Journal
BRAIN
Volume 137, Issue -, Pages 3047-3060Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awu248
Keywords
frontotemporal dementia; functional connectivity; dementia; biomarkers; amyotrophic lateral sclerosis
Categories
Funding
- National Institute on Aging [K23 AG039414, P50 AG023501, RC1 AG035610, R01 AG026938, R01 AG031278, R01 AG038791, R01 AG032289, R01 AG032306, P01 AG019724]
- National Institute of Neurological Disorders and Stroke (NINDS) [T32 NS048004-07, R01 NS080882]
- Larry L. Hillblom Foundation [2012-A-015-FEL, 2007/2I]
- Bluefield Project to Cure FTD, Association for FTD, Alzheimer's Drug Discovery Foundation
- Tau Consortium
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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 topo-graphically 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 earlystage 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 earlystage disease in C9orf72 carriers and may provide a unifying biomarker across diverse anatomical variants.
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