TY - JOUR
T1 - Relationships between flortaucipir PET tau binding and amyloid burden, clinical diagnosis, age and cognition
AU - Pontecorvo, Michael J.
AU - Devous, Michael D.
AU - Navitsky, Michael
AU - Lu, Ming
AU - Salloway, Stephen
AU - Schaerf, Frederick W.
AU - Jennings, Danna
AU - Arora, Anupa K.
AU - McGeehan, Anne
AU - Lim, Nathaniel C.
AU - Xiong, Hui
AU - Joshi, Abhinay D.
AU - Siderowf, Andrew
AU - Mintun, Mark A.
AU - 18F-AV-1451-A05 investigators
N1 - Funding Information:
The authors would like to acknowledge Brian F. Teske, Ph.D (Eli Lilly and Company) for assistance in manuscript preparation. This study was sponsored by Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly and Company.
Publisher Copyright:
© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.
PY - 2017/3/1
Y1 - 2017/3/1
N2 - The advent of tau-targeted positron emission tomography tracers such as flortaucipir (18F-AV-1451, also known as18F-T807) have made it possible to investigate the sequence of development of tau and amyloid-b 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 410). Images were evaluated visually and quantitatively by regional and voxel-based cortical to cerebellar standard uptake value ratios. For amyloid positron emission tomography positive (Ab +) subjects, flortaucipir neocortical standard uptake value ratio was significantly higher with more advanced clinical stage (Alzheimer’s disease 4 mild cognitive impairment 4 older cognitively normal) and was significantly elevated for Ab + mild cognitive impairment and Alzheimer’s disease subjects relative to the respective Ab subjects. In contrast, florbetapir Ab 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 Ab older cognitively normal or clinically diagnosed Alzheimer’s disease or mild cognitive impairment subjects. The pattern of flortaucipir distribution among Ab + 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 Ab + cognitively normal subjects. However, there was large variability in extent/density of flortaucipir tau binding among Ab + subjects. Although high neocortical flortaucipir retention was consistently associated with an Ab + florbetapir positron emission tomography scan, not all Ab + subjects had elevated flortaucipir standard uptake value ratios. Finally, within the Ab + 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.
AB - The advent of tau-targeted positron emission tomography tracers such as flortaucipir (18F-AV-1451, also known as18F-T807) have made it possible to investigate the sequence of development of tau and amyloid-b 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 410). Images were evaluated visually and quantitatively by regional and voxel-based cortical to cerebellar standard uptake value ratios. For amyloid positron emission tomography positive (Ab +) subjects, flortaucipir neocortical standard uptake value ratio was significantly higher with more advanced clinical stage (Alzheimer’s disease 4 mild cognitive impairment 4 older cognitively normal) and was significantly elevated for Ab + mild cognitive impairment and Alzheimer’s disease subjects relative to the respective Ab subjects. In contrast, florbetapir Ab 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 Ab older cognitively normal or clinically diagnosed Alzheimer’s disease or mild cognitive impairment subjects. The pattern of flortaucipir distribution among Ab + 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 Ab + cognitively normal subjects. However, there was large variability in extent/density of flortaucipir tau binding among Ab + subjects. Although high neocortical flortaucipir retention was consistently associated with an Ab + florbetapir positron emission tomography scan, not all Ab + subjects had elevated flortaucipir standard uptake value ratios. Finally, within the Ab + 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.
KW - 18F-AV-1451
KW - Florbetapir
KW - Flortaucipir
KW - PET
KW - Tau
UR - http://www.scopus.com/inward/record.url?scp=85013430405&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85013430405&partnerID=8YFLogxK
U2 - 10.1093/brain/aww334
DO - 10.1093/brain/aww334
M3 - Article
C2 - 28077397
AN - SCOPUS:85013430405
SN - 0006-8950
VL - 140
SP - 748
EP - 763
JO - Brain
JF - Brain
IS - 3
ER -