MRI Relaxometry for Quantitative Analysis of USPIO Uptake in Cerebral Small Vessel Disease

Abstract

A protocol for evaluating ultrasmall superparamagnetic particles of iron oxide (USPIO) uptake and elimination in cerebral small vessel disease patients was developed and piloted. B1-insensitive R1 measurement was evaluated in vitro. Twelve participants with history of minor stroke were scanned at 3-T MRI including structural imaging, and R1 and R2* mapping. Participants were scanned (i) before and (ii) after USPIO (ferumoxytol) infusion, and again at (iii) 24–30 h and (iv) one month. Absolute and blood-normalised changes in R1 and R2* were measured in white matter (WM), deep grey matter (GM), white matter hyperintensity (WMH) and stroke lesion regions. R1 measurements were accurate across a wide range of values. R1 (p < 0.05) and R2* (p < 0.01) mapping detected increases in relaxation rate in all tissues immediately post-USPIO and at 24–30 h. R2* returned to baseline at one month. Blood-normalised R1 and R2* changes post-infusion and at 24–30 h were similar, and were greater in GM versus WM (p < 0.001). Narrower distributions were seen with R2* than for R1 mapping. R1 and R2* changes were correlated at 24–30 h (p < 0.01). MRI relaxometry permits quantitative evaluation of USPIO uptake; R2* appears to be more sensitive to USPIO than R1. Our data are explained by intravascular uptake alone, yielding estimates of cerebral blood volume, and did not support parenchymal uptake. Ferumoxytol appears to be eliminated at 1 month. The approach should be valuable in future studies to quantify both blood-pool USPIO and parenchymal uptake associated with inflammatory cells or blood-brain barrier leak.

A novel gamma GLM approach to MRI relaxometry comparisons

“…Log‐transforms compare % change in R i , whereas GGLM‐ID compares absolute differences. This is important in MRI relaxometry, where the important metric for assessing phenomenon such as CA uptake or cerebral blood volume is and not . is a direct surrogate biomarker for CA concentration, whereas can be small at higher concentrations even if is large and vice versa.…”

“…As MRI relaxometry becomes more widespread, there is an increasing need to develop an appropriate statistical framework to accurately quantify differences in relaxometric biomarkers, and correlate these differences to physiological phenomenon. Currently, most comparisons are performed using t ‐tests, analysis of variance (ANOVA), or ordinary least squares (OLS) regression that all fall under the category of standard linear models . In fact, both Student’s t ‐test and ANOVA are special cases of OLS regression with categorical variables .…”

“…Estimates from OLS are also somewhat robust to violations of assumption 2, especially for large sample sizes. However, assumption 3 is often violated in the context of MRI relaxometry data, where the absolute error in the relaxation time ( T 1 , T 2 , or ) or rate ( R 1 , R 2 , ) often tends to increase with the measured value itself (heteroscedasticity) . Much of the literature on reproducibility in MRI relaxometry is focused on measuring the coefficient of variation (CV), which implies a constant relative error rather than absolute error.…”

Pathophysiology, classification, and MRI parallels in microvascular disease of the heart and brain

“…An example of ferumoxytol‐enhanced CBV mapping using MRI is shown in Figure 5. In addition, recent work examining USPIO contrast agents in the setting of CSVD has noted measurable changes in relaxation rate, 110 which may be clinically useful in the near future. The reader is referred to cited references for detailed description of other techniques.…”

“…Thus, combined use of CBV measurements with T1‐ and T2‐weighted imaging may enable unique characterization of tissue pathology. While early work with ferumoxytol‐enhanced MRI has been promising for characterization of CSVD, 110 more extensive investigations are necessary.…”