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February 12, 2019; 92 (7) Article

The influence of β-amyloid on [18F]AV-1451 in semantic variant of primary progressive aphasia

Jennifer L. Whitwell, Peter R. Martin, Joseph R. Duffy, Heather M. Clark, Mary M. Machulda, Christopher G. Schwarz, Stephen D. Weigand, Irene Sintini, Matthew L. Senjem, Nilufer Ertekin-Taner, Hugo Botha, Rene L. Utianski, Jonathan Graff-Radford, David T. Jones, Bradley F. Boeve, David S. Knopman, Ronald C. Petersen, Clifford R. Jack, Val J. Lowe, Keith A. Josephs
First published January 11, 2019, DOI: https://doi.org/10.1212/WNL.0000000000006913
Jennifer L. Whitwell
From the Departments of Radiology (J.L.W., C.G.S., I.S., M.L.S., C.R.J., V.J.L.), Health Science Research (Biostatistics) (P.R.M., S.D.W.), Neurology (Speech Pathology) (J.R.D., H.M.C., R.L.U.), Psychiatry and Psychology (M.M.M.), Neurology (Behavioral Neurology) (H.B., J.G.-R., D.T.J., B.F.B., D.S.K., R.C.P., K.A.J.), and Information Technology (M.L.S.), Mayo Clinic, Rochester, MN; and Department of Neuroscience (N.E.-T.), Mayo Clinic, Jacksonville, FL.
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Peter R. Martin
From the Departments of Radiology (J.L.W., C.G.S., I.S., M.L.S., C.R.J., V.J.L.), Health Science Research (Biostatistics) (P.R.M., S.D.W.), Neurology (Speech Pathology) (J.R.D., H.M.C., R.L.U.), Psychiatry and Psychology (M.M.M.), Neurology (Behavioral Neurology) (H.B., J.G.-R., D.T.J., B.F.B., D.S.K., R.C.P., K.A.J.), and Information Technology (M.L.S.), Mayo Clinic, Rochester, MN; and Department of Neuroscience (N.E.-T.), Mayo Clinic, Jacksonville, FL.
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Joseph R. Duffy
From the Departments of Radiology (J.L.W., C.G.S., I.S., M.L.S., C.R.J., V.J.L.), Health Science Research (Biostatistics) (P.R.M., S.D.W.), Neurology (Speech Pathology) (J.R.D., H.M.C., R.L.U.), Psychiatry and Psychology (M.M.M.), Neurology (Behavioral Neurology) (H.B., J.G.-R., D.T.J., B.F.B., D.S.K., R.C.P., K.A.J.), and Information Technology (M.L.S.), Mayo Clinic, Rochester, MN; and Department of Neuroscience (N.E.-T.), Mayo Clinic, Jacksonville, FL.
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Heather M. Clark
From the Departments of Radiology (J.L.W., C.G.S., I.S., M.L.S., C.R.J., V.J.L.), Health Science Research (Biostatistics) (P.R.M., S.D.W.), Neurology (Speech Pathology) (J.R.D., H.M.C., R.L.U.), Psychiatry and Psychology (M.M.M.), Neurology (Behavioral Neurology) (H.B., J.G.-R., D.T.J., B.F.B., D.S.K., R.C.P., K.A.J.), and Information Technology (M.L.S.), Mayo Clinic, Rochester, MN; and Department of Neuroscience (N.E.-T.), Mayo Clinic, Jacksonville, FL.
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Mary M. Machulda
From the Departments of Radiology (J.L.W., C.G.S., I.S., M.L.S., C.R.J., V.J.L.), Health Science Research (Biostatistics) (P.R.M., S.D.W.), Neurology (Speech Pathology) (J.R.D., H.M.C., R.L.U.), Psychiatry and Psychology (M.M.M.), Neurology (Behavioral Neurology) (H.B., J.G.-R., D.T.J., B.F.B., D.S.K., R.C.P., K.A.J.), and Information Technology (M.L.S.), Mayo Clinic, Rochester, MN; and Department of Neuroscience (N.E.-T.), Mayo Clinic, Jacksonville, FL.
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Christopher G. Schwarz
From the Departments of Radiology (J.L.W., C.G.S., I.S., M.L.S., C.R.J., V.J.L.), Health Science Research (Biostatistics) (P.R.M., S.D.W.), Neurology (Speech Pathology) (J.R.D., H.M.C., R.L.U.), Psychiatry and Psychology (M.M.M.), Neurology (Behavioral Neurology) (H.B., J.G.-R., D.T.J., B.F.B., D.S.K., R.C.P., K.A.J.), and Information Technology (M.L.S.), Mayo Clinic, Rochester, MN; and Department of Neuroscience (N.E.-T.), Mayo Clinic, Jacksonville, FL.
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Stephen D. Weigand
From the Departments of Radiology (J.L.W., C.G.S., I.S., M.L.S., C.R.J., V.J.L.), Health Science Research (Biostatistics) (P.R.M., S.D.W.), Neurology (Speech Pathology) (J.R.D., H.M.C., R.L.U.), Psychiatry and Psychology (M.M.M.), Neurology (Behavioral Neurology) (H.B., J.G.-R., D.T.J., B.F.B., D.S.K., R.C.P., K.A.J.), and Information Technology (M.L.S.), Mayo Clinic, Rochester, MN; and Department of Neuroscience (N.E.-T.), Mayo Clinic, Jacksonville, FL.
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Irene Sintini
From the Departments of Radiology (J.L.W., C.G.S., I.S., M.L.S., C.R.J., V.J.L.), Health Science Research (Biostatistics) (P.R.M., S.D.W.), Neurology (Speech Pathology) (J.R.D., H.M.C., R.L.U.), Psychiatry and Psychology (M.M.M.), Neurology (Behavioral Neurology) (H.B., J.G.-R., D.T.J., B.F.B., D.S.K., R.C.P., K.A.J.), and Information Technology (M.L.S.), Mayo Clinic, Rochester, MN; and Department of Neuroscience (N.E.-T.), Mayo Clinic, Jacksonville, FL.
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Matthew L. Senjem
From the Departments of Radiology (J.L.W., C.G.S., I.S., M.L.S., C.R.J., V.J.L.), Health Science Research (Biostatistics) (P.R.M., S.D.W.), Neurology (Speech Pathology) (J.R.D., H.M.C., R.L.U.), Psychiatry and Psychology (M.M.M.), Neurology (Behavioral Neurology) (H.B., J.G.-R., D.T.J., B.F.B., D.S.K., R.C.P., K.A.J.), and Information Technology (M.L.S.), Mayo Clinic, Rochester, MN; and Department of Neuroscience (N.E.-T.), Mayo Clinic, Jacksonville, FL.
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Nilufer Ertekin-Taner
From the Departments of Radiology (J.L.W., C.G.S., I.S., M.L.S., C.R.J., V.J.L.), Health Science Research (Biostatistics) (P.R.M., S.D.W.), Neurology (Speech Pathology) (J.R.D., H.M.C., R.L.U.), Psychiatry and Psychology (M.M.M.), Neurology (Behavioral Neurology) (H.B., J.G.-R., D.T.J., B.F.B., D.S.K., R.C.P., K.A.J.), and Information Technology (M.L.S.), Mayo Clinic, Rochester, MN; and Department of Neuroscience (N.E.-T.), Mayo Clinic, Jacksonville, FL.
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Hugo Botha
From the Departments of Radiology (J.L.W., C.G.S., I.S., M.L.S., C.R.J., V.J.L.), Health Science Research (Biostatistics) (P.R.M., S.D.W.), Neurology (Speech Pathology) (J.R.D., H.M.C., R.L.U.), Psychiatry and Psychology (M.M.M.), Neurology (Behavioral Neurology) (H.B., J.G.-R., D.T.J., B.F.B., D.S.K., R.C.P., K.A.J.), and Information Technology (M.L.S.), Mayo Clinic, Rochester, MN; and Department of Neuroscience (N.E.-T.), Mayo Clinic, Jacksonville, FL.
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Rene L. Utianski
From the Departments of Radiology (J.L.W., C.G.S., I.S., M.L.S., C.R.J., V.J.L.), Health Science Research (Biostatistics) (P.R.M., S.D.W.), Neurology (Speech Pathology) (J.R.D., H.M.C., R.L.U.), Psychiatry and Psychology (M.M.M.), Neurology (Behavioral Neurology) (H.B., J.G.-R., D.T.J., B.F.B., D.S.K., R.C.P., K.A.J.), and Information Technology (M.L.S.), Mayo Clinic, Rochester, MN; and Department of Neuroscience (N.E.-T.), Mayo Clinic, Jacksonville, FL.
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Jonathan Graff-Radford
From the Departments of Radiology (J.L.W., C.G.S., I.S., M.L.S., C.R.J., V.J.L.), Health Science Research (Biostatistics) (P.R.M., S.D.W.), Neurology (Speech Pathology) (J.R.D., H.M.C., R.L.U.), Psychiatry and Psychology (M.M.M.), Neurology (Behavioral Neurology) (H.B., J.G.-R., D.T.J., B.F.B., D.S.K., R.C.P., K.A.J.), and Information Technology (M.L.S.), Mayo Clinic, Rochester, MN; and Department of Neuroscience (N.E.-T.), Mayo Clinic, Jacksonville, FL.
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David T. Jones
From the Departments of Radiology (J.L.W., C.G.S., I.S., M.L.S., C.R.J., V.J.L.), Health Science Research (Biostatistics) (P.R.M., S.D.W.), Neurology (Speech Pathology) (J.R.D., H.M.C., R.L.U.), Psychiatry and Psychology (M.M.M.), Neurology (Behavioral Neurology) (H.B., J.G.-R., D.T.J., B.F.B., D.S.K., R.C.P., K.A.J.), and Information Technology (M.L.S.), Mayo Clinic, Rochester, MN; and Department of Neuroscience (N.E.-T.), Mayo Clinic, Jacksonville, FL.
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Bradley F. Boeve
From the Departments of Radiology (J.L.W., C.G.S., I.S., M.L.S., C.R.J., V.J.L.), Health Science Research (Biostatistics) (P.R.M., S.D.W.), Neurology (Speech Pathology) (J.R.D., H.M.C., R.L.U.), Psychiatry and Psychology (M.M.M.), Neurology (Behavioral Neurology) (H.B., J.G.-R., D.T.J., B.F.B., D.S.K., R.C.P., K.A.J.), and Information Technology (M.L.S.), Mayo Clinic, Rochester, MN; and Department of Neuroscience (N.E.-T.), Mayo Clinic, Jacksonville, FL.
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David S. Knopman
From the Departments of Radiology (J.L.W., C.G.S., I.S., M.L.S., C.R.J., V.J.L.), Health Science Research (Biostatistics) (P.R.M., S.D.W.), Neurology (Speech Pathology) (J.R.D., H.M.C., R.L.U.), Psychiatry and Psychology (M.M.M.), Neurology (Behavioral Neurology) (H.B., J.G.-R., D.T.J., B.F.B., D.S.K., R.C.P., K.A.J.), and Information Technology (M.L.S.), Mayo Clinic, Rochester, MN; and Department of Neuroscience (N.E.-T.), Mayo Clinic, Jacksonville, FL.
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Ronald C. Petersen
From the Departments of Radiology (J.L.W., C.G.S., I.S., M.L.S., C.R.J., V.J.L.), Health Science Research (Biostatistics) (P.R.M., S.D.W.), Neurology (Speech Pathology) (J.R.D., H.M.C., R.L.U.), Psychiatry and Psychology (M.M.M.), Neurology (Behavioral Neurology) (H.B., J.G.-R., D.T.J., B.F.B., D.S.K., R.C.P., K.A.J.), and Information Technology (M.L.S.), Mayo Clinic, Rochester, MN; and Department of Neuroscience (N.E.-T.), Mayo Clinic, Jacksonville, FL.
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Clifford R. Jack
From the Departments of Radiology (J.L.W., C.G.S., I.S., M.L.S., C.R.J., V.J.L.), Health Science Research (Biostatistics) (P.R.M., S.D.W.), Neurology (Speech Pathology) (J.R.D., H.M.C., R.L.U.), Psychiatry and Psychology (M.M.M.), Neurology (Behavioral Neurology) (H.B., J.G.-R., D.T.J., B.F.B., D.S.K., R.C.P., K.A.J.), and Information Technology (M.L.S.), Mayo Clinic, Rochester, MN; and Department of Neuroscience (N.E.-T.), Mayo Clinic, Jacksonville, FL.
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Val J. Lowe
From the Departments of Radiology (J.L.W., C.G.S., I.S., M.L.S., C.R.J., V.J.L.), Health Science Research (Biostatistics) (P.R.M., S.D.W.), Neurology (Speech Pathology) (J.R.D., H.M.C., R.L.U.), Psychiatry and Psychology (M.M.M.), Neurology (Behavioral Neurology) (H.B., J.G.-R., D.T.J., B.F.B., D.S.K., R.C.P., K.A.J.), and Information Technology (M.L.S.), Mayo Clinic, Rochester, MN; and Department of Neuroscience (N.E.-T.), Mayo Clinic, Jacksonville, FL.
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Keith A. Josephs
From the Departments of Radiology (J.L.W., C.G.S., I.S., M.L.S., C.R.J., V.J.L.), Health Science Research (Biostatistics) (P.R.M., S.D.W.), Neurology (Speech Pathology) (J.R.D., H.M.C., R.L.U.), Psychiatry and Psychology (M.M.M.), Neurology (Behavioral Neurology) (H.B., J.G.-R., D.T.J., B.F.B., D.S.K., R.C.P., K.A.J.), and Information Technology (M.L.S.), Mayo Clinic, Rochester, MN; and Department of Neuroscience (N.E.-T.), Mayo Clinic, Jacksonville, FL.
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Citation
The influence of β-amyloid on [18F]AV-1451 in semantic variant of primary progressive aphasia
Jennifer L. Whitwell, Peter R. Martin, Joseph R. Duffy, Heather M. Clark, Mary M. Machulda, Christopher G. Schwarz, Stephen D. Weigand, Irene Sintini, Matthew L. Senjem, Nilufer Ertekin-Taner, Hugo Botha, Rene L. Utianski, Jonathan Graff-Radford, David T. Jones, Bradley F. Boeve, David S. Knopman, Ronald C. Petersen, Clifford R. Jack, Val J. Lowe, Keith A. Josephs
Neurology Feb 2019, 92 (7) e710-e722; DOI: 10.1212/WNL.0000000000006913

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Abstract

Objective To compare [18F]AV-1451 uptake in the semantic variant of primary progressive aphasia (svPPA) to Alzheimer dementia, and determine whether increased uptake in svPPA is associated with the presence of β-amyloid (Aβ).

Methods Thirty-one participants with svPPA underwent MRI and Pittsburgh compound B–PET scanning, and 17 of these also underwent [18F]AV-1451 tau-PET. A global Pittsburgh compound B standardized uptake value ratio was calculated for all participants, with a cutoff of 1.42 used to define Aβ(+) participants. We assessed region and voxel-level [18F]AV-1451 uptake in the whole svPPA cohort and separately in Aβ(+) and Aβ(−) svPPA groups, compared to 12 Aβ(+) participants with Alzheimer dementia and 170 cognitively normal, Aβ(−) controls.

Results Of the entire cohort of participants with svPPA, 26% were Aβ(+). The Aβ(+) participants were older at scan compared to the Aβ(−) participants. svPPA showed elevated [18F]AV-1451 uptake in anteromedial temporal regions but the degree of uptake was lower than in Alzheimer dementia. After controlling for age, Aβ(+) status in svPPA was associated with significantly higher uptake in all anteromedial and inferior/middle lateral temporal regions, but uptake was still lower than in Alzheimer dementia.

Conclusion Although [18F]AV-1451 uptake is focally elevated in svPPA, the level of uptake is much less than what occurs in Alzheimer dementia and appears to be at least partially related to Aβ. Therefore, it is possible that some of the increased uptake of [18F]AV-1451 in svPPA is related to binding paired helical filament tau.

Glossary

Aβ=
β-amyloid;
FDG=
[18F]-fluorodeoxyglucose;
MCALT=
Mayo Clinic Adult Lifespan Template;
MP-RAGE=
magnetization-prepared rapid-acquisition gradient echo;
PART=
primary age-related tauopathy;
PiB=
Pittsburgh compound B;
ROI=
region of interest;
SUVR=
standardized uptake value ratio;
svPPA=
semantic variant of primary progressive aphasia;
TDP-43=
TAR DNA binding protein of 43 kDa

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Received May 18, 2018.
  • Accepted in final form October 11, 2018.
  • © 2019 American Academy of Neurology
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