title: Increased functional connectivity common to symptomatic amyotrophic lateral sclerosis and those at genetic risk.
abstract: To discern presymptomatic changes in brain structure or function using advanced MRI in carriers of mutations predisposing to amyotrophic lateral sclerosis (ALS).
  
  
  
  T1-weighted, diffusion weighted and resting state functional MRI data were acquired at 3 T for 12 asymptomatic mutation carriers (psALS), 12 age-matched controls and affected patients with ALS. Cortical thickness analysis, voxel-based morphometry, volumetric and shape analyses of subcortical structures, tract-based spatial statistics of metrics derived from the diffusion tensor, and resting state functional connectivity (FC) analyses were performed.
  
  
  
  Grey matter cortical thickness and shape analysis revealed significant atrophy in patients with ALS (but not psALS) compared with controls in the right primary motor cortex and right caudate. Comparison of diffusion tensor metrics showed widespread fractional anisotropy and radial diffusivity differences in patients with ALS compared to controls and the psALS group, encompassing parts of the corpus callosum, corticospinal tracts and superior longitudinal fasciculus. While FC in the resting-state sensorimotor network was similar in psALS and controls, FC between the cerebellum and a network comprising the precuneus, cingulate & middle frontal lobe was significantly higher in psALS and affected ALS compared to controls.
  
  
  
  Rather than structural brain changes, increased FC may be among the earliest detectable brain abnormalities in asymptomatic carriers of ALS-causing gene mutations. With replication and significant refinement, this technique has potential in the future assessment of neuroprotective strategies.
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK FMRIB Centre, John Radcliffe Hospital, University of Oxford, Oxford, UK.
authors.forename: Ricarda A L
authors.initials: RA
authors.lastname: Menke
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Proudfoot
authors.affiliation: Miller School of Medicine, University of Miami, Miami, Florida, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Wuu
authors.affiliation: Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Andersen
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Talbot
authors.affiliation: Miller School of Medicine, University of Miami, Miami, Florida, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Benatar
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK FMRIB Centre, John Radcliffe Hospital, University of Oxford, Oxford, UK.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Turner
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000000981:diagnostic imaging* / Q000235:genetics* / Q000503:physiopathology; D001921:Brain / Q000000981:diagnostic imaging* / Q000503:physiopathology; D000073885:C9orf72 Protein; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000503:physiopathology; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000503:physiopathology; D015331:Cohort Studies; D054893:Cone-Beam Computed Tomography; D003337:Corpus Callosum / Q000000981:diagnostic imaging / Q000503:physiopathology; D038524:Diffusion Magnetic Resonance Imaging; D005260:Female; D005625:Frontal Lobe / Q000000981:diagnostic imaging / Q000503:physiopathology; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006179:Gyrus Cinguli / Q000000981:diagnostic imaging / Q000503:physiopathology; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009415:Nerve Net / Q000000981:diagnostic imaging* / Q000503:physiopathology; D010296:Parietal Lobe / Q000000981:diagnostic imaging / Q000503:physiopathology; D011506:Proteins / Q000235:genetics; D011712:Pyramidal Tracts / Q000000981:diagnostic imaging / Q000503:physiopathology; D000072105:Superoxide Dismutase-1 / Q000235:genetics; D055815:Young Adult
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins; C000606290:SOD1 protein, human; D000072105:Superoxide Dismutase-1