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February 21, 2017; 88 (8) Article

Frontotemporal dementia with the V337M MAPT mutation

Tau-PET and pathology correlations

Salvatore Spina, Daniel R. Schonhaut, Bradley F. Boeve, William W. Seeley, Rik Ossenkoppele, James P. O'Neil, Andreas Lazaris, Howard J. Rosen, Adam L. Boxer, David C. Perry, Bruce L. Miller, Dennis W. Dickson, Joseph E. Parisi, William J. Jagust, Melissa E. Murray, Gil D. Rabinovici
First published January 27, 2017, DOI: https://doi.org/10.1212/WNL.0000000000003636
Salvatore Spina
From the Memory and Aging Center (S.S., D.R.S., W.W.S., R.O., A.L., H.J.R., A.L.B., D.C.P., B.L.M., G.D.R.), Department of Neurology, and Department of Pathology (W.W.S), University of California, San Francisco; Department of Neurology (B.F.B., J.E.P.), Mayo Clinic, Rochester, MN; Helen Wills Neuroscience Institute (R.O., W.J.J., G.D.R.), University of California Berkeley; Alzheimercenter (R.O.), VU University Medical Center, Amsterdam, the Netherlands; Lawrence Berkeley National Laboratory (J.P.O., W.J.J., M.E.M., G.D.R.), Berkeley, CA; and Department of Pathology (D.W.D.), Mayo Clinic, Jacksonville, FL.
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Daniel R. Schonhaut
From the Memory and Aging Center (S.S., D.R.S., W.W.S., R.O., A.L., H.J.R., A.L.B., D.C.P., B.L.M., G.D.R.), Department of Neurology, and Department of Pathology (W.W.S), University of California, San Francisco; Department of Neurology (B.F.B., J.E.P.), Mayo Clinic, Rochester, MN; Helen Wills Neuroscience Institute (R.O., W.J.J., G.D.R.), University of California Berkeley; Alzheimercenter (R.O.), VU University Medical Center, Amsterdam, the Netherlands; Lawrence Berkeley National Laboratory (J.P.O., W.J.J., M.E.M., G.D.R.), Berkeley, CA; and Department of Pathology (D.W.D.), Mayo Clinic, Jacksonville, FL.
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Bradley F. Boeve
From the Memory and Aging Center (S.S., D.R.S., W.W.S., R.O., A.L., H.J.R., A.L.B., D.C.P., B.L.M., G.D.R.), Department of Neurology, and Department of Pathology (W.W.S), University of California, San Francisco; Department of Neurology (B.F.B., J.E.P.), Mayo Clinic, Rochester, MN; Helen Wills Neuroscience Institute (R.O., W.J.J., G.D.R.), University of California Berkeley; Alzheimercenter (R.O.), VU University Medical Center, Amsterdam, the Netherlands; Lawrence Berkeley National Laboratory (J.P.O., W.J.J., M.E.M., G.D.R.), Berkeley, CA; and Department of Pathology (D.W.D.), Mayo Clinic, Jacksonville, FL.
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William W. Seeley
From the Memory and Aging Center (S.S., D.R.S., W.W.S., R.O., A.L., H.J.R., A.L.B., D.C.P., B.L.M., G.D.R.), Department of Neurology, and Department of Pathology (W.W.S), University of California, San Francisco; Department of Neurology (B.F.B., J.E.P.), Mayo Clinic, Rochester, MN; Helen Wills Neuroscience Institute (R.O., W.J.J., G.D.R.), University of California Berkeley; Alzheimercenter (R.O.), VU University Medical Center, Amsterdam, the Netherlands; Lawrence Berkeley National Laboratory (J.P.O., W.J.J., M.E.M., G.D.R.), Berkeley, CA; and Department of Pathology (D.W.D.), Mayo Clinic, Jacksonville, FL.
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Rik Ossenkoppele
From the Memory and Aging Center (S.S., D.R.S., W.W.S., R.O., A.L., H.J.R., A.L.B., D.C.P., B.L.M., G.D.R.), Department of Neurology, and Department of Pathology (W.W.S), University of California, San Francisco; Department of Neurology (B.F.B., J.E.P.), Mayo Clinic, Rochester, MN; Helen Wills Neuroscience Institute (R.O., W.J.J., G.D.R.), University of California Berkeley; Alzheimercenter (R.O.), VU University Medical Center, Amsterdam, the Netherlands; Lawrence Berkeley National Laboratory (J.P.O., W.J.J., M.E.M., G.D.R.), Berkeley, CA; and Department of Pathology (D.W.D.), Mayo Clinic, Jacksonville, FL.
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James P. O'Neil
From the Memory and Aging Center (S.S., D.R.S., W.W.S., R.O., A.L., H.J.R., A.L.B., D.C.P., B.L.M., G.D.R.), Department of Neurology, and Department of Pathology (W.W.S), University of California, San Francisco; Department of Neurology (B.F.B., J.E.P.), Mayo Clinic, Rochester, MN; Helen Wills Neuroscience Institute (R.O., W.J.J., G.D.R.), University of California Berkeley; Alzheimercenter (R.O.), VU University Medical Center, Amsterdam, the Netherlands; Lawrence Berkeley National Laboratory (J.P.O., W.J.J., M.E.M., G.D.R.), Berkeley, CA; and Department of Pathology (D.W.D.), Mayo Clinic, Jacksonville, FL.
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Andreas Lazaris
From the Memory and Aging Center (S.S., D.R.S., W.W.S., R.O., A.L., H.J.R., A.L.B., D.C.P., B.L.M., G.D.R.), Department of Neurology, and Department of Pathology (W.W.S), University of California, San Francisco; Department of Neurology (B.F.B., J.E.P.), Mayo Clinic, Rochester, MN; Helen Wills Neuroscience Institute (R.O., W.J.J., G.D.R.), University of California Berkeley; Alzheimercenter (R.O.), VU University Medical Center, Amsterdam, the Netherlands; Lawrence Berkeley National Laboratory (J.P.O., W.J.J., M.E.M., G.D.R.), Berkeley, CA; and Department of Pathology (D.W.D.), Mayo Clinic, Jacksonville, FL.
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Howard J. Rosen
From the Memory and Aging Center (S.S., D.R.S., W.W.S., R.O., A.L., H.J.R., A.L.B., D.C.P., B.L.M., G.D.R.), Department of Neurology, and Department of Pathology (W.W.S), University of California, San Francisco; Department of Neurology (B.F.B., J.E.P.), Mayo Clinic, Rochester, MN; Helen Wills Neuroscience Institute (R.O., W.J.J., G.D.R.), University of California Berkeley; Alzheimercenter (R.O.), VU University Medical Center, Amsterdam, the Netherlands; Lawrence Berkeley National Laboratory (J.P.O., W.J.J., M.E.M., G.D.R.), Berkeley, CA; and Department of Pathology (D.W.D.), Mayo Clinic, Jacksonville, FL.
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Adam L. Boxer
From the Memory and Aging Center (S.S., D.R.S., W.W.S., R.O., A.L., H.J.R., A.L.B., D.C.P., B.L.M., G.D.R.), Department of Neurology, and Department of Pathology (W.W.S), University of California, San Francisco; Department of Neurology (B.F.B., J.E.P.), Mayo Clinic, Rochester, MN; Helen Wills Neuroscience Institute (R.O., W.J.J., G.D.R.), University of California Berkeley; Alzheimercenter (R.O.), VU University Medical Center, Amsterdam, the Netherlands; Lawrence Berkeley National Laboratory (J.P.O., W.J.J., M.E.M., G.D.R.), Berkeley, CA; and Department of Pathology (D.W.D.), Mayo Clinic, Jacksonville, FL.
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David C. Perry
From the Memory and Aging Center (S.S., D.R.S., W.W.S., R.O., A.L., H.J.R., A.L.B., D.C.P., B.L.M., G.D.R.), Department of Neurology, and Department of Pathology (W.W.S), University of California, San Francisco; Department of Neurology (B.F.B., J.E.P.), Mayo Clinic, Rochester, MN; Helen Wills Neuroscience Institute (R.O., W.J.J., G.D.R.), University of California Berkeley; Alzheimercenter (R.O.), VU University Medical Center, Amsterdam, the Netherlands; Lawrence Berkeley National Laboratory (J.P.O., W.J.J., M.E.M., G.D.R.), Berkeley, CA; and Department of Pathology (D.W.D.), Mayo Clinic, Jacksonville, FL.
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Bruce L. Miller
From the Memory and Aging Center (S.S., D.R.S., W.W.S., R.O., A.L., H.J.R., A.L.B., D.C.P., B.L.M., G.D.R.), Department of Neurology, and Department of Pathology (W.W.S), University of California, San Francisco; Department of Neurology (B.F.B., J.E.P.), Mayo Clinic, Rochester, MN; Helen Wills Neuroscience Institute (R.O., W.J.J., G.D.R.), University of California Berkeley; Alzheimercenter (R.O.), VU University Medical Center, Amsterdam, the Netherlands; Lawrence Berkeley National Laboratory (J.P.O., W.J.J., M.E.M., G.D.R.), Berkeley, CA; and Department of Pathology (D.W.D.), Mayo Clinic, Jacksonville, FL.
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Dennis W. Dickson
From the Memory and Aging Center (S.S., D.R.S., W.W.S., R.O., A.L., H.J.R., A.L.B., D.C.P., B.L.M., G.D.R.), Department of Neurology, and Department of Pathology (W.W.S), University of California, San Francisco; Department of Neurology (B.F.B., J.E.P.), Mayo Clinic, Rochester, MN; Helen Wills Neuroscience Institute (R.O., W.J.J., G.D.R.), University of California Berkeley; Alzheimercenter (R.O.), VU University Medical Center, Amsterdam, the Netherlands; Lawrence Berkeley National Laboratory (J.P.O., W.J.J., M.E.M., G.D.R.), Berkeley, CA; and Department of Pathology (D.W.D.), Mayo Clinic, Jacksonville, FL.
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Joseph E. Parisi
From the Memory and Aging Center (S.S., D.R.S., W.W.S., R.O., A.L., H.J.R., A.L.B., D.C.P., B.L.M., G.D.R.), Department of Neurology, and Department of Pathology (W.W.S), University of California, San Francisco; Department of Neurology (B.F.B., J.E.P.), Mayo Clinic, Rochester, MN; Helen Wills Neuroscience Institute (R.O., W.J.J., G.D.R.), University of California Berkeley; Alzheimercenter (R.O.), VU University Medical Center, Amsterdam, the Netherlands; Lawrence Berkeley National Laboratory (J.P.O., W.J.J., M.E.M., G.D.R.), Berkeley, CA; and Department of Pathology (D.W.D.), Mayo Clinic, Jacksonville, FL.
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William J. Jagust
From the Memory and Aging Center (S.S., D.R.S., W.W.S., R.O., A.L., H.J.R., A.L.B., D.C.P., B.L.M., G.D.R.), Department of Neurology, and Department of Pathology (W.W.S), University of California, San Francisco; Department of Neurology (B.F.B., J.E.P.), Mayo Clinic, Rochester, MN; Helen Wills Neuroscience Institute (R.O., W.J.J., G.D.R.), University of California Berkeley; Alzheimercenter (R.O.), VU University Medical Center, Amsterdam, the Netherlands; Lawrence Berkeley National Laboratory (J.P.O., W.J.J., M.E.M., G.D.R.), Berkeley, CA; and Department of Pathology (D.W.D.), Mayo Clinic, Jacksonville, FL.
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Melissa E. Murray
From the Memory and Aging Center (S.S., D.R.S., W.W.S., R.O., A.L., H.J.R., A.L.B., D.C.P., B.L.M., G.D.R.), Department of Neurology, and Department of Pathology (W.W.S), University of California, San Francisco; Department of Neurology (B.F.B., J.E.P.), Mayo Clinic, Rochester, MN; Helen Wills Neuroscience Institute (R.O., W.J.J., G.D.R.), University of California Berkeley; Alzheimercenter (R.O.), VU University Medical Center, Amsterdam, the Netherlands; Lawrence Berkeley National Laboratory (J.P.O., W.J.J., M.E.M., G.D.R.), Berkeley, CA; and Department of Pathology (D.W.D.), Mayo Clinic, Jacksonville, FL.
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Gil D. Rabinovici
From the Memory and Aging Center (S.S., D.R.S., W.W.S., R.O., A.L., H.J.R., A.L.B., D.C.P., B.L.M., G.D.R.), Department of Neurology, and Department of Pathology (W.W.S), University of California, San Francisco; Department of Neurology (B.F.B., J.E.P.), Mayo Clinic, Rochester, MN; Helen Wills Neuroscience Institute (R.O., W.J.J., G.D.R.), University of California Berkeley; Alzheimercenter (R.O.), VU University Medical Center, Amsterdam, the Netherlands; Lawrence Berkeley National Laboratory (J.P.O., W.J.J., M.E.M., G.D.R.), Berkeley, CA; and Department of Pathology (D.W.D.), Mayo Clinic, Jacksonville, FL.
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Full PDF
Citation
Frontotemporal dementia with the V337M MAPT mutation
Tau-PET and pathology correlations
Salvatore Spina, Daniel R. Schonhaut, Bradley F. Boeve, William W. Seeley, Rik Ossenkoppele, James P. O'Neil, Andreas Lazaris, Howard J. Rosen, Adam L. Boxer, David C. Perry, Bruce L. Miller, Dennis W. Dickson, Joseph E. Parisi, William J. Jagust, Melissa E. Murray, Gil D. Rabinovici
Neurology Feb 2017, 88 (8) 758-766; DOI: 10.1212/WNL.0000000000003636

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Abstract

Objective: To assess the efficacy of [18F]AV1451 PET in visualizing tau pathology in vivo in a patient with frontotemporal dementia (FTD) associated with the V337M microtubule-associated protein tau (MAPT) mutation.

Methods: MAPT mutations are associated with the deposition of hyperphosphorylated tau protein in neurons and glia. The PET tracer [18F]AV1451 binds with high affinity to paired helical filaments tau that comprises neurofibrillary tangles in Alzheimer disease (AD), while postmortem studies suggest lower or absent binding to the tau filaments of the majority of non-AD tauopathies. We describe clinical, structural MRI, and [18F]AV1451 PET findings in a V337M MAPT mutation carrier affected by FTD and pathologic findings in his affected mother and in an unrelated V337M MAPT carrier also affected with FTD. The biochemical similarity between paired helical filament tau in AD and MAPT V337M predicts that the tau pathology associated with this mutation constitutes a compelling target for [18F]AV1451 imaging.

Results: We found a strong association between topography and degree of [18F]AV1451 tracer retention in the proband and distribution of tau pathology in the brain of the proband's mother and the unrelated V337M mutation carrier. We also found a significant correlation between the degree of regional MRI brain atrophy and the extent of [18F]AV1451 binding in the proband and a strong association between the proband's clinical presentation and the extent of regional brain atrophy and tau accumulation as assessed by structural brain MRI and [18F]AV1451PET.

Conclusion: Our study supports the usefulness of [18F]AV1451 to characterize tau pathology in at least a subset of pathogenic MAPT mutations.

GLOSSARY

Aβ=
β-amyloid;
AD=
Alzheimer disease;
bvFTD=
behavioral variant frontotemporal dementia;
4R=
4-repeat;
FTD=
frontotemporal dementia;
FTLD=
frontotemporal lobar degeneration;
MAPT=
microtubule-associated protein tau;
NFT=
neurofibrillary tangle;
PHF=
paired helical filaments;
ROI=
region of interest;
SUVr=
standardized uptake value ratio;
TDP-43=
TAR DNA binding protein–43 kDa;
3R=
3-repeat;
UCSF=
University of California San Francisco;
VBM=
voxel-based morphometry

Footnotes

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

  • Supplemental data at Neurology.org

  • Received July 12, 2016.
  • Accepted in final form November 30, 2016.
  • © 2017 American Academy of Neurology
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