title: Widespread structural brain involvement in ALS is not limited to the C9orf72 repeat expansion.
abstract: In patients with a C9orf72 repeat expansion (C9+), a neuroimaging phenotype with widespread structural cerebral changes has been found. We aimed to investigate the specificity of this neuroimaging phenotype in patients with amyotrophic lateral sclerosis (ALS).
  
  
  
  156 C9- and 14 C9+ patients with ALS underwent high-resolution T1-weighted MRI; a subset (n=126) underwent diffusion-weighted imaging. Cortical thickness, subcortical volumes and white matter integrity were compared between C9+ and C9- patients. Using elastic net logistic regression, a model defining the neuroimaging phenotype of C9+ was determined and applied to C9- patients with ALS.
  
  
  
  C9+ patients showed cortical thinning outside the precentral gyrus, extending to the bilateral pars opercularis, fusiform, lingual, isthmus-cingulate and superior parietal cortex, and smaller volumes of the right hippocampus and bilateral thalamus, and reduced white matter integrity of the inferior and superior longitudinal fasciculus compared with C9- patients (p<0.05). Among 128 C9- patients, we detected a subgroup of 27 (21%) with a neuroimaging phenotype congruent to C9+ patients, while 101 (79%) C9- patients showed cortical thinning restricted to the primary motor cortex. C9- patients with a 'C9+' neuroimaging phenotype had lower performance on the frontal assessment battery, compared with other C9- patients with ALS (p=0.004).
  
  
  
  This study shows that widespread structural brain involvement is not limited to C9+ patients, but also presents in a subgroup of C9- patients with ALS and relates to cognitive deficits. Our neuroimaging findings reveal an intermediate phenotype that may provide insight into the complex relationship between genetic factors and clinical characteristics.
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Westeneng
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Renée
authors.initials: R
authors.lastname: Walhout
authors.affiliation: Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Milou
authors.initials: M
authors.lastname: Straathof
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Ruben
authors.initials: R
authors.lastname: Schmidt
authors.affiliation: Department of Radiology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Hendrikse
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Veldink
authors.affiliation: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Martijn P
authors.initials: MP
authors.lastname: van den Heuvel
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000000981:diagnostic imaging / Q000235:genetics*; D001921:Brain / Q000000981:diagnostic imaging; D042622:DNA Repeat Expansion / Q000235:genetics*; D004292:Dominance, Cerebral / Q000502:physiology; D005260:Female; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D016601:RNA-Binding Proteins / Q000235:genetics*; D012016:Reference Values
chemical_list: C534604:FAM120A protein, human; D016601:RNA-Binding Proteins