No abstract

Hexanucleotide repeat expansion in C9orf72 represents the most common genetic cause of familial and sporadic behavioural variant frontotemporal dementia. Previous studies show that some C9orf72 carriers with behavioural variant frontotemporal dementia exhibit distinctive atrophy patterns whereas others show mild or undetectable atrophy despite severe behavioural impairment. To explore this observation, we examined intrinsic connectivity network integrity in patients with or without the C9orf72 expansion. We studied 28 patients with behavioural variant frontotemporal dementia, including 14 C9orf72 mutation carriers (age 58.3 ± 7.7 years, four females) and 14 non-carriers (age 60.8 ± 6.9 years, four females), and 14 age- and sex-matched healthy controls. Both patient groups included five patients with comorbid motor neuron disease. Neuropsychological data, structural brain magnetic resonance imaging, and task-free functional magnetic resonance imaging were obtained. Voxel-based morphometry delineated atrophy patterns, and seed-based intrinsic connectivity analyses enabled group comparisons of the salience, sensorimotor, and default mode networks. Single-patient analyses were used to explore network imaging as a potential biomarker. Despite contrasting atrophy patterns in C9orf72 carriers versus non-carriers, patient groups showed topographically similar connectivity reductions in the salience and sensorimotor networks. Patients without C9orf72 expansions exhibited increases in default mode network connectivity compared to controls and mutation carriers. Across all patients, behavioural symptom severity correlated with diminished salience network connectivity and heightened default mode network connectivity. In C9orf72 carriers, salience network connectivity reduction correlated with atrophy in the left medial pulvinar thalamic nucleus, and this region further showed diminished connectivity with key salience network hubs. Single-patient analyses revealed salience network disruption and default mode network connectivity enhancement in C9orf72 carriers with early-stage or slowly progressive symptoms. The findings suggest that patients with behavioural variant frontotemporal dementia with or without the C9orf72 expansion show convergent large-scale network breakdowns despite distinctive atrophy patterns. Medial pulvinar degeneration may contribute to the behavioural variant frontotemporal dementia syndrome in C9orf72 carriers by disrupting salience network connectivity. Task-free functional magnetic resonance imaging shows promise in detecting early-stage disease in C9orf72 carriers and may provide a unifying biomarker across diverse anatomical variants.

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 (C9ϩ Results: All C9ϩ patients displayed clinical syndromes of bvFTD, ALS, or FTD-MND. At first evaluation, C9ϩ bvFTD patients had more delusions and greater impairment of working memory, but milder eating dysregulation compared to bvFTD noncarriers. C9ϩFTD-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: GLOSSARYAD ϭ Alzheimer disease; ALS ϭ amyotrophic lateral sclerosis; bvFTD ϭ behavioral variant frontotemporal dementia; CBS ϭ corticobasal syndrome; CDR-SB ϭ Clinical Dementia Rating Scale sum of boxes; FTD ϭ frontotemporal dementia; FWE ϭ familywise error; glm ϭ generalized linear model; lvPPA ϭ logopenic variant primary progressive aphasia; MND ϭ motor neuron disease; nfvPPA ϭ nonfluent variant primary progressive aphasia; NPI ϭ Neuropsychiatric Inventory; PSP ϭ progressive supranuclear palsy; svPPA ϭ semantic variant primary progressive aphasia; UCSF ϭ University of California, San Francisco; VBM ϭ voxel-based morphometry.Frontotemporal dementia (FTD) is a common dementia syndrome among patients presenting before 65 years of age with prevalence equal to Alzheimer disease (AD) dementia.1,2 FTD often overlaps with amyotrophic lateral sclerosis (ALS), with symptoms of FTD occurring in 15%-41% of patients with ALS and features of ALS occurring in 15% of FTD.3,4 Many patients with FTD and ALS exhibit autosomal dominant family histories (FTD 10% 5 ; ALS 5%-10% 6 ; FTD-motor neuron disease [MND] 37% 7 ) and a number of large familial cohorts have been linked to a chromosome 9p region. [7][8][9][10][11][12] Recently, a noncoding expanded hexanucleotide repeat in chromosome 9 open reading frame 72 (C9ORF72) was identified as the cause of chromosome 9p-associated FTD and ALS. 13,14 This mutation is the most common genetic cause of familial and sporadic behavioral variant FTD (bvFTD) and ALS.In one study, the C9ORF72 (C9FTD/ALS) expansion accounted for 11.7% of familial FTD, 22.5% of familial ALS, and 4% of sporadic ALS.13 Previous family studies of chromosome 9p-linked families 7,8,10 suggested that some features may distinguish this mutation from sporadic