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Cerebrospinal fluid biomarkers in autopsy-confirmed Alzheimer disease and frontotemporal lobar degeneration

Mattsson-Carlgren, Niklas LU orcid ; Grinberg, Lea T. ; Boxer, Adam ; Ossenkoppele, Rik LU ; Jonsson, Magnus LU orcid ; Seeley, William ; Ehrenberg, Alexander ; Spina, Salvatore ; Janelidze, Shorena LU and Rojas-Martinex, Julio , et al. (2022) In Neurology 98(11). p.1137-1150
Abstract

Background and Objectives To determine how fully automated Elecsys CSF immunoassays for β-amyloid (Aβ) and tau biomarkers and an ultrasensitive Simoa assay for neurofilament light chain (NFL) correlate with neuropathologic changes of Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD). Methods We studied 101 patients with antemortem CSF and neuropathology data. CSF samples were collected a mean of 2.9 years before death (range 0.2–7.5 years). CSF was analyzed for Aβ40, Aβ42, total tau (T-tau), tau phosphorylated at amino acid residue 181 (P-tau), P-tau/Aβ42 and Aβ42/Aβ40 ratios, and NFL. Neuropathology measures included Thal phases, Braak stages, Consortium to... (More)

Background and Objectives To determine how fully automated Elecsys CSF immunoassays for β-amyloid (Aβ) and tau biomarkers and an ultrasensitive Simoa assay for neurofilament light chain (NFL) correlate with neuropathologic changes of Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD). Methods We studied 101 patients with antemortem CSF and neuropathology data. CSF samples were collected a mean of 2.9 years before death (range 0.2–7.5 years). CSF was analyzed for Aβ40, Aβ42, total tau (T-tau), tau phosphorylated at amino acid residue 181 (P-tau), P-tau/Aβ42 and Aβ42/Aβ40 ratios, and NFL. Neuropathology measures included Thal phases, Braak stages, Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) scores, AD neuropathologic change (ADNC), and primary and contributory pathologic diagnoses. Associations between CSF biomarkers and neuropathologic features were tested in regression models adjusted for age, sex, and time from sampling to death. Results CSF biomarkers were associated with neuropathologic measures of Aβ (Thal, CERAD score), tau (Braak stage), and overall ADNC. The CSF P-tau/Aβ42 and Aβ42/Aβ40 ratios had high sensitivity, specificity, and overall diagnostic performance for intermediate-high ADNC (area under the curve range 0.95–0.96). Distinct biomarker patterns were seen in different FTLD subtypes, with increased NFL and reduced P-tau/T-tau in FTLD–TAR DNA-binding protein 43 and reduced T-tau in progressive supranuclear palsy compared to other FTLD variants. Discussion CSF biomarkers, including P-tau, T-tau, Aβ42, Aβ40, and NFL, support in vivo identification of AD neuropathology and correlate with FTLD neuropathology.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Neurology
volume
98
issue
11
pages
1137 - 1150
publisher
Lippincott Williams & Wilkins
external identifiers
  • scopus:85126490649
  • pmid:35173015
ISSN
0028-3878
DOI
10.1212/WNL.0000000000200040
language
English
LU publication?
yes
additional info
Funding Information: This work was partially funded by Roche Diagnostics (assay kits, materials, and employee salaries for U.E. and G.K). ELECSYS is a registered trademark of Roche. The Elecsys CSF Aβ, Aβ, P-tau, and T-tau immunoassays are not yet cleared or approved for clinical use in the United States. The NeuroToolKit robust prototype assays are for investigational purposes only and are not approved for clinical use. All other product names and trademarks are the property of their respective owners. Work at the authors' laboratory is funded by Knut and Alice Wallenberg Foundation, the Medical Faculty at Lund University, Region Skåne, the European Research Council, the Swedish Research Council, the Strategic Research Area MultiPark at Lund University, the Swedish Alzheimer Foundation, the Swedish Brain Foundation, The Parkinson Foundation of Sweden, The Parkinson Research Foundation, the Skåne University Hospital Foundation, the Swedish federal government under the ALF agreement, and the Bundy Academy. Work at UCSF was supported by NIH/National Institute on Aging grants (P30-AG062422, P01-AG019724, R01-AG038791, K08-AG052648, R01-NS050915, P50 AG023501, R01 AG045611, U19AG063911, K24053435, U54NS092089, R01AG031278, K99AG065501). 42 40 Funding Information: The Article Processing Charge was funded by the authors. Publisher Copyright: Copyright © 2022 The Author(s).
id
44c4f633-bcde-4ffc-84c4-a7be5d00e36b
date added to LUP
2022-05-09 09:41:18
date last changed
2024-06-08 22:39:30
@article{44c4f633-bcde-4ffc-84c4-a7be5d00e36b,
  abstract     = {{<p>Background and Objectives To determine how fully automated Elecsys CSF immunoassays for β-amyloid (Aβ) and tau biomarkers and an ultrasensitive Simoa assay for neurofilament light chain (NFL) correlate with neuropathologic changes of Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD). Methods We studied 101 patients with antemortem CSF and neuropathology data. CSF samples were collected a mean of 2.9 years before death (range 0.2–7.5 years). CSF was analyzed for Aβ<sub>40</sub>, Aβ<sub>42</sub>, total tau (T-tau), tau phosphorylated at amino acid residue 181 (P-tau), P-tau/Aβ<sub>42</sub> and Aβ<sub>42</sub>/Aβ<sub>40</sub> ratios, and NFL. Neuropathology measures included Thal phases, Braak stages, Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) scores, AD neuropathologic change (ADNC), and primary and contributory pathologic diagnoses. Associations between CSF biomarkers and neuropathologic features were tested in regression models adjusted for age, sex, and time from sampling to death. Results CSF biomarkers were associated with neuropathologic measures of Aβ (Thal, CERAD score), tau (Braak stage), and overall ADNC. The CSF P-tau/Aβ<sub>42</sub> and Aβ<sub>42</sub>/Aβ<sub>40</sub> ratios had high sensitivity, specificity, and overall diagnostic performance for intermediate-high ADNC (area under the curve range 0.95–0.96). Distinct biomarker patterns were seen in different FTLD subtypes, with increased NFL and reduced P-tau/T-tau in FTLD–TAR DNA-binding protein 43 and reduced T-tau in progressive supranuclear palsy compared to other FTLD variants. Discussion CSF biomarkers, including P-tau, T-tau, Aβ<sub>42</sub>, Aβ<sub>40</sub>, and NFL, support in vivo identification of AD neuropathology and correlate with FTLD neuropathology.</p>}},
  author       = {{Mattsson-Carlgren, Niklas and Grinberg, Lea T. and Boxer, Adam and Ossenkoppele, Rik and Jonsson, Magnus and Seeley, William and Ehrenberg, Alexander and Spina, Salvatore and Janelidze, Shorena and Rojas-Martinex, Julio and Rosen, Howard and la Joie, Renaud and Lesman-Segev, Orit and Iaccarino, Leonardo and Kollmorgen, Gwendlyn and Ljubenkov, Peter and Eichenlaub, Udo and Gorno-Tempini, Maria Luisa and Miller, Bruce and Hansson, Oskar and Rabinovici, Gil Dan}},
  issn         = {{0028-3878}},
  language     = {{eng}},
  number       = {{11}},
  pages        = {{1137--1150}},
  publisher    = {{Lippincott Williams & Wilkins}},
  series       = {{Neurology}},
  title        = {{Cerebrospinal fluid biomarkers in autopsy-confirmed Alzheimer disease and frontotemporal lobar degeneration}},
  url          = {{http://dx.doi.org/10.1212/WNL.0000000000200040}},
  doi          = {{10.1212/WNL.0000000000200040}},
  volume       = {{98}},
  year         = {{2022}},
}