Boris Keil

The Human Connectome Project and beyond: initial applications of 300 mT/m gradients.

The engineering of a 3 T human MRI scanner equipped with 300 mT/m gradients - the strongest gradients ever built for an in vivo human MRI scanner - was a major component of the NIH Blueprint Human Connectome Project (HCP). This effort was motivated by the HCPs goal of mapping, as completely as possible, the macroscopic structural connections of the in vivo healthy, adult human brain using diffusion tractography. Yet, the 300 mT/m gradient system is well suited to many additional types of diffusion measurements. Here, we present three initial applications of the 300 mT/m gradients that fall outside the immediate scope of the HCP. These include: 1) diffusion tractography to study the anatomy of consciousness and the mechanisms of brain recovery following traumatic coma; 2) q-space measurements of axon diameter distributions in the in vivo human brain and 3) postmortem diffusion tractography as an adjunct to standard histopathological analysis. We show that the improved sensitivity and diffusion-resolution provided by the gradients are rapidly enabling human applications of techniques that were previously possible only for in vitro and animal models on small-bore scanners, thereby creating novel opportunities to map the microstructure of the human brain in health and disease.

Exendin-4–Based Radiopharmaceuticals for Glucagonlike Peptide-1 Receptor PET/CT and SPECT/CT

Strong overexpression of glucagonlike peptide-1 (GLP-1) receptors in human insulinoma provides an attractive target for imaging. The first clinical trials demonstrated that GLP-1 receptor SPECT/CT using [Lys40(Ahx [6-aminohexanoic acid]-DOTA-111In)NH2]-exendin-4 can localize hardly detectable insulinomas. However, [Lys40(Ahx-DOTA-111In)NH2]-exendin-4 imaging has drawbacks related to the use of 111In in that it is costly and carries a relatively high radiation burden for the patient. The aim of this study was the preclinical evaluation of [Lys40(Ahx-DOTA-68Ga)NH2]-exendin-4 for PET/CT and [Lys40(Ahx-hydrazinonicotinamide [HYNIC]-99mTc)NH2]-exendin-4 for SPECT/CT. Methods: Internalization, biodistribution, dosimetry, and imaging studies were performed in the Rip1Tag2 mouse model of pancreatic β-cell carcinogenesis and compared with our gold standard [Lys40(Ahx-DOTA-111In)NH2]-exendin-4. Poly-glutamic acid and Gelofusine, a gelatin-based plasma expander, were used for renal uptake reduction studies. Results: The tumor uptake of [Lys40(Ahx-DOTA-68Ga)NH2]-exendin-4 was 205 ± 59 percentage injected activity per gram of tissue at 4 h. Other GLP-1 receptor–positive organs showed more than 4.8 times lower radioactivity uptake. [Lys40(Ahx-HYNIC-99mTc/ethylenediaminediacetic acid [EDDA])NH2]-exendin-4, compared with its 111In- and 68Ga-labeled sister compounds, showed significantly less tumor and organ uptake. The significantly lower tumor and organ uptake of [Lys40(Ahx-HYNIC-99mTc/EDDA)NH2]-exendin-4 did not result in inferior tumor-to-organ ratios or reduced image quality. All radiopeptides tested showed a high tumor-to-background ratio, resulting in the visualization of small tumors (maximum diameter between 1.0 and 3.2 mm) by SPECT and PET. The only exception was the kidneys, which also showed high uptake. This uptake could be reduced by 49%−78% using poly-glutamic acid, Gelofusine, or a combination of the 2. The estimated effective radiation dose was 3.7 μSv/MBq for [Lys40(Ahx-HYNIC-99mTc/EDDA)NH2]-exendin-4, which was 8 times less than that for [Lys40(Ahx-DOTA-68Ga)NH2]-exendin-4 and 43 times less than that for [Lys40(Ahx-DOTA-111In)NH2]-exendin-4. Conclusion: These promising pharmacokinetic and imaging data show that [Lys40(Ahx-DOTA-68Ga)NH2]-exendin-4 and [Lys40(Ahx-HYNIC-99mTc/EDDA)NH2]-exendin-4 are suitable candidates for clinical GLP-1 receptor imaging studies.

Deregulation of tumor angiogenesis and blockade of tumor growth in PPARβ-deficient mice

The peroxisome proliferator‐activated receptor‐β (PPARβ) has been implicated in tumorigenesis, but its precise role remains unclear. Here, we show that the growth of syngeneic Pparb wild‐type tumors is impaired in Pparb−/− mice, concomitant with a diminished blood flow and an abundance of hyperplastic microvascular structures. Matrigel plugs containing pro‐angiogenic growth factors harbor increased numbers of morphologically immature, proliferating endothelial cells in Pparb−/− mice, and retroviral transduction of Pparb triggers microvessel maturation. We have identified the Cdkn1c gene encoding the cell cycle inhibitor p57Kip2 as a PPARβ target gene and a mediator of the PPARβ‐mediated inhibition of cell proliferation, which provides a possible mechanistic explanation for the observed tumor endothelial hyperplasia and deregulation of tumor angiogenesis in Pparb−/− mice. Our data point to an unexpected essential role for PPARβ in constraining tumor endothelial cell proliferation to allow for the formation of functional tumor microvessels.

A 64-channel 3T array coil for accelerated brain MRI.

A 64‐channel brain array coil was developed and compared to a 32‐channel array constructed with the same coil former geometry to precisely isolate the benefit of the 2‐fold increase in array coil elements. The constructed coils were developed for a standard clinical 3T MRI scanner and used a contoured head‐shaped curved former around the occipital pole and tapered in at the neck to both improve sensitivity and patient comfort. Additionally, the design is a compact, split‐former design intended for robust daily use. Signal‐to‐noise ratio and noise amplification (G‐factor) for parallel imaging were quantitatively evaluated in human imaging and compared to a size and shape‐matched 32‐channel array coil. For unaccelerated imaging, the 64‐channel array provided similar signal‐to‐noise ratio in the brain center to the 32‐channel array and 1.3‐fold more signal‐to‐noise ratio in the brain cortex. Reduced noise amplification during highly parallel imaging of the 64‐channel array provided the ability to accelerate at approximately one unit higher at a given noise amplification compared to the sized‐matched 32‐channel array. For example, with a 4‐fold acceleration rate, the central brain and cortical signal‐to‐noise ratio of the 64‐channel array was 1.2‐ and 1.4‐fold higher, respectively, compared to the 32‐channel array. The characteristics of the coil are demonstrated in accelerated brain imaging. Magn Reson Med, 2013.

A new technique for in vivo imaging of specific GLP-1 binding sites: First results in small rodents

EXPERIMENTAL OBJECTIVES In vivo imaging of GLP-1 receptor-positive tissues may allow examination of physiologic and pathophysiologic processes. Based on the GLP-1 analog Exendin 4, we have developed a radiolabeled compound specifically targeting the GLP-1 receptor (DTPA-Lys40-Exendin 4). This work aims to detect GLP-1 receptor-positive tissues by biodistribution studies and in vivo small animal imaging studies. For in vivo imaging, a high-resolution multi-pinhole SPECT (single photon emission computed tomography) system was used in conjunction with an MRI (magnetic resonance imaging) system for image fusion. RESULTS DTPA-Lys40-Exendin 4 can be labeled with 111In to high specific activity (40 GBq/micromol). The radiochemical purity reliably exceeded 95%. Using this compound for in vivo small animal imaging of rats and mice as well as for biodistribution studies, specific GLP-1 binding sites could be detected in stomach, pancreas, lung, adrenals, and pituitary. Receptor-positive tissues were visualized with a high-resolution SPECT system with a resolution of less than 1 mm. CONCLUSIONS The new technique using DTPA-Lys40-Exendin 4 allows highly sensitive imaging of GLP-1 receptor-positive tissues in vivo. Therefore, intra-individual follow-up studies of GLP-1 receptor-positive tissue could be conducted in vivo.

Size-optimized 32-Channel Brain Arrays for 3 T Pediatric Imaging

Size‐optimized 32‐channel receive array coils were developed for five age groups, neonates, 6 months old, 1 year old, 4 years old, and 7 years old, and evaluated for pediatric brain imaging. The array consisted of overlapping circular surface coils laid out on a close‐fitting coil‐former. The two‐section coil former design was obtained from surface contours of aligned three‐dimensional MRI scans of each age group. Signal‐to‐noise ratio and noise amplification for parallel imaging were evaluated and compared to two coils routinely used for pediatric brain imaging; a commercially available 32‐channel adult head coil and a pediatric‐sized birdcage coil. Phantom measurements using the neonate, 6‐month‐old, 1‐year‐old, 4‐year‐old, and 7‐year‐old coils showed signal‐to‐noise ratio increases at all locations within the brain over the comparison coils. Within the brain cortex the five dedicated pediatric arrays increased signal‐to‐noise ratio by up to 3.6‐, 3.0‐, 2.6‐, 2.3‐, and 1.7‐fold, respectively, compared to the 32‐channel adult coil, as well as improved G‐factor maps for accelerated imaging. This study suggests that a size‐tailored approach can provide significant sensitivity gains for accelerated and unaccelerated pediatric brain imaging. Magn Reson Med, 2011.

Efficacy of 99mTc pertechnetate and 131I radioisotope therapy in sodium/iodide symporter (NIS)-expressing neuroendocrine tumors in vivo

PurposeThere is growing interest in the human sodium/iodide symporter (NIS) gene both as a molecular imaging reporter gene and as a therapeutic gene. Here, we show the feasibility of radioisotope therapy of neuroendocrine tumors. As a separate application of NIS gene transfer, we image NIS-expressing tumors with pinhole SPECT in living subjects.MethodsBiodistribution studies and in vivo therapy experiments were performed in nude mice carrying stably NIS-expressing neuroendocrine tumor xenografts following i.v. injection of 131I and 99mTc pertechnetate. To show the usefulness of NIS as an imaging reporter gene, 99mTc pertechnetate uptake was imaged in vivo using a clinical gamma camera in combination with a custom-made single pinhole collimator, followed by SPECT/small animal MRI data coregistration.ResultsNIS-expressing neuroendocrine tumors strongly accumulated 131I and 99mTc pertechnetate, as did thyroid, stomach, and salivary gland. The volume of NIS-expressing neuroendocrine tumors decreased significantly after therapeutic administration of 131I or 99mTc pertechnetate, whereas control tumors continued to grow. NIS-mediated uptake of 99mTc pertechnetate could be imaged in vivo at high resolution with a clinical gamma camera equipped with a custom-made single pinhole collimator. High-resolution functional and morphologic information could be combined in a single three-dimensional data set by coregistration of SPECT and small animal MRI data. Lastly, we demonstrated a therapeutic effect of 99mTc pertechnetate on NIS-expressing neuroendocrine tumors in cell culture and, for the first time, in vivo, thought to be due to emitted Auger and conversion electrons.ConclusionsNIS-expressing neuroendocrine tumors efficiently concentrate radioisotopes, allowing for in vivo high-resolution small animal SPECT imaging as well as rendering possible successful radioisotope therapy of neuroendocrine tumors.

MGH-USC Human Connectome Project datasets with ultra-high b-value diffusion MRI

The MGH-USC CONNECTOM MRI scanner housed at the Massachusetts General Hospital (MGH) is a major hardware innovation of the Human Connectome Project (HCP). The 3T CONNECTOM scanner is capable of producing a magnetic field gradient of up to 300 mT/m strength for in vivo human brain imaging, which greatly shortens the time spent on diffusion encoding, and decreases the signal loss due to T2 decay. To demonstrate the capability of the novel gradient system, data of healthy adult participants were acquired for this MGH-USC Adult Diffusion Dataset (N=35), minimally preprocessed, and shared through the Laboratory of Neuro Imaging Image Data Archive (LONI IDA) and the WU-Minn Connectome Database (ConnectomeDB). Another purpose of sharing the data is to facilitate methodological studies of diffusion MRI (dMRI) analyses utilizing high diffusion contrast, which perhaps is not easily feasible with standard MR gradient system. In addition, acquisition of the MGH-Harvard-USC Lifespan Dataset is currently underway to include 120 healthy participants ranging from 8 to 90 years old, which will also be shared through LONI IDA and ConnectomeDB. Here we describe the efforts of the MGH-USC HCP consortium in acquiring and sharing the ultra-high b-value diffusion MRI data and provide a report on data preprocessing and access. We conclude with a demonstration of the example data, along with results of standard diffusion analyses, including q-ball Orientation Distribution Function (ODF) reconstruction and tractography.

A 32‐channel combined RF and B0 shim array for 3T brain imaging

We add user‐controllable direct currents (DC) to the individual elements of a 32‐channel radio‐frequency (RF) receive array to provide B0 shimming ability while preserving the arrays reception sensitivity and parallel imaging performance.

Nineteen‐channel receive array and four‐channel transmit array coil for cervical spinal cord imaging at 7T

To design and validate a radiofrequency (RF) array coil for cervical spinal cord imaging at 7T.