Peter R. Seevinck

Magnetic resonance imaging of brain angiogenesis after stroke

Stroke is a major cause of mortality and long-term disability worldwide. The initial changes in local perfusion and tissue status underlying loss of brain function are increasingly investigated with noninvasive imaging methods. In addition, there is a growing interest in imaging of processes that contribute to post-stroke recovery. In this review, we discuss the application of magnetic resonance imaging (MRI) to assess the formation of new vessels by angiogenesis, which is hypothesized to participate in brain plasticity and functional recovery after stroke. The excellent soft tissue contrast, high spatial and temporal resolution, and versatility render MRI particularly suitable to monitor the dynamic processes involved in vascular remodeling after stroke. Here we review recent advances in the field of MR imaging that are aimed at assessment of tissue perfusion and microvascular characteristics, including cerebral blood flow and volume, vascular density, size and integrity. The potential of MRI to noninvasively monitor the evolution of post-ischemic angiogenic processes is demonstrated from a variety of in vivo studies in experimental stroke models. Finally, we discuss some pitfalls and limitations that may critically affect the accuracy and interpretation of MRI-based measures of (neo)vascularization after stroke.

Highly localized positive contrast of small paramagnetic objects using 3D center-out radial sampling with off-resonance reception

In this article, we present a 3D imaging technique, applying center‐out RAdial Sampling with Off‐Resonance reception, to accurately depict and localize small paramagnetic objects with high positive contrast while suppressing long T2* components. The center‐out RAdial Sampling with Off‐Resonance reception imaging technique is a fully frequency‐encoded 3D ultrashort echo time acquisition method, which uses a large excitation bandwidth and off‐resonance reception. By manually introducing an offset, Δf0, to the central reception frequency (f0), the typical radial signal pileup observed in 3D center‐out sampling caused by a dipolar magnetic field disturbance can be shifted toward the source of the field disturbance, resulting in a hyperintense signal at the magnetic center of the small paramagnetic object. This was demonstrated both theoretically and using 1D time domain simulations. Experimental verification was done in a gel phantom and in inhomogeneous porcine tissue containing various objects with very different geometry and susceptibility, namely, subvoxel stainless steel spheres, a puncture needle, and paramagnetic brachytherapy seeds. In all cases, center‐out RAdial Sampling with Off‐Resonance reception was shown to generate high positive contrast exactly at the location of the paramagnetic object, as was confirmed by X‐ray computed tomography. Magn Reson Med, 2010.

Factors Affecting the Sensitivity and Detection Limits of MRI, CT, and SPECT for Multimodal Diagnostic and Therapeutic Agents

Noninvasive imaging techniques like magnetic resonance imaging (MRI), computed tomography (CT) and single photon emission computed tomography (SPECT) play an increasingly important role in the diagnostic workup and treatment of cancerous disease. In this context, a distinct trend can be observed towards the development of contrast agents and radiopharmaceuticals that open up perspectives on a multimodality imaging approach, involving all three aforementioned techniques. To promote insight into the potentialities of such an approach, we prepared an overview of the strengths and limitations of the various imaging techniques, in particular with regard to their capability to quantify the spatial distribution of a multimodal diagnostic agent. To accomplish this task, we used a two-step approach. In the first step, we examined the situation for a particular therapeutic anti-cancer agent with multimodal imaging opportunities, viz. holmium-loaded microspheres (HoMS). Physical phantom experiments were performed to enable a comparative evaluation of the three modalities assuming the use of standard equipment, standard clinical scan protocols, and signal-known-exactly conditions. These phantom data were then analyzed so as to obtain first order estimates of the sensitivity and detection limits of MRI, CT and SPECT for HoMS. In the second step, the results for HoMS were taken as a starting point for a discussion of the factors affecting the sensitivity and detection limits of MRI, CT and SPECT for multimodal agents in general. In this, emphasis was put on the factors that must be taken into account when extrapolating the findings for HoMS to other diagnostic tasks, other contrast agents, other experimental conditions, and other scan protocols.

Towards inherently distortion-free MR images for image-guided radiotherapy on an MRI accelerator

In MR-guided interventions, it is mandatory to establish a solid relationship between the imaging coordinate system and world coordinates. This is particularly important in image-guided radiotherapy (IGRT) on an MRI accelerator, as the interaction of matter with γ-radiation cannot be visualized. In conventional acquisitions, off-resonance effects cause discrepancies between coordinate systems. We propose to mitigate this by using only phase encoding and to reduce the longer acquisitions by under-sampling and regularized reconstruction. To illustrate the performance of this acquisition in the presence of off-resonance phenomena, phantom and in vivo images are acquired using spin-echo (SE) and purely phase-encoded sequences. Data are retrospectively under-sampled and reconstructed iteratively. We observe accurate geometries in purely phase-encoded images for all cases, whereas SE images of the same phantoms display image distortions. Regularized reconstruction yields accurate phantom images under high acceleration factors. In vivo images were reconstructed faithfully while using acceleration factors up to 4. With the proposed technique, inherently undistorted images with one-to-one correspondence to world coordinates can be obtained. It is a valuable tool in geometry quality assurance, treatment planning and online image guidance. Under-sampled acquisition combined with regularized reconstruction can be used to accelerate the acquisition while retaining geometrical accuracy.

Deep MR to CT Synthesis Using Unpaired Data

MR-only radiotherapy treatment planning requires accurate MR-to-CT synthesis. Current deep learning methods for MR-to-CT synthesis depend on pairwise aligned MR and CT training images of the same patient. However, misalignment between paired images could lead to errors in synthesized CT images. To overcome this, we propose to train a generative adversarial network (GAN) with unpaired MR and CT images. A GAN consisting of two synthesis convolutional neural networks (CNNs) and two discriminator CNNs was trained with cycle consistency to transform 2D brain MR image slices into 2D brain CT image slices and vice versa. Brain MR and CT images of 24 patients were analyzed. A quantitative evaluation showed that the model was able to synthesize CT images that closely approximate reference CT images, and was able to outperform a GAN model trained with paired MR and CT images.

Center-out radial sampling with off-resonant reconstruction for efficient and accurate localization of punctate and elongated paramagnetic structures

Accurate localization of interventional devices, for example, needles and brachytherapy seeds, is desired for interventional procedures. MRI is usually considered unsuitable for this purpose, as the induced signal voids and signal pile‐ups do not necessarily represent the exact location of the devices. Center‐out radial sampling with off‐resonance reception (co‐RASOR) has been shown to solve this problem by repositioning the signal pile‐up into the geometrical center of the interventional devices. However, the multiple acquisitions required for co‐RASOR resulted in a low efficiency and unsuitability for near real‐time interventional purposes. Herein, we aim to increase the efficiency of co‐RASOR by relying on multiple off‐resonance reconstructions of a single acquisition rather than on multiple acquisitions. The soundness of this approach is shown by demonstrating the equivalence of acquisition co‐RASOR and reconstruction co‐RASOR, both theoretically and experimentally. An algorithm is proposed and evaluated to obtain the geometric centers of the devices, while suppressing the background. This procedure is shown to be effective, in vitro as well as ex vivo, and to yield signal intensity increases in the order of 150–400% of the average signal, in the geometric center of a brachytherapy seed and a needle, respectively. The geometric accuracy of the resultant images is confirmed by computed tomography. Magn Reson Med, 2013.

FID sampling superior to spin‐echo sampling for T 2*‐based quantification of holmium‐loaded microspheres: Theory and experiment

This work demonstrates both theoretically and experimentally that multiple gradient‐echo sampling of free induction decay (MGEFID) is superior to MGE sampling of spin echo (MGESE) for T  2* ‐based quantification of holmium‐loaded microspheres (HoMS). An interleaved sampling strategy was applied in great detail to characterize the MR signal behavior of FID and SE signals of gels and perfused rabbit livers containing HoMS in great detail. Diffusion sensitivity was demonstrated for MGESE sampling, resulting in non‐exponential signal decay on both sides of the SE peak and in an underestimation of the HoMS concentration. Other than MGESE sampling, MGEFID sampling was demonstrated to be insensitive to diffusion, to exhibit exponential signal decay, and to allow accurate T  2* ‐based quantification of HoMS. Furthermore, a fit procedure was proposed extending the upper limit of quantifiable R  2* relaxation rates to at least 1500 sec–1. With this post‐processing step incorporated, MGEFID was shown to correctly estimate the integral amount of inhomogeneously distributed HoMS in liver tissue, up to a clinically relevant limit. All experimental findings could be explained with the theory of nuclear magnetic resonance (NMR) signal behavior in magnetically inhomogeneous tissues. HoMS were shown to satisfy the static dephasing regime when investigated with MGEFID and to violate the static dephasing conditions for MGESE at longer echo times typically used in SE. Magn Reson Med 60:1466–1476, 2008.

Alginate–lanthanide microspheres for MRI-guided embolotherapy

In cancer therapy, a promising treatment option to accomplish a high tumor-to-normal-tissue ratio is endovascular intervention with microsized particles, such as embolotherapy. In this study, alginate microspheres (ams) were prepared with the JetCutter technique, which is based on cutting a sodium alginate solution jet stream into small droplets of uniform size which are then cross-linked with different lanthanides or iron-III, resulting in microspheres of a predefined size which can be visualized by magnetic resonance imaging (MRI). The microspheres were investigated for their size and morphology (light microscopy and scanning electron microscopy analysis), cation content and MRI properties. The lanthanide-ams formulations, with a uniform size of 250 μm and a cation content between 0.72-0.94%, showed promising results for MR imaging. This was further demonstrated for Ho(3+)-cross-linked alginate microspheres (Ho(3+)-ams), the most potent microsphere formulation with respect to MR visualization, allowing single sphere detection and detailed microsphere distribution examination. Intravascular infusion of Ho(3+)-ams by catherization of ex vivo rabbit and porcine liver tissue and assessment of the procedure with MRI clearly showed accumulation and subsequently embolization of the targeted vessels, allowing accurate monitoring of the microsphere biodistribution throughout the tissue. Therefore, the different alginate-lanthanide microsphere formulations developed in this study show great potential for utilization as image-guided embolotherapy agents.

Microspheres with ultrahigh holmium content for radioablation of malignancies

PurposeThe aim of this study was to develop microspheres with an ultra high holmium content which can be neutron activated for radioablation of malignancies. These microspheres are proposed to be delivered selectively through either intratumoral injections into solid tumors or administered via an intravascularly placed catheter.MethodsMicrospheres were prepared by solvent evaporation, using holmium acetylacetonate (HoAcAc) crystals as the sole ingredient. Microspheres were characterized using light and scanning electron microscopy, coulter counter, titrimetry, infrared and Raman spectroscopy, differential scanning calorimetry, X-ray powder diffraction, magnetic resonance imaging (MRI), and X-ray computed tomography (CT).ResultsMicrospheres, thus prepared displayed a smooth surface. The holmium content of the HoAcAc microspheres (44% (w/w)) was higher than the holmium content of the starting material, HoAcAc crystals (33% (w/w)). This was attributed to the loss of acetylacetonate from the HoAcAc complex, during rearrangement of acetylacetonate around the holmium ion. The increase of the holmium content allows for the detection of (sub)microgram amounts of microspheres using MRI and CT.ConclusionsHoAcAc microspheres with an ultra-high holmium content were prepared. These microspheres are suitable for radioablation of tumors by intratumoral injections or treatment of liver tumors through transcatheter administration.

Intratumoral administration of Holmium-166 Acetylacetonate Microspheres: antitumor efficacy and feasibility of multimodality imaging in renal cancer

Purpose The increasing incidence of small renal tumors in an aging population with comorbidities has stimulated the development of minimally invasive treatments. This study aimed to assess the efficacy and demonstrate feasibility of multimodality imaging of intratumoral administration of holmium-166 microspheres (166HoAcAcMS). This new technique locally ablates renal tumors through high-energy beta particles, while the gamma rays allow for nuclear imaging and the paramagnetism of holmium allows for MRI. Methods 166HoAcAcMS were administered intratumorally in orthotopic renal tumors (Balb/C mice). Post administration CT, SPECT and MRI was performed. At several time points (2 h, 1, 2, 3, 7 and 14 days) after MS administration, tumors were measured and histologically analyzed. Holmium accumulation in organs was measured using inductively coupled plasma mass spectrometry. Results 166HoAcAcMS were successfully administered to tumor bearing mice. A striking near-complete tumor-control was observed in 166HoAcAcMS treated mice (0.10±0.01 cm3 vs. 4.15±0.3 cm3 for control tumors). Focal necrosis and inflammation was present from 24 h following treatment. Renal parenchyma outside the radiated region showed no histological alterations. Post administration CT, MRI and SPECT imaging revealed clear deposits of 166HoAcAcMS in the kidney. Conclusions Intratumorally administered 166HoAcAcMS has great potential as a new local treatment of renal tumors for surgically unfit patients. In addition to strong cancer control, it provides powerful multimodality imaging opportunities.