Protocol optimization of the filter exchange imaging (FEXI) sequence and implications on group sizes : a test-retest study

Abstract: Diffusion weighted imaging (DWI) is a branch within the field of magnetic resonance imaging (MRI) that relies on the diffusion of water molecules for its contrast. Its clinical applications include the early diagnosis of ischemic stroke and mapping of the nerve tracts of the brain. The recent development of filter exchange imaging (FEXI) and the introduction of the apparent exchange rate (AXR) present a new DWI based technique that uses the exchange of water between compartments as contrast. FEXI could offer new clinical possibilities in diagnosis, differentiation and treatment follow-up of conditions involving edema or altered membrane permeability, such as tumors, cerebral edema, multiple sclerosis and stroke. Necessary steps in determining the potential of AXR as a new biomarker include running comparative studies between controls and different patient groups, looking for conditions showing large AXR-changes. However, before designing such studies, the experimental protocol of FEXI should be optimized to minimize the experimental variance. Such optimization would improve the data quality, shorten the scan time and keep the required study group sizes smaller.  Here, optimization was done using an active imaging approach and the Cramer-Rao lower bound (CRLB) of Fisher information theory. Three optimal protocols were obtained, each specialized at different tissue types, and the CRLB method was verified by bootstrapping. A test-retest study of 18 volunteers was conducted in order to investigate the reproducibility of the AXR as measured by one of the protocols, adapted for the scanner. Group sizes required were calculated based on both CRLB and the variability of the test-retest data, as well as choices in data analysis such as region of interest (ROI) size. The result of this study is new protocols offering a reduction in coefficient of variation (CV) of around 30%, as compared to previously presented protocols. Calculations of group sizes required showed that they can be used to decide whether any patient group, in a given brain region, has large alterations of AXR using as few as four individuals per group, on average, while still keeping the scan time below 15 minutes. The test-retest study showed a larger than expected variability however, and uncovered artifact like changes in AXR between measurements. Reproducibility of AXR values ranged from modest to acceptable, depending on the brain region. Group size estimations based on the collected data showed that it is still possible to detect AXR difference larger than 50% in most brain regions using fewer than ten individuals. Limitations of this study include an imprecise knowledge of model priors and a possibly suboptimal modeling of the bias caused by weak signals. Future studies on FEXI methodology could improve the method further by addressing these matters and possibly also the unknown source of variability. For minimal variability, comparative studies of AXR in patient groups could use a protocol among those presented here, while choosing large ROI sizes and calculating the AXR based on averaged signals.