Relationships between flortaucipir PET tau binding and amyloid burden, clinical diagnosis, age and cognition

Michael J Pontecorvo, Michael D Devous Sr, Michael Navitsky, Ming Lu, Stephen Salloway, Frederick W Schaerf, Danna Jennings, Anupa K Arora, Anne McGeehan, Nathaniel C Lim, Hui Xiong, Abhinay D Joshi, Andrew Siderowf, Mark A Mintun, 18F-AV-1451-A05 investigators, Michael J Pontecorvo, Michael D Devous Sr, Michael Navitsky, Ming Lu, Stephen Salloway, Frederick W Schaerf, Danna Jennings, Anupa K Arora, Anne McGeehan, Nathaniel C Lim, Hui Xiong, Abhinay D Joshi, Andrew Siderowf, Mark A Mintun, 18F-AV-1451-A05 investigators

Abstract

The advent of tau-targeted positron emission tomography tracers such as flortaucipir (18F-AV-1451, also known as 18F-T807) have made it possible to investigate the sequence of development of tau and amyloid-β in relationship to age, and to the development of cognitive impairment due to Alzheimer's disease. In this study, flortaucipir tau and florbetapir amyloid positron emission tomography were obtained for 217 subjects including 16 young and 58 older cognitively normal subjects, 95 subjects with mild cognitive impairment (Mini-Mental State Examination 24-30) and 48 subjects with clinically-defined possible or probable Alzheimer's disease (Mini-Mental State Examination >10). Images were evaluated visually and quantitatively by regional and voxel-based cortical to cerebellar standard uptake value ratios. For amyloid positron emission tomography positive (Aβ+) subjects, flortaucipir neocortical standard uptake value ratio was significantly higher with more advanced clinical stage (Alzheimer's disease > mild cognitive impairment > older cognitively normal) and was significantly elevated for Aβ+ mild cognitive impairment and Alzheimer's disease subjects relative to the respective Aβ- subjects. In contrast, florbetapir Aβ- older cognitively normal subjects showed an increase in flortaucipir standard uptake value ratios in mesial temporal lobe regions (amygdala, hippocampus/choroid plexus region of interest) compared to younger cognitively normal subjects, but no increased standard uptake value ratios in neocortical regions. Analysis of covariance with planned contrasts showed no differences in regional or composite posterior neocortical flortaucipir standard uptake value ratio as a function of diagnostic group among Aβ- older cognitively normal or clinically diagnosed Alzheimer's disease or mild cognitive impairment subjects. The pattern of flortaucipir distribution among Aβ+ subjects was reminiscent of the cross-sectional distribution of tau reported in post-mortem pathology studies, in that the most commonly affected regions were the inferior and lateral temporal lobes, the same regions where the first signs of increased retention appeared in Aβ+ cognitively normal subjects. However, there was large variability in extent/density of flortaucipir tau binding among Aβ+ subjects. Although high neocortical flortaucipir retention was consistently associated with an Aβ+ florbetapir positron emission tomography scan, not all Aβ+ subjects had elevated flortaucipir standard uptake value ratios. Finally, within the Aβ+ group, increasing levels of flortaucipir tau binding were associated with increased cognitive impairment, as assessed by Mini-Mental State Examination and Alzheimer's Disease Assessment Scale. These results suggest development of tau beyond the mesial temporal lobe is associated with, and may be dependent on, amyloid accumulation. Further, the results are consistent with the hypothesis that cortical tau is associated with cognitive impairment.

Keywords: 18F-AV-1451; PET; florbetapir; flortaucipir; tau.

© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

Figures

Figure 1
Figure 1
Mean flortaucipir voxel-wise SUVr images for each age/diagnostic cohort by florbetapir PET amyloid status (Aβ+ or Aβ−). Images are scaled from 1–2.5 SUVr units and overlaid on an average of MRI from all study patients in radiologic orientation such that the right side of each image represents left hemisphere of the brain. (A) Aβ−; (B) Aβ+. AD = Alzheimer’s disease; ROI = region of interest.
Figure 2
Figure 2
Flortaucipir voxel-wise SUVr images for representative individual Aβ− control (YCN/OCN) and Aβ+ OCN, MCI, and Alzheimer’s disease subjects. (A) Aβ− control (YNC/OCN), (B–D) Aβ+ OCN, MCI and Alzheimer’s disease subjects, respectively. PET images are scaled from 1–2.5 SUVr units and overlaid on each subject’s respective MRI. Note in addition to differences in overall extent of retention, there are also subjects with relatively limbic sparing (D, first row) and limbic predominant (D, third row) patterns (arrows) consistent with the pathology literature (Murray et al., 2011). AD = Alzheimer’s disease; y/o = years old.
Figure 3
Figure 3
Posterior neocortical composite SUVr for individual subjects by diagnostic category.X-axis: (diagnostic group, amyloid status), YCN are shown in red. Y-axis: flortaucipir (AV1451) combination SUVr. Horizontal reference line shows upper 99% confidence limit for YCN. AD = Alzheimer’s disease; CN = cognitively normal.
Figure 4
Figure 4
Aβ+ subjects with low cortical average SUVR values. Subjects with low flortaucipir SUVr values may still have abnormal tracer retention in limited cortical regions. AD = Alzheimer’s disease; CN = cognitively normal; ROI = region of interest.
Figure 5
Figure 5
Relationship between florbetapir PET SUVr, flortaucipir SUVr, diagnosis, age and ADAS score. (A) Scatterplot of relationship between florbetapir and flortaucipir SUVr for individual subjects by age, diagnosis and amyloid status. (B) Scatterplot of relationship between age and flortaucipir SUVr for individual subjects by age, diagnosis and amyloid status (r and P-values refer to Aβ+ subjects only). (C and D) Scatterplot of relationship between flortaucipir SUVr and cognition for individual subjects by diagnosis and amyloid status and age (<75 years, C; >75 years D). AD = Alzheimer’s disease; CN = cognitively normal.
Figure 6
Figure 6
Mean flortaucipir voxel-wise SUVr images for Aβ+ MCI and Alzheimer’s disease subjects <75 years and ≥75 years old. Note the similarity between the pattern of demented (Alzheimer’s disease) subjects ≥75 years to MCI subjects <75 years of age. AD = Alzheimer’s disease.

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