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.

Keywords: MRI; USPIO; cerebral small vessel disease; ferumoxytol; inflammation; relaxometry.

Figure 1

(a) Errors in the R₁ measurements versus gold-standard inversion-recovery spin-echo (IRSE) values, measured in a phantom using DESPOT1-HIFI with the Deichmann signal model, an approximate signal model neglecting effects of the pulse train and using the variable flip angle method; (b) Calculated inversion-recovery prepared spoiled gradient echo (IR-sGRE) signal (assuming s₀ = 100) for the acquisition parameters given in Table 5 using both the full mathematical description of Brix et al., the model by Deichmann et al. and the simplified model as described in the text. Note that the Deichmann prediction is almost identical to that of the Brix model and is consequently not visible.

Figure 2

(a) R₁ maps for a single patient at three time points: pre-ultrasmall superparamagnetic particles of iron oxide (USPIO) (scan 1_pre), immediately post-USPIO (scan 1_post), and at 24–30 h post-USPIO (scan 2). The corresponding relative flip angle (i.e., k: the actual flip angle divided by the nominal value) map measured at baseline is shown on the right, illustrating both variation due to B₁ inhomogeneity and the (axial) slab excitation profile; (b) R₂* maps in the same patient, obtained at the same time points and at 1 month post-USPIO (scan 3); (c) Parametric maps in another patient (79 year old male, first visit 31 days post-infarct in the left basal ganglia). R₁ is seen to increase visibly in the stroke lesion following USPIO administration. The corresponding change to R₂* is more subtle in the stroke lesion, but a visible increase is seen in the neighbouring background tissue.

Figure 3

Median relaxation rates (a) R₁ and (b) R₂* for each participant and tissue region at scan 1_pre (pre-USPIO), scan 1_post (immediately post-USPIO), scan 2 (24–30 h post-USPIO) and scan 3 (1-month post-USPIO, R₂* only). Abbreviations: WM: normal-appearing white matter, GM: grey matter, WMH: white matter hyperintensities, SL: stroke lesion.

Figure 4

Change in R₂* (ΔR₂*) versus change in R₁ (ΔR₁) at scan 1_post (immediately post-USPIO; circles) and at scan 2 (24–30 h post-USPIO; crosses). Each data point represents the change in relaxation rate for a subject relative to the value measured at scan 1 (pre-USPIO). Dotted lines show the best fit to the data at scan 2; full linear regression results are given in Table 3.

Figure 5

Blood-normalised relaxation rate changes (a) ∆R_1,norm and (b) $\Delta R_{2,\mathrm{norm}}^{*}$ at scan 1_post (immediately post-USPIO) and scan 2 (24–30 h post-USPIO). Changes are relative to baseline values measured at scan 1_pre (pre-USPIO) and are normalised to corresponding R₁ changes in blood. Values at scan 1_post are approximately equivalent (∆R_1,norm) or proportional ($\Delta R_{2,\mathrm{norm}}^{*}$ ) to cerebral blood volume fraction, while values at scan 2 are potentially influenced by additional parenchymal USPIO uptake. Abbreviations: WM: normal-appearing white matter, GM: grey matter, WMH: white matter hyperintensities, SL: stroke lesion.

Figure 6

Regions of interest overlaid on the first image of the DESPOT1-HIFI series prior to USPIO infusion. Regions and segmentation masks shown are the manually drawn thalamus ROI (red), normal-appearing white matter (green), white matter hyperintensities (yellow) and the manually drawn stroke lesion ROI (blue).