Unravelling the Association Between Amyloid-PET and Cerebrospinal Fluid Biomarkers in the Alzheimer’s Disease Spectrum: Who Really Deserves an A+?

Article type: Research Article

Authors: Sacchi, Luca^{a; b; *} | Carandini, Tiziana^b | Fumagalli, Giorgio Giulio^b | Pietroboni, Anna Margherita^{a; b} | Contarino, Valeria Elisa^b | Siggillino, Silvia^b | Arcaro, Marina^b | Fenoglio, Chiara^{a; b} | Zito, Felicia^{a; b} | Marotta, Giorgio^{a; b} | Castellani, Massimo^{a; b} | Triulzi, Fabio^{a; b} | Galimberti, Daniela^{a; b} | Scarpini, Elio^{a; b} | Arighi, Andrea^{a; b}

Affiliations: [a] University of Milan, Milan, Italy | [b] Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

Correspondence: [*] Correspondence to: Luca Sacchi, Fondazione IRCCS Ca’ Granda Ospedale Policlinico, Via F. Sforza 35, 20122 Milan, Italy. Tel.: +393489389482; E-mail: luca.sacchi1@unimi.it.

Abstract: Background: Association between cerebrospinal fluid (CSF)-amyloid-β (Aβ)42 and amyloid-PET measures is inconstant across the Alzheimer’s disease (AD) spectrum. However, they are considered interchangeable, along with Aβ42/40 ratio, for defining ‘Alzheimer’s Disease pathologic change’ (A+). Objective: Herein, we further characterized the association between amyloid-PET and CSF biomarkers and tested their agreement in a cohort of AD spectrum patients. Methods: We included 23 patients who underwent amyloid-PET, MRI, and CSF analysis showing reduced levels of Aβ42 within a 365-days interval. Thresholds used for dichotomization were: Aβ42 < 640 pg/mL (Aβ42+); pTau > 61 pg/mL (pTau+); and Aβ42/40 < 0.069 (ADratio+). Amyloid-PET scans were visually assessed and processed by four pipelines (SPMCL, SPMAAL, FSGM, FSWC). Results: Different pipelines gave highly inter-correlated standardized uptake value ratios (SUVRs) (rho = 0.93–0.99). The most significant findings were: pTau positive correlation with SPMCL SUVR (rho = 0.56, p = 0.0063) and Aβ42/40 negative correlation with SPMCL and SPMAAL SUVRs (rho = –0.56, p = 0.0058; rho = –0.52, p = 0.0117 respectively). No correlations between CSF-Aβ42 and global SUVRs were observed. In subregion analysis, both pTau and Aβ42/40 values significantly correlated with cingulate SUVRs from any pipeline (R2 = 0.55–0.59, p < 0.0083), with the strongest associations observed for the posterior/isthmus cingulate areas. However, only associations observed for Aβ42/40 ratio were still significant in linear regression models. Moreover, combining pTau with Aβ42 or using Aβ42/40, instead of Aβ42 alone, increased concordance with amyloid-PET status from 74% to 91% based on visual reads and from 78% to 96% based on Centiloids. Conclusion: We confirmed that, in the AD spectrum, amyloid-PET measures show a stronger association and a better agreement with CSF-Aβ42/40 and secondarily pTau rather than Aβ42 levels.

Keywords: Alzheimer’s disease, Aβ_42/40 ratio, amyloid, amyloid-PET, biomarkers, centiloids, cerebrospinal fluid, Florbetaben, standardized uptake value ratio, tau

DOI: 10.3233/JAD-210593

Journal: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1009-1020, 2022