Date Published: March 21, 2019
Publisher: BioMed Central
Author(s): 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.
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
The online version of this article (10.1186/s13195-019-0478-z) contains supplementary material, which is available to authorized users.
Aggregation of β-amyloid (Aβ) is a neuropathological hallmark of Alzheimer disease (AD) and occurs decades before the onset of clinical symptoms occur [1, 2]. Both amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) Aβ42 measurement are established biomarkers of Aβ deposition that highly correlate with post-mortem [3, 4] and brain biopsy findings  and serving as in vivo proxies of AD pathological findings that can be assessed in vivo. They are included as part of the biological definition of AD in the recent NIA-AA 2018 research framework  for the definition of preclinical stages of AD  and as well as inclusion criteria in clinical trials . CSF Aβ42 and amyloid PET show a high degree of agreement [9–19], even though they probably measure two different pools of amyloid. While the signal detected by amyloid PET may reflect fibrillary amyloid , the decrease of CSF Aβ42 levels more likely reflects both fibrillar and non-fibrillar Aβ deposits. Another difference is that CSF Aβ42 may become abnormal before amyloid PET [21, 22], while amyloid PET has been suggested to be superior for grading early symptomatic AD stages .
In this paper, we sought to calculate the optimal Centiloid cut-off values from amyloid PET data to maximize the agreement against previously established thresholds for positivity on core AD CSF biomarkers. At a first glance, this might be regarded as a circular exercise, since these CSF cut-offs were originally derived to maximally concord with positive visual reading of PET scans. Under this rationale, all resulting Centiloid cut-offs would have be expected to fall in the range that optimally discriminates negative from positive visual reads, which is between 25 and 35 CL [25, 26]. On the contrary, optimal agreement for CSF Aβ42 was observed for a cut-off of 12 CL. This seemingly unexpected result can be explained by the clearly non-linear relationship between amyloid PET Centiloids and CSF Aβ42, as previously reported . Almost all subjects with CSF Aβ42 over 1000 pg/ml showed Centiloid values below 20, and only for CSF values < 1000 pg/ml, a linear association could be intuited. This nonlinear association makes goodness criteria (both the Youden’s Index and the overall percentage agreement) to plateau between 10 and 40 CL (Fig. 2). Under these circumstances, to derive stable optimal cut-offs, it is critical to make use of a test sample comprising both sufficient concordant positive and negative cases as well as a good representation of individuals falling within intermediate amyloid ranges (10 < CL < 40 and 500 < CSF Aβ42 < 1000 pg/ml). In this study, this was achieved by pooling the ADNI and ALFA+ datasets. Source: http://doi.org/10.1186/s13195-019-0478-z