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

Background: Association between cerebrospinal fluid (CSF)-amyloid-beta (A beta)(42) and amyloid-PET measures is inconstant across the Alzheimer's disease (AD) spectrum. However, they are considered interchangeable, along with A beta(42/40) 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 A beta(42) within a 365-days interval. Thresholds used for dichotomization were: A beta(42) < 640 pg/mL (A beta(42)+); pTau > 61 pg/mL (pTau+); and A beta(42/40) < 0.069 (AD(ratio)+). 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 A beta(42/40) negative correlation with SPMCL and SPMAAL SUVRs (rho = -0.56, p = 0.0058; rho = -0.52, p = 0.0117 respectively). No correlations between CSF-A beta(42) and global SUVRs were observed. In subregion analysis, both pTau and A beta 6(42/40) values significantly correlated with cingulate SUVRs from any pipeline (R-2 = 0.55-0.59, p < 0.0083), with the strongest associations observed for the posterior/isthmus cingulate areas. However, only associations observed for A beta(42/40) ratio were still significant in linear regression models. Moreover, combining pTau with A beta(42) or using A beta(42/40), instead of A beta(42) 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-A beta(42/40) and secondarily pTau rather than A beta(42) levels.