Glymphatic-assisted perivascular brain delivery of intrathecal small gold nanoparticles.

Nanoparticles are ultrafine particulate matter having considerable potential for treatment of central nervous system (CNS) disorders. Despite their tiny size, the blood-brain barrier (BBB) restricts their access to the CNS. Their direct cerebrospinal fluid (CSF) administration bypasses the BBB endothelium, but still fails to give adequate brain uptake. We present a novel approach for efficient CNS delivery of 111In-radiolabelled gold nanoparticles (AuNPs; 10-15 nm) via intra-cisterna magna administration, with tracking by SPECT imaging. To accelerate CSF brain influx, we administered AuNPs intracisternally in conjunction with systemic hypertonic saline, which dramatically increased the parenchymal AuNP uptake, especially in deep brain regions. AuNPs entered the CNS along periarterial spaces as visualized by MRI of gadolinium-labelled AuNPs and were cleared from brain within 24 h and excreted through the kidneys. Thus, the glymphatic-assisted perivascular network augment by systemic hypertonic saline is a pathway for highly efficient brain-wide distribution of small AuNPs.

EXIRAD-3D: Fast automated three-dimensional autoradiography.

INTRODUCTION: Autoradiography is an established technique for high-resolution imaging of radiolabelled molecules in biological tissue slices. Unfortunately, creating a 3D image from a set of these 2D images is extremely time-consuming and error-prone. MicroSPECT systems provide such 3D images but have a low resolution. Here we present EXIRAD-3D, a fast automated method as an alternative for 3D autoradiography from coupes based on ultra-high resolution microSPECT technology. METHODS: EXIRAD-3D uses a very small bore focusing multi-pinhole collimator mounted in a SPECT system with stationary detectors (U-SPECT/CT, MILabs B.V. The Netherlands) using a sample holder with integrated tissue cooling to avoid activity leaking or tissue deformation during the scan. The system performance was experimentally evaluated using various phantoms and tissue samples of animals in vivo injected with technetium-99m and iodine-123. RESULTS: The reconstructed spatial resolution obtained with a Derenzo hot rod phantom was 120 µm (or 1.7 nl). The voxel values of a syringe phantom image appear to be uniform and scale linearly with activity. Uptake in tiny details of the mouse knee joint, thyroid, and kidney could be clearly visualized. CONCLUSION: EXIRAD-3D opens up the possibility for fast and quantitative 3D imaging of radiolabelled molecules at a resolution far better than in vivo microSPECT and saves tremendous amounts of work compared to obtaining 3D data from a set of 2D autoradiographs. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: EXIRAD-3D offers superior image resolution over microSPECT, and it can be a very efficient alternative for autoradiography in pharmaceutical and biological studies.

Accelerated image reconstruction by a combined dual-matrix dual-voxel approach.

Today, versatile emission computed tomography (VECTor) technology using dedicated high-energy collimation enables simultaneous positron emission tomography (PET) and single photon emission computed tomography (SPECT) down to 0.6 mm and 0.4 mm resolution in mice, respectively. We recently showed that for optimal resolution and quantitative accuracy of PET images the long tails of the 511 keV point spread functions (PSFs) need to be fully modelled during image reconstruction. This, however, leads to very time consuming reconstructions and thus significant acceleration in reconstruction speed is highly desirable. To this end we propose and validate a combined dual-matrix dual-voxel (DM-DV) approach: for the forward projection the slowly varying PSF tails are modelled on a three times rougher voxel grid than the central parts of the PSFs, while in the backprojection only parts of the PSF tails are included. DM-DV reconstruction is implemented in pixel-based ordered subsets expectation maximization (POSEM) and in a recently proposed accelerated pixel-based similarity-regulated ordered subsets expectation maximization (SROSEM). Both a visual assessment and a quantitative contrast-noise analysis confirm that images of a hot-rod phantom are practically identical when reconstructed with standard POSEM, DM-DV-POSEM or DM-DV-SROSEM. However, compared to POSEM, DM-DV-POSEM can reach the same contrast 5.0 times faster, while with DM-DV-SROSEM this acceleration factor increases to 11.5. Furthermore, mouse cardiac and bone images reconstructed with DM-DV-SROSEM are visually almost indistinguishable from POSEM reconstructed images but typically need an order of magnitude less reconstruction time.

Evaluation of pinhole collimator materials for micron-resolution ex vivo SPECT.

Pinhole collimation is widely recognized for offering superior resolution-sensitivity trade-off in SPECT imaging of small subjects. The newly developed EXIRAD-3D autoradiography technique (MILabs B.V.) based on a highly focusing multi-pinhole collimator achieves micron-resolution SPECT for cryo-cooled tissue samples. For such high resolutions, the choice of pinhole material may have a significant impact on images. Therefore, this paper aims to compare the performance of EXIRAD-3D with lead, tungsten, gold, and depleted uranium pinhole collimators designed such that they achieve equal sensitivities. Performance in terms of resolution is characterized for several radioisotopes, namely 111In (171 keV and 245 keV), 99mTc (140 keV), 201Tl (71 keV), and 125I (27 keV). Using Monte Carlo simulation, point spread functions were generated and their profiles as well as their full-width-at-half-maximum and full-width-at-tenth-maximum were determined and evaluated for different materials and isotopes. Additionally, simulated reconstructions of a Derenzo resolution phantom, validated with experimental data, were judged by assessment of the resolvable rods as well as a contrast-to-noise ratio (CNR) analysis. Our results indicate that using materials with higher photon-stopping power yields images with better CNR for the studied isotopes with improvements ranging from 1.9% to 36.6%. Visual assessment on the reconstructed images suggests that for EXIRAD-3D, the tungsten collimator is generally a good choice for a wide range of SPECT isotopes. For relatively high-energy isotopes such as 111In, using gold inserts can be beneficial.

Comparison of methods for thyroid volume estimation in patients with Graves' disease.

Individualised dosage models are frequently applied for radioiodine therapy in patients with Graves' hyperthyroidism, especially in Europe. In these dosage schemes the thyroid volume is an important parameter. Thyroid volume determinations are usually made with ultrasonography or with thyroid scintigraphy, although the accuracy of planar scintigraphy for this purpose is not well established. The aim of this study was to compare the accuracy of three modalities for the determination of the thyroid volume in patients with Graves' disease: planar scintigraphy (PS), single-photon emission tomography (SPET) and ultrasonography (US). These three modalities were compared with magnetic resonance imaging (MRI) as the gold standard. Thyroid volume estimations were performed in 25 patients with Graves' disease. The PS images were subjected to filtering and thresholding, and a standard surface formula was used to calculate the thyroid volume. With SPET the iteratively reconstructed thyroid images were filtered, and after applying a threshold method an automatic segmentation algorithm was used for the volume determinations. Thyroid volumes were estimated from the US images using the ellipsoid volume model for multiple two-dimensional measurements. For MRI, thyroid segmentation was performed manually in gadolinium-enhanced T1-weighted images and a summation-of-areas technique was used for the volume measurements. The thyroid volumes calculated with MRI were 25.0+/-13.8 ml (mean+/-SD, range 7.0-56.3 ml). PS correlated poorly with MRI ( R(2)=0.61) and suffered from a considerable bias (-4.0+/-17.6 ml). The differences between PS and MRI volume estimations had a very large spread (33+/-58%). For SPET both the correlation with MRI ( R(2)=0.84) and the bias (1.8+/-11.9 ml) were better than for PS. US had by far the best correlation with MRI ( R(2)=0.97) and the best precision, but the bias (6.8+/-7.5 ml) was not negligible. In conclusion, SPET is preferred over PS for accurate measurements of thyroid volume. US is the most accurate of the three modalities, if a correction is made for bias.