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Cited by 195Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsMedical Imaging Techniques and Applications

Centiloid cut-off values for optimal agreement between PET and CSF core AD biomarkers

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for the Alzheimer’s Disease Neuroimaging Initiative, for the ALFA Study, Salvadó, Gemma, Molinuevo, José Luis, Brugulat-Serrat, Anna, Falcon, Carles, Grau-Rivera, Oriol, Suárez-Calvet, Marc, Pavia, Javier +8 more·2019·Alzheimer's Research & Therapy
DOI 10.1186/s13195-019-0478-zPMC PMC6429814
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Abstract

The Centiloid scale has been developed to standardize measurements of amyloid PET imaging. Reference cut-off values of this continuous measurement enable the consistent operationalization of decision-making for multicentre research studies and clinical trials. In this study, we aimed at deriving reference Centiloid thresholds that maximize the agreement against core Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers in two large independent cohorts. A total of 516 participants of the ALFA+ Study (N = 205) and ADNI (N = 311) underwent amyloid PET imaging ([18F]flutemetamol and [18F]florbetapir, respectively) and core AD CSF biomarker determination using Elecsys® tests. Tracer uptake was quantified in Centiloid units (CL). Optimal Centiloid cut-offs were sought that maximize the agreement between PET and dichotomous determinations based on CSF levels of Aβ42, tTau, pTau, and their ratios, using pre-established reference cut-off values. To this end, a receiver operating characteristic analysis (ROC) was conducted, and Centiloid cut-offs were calculated as those that maximized the Youden’s J Index or the overall percentage agreement recorded. All Centiloid cut-offs fell within the range of 25–35, except for CSF Aβ42 that rendered an optimal cut-off value of 12 CL. As expected, the agreement of tau/Aβ42 ratios was higher than that of CSF Aβ42. Centiloid cut-off robustness was confirmed even when established in an independent cohort and against variations of CSF cut-offs. A cut-off of 12 CL matches previously reported values derived against postmortem measures of AD neuropathology. Together with these previous findings, our results flag two relevant inflection points that would serve as boundary of different stages of amyloid pathology: one around 12 CL that marks the transition from the absence of pathology to subtle pathology and another one around 30 CL indicating the presence of established pathology. The derivation of robust and generalizable cut-offs for core AD biomarkers requires cohorts with adequate representation of intermediate levels. ALFA+ Study, NCT02485730 ALFA PET Sub-study, NCT02685969

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  • Amyloid PET processing was performed after a validated Centiloid pipeline.

    “Amyloid PET processing was performed after a validated Centiloid pipeline27 using SPM12 (ref. 18).”

    From Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer’s disease (2022) · cites this paper as [18]

    The Methods > Image processing passage says that all PET images were preprocessed following the Centiloid pipeline using SPM12. It does not say that the pipeline was validated; the only explicit validation mentioned in the Introduction concerns a CSF cut-off, not PET processing. Page numbers are unavailable in our copy. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • The 12-Centiloid threshold is the optimal cut-off validated in neuropathology to detect CERAD moderate-to-frequent neuritic plaque scores, early detection of Aβ abnormalities by PET, and agreement against CSF AD biomarkers.

    “The 12-Centiloid threshold is the optimal cut-off validated in neuropathology to detect CERAD moderate-to-frequent, neuritic plaque scores19, early detection of Aβ abnormalities by PET22 and agreement against CSF AD biomarkers18.”

    From Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer’s disease (2022) · cites this paper as [18]

    The citation to this paper is attached to agreement with CSF AD biomarkers, not the separately cited neuropathology and early-PET claims. The Discussion reports that 12 CL optimally corresponded to CSF Aβ42 positivity, but the Abstract Results say other CSF biomarker cut-offs were 25–35 CL. Thus 12 CL is not the optimal cut-off for agreement with CSF AD biomarkers generally. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • 30 Centiloids has the best agreement with the CSF t-tau/Aβ42 ratio in pooled data of ALFA+ and ADNI cohort biomarkers.

    “Our choice of 30 Centiloids as a later cut-off was based on our previous findings that it has the best agreement with the CSF t-tau/Aβ42 ratio in pooled data of ALFA+ and AD neuroimaging (ADNI) cohort biomarkers18.”

    From Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer’s disease (2022) · cites this paper as [18]

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Authors
for the Alzheimer’s Disease Neuroimaging Initiative, F. T. A. S., Salvadó, G., Molinuevo, J. L., Brugulat-Serrat, A., Falcon, C., Grau-Rivera, O., Suárez-Calvet, M., Pavia, J., Niñerola-Baizán, A., Perissinotti, A., Lomeña, F., Minguillon, C., Fauria, K., Zetterberg, H., Blennow, K., & Gispert, J. D.
Affiliations
  • Pasqual Maragall Foundation (ES)
  • Hospital Clínic de Barcelona (ES)
  • Sahlgrenska University Hospital (SE)
  • Universitat Pompeu Fabra (ES)
Corresponding author
Gispert, Juan Domingo
ORCID
Venue
Alzheimer's Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2019-03-21
Volume
11
Issue
1
Pages
27-27
ISSN
1758-9193 (ISSN-L)
DOI
10.1186/s13195-019-0478-z
PMC
PMC6429814
OpenAlex
W2923868521
Cited by
195
References
12
Citations by year
2026: 27 · 2025: 32 · 2024: 41 · 2023: 22 · 2022: 24 · 2021: 35 · 2020: 10 · 2019: 4
FWCI
14.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s Research & Therapy (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • UCL Discovery (University College London) (submittedVersion)
  • Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, cc-by)
Funders
  • “la Caixa” Foundation (LCF/PR/GN17/10300004)
  • Alzheimer's Association (NA)
  • Ministerio de Economía, Industria y Competitividad, Gobierno de España (RYC-2013-13054, IEDI-2016-00690)
  • H2020 Marie Skłodowska-Curie Actions (752310)
  • Royal Swedish Academy of Sciences (NA)
  • Swedish Research Council (2017-00915, NA)
  • Swedish Alzheimer Foundation (AF-742881)
  • H2020 European Research Council (N/A)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Medical Imaging Techniques and Applications
Keywords
centiloid, amyloid PET, Alzheimer's disease, cerebrospinal fluid biomarkers, cut-off values, 18F-flutemetamol, 18F-florbetapir, CSF amyloid-beta 42, tau protein, Alzheimer's disease staging, ADNI
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Female, Humans, Male, Middle Aged, Reference Values, ROC Curve, Cohort Studies, Biomarkers, Amyloid beta-Peptides, tau Proteins, Positron-Emission Tomography

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