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

Gemma Salvadó, José Luis Molinuevo, Anna Brugulat-Serrat, Carles Falcon, Oriol Grau-Rivera, Marc Suárez-Calvet, Javier Pavia, Aida Niñerola-Baizán, Andrés Perissinotti, Francisco Lomeña, Carolina Minguillon, Karine Fauria, Henrik Zetterberg, Kaj Blennow, Juan Domingo Gispert, Alzheimer’s Disease Neuroimaging Initiative, for the ALFA Study, Jordi Camí, Raffaele Cacciaglia, Marta Crous-Bou, Carme Deulofeu, Ruth Dominguez, Xavi Gotsens, Nina Gramunt, Laura Hernandez, Gema Huesa, Jordi Huguet, María León, Paula Marne, Tania Menchón, Marta Milà, Grégory Operto, Maria Pascual, Albina Polo, Sandra Pradas, Aleix Sala-Vila, Gonzalo Sánchez-Benavides, Sabrina Segundo, Anna Soteras, Laia Tenas, Marc Vilanova, Natalia Vilor-Tejedor, Gemma Salvadó, José Luis Molinuevo, Anna Brugulat-Serrat, Carles Falcon, Oriol Grau-Rivera, Marc Suárez-Calvet, Javier Pavia, Aida Niñerola-Baizán, Andrés Perissinotti, Francisco Lomeña, Carolina Minguillon, Karine Fauria, Henrik Zetterberg, Kaj Blennow, Juan Domingo Gispert, Alzheimer’s Disease Neuroimaging Initiative, for the ALFA Study, Jordi Camí, Raffaele Cacciaglia, Marta Crous-Bou, Carme Deulofeu, Ruth Dominguez, Xavi Gotsens, Nina Gramunt, Laura Hernandez, Gema Huesa, Jordi Huguet, María León, Paula Marne, Tania Menchón, Marta Milà, Grégory Operto, Maria Pascual, Albina Polo, Sandra Pradas, Aleix Sala-Vila, Gonzalo Sánchez-Benavides, Sabrina Segundo, Anna Soteras, Laia Tenas, Marc Vilanova, Natalia Vilor-Tejedor

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Trial registration: ALFA+ Study, NCT02485730 ALFA PET Sub-study, NCT02685969.

Keywords: AD pathophysiology; Biomarker categorization; Biomarker concordance; Early detection; Phosphorylated tau; Positivity; Positron emission tomography; Preclinical; Threshold.

Conflict of interest statement

Ethics approval and consent to participate

The ALFA study and the PET sub-study protocols have been approved by an independent Ethics Committee Parc de Salut Mar Barcelona and registered at Clinicaltrials.gov (ALFA Identifier: NCT02485730; PET sub-study Identifier: NCT02685969). Both studies have been conducted in accordance with the directives of the Spanish Law 14/ 2007, of 3rd of July, on Biomedical Research (Ley 14/ 2007 de Investigación Biomédica).

Consent for publication

Not applicable.

Competing interests

JLM is a consultant for the following for-profit companies: Alergan, Roche diagnostics, Genentech, Novartis, Lundbeck, Oryzon, Biogen, Lilly, Janssen, Green Valley, MSD, Eisai, Alector, Raman Health.

Other authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Summary of ROC curves for Centiloid cut-off derivation against CSF biomarkers. pTau, phosphorylated tau; tTau, total tau; CSF, cerebrospinal fluid; ROC, receiver operating characteristic
Fig. 2
Fig. 2
Derivation of amyloid PET Centiloid cut-offs using Aβ42 CSF biomarker. Upper row shows a scatterplot of PET quantitative measures in Centiloids against CSF Aβ42 biomarker values for both ALFA+ (blue) and ADNI (red) participants. Vertical lines depict previously published CSF threshold (Aβ42 1098 pg/ml [22, 30]), and horizontal lines depict optimal cut-offs derived in this study (YI derived: green, OPA derived: yellow). Two outliers were excluded of this picture for having CL value higher than 200. Second row shows this cut-offs derivation by the maximization of YI (left) and OPA (right). The YI (green) was calculated from PPA (blue) and NPA (red) values. The OPA (green) was calculated from PPV (blue) and NPV (red) values. Derivation was done with participants of both cohorts merged. Aβ, amyloid; CSF, cerebrospinal fluid; YI, Youden’s J index; PPA, positive percentage agreement; NPA, negative percentage agreement; CL, Centiloids
Fig. 3
Fig. 3
Derivation of amyloid PET Centiloid cut-offs for CSF pTau/Aβ42. Top row shows scatterplots of PET quantitative measures in Centiloids against CSF pTau/Aβ42 biomarker values for both ALFA+ (blue) and ADNI (red) participants. Vertical line depicts previously published CSF thresholds (pTau/Aβ42 0.022 [22, 30]), and horizontal line depicts optimal cut-offs derived in this study (YI and OPA derived cut-offs are equal). Two outliers were excluded of this picture for having CL value higher than 200. Second row shows this cut-off derivation by maximization of YI (left) and OPA (right). The YI (green) was calculated from PPA (blue) and NPA (red) values. The OPA (green) was calculated from PPV (blue) and NPV (red) values. Derivation was done with participants of both cohorts merged. pTau, phosphorylated tau; CSF, cerebrospinal fluid; YI, Youden’s J index; PPA, positive percentage agreement; NPA, negative percentage agreement; CL, Centiloids
Fig. 4
Fig. 4
Derivation of amyloid PET Centiloid cut-offs for CSF tTau/Aβ42. Top row shows scatterplots of PET quantitative measures in Centiloids against CSF tTau/Aβ42 biomarker values for both ALFA+ (blue) and ADNI (red) participants. Vertical line depicts previously published CSF thresholds (tTau/Aβ42 0.26 [22, 30]), and horizontal lines depict optimal cut-offs derived in this study (YI derived: green, OPA derived: yellow). Two outliers were excluded of this picture for having CL value higher than 200. Second row shows this cut-off derivation by maximization of YI (left) and OPA (right). The YI (green) was calculated from PPA (blue) and NPA (red) values. The OPA (green) was calculated from PPV (blue) and NPV (red) values. Derivation was done with participants of both cohorts merged. tTau, total tau; CSF, cerebrospinal fluid; YI, Youden’s J index; PPA, positive percentage agreement; NPA, negative percentage agreement; CL, Centiloids

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