A Visual Interpretation Algorithm for Assessing Brain Tauopathy with 18-F MK-6240 Positron Emission Tomography.

Introduction: In vivo characterization of pathologic deposition of tau protein in the human brain by PET imaging is a promising tool in drug development trials of Alzheimer's disease (AD). 18-F MK- 6240 is a radiotracer with high selectivity and sub-nanomolar affinity for neurofibrillary tangles (NFTs) that shows favorable non-specific brain penetration and excellent kinetic properties. The purpose of the present investigation was to develop a visual assessment method that provides both an overall assessment of brain tauopathy and regional characterization of abnormal tau deposition. Methods: 18-F MK-6240 scans from 102 participants (including healthy volunteers, patients with AD or other neurodegenerative disorders) were reviewed by an expert nuclear medicine physician blind to participants' diagnosis to identify common patterns of brain uptake. This initial visual read method was field tested in a separate, non-overlapping cohort of 102 participants with 2 additional naïve readers trained on the method. Visual read outcomes were compared with semiquantitative assessments using volume of interest (VOI) SUVr. Results: For the visual read eight gray-matter regions per hemisphere were assessed as negative (no abnormal uptake) or positive (1-25% of the region involved, 25-75% involvement, or >75% involvement), then characterized the tau binding pattern as positive or negative for evidence of tau, and if positive, whether brain uptake is in an AD pattern. Readers demonstrated agreement 94% of the time for overall positivity/negativity. Concordance on the determination of the regional binary outcomes (negative or positive) showed agreement of 74.3 % and Fleiss' k of 0.912. Using clinical diagnosis as the ground truth, readers demonstrated a sensitivity of 73-79% and specificity of 91-93, with combined reader concordance sensitivity of 80% and specificity 93%. Cortical regions average SUVr showed a robust correlation with visually-derived ratings of regional involvement (r = .73, P < .0001). Conclusion: We developed a visual read algorithm for 18-F MK-6240 PET offering both determination of scan positivity and the regional degree of cortical involvement. These cross-sectional results show strong inter-reader concordance on both binary and regional assessments of tau deposition, as well as good sensitivity and excellent specificity supporting use as a tool for clinical trials.