Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer's disease

Rik Ossenkoppele; Daniel R. Schonhaut; Michael Schöll; Samuel N. Lockhart; Nagehan Ayakta; Suzanne L. Baker; James P. O'Neil; Mustafa Janabi; Andreas Lazaris; Averill Cantwell; Jacob Vogel; Miguel Santos; Zachary A. Miller; Brianne M. Bettcher; Keith A. Vossel; Joel H. Kramer; Maria L. Gorno-Tempini; Bruce L. Miller; William J. Jagust; Gil D. Rabinovici

doi:10.1093/brain/aww027

Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer's disease

Rik Ossenkoppele, Daniel R. Schonhaut, Michael Schöll, Samuel N. Lockhart, Nagehan Ayakta, Suzanne L. Baker, James P. O'Neil, Mustafa Janabi, Andreas Lazaris, Averill Cantwell, Jacob Vogel, Miguel Santos, Zachary A. Miller, Brianne M. Bettcher, Keith A. Vossel, Joel H. Kramer, Maria L. Gorno-Tempini, Bruce L. Miller, William J. Jagust, Gil D. Rabinovici

Neurology

Research output: Contribution to journal › Article › peer-review

749 Scopus citations

Abstract

The advent of the positron emission tomography tracer ¹⁸F-AV1451 provides the unique opportunity to visualize the regional distribution of tau pathology in the living human brain. In this study, we tested the hypothesis that tau pathology is closely linked to symptomatology and patterns of glucose hypometabolism in Alzheimer's disease, in contrast to the more diffuse distribution of amyloid-β pathology. We included 20 patients meeting criteria for probable Alzheimer's disease dementia or mild cognitive impairment due to Alzheimer's disease, presenting with a variety of clinical phenotypes, and 15 amyloid-β-negative cognitively normal individuals, who underwent ¹⁸F-AV1451 (tau), ¹¹C-PiB (amyloid-β) and ¹⁸F-FDG (glucose metabolism) positron emission tomography, apolipoprotein E (APOE) genotyping and neuropsychological testing. Voxel-wise contrasts against controls (at P < 0.05 family-wise error corrected) showed that ¹⁸F-AV1451 and ¹⁸F-FDG patterns in patients with posterior cortical atrophy ('visual variant of Alzheimer's disease', n = 7) specifically targeted the clinically affected posterior brain regions, while ¹¹C-PiB bound diffusely throughout the neocortex. Patients with an amnestic-predominant presentation (n = 5) showed highest ¹⁸F-AV1451 retention in medial temporal and lateral temporoparietal regions. Patients with logopenic variant primary progressive aphasia ('language variant of Alzheimer's disease', n = 5) demonstrated asymmetric left greater than right hemisphere ¹⁸F-AV1451 uptake in three of five patients. Across 30 FreeSurfer-defined regions of interest in 16 Alzheimer's disease patients with all three positron emission tomography scans available, there was a strong negative association between ¹⁸F-AV1451 and ¹⁸F-FDG uptake (Pearson's r =-0.49 ± 0.07, P < 0.001) and less pronounced positive associations between ¹¹C-PiB and ¹⁸F-FDG (Pearson's r = 0.16 ± 0.09, P < 0.001) and ¹⁸F-AV1451 and ¹¹C-PiB (Pearson's r = 0.18 ± 0.09, P < 0.001). Voxel-wise linear regressions thresholded at P < 0.05 (uncorrected) showed that, across all patients, younger age was associated with greater ¹⁸F-AV1451 uptake in wide regions of the neocortex, while older age was associated with increased ¹⁸F-AV1451 in the medial temporal lobe. APOE Ïμ 4 carriers showed greater temporal and parietal ¹⁸F-AV1451 uptake than non-carriers. Finally, worse performance on domain-specific neuropsychological tests was associated with greater ¹⁸F-AV1451 uptake in key regions implicated in memory (medial temporal lobes), visuospatial function (occipital, right temporoparietal cortex) and language (left > right temporoparietal cortex). In conclusion, tau imaging-contrary to amyloid-β imaging-shows a strong regional association with clinical and anatomical heterogeneity in Alzheimer's disease. Although preliminary, these results are consistent with and expand upon findings from post-mortem, animal and cerebrospinal fluid studies, and suggest that the pathological aggregation of tau is closely linked to patterns of neurodegeneration and clinical manifestations of Alzheimer's disease.

Original language	English (US)
Pages (from-to)	1551-1567
Number of pages	17
Journal	Brain
Volume	139
Issue number	5
DOIs	https://doi.org/10.1093/brain/aww027
State	Published - May 1 2016

Bibliographical note

Funding Information:
This research was funded by Marie Curie FP7 International Outgoing Fellowship (628812; to R.O.); The donors of (Alzheimer's Disease Research), a program of BrightFocus Foundation (to R.O.); Tau Consortium (to G.D.R. and W.J.J); National Institute on Aging grants (R01-AG045611; to G.D.R.), (R01-AG034570; to W.J.J.), (P50-AG023501; to B.L.M.), and (K23-AG038357; to K.A.V.); John Douglas French Alzheimer's Foundation (to G.D.R. and B.L.M.); State of California Department of Health Services Alzheimer's Disease Research Centre of California grant (04-33516; to B.L.M); Swedish Medical Association and the Swedish Foundation of Nuclear Medicine (to M.S.). Avid Radiopharmaceuticals enabled use of the 18F-AV1451 tracer, but did not provide direct funding and was not involved in data analysis or interpretation.

Publisher Copyright:
© 2016 The Author.

Keywords

APOE
AV1451 PET
Alzheimer's disease
cognition
tau

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Ossenkoppele, R., Schonhaut, D. R., Schöll, M., Lockhart, S. N., Ayakta, N., Baker, S. L., O'Neil, J. P., Janabi, M., Lazaris, A., Cantwell, A., Vogel, J., Santos, M., Miller, Z. A., Bettcher, B. M., Vossel, K. A., Kramer, J. H., Gorno-Tempini, M. L., Miller, B. L., Jagust, W. J., & Rabinovici, G. D. (2016). Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer's disease. Brain, 139(5), 1551-1567. https://doi.org/10.1093/brain/aww027

Ossenkoppele, R, Schonhaut, DR, Schöll, M, Lockhart, SN, Ayakta, N, Baker, SL, O'Neil, JP, Janabi, M, Lazaris, A, Cantwell, A, Vogel, J, Santos, M, Miller, ZA, Bettcher, BM, Vossel, KA, Kramer, JH, Gorno-Tempini, ML, Miller, BL, Jagust, WJ & Rabinovici, GD 2016, 'Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer's disease', Brain, vol. 139, no. 5, pp. 1551-1567. https://doi.org/10.1093/brain/aww027

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abstract = "The advent of the positron emission tomography tracer 18F-AV1451 provides the unique opportunity to visualize the regional distribution of tau pathology in the living human brain. In this study, we tested the hypothesis that tau pathology is closely linked to symptomatology and patterns of glucose hypometabolism in Alzheimer's disease, in contrast to the more diffuse distribution of amyloid-β pathology. We included 20 patients meeting criteria for probable Alzheimer's disease dementia or mild cognitive impairment due to Alzheimer's disease, presenting with a variety of clinical phenotypes, and 15 amyloid-β-negative cognitively normal individuals, who underwent 18F-AV1451 (tau), 11C-PiB (amyloid-β) and 18F-FDG (glucose metabolism) positron emission tomography, apolipoprotein E (APOE) genotyping and neuropsychological testing. Voxel-wise contrasts against controls (at P < 0.05 family-wise error corrected) showed that 18F-AV1451 and 18F-FDG patterns in patients with posterior cortical atrophy ('visual variant of Alzheimer's disease', n = 7) specifically targeted the clinically affected posterior brain regions, while 11C-PiB bound diffusely throughout the neocortex. Patients with an amnestic-predominant presentation (n = 5) showed highest 18F-AV1451 retention in medial temporal and lateral temporoparietal regions. Patients with logopenic variant primary progressive aphasia ('language variant of Alzheimer's disease', n = 5) demonstrated asymmetric left greater than right hemisphere 18F-AV1451 uptake in three of five patients. Across 30 FreeSurfer-defined regions of interest in 16 Alzheimer's disease patients with all three positron emission tomography scans available, there was a strong negative association between 18F-AV1451 and 18F-FDG uptake (Pearson's r =-0.49 ± 0.07, P < 0.001) and less pronounced positive associations between 11C-PiB and 18F-FDG (Pearson's r = 0.16 ± 0.09, P < 0.001) and 18F-AV1451 and 11C-PiB (Pearson's r = 0.18 ± 0.09, P < 0.001). Voxel-wise linear regressions thresholded at P < 0.05 (uncorrected) showed that, across all patients, younger age was associated with greater 18F-AV1451 uptake in wide regions of the neocortex, while older age was associated with increased 18F-AV1451 in the medial temporal lobe. APOE {\"I}μ 4 carriers showed greater temporal and parietal 18F-AV1451 uptake than non-carriers. Finally, worse performance on domain-specific neuropsychological tests was associated with greater 18F-AV1451 uptake in key regions implicated in memory (medial temporal lobes), visuospatial function (occipital, right temporoparietal cortex) and language (left > right temporoparietal cortex). In conclusion, tau imaging-contrary to amyloid-β imaging-shows a strong regional association with clinical and anatomical heterogeneity in Alzheimer's disease. Although preliminary, these results are consistent with and expand upon findings from post-mortem, animal and cerebrospinal fluid studies, and suggest that the pathological aggregation of tau is closely linked to patterns of neurodegeneration and clinical manifestations of Alzheimer's disease.",

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note = "Funding Information: This research was funded by Marie Curie FP7 International Outgoing Fellowship (628812; to R.O.); The donors of (Alzheimer's Disease Research), a program of BrightFocus Foundation (to R.O.); Tau Consortium (to G.D.R. and W.J.J); National Institute on Aging grants (R01-AG045611; to G.D.R.), (R01-AG034570; to W.J.J.), (P50-AG023501; to B.L.M.), and (K23-AG038357; to K.A.V.); John Douglas French Alzheimer's Foundation (to G.D.R. and B.L.M.); State of California Department of Health Services Alzheimer's Disease Research Centre of California grant (04-33516; to B.L.M); Swedish Medical Association and the Swedish Foundation of Nuclear Medicine (to M.S.). Avid Radiopharmaceuticals enabled use of the 18F-AV1451 tracer, but did not provide direct funding and was not involved in data analysis or interpretation. Publisher Copyright: {\textcopyright} 2016 The Author.",

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T1 - Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer's disease

AU - Ossenkoppele, Rik

AU - Schonhaut, Daniel R.

AU - Schöll, Michael

AU - Lockhart, Samuel N.

AU - Ayakta, Nagehan

AU - Baker, Suzanne L.

AU - O'Neil, James P.

AU - Janabi, Mustafa

AU - Lazaris, Andreas

AU - Cantwell, Averill

AU - Vogel, Jacob

AU - Santos, Miguel

AU - Miller, Zachary A.

AU - Bettcher, Brianne M.

AU - Vossel, Keith A.

AU - Kramer, Joel H.

AU - Gorno-Tempini, Maria L.

AU - Miller, Bruce L.

AU - Jagust, William J.

AU - Rabinovici, Gil D.

N1 - Funding Information: This research was funded by Marie Curie FP7 International Outgoing Fellowship (628812; to R.O.); The donors of (Alzheimer's Disease Research), a program of BrightFocus Foundation (to R.O.); Tau Consortium (to G.D.R. and W.J.J); National Institute on Aging grants (R01-AG045611; to G.D.R.), (R01-AG034570; to W.J.J.), (P50-AG023501; to B.L.M.), and (K23-AG038357; to K.A.V.); John Douglas French Alzheimer's Foundation (to G.D.R. and B.L.M.); State of California Department of Health Services Alzheimer's Disease Research Centre of California grant (04-33516; to B.L.M); Swedish Medical Association and the Swedish Foundation of Nuclear Medicine (to M.S.). Avid Radiopharmaceuticals enabled use of the 18F-AV1451 tracer, but did not provide direct funding and was not involved in data analysis or interpretation. Publisher Copyright: © 2016 The Author.

PY - 2016/5/1

Y1 - 2016/5/1

N2 - The advent of the positron emission tomography tracer 18F-AV1451 provides the unique opportunity to visualize the regional distribution of tau pathology in the living human brain. In this study, we tested the hypothesis that tau pathology is closely linked to symptomatology and patterns of glucose hypometabolism in Alzheimer's disease, in contrast to the more diffuse distribution of amyloid-β pathology. We included 20 patients meeting criteria for probable Alzheimer's disease dementia or mild cognitive impairment due to Alzheimer's disease, presenting with a variety of clinical phenotypes, and 15 amyloid-β-negative cognitively normal individuals, who underwent 18F-AV1451 (tau), 11C-PiB (amyloid-β) and 18F-FDG (glucose metabolism) positron emission tomography, apolipoprotein E (APOE) genotyping and neuropsychological testing. Voxel-wise contrasts against controls (at P < 0.05 family-wise error corrected) showed that 18F-AV1451 and 18F-FDG patterns in patients with posterior cortical atrophy ('visual variant of Alzheimer's disease', n = 7) specifically targeted the clinically affected posterior brain regions, while 11C-PiB bound diffusely throughout the neocortex. Patients with an amnestic-predominant presentation (n = 5) showed highest 18F-AV1451 retention in medial temporal and lateral temporoparietal regions. Patients with logopenic variant primary progressive aphasia ('language variant of Alzheimer's disease', n = 5) demonstrated asymmetric left greater than right hemisphere 18F-AV1451 uptake in three of five patients. Across 30 FreeSurfer-defined regions of interest in 16 Alzheimer's disease patients with all three positron emission tomography scans available, there was a strong negative association between 18F-AV1451 and 18F-FDG uptake (Pearson's r =-0.49 ± 0.07, P < 0.001) and less pronounced positive associations between 11C-PiB and 18F-FDG (Pearson's r = 0.16 ± 0.09, P < 0.001) and 18F-AV1451 and 11C-PiB (Pearson's r = 0.18 ± 0.09, P < 0.001). Voxel-wise linear regressions thresholded at P < 0.05 (uncorrected) showed that, across all patients, younger age was associated with greater 18F-AV1451 uptake in wide regions of the neocortex, while older age was associated with increased 18F-AV1451 in the medial temporal lobe. APOE Ïμ 4 carriers showed greater temporal and parietal 18F-AV1451 uptake than non-carriers. Finally, worse performance on domain-specific neuropsychological tests was associated with greater 18F-AV1451 uptake in key regions implicated in memory (medial temporal lobes), visuospatial function (occipital, right temporoparietal cortex) and language (left > right temporoparietal cortex). In conclusion, tau imaging-contrary to amyloid-β imaging-shows a strong regional association with clinical and anatomical heterogeneity in Alzheimer's disease. Although preliminary, these results are consistent with and expand upon findings from post-mortem, animal and cerebrospinal fluid studies, and suggest that the pathological aggregation of tau is closely linked to patterns of neurodegeneration and clinical manifestations of Alzheimer's disease.

AB - The advent of the positron emission tomography tracer 18F-AV1451 provides the unique opportunity to visualize the regional distribution of tau pathology in the living human brain. In this study, we tested the hypothesis that tau pathology is closely linked to symptomatology and patterns of glucose hypometabolism in Alzheimer's disease, in contrast to the more diffuse distribution of amyloid-β pathology. We included 20 patients meeting criteria for probable Alzheimer's disease dementia or mild cognitive impairment due to Alzheimer's disease, presenting with a variety of clinical phenotypes, and 15 amyloid-β-negative cognitively normal individuals, who underwent 18F-AV1451 (tau), 11C-PiB (amyloid-β) and 18F-FDG (glucose metabolism) positron emission tomography, apolipoprotein E (APOE) genotyping and neuropsychological testing. Voxel-wise contrasts against controls (at P < 0.05 family-wise error corrected) showed that 18F-AV1451 and 18F-FDG patterns in patients with posterior cortical atrophy ('visual variant of Alzheimer's disease', n = 7) specifically targeted the clinically affected posterior brain regions, while 11C-PiB bound diffusely throughout the neocortex. Patients with an amnestic-predominant presentation (n = 5) showed highest 18F-AV1451 retention in medial temporal and lateral temporoparietal regions. Patients with logopenic variant primary progressive aphasia ('language variant of Alzheimer's disease', n = 5) demonstrated asymmetric left greater than right hemisphere 18F-AV1451 uptake in three of five patients. Across 30 FreeSurfer-defined regions of interest in 16 Alzheimer's disease patients with all three positron emission tomography scans available, there was a strong negative association between 18F-AV1451 and 18F-FDG uptake (Pearson's r =-0.49 ± 0.07, P < 0.001) and less pronounced positive associations between 11C-PiB and 18F-FDG (Pearson's r = 0.16 ± 0.09, P < 0.001) and 18F-AV1451 and 11C-PiB (Pearson's r = 0.18 ± 0.09, P < 0.001). Voxel-wise linear regressions thresholded at P < 0.05 (uncorrected) showed that, across all patients, younger age was associated with greater 18F-AV1451 uptake in wide regions of the neocortex, while older age was associated with increased 18F-AV1451 in the medial temporal lobe. APOE Ïμ 4 carriers showed greater temporal and parietal 18F-AV1451 uptake than non-carriers. Finally, worse performance on domain-specific neuropsychological tests was associated with greater 18F-AV1451 uptake in key regions implicated in memory (medial temporal lobes), visuospatial function (occipital, right temporoparietal cortex) and language (left > right temporoparietal cortex). In conclusion, tau imaging-contrary to amyloid-β imaging-shows a strong regional association with clinical and anatomical heterogeneity in Alzheimer's disease. Although preliminary, these results are consistent with and expand upon findings from post-mortem, animal and cerebrospinal fluid studies, and suggest that the pathological aggregation of tau is closely linked to patterns of neurodegeneration and clinical manifestations of Alzheimer's disease.

KW - APOE

KW - AV1451 PET

KW - Alzheimer's disease

KW - cognition

KW - tau

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DO - 10.1093/brain/aww027

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AN - SCOPUS:84962895547

SN - 0006-8950

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SP - 1551

EP - 1567

JO - Brain

JF - Brain

IS - 5

ER -

Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer's disease

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