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Robustness of CSF Aβ42/40 and Aβ42/P-tau181 measured using fully automated immunoassays to detect AD-related outcomes

Leuzy, Antoine LU ; Mattsson-Carlgren, Niklas LU orcid ; Cullen, Nicholas C. LU ; Stomrud, Erik LU orcid ; Palmqvist, Sebastian LU orcid ; La Joie, Renaud ; Iaccarino, Leonardo ; Zetterberg, Henrik LU ; Rabinovici, Gil and Blennow, Kaj LU , et al. (2023) In Alzheimer's and Dementia 19(7). p.2994-3004
Abstract

Introduction: This study investigated the comparability of cerebrospinal fluid (CSF) cutoffs for Elecsys immunoassays for amyloid beta (Aβ)42/Aβ40 or Aβ42/phosphorylated tau (p-tau)181 and the effects of measurement variability when predicting Alzheimer's disease (AD)-related outcomes (i.e., Aβ-positron emission tomography [PET] visual read and AD neuropathology). Methods: We studied 750 participants (BioFINDER study, Alzheimer's Disease Neuroimaging Initiative [ADNI], and University of California San Francisco [UCSF]). Youden's index was used to identify cutoffs and to calculate accuracy (Aβ-PET visual read as outcome). Using longitudinal variability in Aβ-negative controls, we identified a gray zone around cut-points where the risk of... (More)

Introduction: This study investigated the comparability of cerebrospinal fluid (CSF) cutoffs for Elecsys immunoassays for amyloid beta (Aβ)42/Aβ40 or Aβ42/phosphorylated tau (p-tau)181 and the effects of measurement variability when predicting Alzheimer's disease (AD)-related outcomes (i.e., Aβ-positron emission tomography [PET] visual read and AD neuropathology). Methods: We studied 750 participants (BioFINDER study, Alzheimer's Disease Neuroimaging Initiative [ADNI], and University of California San Francisco [UCSF]). Youden's index was used to identify cutoffs and to calculate accuracy (Aβ-PET visual read as outcome). Using longitudinal variability in Aβ-negative controls, we identified a gray zone around cut-points where the risk of an inconsistent predicted outcome was >5%. Results: For Aβ42/Aβ40, cutoffs across cohorts were <0.059 (BioFINDER), <0.057 (ADNI), and <0.058 (UCSF). For Aβ42/p-tau181, cutoffs were <41.90 (BioFINDER), <39.20 (ADNI), and <46.02 (UCSF). Accuracy was ≈90% for both Aβ42/Aβ40 and Aβ42/p-tau181 using these cutoffs. Using Aβ-PET as an outcome, 8.7% of participants fell within a gray zone interval for Aβ42/Aβ40, compared to 4.5% for Aβ42/p-tau181. Similar findings were observed using a measure of overall AD neuropathologic change (7.7% vs. 3.3%). In a subset with CSF and plasma Aβ42/40, the number of individuals within the gray zone was ≈1.5 to 3 times greater when using plasma Aβ42/40. Discussion: CSF Aβ42/p-tau181 was more robust to the effects of measurement variability, suggesting that it may be the preferred Elecsys-based measure in clinical practice and trials.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer's disease, amyloid beta 42/amyloid beta 40, amyloid beta 42/phosphorylated tau 181, amyloid beta positron emission tomography, cerebrospinal fluid, Elecsys, plasma
in
Alzheimer's and Dementia
volume
19
issue
7
pages
2994 - 3004
publisher
Wiley
external identifiers
  • pmid:36681387
  • scopus:85147028083
ISSN
1552-5260
DOI
10.1002/alz.12897
language
English
LU publication?
yes
id
190814ad-dca1-43cc-9e7a-b2f8f66215c0
date added to LUP
2023-02-13 12:35:39
date last changed
2024-06-13 23:35:34
@article{190814ad-dca1-43cc-9e7a-b2f8f66215c0,
  abstract     = {{<p>Introduction: This study investigated the comparability of cerebrospinal fluid (CSF) cutoffs for Elecsys immunoassays for amyloid beta (Aβ)42/Aβ40 or Aβ42/phosphorylated tau (p-tau)181 and the effects of measurement variability when predicting Alzheimer's disease (AD)-related outcomes (i.e., Aβ-positron emission tomography [PET] visual read and AD neuropathology). Methods: We studied 750 participants (BioFINDER study, Alzheimer's Disease Neuroimaging Initiative [ADNI], and University of California San Francisco [UCSF]). Youden's index was used to identify cutoffs and to calculate accuracy (Aβ-PET visual read as outcome). Using longitudinal variability in Aβ-negative controls, we identified a gray zone around cut-points where the risk of an inconsistent predicted outcome was &gt;5%. Results: For Aβ42/Aβ40, cutoffs across cohorts were &lt;0.059 (BioFINDER), &lt;0.057 (ADNI), and &lt;0.058 (UCSF). For Aβ42/p-tau181, cutoffs were &lt;41.90 (BioFINDER), &lt;39.20 (ADNI), and &lt;46.02 (UCSF). Accuracy was ≈90% for both Aβ42/Aβ40 and Aβ42/p-tau181 using these cutoffs. Using Aβ-PET as an outcome, 8.7% of participants fell within a gray zone interval for Aβ42/Aβ40, compared to 4.5% for Aβ42/p-tau181. Similar findings were observed using a measure of overall AD neuropathologic change (7.7% vs. 3.3%). In a subset with CSF and plasma Aβ42/40, the number of individuals within the gray zone was ≈1.5 to 3 times greater when using plasma Aβ42/40. Discussion: CSF Aβ42/p-tau181 was more robust to the effects of measurement variability, suggesting that it may be the preferred Elecsys-based measure in clinical practice and trials.</p>}},
  author       = {{Leuzy, Antoine and Mattsson-Carlgren, Niklas and Cullen, Nicholas C. and Stomrud, Erik and Palmqvist, Sebastian and La Joie, Renaud and Iaccarino, Leonardo and Zetterberg, Henrik and Rabinovici, Gil and Blennow, Kaj and Janelidze, Shorena and Hansson, Oskar}},
  issn         = {{1552-5260}},
  keywords     = {{Alzheimer's disease; amyloid beta 42/amyloid beta 40; amyloid beta 42/phosphorylated tau 181; amyloid beta positron emission tomography; cerebrospinal fluid; Elecsys; plasma}},
  language     = {{eng}},
  number       = {{7}},
  pages        = {{2994--3004}},
  publisher    = {{Wiley}},
  series       = {{Alzheimer's and Dementia}},
  title        = {{Robustness of CSF Aβ42/40 and Aβ42/P-tau181 measured using fully automated immunoassays to detect AD-related outcomes}},
  url          = {{http://dx.doi.org/10.1002/alz.12897}},
  doi          = {{10.1002/alz.12897}},
  volume       = {{19}},
  year         = {{2023}},
}