Validation Of the Tau Heterogeneity Evaluation in Alzheimer’s Disease (THETA) Score Using Longitudinal and Histopathology Data

BACKGROUND: We recently developed a novel tau-PET summary measure THETA, capturing regional heterogeneity and identifying tau status, using ground truth visual assessments from a large single-center cross-sectional dataset and validated on independent cohorts [1, 2]. In this study, we aimed to evaluate the performance of THETA on longitudinal and histopathology data. METHOD: We included longitudinal tau-PET ([18F]flortaucipir) data from 696 Mayo Clinic Study of Aging (MCSA) and ADRC participants, with histopathology in n = 90. Fig. 1 shows the model that uses regional standard uptake value ratios (SUVR) and a target of binary class of tau positivity for prediction of THETA. This model was applied to predict tau status on each followup scan. Slopes of the meta-ROIs' tau SUVRs and THETA were evaluated by diagnostic group and as a function of baseline amyloid SUVR in discordant CU participants (where meta-ROI and visual assessments did not match at baseline) and in incident-THETA+ CU participants (whose THETA moved from below to above 1 over serial tau-PET scans). We evaluated tau measurements as a function of Braak stages for neurofibrillary tangles. RESULT: Longitudinal plots of meta-ROIs for diagnostic groups were very similar, but the expanded range of THETA based on visual positivity prediction clearly identified tau positive or tau-negative scans. In discordant-CU (n = 97) and incident-THETA+ CU participants (n = 14 all amyloid positive at follow-up but only 65% at baseline), the relationship between baseline amyloid and rate of tau increase was stronger for THETA than temporal meta-ROI (Fig. 2). Separation between baseline and follow-up was greater for THETA (t-statistics = 90) compared to temporal meta-ROI (t-statistics = 20) (p<0.01) in the incident-THETA+ CU participants. THETA showed a slightly stronger association with Braak stage than meta-ROIs (rho = 0.87 vs. ≤0.83, p<0.05), with better separation of clinical diagnoses (Fig. 3). CONCLUSION: THETA remained clearly negative or positive in MCI and AD, providing consistent information on underlying etiology of impairment at both baseline and follow-up. Although binary in its construction, THETA both provided separation of values based on tau status and its change correlated with baseline amyloid burden especially in discordant-CU where tau deposition is not in typical meta-ROIs. Further work is needed to confirm if THETA captures early tau changes.