TY - JOUR
T1 - In vivo 18 F-AV-1451 tau PET signal in MAPT mutation carriers varies by expected tau isoforms
AU - Jones, David T.
AU - Knopman, David S.
AU - Graff-Radford, Jonathan
AU - Syrjanen, Jeremy A.
AU - Senjem, Matthew L.
AU - Schwarz, Christopher G.
AU - Dheel, Christina
AU - Wszolek, Zbigniew
AU - Rademakers, Rosa
AU - Kantarci, Kejal
AU - Petersen, Ronald C.
AU - Jack, Clifford R.
AU - Lowe, Val J.
AU - Boeve, Bradley F.
N1 - Publisher Copyright:
© 2018 American Academy of Neurology.
PY - 2018/3/13
Y1 - 2018/3/13
N2 - Objective To evaluate 18 F-AV-1451 tau PET binding among microtubule-Associated protein tau (MAPT) mutation carriers. Methods Using a case-control study, we quantitatively and qualitatively compared tau PET scans in 10 symptomatic and 3 asymptomatic MAPT mutation carriers (n = 13, age range 42-67 years) with clinically normal (CN) participants (n = 241, age range 42-67 years) and an Alzheimer disease (AD) dementia cohort (n = 30, age range 52-67 years). Eight participants had MAPT mutations that involved exon 10 (N279K n = 5, S305N n = 2, P301L n = 1) and tend to form 4R tau pathology, and 5 had mutations outside exon 10 (V337M n = 2, R406W n = 3) and tend to form mixed 3R/4R tau pathology. Results Tau PET signal was qualitatively and quantitatively different between participants with AD, CN participants, and MAPT mutation carriers, with the greatest signal intensity in those with AD and minimal regional signal in MAPT mutation carries with mutations in exon 10. However, MAPT mutation carriers with mutations outside exon 10 had uptake levels within the AD range, which was significantly higher than both MAPT mutation carriers with mutations in exon 10 and controls. Conclusions Tau PET shows higher magnitude of binding in MAPT mutation carriers who harbor mutations that are more likely to produce AD-like tau pathology (e.g., in our series, the non-exon 10 families tend to accumulate mixed 3R/4R aggregates). Exon 10 splicing determines the balance of 3R and 4R tau isoforms, with some mutations involving exon 10 predisposing to a greater proportion of 4R aggregates and consequently a lower level of AV-1451 binding, as seen in this case series, thus supporting the notion that this tau PET ligand has specific binding properties for AD-like tau pathology.
AB - Objective To evaluate 18 F-AV-1451 tau PET binding among microtubule-Associated protein tau (MAPT) mutation carriers. Methods Using a case-control study, we quantitatively and qualitatively compared tau PET scans in 10 symptomatic and 3 asymptomatic MAPT mutation carriers (n = 13, age range 42-67 years) with clinically normal (CN) participants (n = 241, age range 42-67 years) and an Alzheimer disease (AD) dementia cohort (n = 30, age range 52-67 years). Eight participants had MAPT mutations that involved exon 10 (N279K n = 5, S305N n = 2, P301L n = 1) and tend to form 4R tau pathology, and 5 had mutations outside exon 10 (V337M n = 2, R406W n = 3) and tend to form mixed 3R/4R tau pathology. Results Tau PET signal was qualitatively and quantitatively different between participants with AD, CN participants, and MAPT mutation carriers, with the greatest signal intensity in those with AD and minimal regional signal in MAPT mutation carries with mutations in exon 10. However, MAPT mutation carriers with mutations outside exon 10 had uptake levels within the AD range, which was significantly higher than both MAPT mutation carriers with mutations in exon 10 and controls. Conclusions Tau PET shows higher magnitude of binding in MAPT mutation carriers who harbor mutations that are more likely to produce AD-like tau pathology (e.g., in our series, the non-exon 10 families tend to accumulate mixed 3R/4R aggregates). Exon 10 splicing determines the balance of 3R and 4R tau isoforms, with some mutations involving exon 10 predisposing to a greater proportion of 4R aggregates and consequently a lower level of AV-1451 binding, as seen in this case series, thus supporting the notion that this tau PET ligand has specific binding properties for AD-like tau pathology.
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U2 - 10.1212/WNL.0000000000005117
DO - 10.1212/WNL.0000000000005117
M3 - Article
C2 - 29440563
AN - SCOPUS:85053934802
SN - 0028-3878
VL - 90
SP - e947-e954
JO - Neurology
JF - Neurology
IS - 11
ER -