TY - JOUR
T1 - Neuroimaging signatures of frontotemporal dementia genetics
T2 - C9ORF72, tau, progranulin and sporadics
AU - Whitwell, Jennifer L.
AU - Weigand, Stephen D.
AU - Boeve, Bradley F.
AU - Senjem, Matthew L.
AU - Gunter, Jeffrey L.
AU - Dejesus-Hernandez, Mariely
AU - Rutherford, Nicola J.
AU - Baker, Matthew
AU - Knopman, David S.
AU - Wszolek, Zbigniew K.
AU - Parisi, Joseph E.
AU - Dickson, Dennis W.
AU - Petersen, Ronald C.
AU - Rademakers, Rosa
AU - Jack, Clifford R.
AU - Josephs, Keith A.
N1 - Funding Information:
NIH (grants R21 AG38736, R01 DC010367, R01 AG037491, R01 AG11378, P50 AG16574, U01 AG024904, R01-AG023195, U01 AG06786, R01 HL70825, U24 AG026395, U01 AG03949, RO1 NS065782-01, R56 AG26251-03, P50-AG25711, P50-NS40256, P01-AG17216, R01-AG15866, R01-NS65782, R01-AG26251, 1RC2NS070276, NS057567, P50 NS072187-01S2); the Dana Foundation; the Pacific Alzheimer Research Foundation (Canada); the Amyotrophic Lateral Sclerosis Association; Mayo Clinic Florida (MCF) Research Committee CR program (MCF #90052030); Dystonia Medical Research Foundation; a gift from Carl Edward Bolch, Jr and Susan Bass Bolch (MCF #90052031/ PAU #90052); the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Foundation; and the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program of the Mayo Foundation.
PY - 2012/3
Y1 - 2012/3
N2 - A major recent discovery was the identification of an expansion of a non-coding GGGGCC hexanucleotide repeat in the C9ORF72 gene in patients with frontotemporal dementia and amyotrophic lateral sclerosis. Mutations in two other genes are known to account for familial frontotemporal dementia: microtubule-associated protein tau and progranulin. Although imaging features have been previously reported in subjects with mutations in tau and progranulin, no imaging features have been published in C9ORF72. Furthermore, it remains unknown whether there are differences in atrophy patterns across these mutations, and whether regional differences could help differentiate C9ORF72 from the other two mutations at the single-subject level. We aimed to determine the regional pattern of brain atrophy associated with the C9ORF72 gene mutation, and to determine which regions best differentiate C9ORF72 from subjects with mutations in tau and progranulin, and from sporadic frontotemporal dementia. A total of 76 subjects, including 56 with a clinical diagnosis of behavioural variant frontotemporal dementia and a mutation in one of these genes (19 with C9ORF72 mutations, 25 with tau mutations and 12 with progranulin mutations) and 20 sporadic subjects with behavioural variant frontotemporal dementia (including 50% with amyotrophic lateral sclerosis), with magnetic resonance imaging were included in this study. Voxel-based morphometry was used to assess and compare patterns of grey matter atrophy. Atlas-based parcellation was performed utilizing the automated anatomical labelling atlas and Statistical Parametric Mapping software to compute volumes of 37 regions of interest. Hemispheric asymmetry was calculated. Penalized multinomial logistic regression was utilized to create a prediction model to discriminate among groups using regional volumes and asymmetry score. Principal component analysis assessed for variance within groups. C9ORF72 was associated with symmetric atrophy predominantly involving dorsolateral, medial and orbitofrontal lobes, with additional loss in anterior temporal lobes, parietal lobes, occipital lobes and cerebellum. In contrast, striking anteromedial temporal atrophy was associated with tau mutations and temporoparietal atrophy was associated with progranulin mutations. The sporadic group was associated with frontal and anterior temporal atrophy. A conservative penalized multinomial logistic regression model identified 14 variables that could accurately classify subjects, including frontal, temporal, parietal, occipital and cerebellum volume. The principal component analysis revealed similar degrees of heterogeneity within all disease groups. Patterns of atrophy therefore differed across subjects with C9ORF72, tau and progranulin mutations and sporadic frontotemporal dementia. Our analysis suggested that imaging has the potential to be useful to help differentiate C9ORF72 from these other groups at the single-subject level.
AB - A major recent discovery was the identification of an expansion of a non-coding GGGGCC hexanucleotide repeat in the C9ORF72 gene in patients with frontotemporal dementia and amyotrophic lateral sclerosis. Mutations in two other genes are known to account for familial frontotemporal dementia: microtubule-associated protein tau and progranulin. Although imaging features have been previously reported in subjects with mutations in tau and progranulin, no imaging features have been published in C9ORF72. Furthermore, it remains unknown whether there are differences in atrophy patterns across these mutations, and whether regional differences could help differentiate C9ORF72 from the other two mutations at the single-subject level. We aimed to determine the regional pattern of brain atrophy associated with the C9ORF72 gene mutation, and to determine which regions best differentiate C9ORF72 from subjects with mutations in tau and progranulin, and from sporadic frontotemporal dementia. A total of 76 subjects, including 56 with a clinical diagnosis of behavioural variant frontotemporal dementia and a mutation in one of these genes (19 with C9ORF72 mutations, 25 with tau mutations and 12 with progranulin mutations) and 20 sporadic subjects with behavioural variant frontotemporal dementia (including 50% with amyotrophic lateral sclerosis), with magnetic resonance imaging were included in this study. Voxel-based morphometry was used to assess and compare patterns of grey matter atrophy. Atlas-based parcellation was performed utilizing the automated anatomical labelling atlas and Statistical Parametric Mapping software to compute volumes of 37 regions of interest. Hemispheric asymmetry was calculated. Penalized multinomial logistic regression was utilized to create a prediction model to discriminate among groups using regional volumes and asymmetry score. Principal component analysis assessed for variance within groups. C9ORF72 was associated with symmetric atrophy predominantly involving dorsolateral, medial and orbitofrontal lobes, with additional loss in anterior temporal lobes, parietal lobes, occipital lobes and cerebellum. In contrast, striking anteromedial temporal atrophy was associated with tau mutations and temporoparietal atrophy was associated with progranulin mutations. The sporadic group was associated with frontal and anterior temporal atrophy. A conservative penalized multinomial logistic regression model identified 14 variables that could accurately classify subjects, including frontal, temporal, parietal, occipital and cerebellum volume. The principal component analysis revealed similar degrees of heterogeneity within all disease groups. Patterns of atrophy therefore differed across subjects with C9ORF72, tau and progranulin mutations and sporadic frontotemporal dementia. Our analysis suggested that imaging has the potential to be useful to help differentiate C9ORF72 from these other groups at the single-subject level.
KW - C9ORF72
KW - frontotemporal dementia
KW - magnetic resonance imaging
KW - progranulin
KW - tau
UR - http://www.scopus.com/inward/record.url?scp=84857588946&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84857588946&partnerID=8YFLogxK
U2 - 10.1093/brain/aws001
DO - 10.1093/brain/aws001
M3 - Article
C2 - 22366795
AN - SCOPUS:84857588946
SN - 0006-8950
VL - 135
SP - 794
EP - 806
JO - Brain
JF - Brain
IS - 3
ER -