S. Sendhil Velan

Simultaneous MRI and PET imaging of a rat brain.

Multi-modality imaging is rapidly becoming a valuable tool in the diagnosis of disease and in the development of new drugs. Functional images produced with PET fused with anatomical structure images created by MRI will allow the correlation of form with function. Our group is developing a system to acquire MRI and PET images contemporaneously. The prototype device consists of two opposed detector heads, operating in coincidence mode. Each MRI-PET detector module consists of an array of LSO detector elements coupled through a long fibre optic light guide to a single Hamamatsu flat panel position-sensitive photomultiplier tube (PSPMT). The use of light guides allows the PSPMTs to be positioned outside the bore of a 3T MRI scanner where the magnetic field is relatively small. To test the device, simultaneous MRI and PET images of the brain of a male Sprague Dawley rat injected with FDG were successfully obtained. The images revealed no noticeable artefacts in either image set. Future work includes the construction of a full ring PET scanner, improved light guides and construction of a specialized MRI coil to permit higher quality MRI imaging.

Electron paramagnetic resonance oxygen mapping (EPROM): direct visualization of oxygen concentration in tissue.

Tissue oxygen content is a central parameter in physiology but is difficult to measure. We report a novel procedure for spatial mapping of oxygen by electron paramagnetic resonance (EPR) utilizing a spectral‐spatial imaging data set, in which an EPR spectrum is obtained from each image volume element. From this data set, spatial maps corresponding to local spin density and maximum EPR spectral line amplitude are generated. A map of local EPR spectral linewidth is then computed. Because linewidth directly correlates with oxygen concentration, the linewidth image provides a map of oxygenation. This method avoids a difficulty inherent in other oxygen content mapping techniques using EPR, that is, the unwanted influence of local spin probe density on the image. We provide simulation results and data from phantom studies demonstrating the validity of this method. We then apply the method to map oxygen content in rat tail tissue and vasculature. This method provides a new, widely applicable, approach to direct visualization of oxygen concentration in living tissue. Magn Reson Med 43:804–809, 2000.

Investigation of muscle lipid metabolism by localized one- and two-dimensional MRS techniques using a clinical 3T MRI/MRS scanner

To demonstrate the feasibility of estimating the relative intra‐ and extramyocellular lipid (IMCL and EMCL) pool magnitudes and calculating the degree of lipid unsaturation within soleus muscle using single‐voxel localized one‐ and two‐dimensional (1D and 2D) MR spectroscopy (MRS).

Distinct patterns of fat metabolism in skeletal muscle of normal-weight, overweight, and obese humans

The link between body weight, lipid metabolism, and health risks is poorly understood and difficult to study. Magnetic resonance spectroscopy (MRS) permits noninvasive investigation of lipid metabolism. We extended existing two-dimensional MRS techniques to permit quantification of intra- and extramyocellular lipid (IMCL and EMCL, respectively) compartments and their degree of unsaturation in human subjects and correlated these results with body mass index (BMI). Using muscle creatine for normalization, we observed a statistically significant (P < 0.01) increase in the IMCL-to-creatine ratio with BMI (n = 8 subjects per group): 5.9 +/- 1.7 at BMI < 25, 10.9 +/- 1.82 at 25 < BMI < 30, and 13.1 +/- 0.87 at BMI > 30. Similarly, the degree of IMCL unsaturation decreased significantly (P < 0.01) with BMI: 1.51 +/- 0.08 at BMI < 25, 1.30 +/- 0.11 at 25 < BMI < 30, and 0.90 +/- 0.14 at BMI > 30. We conclude that important aspects of lipid metabolism can be evaluated by two-dimensional MRS and propose that degree of unsaturation measured noninvasively may serve as a biomarker for lipid metabolic defects associated with obesity.

Investigation of breast cancer using two-dimensional MRS

Proton (1H) MRS enables non‐invasive biochemical assay with the potential to characterize malignant, benign and healthy breast tissues. In vitro studies using perchloric acid extracts and ex vivo magic angle spinning spectroscopy of intact biopsy tissues have been used to identify detectable metabolic alterations in breast cancer. The challenges of 1H MRS in vivo include low sensitivity and significant overlap of resonances due to limited chemical shift dispersion and significant inhomogeneous broadening at most clinical magnetic field strengths. Improvement in spectral resolution can be achieved in vivo and in vitro by recording the MR spectra spread over more than one dimension, thus facilitating unambiguous assignment of metabolite and lipid resonances in breast cancer. This article reviews the recent progress with two‐dimensional MRS of breast cancer in vitro, ex vivo and in vivo. The discussion includes unambiguous detection of saturated and unsaturated fatty acids, as well as choline‐containing groups such as free choline, phosphocholine, glycerophosphocholine and ethanolamines using two‐dimensional MRS. In addition, characterization of invasive ductal carcinomas and healthy fatty/glandular breast tissues non‐invasively using the classification and regression tree (CART) analysis of two‐dimensional MRS data is reviewed. Copyright

EPR oxygen mapping (EPROM) of engineered cartilage grown in a hollow-fiber bioreactor

A novel electron paramagnetic resonance (EPR)‐based oxygen mapping procedure (EPROM) is applied to cartilage grown in a single‐, hollow‐fiber bioreactor (HFBR) system. Chondrocytes harvested from the sterna of 17‐day‐old chick embryos were inoculated into an HFBR and produced hyaline cartilage over a period of 4 weeks. Tissue oxygen maps were generated according to the EPROM technique (Velan et al., Magn Reson Med 2000;43:804–809) by making use of the line‐broadening effects of oxygen on the signal generated from nitroxide spin probes. In addition, the effect on oxygen consumption of the addition of cyanide to the tissue was investigated. Cyanide is a potent inhibitor of oxidative phosphorylation, and accordingly, given the constant provision of oxygen to the tissue, it would be expected to increase oxygen levels within the HFBR. The EPROM measurements showed a significant increase in oxygen concentration in the cartilage after the addition of cyanide. In contrast to other methods for studying oxygen in cartilage, EPROM can provide direct, noninvasive visualization of local concentrations in three dimensions. Magn Reson Med 46:819–826, 2001.

Automated segmentation of visceral and subcutaneous (deep and superficial) adipose tissues in normal and overweight men.

To develop an automatic segmentation algorithm to classify abdominal adipose tissues into visceral fat (VAT), deep (DSAT), and superficial (SSAT) subcutaneous fat compartments and evaluate its performance against manual segmentation.

Body Fat Partitioning Does Not Explain the Interethnic Variation in Insulin Sensitivity Among Asian Ethnicity: The Singapore Adults Metabolism Study

We previously showed that ethnicity modifies the association between adiposity and insulin resistance. We sought to determine whether differential body fat partitioning or abnormalities in muscle insulin signaling associated with higher levels of adiposity might underlie this observation. We measured the insulin sensitivity index (ISI), percentage of body fat (%body fat), visceral (VAT) and subcutaneous (SAT) adipose tissue, liver fat, and intramyocellular lipids (IMCL) in 101 Chinese, 82 Malays, and 81 South Asians, as well as phosphorylated (p)-Akt levels in cultured myoblasts from Chinese and South Asians. Lean Chinese and Malays had higher ISI than South Asians. Although the ISI was lower in all ethnic groups when %body fat was higher, this association was stronger in Chinese and Malays, such that no ethnic differences were observed in overweight individuals. These ethnic differences were observed even when %body fat was replaced with fat in other depots. Myoblasts obtained from lean South Asians had lower p-Akt levels than those from lean Chinese. Higher adiposity was associated with lower p-Akt levels in Chinese but not in South Asians, and no ethnic differences were observed in overweight individuals. With higher %body fat, Chinese exhibited smaller increases in deep SAT and IMCL compared with Malays and South Asians, which did not explain the ethnic differences observed. Our study suggests that body fat partitioning does not explain interethnic differences in insulin sensitivity among Asian ethnic groups. Although higher adiposity had greater effect on skeletal muscle insulin sensitivity among Chinese, obesity-independent pathways may be more relevant in South Asians.

Two-dimensional MR spectroscopy of healthy and cancerous prostates in vivo

ObjectivesA major goal of this article is to summarize the current status of evaluating prostate metabolites non-invasively using spatially resolved two-dimensional (2D) MR Spectroscopy (MRS).Materials and MethodsDue to various technical challenges, the spatially resolved versions of 2D MRS techniques are currently going through the developmental stage. During the last decade, four different versions of 2D MRS sequences have been successfully implemented on 3T and 1.5T MRI scanners manufactured by three different vendors. These sequences include half and maximum echo sampled J-resolved spectroscopy (JPRESS), S-PRESS and L-COSY, which are single volume localizing sequences, and the multi-voxel based JPRESS sequence.ResultsEven though greater than 1ml voxels have been used, preliminary evaluations of 2D JPRESS, S-PRESS and L-COSY sequences have demonstrated unambiguous detection of citrate, creatine, choline, spermine and more metabolites in human prostates. ProFIT-based quantitation of JPRESS and L-COSY data clearly shows the superiority of 2D MRS over conventional one-dimensional (1D) MRS and more than six metabolites have been successfully quantified. These sequences have been evaluated in a small group of prostate pathologies and pilot investigations using these sequences show promising results in prostate pathologies.ConclusionImplementation of the state-of-the-art 2D MRS techniques and preliminary evaluation in prostate pathologies are discussed in this review. Even though these techniques are going through developmental and early testing phases, it is evident that 2D MRS can be easily added on to any clinical Magnetic Resonance Imaging (MRI) protocol to non-invasively record the biochemical contents of the prostate.

Fat Storage-inducing Transmembrane Protein 2 Is Required for Normal Fat Storage in Adipose Tissue

Background: FIT2 is an ER protein purported to be important for triglyceride lipid droplet formation. Results: FIT2 deficiency in adipose tissue results in lipodystrophy and metabolic dysfunction. Conclusion: FIT2 is required for normal triglyceride storage in adipose tissue. Significance: This study provides the first proof-of-principle mouse models indicating that FIT2 is essential for normal triglyceride storage in adipose tissue. Triglycerides within the cytosol of cells are stored in a phylogenetically conserved organelle called the lipid droplet (LD). LDs can be formed at the endoplasmic reticulum, but mechanisms that regulate the formation of LDs are incompletely understood. Adipose tissue has a high capacity to form lipid droplets and store triglycerides. Fat storage-inducing transmembrane protein 2 (FITM2/FIT2) is highly expressed in adipocytes, and data indicate that FIT2 has an important role in the formation of LDs in cells, but whether FIT2 has a physiological role in triglyceride storage in adipose tissue remains unproven. Here we show that adipose-specific deficiency of FIT2 (AF2KO) in mice results in progressive lipodystrophy of white adipose depots and metabolic dysfunction. In contrast, interscapular brown adipose tissue of AF2KO mice accumulated few but large LDs without changes in cellular triglyceride levels. High fat feeding of AF2KO mice or AF2KO mice on the genetically obese ob/ob background accelerated the onset of lipodystrophy. At the cellular level, primary adipocyte precursors of white and brown adipose tissue differentiated in vitro produced fewer but larger LDs without changes in total cellular triglyceride or triglyceride biosynthesis. These data support the conclusion that FIT2 plays an essential, physiological role in fat storage in vivo.