Flortaucipir F 18 Quantitation Using Parametric Estimation of Reference Signal Intensity

Abstract

PET imaging of tau pathology in Alzheimer disease may benefit from the use of white matter reference regions. These regions have shown reduced variability compared with conventional cerebellar regions in amyloid imaging. However, they are susceptible to contamination from partial-volume blurring of tracer uptake in the cortex. We present a new technique, PERSI (Parametric Estimation of Reference Signal Intensity), for flortaucipir F 18 count normalization that leverages the advantages of white matter reference regions while mitigating potential partial-volume effects. Subjects with a clinical diagnosis of Alzheimer disease, mild cognitive impairment, or normal cognition underwent T1-weighted MRI and florbetapir imaging (to determine amyloid [Aβ] status) at screening and flortaucipir F 18 imaging at single or multiple time points. Flortaucipir F 18 images, acquired as 4 × 5 min frames 80 min after a 370-MBq injection, were motion-corrected, averaged, and transformed to Montreal Neurological Institute (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: whole cerebellum, cerebellar gray matter, atlas-based white matter, and subject-specific white matter. SUVr (standardized uptake value ratio) was calculated for a statistically defined neocortical volume of interest. Performance was evaluated with respect to test-retest variability in a phase 2 study of 21 subjects (5-34 d between scans). Baseline variability in controls (SD of SUVr and ΔSUVr) and effect sizes for group differences (Cohen d; Aβ-positive impaired vs. Aβ-negative normal) were evaluated in another phase 2 study with cross-sectional data ( = 215) and longitudinal data ( = 142/215; 18 ± 2 mo between scans). PERSI showed superior test-retest reproducibility (1.84%) and group separation ability (cross-sectional Cohen d = 9.45; longitudinal Cohen d = 2.34) compared with other reference regions. Baseline SUVr variability and ΔSUVr were minimal in Aβ control subjects with no specific flortaucipir F 18 uptake (SUVr, 1.0 ± 0.04; ΔSUVr, 0.0 ± 0.02). 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 therapies.

Longitudinal tau accumulation and atrophy in aging and alzheimer disease

“…The distinction between AD and OA may reflect acceleration of tau deposition in AD, or greater vulnerability to tau in temporoparietal cortex than prefrontal regions. 11,12 We did not observe a difference in FTP change between PiB + and PiB − groups. It is also possible that the rate of tau accumulation slows over time, similar to amyloid accumulation.…”

“…In contrast to previous data showing a lack of FTP increase in Aβ-negative normal adults, we found that FTP increased across ROIs in our OA cohort. 12 Our results, however, indicate our approach is a robust way to measure the spatial topography of FTP change. Across the OA group, our estimates of APC were higher than previous work, which measured 0.5% APC in PiB + normal controls.…”

“…Previous work has shown that cross-sectional FTP is associated with cross-sectional atrophy patterns in AD, 10,21 but our study extends these findings by revealing that FTP longitudinal accumulation occurs in regions that are relatively less affected by atrophy. 11,12 Work in our laboratory has indicated that FTP signal in WM and GM are still correlated even after PVC. Patients with AD had significantly greater accumulation in the 2 larger ROIs we examined, the temporal Meta ROI and Braak III/IV regions, but there was no significant difference in mean FTP change in ERC between OA and AD, consistent with other reports.…”

“…Patients with AD had significantly greater accumulation in the 2 larger ROIs we examined, the temporal Meta ROI and Braak III/IV regions, but there was no significant difference in mean FTP change in ERC between OA and AD, consistent with other reports. 12 Another possible advantage of WM as a reference is the relatively large size of the region, as nonspecific signal in larger regions is likely to be more stable over time. In contrast to previous data showing a lack of FTP increase in Aβ-negative normal adults, we found that FTP increased across ROIs in our OA cohort.…”

“…[5][6][7][8][9] Furthermore, FTP signal has been shown to relate to cognition in normal controls and patients with AD. 11,12 These longitudinal studies employed markedly different methods and reported conflicting results in regard to rate of FTP accumulation, highlighting the need for further exploration of the optimal methods for analyzing longitudinal FTP data. 11,12 These longitudinal studies employed markedly different methods and reported conflicting results in regard to rate of FTP accumulation, highlighting the need for further exploration of the optimal methods for analyzing longitudinal FTP data.…”