TY - JOUR
T1 - Genetic screen in a large series of patients with primary progressive aphasia
AU - Ramos, Eliana Marisa
AU - Dokuru, Deepika Reddy
AU - Van Berlo, Victoria
AU - Wojta, Kevin
AU - Wang, Qing
AU - Huang, Alden Y.
AU - Miller, Zachary A.
AU - Karydas, Anna M.
AU - Bigio, Eileen H.
AU - Rogalski, Emily
AU - Weintraub, Sandra
AU - Rader, Benjamin
AU - Miller, Bruce L.
AU - Gorno-Tempini, Maria Luisa
AU - Mesulam, Marek Marsel
AU - Coppola, Giovanni
N1 - Funding Information:
This work was supported by the NIH ( RC1 AG035610 and R01 AG26938 to G.C., P50 AG023501 and P01 AG019724 to B.L.M., NS050915 , AG052943 , and DC015544 to M.L.G.-T., DC008552 and AG13854 to M.-M.M.), the John Douglas French Alzheimer's Foundation, and the Tau Consortium. Samples from the National Cell Repository for Alzheimer's Disease (NCRAD), which receives government support under a cooperative agreement grant ( U24 AG21886 ) awarded by the National Institute on Aging (NIA), were used in this study.
PY - 2019/4
Y1 - 2019/4
N2 - Introduction: Primary progressive aphasia (PPA) is a neurological syndrome, associated with both frontotemporal dementia and Alzheimer's disease, in which progressive language impairment emerges as the most salient clinical feature during the initial stages of disease. Methods: We screened the main genes associated with Alzheimer's disease and frontotemporal dementia for pathogenic and risk variants in a cohort of 403 PPA cases. Results: In this case series study, 14 (3.5%) cases carried (likely) pathogenic variants: four C9orf72 expansions, nine GRN, and one TARDBP mutation. Rare risk variants, TREM2 R47H and MAPT A152T, were associated with a three- to seven-fold increase in risk for PPA. Discussion: Our results show that while pathogenic variants within the most common dementia genes were rarely associated with PPA, these were found almost exclusively in GRN and C9orf72, suggesting that PPA is more TDP43- than tau-related in our series. This is consistent with the finding that PPA frequency in dominantly inherited dementias is the highest in kindreds with GRN variants.
AB - Introduction: Primary progressive aphasia (PPA) is a neurological syndrome, associated with both frontotemporal dementia and Alzheimer's disease, in which progressive language impairment emerges as the most salient clinical feature during the initial stages of disease. Methods: We screened the main genes associated with Alzheimer's disease and frontotemporal dementia for pathogenic and risk variants in a cohort of 403 PPA cases. Results: In this case series study, 14 (3.5%) cases carried (likely) pathogenic variants: four C9orf72 expansions, nine GRN, and one TARDBP mutation. Rare risk variants, TREM2 R47H and MAPT A152T, were associated with a three- to seven-fold increase in risk for PPA. Discussion: Our results show that while pathogenic variants within the most common dementia genes were rarely associated with PPA, these were found almost exclusively in GRN and C9orf72, suggesting that PPA is more TDP43- than tau-related in our series. This is consistent with the finding that PPA frequency in dominantly inherited dementias is the highest in kindreds with GRN variants.
KW - C9orf72
KW - GRN
KW - Genetics
KW - Primary progressive aphasia
KW - TARDBP
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U2 - 10.1016/j.jalz.2018.10.009
DO - 10.1016/j.jalz.2018.10.009
M3 - Article
C2 - 30599136
AN - SCOPUS:85060338124
VL - 15
SP - 553
EP - 560
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
SN - 1552-5260
IS - 4
ER -