Effect of MRI acquisition acceleration via compressed sensing and parallel imaging on brain volumetry.

OBJECTIVES: To investigate the effect of compressed SENSE (CS), an acceleration technique combining parallel imaging and compressed sensing, on potential bias and precision of brain volumetry and evaluate it in the context of normative brain volumetry. MATERIALS AND METHODS: In total, 171 scans from scan-rescan experiments on three healthy subjects were analyzed. Each subject received 3D-T1-weighted brain MRI scans at increasing degrees of acceleration (CS-factor = 1/4/8/12/16/20/32). Single-scan acquisition times ranged from 00:41 min (CS-factor = 32) to 21:52 min (CS-factor = 1). Brain segmentation and volumetry was performed using two different software tools: md.brain, a proprietary software based on voxel-based morphometry, and FreeSurfer, an open-source software based on surface-based morphometry. Four sub-volumes were analyzed: brain parenchyma (BP), total gray matter, total white matter, and cerebrospinal fluid (CSF). Coefficient of variation (CoV) of the repeated measurements as a measure of intra-subject reliability was calculated. Intraclass correlation coefficient (ICC) with regard to increasing CS-factor was calculated as another measure of reliability. Noise-to-contrast ratio as a measure of image quality was calculated for each dataset to analyze the association between acceleration factor, noise and volumetric brain measurements. RESULTS: For all sub-volumes, there is a systematic bias proportional to the CS-factor which is dependent on the utilized software and subvolume. Measured volumes deviated significantly from the reference standard (CS-factor = 1), e.g. ranging from 1 to 13% for BP. The CS-induced systematic bias is driven by increased image noise. Except for CSF, reliability of brain volumetry remains high, demonstrated by low CoV (< 1% for CS-factor up to 20) and good to excellent ICC for CS-factor up to 12. CONCLUSION: CS-acceleration has a systematic biasing effect on volumetric brain measurements.

Time-resolved monitoring of enzyme activity with ultrafast Hyper-CEST spectroscopy.

We propose a method to dynamically monitor the progress of an enzymatic reaction using NMR of hyperpolarized 129 Xe in a host-guest system. It is based on a displacement assay originally designed for fluorescence experiments that exploits the competitive binding of the enzymatic product on the one hand and a reporter dye on the other hand to a supramolecular host. Recently, this assay has been successfully transferred to NMR, using xenon as a reporter, cucurbit[6]uril as supramolecular host, and chemical exchange saturation transfer with hyperpolarized Xe (Hyper-CEST) as detection technique. Its advantage is that the enzyme acts on the unmodified substrate and that only the product is detected through immediate inclusion into the host. We here apply a method that drastically accelerates the acquisition of Hyper-CEST spectra in vitro using magnetic field gradients. This allows monitoring the dynamic progress of the conversion of lysine to cadaverine with a temporal resolution of ~30 s. Moreover, the method only requires to sample the very early onset of the reaction (<0.5% of substrate conversion where the host itself is required only at µM concentrations) at comparatively low reaction rates, thus saving enzyme material and reducing NMR acquisition time. The obtained value for the specific activity agrees well with previously published results from fluorescence assays. We furthermore outline how the Hyper-CEST results correlate with xenon T2 measurements performed during the enzymatic reaction. This suggests that ultrafast Hyper-CEST spectroscopy can be used for dynamically monitoring enzymatic activity with NMR.

Supramolecular Assays for Mapping Enzyme Activity by Displacement-Triggered Change in Hyperpolarized (129)Xe Magnetization Transfer NMR Spectroscopy.

Reversibly bound Xe is a sensitive NMR and MRI reporter with its resonance frequency being influenced by the chemical environment of the host. Molecular imaging of enzyme activity presents a promising approach for disease identification, but current Xe biosensing concepts are limited since substrate conversion typically has little impact on the chemical shift of Xe inside tailored cavities. Herein, we exploit the ability of the product of the enzymatic reaction to bind itself to the macrocyclic hosts CB6 and CB7 and thereby displace Xe. We demonstrate the suitability of this method to map areas of enzyme activity through changes in magnetization transfer with hyperpolarized Xe under different saturation scenarios.

Ultrafast CEST imaging.

We describe a new MR imaging method for the rapid characterization or screening of chemical exchange saturation transfer (CEST) contrast agents. It is based on encoding the chemical shift dimension with an additional gradient as proposed in previous ultrafast CEST spectroscopy approaches, but extends these with imaging capabilities. This allows us to investigate multiple compounds simultaneously with an arbitrary sample tube arrangement. The technique requires a fast multislice readout to ensure the saturation is not lost during data acquisition due to T1 relaxation. We therefore employ radial subsampling, acquiring only 10 projections per CEST image with a 128×128 matrix. To recover the images, we use a heuristic reconstruction algorithm that incorporates low rank and limited object support as prior knowledge. This way, we are able to acquire a spectral CEST data set consisting of 15 saturation offsets more than 16 times faster than compared with conventional CEST imaging.

Sensitivity enhancement of (Hyper-)CEST image series by exploiting redundancies in the spectral domain.

CEST has proven to be a valuable technique for the detection of hyperpolarized xenon-based functionalized contrast agents. Additional information can be encoded in the spectral dimension, allowing the simultaneous detection of multiple different biosensors. However, owing to the low concentration of dissolved xenon in biological tissue, the signal-to-noise ratio (SNR) of Hyper-CEST data is still a critical issue. In this work, we present two techniques aiming to increase SNR by exploiting the typically high redundancy in spectral CEST image series: PCA-based post-processing and sub-sampled acquisition with low-rank reconstruction. Each of them yields a significant SNR enhancement, demonstrating the feasibility of the two approaches. While the first method is directly applicable to proton CEST experiments as well, the second one is particularly beneficial when dealing with hyperpolarized nuclei, since it distributes the non-renewable initial polarization more efficiently over the sampling points. The results obtained are a further step towards the detection of xenon biosensors with spectral Hyper-CEST imaging in vivo.

Fast gradient-encoded CEST spectroscopy of hyperpolarized xenon.

Breaking speed limits: The acquisition of xenon-129 Hyper-CEST spectra is drastically accelerated by utilizing gradients to encode the chemical shift dimension. The signal is increased by using repeated spin-echo refocussing. The additional application of a variable flip angle makes the experiment independent from a constant Xe redelivery.

Cell tracking with caged xenon: using cryptophanes as MRI reporters upon cellular internalization.

Caged xenon has great potential in overcoming sensitivity limitations for solution-state NMR detection of dilute molecules. However, no application of such a system as a magnetic resonance imaging (MRI) contrast agent has yet been performed with live cells. We demonstrate MRI localization of cells labeled with caged xenon in a packed-bed bioreactor working under perfusion with hyperpolarized-xenon-saturated medium. Xenon hosts enable NMR/MRI experiments with switchable contrast and selectivity for cell-associated versus unbound cages. We present MR images with 10(3) -fold sensitivity enhancement for cell-internalized, dual-mode (fluorescence/MRI) xenon hosts at low micromolar concentrations. Our results illustrate the capability of functionalized xenon to act as a highly sensitive cell tracer for MRI detection even without signal averaging. The method will bridge the challenging gap for translation to in vivo studies for the optimization of targeted biosensors and their multiplexing applications.

Slice-selective gradient-encoded CEST spectroscopy for monitoring dynamic parameters and high-throughput sample characterization.

Chemical Exchange Saturation Transfer (CEST) NMR is an increasingly used technique for generating molecule or microenvironment specific signal contrast. To characterize CEST agents and to extract parameters such as temperature and pH, it is often required to resolve the spectral dimension. This is achieved by recording so called CEST- or z-spectra, where the spectral CEST information is conventionally acquired point by point, leading to long acquisition times. Here, we employ gradient-encoding to substantially accelerate the acquisition process of z-spectra in phantom experiments, reducing it to only two scans. This speedup allows us to monitor dynamic processes such as rapid temperature changes in a PARACEST sample that would be inaccessible with the conventional encoding. Furthermore, we combine the gradient-encoding approach with multi-slice selection, thus reserving one spatial dimension for the simultaneous investigation of heterogeneous PARACEST sample packages within one experiment. Hence, gradient-encoded CEST might be of great use for high-throughput screening of CEST contrast agents.

Characterization of a chip-based bioreactor for three-dimensional cell cultivation via Magnetic Resonance Imaging.

We describe the characterization of a chip-based platform (3(D)-KITChip) for the three-dimensional cultivation of cells under perfusion conditions via magnetic resonance imaging (MRI). Besides the chip, the microfluidic system is comprised of a bioreactor housing, a medium supply, a pump for generating active flow conditions as well as a gas mixing station. The closed circulation loop is ideally suited for a characterization via MRI since the small bioreactor setup with active perfusion, driven by the pump from outside the coils, not only is completely MRI-compatible but also can be transferred into the magnetic coil of an experimental animal scanner. We have found that the two halves of the chip inside the bioreactor are homogeneously perfused with cell culture medium both with and without cells inside the 3(D)-KITChip. In addition, the homogeneity of perfusion is nearly independent from the flow rates investigated in this study, and furthermore, the setup shows excellent washout characteristics after spiking with Gadolinium-DOTA which makes it an ideal candidate for drug screening purposes. We, therefore, conclude that the 3(D)-KITChip is well suited as a platform for high-density three-dimensional cell cultures, especially those requiring a defined medium flow and/or gas supply in a precisely controllable three dimensional environment, like stem cells.

Hyperpolarized xenon for NMR and MRI applications.

Nuclear magnetic resonance (NMR) spectroscopy and imaging (MRI) suffer from intrinsic low sensitivity because even strong external magnetic fields of ~10 T generate only a small detectable net-magnetization of the sample at room temperature (1). Hence, most NMR and MRI applications rely on the detection of molecules at relative high concentration (e.g., water for imaging of biological tissue) or require excessive acquisition times. This limits our ability to exploit the very useful molecular specificity of NMR signals for many biochemical and medical applications. However, novel approaches have emerged in the past few years: Manipulation of the detected spin species prior to detection inside the NMR/MRI magnet can dramatically increase the magnetization and therefore allows detection of molecules at much lower concentration (2). Here, we present a method for polarization of a xenon gas mixture (2-5% Xe, 10% N2, He balance) in a compact setup with a ca. 16000-fold signal enhancement. Modern line-narrowed diode lasers allow efficient polarization (7) and immediate use of gas mixture even if the noble gas is not separated from the other components. The SEOP apparatus is explained and determination of the achieved spin polarization is demonstrated for performance control of the method. The hyperpolarized gas can be used for void space imaging, including gas flow imaging or diffusion studies at the interfaces with other materials (8,9). Moreover, the Xe NMR signal is extremely sensitive to its molecular environment (6). This enables the option to use it as an NMR/MRI contrast agent when dissolved in aqueous solution with functionalized molecular hosts that temporarily trap the gas (10,11). Direct detection and high-sensitivity indirect detection of such constructs is demonstrated in both spectroscopic and imaging mode.

Investigation of prostate cancer using diffusion-weighted intravoxel incoherent motion imaging.

PURPOSE: The objective of this work was to evaluate the diagnostic performance of the intravoxel incoherent motion (IVIM) model to differentiate between healthy and malignant prostate tissue. MATERIALS AND METHODS: Regions of interest were drawn in healthy and cancerous tissue of 13 patients with histologically proven prostate carcinoma and fitted to a monoexponential model [yielding the apparent diffusion coefficient (ADC)] and the IVIM signal equation (yielding the perfusion fraction f, the diffusion constant D and the pseudodiffusion coefficient of perfusion D⁎). Parameter maps were calculated for all parameters. RESULTS: The ADC, D and f were significantly (P<.005) lowered in cancerous tissue (1.01±0.22 µm(2)/ms, 0.84±0.19 µm(2)/ms and 14.27±7.10%, respectively) compared to benign tissue (1.49±0.17 µm(2)/ms, 1.21±0.22 µm(2)/ms and 21.25±8.32%, respectively). Parameter maps of D and f allowed for a delineation of the tumor, but showed higher variations compared to the ADC map. CONCLUSION: Apparent diffusion coefficient maps provide better diagnostic performance than IVIM maps for tumor detection. However, the results suggest that the reduction of the ADC in prostate cancer stems not only from changes in cellularity but also from perfusion effects. IVIM imaging might hold promise for the diagnosis of other prostatic lesions.