Phosphorus metabolism in the brain of cognitively normal midlife individuals at risk for Alzheimer's disease.

Background: Neurometabolic abnormalities and amyloid-beta plaque deposition are important early pathophysiologic changes in Alzheimer's disease (AD). This study investigated the relationship between high-energy phosphorus-containing metabolites, glucose uptake, and amyloid plaque using phosphorus magnetic resonance spectroscopy (31P-MRS) and positron emission tomography (PET). Methods: We measured 31P-MRS, fluorodeoxyglucose (FDG)-PET, and Pittsburgh Compound B (PiB)-PET in a cohort of 20 cognitively normal middle-aged adults at risk for AD. We assessed 31P-MRS reliability by scanning a separate cohort of 13 healthy volunteers twice each. We calculated the coefficient-of-variation (CV) of metabolite ratios phosphocreatine-to-adenosine triphosphate (PCr/α-ATP), inorganic phosphate (Pi)-to-α-ATP, and phosphomonoesters-to-phosphodiesters (PME/PDE), and pH in pre-defined brain regions. We performed linear regression analysis to determine the relationship between 31P measurements and tracer uptake, and Dunn's multiple comparison tests to investigate regional differences in phosphorus metabolism. Finally, we performed linear regression analysis on 31P-MRS measurements in both cohorts to investigate the relationship of phosphorus metabolism with age. Results: Most regional 31P metabolite ratio and pH inter- and intra-day CVs were well below 10%. There was an inverse relationship between FDG-SUV levels and metabolite ratios PCr/α-ATP, Pi/α-ATP, and PME/PDE in several brain regions in the AD risk group. There were also several regional differences among 31P metabolites and pH in the AD risk group including elevated PCr/α-ATP, depressed PME/PDE, and elevated pH in the temporal cortices. Increased PCr/α-ATP throughout the brain was associated with aging. Conclusions: Phosphorus spectroscopy in the brain can be performed with high repeatability. Phosphorus metabolism varies with region and age, and is related to glucose uptake in adults at risk for AD. Phosphorus spectroscopy may be a valuable approach to study early changes in brain energetics in high-risk populations.

Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes.

Body fat distribution is a major, heritable risk factor for cardiometabolic disease, independent of overall adiposity. Using exome-sequencing in 618,375 individuals (including 160,058 non-Europeans) from the UK, Sweden and Mexico, we identify 16 genes associated with fat distribution at exome-wide significance. We show 6-fold larger effect for fat-distribution associated rare coding variants compared with fine-mapped common alleles, enrichment for genes expressed in adipose tissue and causal genes for partial lipodystrophies, and evidence of sex-dimorphism. We describe an association with favorable fat distribution (p = 1.8 × 10-09), favorable metabolic profile and protection from type 2 diabetes (~28% lower odds; p = 0.004) for heterozygous protein-truncating mutations in INHBE, which encodes a circulating growth factor of the activin family, highly and specifically expressed in hepatocytes. Our results suggest that inhibin ßE is a liver-expressed negative regulator of adipose storage whose blockade may be beneficial in fat distribution-associated metabolic disease.

Germline Mutations in CIDEB and Protection against Liver Disease.

BACKGROUND: Exome sequencing in hundreds of thousands of persons may enable the identification of rare protein-coding genetic variants associated with protection from human diseases like liver cirrhosis, providing a strategy for the discovery of new therapeutic targets. METHODS: We performed a multistage exome sequencing and genetic association analysis to identify genes in which rare protein-coding variants were associated with liver phenotypes. We conducted in vitro experiments to further characterize associations. RESULTS: The multistage analysis involved 542,904 persons with available data on liver aminotransferase levels, 24,944 patients with various types of liver disease, and 490,636 controls without liver disease. We found that rare coding variants in APOB, ABCB4, SLC30A10, and TM6SF2 were associated with increased aminotransferase levels and an increased risk of liver disease. We also found that variants in CIDEB, which encodes a structural protein found in hepatic lipid droplets, had a protective effect. The burden of rare predicted loss-of-function variants plus missense variants in CIDEB (combined carrier frequency, 0.7%) was associated with decreased alanine aminotransferase levels (beta per allele, -1.24 U per liter; 95% confidence interval [CI], -1.66 to -0.83; P = 4.8×10-9) and with 33% lower odds of liver disease of any cause (odds ratio per allele, 0.67; 95% CI, 0.57 to 0.79; P = 9.9×10-7). Rare coding variants in CIDEB were associated with a decreased risk of liver disease across different underlying causes and different degrees of severity, including cirrhosis of any cause (odds ratio per allele, 0.50; 95% CI, 0.36 to 0.70). Among 3599 patients who had undergone bariatric surgery, rare coding variants in CIDEB were associated with a decreased nonalcoholic fatty liver disease activity score (beta per allele in score units, -0.98; 95% CI, -1.54 to -0.41 [scores range from 0 to 8, with higher scores indicating more severe disease]). In human hepatoma cell lines challenged with oleate, CIDEB small interfering RNA knockdown prevented the buildup of large lipid droplets. CONCLUSIONS: Rare germline mutations in CIDEB conferred substantial protection from liver disease. (Funded by Regeneron Pharmaceuticals.).

Lower extremity MRI following 10-week supervised exercise intervention in patients with diabetic peripheral neuropathy.

INTRODUCTION: The purpose of this study was to characterize using MRI the effects of a 10-week supervised exercise program on lower extremity skeletal muscle composition, nerve microarchitecture, and metabolic function in individuals with diabetic peripheral neuropathy (DPN). RESEARCH DESIGN AND METHODS: Twenty participants with DPN completed a longitudinal trial consisting of a 30-day control period, during which subjects made no change to their lifestyle, followed by a 10-week intervention program that included three supervised aerobic and resistance exercise sessions per week targeting the upper and lower extremities. The participants' midcalves were scanned with multinuclear MRI two times prior to intervention (baseline1 and baseline2) and once following intervention to measure relaxation times (T1, T1ρ, and T2), phosphocreatine recovery, fat fraction, and diffusion parameters. RESULTS: There were no changes between baseline1 and baseline2 MRI metrics (p>0.2). Significant changes (p<0.05) between baseline2 and postintervention MRI metrics were: gastrocnemius medialis (GM) T1 -2.3%±3.0% and soleus T2 -3.2%±3.1%. Trends toward significant changes (0.050.3) and tibial nerve fractional anisotropy (p>0.6) and apparent diffusion coefficient (p>0.4). CONCLUSIONS: The 10-week supervised exercise intervention program successfully reduced adiposity and altered resting tissue properties in the lower leg in DPN. Gastrocnemius mitochondrial oxidative capacity and tibial nerve microarchitecture changes were not observed, either due to lack of response to therapy or to lack of measurement sensitivity.

Dynamic phosphocreatine imaging with unlocalized pH assessment of the human lower leg muscle following exercise at 3T.

PURPOSE: To develop a high temporal resolution imaging method that measures muscle-specific phosphocreatine (PCr) resynthesis time constant (τPCr ) and pH changes in muscles of the lower leg following exercise on a clinical 3T MRI scanner. METHODS: We developed a frequency-selective 3D non-Cartesian FLORET sequence to measure PCr with 17-mm nominal isotropic resolution (28 mm actual resolution) and 6-s temporal resolution to capture dynamic metabolic muscle activity. The sequence was designed to additionally collect inorganic phosphate spectra for pH quantification, which were localized using sensitivity profiles of individual coil elements. Nineteen healthy volunteers were scanned while performing a plantar flexion exercise on an in-house developed ergometer. Data were acquired with a dual-tuned multichannel coil array that enabled phosphorus imaging and proton localization for muscle segmentation. RESULTS: After a 90-s plantar flexion exercise at 0.66 Hz with resistance set to 40% of the maximum voluntary contraction, τPCr was estimated at 22.9 ± 8.8 s (mean ± standard deviation) with statistical coefficient of determination r2 = 0.89 ± 0.05. The corresponding pH values after exercise were in the range of 6.9-7.1 in the gastrocnemius muscle. CONCLUSION: The developed technique allows measurement of muscle-specific PCr resynthesis kinetics and pH changes following exercise, with a temporal resolution and accuracy comparable to that of single voxel 31 P-MRS sequences. Magn Reson Med 79:974-980, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Declining Skeletal Muscle Function in Diabetic Peripheral Neuropathy.

PURPOSE: The present review highlights current concepts regarding the effects of diabetic peripheral neuropathy (DPN) in skeletal muscle. It discusses the lack of effective pharmacologic treatments and the role of physical exercise intervention in limb protection and symptom reversal. It also highlights the importance of magnetic resonance imaging (MRI) techniques in providing a mechanistic understanding of the disease and helping develop targeted treatments. METHODS: This review provides a comprehensive reporting on the effects of DPN in the skeletal muscle of patients with diabetes. It also provides an update on the most recent trials of exercise intervention targeting DPN pathology. Lastly, we report on emerging MRI techniques that have shown promise in providing a mechanistic understanding of DPN and can help improve the design and implementation of clinical trials in the future. FINDINGS: Impairments in lower limb muscles reduce functional capacity and contribute to altered gait, increased fall risk, and impaired balance in patients with DPN. This finding is an important concern for patients with DPN because their falls are likely to be injurious and lead to bone fractures, poorly healing wounds, and chronic infections that may require amputation. Preliminary studies have shown that moderate-intensity exercise programs are well tolerated by patients with DPN. They can improve their cardiorespiratory function and partially reverse some of the symptoms of DPN. MRI has the potential to bring new mechanistic insights into the effects of DPN as well as to objectively measure small changes in DPN pathology as a result of intervention. IMPLICATIONS: Noninvasive exercise intervention is particularly valuable in DPN because of its safety, low cost, and potential to augment pharmacologic interventions. As we gain a better mechanistic understanding of the disease, more targeted and effective interventions can be designed.

A low-cost Mr compatible ergometer to assess post-exercise phosphocreatine recovery kinetics.

OBJECTIVE: To develop a low-cost pedal ergometer compatible with ultrahigh (7 T) field MR systems to reliably quantify metabolic parameters in human lower leg muscle using phosphorus magnetic resonance spectroscopy. MATERIALS AND METHODS: We constructed an MR compatible ergometer using commercially available materials and elastic bands that provide resistance to movement. We recruited ten healthy subjects (eight men and two women, mean age ± standard deviation: 32.8 ± 6.0 years, BMI: 24.1 ± 3.9 kg/m2). All subjects were scanned on a 7 T whole-body magnet. Each subject was scanned on two visits and performed a 90 s plantar flexion exercise at 40% maximum voluntary contraction during each scan. During the first visit, each subject performed the exercise twice in order for us to estimate the intra-exam repeatability, and once during the second visit in order to estimate the inter-exam repeatability of the time constant of phosphocreatine recovery kinetics. We assessed the intra and inter-exam reliability in terms of the within-subject coefficient of variation (CV). RESULTS: We acquired reliable measurements of PCr recovery kinetics with an intra- and inter-exam CV of 7.9% and 5.7%, respectively. CONCLUSION: We constructed a low-cost pedal ergometer compatible with ultrahigh (7 T) field MR systems, which allowed us to quantify reliably PCr recovery kinetics in lower leg muscle using 31P-MRS.

Magnetic Resonance Imaging of Phosphocreatine and Determination of BOLD Kinetics in Lower Extremity Muscles using a Dual-Frequency Coil Array.

Magnetic resonance imaging (MRI) provides the unique ability to study metabolic and microvasculature functions in skeletal muscle using phosphorus and proton measurements. However, the low sensitivity of these techniques can make it difficult to capture dynamic muscle activity due to the temporal resolution required for kinetic measurements during and after exercise tasks. Here, we report the design of a dual-nuclei coil array that enables proton and phosphorus MRI of the human lower extremities with high spatial and temporal resolution. We developed an array with whole-volume coverage of the calf and a phosphorus signal-to-noise ratio of more than double that of a birdcage coil in the gastrocnemius muscles. This enabled the local assessment of phosphocreatine recovery kinetics following a plantar flexion exercise using an efficient sampling scheme with a 6 s temporal resolution. The integrated proton array demonstrated image quality approximately equal to that of a clinical state-of-the-art knee coil, which enabled fat quantification and dynamic blood oxygen level-dependent measurements that reflect microvasculature function. The developed array and time-efficient pulse sequences were combined to create a localized assessment of calf metabolism using phosphorus measurements and vasculature function using proton measurements, which could provide new insights into muscle function.

A nested phosphorus and proton coil array for brain magnetic resonance imaging and spectroscopy.

A dual-nuclei radiofrequency coil array was constructed for phosphorus and proton magnetic resonance imaging and spectroscopy of the human brain at 7T. An eight-channel transceive degenerate birdcage phosphorus module was implemented to provide whole-brain coverage and significant sensitivity improvement over a standard dual-tuned loop coil. A nested eight-channel proton module provided adequate sensitivity for anatomical localization without substantially sacrificing performance on the phosphorus module. The developed array enabled phosphorus spectroscopy, a saturation transfer technique to calculate the global creatine kinase forward reaction rate, and single-metabolite whole-brain imaging with 1.4cm nominal isotropic resolution in 15min (2.3cm actual resolution), while additionally enabling 1mm isotropic proton imaging. This study demonstrates that a multi-channel array can be utilized for phosphorus and proton applications with improved coverage and/or sensitivity over traditional single-channel coils. The efficient multi-channel coil array, time-efficient pulse sequences, and the enhanced signal strength available at ultra-high fields can be combined to allow volumetric assessment of the brain and could provide new insights into the underlying energy metabolism impairment in several neurodegenerative conditions, such as Alzheimer's and Parkinson's diseases, as well as mental disorders such as schizophrenia.

Feasibility of mapping unidirectional Pi-to-ATP fluxes in muscles of the lower leg at 7.0 Tesla.

PURPOSE: To assess the feasibility of mapping the kinetics and unidirectional fluxes of inorganic phosphate (Pi) to adenosine triphosphate (ATP) reactions in the entire volume of the lower leg muscles using a three-dimensional saturation transfer (ST) phosphorus (31 P) imaging sequence. THEORY AND METHODS: We imaged the lower leg muscles of five healthy subjects at 7.0 Tesla. The total experimental time was 45 min. We quantified muscle-specific forward reaction rate constants (k'f ) and metabolic fluxes (Vf ) of the Pi-to-ATP reaction in the tibialis anterior, the gastrocnemius, and the soleus. RESULTS: In the tibialis anterior, k'f and Vf were 0.11 s-1 ± 0.03 (mean ± standard deviation) and 0.34 mM s-1 ± 0.10, respectively. In the gastrocnemius, k'f was 0.11 s-1 ± 0.04 and Vf was 0.37 mM s-1 ± 0.11, while in the soleus muscle k'f was 0.10 s-1 ± 0.02 and Vf was 0.36 mM s-1 ± 0.14. CONCLUSION: Our results suggest that mapping the kinetics and unidirectional fluxes from Pi-to-ATP in both the anterior and posterior muscles of the lower leg is feasible at ultra-high field and may provide useful insights for the study of insulin resistance, diabetes and aging. Magn Reson Med 74:225-230, 2015. © 2014 Wiley Periodicals, Inc.

Three-dimensional saturation transfer ³¹P-MRI in muscles of the lower leg at 3.0 T.

The creatine kinase (CK) reaction plays a critical role in skeletal muscle function, and can be studied non-invasively using phosphorus ((31)P) saturation transfer (ST) techniques. However, due to the low MR sensitivity of the (31)P nucleus, most studies on clinically approved magnetic fields (≤3.0 T) have been performed with coarse resolution and limited tissue coverage. However, such methods are not able to detect spatially resolved metabolic heterogeneities, which may be important in diseases of the skeletal muscle. In this study, our aim was to develop and implement a (31)P-MRI method for mapping the kinetics of the CK reaction, and the unidirectional phosphocreatine (PCr) to adenosine triphosphate (ATP) metabolic fluxes in muscles of the lower leg on a clinical 3.0 T MR scanner. We imaged the lower leg muscles of ten healthy volunteers (total experimental time: 40 min, nominal voxel sizes 0.5 mL), and found statistically significant differences between the kinetics of the CK reaction among muscle groups. Our developed technique may allow in the future the early detection of focal metabolic abnormalities in diseases that affect the function of the skeletal muscle.

Uniform magnetization transfer in chemical exchange saturation transfer magnetic resonance imaging.

The development of chemical exchange saturation transfer (CEST) has led to the establishment of new contrast mechanisms in magnetic resonance imaging, which serve as enablers for advanced molecular imaging strategies. Macromolecules in tissues and organs often give rise to broad and asymmetric exchange effects, called magnetization transfer (MT) effects, which can mask the CEST contrast of interest. We show here that the saturation of these macromolecular pools simultaneously at two distinct frequencies can level out the asymmetric MT effects, thus allowing one to isolate the CEST effects in vivo. For the first time, clean CEST contrast for glycosaminoglycans (gagCEST) in cartilage in the human knee joint is presented. In addition, the method allows one to clearly demarcate glycosaminoglycan measurements from cartilage and synovial fluid regions. This uniform-MT CEST methodology has wide applicability in in vivo molecular imaging (such as brain, skeletal muscle, etc).

Three-dimensional mapping of the creatine kinase enzyme reaction rate in muscles of the lower leg.

Phosphorus ((31) P) magnetization transfer (MT) techniques enable the non-invasive measurement of metabolic turnover rates of important enzyme-catalyzed reactions, such as the creatine kinase reaction (CK), a major transducing reaction involving adenosine triphosphate and phosphocreatine. Alteration in the kinetics of the CK reaction rate appears to play a central role in many disease states. In this study, we developed and implemented at ultra-high field (7T) a novel three-dimensional (31) P-MT imaging sequence that maps the kinetics of CK in the entire volume of the lower leg at relatively high resolution (0.52 mL voxel size), and within acquisition times that can be tolerated by patients (below 60 min). We tested the sequence on five healthy and two clinically diagnosed type 2 diabetic subjects. Overall, we obtained measurements that are in close agreement with measurements reported previously using spectroscopic methods. Importantly, our spatially resolved method allowed us to measure local CK reaction rate constants and metabolic fluxes in individual muscles in a non-invasive manner. Furthermore, it allowed us to detect variations of the CK rates of different muscles, which would not have been possible using unlocalized MRS methods. The results of this work suggest that 3D mapping of the CK reaction rates and metabolic fluxes can be achieved in the skeletal muscle in vivo at relatively high spatial resolution and with acquisition times well tolerated by patients. The ability to measure bioenergetics simultaneously in large areas of muscles will bring new insights into possible heterogeneous patterns of muscle metabolism associated with several diseases and serve as a valuable tool for monitoring the efficacy of interventions.

3D-mapping of phosphocreatine concentration in the human calf muscle at 7 T: comparison to 3 T.

PURPOSE: The development and implementation of a spectrally selective 3D-Turbo Spin Echo sequence for quantitative mapping of phosphocreatine (PCr) concentration in different muscles of the lower leg of healthy volunteers both at 3 T and 7 T. METHODS: Nine healthy volunteers were recruited, all of whom where scanned at 3 T and 7 T. Three dimensional PCr concentration maps were obtained after images were corrected for B1 inhomogeneities, T1 relaxation weighting, and partial volume of fatty tissue in the muscles. Two volunteers performed plantar flexions inside the magnet, and the oxidative capacity of their muscles was estimated. RESULTS: Three dimensional PCr concentration maps were obtained, with full muscle coverage and nominal voxel size of 0.52 mL at both fields. At 7 T a 2.7-fold increase of signal-to-noise ratio was achieved compared to 3 T. CONCLUSION: Imaging (31) P metabolites at 7 T allowed for significant increase in signal to noise ratio compared to imaging at 3 T, while quantification of the PCr concentration remained unaffected. The importance of such an increase in signal-to-noise ratio is 2-fold, first higher resolution images with reduced partial volume effects can be acquired, and second multiple measurements such as dynamic imaging of PCr post-exercise, (31) P magnetization transfer, or other (1) H measurements, can be acquired in a single imaging session.

High-resolution MRI of early-stage mouse embryos.

Both the availability of methods to manipulate genes and the completion of the mouse genome sequence have led to the generation of thousands of genetically modified mouse lines that provide a new platform for the study of mammalian development and developmental diseases. Phenotyping of mouse embryos has traditionally been performed on fixed embryos by the use of ex vivo histological, optical and high-resolution MRI techniques. Although potentially powerful, longitudinal imaging of individual animals is difficult or impossible with conventional optical methods because of the inaccessibility of mouse embryos inside the maternal uterus. To address this problem, we present a method of imaging the mouse embryo from stages as early as embryonic day (E)10.5, close to the onset of organogenesis in most physiological systems. This method uses a self-gated MRI protocol, combined with image registration, to obtain whole-embryo high-resolution (100 µm isotropic) three-dimensional images. Using this approach, we demonstrate high contrast in the cerebral vasculature, limbs, spine and central nervous system without the use of contrast agents. These results indicate the potential of MRI for the longitudinal imaging of developing mouse embryos in utero and for future applications in analyzing mutant mouse phenotypes.

Spectrally selective 3D TSE imaging of phosphocreatine in the human calf muscle at 3 T.

Quantitative information about concentrations of several metabolites in human skeletal muscle can be obtained through localized (31)P magnetic resonance spectroscopy methods. However, these methods have shortcomings: long acquisition times, limited volume coverage, and coarse resolution. Significantly higher spatial and temporal resolution of imaging of single metabolites can be achieved through spectrally selective three-dimensional imaging methods. This study reports the implementation of a three-dimensional spectrally selective turbo spin-echo sequence, on a 3T clinical system, to map the concentration of phosphocreatine in the human calf muscle with significantly increased spatial resolution and in a clinically feasible scan time. Absolute phosphocreatine quantification was performed with the use of external phantoms after relaxation and flip angle correction of the turbo spin-echo voxel signal. The mean ± standard deviation of the phosphocreatine concentration measured in five healthy volunteers was 29.4 ± 2.5 mM with signal-to-noise ratio of 14:1 and voxel size of 0.52 mL.

Dynamic three-dimensional imaging of phosphocreatine recovery kinetics in the human lower leg muscles at 3T and 7T: a preliminary study.

The rate of phosphocreatine (PCr) resynthesis after physical exercise has been extensively studied with phosphorus (³¹P)-MRS. Previous studies have used small surface coils that were limited to measuring one superficial muscle per experiment. This study focuses on the development and implementation of a spectrally selective three-dimensional turbo spin echo (3D-TSE) sequence at 3T and 7T with temporal resolution of 24 s, using two geometrically identical volume coils. We acquired imaging data of PCr recovery from four healthy volunteers and one diabetic patient, who performed plantar flexions using resistance bands. We segmented the anatomical regions of six different muscles from the lower leg, namely the gastrocnemius [lateral (GL) and medial (GM)], the tibialis [anterior (TA) and posterior (TP)], the soleus (S) and the peroneus (P) and measured the local PCr resynthesis rate constants. During the same examination, we also acquired unlocalized (³¹P-MRS data at a temporal resolution of 6 s. At 3T, the PCr resynthesis rate constants were measured at 25.4 ± 3.7 s [n = 4, mean ± standard deviation (SD)] using the MRS method and 25.6 ± 4.4 s using the MRI method. At 7T, the measured rates were 26.4 ± 3.2 s and 26.2 ± 4.7 s for MRS and MRI. Using our imaging method, we measured the local PCr resynthesis rate constants in six individual muscles of the lower leg (min/max 20.2/31.7 ). The recovery rate constants measured for the diabetic patient were 55.5 s (MRS) and 52.7 s (MRI). The successful implementation of our 3D-method suggests that imaging is possible at both fields with a relatively high spatial resolution (voxel size: 4.2 mL at 3T and 1.6 mL at 7T) using volume coils and that local PCr resynthesis rates can be obtained in a single measurement. The advantage of the imaging method is that it can highlight differences in PCr resynthesis rates between different muscles in a single measurement in order to study spatial gradients of metabolic properties of diseased states for which very little is currently known.

Rapid 3D-imaging of phosphocreatine recovery kinetics in the human lower leg muscles with compressed sensing.

The rate of phosphocreatine (PCr) resynthesis following physical exercise is an accepted index of mitochondrial oxidative metabolism and has been studied extensively with unlocalized (31)P-MRS methods and small surface coils. Imaging experiments using volume coils that measure several muscles simultaneously can provide new insights into the variability of muscle function in healthy and diseased states. However, they are limited by long acquisition times relative to the dynamics of PCr recovery. This work focuses on the implementation of a compressed sensing technique to accelerate imaging of PCr resynthesis following physical exercise, using a modified three-dimensional turbo-spin-echo sequence and principal component analysis as sparsifying transform. The compressed sensing technique was initially validated using 2-fold retrospective undersampling of fully sampled data from four volunteers acquired on a 7T MRI system (voxel size: 1.6 mL, temporal resolution: 24 s), which led to an accurate estimation of the mono-exponential PCr resynthesis rate constant (mean error <6.4%). Acquisitions with prospective 2-fold acceleration (temporal resolution: 12 s) demonstrated that three-dimensional mapping of PCr resynthesis is possible at a temporal resolution that is sufficiently high for characterizing the recovery curve of several muscles in a single measurement.

In utero phenotyping of mouse embryonic vasculature with MRI.

The vasculature is the earliest developing organ in mammals and its proper formation is critical for embryonic survival. MRI approaches have been used previously to analyze complex three-dimensional vascular patterns and defects in fixed mouse embryos. Extending vascular imaging to an in utero setting with potential for longitudinal studies would enable dynamic analysis of the vasculature in normal and genetically engineered mouse embryos, in vivo. In this study, we employed an in utero MRI approach that corrects for motion, using a combination of interleaved gated acquisition and serial coregistration of rapidly acquired three-dimensional images. We tested the potential of this method by acquiring and analyzing images from wildtype and Gli2 mutant embryos, demonstrating a number of Gli2 phenotypes in the brain and cerebral vasculature. These results show that in utero MRI can be used for in vivo phenotype analysis of a variety of mutant mouse embryos.

Optimal k-space sampling for single point imaging of transient systems.

A novel approach for sampling k-space in a pure phase encoding imaging sequence is presented using the Single Point Imaging (SPI) technique. The sequence is optimised with respect to the achievable Signal-to-Noise ratio (SNR) for a given time interval via selective sparse k-space sampling, dictated by prior knowledge of the overall object of interest's shape. This allows dynamic processes featuring short T(2)( *) NMR signal to be more readily followed, in our case the absorption of moisture by a cereal-based wafer material. Further improvements in image quality are also shown via the use of complete sampling of k-space at the start or end of the series of imaging experiments; followed by subsequent use of this data for un-sampled k-space points as opposed to zero filling.