Longitudinal and cross-sectional analysis of atrophy in Alzheimer's disease: Cross-validation of BSI, SIENA and SIENAX Stephen M. Smith, a, ⁎ Anil Rao, b Nicola De Stefano, c Mark Jenkinson, a Jonathan M. Schott, d Paul M. Matthews, a,b and Nick C. Fox d a Oxford University Centre for Functional MRI of the Brain (FMRIB), Oxford, UK b GlaxoSmithKline Clinical Imaging Centre, Hammersmith, UK c Department of Neurological and Behavioural Sciences, University of Siena, Italy d Dementia Research Centre, Institute of Neurology, UCL, UK Received 21 February 2007; revised 28 March 2007; accepted 12 April 2007 Available online 27 April 2007 Brain volume loss (atrophy) is widely used as a marker of disease progression. Atrophy has been measured with a variety of methods, some estimating atrophy rate from two temporally separated scans, and others estimating atrophy state from a single scan. Three popular tools for measuring brain atrophy are BSI and SIENA (rate) and SIENAX (state). Previous papers have shown BSI and SIENA to have similar accuracy, but no work has carefully compared both methods using the same data set. Here we compare these methods, using data from patients with Alzheimer's disease and age-matched controls. We also compare the SIENA longitudinal measure with atrophy state estimated by SIENAX using just the earliest scan taken from each subject. We show strong correspondence and similar sensitivity to atrophy between all 3 measures. © 2007 Elsevier Inc. All rights reserved. Introduction Brain volume loss, as measured with MRI structural imaging, is accepted as a sensitive and objective marker of disease progression in various pathologies such as multiple sclerosis (MS) and Alzheimer's disease (AD) (Filippi et al., 2004; De Stefano et al., 2003b; Fox et al., 1996; Fox and Freeborough, 1997). Atrophy has been measured with a variety of methods, some of which are longitudinal (measuring atrophy rate, for example, percentage brain volume change, using two or more temporally separated scans per subject) and others being cross-sectional (measuring atrophy state, for example, brain volume normalised for head size, with a single scan per subject). Three validated analysis tools for measuring brain atrophy are BSI [Boundary Shift Interval (Fox et al., 1996; Fox and Freeborough, 1997; Freeborough et al., 1996; Freeborough and Fox, 1997, 1998)] and SIENA [Structural Image Evaluation, using Normalisation, of Atrophy (Smith et al., 2001, 2002)] for longitudinal measurement, and SIENAX (Smith et al., 2002) for cross-sectional measurement. Previous papers have shown BSI and SIENA to have similar accuracy – around 0.2% error in PBVC (% brain volume change) – but to date, no papers have carefully compared both methods using the same data set. In this paper, we present a comparison of these methods, using data from a study investigating atrophy in AD and age-matched normals. We compare the results of estimating longitudinal atrophy with BSI and with SIENA. We also compare estimated longitudinal atrophy with the cross- sectional atrophy state, as estimated by SIENAX using the earliest scan taken from each subject. Methods explicitly tuned to measure longitudinal change are expected to provide a more sensitive measure of the atrophy process than cross-sectional measures, primarily because cross-subject variation in head size is not a major confound when using atrophy rate as a marker, whereas it is when using atrophy state, derived from a single time-point image. Furthermore, whereas BSI and SIENA have previously been shown to give PBVC errors of around 0.2% (of the brain volume), the error in the SIENAX NBV (normalised brain volume) measure is generally at least double this. However, SIENAX, by measuring atrophy state rather than rate, has the advantage of being able to give an immediate indication of the brain state upon the first imaging, rather than needing to wait for the second imaging session after an appropriate duration. If pathology has already resulted in some atrophy before the start of a study, one would expect correlation between state and rate, and hence a cross- sectional measure should be an earlier, if noisier, marker of what will be found later upon re-examination. In a population chosen to include patients at similar early stages of clinical expression of the disease, normalised brain volume may be predictive of the relative rate of subsequent brain atrophy. We are interested, in this paper, to test how good a marker the early measure of NBV is, compared with later atrophy rate measurements. www.elsevier.com/locate/ynimg NeuroImage 36 (2007) 1200 – 1206 ⁎ Corresponding author. E-mail address: steve@fmrib.ox.ac.uk (S.M. Smith). Available online on ScienceDirect (www.sciencedirect.com). 1053-8119/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2007.04.035