Pre-clinical imaging of transgenic mouse models of neuroblastoma using a dedicated 3-element solenoid coil on a clinical 3T platform

Abstract

Background: The use of clinical MRI scanners to conduct pre-clinical research facilitates comparisons with clinical studies. Here the utility and sensitivity of anatomical and functional MRI data/biomarkers acquired from transgenic mouse models of neuroblastoma using a dedicated radiofrequency (RF) coil on a clinical 3T scanner was evaluated.

Methods: Multiparametric MRI of transgenic mice bearing abdominal neuroblastomas was performed at 3T, and data cross-referenced to that acquired from the same mice on a pre-clinical 7T MRI system. T₂-weighted imaging, quantitation of the native longitudinal relaxation time (T₁) and the transverse relaxation rate (R₂*), and dynamic contrast-enhanced (DCE)-MRI, was used to assess tumour volume, phenotype and response to cyclophosphamide or cabozantinib.

Results: Excellent T₂-weighted image contrast enabled clear tumour delineation at 3T. Significant correlations of tumour volume (R=0.98, P<0.0001) and R₂* (R=0.87, P<0.002) measured at 3 and 7T were established. Mice with neuroblastomas harbouring the anaplastic lymphoma kinase mutation exhibited a significantly slower R₂* (P<0.001), consistent with impaired tumour perfusion. DCE-MRI was performed simultaneously on three transgenic mice, yielding estimates of K^trans for each tumour (median K^trans values of 0.202, 0.168 and 0.114 min^-1). Cyclophosphamide elicited a significant reduction in both tumour burden (P<0.002) and native T₁ (P<0.01), whereas cabozantinib induced significant (P<0.01) tumour growth delay.

Conclusions: Simultaneous multiparametric MRI of multiple tumour-bearing animals using this coil arrangement at 3T can provide high efficiency/throughput for both phenotypic characterisation and evaluation of novel therapeutics, and facilitate the introduction of functional MRI biomarkers into aligned imaging-embedded clinical trials.

Figure 1

‘Mouse hotel’ coil and the 3T clinical scanner. Photographs of the coil arrangement on the 3T scanner, and the high resolution 3-channel/3-animal MR RF coil. The yellow arrows indicate the three individual mouse beds and the red circles the centre of each element of the coil. Positioning of the coil in the scanner as shown means the mice are perpendicular to the B₀ field.

Figure 2

Anatomical imaging at 3 and 7T. (A) Anatomical T₂-weighted coronal images acquired simultaneously from three Th-MYCN mice with abdominal neuroblastoma using the high resolution 3-channel/3-animal MR RF coil on the 3T clinical scanner, with a scale bar in blue. Each tumour is indicated by yellow arrows, with kidney (K) and lungs (L) also annotated. An additional thoracic lesion identified in one of the mice is indicated with a red arrow. (B) Expanded T₂-weighted image of the abdomen of the first mouse in (A) acquired at 3T, and the corresponding T₂-weighted image acquired from the same mouse at 7T, with corresponding scale bars in blue. (C) Linear regression analysis of the volumetric measurements determined from T₂-weighted MRI of tumour-bearing transgenic mice imaged at 3 and 7T revealed a positive and highly significant correlation (R=0.98, P<0.0001).

Figure 3

Functional MRI of neuroblastomas at 3 and 7T. (A) Parametric R₂* maps acquired at 3 and 7T from the same Th-MYCN transgenic mouse bearing an abdominal neuroblastoma. Note the difference in dynamic range used to display the R₂* maps at the two field strengths. (B) Linear regression analysis of R₂* measurements obtained from tumour-bearing transgenic mice imaged at both 3 and 7T revealed a significant positive correlation (R=0.87, P=0.0012). Parametric (C) T₁ and (D) R₂* maps acquired at 3T from representative tumour-bearing Th-MYCN and Th-ALK^F1174L/Th-MYCN transgenic mice. Summary plots showing the quantitative data for (E) native T₁ and (F) R₂*. Data are individual tumour medians, and the mean±1 s.e.m., ***P<0.001.

Figure 4

Simultaneous DCE-MRI at 3T. Parametric K^trans maps obtained from three tumour-bearing transgenic mice from which DCE-MRI data were simultaneously acquired using the high resolution 3-channel/3-animal MR RF coil on the 3T clinical scanner, showing a heterogeneous distribution of vascular permeability/perfusion across all three neuroblastomas. Gadolinium uptake curves obtained from one mouse for ROIs positioned over the tumour, kidney and paraspinal muscle are shown. Median K^trans values of 0.202, 0.168 and 0.114 min⁻¹ were estimated from the upper, middle and lower tumour ROIs, respectively.

Figure 5

Assessment of tumour response to CPM or CBZ treatment using the 3T platform. (A) T₂-weighted coronal images acquired at 3T using the high resolution 3-channel/3-animal MR RF coil from Th-MYCN transgenic mice bearing abdominal neuroblastomas prior to and 24 h after treatment with either saline (control) or CPM. Each tumour is delineated in yellow. Treatment with CPM resulted in a consistent and significant (**P<0.01) reduction in tumour volume. Parametric maps of tumour (B) native T₁ and (C) R₂* acquired at 3T from Th-MYCN mice prior to and 24 h after treatment with either saline (control) or CPM. While treatment with CPM elicited a significant reduction in native T₁ (**P<0.01), there was no change in tumour R₂*. Relative changes in tumour volume, native T₁ and R₂* determined from Th-MYCN mice treated with vehicle, or either CPM or CBZ, are shown in (D) and (E) respectively. Data shown are the individual tumour median values and the mean±1 s.e.m. (***P<0.001, **P<0.01).