title: Variance in brain volume with advancing age: implications for defining the limits of normality.
abstract: BACKGROUND
  Statistical models of normal ageing brain tissue volumes may support earlier diagnosis of increasingly common, yet still fatal, neurodegenerative diseases. For example, the statistically defined distribution of normal ageing brain tissue volumes may be used as a reference to assess patient volumes. To date, such models were often derived from mean values which were assumed to represent the distributions and boundaries, i.e. percentile ranks, of brain tissue volume. Since it was previously unknown, the objective of the present study was to determine if this assumption was robust, i.e. whether regression models derived from mean values accurately represented the distributions and boundaries of brain tissue volume at older ages.
  
  
  METHODS
  We acquired T1-w magnetic resonance (MR) brain images of 227 normal and 219 Alzheimer's disease (AD) subjects (aged 55-89 years) from publicly available databanks. Using nonlinear regression within both samples, we compared mean and percentile rank estimates of whole brain tissue volume by age.
  
  
  RESULTS
  In both the normal and AD sample, mean regression estimates of brain tissue volume often did not accurately represent percentile rank estimates (errors=-74% to 75%). In the normal sample, mean estimates generally underestimated differences in brain volume at percentile ranks below the mean. Conversely, in the AD sample, mean estimates generally underestimated differences in brain volume at percentile ranks above the mean. Differences between ages at the 5(th) percentile rank of normal subjects were ~39% greater than mean differences in the AD subjects.
  
  
  CONCLUSIONS
  While more data are required to make true population inferences, our results indicate that mean regression estimates may not accurately represent the distributions of ageing brain tissue volumes. This suggests that percentile rank estimates will be required to robustly define the limits of brain tissue volume in normal ageing and neurodegenerative disease.
authors.affiliation: Brain Research Imaging Centre (BRIC), The University of Edinburgh, Neuroimaging Sciences, Western General Hospital, Edinburgh, United Kingdom ; Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) collaboration, Edinburgh, United Kingdom.
authors.forename: David Alexander
authors.initials: DA
authors.lastname: Dickie
authors.affiliation: Brain Research Imaging Centre (BRIC), The University of Edinburgh, Neuroimaging Sciences, Western General Hospital, Edinburgh, United Kingdom ; Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) collaboration, Edinburgh, United Kingdom.
authors.forename: Dominic E
authors.initials: DE
authors.lastname: Job
authors.affiliation: Brain Research Imaging Centre (BRIC), The University of Edinburgh, Neuroimaging Sciences, Western General Hospital, Edinburgh, United Kingdom ; Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) collaboration, Edinburgh, United Kingdom.
authors.forename: David Rodriguez
authors.initials: DR
authors.lastname: Gonzalez
authors.affiliation: Geriatric Medicine Unit, The University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom ; Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) collaboration, Edinburgh, United Kingdom.
authors.forename: Susan D
authors.initials: SD
authors.lastname: Shenkin
authors.affiliation: Aberdeen Biomedical Imaging Centre, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom ; Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) collaboration, Edinburgh, United Kingdom.
authors.forename: Trevor S
authors.initials: TS
authors.lastname: Ahearn
authors.affiliation: Aberdeen Biomedical Imaging Centre, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom ; Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) collaboration, Edinburgh, United Kingdom.
authors.forename: Alison D
authors.initials: AD
authors.lastname: Murray
authors.affiliation: Brain Research Imaging Centre (BRIC), The University of Edinburgh, Neuroimaging Sciences, Western General Hospital, Edinburgh, United Kingdom ; Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) collaboration, Edinburgh, United Kingdom.
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Wardlaw
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000473:pathology*; D000544:Alzheimer Disease / Q000473:pathology; D001921:Brain / Q000033:anatomy & histology* / Q000473:pathology*; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging / Q000592:standards*; D008297:Male; D008875:Middle Aged; D009929:Organ Size; D012016:Reference Values; D012044:Regression Analysis