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

• Published in: Alzheimer's research & therapy Vol. 11; no. 1; p. 27
• Main Authors: Salvadó, Gemma, Molinuevo, José Luis, Brugulat-Serrat, Anna, Falcon, Carles, Grau-Rivera, Oriol, Suárez-Calvet, Marc, Pavia, Javier, Niñerola-Baizán, Aida, Perissinotti, Andrés, Lomeña, Francisco, Minguillon, Carolina, Fauria, Karine, Zetterberg, Henrik, Blennow, Kaj, Gispert, Juan Domingo
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 21.03.2019; BioMed Central; BMC
• Subjects: accuracy; AD pathophysiology; Advertising executives; Aged; Aged, 80 and over; Alzheimer Disease - cerebrospinal fluid; Alzheimer Disease - diagnostic imaging; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - cerebrospinal fluid; association; Automation; beta-amyloid 42; Biological markers; Biomarker categorization; Biomarker concordance; Biomarkers; Biomarkers - cerebrospinal fluid; Biomarkers - metabolism; Cerebrospinal fluid; Clinical trials; Cohort Studies; Decision making; Dementia; deposition; Diagnosis; Disease prevention; Early detection; Female; Florbetapir; Humans; Immunoassay; Male; Measurement units and standards; Medical imaging; Medical research; Middle Aged; Neurosciences; Neurosciences & Neurology; Neurovetenskaper; NMR; Nuclear magnetic resonance; Phosphorylated tau; Positivity; Positron emission tomography; Preclinical; preclinical alzheimers-disease; prevention; Reference Values; ROC Curve; tau Proteins - cerebrospinal fluid; Testing; Threshold; Tracers (Biology); Biomarker concordance; Positivity; Phosphorylated tau; Preclinical; Biomarker categorization; Positron emission tomography; Early detection; AD pathophysiology; Threshold
• ISSN: 1758-9193; 1758-9193
• DOI: 10.1186/s13195-019-0478-z

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 ([ F]flutemetamol and [ F]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 Aβ , 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 Aβ that rendered an optimal cut-off value of 12 CL. As expected, the agreement of tau/Aβ ratios was higher than that of CSF Aβ . 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.