Timing and significance of pathological features in C9orf72 expansion-associated frontotemporal dementia

Sarat C. Vatsavayai, Soo Jin Yoon, Raquel C. Gardner, Tania F. Gendron, Jose Norberto S. Vargas, Andrew Trujillo, Mochtar Pribadi, Joanna J. Phillips, Stephanie E. Gaus, John D. Hixson, Paul A. Garcia, Gil D. Rabinovici, Giovanni Coppola, Daniel H. Geschwind, Leonard Petrucelli, Bruce L. Miller, William W. Seeley

Research output: Contribution to journalArticlepeer-review

66 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)3202-3216
Number of pages15
Issue number12
StatePublished - Dec 2016


  • Frontotemporal dementia
  • Protein aggregation
  • TDP-43

ASJC Scopus subject areas

  • Clinical Neurology


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