title: Neuroanatomical correlates of prion disease progression - a 3T longitudinal voxel-based morphometry study.
abstract: MRI has become an essential tool for prion disease diagnosis. However there exist only a few serial MRI studies of prion patients, and these mostly used whole brain summary measures or region of interest based approaches. We present here the first longitudinal voxel-based morphometry (VBM) study in prion disease. The aim of this study was to systematically characterise progressive atrophy in patients with prion disease and identify whether atrophy in specific brain structures correlates with clinical assessment.
  
  
  
  Twenty-four prion disease patients with early stage disease (3 sporadic, 2 iatrogenic, 1 variant and 18 inherited CJD) and 25 controls were examined at 3T with a T1-weighted 3D MPRAGE sequence at multiple time-points (2-6 examinations per subject, interval range 0.1-3.2 years). Longitudinal VBM provided intra-subject and inter-subject image alignment, allowing voxel-wise comparison of progressive structural change. Clinical disease progression was assessed using the MRC Prion Disease Rating Scale. Firstly, in patients, we determined the brain regions where grey and white matter volume change between baseline and final examination correlated with the corresponding change in MRC Scale score. Secondly, in the 21/24 patients with interscan interval longer than 3 months, we identified regions where annualised rates of regional volume change in patients were different from rates in age-matched controls. Given the heterogeneity of the cohort, the regions identified reflect the common features of the different prion sub-types studied.
  
  
  
  In the patients there were multiple regions where volume loss significantly correlated with decreased MRC scale, partially overlapping with anatomical regions where yearly rates of volume loss were significantly greater than controls. The key anatomical areas involved included: the basal ganglia and thalamus, pons and medulla, the hippocampal formation and the superior parietal lobules. There were no areas demonstrating volume loss significantly higher in controls than patients or negative correlation between volume and MRC Scale score.
  
  
  
  Using 3T MRI and longitudinal VBM we have identified key anatomical regions of progressive volume loss which correlate with an established clinical disease severity index and are relevant to clinical deterioration. Localisation of the regions of progressive brain atrophy correlating most strongly with clinical decline may help to provide more targeted imaging endpoints for future clinical trials.
authors.affiliation: Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, UCLH Hospitals NHS Foundation Trust, Box 65, Queen Square, London WC1N 3BG, United Kingdom; Neuroradiological Academic Unit, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: Enrico
authors.initials: E
authors.lastname: De Vita
authors.affiliation: Wellcome Trust Centre for Neuroimaging, UCL Institute of Neurology, 12 Queen Square, London WC1N 3BG, United Kingdom; FMRIB Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom.
authors.forename: Gerard R
authors.initials: GR
authors.lastname: Ridgway
authors.affiliation: Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, UCLH Hospitals NHS Foundation Trust, Box 65, Queen Square, London WC1N 3BG, United Kingdom; Neuroradiological Academic Unit, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: White
authors.affiliation: National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCLH Hospitals NHS Foundation Trust, Box 98, Queen Square, London WC1N 3BG, United Kingdom; MRC Prion Unit, Department of Neurodegenerative Diseases, UCL Institute of Neurology, Queen Square House, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Porter
authors.affiliation: National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCLH Hospitals NHS Foundation Trust, Box 98, Queen Square, London WC1N 3BG, United Kingdom; MRC Prion Unit, Department of Neurodegenerative Diseases, UCL Institute of Neurology, Queen Square House, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: Diana
authors.initials: D
authors.lastname: Caine
authors.affiliation: National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCLH Hospitals NHS Foundation Trust, Box 98, Queen Square, London WC1N 3BG, United Kingdom; MRC Prion Unit, Department of Neurodegenerative Diseases, UCL Institute of Neurology, Queen Square House, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Rudge
authors.affiliation: National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCLH Hospitals NHS Foundation Trust, Box 98, Queen Square, London WC1N 3BG, United Kingdom; MRC Prion Unit, Department of Neurodegenerative Diseases, UCL Institute of Neurology, Queen Square House, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Collinge
authors.affiliation: Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, UCLH Hospitals NHS Foundation Trust, Box 65, Queen Square, London WC1N 3BG, United Kingdom; Neuroradiological Academic Unit, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: Tarek A
authors.initials: TA
authors.lastname: Yousry
authors.affiliation: Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, UCLH Hospitals NHS Foundation Trust, Box 65, Queen Square, London WC1N 3BG, United Kingdom; Neuroradiological Academic Unit, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: Hans Rolf
authors.initials: HR
authors.lastname: Jager
authors.affiliation: National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCLH Hospitals NHS Foundation Trust, Box 98, Queen Square, London WC1N 3BG, United Kingdom; MRC Prion Unit, Department of Neurodegenerative Diseases, UCL Institute of Neurology, Queen Square House, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Mead
authors.affiliation: Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, UCLH Hospitals NHS Foundation Trust, Box 65, Queen Square, London WC1N 3BG, United Kingdom; Neuroradiological Academic Unit, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: John S
authors.initials: JS
authors.lastname: Thornton
authors.affiliation: National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCLH Hospitals NHS Foundation Trust, Box 98, Queen Square, London WC1N 3BG, United Kingdom; MRC Prion Unit, Department of Neurodegenerative Diseases, UCL Institute of Neurology, Queen Square House, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: Harpreet
authors.initials: H
authors.lastname: Hyare
mesh_terms: D000328:Adult; D000368:Aged; D001284:Atrophy / Q000473:pathology; D018450:Disease Progression; D005260:Female; D066128:Gray Matter / Q000000981:diagnostic imaging / Q000473:pathology*; D006801:Humans; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008875:Middle Aged; D017096:Prion Diseases / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D066127:White Matter / Q000000981:diagnostic imaging / Q000473:pathology*; D055815:Young Adult
keywords: 3T MRI; CJD; Longitudinal voxel based morphometry; Prion disease; Structural MRI