Flortaucipir F 18 Quantitation using a Parametric Estimate of Reference Signal Intensity (PERSI)

Introduction: PET imaging of tau pathology in Alzheimer's disease may benefit from the use of white matter reference regions. These regions have shown reduced variability compared to conventional cerebellar regions in amyloid imaging. However, they are susceptible to contamination from partial-volume blurring of tracer uptake in cortex. We present a new technique (PERSI) for Flortaucipir F 18 count normalization that leverages the advantages of white matter reference regions while mitigating potential partial-volume effects. Methods: Subjects with clinical diagnoses of Alzheimer's Disease (AD), mild cognitive impairment (MCI) or normal cognition (CN) underwent T1 MRI and florbetapir imaging (to determine amyloid (Aβ) status) at screening, and flortaucipir imaging at single or multiple time points. Flortaucipir images acquired as 4x5 minute frames, 80 minutes after a 370 MBq injection, were motion corrected, averaged and transformed to MNI space. The PERSI reference region was calculated for each scan by fitting a bimodal Gaussian distribution to the voxel-intensity histogram within an atlas-based white matter region, and using the center and width of the lower-intensity peak to identify the voxel intensities to be included. Four conventional reference regions were also evaluated: 1) whole cerebellum, 2) cerebellar gray matter, 3) atlas-based white matter, and 4) subject-specific white matter. SUVr was calculated for a statistically-defined neocortical volume-of-interest (MUBADA). Performance was evaluated with respect to test-retest variability in a Phase 2 study of 21 subjects (5-34 days between scans). Baseline variability in controls (SD of SUVr and SUVr values) and effect sizes for group differences (Cohen's d; Aβ+ impaired vs. Aβ- normal) were evaluated in another Phase 2 study with cross-sectional (n = 215) and longitudinal (n = 142/215; 18±2 months between scans) data. Results: PERSI showed superior test-retest reproducibility (1.84%) and group separation ability (cross-sectional Cohen's d=9.45; longitudinal Cohen's d=2.34) compared to other reference regions. Baseline SUVr variability and SUVr were minimal in Aβ- control subjects with no specific flortaucipir uptake (SUVr 1.0±0.04, SUVr 0.0±0.02). Conclusion: PERSI reduced variability while enhancing discrimination between diagnostic cohorts. Such improvements could lead to more accurate disease staging and robust measurements of changes in tau burden over time for the evaluation of putative therapeutic treatments.

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