Cognitive decline and reduced survival in C9orf72 expansion frontotemporal degeneration and amyotrophic lateral sclerosis

David J. Irwin, Corey T. McMillan, Johannes Brettschneider, David J. Libon, John Powers, Katya Rascovsky, Jon B. Toledo, Ashley Boller, Jonathan Bekisz, Keerthi Chandrasekaran, Elisabeth Mc Carty Wood, Leslie M. Shaw, John H. Woo, Philip A. Cook, David A. Wolk, Steven E. Arnold, Vivianna M. Van Deerlin, Leo F. McCluskey, Lauren Elman, Virginia M.Y. LeeJohn Q. Trojanowski, Murray Grossman

Research output: Contribution to journalArticlepeer-review

121 Scopus citations


Background: Significant heterogeneity in clinical features of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) cases with the pathogenic C9orf72 expansion (C9P) have been described. To clarify this issue, we compared a large C9P cohort with carefully matched non-expansion (C9N) cases with a known or highly-suspected underlying TAR DNA-binding protein 43 (TDP-43) proteinopathy. Methods: A retrospective case-control study was carried out using available cross-sectional and longitudinal clinical and neuropsychological data, MRI voxel-based morphometry (VBM) and neuropathological assessment from 64 C9P cases (ALS=31, FTLD=33) and 79 C9N cases (ALS=36, FTLD=43). Results: C9P cases had an earlier age of onset (p=0.047) and, in the subset of patients who were deceased, an earlier age of death (p=0.014) than C9N. C9P had more rapid progression than C9N: C9P ALS cases had a shortened survival (2.6±0.3 years) compared to C9N ALS (3.8±0.4 years; log-rank λ2=4.183, p=0.041), and C9P FTLD showed a significantly greater annualised rate of decline in letter fluency (4.5±1.3 words/year) than C9N FTLD (1.4±0.8 words/year, p=0.023). VBM revealed greater atrophy in the right frontoinsular, thalamus, cerebellum and bilateral parietal regions for C9P FTLD relative to C9N FTLD, and regression analysis related verbal fluency scores to atrophy in frontal and parietal regions. Neuropathological analysis found greater neuronal loss in the mid-frontal cortex in C9P FTLD, and mid-frontal cortex TDP-43 inclusion severity correlated with poor letter fluency performance. Conclusions: C9P cases may have a shorter survival in ALS and more rapid rate of cognitive decline related to frontal and parietal disease in FTLD. C9orf72 genotyping may provide useful prognostic and diagnostic clinical information for patients with ALS and FTLD.

Original languageEnglish (US)
Pages (from-to)163-169
Number of pages7
JournalJournal of Neurology, Neurosurgery and Psychiatry
Issue number2
StatePublished - Feb 2013

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology
  • Psychiatry and Mental health


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