Trajectory of lobar atrophy in asymptomatic and symptomatic GRN mutation carriers: a longitudinal MRI study.

Abstract

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.

• Authors: Qin Chen, Bradley F Boeve, Matthew Senjem, Nirubol Tosakulwong, Timothy Lesnick, Danielle Brushaber, Christina Dheel, Julie Fields, Leah Forsberg, Ralitza Gavrilova, Debra Gearhart, Jonathan Graff-Radford, Neill Graff-Radford, Clifford R Jack Jr, David Jones, David Knopman, Walter K Kremers, Maria Lapid, Rosa Rademakers, Eliana Marisa Ramos, Jeremy Syrjanen, Adam L Boxer, Howie Rosen, Zbigniew K Wszolek, Kejal Kantarci
• Journal: Neurobiology of aging (Neurobiol Aging) Vol. 88 Pg. 42-50 (04 2020) ISSN: 1558-1497 [Electronic] United States
• PMID: 31918955 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• GRN protein, human
• Progranulins

Topics

• Adult
• Asymptomatic Diseases
• Atrophy
• Female
• Frontotemporal Lobar Degeneration (diagnostic imaging, genetics, pathology)
• Heterozygote
• Humans
• Loss of Function Mutation
• Magnetic Resonance Imaging (methods)
• Male
• Middle Aged
• Progranulins (genetics)
• Temporal Lobe (diagnostic imaging, pathology)
• Young Adult