Altered network connectivity in frontotemporal dementia with C9orf72 hexanucleotide repeat expansion

被引:121
作者
Lee, Suzee E. [1 ]
Khazenzon, Anna M. [1 ]
Trujillo, Andrew J. [1 ]
Guo, Christine C. [1 ]
Yokoyama, Jennifer S. [1 ]
Sha, Sharon J. [1 ]
Takada, Leonel T. [2 ]
Karydas, Anna M. [1 ]
Block, Nikolas R. [1 ]
Coppola, Giovanni [3 ,4 ]
Pribadi, Mochtar [3 ,4 ]
Geschwind, Daniel H. [3 ,4 ]
Rademakers, Rosa [5 ]
Fong, Jamie C. [1 ]
Weiner, Michael W. [6 ,7 ]
Boxer, Adam L. [1 ]
Kramer, Joel H. [1 ]
Rosen, Howard J. [1 ]
Miller, Bruce L. [1 ]
Seeley, William W. [1 ,8 ]
机构
[1] UCSF, Memory & Ageing Ctr, Dept Neurol, San Francisco, CA 94158 USA
[2] Univ Sao Paulo, Sch Med, Hosp Clinicas, Dept Neurol, BR-05508 Sao Paulo, Brazil
[3] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Dept Neurol, Los Angeles, CA 90095 USA
[4] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Dept Psychiat, Los Angeles, CA 90095 USA
[5] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA
[6] Dept Vet Affairs Med Ctr, Ctr Imaging Neurodegenerat Dis, San Francisco, CA 94121 USA
[7] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA
[8] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA
关键词
frontotemporal dementia; functional connectivity; dementia; biomarkers; amyotrophic lateral sclerosis; AMYOTROPHIC-LATERAL-SCLEROSIS; BEHAVIORAL VARIANT; MEDIAL PULVINAR; FUNCTIONAL CONNECTIVITY; DEFAULT MODE; THALAMIC DEMENTIA; RECEPTOR-BINDING; DEGENERATION; CORTEX; MEMORY;
D O I
10.1093/brain/awu248
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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.
引用
收藏
页码:3047 / 3060
页数:14
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