Reference Tissue-Based Kinetic Evaluation of 18F-AV-1451 for Tau Imaging

Abstract

The goal of this paper was to evaluate the in vivo kinetics of the novel tau-specific PET radioligand ¹⁸F-AV-1451 in cognitively healthy control (HC) and Alzheimer disease (AD) subjects, using reference region analyses.

Methods: ¹⁸F-AV-1451 PET imaging was performed on 43 subjects (5 young HCs, 23 older HCs, and 15 AD subjects). Data were collected from 0 to 150 min after injection, with a break from 100 to 120 min. T1-weighted MR images were segmented using FreeSurfer to create 14 bilateral regions of interest (ROIs). In all analyses, cerebellar gray matter was used as the reference region. Nondisplaceable binding potentials (BP_NDs) were calculated using the simplified reference tissue model (SRTM) and SRTM2; the Logan graphical analysis distribution volume ratio (DVR) was calculated for 30-150 min (DVR30-150). These measurements were compared with each other and used as reference standards for defining an appropriate 20-min window for the SUV ratio (SUVR). Pearson correlations were used to compare the reference standards to 20-min SUVRs (start times varied from 30 to 130 min), for all values, for ROIs with low ¹⁸F-AV-1451 binding (lROIs, mean of BP_ND + 1 and DVR30-150 < 1.5), and for ROIs with high ¹⁸F-AV-1451 binding (hROIs, mean of BP_ND + 1 and DVR30-150 > 1.5).

Results: SRTM2 BP_ND + 1 and DVR30-150 were in good agreement. Both were in agreement with SRTM BP_ND + 1 for lROIs but were greater than SRTM BP_ND + 1 for hROIs, resulting in a nonlinear relationship. hROI SUVRs increased from 80-100 to 120-140 min by 0.24 ± 0.15. The SUVR time interval resulting in the highest correlation and slope closest to 1 relative to the reference standards for all values was 120-140 min for hROIs, 60-80 min for lROIs, and 80-100 min for lROIs and hROIs. There was minimal difference between methods when statistical significance between ADs and HCs was calculated.

Conclusion: Despite later time periods providing better agreement between reference standards and SUVRs for hROIs, a good compromise for studying lROIs and hROIs is SUVR80-100. The lack of SUVR plateau for hROIs highlights the importance of precise acquisition time for longitudinal assessment.

Keywords: 18F-AV-1451; Alzheimer’s; kinetics; tau.

FIGURE 1.

(A and B) Time–activity curves for HC and AD subjects, respectively. PET data are represented by ●, solid line is SRTM fit to the data, dashed line is SRTM2 fit. (C) SUVR for single HC subject shown in A, and mean ± SD of all HC subjects (solid/dotted lines). (D) SUVRs for AD subject shown in B and mean ± SD of all AD subjects in (solid/dotted lines). Circles represent single subject SUVR, solid line is mean across subject groups, and dashed line represents SD of subject group. Putamen represents off-target binding with quantification challenges.

FIGURE 2.

SRTM k₂’ agglomerative hierarchical clustering for AD subjects. Plot shows SRTM k₂’ values of ROIs in AD subjects used to perform the clustering. Branches show levels of clustering. Gray boxes show 10th–90th percentile of SRTM k₂’ for HC, white line is mean of HC; HC subjects not used in clustering.

FIGURE 3.

SRTM2 k₂’ values for yHC, HC, and AD subjects.

FIGURE 4.

LGA DVR for HC (A) and AD (B) subjects from Figure 1. DVR values for 40–70 (x), 70–100 (□), and 120–150 (○) for HC putamen = 1.41, 1.40, 1.33; HC ENTO = 0.93, 0.93, 0.91; HC TEMP = 1.09, 1.14, 1.14; AD putamen = 1.48, 1.39, 1.33; AD ENTO = 1.51, 1.41, 1.47; and AD TEMP = 2.28, 2.29, 2.45.

FIGURE 5.

Results of linear regression of SRTM BP_ND + 1, SRTM2 BP_ND + 1, and DVR130–150 with SUVR at various time windows. (A) r². (B) Slope. Regression included 43 subjects and 10 ROIs (FRONT, PAR, OCC, TEMP, ENTO, brain stem, ACING, PCING, hippocampus, and precuneus).

FIGURE 6.

SUVR images for AD (A–C) and HC subjects (D–F) from Figures 1 and 4. SUVRs were calculated from 60–80 (A and D), 80–100 (B and E), and 120–140 min (C and F). Color map ranges for SUVR normalized by cerebellar gray from 1 to 5 for all images.

FIGURE 7.

Welch’s t test between HCs and ADs in SRTM BP_ND + 1 (A), DVR30–150 (B), and SUVR130–150 (C). Boundaries of boxes represent 25th–75th percentiles, solid horizontal white line is median, dashed horizontal white line is mean, dashed vertical line is 5th–95th percentiles. **P < 0.001. *P < 0.01, Bonferroni-corrected.