Deuterium metabolic imaging of the human brain in vivo at 7 T.

PURPOSE: To explore the potential of deuterium metabolic imaging (DMI) in the human brain in vivo at 7 T, using a multi-element deuterium (2 H) RF coil for 3D volume coverage. METHODS: 1 H-MR images and localized 2 H MR spectra were acquired in vivo in the human brain of 3 healthy subjects to generate DMI maps of 2 H-labeled water, glucose, and glutamate/glutamine (Glx). In addition, non-localized 2 H-MR spectra were acquired both in vivo and in vitro to determine T1 and T2 relaxation times of deuterated metabolites at 7 T. The performance of the 2 H coil was assessed through numeric simulations and experimentally acquired B1 + maps. RESULTS: 3D DMI maps covering the entire human brain in vivo were obtained from well-resolved deuterated (2 H) metabolite resonances of water, glucose, and Glx. The T1 and T2 relaxation times were consistent with those reported at adjacent field strengths. Experimental B1 + maps were in good agreement with simulations, indicating efficient and homogeneous B1 + transmission and low RF power deposition for 2 H, consistent with a similar array coil design reported at 9.4 T. CONCLUSION: Here, we have demonstrated the successful implementation of 3D DMI in the human brain in vivo at 7 T. The spatial and temporal nominal resolutions achieved at 7 T (i.e., 2.7 mL in 28 min, respectively) were close to those achieved at 9.4 T and greatly outperformed DMI at lower magnetic fields. DMI at 7 T and beyond has clear potential in applications dealing with small brain lesions.

Preclinical evaluation of a brain penetrant PARP PET imaging probe in rat glioblastoma and nonhuman primates.

PURPOSE: Currently, there are multiple active clinical trials involving poly(ADP-ribose) polymerase (PARP) inhibitors in the treatment of glioblastoma. The noninvasive quantification of baseline PARP expression using positron emission tomography (PET) may provide prognostic information and lead to more precise treatment. Due to the lack of brain-penetrant PARP imaging agents, the reliable and accurate in vivo quantification of PARP in the brain remains elusive. Herein, we report the synthesis of a brain-penetrant PARP PET tracer, (R)-2-(2-methyl-1-(methyl-11C)pyrrolidin-2-yl)-1H-benzo[d]imidazole-4-carboxamide ([11C]PyBic), and its preclinical evaluations in a syngeneic RG2 rat glioblastoma model and healthy nonhuman primates. METHODS: We synthesized [11C]PyBic using veliparib as the labeling precursor, performed dynamic PET scans on RG2 tumor-bearing rats and calculated the distribution volume ratio (DVR) using simplified reference region method 2 (SRTM2) with the contralateral nontumor brain region as the reference region. We performed biodistribution studies, western blot, and immunostaining studies to validate the in vivo PET quantification results. We characterized the brain kinetics and binding specificity of [11C]PyBic in nonhuman primates on FOCUS220 scanner and calculated the volume of distribution (VT), nondisplaceable volume of distribution (VND), and nondisplaceable binding potential (BPND) in selected brain regions. RESULTS: [11C]PyBic was synthesized efficiently in one step, with greater than 97% radiochemical and chemical purity and molar activity of 148 ± 85 MBq/nmol (n = 6). [11C]PyBic demonstrated PARP-specific binding in RG2 tumors, with 74% of tracer binding in tumors blocked by preinjected veliparib (i.v., 5 mg/kg). The in vivo PET imaging results were corroborated by ex vivo biodistribution, PARP1 immunohistochemistry and immunoblotting data. Furthermore, brain penetration of [11C]PyBic was confirmed by quantitative monkey brain PET, which showed high specific uptake (BPND > 3) and low nonspecific uptake (VND < 3 mL/cm3) in the monkey brain. CONCLUSION: [11C]PyBic is the first brain-penetrant PARP PET tracer validated in a rat glioblastoma model and healthy nonhuman primates. The brain kinetics of [11C]PyBic are suitable for noninvasive quantification of available PARP binding in the brain, which posits [11C]PyBic to have broad applications in oncology and neuroimaging.

Interleaved fluid-attenuated inversion recovery (FLAIR) MRI and deuterium metabolic imaging (DMI) on human brain in vivo.

PURPOSE: To integrate deuterium metabolic imaging (DMI) with clinical MRI through an interleaved MRI and DMI acquisition workflow. Interleaved MRI-DMI was enabled with hardware and pulse sequence modifications, and the performance was demonstrated using fluid-attenuated inversion recovery (FLAIR) MRI as an example. METHODS: Interleaved FLAIR-DMI was developed by interleaving the 2 H excitation and acquisition time windows into the intrinsic delay periods presented in the FLAIR method. All 2 H MR signals were up-converted to the 1 H Larmor frequency using a custom-built hardware unit, which also achieved frequency and phase locking of the output signal in real-time. The interleaved measurements were compared with direct measurements both in phantom and in the human brain in vivo. RESULTS: The interleaved MRI-DMI acquisition strategy allowed simultaneous detection of FLAIR MRI and DMI in the same scan time as a FLAIR-only MRI acquisition. Both phantom and in vivo data showed that the MR image quality, DMI sensitivity as well as information content were preserved using interleaved MRI-DMI. CONCLUSION: The interleaved MRI-DMI technology can be used to extend clinical MRI protocols with DMI, thereby offering a metabolic component to the MR imaging contrasts without a penalty on patient comfort or scan time.

Deuterium metabolic imaging in the human brain at 9.4 Tesla with high spatial and temporal resolution.

PURPOSE: To present first highly spatially resolved deuterium metabolic imaging (DMI) measurements of the human brain acquired with a dedicated coil design and a fast chemical shift imaging (CSI) sequence at an ultrahigh field strength of B0 = 9.4 T. 2H metabolic measurements with a temporal resolution of 10 min enabled the investigation of the glucose metabolism in healthy human subjects. METHODS: The study was performed with a double-tuned coil with 10 TxRx channels for 1H and 8TxRx/2Rx channels for 2H and an Ernst angle 3D CSI sequence with a nominal spatial resolution of 2.97 ml and a temporal resolution of 10 min. RESULTS: The metabolism of [6,6'-2H2]-labeled glucose due to the TCA cycle could be made visible in high resolution metabolite images of deuterated water, glucose and Glx over the entire human brain. CONCLUSION: X-nuclei MRSI as DMI can highly benefit from ultrahigh field strength enabling higher temporal and spatial resolutions.

NMR visibility of deuterium-labeled liver glycogen in vivo.

PURPOSE: Deuterium metabolic imaging (DMI) combined with [6,6'-2 H2 ]-glucose has the potential to detect glycogen synthesis in the liver. However, the similar chemical shifts of [6,6'-2 H2 ]-glucose and [6,6'-2 H2 ]-glycogen in the 2 H NMR spectrum make unambiguous detection and separation difficult in vivo, in contrast to comparable approaches using 13 C MRS. Here the NMR visibility of 2 H-labeled glycogen is investigated to better understand its potential contribution to the observed signal in liver following administration of [6,6'-2 H2 ]-glucose. METHODS: Mice were provided drinking water containing 2 H-labeled glucose. High-resolution NMR analyses was performed of isolated liver glycogen in solution, before and after the addition of the glucose-releasing enzyme amyloglucosidase. RESULTS: 2 H-labeled glycogen was barely detectable in solution using 2 H NMR because of the very short T2 (<2 ms) of 2 H-labeled glycogen, giving a spectral line width that is more than five times as broad as that of 13 C-labeled glycogen (T2 = ~10 ms). CONCLUSION: 2 H-labeled glycogen is not detectable with 2 H MRS(I) under in vivo conditions, leaving 13 C MRS as the preferred technique for in vivo detection of glycogen.

ECLIPSE utilizing gradient-modulated offset-independent adiabaticity (GOIA) pulses for highly selective human brain proton MRSI.

A multitude of extracranial lipid suppression methods exist for proton MRSI acquisitions. Popular and emerging lipid suppression methods each have their inherent set of advantages and disadvantages related to the achievable level of lipid suppression, RF power deposition, insensitivity to B1+ field and lipid T1 heterogeneity, brain coverage, spatial selectivity, chemical shift displacement (CSD) errors and the reliability of spectroscopic data spanning the observed 0.9-4.7 ppm band. The utility of elliptical localization with pulsed second order fields (ECLIPSE) was previously demonstrated with a greater than 100-fold in extracranial lipid suppression and low power requirements utilizing 3 kHz bandwidth AFP pulses. Like all gradient-based localization methods, ECLIPSE is sensitive to CSD errors, resulting in a modified metabolic profile in edge-of-ROI voxels. In this work, ECLIPSE is extended with 15 kHz bandwidth second order gradient-modulated RF pulses based on the gradient offset-independent adiabaticity (GOIA) algorithm to greatly reduce CSD and improve spatial selectivity. An adiabatic double spin-echo ECLIPSE inner volume selection (TE = 45 ms) MRSI method and an ECLIPSE outer volume suppression (TE = 3.2 ms) FID-MRSI method were implemented. Both GOIA-ECLIPSE MRSI sequences provided artifact-free metabolite spectra in vivo, with a greater than 100-fold in lipid suppression and less than 2.6 mm in-plane CSD and less than 3.3 mm transition width for edge-of-ROI voxels, representing an ~5-fold improvement compared with the parent, nongradient-modulated method. Despite the 5-fold larger bandwidth, GOIA-ECLIPSE only required a 1.9-fold increase in RF power. The highly robust lipid suppression combined with low CSD and sharp ROI edge transitions make GOIA-ECLIPSE an attractive alternative to commonly employed lipid suppression methods. Furthermore, the low RF power deposition demonstrates that GOIA-ECLIPSE is very well suited for high field (≥3 T) MRSI applications.

Robust outer volume suppression utilizing elliptical pulsed second order fields (ECLIPSE) for human brain proton MRSI.

PURPOSE: The robust and reliable utilization of proton magnetic resonance spectroscopic imaging (MRSI) at high fields is hampered by several key technical difficulties, including contamination from extracranial lipids. To that end, this work presents novel lipid suppression sequences for proton MRSI in the human brain utilizing elliptical localization with pulsed second-order fields (ECLIPSE). METHODS: Two lipid suppression methods were implemented with the ECLIPSE gradient insert. One method is a variable power, 4-pulse sequence optimized to achieve outer volume suppression (OVS) and compared against a standard, 8-slice OVS method. The second ECLIPSE method is implemented as an inversion recovery (IR) sequence with elliptical inner volume selection (IVS) and compared against a global IR method. RESULTS: The ECLIPSE-OVS sequence provided a 116-fold mean lipid suppression (range, 104-134), whereas an optimized 8-slice OVS sequence achieved 15-fold suppression (range, 13-18). Furthermore, the superior ECLIPSE-OVS suppression was achieved at 30% of the radiofrequency (RF) power required by 8-slice OVS. The ECLIPSE-based IR sequence suppressed skull lipids by 155-fold (range, 122-257), compared to 16-fold suppression (range, 14-19) achieved with IR. CONCLUSION: OVS and IVS executed with ECLIPSE provide robust and effective lipid suppression at reduced RF power with high immunity to variations in B1 and T1 .

On the magnetic field dependence of deuterium metabolic imaging.

Deuterium metabolic imaging (DMI) is a novel MR-based method to spatially map metabolism of deuterated substrates such as [6,6'-2 H2 ]-glucose in vivo. Compared with traditional 13 C-MR-based metabolic studies, the MR sensitivity of DMI is high due to the larger 2 H magnetic moment and favorable T1 and T2 relaxation times. Here, the magnetic field dependence of DMI sensitivity and transmit efficiency is studied on phantoms and rat brain postmortem at 4, 9.4 and 11.7 T. The sensitivity and spectral resolution on human brain in vivo are investigated at 4 and 7 T before and after an oral dose of [6,6'-2 H2 ]-glucose. For small animal surface coils (Ø 30 mm), the experimentally measured sensitivity and transmit efficiency scale with the magnetic field to a power of +1.75 and -0.30, respectively. These are in excellent agreement with theoretical predictions made from the principle of reciprocity for a coil noise-dominant regime. For larger human surface coils (Ø 80 mm), the sensitivity scales as a +1.65 power. The spectral resolution increases linearly due to near-constant linewidths. With optimal multireceiver arrays the acquisition of DMI at a nominal 1 mL spatial resolution is feasible at 7 T.

In vivo 13 C and 1 H-[13 C] MRS studies of neuroenergetics and neurotransmitter cycling, applications to neurological and psychiatric disease and brain cancer.

In the last 25 years 13 C MRS has been established as the only noninvasive method for measuring glutamate neurotransmission and cell specific neuroenergetics. Although technically and experimentally challenging 13 C MRS has already provided important new information on the relationship between neuroenergetics and neuronal function, the high energy cost of brain function in the resting state and the role of altered neuroenergetics and neurotransmitter cycling in disease. In this paper we review the metabolic and neurotransmitter pathways that can be measured by 13 C MRS and key findings on the linkage between neuroenergetics, neurotransmitter cycling, and brain function. Applications of 13 C MRS to neurological and psychiatric disease as well as brain cancer are reviewed. Recent technological developments that may help to overcome spatial resolution and brain coverage limitations of 13 C MRS are discussed.

In vivo proton observed carbon edited (POCE) 13 C magnetic resonance spectroscopy of the rat brain using a volumetric transmitter and receive-only surface coil on the proton channel.

PURPOSE: In vivo carbon-13 (13 C) MR spectroscopy (MRS) is capable of measuring energy metabolism and neuroenergetics, noninvasively in the brain. Indirect (1 H-[13 C]) MRS provides sensitivity benefits compared with direct 13 C methods, and normally includes a 1 H surface coil for both localization and signal reception. The aim was to develop a coil platform with homogenous B1+ and use short conventional pulses for short echo time proton observed carbon edited (POCE) MRS. METHODS: A 1 H-[13 C] MRS coil platform was designed with a volumetric resonator for 1 H transmit, and surface coils for 1 H reception and 13 C transmission. The Rx-only 1 H surface coil nullifies the requirement for a T/R switch before the 1 H preamplifier; the highpass filter and preamplifier can be placed proximal to the coil, thus minimizing sensitivity losses inherent with POCE-MRS systems described in the literature. The coil platform was evaluated with a PRESS-POCE sequence (TE = 12.6 ms) on a rat model. RESULTS: The coil provided excellent localization, uniform spin nutation, and sensitivity. 13 C labeling of Glu-H4 and Glx-H3 peaks, and the Glx-H2 peaks were observed approximately 13 and 21 min following the infusion of 1-13 C glucose, respectively. CONCLUSION: A convenient and sensitive platform to study energy metabolism and neurotransmitter cycling is presented. Magn Reson Med 79:628-635, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Selective proton-observed, carbon-edited (selPOCE) MRS method for measurement of glutamate and glutamine 13 C-labeling in the human frontal cortex.

PURPOSE: 13 C magnetic resonance spectroscopy (MRS) in combination with infusion of 13 C-labeled substrates has led to unique insights into human brain metabolism and neurotransmitter cycling. However, the low sensitivity of direct 13 C MRS and high radiofrequency power requirements has limited 13 C MRS studies to predominantly data acquisition in large volumes of the occipital cortex. The purpose of this study is to develop an MRS technique for localized detection of 13 C-labeling of glutamate and glutamine in the human frontal lobe. METHODS: We used an indirect (1 H-[13 C]), proton-observed, carbon-edited MRS sequence (selPOCE) for detection of 13 C-labeled metabolites in relatively small volumes located in the frontal lobe at 4 T. The SelPOCE method allows for selective and separate detection of glutamate and glutamine resonances, which significantly overlap at magnetic field strengths used for clinical MRI. RESULTS: Phantom data illustrate how selPOCE can be tuned to selectively detect 13 C labeling in different metabolites. Three-dimensional specific absorption rate simulations of radiofrequency power deposition show that the selPOCE method operates comfortably within the global and local Food and Drug Administration specific absorption rate guidelines. In vivo selPOCE data are presented, which were acquired from a 45-mL volume in the frontal lobe of healthy subjects. The in vivo data show the time-dependent 13 C-labeling of glutamate and glutamine during intravenous infusion of [1-13 C]-glucose. Metrics describing spectral fitting quality of the glutamate and glutamine resonances are reported. CONCLUSIONS: The SelPOCE sequence allows the detection of 13 C-labeling in glutamate and glutamine from a relatively small volume in the human frontal lobe at low radiofrequency power requirements. Magn Reson Med 80:11-20, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Elliptical localization with pulsed second-order fields (ECLIPSE) for robust lipid suppression in proton MRSI.

Proton MRSI has great clinical potential for metabolic mapping of the healthy and pathological human brain. Unfortunately, the promise has not yet been fully achieved due to numerous technical challenges related to insufficient spectral quality caused by magnetic field inhomogeneity, insufficient RF transmit power and incomplete lipid suppression. Here a robust, novel method for lipid suppression in 1 H MRSI is presented. The method is based on 2D spatial localization of an elliptical region of interest using pulsed second-order spherical harmonic (SH) magnetic fields. A dedicated, high-amplitude second-order SH gradient setup was designed and constructed, containing coils to generate Z2, X2Y2 and XY magnetic fields. Simulations and phantom MRI results are used to demonstrate the principles of the method and illustrate the manifestation of chemical shift displacement. 1 H MRSI on human brain in vivo demonstrates high quality, robust suppression of extracranial lipids. The method allows a wide range of inner or outer volume selection or suppression and should find application in MRSI, reduced-field-of-view MRI and single-volume MRS.

Detection of cerebral NAD+ in humans at 7T.

PURPOSE: To develop 1 H-based MR detection of nicotinamide adenine dinucleotide (NAD+ ) in the human brain at 7T and validate the 1 H results with NAD+ detection based on 31 P-MRS. METHODS: 1 H-MR detection of NAD+ was achieved with a one-dimensional double-spin-echo method on a slice parallel to the surface coil transceiver. Perturbation of the water resonance was avoided through the use of frequency-selective excitation. 31 P-MR detection of NAD+ was performed with an unlocalized pulse-acquire sequence. RESULTS: Both 1 H- and 31 P-MRS allowed the detection of NAD+ signals on every subject in 16 min. Spectral fitting provided an NAD+ concentration of 107 ± 28 µM for 1 H-MRS and 367 ± 78 µM and 312 ± 65 µM for 31 P-MRS when uridine diphosphate glucose (UDPG) was excluded and included, respectively, as an overlapping signal. CONCLUSIONS: NAD+ detection by 1 H-MRS is a simple method that comes at the price of reduced NMR visibility. NAD+ detection by 31 P-MRS has near-complete NMR visibility, but it is complicated by spectral overlap with NADH and UDPG. Overall, the 1 H- and 31 P-MR methods both provide exciting opportunities to study NAD+ metabolism on human brain in vivo. © 2016 International Society for Magnetic Resonance in Medicine. Magn Reson Med 78:828-835, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Imaging the intratumoral-peritumoral extracellular pH gradient of gliomas.

Solid tumors have an acidic extracellular pH (pHe ) but near neutral intracellular pH (pHi ). Because acidic pHe milieu is conducive to tumor growth and builds resistance to therapy, simultaneous mapping of pHe inside and outside the tumor (i.e., intratumoral-peritumoral pHe gradient) fulfills an important need in cancer imaging. We used Biosensor Imaging of Redundant Deviation in Shifts (BIRDS), which utilizes shifts of non-exchangeable protons from macrocyclic chelates (e.g., 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylene phosphonate) or DOTP(8-) ) complexed with paramagnetic thulium (Tm(3) (+) ) ion, to generate in vivo pHe maps in rat brains bearing 9L and RG2 tumors. Upon TmDOTP(5-) infusion, MRI identified the tumor boundary by enhanced water transverse relaxation and BIRDS allowed imaging of intratumoral-peritumoral pHe gradients. The pHe measured by BIRDS was compared with pHi measured with (31) P-MRS. In normal tissue, pHe was similar to pHi , but inside the tumor pHe was lower than pHi . While the intratumoral pHe was acidic for both tumor types, peritumoral pHe varied with tumor type. The intratumoral-peritumoral pHe gradient was much larger for 9L than RG2 tumors because in RG2 tumors acidic pHe was found in distal peritumoral regions. The increased presence of Ki-67 positive cells beyond the RG2 tumor border suggested that RG2 was more invasive than the 9L tumor. These results indicate that extensive acidic pHe beyond the tumor boundary correlates with tumor cell invasion. In summary, BIRDS has sensitivity to map the in vivo intratumoral-peritumoral pHe gradient, thereby creating preclinical applications in monitoring cancer therapeutic responses (e.g., with pHe -altering drugs). Copyright © 2016 John Wiley & Sons, Ltd.

High-sensitivity, broadband-decoupled (13) C MR spectroscopy in humans at 7T using two-dimensional heteronuclear single-quantum coherence.

PURPOSE: Carbon-13 ((13) C) magnetic resonance spectroscopy (MRS) has an intrinsically low NMR sensitivity that often leads to large acquisition volumes or long scan times. While the use of higher magnetic fields can overcome the sensitivity limitations, high radiofrequency (RF) power deposition associated with proton-decoupling limits the achievable gain. Two-dimensional (2D) heteronuclear single quantum coherence (HSQC) MRS is a method that uses the high chemical specificity of (13) C MRS while retaining the high sensitivity of (1) H detection. Due to the 2D nature of the method, proton-decoupled (13) C MR spectra can be obtained without the use of high-powered decoupling pulses. METHODS: A novel three-dimensional (3D) localized 2D HSQC method based on 3D STEAM localization is presented and implemented at 7T. The low RF power deposition of the method allows TR variation along the indirect dimension which, in combination with controlled aliasing, leads to an acceleration of 11.8 relative to a standard 2D NMR acquisition. RESULTS: Artifact-free, high-quality and high-sensitivity 2D HSQC spectra were obtained for all subjects in 19 min from a small (9 mL) volume placed in the leg adipose tissue. Complete proton decoupling was achieved along the indirect (13) C dimension despite the absence of broadband proton-decoupling pulses. The high chemical specificity along the indirect (13) C dimension allowed the detection of 19 unique resonances from which the lipids could be characterized in terms of saturation and omega-6/omega-3 fatty acid ratio. CONCLUSION: It has been demonstrated that high-quality 2D HSQC NMR spectra can be acquired from human adipose tissue at 7T. The HSQC method is methodologically simple and robust and is flexible regarding trade-offs between temporal and spectral resolution. 2D HSQC has a strong potential to become a default method in natural-abundance or (13) C-enriched studies of human metabolism in vivo.

Mapping of exogenous choline uptake and metabolism in rat glioblastoma using deuterium metabolic imaging (DMI).

Introduction: There is a lack of robust metabolic imaging techniques that can be routinely applied to characterize lesions in patients with brain tumors. Here we explore in an animal model of glioblastoma the feasibility to detect uptake and metabolism of deuterated choline and describe the tumor-to-brain image contrast. Methods: RG2 cells were incubated with choline and the level of intracellular choline and its metabolites measured in cell extracts using high resolution 1H NMR. In rats with orthotopically implanted RG2 tumors deuterium metabolic imaging (DMI) was applied in vivo during, as well as 1 day after, intravenous infusion of 2H9-choline. In parallel experiments, RG2-bearing rats were infused with [1,1',2,2'-2H4]-choline and tissue metabolite extracts analyzed with high resolution 2H NMR to identify molecule-specific 2H-labeling in choline and its metabolites. Results: In vitro experiments indicated high uptake and fast phosphorylation of exogenous choline in RG2 cells. In vivo DMI studies revealed a high signal from the 2H-labeled pool of choline + metabolites (total choline, 2H-tCho) in the tumor lesion but not in normal brain. Quantitative DMI-based metabolic maps of 2H-tCho showed high tumor-to-brain image contrast in maps acquired both during, and 24 h after deuterated choline infusion. High resolution 2H NMR revealed that DMI data acquired during 2H-choline infusion consists of free choline and phosphocholine, while the data acquired 24 h later represent phosphocholine and glycerophosphocholine. Discussion: Uptake and metabolism of exogenous choline was high in RG2 tumors compared to normal brain, resulting in high tumor-to-brain image contrast on DMI-based metabolic maps. By varying the timing of DMI data acquisition relative to the start of the deuterated choline infusion, the metabolic maps can be weighted toward detection of choline uptake or choline metabolism. These proof-of-principle experiments highlight the potential of using deuterated choline combined with DMI to metabolically characterize brain tumors.

Parallel detection of multi-contrast MRI and Deuterium Metabolic Imaging (DMI) for time-efficient characterization of neurological diseases.

Deuterium Metabolic Imaging (DMI) is a novel method that can complement traditional anatomical magnetic resonance imaging (MRI) of the brain. DMI relies on the MR detection of metabolites that become labeled with deuterium (2H) after administration of a deuterated substrate and can provide images with highly specific metabolic information. However, clinical adoption of DMI is complicated by its relatively long scan time. Here, we demonstrate a strategy to interleave DMI data acquisition with MRI that results in a comprehensive neuro-imaging protocol without adding scan time. The interleaved MRI-DMI routine includes four essential clinical MRI scan types, namely T1-weighted MP-RAGE, FLAIR, T2-weighted Imaging (T2W) and susceptibility weighted imaging (SWI), interwoven with DMI data acquisition. Phantom and in vivo human brain data show that MR image quality, DMI sensitivity, as well as information content are preserved in the MRI-DMI acquisition method. The interleaved MRI-DMI technology provides full flexibility to upgrade traditional MRI protocols with DMI, adding unique metabolic information to existing types of anatomical image contrast, without extra scan time.

Intrathecal delivery of nanoparticle PARP inhibitor to the cerebrospinal fluid for the treatment of metastatic medulloblastoma.

The morbidity associated with pediatric medulloblastoma, in particular in patients who develop leptomeningeal metastases, remains high in the absence of effective therapies. Administration of substances directly into the cerebrospinal fluid (CSF) is one approach to circumvent the blood-brain barrier and focus delivery of drugs to the site of tumor. However, high rates of CSF turnover prevent adequate drug accumulation and lead to rapid systemic clearance and toxicity. Here, we show that PLA-HPG nanoparticles, made with a single-emulsion, solvent evaporation process, can encapsulate talazoparib, a PARP inhibitor (BMN-673). These degradable polymer nanoparticles improve the therapeutic index when delivered intrathecally and lead to sustained drug retention in the tumor as measured with PET imaging and fluorescence microscopy. We demonstrate that administration of these particles into the CSF, alone or in combination with systemically administered temozolomide, is a highly effective therapy for tumor regression and prevention of leptomeningeal spread in xenograft mouse models of medulloblastoma. These results provide a rationale for harnessing nanoparticles for the delivery of drugs limited by brain penetration and therapeutic index and demonstrate important advantages in tolerability and efficacy for encapsulated drugs delivered locoregionally.

In vivo imaging of cerebral glucose metabolism informs on subacute to chronic post-stroke tissue status - A pilot study combining PET and deuterium metabolic imaging.

Recanalization therapy after acute ischemic stroke enables restoration of cerebral perfusion. However, a significant subset of patients has poor outcome, which may be caused by disruption of cerebral energy metabolism. To assess changes in glucose metabolism subacutely and chronically after recanalization, we applied two complementary imaging techniques, fluorodeoxyglucose (FDG) positron emission tomography (PET) and deuterium (2H) metabolic imaging (DMI), after 60-minute transient middle cerebral artery occlusion (tMCAO) in C57BL/6 mice. Glucose uptake, measured with FDG PET, was reduced at 48 hours after tMCAO and returned to baseline value after 11 days. DMI revealed effective glucose supply as well as elevated lactate production and reduced glutamate/glutamine synthesis in the lesion area at 48 hours post-tMCAO, of which the extent was dependent on stroke severity. A further decrease in oxidative metabolism was evident after 11 days. Immunohistochemistry revealed significant glial activation in and around the lesion, which may play a role in the observed metabolic profiles. Our findings indicate that imaging (altered) active glucose metabolism in and around reperfused stroke lesions can provide substantial information on (secondary) pathophysiological changes in post-ischemic brain tissue.

Myofibrillar distribution of succinate dehydrogenase activity and lipid stores differs in skeletal muscle tissue of paraplegic subjects.

Lack of physical activity has been related to an increased risk of developing insulin resistance. This study aimed to assess the impact of chronic muscle deconditioning on whole body insulin sensitivity, muscle oxidative capacity, and intramyocellular lipid (IMCL) content in subjects with paraplegia. Nine subjects with paraplegia and nine able-bodied, lean controls were recruited. An oral glucose tolerance test was performed to assess whole body insulin sensitivity. IMCL content was determined both in vivo and in vitro using (1)H-magnetic resonance spectroscopy and fluorescence microscopy, respectively. Muscle biopsy samples were stained for succinate dehydrogenase (SDH) activity to measure muscle fiber oxidative capacity. Subcellular distributions of IMCL and SDH activity were determined by defining subsarcolemmal and intermyofibrillar areas on histological samples. SDH activity was 57 ± 14% lower in muscle fibers derived from subjects with paraplegia when compared with controls (P < 0.05), but IMCL content and whole body insulin sensitivity did not differ between groups. In muscle fibers taken from controls, both SDH activity and IMCL content were higher in the subsarcolemmal region than in the intermyofibrillar area. This typical subcellular SDH and IMCL distribution pattern was lost in muscle fibers collected from subjects with paraplegia and had changed toward a more uniform distribution. In conclusion, the lower metabolic demand in deconditioned muscle of subjects with paraplegia results in a significant decline in muscle fiber oxidative capacity and is accompanied by changes in the subcellular distribution patterns of SDH activity and IMCL. However, loss of muscle activity due to paraplegia is not associated with substantial lipid accumulation in skeletal muscle tissue.