Frontotemporal dementia due to C9ORF72 mutations: clinical and imaging features

Abstract

Objective: To describe the phenotype of patients with C9FTD/ALS (C9ORF72) hexanucleotide repeat expansion.

Methods: A total of 648 patients with frontotemporal dementia (FTD)-related clinical diagnoses and Alzheimer disease (AD) dementia were tested for C9ORF72 expansion and 31 carried expanded repeats (C9+). Clinical and neuroimaging data were compared between C9+ (15 behavioral variant FTD [bvFTD], 11 FTD-motor neuron disease [MND], 5 amyotrophic lateral sclerosis [ALS]) and sporadic noncarriers (48 bvFTD, 19 FTD-MND, 6 ALS).

Results: All C9+ patients displayed clinical syndromes of bvFTD, ALS, or FTD-MND. At first evaluation, C9+ bvFTD patients had more delusions and greater impairment of working memory, but milder eating dysregulation compared to bvFTD noncarriers. C9+FTD-MND patients had a trend for longer survival and had an earlier age at onset than FTD-MND noncarriers. Voxel-based morphometry demonstrated more thalamic atrophy in FTD and FTD-MND carriers than in noncarriers.

Conclusions: Patients with the C9ORF72 hexanucleotide repeat expansion develop bvFTD, ALS, or FTD-MND with similar clinical and imaging features to sporadic cases. Other FTD spectrum diagnoses and AD dementia appear rare or absent among C9+ individuals. Longer survival in C9+ FTD-MND suggests slower disease progression and thalamic atrophy represents a novel and unexpected feature.

Figure 1. Subjects included in clinical analyses

(A) Subjects in gray bar were included in demographic and family history analyses shown in table 1. The patients in the dashed boxes inside the gray bar were used for motor symptoms assessment. (B) Subjects in the gray boxes in the bottom row were included in neuropsychiatric, neuropsychological, and survival analyses shown in table 2 and table e-1. ^aRight temporal variant in 20 patients with semantic variant primary progressive aphasia (svPPA). ^bBehavioral variant frontotemporal dementia (bvFTD) groups were matched for disease severity (Clinical Dementia Rating sum of boxes) by removing 3 noncarriers. AD = Alzheimer disease dementia; ALS = amyotrophic lateral sclerosis; CBS = corticobasal syndrome; DLB + AD = dementia with Lewy bodies with Alzheimer disease; FHx+ = family history with autosomal dominant pattern of inheritance but no known frontotemporal dementia–associated mutation; FTD-MND = frontotemporal dementia–motor neuron disease; lvPPA = logopenic variant of primary progressive aphasia; MCI = mild cognitive impairment; nfvPPA = nonfluent variant of primary progressive aphasia; PCA = posterior cortical atrophy; PiB+ = positive PET scan with β-amyloid ligand [¹¹C]–Pittsburgh compound B; PSP = progressive supranuclear palsy. Individuals with known MAPT or GRN mutations were not screened for C9ORF72 mutations.

Figure 2. Survival curves for C9+/noncarriers behavioral variant frontotemporal dementia (bvFTD) and frontotemporal dementia–motor neuron disease (FTD-MND)

Survival (means ± standard error) for C9+ bvFTD = 15.1 ± 2.8 years and bvFTD noncarriers = 10.6 ± 0.4 years (p = 0.38). Survival for C9+ FTD-MND = 11.7 ± 2.2 years and FTD-MND noncarriers = 5.5 ± 0.7 years (p = 0.02).

Figure 3. C9ORF72 differential brain atrophy patterns

(A, B) Overlay of C9+ and noncarrier atrophy patterns for behavioral variant frontotemporal dementia (bvFTD) and frontotemporal dementia–motor neuron disease (FTD-MND). Atrophy patterns compared for C9ORF72 variant carriers (C9+, in red) and noncarriers (in green) for 2 clinical syndromes, bvFTD (A) and FTD-MND (B). Yellow regions represent overlapping atrophy patterns. Results are shown for T scores thresholded at p_FWE ≤ 0.05. Brain sections are indicated on rightmost image. The left side of the image corresponds to left side of the brain for axial sections. (C, D) Interaction effects of the C9ORF72 expansion repeat with bvFTD or FTD-MND diagnoses. bvFTD (C) and FTD-MND (D) C9 carriers (C9+) show differential atrophy as compared to noncarriers of the same diagnostic group and normal controls. Color bars indicate the range of T scores for respective analyses thresholded at p_FWE ≤ 0.05. In both sections, the left side of the image corresponds to left side of the brain, and slice Montreal Neurological Institute coordinates are provided below. Results for A–D shown using MRIcron (version 12/2009, http://www.cabiatl.com/mricro/mricron/index.html), overlaid on a high-resolution 1.5 T template image from a single normal subject (MRIcron: ch2.nii.gz).