TitleTiming and significance of pathological features in C9orf72 expansion-associated frontotemporal dementia.
Publication TypeJournal Article
Year of Publication2016
AuthorsVatsavayai SC, Yoon SJin, Gardner RC, Gendron TF, Vargas JNorberto S, Trujillo A, Pribadi M, Phillips JJ, Gaus SE, Hixson JD, Garcia PA, Rabinovici GD, Coppola G, Geschwind DH, Petrucelli L, Miller BL, Seeley WW
IssuePt 12
Date Published2016 12
KeywordsAged, C9orf72 Protein, DNA Repeat Expansion, DNA-Binding Proteins, Female, Frontotemporal Dementia, Humans, Proteins

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.

Alternate JournalBrain
PubMed ID27797809
PubMed Central IDPMC5790143
Grant ListP50 AG023501 / AG / NIA NIH HHS / United States
R21 NS089979 / NS / NINDS NIH HHS / United States
P50 AG016574 / AG / NIA NIH HHS / United States
R01 NS063964 / NS / NINDS NIH HHS / United States
P01 AG019724 / AG / NIA NIH HHS / United States
R01 NS088689 / NS / NINDS NIH HHS / United States
K23 NS095755 / NS / NINDS NIH HHS / United States
P01 NS084974 / NS / NINDS NIH HHS / United States
R21 NS084528 / NS / NINDS NIH HHS / United States
R01 ES020395 / ES / NIEHS NIH HHS / United States
R01 NS077402 / NS / NINDS NIH HHS / United States
P30 AG044281 / AG / NIA NIH HHS / United States