Atrophy quantification is fundamental for understanding brain development and diagnosing and monitoring brain diseases. FSL-SIENA is a well-known fully automated method that has been widely used in brain magnetic resonance imaging studies. However, intensity variations arising during image acquisition may compromise evaluation, analysis and even diagnosis. In this work, we studied whether intensity standardisation could improve longitudinal atrophy quantification using FSL-SIENA. We evaluated the effect of six intensity standardisation methods—z-score, fuzzy c-means, Gaussian mixture model, kernel density estimation, histogram matching and WhiteStripe—on atrophy detected by FSL-SIENA. First, we evaluated scan–rescan repeatability using scans taken during the same session from OASIS (n=122). Except for WhiteStripe, intensity standardisation did not compromise the scan–rescan repeatability of FSL-SIENA. Second, we compared the mean annual atrophy for Alzheimer’s and control subjects from OASIS (n=122) and ADNI (n=147) yielded by FSL-SIENA with and without intensity standardisation, after adjusting for covariates. Our findings were threefold: First, the use of histogram matching was counterproductive, primarily as its assumption of equal tissue proportions does not necessarily hold in longitudinal studies. Second, standardising with z-score and WhiteStripe before registration affected the registration performance, thus leading to erroneous estimates. Third, z-score was the only method that consistently led to increased effect sizes compared to when omitted (no standardisation: 0.39 and 0.43 for OASIS and ADNI; z-score: 0.45 for both datasets). Overall, we found that incorporating z-score right after registration led to reduced inter-subject inter-scan intensity variability and benefited FSL-SIENA. Our work evinces the relevance of appropriate intensity standardisation in longitudinal cerebral atrophy assessments using FSL-SIENA
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