title: Cognitive decline and reduced survival in C9orf72 expansion frontotemporal degeneration and amyotrophic lateral sclerosis.
abstract: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Alzheimer’s Disease Core Center, Institute on Aging, Philadelphia, Pennsylvania, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Irwin
authors.forename: Corey T
authors.initials: CT
authors.lastname: McMillan
authors.forename: Johannes
authors.initials: J
authors.lastname: Brettschneider
authors.forename: David J
authors.initials: DJ
authors.lastname: Libon
authors.forename: John
authors.initials: J
authors.lastname: Powers
authors.forename: Katya
authors.initials: K
authors.lastname: Rascovsky
authors.forename: Jon B
authors.initials: JB
authors.lastname: Toledo
authors.forename: Ashley
authors.initials: A
authors.lastname: Boller
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bekisz
authors.forename: Keerthi
authors.initials: K
authors.lastname: Chandrasekaran
authors.forename: Elisabeth McCarty
authors.initials: EM
authors.lastname: Wood
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Shaw
authors.forename: John H
authors.initials: JH
authors.lastname: Woo
authors.forename: Philip A
authors.initials: PA
authors.lastname: Cook
authors.forename: David A
authors.initials: DA
authors.lastname: Wolk
authors.forename: Steven E
authors.initials: SE
authors.lastname: Arnold
authors.forename: Vivianna M
authors.initials: VM
authors.lastname: Van Deerlin
authors.forename: Leo F
authors.initials: LF
authors.lastname: McCluskey
authors.forename: Lauren
authors.initials: L
authors.lastname: Elman
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Murray
authors.initials: M
authors.lastname: Grossman
mesh_terms: D017668:Age of Onset; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000401:mortality* / Q000473:pathology / Q000523:psychology*; D001284:Atrophy / Q000473:pathology; D001921:Brain / Q000473:pathology; D000073885:C9orf72 Protein; D016022:Case-Control Studies; D003072:Cognition Disorders / Q000150:complications / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D042622:DNA Repeat Expansion / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D018450:Disease Progression; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000401:mortality* / Q000473:pathology / Q000523:psychology*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods / Q000523:psychology; D008297:Male; D008875:Middle Aged; D059906:Neuroimaging / Q000379:methods / Q000523:psychology*; D009483:Neuropsychological Tests / Q000706:statistics & numerical data; D011506:Proteins / Q000235:genetics*; D016019:Survival Analysis
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; D011506:Proteins