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Title: 18F-flortaucipir (AV-1451) tau PET in frontotemporal dementia syndromes

Abstract

The tau positron emission tomography (PET) ligand 18F-flortaucipir binds to paired helical filaments of tau in aging and Alzheimer's disease (AD), but its utility in detecting tau aggregates in frontotemporal dementia (FTD) is uncertain. We performed 18F-flortaucipir imaging in patients with the FTD syndromes ( n = 45): nonfluent variant primary progressive aphasia (nfvPPA) ( n = 11), corticobasal syndrome (CBS) ( n = 10), behavioral variant frontotemporal dementia (bvFTD) ( n = 10), semantic variant primary progressive aphasia (svPPA) ( n = 2) and FTD associated pathogenic genetic mutations microtubule-associated protein tau ( MAPT) ( n = 6), chromosome 9 open reading frame 72 ( C9ORF72) ( n = 5), and progranulin ( GRN) ( n = 1). All patients underwent MRI and β-amyloid biomarker testing via 11C-PiB or cerebrospinal fluid. 18F-flortaucipir uptake in patients was compared to 53 β-amyloid negative normal controls using voxelwise and pre-specified region of interest approaches. On qualitative assessment, patients with nfvPPA showed elevated 18F-flortacupir binding in the left greater than right inferior frontal gyrus. Patients with CBS showed elevated binding in frontal white matter, with higher cortical gray matter uptake in a subset of β-amyloid-positive patients. Five of ten patients with sporadic bvFTDmore » demonstrated increased frontotemporal binding. MAPT mutation carriers had elevated 18F-flortaucipir retention primarily, but not exclusively, in mutations with Alzheimer's-like neurofibrillary tangles. However, tracer retention was also seen in patients with svPPA, and the mutations C9ORF72, GRN predicted to have TDP-43 pathology. Quantitative region-of-interest differences between patients and controls were seen only in inferior frontal gyrus in nfvPPA and left insula and bilateral temporal poles in MAPT carriers. No significant regional differences were found in CBS or sporadic bvFTD. Two patients underwent postmortem neuropathological examination. A patient with C9ORF72, TDP-43-type B pathology, and incidental co-pathology of scattered neurofibrillary tangles in the middle frontal, inferior temporal gyrus showed corresponding mild 18F-flortaucipir retention without additional uptake matching the widespread TDP-43 type B pathology. A patient with sporadic bvFTD demonstrated punctate inferior temporal and hippocampus tracer retention, corresponding to the area of severe argyrophilic grain disease pathology. 18F-flortaucipir in patients with FTD and predicted tauopathy or TDP-43 pathology demonstrated limited sensitivity and specificity. Further postmortem pathological confirmation and development of FTD tau-specific ligands are needed.« less

Authors:
ORCiD logo [1];  [1];  [1];  [1];  [1];  [1];  [2];  [2];  [2];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [3];  [3];  [1];  [1] more »;  [1];  [4];  [1];  [1] « less
  1. Univ. of California, San Francisco, CA (United States)
  2. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  3. Univ. of California, Los Angeles, CA (United States)
  4. Univ. of California, San Francisco, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1579333
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Alzheimer's Research & Therapy
Additional Journal Information:
Journal Volume: 11; Journal Issue: 1; Journal ID: ISSN 1758-9193
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; biomarkers; frontotemporal dementia; tau imaging; neuropathology; tau

Citation Formats

Tsai, Richard M., Bejanin, Alexandre, Lesman-Segev, Orit, LaJoie, Renaud, Visani, Adrienne, Bourakova, Viktoriya, O’Neil, James P., Janabi, Mustafa, Baker, Suzanne, Lee, Suzee E., Perry, David C., Bajorek, Lynn, Karydas, Anna, Spina, Salvatore, Grinberg, Lea T., Seeley, William W., Ramos, Eliana M., Coppola, Giovanni, Gorno-Tempini, Maria Luisa, Miller, Bruce L., Rosen, Howard J., Jagust, William, Boxer, Adam L., and Rabinovici, Gil D. 18F-flortaucipir (AV-1451) tau PET in frontotemporal dementia syndromes. United States: N. p., 2019. Web. doi:10.1186/s13195-019-0470-7.
Tsai, Richard M., Bejanin, Alexandre, Lesman-Segev, Orit, LaJoie, Renaud, Visani, Adrienne, Bourakova, Viktoriya, O’Neil, James P., Janabi, Mustafa, Baker, Suzanne, Lee, Suzee E., Perry, David C., Bajorek, Lynn, Karydas, Anna, Spina, Salvatore, Grinberg, Lea T., Seeley, William W., Ramos, Eliana M., Coppola, Giovanni, Gorno-Tempini, Maria Luisa, Miller, Bruce L., Rosen, Howard J., Jagust, William, Boxer, Adam L., & Rabinovici, Gil D. 18F-flortaucipir (AV-1451) tau PET in frontotemporal dementia syndromes. United States. doi:10.1186/s13195-019-0470-7.
Tsai, Richard M., Bejanin, Alexandre, Lesman-Segev, Orit, LaJoie, Renaud, Visani, Adrienne, Bourakova, Viktoriya, O’Neil, James P., Janabi, Mustafa, Baker, Suzanne, Lee, Suzee E., Perry, David C., Bajorek, Lynn, Karydas, Anna, Spina, Salvatore, Grinberg, Lea T., Seeley, William W., Ramos, Eliana M., Coppola, Giovanni, Gorno-Tempini, Maria Luisa, Miller, Bruce L., Rosen, Howard J., Jagust, William, Boxer, Adam L., and Rabinovici, Gil D. Thu . "18F-flortaucipir (AV-1451) tau PET in frontotemporal dementia syndromes". United States. doi:10.1186/s13195-019-0470-7. https://www.osti.gov/servlets/purl/1579333.
@article{osti_1579333,
title = {18F-flortaucipir (AV-1451) tau PET in frontotemporal dementia syndromes},
author = {Tsai, Richard M. and Bejanin, Alexandre and Lesman-Segev, Orit and LaJoie, Renaud and Visani, Adrienne and Bourakova, Viktoriya and O’Neil, James P. and Janabi, Mustafa and Baker, Suzanne and Lee, Suzee E. and Perry, David C. and Bajorek, Lynn and Karydas, Anna and Spina, Salvatore and Grinberg, Lea T. and Seeley, William W. and Ramos, Eliana M. and Coppola, Giovanni and Gorno-Tempini, Maria Luisa and Miller, Bruce L. and Rosen, Howard J. and Jagust, William and Boxer, Adam L. and Rabinovici, Gil D.},
abstractNote = {The tau positron emission tomography (PET) ligand 18F-flortaucipir binds to paired helical filaments of tau in aging and Alzheimer's disease (AD), but its utility in detecting tau aggregates in frontotemporal dementia (FTD) is uncertain. We performed 18F-flortaucipir imaging in patients with the FTD syndromes (n = 45): nonfluent variant primary progressive aphasia (nfvPPA) (n = 11), corticobasal syndrome (CBS) (n = 10), behavioral variant frontotemporal dementia (bvFTD) (n = 10), semantic variant primary progressive aphasia (svPPA) (n = 2) and FTD associated pathogenic genetic mutations microtubule-associated protein tau (MAPT) (n = 6), chromosome 9 open reading frame 72 (C9ORF72) (n = 5), and progranulin (GRN) (n = 1). All patients underwent MRI and β-amyloid biomarker testing via 11C-PiB or cerebrospinal fluid. 18F-flortaucipir uptake in patients was compared to 53 β-amyloid negative normal controls using voxelwise and pre-specified region of interest approaches. On qualitative assessment, patients with nfvPPA showed elevated 18F-flortacupir binding in the left greater than right inferior frontal gyrus. Patients with CBS showed elevated binding in frontal white matter, with higher cortical gray matter uptake in a subset of β-amyloid-positive patients. Five of ten patients with sporadic bvFTD demonstrated increased frontotemporal binding. MAPT mutation carriers had elevated 18F-flortaucipir retention primarily, but not exclusively, in mutations with Alzheimer's-like neurofibrillary tangles. However, tracer retention was also seen in patients with svPPA, and the mutations C9ORF72, GRN predicted to have TDP-43 pathology. Quantitative region-of-interest differences between patients and controls were seen only in inferior frontal gyrus in nfvPPA and left insula and bilateral temporal poles in MAPT carriers. No significant regional differences were found in CBS or sporadic bvFTD. Two patients underwent postmortem neuropathological examination. A patient with C9ORF72, TDP-43-type B pathology, and incidental co-pathology of scattered neurofibrillary tangles in the middle frontal, inferior temporal gyrus showed corresponding mild 18F-flortaucipir retention without additional uptake matching the widespread TDP-43 type B pathology. A patient with sporadic bvFTD demonstrated punctate inferior temporal and hippocampus tracer retention, corresponding to the area of severe argyrophilic grain disease pathology. 18F-flortaucipir in patients with FTD and predicted tauopathy or TDP-43 pathology demonstrated limited sensitivity and specificity. Further postmortem pathological confirmation and development of FTD tau-specific ligands are needed.},
doi = {10.1186/s13195-019-0470-7},
journal = {Alzheimer's Research & Therapy},
issn = {1758-9193},
number = 1,
volume = 11,
place = {United States},
year = {2019},
month = {1}
}

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