title: Longitudinal neuroimaging and neuropsychological profiles of frontotemporal dementia with C9ORF72 expansions.
abstract: BACKGROUND
  Frontotemporal dementia (FTD) is a common cause of early-onset dementia with a significant genetic component, as underlined by the recent identification of repeat expansions in the gene C9ORF72 as a major cause of FTD and motor neuron disease. Understanding the neurobiology and clinical phenomenology of this novel mutation is currently a major research focus. However, few data are available concerning the longitudinal evolution of this genetic disease. Here we present longitudinal neuropsychological and neuroimaging data on a cohort of patients with pathological repeat expansions in C9ORF72.
  
  
  METHODS
  Following a review of the University College London FTD DNA database, 20 cases were retrospectively identified with a C9ORF72 expansion. Twelve cases had longitudinal neuropsychology data available and six of these cases also had longitudinal volumetric brain magnetic resonance imaging. Cortical and subcortical volumes were extracted using FreeSurfer. Rates of whole brain, hemispheric, cerebellar and ventricular change were calculated for each subject. Nonlinear fluid registration of follow-up to baseline scan was performed to visualise longitudinal intra-subject patterns of brain atrophy and ventricular expansion.
  
  
  RESULTS
  Patients had low average verbal and performance IQ at baseline that became impaired (< 5th percentile) at follow-up. In particular, visual memory, naming and dominant parietal skills all showed deterioration. Mean rates of whole brain atrophy (1.4%/year) and ventricular expansion (3.2 ml/year) were substantially greater in patients with the C9ORF72 mutation than in healthy controls; atrophy was symmetrical between the cerebral hemispheres within the C9ORF72 mutation group. The thalamus and cerebellum showed significant atrophy whereas no cortical areas were preferentially affected. Longitudinal fluid imaging in individual patients demonstrated heterogeneous patterns of progressive volume loss; however, ventricular expansion and cerebellar volume loss were consistent findings.
  
  
  CONCLUSIONS
  Disease evolution in C9ORF72-associated FTD is linked neuropsychologically with increasing involvement of parietal and amnestic functions, and neuroanatomically with rather diffuse and variable cortical and central atrophy but more consistent involvement of the cerebellum and thalamus. These longitudinal profiles are consistent with disease spread within a distributed subcortical network and demonstrate the feasibility of longitudinal biomarkers for tracking the evolution of the C9ORF72 mutation phenotype.
authors.affiliation: Dementia Research Centre, University College London Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Mahoney
authors.affiliation: Dementia Research Centre, University College London Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Downey
authors.affiliation: Wellcome Trust Centre for Neuroimaging, University College London Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Gerard R
authors.initials: GR
authors.lastname: Ridgway
authors.affiliation: MRC Prion Unit, University College London Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Jon
authors.initials: J
authors.lastname: Beck
authors.affiliation: Dementia Research Centre, University College London Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Shona
authors.initials: S
authors.lastname: Clegg
authors.affiliation: Dementia Research Centre, University College London Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Melanie
authors.initials: M
authors.lastname: Blair
authors.affiliation: Dementia Research Centre, University College London Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Finnegan
authors.affiliation: Dementia Research Centre, University College London Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Kelvin K
authors.initials: KK
authors.lastname: Leung
authors.affiliation: Dementia Research Centre, University College London Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Yeatman
authors.affiliation: Dementia Research Centre, University College London Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Hannah
authors.initials: H
authors.lastname: Golden
authors.affiliation: MRC Prion Unit, University College London Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Mead
authors.affiliation: Dementia Research Centre, University College London Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Rohrer
authors.affiliation: Dementia Research Centre, University College London Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Nick C
authors.initials: NC
authors.lastname: Fox
authors.affiliation: Dementia Research Centre, University College London Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Warren