Robust atrophy rate measurement in Alzheimer's disease using multi-site serial MRI: tissue-specific intensity normalization and parameter selection

Abstract

We describe an improved method of measuring brain atrophy rates from serial MRI for multi-site imaging studies of Alzheimer's disease (AD). The method (referred to as KN-BSI) improves an existing brain atrophy measurement technique-the boundary shift integral (classic-BSI), by performing tissue-specific intensity normalization and parameter selection. We applied KN-BSI to measure brain atrophy rates of 200 normal and 141 AD subjects using baseline and 1-year MRI scans downloaded from the Alzheimer's Disease Neuroimaging Initiative database. Baseline and repeat images were reviewed as pairs by expert raters and given quality scores. Including all image pairs, regardless of quality score, mean KN-BSI atrophy rates were 0.09% higher (95% CI 0.03% to 0.16%, p=0.007) than classic-BSI rates in controls and 0.07% higher (-0.01% to 0.16%, p=0.07) higher in ADs. The SD of the KN-BSI rates was 22% lower (15% to 29%, p<0.001) in controls and 13% lower (6% to 20%, p=0.001) in ADs, compared to classic-BSI. Using these results, the estimated sample size (needed per treatment arm) for a hypothetical trial of a treatment for AD (80% power, 5% significance to detect a 25% reduction in atrophy rate) would be reduced from 120 to 81 (a 32% reduction, 95% CI=18% to 45%, p<0.001) when using KN-BSI instead of classic-BSI. We concluded that KN-BSI offers more robust brain atrophy measurement than classic-BSI and substantially reduces sample sizes needed in clinical trials.

Keywords: Alzheimer’s disease; Atrophy; BSI; Boundary shift integral; Intensity normalization; KN-BSI; MRI.

Fig. 1

An overview of classic-BSI and KN-BSI processing pipelines. See Classic-BSI and KN-BSI sections for more details of each step.

Fig. 2

Results of intensity normalization using classic-BSI and KN-BSI. Notice the subtle change in contrast between CSF and GM/WM in the ventricles in the baseline and normalized repeat image using classic-BSI (a and b). This caused the darkening in the ventricles in the subtraction image (d). Panel e shows similar contrast between CSF and GM/WM in the baseline and normalized repeat image using KN-BSI. Panel f shows the difference between the normalized repeat images using classic-BSI and KN-BSI.

Fig. 3

The box plot shows the difference in brain atrophy rates between classic-BSI and KN-BSI for each imaging site. The horizontal line in the box represents the median value, and the box represents the interquartile range (IQR). The whiskers represent the upper and lower adjacent values, which are the highest value not greater than 75th percentile+1.5 times IQR and the lowest value not less than 25th percentile −1.5 times IQR. Values outside the whiskers are marked as crosses.

Fig. 4

The mean upper intensity window versus mean lower intensity window organized by the scanner make. The error bars denote the 95% confidence interval. The numbers of subjects (N) scanned at each scanner make are GE Genesis (N=31), GE Excite (N=135), GE HDx (N=7), Philips Intera (N=43), Siemens Avanto (N=30), Siemens Sonata (N=34), and Siemens Symphony (N=61). The automatically chosen intensity window has been normalized by the mean brain intensity to allow comparison with the manually chosen intensity window.