TY - JOUR
T1 - Tau PET in autosomal dominant Alzheimer's disease
T2 - Relationship with cognition, dementia and other biomarkers
AU - Gordon, Brian A.
AU - Blazey, Tyler M.
AU - Christensen, Jon
AU - Dincer, Aylin
AU - Flores, Shaney
AU - Keefe, Sarah
AU - Chen, Charles
AU - Su, Yi
AU - McDade, Eric M.
AU - Wang, Guoqiao
AU - Li, Yan
AU - Hassenstab, Jason
AU - Aschenbrenner, Andrew
AU - Hornbeck, Russ
AU - Jack, Clifford R.
AU - Ances, Beau M.
AU - Berman, Sarah B.
AU - Brosch, Jared R.
AU - Galasko, Douglas
AU - Gauthier, Serge
AU - Lah, James J.
AU - Masellis, Mario
AU - Van Dyck, Christopher H.
AU - Mintun, Mark A.
AU - Klein, Gregory
AU - Ristic, Smiljana
AU - Cairns, Nigel J.
AU - Marcus, Daniel S.
AU - Xiong, Chengjie
AU - Holtzman, David M.
AU - Raichle, Marcus E.
AU - Morris, John C.
AU - Bateman, Randall J.
AU - Benzinger, Tammie L.S.
N1 - Publisher Copyright:
© 2019 The Author(s).
PY - 2019/4/1
Y1 - 2019/4/1
N2 - Tauopathy is a hallmark pathology of Alzheimer's disease with a strong relationship with cognitive impairment. As such, understanding tau may be a key to clinical interventions. In vivo tauopathy has been measured using cerebrospinal fluid assays, but these do not provide information about where pathology is in the brain. The introduction of PET ligands that bind to paired helical filaments provides the ability to measure the amount and distribution of tau pathology. The heritability of the age of dementia onset tied to the specific mutations found in autosomal dominant Alzheimer's disease families provides an elegant model to study the spread of tau across the course of the disease as well as the cross-modal relationship between tau and other biomarkers. To better understand the pathobiology of Alzheimer's disease we measured levels of tau PET binding in individuals with dominantly inherited Alzheimer's disease using data from the Dominantly Inherited Alzheimer Network (DIAN). We examined cross-sectional measures of amyloid-b, tau, glucose metabolism, and grey matter degeneration in 15 cognitively normal mutation non-carriers, 20 asymptomatic carriers, and 15 symptomatic mutation carriers. Linear models examined the association of pathology with group, estimated years to symptom onset, as well as cross-modal relationships. For comparison, tau PET was acquired on 17 older adults with sporadic, late onset Alzheimer disease. Tau PET binding was starkly elevated in symptomatic DIAN individuals throughout the cortex. The brain areas demonstrating elevated tau PET binding overlapped with those seen in sporadic Alzheimer's disease, but with a greater cortical involvement and greater levels of binding despite similar cognitive impairment. Tau PET binding was elevated in the temporal lobe, but the most prominent loci of pathology were in the precuneus and lateral parietal regions. Symptomatic mutation carriers also demonstrated elevated tau PET binding in the basal ganglia, consistent with prior work with amyloid-b. The degree of tau tracer binding in symptomatic individuals was correlated to other biomarkers, particularly markers of neurodegeneration. In addition to the differences seen with tau, amyloid-b was increased in both asymptomatic and symptomatic groups relative to non-carriers. Glucose metabolism showed decline primarily in the symptomatic group. MRI indicated structural degeneration in both asymptomatic and symptomatic cohorts. We demonstrate that tau PET binding is elevated in symptomatic individuals with dominantly inherited Alzheimer's disease. Tau PET uptake was tied to the onset of cognitive dysfunction, and there was a higher amount, and different regional pattern of binding compared to late onset, nonfamilial Alzheimer's disease.
AB - Tauopathy is a hallmark pathology of Alzheimer's disease with a strong relationship with cognitive impairment. As such, understanding tau may be a key to clinical interventions. In vivo tauopathy has been measured using cerebrospinal fluid assays, but these do not provide information about where pathology is in the brain. The introduction of PET ligands that bind to paired helical filaments provides the ability to measure the amount and distribution of tau pathology. The heritability of the age of dementia onset tied to the specific mutations found in autosomal dominant Alzheimer's disease families provides an elegant model to study the spread of tau across the course of the disease as well as the cross-modal relationship between tau and other biomarkers. To better understand the pathobiology of Alzheimer's disease we measured levels of tau PET binding in individuals with dominantly inherited Alzheimer's disease using data from the Dominantly Inherited Alzheimer Network (DIAN). We examined cross-sectional measures of amyloid-b, tau, glucose metabolism, and grey matter degeneration in 15 cognitively normal mutation non-carriers, 20 asymptomatic carriers, and 15 symptomatic mutation carriers. Linear models examined the association of pathology with group, estimated years to symptom onset, as well as cross-modal relationships. For comparison, tau PET was acquired on 17 older adults with sporadic, late onset Alzheimer disease. Tau PET binding was starkly elevated in symptomatic DIAN individuals throughout the cortex. The brain areas demonstrating elevated tau PET binding overlapped with those seen in sporadic Alzheimer's disease, but with a greater cortical involvement and greater levels of binding despite similar cognitive impairment. Tau PET binding was elevated in the temporal lobe, but the most prominent loci of pathology were in the precuneus and lateral parietal regions. Symptomatic mutation carriers also demonstrated elevated tau PET binding in the basal ganglia, consistent with prior work with amyloid-b. The degree of tau tracer binding in symptomatic individuals was correlated to other biomarkers, particularly markers of neurodegeneration. In addition to the differences seen with tau, amyloid-b was increased in both asymptomatic and symptomatic groups relative to non-carriers. Glucose metabolism showed decline primarily in the symptomatic group. MRI indicated structural degeneration in both asymptomatic and symptomatic cohorts. We demonstrate that tau PET binding is elevated in symptomatic individuals with dominantly inherited Alzheimer's disease. Tau PET uptake was tied to the onset of cognitive dysfunction, and there was a higher amount, and different regional pattern of binding compared to late onset, nonfamilial Alzheimer's disease.
KW - Alzheimer's
KW - Amyloid
KW - FDG
KW - Flortaucipir
KW - MRI
UR - http://www.scopus.com/inward/record.url?scp=85063736602&partnerID=8YFLogxK
U2 - 10.1093/brain/awz019
DO - 10.1093/brain/awz019
M3 - Article
C2 - 30753379
AN - SCOPUS:85063736602
SN - 0006-8950
VL - 142
SP - 1063
EP - 1076
JO - Brain
JF - Brain
IS - 4
ER -