Synopsis

Multi-center clinical trials utilizing quantitative diffusion kurtosis imaging (DKI) protocols require accurate, precise, and stable phantoms for validation of derived imaging metrics. This study examines the precision and reproducibility of isotropic (i)DKI parameters obtained from a phantom based on nanostructured vesicles that restrict diffusion and mimic tissue cellularity. Ten test-retest iDKI studies were performed on four scanners at three imaging centers over a six-month period. The tested prototype phantoms exhibited physiologically-relevant and highly-repeatable apparent diffusion and kurtosis parameters. Achieved precision was sufficient to characterize thermal and temporal stability trends to guide robust quantitative iDKI phantom production.

Introduction

Methods

The developed prototype iDKI phantom consisted of seven sample vials immersed in water bath. Four restricted diffusion materials were tested based on water solutions of cetyltrimethylammonium bromide (CTAB) or behentriammonium chloride (BTAC) and cetearyl (CA) or decyl (DEC) alcohols, as well as prolipid 161 (PL161). Three negative control, mono-exponential diffusion samples included polyvinylpirrolidone (PVP) solutions in water at 0, 20% and 40%. The constructed iDKI phantoms were scanned at three imaging centers on four MRI scanners (two at 1.5T and 3T each) at ambient temperature over a period of six months. Shared multi-b DKI scan protocol included 11 b-values (b = 0, 50, 100, 200, 500, 800, 1000, 1500, 2000, 2500, 3000s/mm²), repeated two times. All image and statistical analysis was automated using MATLAB R2015b (Mathworks, Natick MA).

Seven circular ROIs (12mm diameter, 155 pixels) were defined separately for the test-retest runs on DWI(b=0) for phantom tubes (Figure 1A) avoiding air-bubble susceptibility artifacts. The parametric maps of apparent diffusion, D_app , and kurtosis, K_app, coefficients (Fig.1B) were derived using linear-least-squares fit of voxel DWI log-signal to quadratic dependence on b-value⁴ (Fig.1C). To satisfy iDKI model⁴ convergence and ensure SNR_bmax>2, maximum fit b-values were constrained to b_max=1500 s/mm² for CA-BTAC (V2), and b_max=2000 s/mm² for water (V4) and PL-161 (V6) vials (Fig.1C, D). The apparent scan temperature (T_a) was self-calibrated using water (V4) ADC(b_max=1000 s/mm²) based on Speedy-Angell relation⁸, and ranged between 19.5 and 25.5 (±1^oC).

Bland-Altman (BA) repeatability analysis was performed for D_app and K_app across all test-retest sample scans (pool of 70), excluding outliers outside 1.5 interquartile ranges above/below the upper/lower quartiles. Sample-specific coefficient of variance (wCV) and corresponding 95% confidence interval (CI) were assessed¹ (including BA-outliers) for all test-retest parameter values. Thermal and temporal phantom stability was evaluated by inter-scan Pearson correlation, R, for the derived kurtosis parameters versus T_a and days from phantom manufacturing (using R-significance threshold of p_R<0.05). Temperature and scan date were independent covariates (R=0.13, p_R=0.66).

Results and Discussion

Four different chemical designs tested for iDKI phantom materials in V1, V2, V6, and V7 (Figure 1) exhibited restricted diffusion at high b-values (>1000 s/mm²), with DWI signals sustained above 20% of S₀ (Fig.1C) and K_app exceeding negative control noise-induced bias (Fig.1B, K_app<0.1). All four tested iDKI materials allowed physiologically-relevant K_app ranges 0.4-1.7(Table 1). Except for V7 (K_app) outlier, the achieved intra-scan iDKI parameter precision (95% CI) was 1%-3.5% (Figure 2, Table 1) and independent of magnetic field (SNR).

The inter-scan variability of D_app for the negative control samples (not shown) was fully explained by dependence on scanner ambient temperature (R>0.96, p_R<1e-7). Observed kurtosis phantom D_app sensitivity to temperature (2-3%/ ^oC) was higher than that of K_app (Figure 3A,B). All iDKI phantom materials underwent initial parameter stabilization period of 3-4 weeks following preparation (Fig.3C,D), coincidental with evident sample degassing, when parameters changed by 6-22%. The parameter values for vesicular phase materials remained temporally stable post initial stabilization period (Fig.3C,D).

The candidate materials based on more-viscous multi-lamellar vesicle phase, exhibited either poor temporal stability (V6:PL161) or notable dependence on site storage and thermal equilibrium conditions (V1:DEC-CTAB). The kurtosis parameter values of CA-CTAB vesicular material had limited K_app precision (9%, Table 1) and large (22%) initial D_app stabilization change (Fig.3C(V7), due to apparent formation of in-volume gas micro-bubbles), but provided good thermal stability (no significant T_a dependence). CA-BTAC (V2) phantom has shown best intra-scan repeatability and inter-scan stability with the lowest 6% change in D_app during stabilization stage and moderate thermal dependence (2%/ ^oC; R=0.87, p_R=1.2e-4).

Conclusion

Acknowledgements

This research was funded by National Institutes of Health Grants: U01CA166104, U01 CA211205, R01CA190299, P01CA085878 and P30 CA008748

Disclosure: S.D.Swanson, D.I.Malyarenko and T.L.Chenevert are co-inventors on intellectual property assigned to and managed by the University of Michigan for the technology underlying the manufacturing of the quantitative diffusion kurtosis phantoms utilized in this manuscript.

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