Voxel‐wise Staging of Tau Pathology using [18F]RO‐948 PET in the Early AD Continuum

Abstract

AbstractBackgroundTau positron emission tomography (PET) is a useful biomarker for detecting tau aggregation, one of the hallmark pathological findings in Alzheimer's disease (AD). The goal of this study is to characterize and stage the pattern of spreading of tau pathology across the brain in the early AD continuum.MethodForty‐seven cognitively unimpaired individuals from ALFA+ cohort had [18F]RO‐948 and [18F]flutemetamol PET, T1‐weighted magnetic resonance imaging(MRI), two cognitive assessments, cerebrospinal fluid(CSF), and blood biomarkers. Standardized uptake value ratio(SUVr) maps of [18F]RO‐948 PET images in MNI space created using inferior cerebellum as reference region. Participants were categorized according to the A/T system using pre‐established thresholds for CSF amyloid(A) and tau(T) positivity(Table1). A voxel‐wise hierarchical staging model was constructed based on data from the control group(A‐T‐). Voxel positivity was defined as SUVr higher than mean plus two standard deviations of control group(Figure1). Then, each voxel was assigned to one of 3 stages based on the frequency of its abnormality across the control group, dividing the voxel frequency histogram into 3 equally‐distributed groups. A given stage was assigned to each scan if, at least, 50% of the voxels on the stage mask were positive, hierarchically. That is, to determine stage 2, stage 1 needs to be positive as well. Otherwise, the scan is labeled as non‐stageable. Staging model performance was evaluated by recording the number of non‐stageable scans as well as by performing non‐parametric correlations between tau stages and CSF, blood biomarkers, cortical thickness, Centiloid(CL) as well as changes in cognition composites. Post‐hoc between‐stage comparisons were performed using the Kruskal‐Wallis test followed by a Bonferroni correction.ResultsAll scans were stageable. Twenty‐three scans were assigned to stage 0, 11 to stage 1, and 3 to stage 2(Figure2). Significant correlations between tau stages and CSF, blood biomarkers, Centiloid, cortical thickness as well as memory and attention changes were observed(Table2). Between‐group comparisons of tau stages vs biomarkers and changes in memory and attention were statistically significant(Figure3).ConclusionOur results suggest that the proposed voxel‐wise staging model is sensitive to capturing the spread of early tau pathology and useful for studying early AD pathophysiological mechanisms.