐year clinical decline in patients with mild cognitive impairment. Strikingly, tau/Aβ ratios were as accurate as semiquantitative PET image assessment in predicting visual read–based outcomes. Discussion: Elecsys CSF biomarker assays may provide reliable alternatives to PET in Alzheimer's disease diagnosis.

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Fig. 1 Schematic of three-part strategy for evaluating CSF biomarker concordance with amyloid PET concordance. Abbreviations: CSF, cerebrospinal fluid; ADNI, Alzheimer’s Disease Neuroimaging Initiative.
Fig. 1 Schematic of three-part strategy for evaluating CSF biomarker concordance with amyloid PET concordance. Abbreviations: CSF, cerebrospinal fluid; ADNI, Alzheimer’s Disease Neuroimaging Initiative.CC BY-NC-ND · PubMed Central
Fig. 2 Distribution of the CSF biomarkers colored by PET visual read classification. (A–C) (BioFINDER cohort) and (F–H) (ADNI cohort): Frequency distribution of Aβ(1–42), log(pTau/Aβ[1–42]) and log(tTau/Aβ[1–42]), respectively, by PET classification. (D and E) (BioFINDER cohort) and (I and J) (ADNI cohort): Scatterplots of Aβ(1–42) versus pTau (D and I) and tTau (E and J) with the cutoffs for the respective ratio pTau/Aβ(1–42) (BioFINDER: 0.022, ADNI: 0.028) and tTau/Aβ(1–42) (BioFINDER: 0.26, ADNI: 0.33) shown as diagonal lines. n = 277 (BioFINDER A–E) and n = 646 (ADNI, F–J). Red bars or triangles, PET-positive; blue bars or dots, PET-negative. Abbreviations: CSF, cerebrospinal fluid; ADNI, Alzheimer’s Disease Neuroimaging Initiative; tTau, total tau; pTau, phosphorylated tau; Aβ, amyloid β.
Fig. 2 Distribution of the CSF biomarkers colored by PET visual read classification. (A–C) (BioFINDER cohort) and (F–H) (ADNI cohort): Frequency distribution of Aβ(1–42), log(pTau/Aβ[1–42]) and log(tTau/Aβ[1–42]), respectively, by PET classification. (D and E) (BioFINDER cohort) and (I and J) (ADNI cohort): Scatterplots of Aβ(1–42) versus pTau (D and I) and tTau (E and J) with the cutoffs for the respective ratio pTau/Aβ(1–42) (BioFINDER: 0.022, ADNI: 0.028) and tTau/Aβ(1–42) (BioFINDER: 0.26, ADNI: 0.33) shown as diagonal lines. n = 277 (BioFINDER A–E) and n = 646 (ADNI, F–J). Red bars or triangles, PET-positive; blue bars or dots, PET-negative. Abbreviations: CSF, cerebrospinal fluid; ADNI, Alzheimer’s Disease Neuroimaging Initiative; tTau, total tau; pTau, phosphorylated tau; Aβ, amyloid β.CC BY-NC-ND · PubMed Central
Fig. 3 Scatterplots of CSF biomarkers versus SUVRs in BioFINDER (A–C) and ADNI (D–F). Color and symbols indicate visual read PET-positive (red triangles) and PET-negative (blue dots) patients; vertical and horizontal dashed lines correspond to SUVR and CSF biomarker cutoff values, respectively. (A and D) Aβ(1–42), (B and E) pTau/Aβ(1–42) ratio, and (C and F) tTau/Aβ(1–42) ratio. Number of samples is reduced to N = 233 in BioFINDER and N = 645 in ADNI as the SUVRs were not available for all patients with PET scans. Abbreviations: CSF, cerebrospinal fluid; SUVR, standardized uptake value ratio; tTau, total tau; pTau, phosphorylated tau; Aβ, amyloid β.
Fig. 3 Scatterplots of CSF biomarkers versus SUVRs in BioFINDER (A–C) and ADNI (D–F). Color and symbols indicate visual read PET-positive (red triangles) and PET-negative (blue dots) patients; vertical and horizontal dashed lines correspond to SUVR and CSF biomarker cutoff values, respectively. (A and D) Aβ(1–42), (B and E) pTau/Aβ(1–42) ratio, and (C and F) tTau/Aβ(1–42) ratio. Number of samples is reduced to N = 233 in BioFINDER and N = 645 in ADNI as the SUVRs were not available for all patients with PET scans. Abbreviations: CSF, cerebrospinal fluid; SUVR, standardized uptake value ratio; tTau, total tau; pTau, phosphorylated tau; Aβ, amyloid β.CC BY-NC-ND · PubMed Central
Fig. 4 Time course of pTau/Aβ(1–42) ratio in patients with MCI in the ADNI cohort over 2 years. LS-means with standard errors by biomarker group (red: pTau/Aβ(1–42) biomarker-positive at baseline; blue: pTau/Aβ(1–42) biomarker-negative at baseline). Increasing CDR-SB score indicates a clinical decline. N = 619. No adjustment for ApoE4 status. Abbreviations: pTau, phosphorylated tau; Aβ, amyloid β; ADNI, Alzheimer’s Disease Neuroimaging Initiative; MCI, mild cognitive impairment; CDR-SB, clinical dementia rating–sum of boxes; APOE, apolipoprotein E.
Fig. 4 Time course of pTau/Aβ(1–42) ratio in patients with MCI in the ADNI cohort over 2 years. LS-means with standard errors by biomarker group (red: pTau/Aβ(1–42) biomarker-positive at baseline; blue: pTau/Aβ(1–42) biomarker-negative at baseline). Increasing CDR-SB score indicates a clinical decline. N = 619. No adjustment for ApoE4 status. Abbreviations: pTau, phosphorylated tau; Aβ, amyloid β; ADNI, Alzheimer’s Disease Neuroimaging Initiative; MCI, mild cognitive impairment; CDR-SB, clinical dementia rating–sum of boxes; APOE, apolipoprotein E.CC BY-NC-ND · PubMed Central

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Authors
Hansson, O., Seibyl, J., Stomrud, E., Zetterberg, H., Trojanowski, J. Q., Bittner, T., Lifke, V., Corradini, V., Eichenlaub, U., Batrla, R., Buck, K., Zink, K., Rabe, C., Blennow, K., Shaw, L. M., for the Swedish BioFINDER study group, & Initiative, A. D. N.
Affiliations
  • Lund University (SE)
  • Institute for Neurodegenerative Disorders (US)
  • Sahlgrenska University Hospital (SE)
  • University of Pennsylvania (US)
  • Former Employee of Roche Diagnostics GmbH Penzberg Germany
  • Roche Diagnostics GmbH Penzberg Germany
  • F. Hoffmann-La Roche AG (CH)
  • Alzheimer’s Disease Neuroimaging Initiative (US)
Corresponding author
  • Hansson, Oskar
  • Blennow, Kaj
  • Shaw, Leslie M.
ORCID
Venue
Alzheimer's & Dementia
Publisher
Wiley
Published
2018-02-27
Volume
14
Issue
11
Pages
1470-1481
ISSN
  • 1552-5260 (ISSN-L)
  • 1552-5279
DOI
10.1016/j.jalz.2018.01.010
PMC
PMC6119541
OpenAlex
W2789976306
Cited by
808
References
45
Citations by year
2026: 84 · 2025: 117 · 2024: 146 · 2023: 96 · 2022: 98 · 2021: 95 · 2020: 97 · 2019: 56 · 2018: 15
FWCI
51.74
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s & Dementia (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
  • UCL Discovery (University College London) (submittedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
Funders
  • Michael J. Fox Foundation for Parkinson's Research
  • Eli Lilly and Company
  • Göteborgs Universitet
  • National Institutes of Health
  • National Institute on Aging (P30AG010124)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
Keywords
Alzheimer's disease, cerebrospinal fluid biomarkers
MeSH terms
Aged, Alzheimer Disease, Aniline Compounds, Ethylene Glycols, Female, Humans, Immunoassay, Male, Cohort Studies, Biomarkers, Amyloid beta-Peptides, tau Proteins, Disease Progression, Radiopharmaceuticals, Positron-Emission Tomography, Automation, Laboratory, Cognitive Dysfunction

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