Brain morphologic changes in asymptomatic C9orf72 repeat expansion carriers

Neurology. 2015 Nov 17;85(20):1780-8. doi: 10.1212/WNL.0000000000002135. Epub 2015 Oct 23.


Objective: To investigate possible effects of the C9orf72 repeat expansion before disease onset, we assessed brain morphology in asymptomatic carriers.

Methods: Aiming to diminish the effects of genetic variation between subjects, apart from the C9orf72 repeat expansion, 16 carriers of the repeat expansion were compared with 23 noncarriers from the same large family with a history of amyotrophic lateral sclerosis (ALS). Cortical thickness, subcortical volumes, and white matter connectivity, as assessed from high-resolution T1-weighted and diffusion-weighted MRIs, were evaluated. For comparison, we included 14 C9orf72 carriers with ALS and 28 healthy, unrelated controls.

Results: We found temporal, parietal, and occipital regions to be thinner (p < 0.05) and the left caudate and putamen to be smaller (p < 0.05) in asymptomatic carriers compared with noncarriers. Cortical thinning of the primary motor cortex and decreased connectivity of white matter pathways (global, corticospinal tract, and corpus callosum) were observed in patients with C9orf72-associated ALS, but not in asymptomatic carriers.

Conclusions: Asymptomatic C9orf72 carriers show cortical and subcortical differences compared with noncarriers from the same family, possibly effects of the C9orf72 repeat expansion on the brain. Of note, changes in the primary motor regions and motor-related tracts were found exclusively in patients with ALS, indicating that such motor changes may be a disease phenomenon.

MeSH terms

  • Adult
  • Aged
  • Amyotrophic Lateral Sclerosis / diagnosis*
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Asymptomatic Diseases*
  • Brain / metabolism
  • Brain / pathology*
  • C9orf72 Protein
  • DNA Repeat Expansion / genetics*
  • Diffusion Magnetic Resonance Imaging
  • Female
  • Heterozygote*
  • Humans
  • Male
  • Middle Aged
  • Pedigree
  • Proteins / genetics*


  • C9orf72 Protein
  • C9orf72 protein, human
  • Proteins