Free water elimination improves test-retest reproducibility of diffusion tensor imaging indices in the brain: A longitudinal multisite study of healthy elderly subjects

Abstract

Free water elimination (FWE) in brain diffusion MRI has been shown to improve tissue specificity in human white matter characterization both in health and in disease. Relative to the classical diffusion tensor imaging (DTI) model, FWE is also expected to increase sensitivity to microstructural changes in longitudinal studies. However, it is not clear if these two models differ in their test-retest reproducibility. This study compares a bi-tensor model for FWE with DTI by extending a previous longitudinal-reproducibility 3T multisite study (10 sites, 7 different scanner models) of 50 healthy elderly participants (55-80 years old) scanned in two sessions at least 1 week apart. We computed the reproducibility of commonly used DTI metrics (FA: fractional anisotropy, MD: mean diffusivity, RD: radial diffusivity, and AXD: axial diffusivity), derived either using a DTI model or a FWE model. The DTI metrics were evaluated over 48 white-matter regions of the JHU-ICBM-DTI-81 white-matter labels atlas, and reproducibility errors were assessed. We found that relative to the DTI model, FWE significantly reduced reproducibility errors in most areas tested. In particular, for the FA and MD metrics, there was an average reduction of approximately 1% in the reproducibility error. The reproducibility scores did not significantly differ across sites. This study shows that FWE improves sensitivity and is thus promising for clinical applications, with the potential to identify more subtle changes. The increased reproducibility allows for smaller sample size or shorter trials in studies evaluating biomarkers of disease progression or treatment effects. Hum Brain Mapp 38:12-26, 2017. © 2016 Wiley Periodicals, Inc.

Keywords: brain diffusion tensor imaging; free-water imaging; healthy elderly; longitudinal; multisite diffusion MRI; test-retest reproducibility.

Figure 1

Reproducibility errors of diffusion metrics: effects of ROI size and free water elimination. Red symbols are for uncorrected maps, blue symbols are for FWE maps, dark red symbols are for free water maps. The statistical significance between the reproducibility of uncorrected and FWE‐corrected data corresponds to the results from Table 1 and is shown here by using different symbols: full circles represent ROIs where FWE significantly reduces reproducibility errors, empty circles where there are no significant differences, and crosses where FWE significantly increases errors. [Color figure can be viewed at http://wileyonlinelibrary.com.]

Figure 2

Reproducibility errors of diffusion metrics: whole‐brain normalized histogram distributions. For each diffusion metric (FA, MD, AXD, RD), the normalized reproducibility histograms for uncorrected (red) and FWE‐corrected data (blue) are shown. [Color figure can be viewed at http://wileyonlinelibrary.com.]

Figure 3

Sample size ratio needed to have the same analysis power using FWE instead of uncorrected data. Effects on diffusion metric (FA, MD, AXD, RD) from three corpus callosum ROIs (body, genu, splenium). Bars represent the percentage of subjects needed after FWE, with error bars showing standard deviations.