Premium
The evolution of brain atrophy across the disease spectrum of familial frontotemporal dementia
Author(s) -
Staffaroni Adam M.,
Goh ShengYang Matthew,
Cobigo Yann,
Ong Elise,
Lee Suzee E.,
Casaletto Kaitlin B.,
Wolf Amy,
Forsberg Leah K.,
Ghoshal Nupur,
GraffRadford Neill R.,
Grossman Murray,
Heuer Hilary W.,
Hsiung GingYuek Robin,
Kantarci Kejal,
Knopman David S.,
Kremers Walter K.,
Mackenzie Ian R.,
Miller Bruce L.,
Pedraza Otto,
Rascovsky Katya,
Tartaglia Carmela,
Wszolek Zbigniew,
Kramer Joel H.,
Kornak John,
Boeve Bradley F.,
Boxer Adam L.,
Rosen Howard J.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.046404
Subject(s) - c9orf72 , frontotemporal dementia , atrophy , frontotemporal lobar degeneration , dementia , clinical dementia rating , pathology , oncology , psychology , medicine , disease
Background Familial frontotemporal dementia (f‐FTLD) is typically caused by mutations in one of three genes: microtubule‐associated protein tau ( MAPT ), progranulin ( GRN ), and a repeat expansion in the chromosome 9 open reading frame 72 ( C9orf72 ) gene. Accurate characterization of the natural history of each mutation is important for clinical prognostication and clinical trial design, and it could shed light on disease biology. Such models have not been thoroughly developed using participants that represent all disease stages, with longitudinal data. We characterized the trajectory of atrophy in each gene by using longitudinal voxel‐wise analyses of gray matter volume, and we assessed whether functional independence declined in tandem. Method F‐FTLD participants (n=100) with a known mutation ( MAPT+ (n=28), GRN+ (n=33), C9orf72+ (n=39)) were grouped according to disease stage (CDR®+NACC FTLD module). We included participants with at least two structural MRIs at a given disease stage: presymptomatic (CDR®+NACC‐FTLD=0, n=57), mild/questionable (CDR®+NACC‐FTLD=0.5, n=15), and symptomatic (CDR®+NACC‐FTLD ≥1, n=28). We fitted longitudinal linear mixed effects models to extract mean atrophy rates in each lobe compared to longitudinal imaging from family members without mutations (n=60). All results presented below were significant at p <.001. Result Using the left frontal lobe as an exemplar, in the presymptomatic stage, MAPT mutation carriers showed the greatest rate of atrophy compared to controls (88 mm 3 /year more volume loss than controls), followed by GRN+ (65 mm 3 /year) and then C9orf72+ (49 mm 3 /year). In the mild/questionable stage, MAPT + showed a greater divergence from controls (374 mm 3 /year) than did GRN+ (107 mm 3 /year) or C9orf72+ (223 mm 3 /year). In the symptomatic stage, MAPT+ again lost volume at the fastest rate (2,099 mm 3 /year), followed by GRN+ (1,360 mm 3 /year). C9orf72 expansion carriers showed a much slower rate of volume loss (115 mm 3 /year). Similar patterns were observed for other brain regions. In contrast to the imaging results, C9orf72+ exhibited similar rates of functional decline compared to GRN+ and MAPT+ at all levels of disease severity. Conclusion The primary f‐FTLD genes show divergent atrophy trajectories as a function of disease stage, with C9orf72 expansion carriers exhibiting a slow degeneration throughout the disease course, possibly due to unique pathophysiological mechanisms.