TY - JOUR
T1 - Trajectory of lobar atrophy in asymptomatic and symptomatic GRN mutation carriers
T2 - a longitudinal MRI study
AU - Chen, Qin
AU - Boeve, Bradley F.
AU - Senjem, Matthew
AU - Tosakulwong, Nirubol
AU - Lesnick, Timothy
AU - Brushaber, Danielle
AU - Dheel, Christina
AU - Fields, Julie
AU - Forsberg, Leah
AU - Gavrilova, Ralitza
AU - Gearhart, Debra
AU - Graff-Radford, Jonathan
AU - Graff-Radford, Neill
AU - Jack, Clifford R.
AU - Jones, David
AU - Knopman, David
AU - Kremers, Walter K.
AU - Lapid, Maria
AU - Rademakers, Rosa
AU - Ramos, Eliana Marisa
AU - Syrjanen, Jeremy
AU - Boxer, Adam L.
AU - Rosen, Howie
AU - Wszolek, Zbigniew K.
AU - Kantarci, Kejal
N1 - Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2020/4
Y1 - 2020/4
N2 - Loss-of-function mutations in the progranulin gene (GRN) are one of the major causes of familial frontotemporal lobar degeneration. Our objective was to determine the rates and trajectories of lobar cortical atrophy from longitudinal structural magnetic resonance imaging in both asymptomatic and symptomatic GRN mutation carriers. Individuals in this study were from the ADRC and LEFFTDS studies at the Mayo Clinic. We identified 13 GRN mutation carriers (8 asymptomatic, 5 symptomatic) and noncarriers (n = 10) who had at least 2 serial T1-weighted structural magnetic resonance images and were followed annually with a median of 3 years (range 1.0–9.8 years). Longitudinal changes in lobar cortical volume were analyzed using the tensor-based morphometry with symmetric normalization (TBM-SyN) algorithm. Linear mixed-effect models were used to model cortical volume change over time among 3 groups. The annual rates of frontal (p < 0.05) and parietal (p < 0.01) lobe cortical atrophy were higher in asymptomatic GRN mutation carriers than noncarriers. The symptomatic GRN mutation carriers also had increased rates of atrophy in the frontal (p < 0.01) and parietal lobe (p < 0.01) cortices than noncarriers. In addition, greater rates of cortical atrophy were observed in the temporal lobe cortices of symptomatic GRN mutation carriers than noncarriers (p < 0.001). We found that a decline in frontal and parietal lobar cortical volume occurs in asymptomatic GRN mutation carriers and continues in the symptomatic GRN mutation carriers, whereas an increased rate of temporal lobe cortical atrophy is observed only in symptomatic GRN mutation carriers. This sequential pattern of cortical involvement in GRN mutation carriers has important implications for using imaging biomarkers of neurodegeneration as an outcome measure in potential treatment trials involving GRN mutation carriers.
AB - Loss-of-function mutations in the progranulin gene (GRN) are one of the major causes of familial frontotemporal lobar degeneration. Our objective was to determine the rates and trajectories of lobar cortical atrophy from longitudinal structural magnetic resonance imaging in both asymptomatic and symptomatic GRN mutation carriers. Individuals in this study were from the ADRC and LEFFTDS studies at the Mayo Clinic. We identified 13 GRN mutation carriers (8 asymptomatic, 5 symptomatic) and noncarriers (n = 10) who had at least 2 serial T1-weighted structural magnetic resonance images and were followed annually with a median of 3 years (range 1.0–9.8 years). Longitudinal changes in lobar cortical volume were analyzed using the tensor-based morphometry with symmetric normalization (TBM-SyN) algorithm. Linear mixed-effect models were used to model cortical volume change over time among 3 groups. The annual rates of frontal (p < 0.05) and parietal (p < 0.01) lobe cortical atrophy were higher in asymptomatic GRN mutation carriers than noncarriers. The symptomatic GRN mutation carriers also had increased rates of atrophy in the frontal (p < 0.01) and parietal lobe (p < 0.01) cortices than noncarriers. In addition, greater rates of cortical atrophy were observed in the temporal lobe cortices of symptomatic GRN mutation carriers than noncarriers (p < 0.001). We found that a decline in frontal and parietal lobar cortical volume occurs in asymptomatic GRN mutation carriers and continues in the symptomatic GRN mutation carriers, whereas an increased rate of temporal lobe cortical atrophy is observed only in symptomatic GRN mutation carriers. This sequential pattern of cortical involvement in GRN mutation carriers has important implications for using imaging biomarkers of neurodegeneration as an outcome measure in potential treatment trials involving GRN mutation carriers.
KW - Asymptomatic
KW - Frontotemporal dementia
KW - GRN
KW - Longitudinal
KW - Magnetic resonance image
UR - http://www.scopus.com/inward/record.url?scp=85077522637&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85077522637&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2019.12.004
DO - 10.1016/j.neurobiolaging.2019.12.004
M3 - Article
C2 - 31918955
AN - SCOPUS:85077522637
SN - 0197-4580
VL - 88
SP - 42
EP - 50
JO - Neurobiology of aging
JF - Neurobiology of aging
ER -