title: Timing and significance of pathological features in C9orf72 expansion-associated frontotemporal dementia.
abstract: SEE SCABER AND TALBOT DOI101093/AWW264 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: A GGGGCC repeat expansion in C9orf72 leads to frontotemporal dementia and/or amyotrophic lateral sclerosis. Diverse pathological features have been identified, and their disease relevance remains much debated. Here, we describe two illuminating patients with frontotemporal dementia due to the C9orf72 repeat expansion. Case 1 was a 65-year-old female with behavioural variant frontotemporal dementia accompanied by focal degeneration in subgenual anterior cingulate cortex, amygdala, and medial pulvinar thalamus. At autopsy, widespread RNA foci and dipeptide repeat protein inclusions were observed, but TDP-43 pathology was nearly absent, even in degenerating brain regions. Case 2 was a 74-year-old female with atypical frontotemporal dementia-motor neuron disease who underwent temporal lobe resection for epilepsy 5 years prior to her first frontotemporal dementia symptoms. Archival surgical resection tissue contained RNA foci, dipeptide repeat protein inclusions, and loss of nuclear TDP-43 but no TDP-43 inclusions despite florid TDP-43 inclusions at autopsy 8 years after first symptoms. These findings suggest that C9orf72-specific phenomena may impact brain structure and function and emerge before first symptoms and TDP-43 aggregation.
authors: 1 Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 94158, USA.
authors: Sarat C
authors: SC
authors: Vatsavayai
authors: 2 Department of Neurology, Eulji University Hospital, Eulji University School of Medicine, Daejeon 35233, South Korea.
authors: Soo Jin
authors: SJ
authors: Yoon
authors: 1 Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 94158, USA.
authors: Raquel C
authors: RC
authors: Gardner
authors: 3 Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
authors: Tania F
authors: TF
authors: Gendron
authors: 1 Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 94158, USA.
authors: Jose Norberto S
authors: JN
authors: Vargas
authors: 1 Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 94158, USA.
authors: Andrew
authors: A
authors: Trujillo
authors: 4 Department of Neurology and Department of Psychiatry, Semel Institute for Neuroscience and Human Behaviour, University of California, Los Angeles, CA 90095, USA.
authors: Mochtar
authors: M
authors: Pribadi
authors: 5 Department of Pathology and Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA.
authors: Joanna J
authors: JJ
authors: Phillips
authors: 1 Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 94158, USA.
authors: Stephanie E
authors: SE
authors: Gaus
authors: 6 Epilepsy Center, Department of Neurology, University of California San Francisco, CA 94143, USA.
authors: John D
authors: JD
authors: Hixson
authors: 6 Epilepsy Center, Department of Neurology, University of California San Francisco, CA 94143, USA.
authors: Paul A
authors: PA
authors: Garcia
authors: 1 Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 94158, USA.
authors: Gil D
authors: GD
authors: Rabinovici
authors: 4 Department of Neurology and Department of Psychiatry, Semel Institute for Neuroscience and Human Behaviour, University of California, Los Angeles, CA 90095, USA.
authors: Giovanni
authors: G
authors: Coppola
authors: 4 Department of Neurology and Department of Psychiatry, Semel Institute for Neuroscience and Human Behaviour, University of California, Los Angeles, CA 90095, USA.
authors: Daniel H
authors: DH
authors: Geschwind
authors: 3 Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
authors: Leonard
authors: L
authors: Petrucelli
authors: 1 Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 94158, USA.
authors: Bruce L
authors: BL
authors: Miller
authors: 1 Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 94158, USA wseeley@memory.ucsf.edu.|7 Department of Pathology, University of California, San Francisco, CA 94143, USA.
authors: William W
authors: WW
authors: Seeley
mesh_terms: D000368:Aged; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D011506:Proteins / Q000235:genetics*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; D011506:Proteins; C000598624:TARDBP protein, human
keywords: TDP-43; frontotemporal dementia; protein aggregation