title: Altered network connectivity in frontotemporal dementia with C9orf72 hexanucleotide repeat expansion.
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.
authors.affiliation: 1 Memory and Ageing Centre, Department of Neurology, University of California, San Francisco, CA 94158, USA suzeelee@memory.ucsf.edu.
authors.forename: Suzee E
authors.initials: SE
authors.lastname: Lee
authors.affiliation: 1 Memory and Ageing Centre, Department of Neurology, University of California, San Francisco, CA 94158, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Khazenzon
authors.affiliation: 1 Memory and Ageing Centre, Department of Neurology, University of California, San Francisco, CA 94158, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Trujillo
authors.affiliation: 1 Memory and Ageing Centre, Department of Neurology, University of California, San Francisco, CA 94158, USA.
authors.forename: Christine C
authors.initials: CC
authors.lastname: Guo
authors.affiliation: 1 Memory and Ageing Centre, Department of Neurology, University of California, San Francisco, CA 94158, USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Yokoyama
authors.affiliation: 1 Memory and Ageing Centre, Department of Neurology, University of California, San Francisco, CA 94158, USA.
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Sha
authors.affiliation: 2 Department of Neurology, Hospital das Clínicas, University of Sao Paulo Medical School, Sao Paolo, Brazil.
authors.forename: Leonel T
authors.initials: LT
authors.lastname: Takada
authors.affiliation: 1 Memory and Ageing Centre, Department of Neurology, University of California, San Francisco, CA 94158, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Karydas
authors.affiliation: 1 Memory and Ageing Centre, Department of Neurology, University of California, San Francisco, CA 94158, USA.
authors.forename: Nikolas R
authors.initials: NR
authors.lastname: Block
authors.affiliation: 3 Department of Neurology and Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.affiliation: 3 Department of Neurology and Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, USA.
authors.forename: Mochtar
authors.initials: M
authors.lastname: Pribadi
authors.affiliation: 3 Department of Neurology and Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
authors.affiliation: 4 Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.affiliation: 1 Memory and Ageing Centre, Department of Neurology, University of California, San Francisco, CA 94158, USA.
authors.forename: Jamie C
authors.initials: JC
authors.lastname: Fong
authors.affiliation: 5 Centre for Imaging of Neurodegenerative Diseases, Department of Veterans Affairs Medical Centre, San Francisco, CA 94121, USA and Department of Radiology, University of California, San Francisco, CA 94143, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Weiner
authors.affiliation: 1 Memory and Ageing Centre, Department of Neurology, University of California, San Francisco, CA 94158, USA.
authors.forename: Adam L
authors.initials: AL
authors.lastname: Boxer
authors.affiliation: 1 Memory and Ageing Centre, Department of Neurology, University of California, San Francisco, CA 94158, USA.
authors.forename: Joel H
authors.initials: JH
authors.lastname: Kramer
authors.affiliation: 1 Memory and Ageing Centre, Department of Neurology, University of California, San Francisco, CA 94158, USA.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Rosen
authors.affiliation: 1 Memory and Ageing Centre, Department of Neurology, University of California, San Francisco, CA 94158, USA.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: 1 Memory and Ageing Centre, Department of Neurology, University of California, San Francisco, CA 94158, USA 6 Department of Pathology, University of California, San Francisco, CA 94143, USA.
authors.forename: William W
authors.initials: WW
authors.lastname: Seeley
mesh_terms: D000368:Aged; D001284:Atrophy / Q000473:pathology / Q000503:physiopathology; D015415:Biomarkers; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion / Q000235:genetics; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D059907:Functional Neuroimaging; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009415:Nerve Net / Q000473:pathology / Q000503:physiopathology*; D011506:Proteins / Q000235:genetics*; D020649:Pulvinar / Q000473:pathology / Q000503:physiopathology*
chemical_list: D015415:Biomarkers; D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins
keywords: amyotrophic lateral sclerosis; biomarkers; dementia; frontotemporal dementia; functional connectivity