Establishing and validating unbiased cut‐offs for tau PET with Gaussian mixture model in Alzheimer’s disease

Abstract

AbstractBackgroundTau PET positivity (T+) is recommended in Alzheimer’s disease (AD) trials involving preclinical and prodromal AD. As unbiased cut‐offs are still lacking, we established and validated data‐driven T+ PET cut‐offs for AD.MethodData were from ADNI (estimation cohort) and Geneva memory center (validation cohort). 18F‐Flortaucipir standardized uptake value ratios (SUVr) were computed for a global temporal meta‐ROI and for cortical regions corresponding to Braak‐based stages I‐VI in amyloid negative (Aβ−) cognitively normal (CN), Aβ+ CN, Aβ+ MCI and AD. For Tau PET data‐driven cut‐off estimation, Gaussian mixture model (GMM) was applied on the global and regional SUVr distributions in Aβ− CN and AD (n = 269). The GMM cut‐offs’ performance was compared with published 18F‐Flortaucipir cut‐offs (Mattsson et al., 2017) by assessing the percentage of T+ subjects within each diagnostic group.ResultCut‐offs were 1.36 for temporal meta‐ROI and ranged 1.20‐1.39 for stages. In the validation cohort, all Aβ− CN were tau negative (T−), while T+ percentage increased along the Aβ+ continuum (CN<MCI<AD) for temporal meta‐ROI (33<64<75) and stages I‐II (50<73<75), III (17<55<58), IV (17<57<75), V (0<18<50) and VI (0<5<33). Previously published cut‐offs reported a higher frequency of T+ in the AD spectrum and identified T+ subjects in the Aβ‐ CN group.ConclusionGMMs unbiased 18F‐Flortaucipir SUVr cut‐offs showed lower T+ percentage in Aβ− CN than published cut‐offs, possibly indicating lower false positive rates and suggesting that they might be useful for the in‐vivo assessment of participants eligibility in future preclinical and prodromal AD trials.