Monocyte MRI Relaxation Rates Are Regulated by Extracellular Iron and Hepcidin.

Many chronic inflammatory conditions are mediated by an increase in the number of monocytes in peripheral circulation, differentiation of monocytes to macrophages, and different macrophage subpopulations during pro- and anti-inflammatory stages of tissue injury. When hepcidin secretion is stimulated during inflammation, the iron export protein ferroportin is targeted for degradation on a limited number of cell types, including monocytes and macrophages. Such changes in monocyte iron metabolism raise the possibility of non-invasively tracking the activity of these immune cells using magnetic resonance imaging (MRI). We hypothesized that hepcidin-mediated changes in monocyte iron regulation influence both cellular iron content and MRI relaxation rates. In response to varying conditions of extracellular iron supplementation, ferroportin protein levels in human THP-1 monocytes decreased two- to eightfold, consistent with paracrine/autocrine regulation of iron export. Following hepcidin treatment, ferroportin protein levels further decreased two- to fourfold. This was accompanied by an approximately twofold increase in total transverse relaxation rate, R2*, compared to non-supplemented cells. A positive correlation between total cellular iron content and R2* improved from moderate to strong in the presence of hepcidin. These findings suggest that hepcidin-mediated changes detected in monocytes using MRI could be valuable for in vivo cell tracking of inflammatory responses.

The Effect of Registration on Voxel-Wise Tofts Model Parameters and Uncertainties from DCE-MRI of Early-Stage Breast Cancer Patients Using 3DSlicer.

We quantitatively investigate the influence of image registration, using open-source software (3DSlicer), on kinetic analysis (Tofts model) of dynamic contrast enhanced MRI of early-stage breast cancer patients. We also show that registration computation time can be reduced by reducing the percent sampling (PS) of voxels used for estimation of the cost function. DCE-MRI breast images were acquired on a 3T-PET/MRI system in 13 patients with early-stage breast cancer who were scanned in a prone radiotherapy position. Images were registered using a BSpline transformation with a 2 cm isotropic grid at 100, 20, 5, 1, and 0.5PS (BRAINSFit in 3DSlicer). Signal enhancement curves were analyzed voxel-by-voxel using the Tofts kinetic model. Comparing unregistered with registered groups, we found a significant change in the 90th percentile of the voxel-wise distribution of Ktrans. We also found a significant reduction in the following: (1) in the standard error (uncertainty) of the parameter value estimation, (2) the number of voxel fits providing unphysical values for the extracellular-extravascular volume fraction (ve > 1), and (3) goodness of fit. We found no significant differences in the median of parameter value distributions (Ktrans, ve) between unregistered and registered images. Differences between parameters and uncertainties obtained using 100PS versus 20PS were small and statistically insignificant. As such, computation time can be reduced by a factor of 2, on average, by using 20PS while not affecting the kinetic fit. The methods outlined here are important for studies including a large number of post-contrast images or number of patient images.

Investigating the Relationship between Transverse Relaxation Rate (R2) and Interecho Time in MagA-Expressing, Iron-Labeled Cells.

Reporter gene-based labeling of cells with iron is an emerging method of providing magnetic resonance imaging contrast for long-term cell tracking and monitoring cellular activities. This report investigates 9.4 T nuclear magnetic resonance properties of mammalian cells overexpressing MagA, a putative iron transport protein from magnetotactic bacteria. MagA-expressing MDA-MB-435 cells were cultured in the presence and absence of iron supplementation and compared to the untransfected control. The relationship between the transverse relaxation rate (R2) and interecho time was investigated using the Carr-Purcell-Meiboom-Gill sequence. This relationship was analyzed using a model based on water diffusion in weak magnetic field inhomogeneities (Jensen-Chandra model) as well as a fast-exchange model (Luz-Meiboom model). Increases in R2 with increasing interecho time were larger in the iron-supplemented, MagA-expressing cells compared to other cells. The dependence of R2 on interecho time in these iron-supplemented, MagA-expressing cells was better represented by the Jensen-Chandra model compared to the Luz-Meiboom model, whereas the Luz-Meiboom model performed better for the remaining cell types. Our findings provide an estimate of the distance scale of microscopic magnetic field variations in MagA-expressing cells, which is thought to be related to the size of iron-containing vesicles.

Hepcidin-mediated Iron Regulation in P19 Cells is Detectable by Magnetic Resonance Imaging.

Magnetic resonance imaging can be used to track cellular activities in the body using iron-based contrast agents. However, multiple intrinsic cellular iron handling mechanisms may also influence the detection of magnetic resonance (MR) contrast: a need to differentiate among those mechanisms exists. In hepcidin-mediated inflammation, for example, downregulation of iron export in monocytes and macrophages involves post-translational degradation of ferroportin. We examined the influence of hepcidin endocrine activity on iron regulation and MR transverse relaxation rates in multi-potent P19 cells, which display high iron import and export activities, similar to alternatively-activated macrophages. Iron import and export were examined in cultured P19 cells in the presence and absence of iron-supplemented medium, respectively. Western blots indicated the levels of transferrin receptor, ferroportin and ubiquitin in the presence and absence of extracellular hepcidin. Total cellular iron was measured by inductively-coupled plasma mass spectrometry and correlated to transverse relaxation rates at 3 Tesla using a gelatin phantom. Under varying conditions of iron supplementation, the level of ferroportin in P19 cells responds to hepcidin regulation, consistent with degradation through a ubiquitin-mediated pathway. This response of P19 cells to hepcidin is similar to that of classically-activated macrophages. The correlation between total cellular iron content and MR transverse relaxation rates was different in hepcidin-treated and untreated P19 cells: slope, Pearson correlation coefficient and relaxation rate were all affected. These findings may provide a tool to non-invasively distinguish changes in endogenous iron contrast arising from hepcidin-ferroportin interactions, with potential utility in monitoring of different macrophage phenotypes involved in pro- and anti-inflammatory signaling. In addition, this work demonstrates that transverse relaxivity is not only influenced by the amount of cellular iron but also by its metabolism.

DCE-MRI assessment of response to neoadjuvant SABR in early stage breast cancer: Comparisons of single versus three fraction schemes and two different imaging time delays post-SABR.

PURPOSE: To determine the effect of dose fractionation and time delay post-neoadjuvant stereotactic ablative radiotherapy (SABR) on dynamic contrast-enhanced (DCE)-MRI parameters in early stage breast cancer patients. MATERIALS AND METHODS: DCE-MRI was acquired in 17 patients pre- and post-SABR. Five patients were imaged 6-7 days post-21 Gy/1fraction (group 1), six 16-19 days post-21 Gy/1fraction (group 2), and six 16-18 days post-30 Gy/3 fractions every other day (group 3). DCE-MRI scans were performed using half the clinical dose of contrast agent. Changes in the surrounding tissue were quantified using a signal-enhancement threshold metric that characterizes changes in signal-enhancement volume (SEV). Tumour response was quantified using Ktrans and ve (Tofts model) pre- and post-SABR. Significance was assessed using a Wilcoxin signed-rank test. RESULTS: All group 1 and 4/6 group 2 patients' SEV increased post-SABR. All group 3 patients' SEV decreased. The mean Ktrans increased for group 1 by 76% (p = 0.043) while group 2 and 3 decreased 15% (p = 0.028) and 34% (p = 0.028), respectively. For ve, there was no significant change in Group 1 (p = 0.35). Groups 2 showed an increase of 24% (p = 0.043), and Group 3 trended toward an increase (23%, p = 0.08). CONCLUSION: Kinetic parameters measured 2.5 weeks post-SABR in both single fraction and three fraction groups were indicative of response but only the single fraction protocol led to enhancement in the surrounding tissue. Our results also suggest that DCE-MRI one-week post-SABR may be too early for response assessment, at least for single fraction SABR, whereas 2.5 weeks appears sufficiently long to minimize confounding acute effects.

Females follow a more "compact" early human brain development model than males. A case-control study of preterm neonates.

The pattern of sexual differentiation of the human brain is not well understood, particularly at the early stages of development when intense growth and multiple maturational phenomena overlap and interrelate. A case-control study of 20 preterm males and females matched for age was conducted. Three-dimensional images were acquired with 3 T MRI. The cerebral volume and the cortical folding area (FA), defined as the surface area of the interface between cortical gray and white matter, were compared between males and females. Females had smaller cerebra than males even after removing the influence of overall size differences between the subjects. The cortical FA increased in relation to volume by a power of 4/3 in both groups. Females had larger cortical FA compared with males with similar cerebral volumes. The study provides in vivo evidence of sexually dimorphic early human brain development. The relatively more "compact" female model may well relate to sex differences in neural circuitry and cognitive domains.

Changes in cerebral oxygen consumption and high-energy phosphates during early recovery in hypoxic-ischemic piglets: a combined near-infrared and magnetic resonance spectroscopy study.

Near-infrared spectroscopy (NIRS) offers the ability to assess brain function at the bedside of critically ill neonates. Our group previously demonstrated a persistent reduction in the cerebral metabolic rate of oxygen (CMRO(2)) after hypoxia-ischemia (HI) in newborn piglets. The purpose of this current study was to determine the causes of this reduction by combining NIRS with magnetic resonance spectroscopy (MRS) to measure high-energy metabolites and diffusion-weighted imaging to measure cellular edema. Nine piglets were exposed to 30 min of HI and nine piglets served as controls. Proton and phosphorous MRS spectra, apparent diffusion coefficient (ADC) maps, and CMRO(2) measurements were collected periodically before and for 5.5 h after HI. A significant decrease in CMRO(2) (26 +/- 7%) was observed after HI. Incomplete recovery of nucleotide triphosphate concentration (8 +/- 3%

Reducing the dose of gadolinium-based contrast agents for DCE-MRI guided SBRT: The effects on inter and intra observer variability for preoperative target volume delineation in early stage breast cancer patients.

BACKGROUND AND PURPOSE: This study aimed to determine the effects of reducing the dose of contrast agent (CA) in a DCE-MRI scan on inter- and intra-observer variability in the context of MRI-guided target volume delineation for stereotactic body radiation therapy of early stage breast cancer patients. This is in hopes of reducing risks to patients due to findings of residual CA in brain and bone. MATERIALS AND METHODS: Twenty-three patients receiving neoadjuvant radiation therapy were enrolled. Five observers delineated the gross target volume (GTV) using DCE-MRI for guidance. 14/23 patients received the full clinical dose of CA and 9/23 received half. Clinical target volumes (CTV) were created through a 0.5 cm uniform expansion. Several metrics were used to quantify the inter and intra-observer reliability including differences in delineation volume and the reliability coefficient. RESULTS: There were no significant differences in the volume, though half contrast patients had a lower median for both the GTV and CTV (difference of 0.26 cm3 and 1.27 cm3, respectively). All indicated a high degree of agreement between and within observers for both dose groups. However, the full dose group had a greater inter-observer variability, most likely due to the full CA causing more pronounced enhancement in the periphery. CONCLUSIONS: Reducing the dose of contrast agent did not significantly alter inter- or intra-observer variability. These results have prompted our centre to reduce the dose of gadolinium in all patients enrolled in the SIGNAL trial.

MagA expression attenuates iron export activity in undifferentiated multipotent P19 cells.

Magnetic resonance imaging (MRI) is a non-invasive imaging modality used in longitudinal cell tracking. Previous studies suggest that MagA, a putative iron transport protein from magnetotactic bacteria, is a useful gene-based magnetic resonance contrast agent. Hemagglutinin-tagged MagA was stably expressed in undifferentiated embryonic mouse teratocarcinoma, multipotent P19 cells to provide a suitable model for tracking these cells during differentiation. Western blot and immunocytochemistry confirmed the expression and membrane localization of MagA in P19 cells. Surprisingly, elemental iron analysis using inductively-coupled plasma mass spectrometry revealed significant iron uptake in both parental and MagA-expressing P19 cells, cultured in the presence of iron-supplemented medium. Withdrawal of this extracellular iron supplement revealed unexpected iron export activity in P19 cells, which MagA expression attenuated. The influence of iron supplementation on parental and MagA-expressing cells was not reflected by longitudinal relaxation rates. Measurement of transverse relaxation rates (R2* and R2) reflected changes in total cellular iron content but did not clearly distinguish MagA-expressing cells from the parental cell type, despite significant differences in the uptake and retention of total cellular iron. Unlike other cell types, the reversible component R2' (R2* ‒ R2) provided only a moderately strong correlation to amount of cellular iron, normalized to amount of protein. This is the first report to characterize MagA expression in a previously unrecognized iron exporting cell type. The interplay between contrast gene expression and systemic iron metabolism substantiates the potential for diverting cellular iron toward the formation of a novel iron compartment, however rudimentary when using a single magnetotactic bacterial gene expression system like magA. Since relatively few mammalian cells export iron, the P19 cell line provides a tractable model of ferroportin activity, suitable for magnetic resonance analysis of key iron-handling activities and their influence on gene-based MRI contrast.

Development of a composite material phantom mimicking the magnetic resonance parameters of the neonatal brain at 3.0 Tesla.

OBJECTIVE: Development of a composite material phantom, comprised of polyvinyl alcohol cryogel (PVA-C) and an agarose additive, to effectively mimic the magnetic resonance relaxation times (T1 and T2) of neonatal white matter (WM) and gray matter (GM) at 3.0 T. MATERIALS AND METHODS: Samples of PVA-C with and without agarose were prepared with 1 cycle of freezing/thawing. Measurements of T1 and T2, at 3.0 T, were performed on the samples at temperatures ranging from 20 degrees C to 40 degrees C. RESULTS: A sample temperature of 40 degrees C was required to achieve a T1 value sufficiently long to represent neonatal WM. At this temperature, neonatal WM relaxation times required 3% PVA-C with 0.3% agarose, whereas gray matter relaxation times required 8% PVA-C with 1.4% agarose. CONCLUSIONS: By adjusting the sample temperature, polyvinyl alcohol concentration, and agarose concentration, the relaxation times of neonatal brain tissues can be obtained using this composite material.

Efficacy of motion artifact reduction in neonatal DW segmented EPI at 3 T using phase correction by numerical optimization and segment data swapping.

Segmented echoplanar imaging (EPI) is a potentially valuable acquisition method for neonatal diffusion-weighted imaging (DWI) due to the lower acoustic noise levels as well as reduced blurring and distortion associated with it, as compared with single-shot EPI. Reduced acoustic noise may be important for the safety of neonates. However, little information regarding the efficacy of segmented EPI motion correction schemes is available for the neonatal population. We quantitatively assessed the efficacy of a postprocessing technique for motion artifact reduction involving phase correction by nonlinear optimization, alone and in combination with a novel method of utilizing a second data set (referred to as segment data swapping). These methods were applied to three-directional eight-segment echoplanar DW images obtained from 13 sedated neonates and to nine-directional DW images from 3 unsedated neonates. For comparison, the efficacy of the nonlinear optimization method was also evaluated in four adults. Motion correction efficacy was quantified using the motion artifact-to-signal ratio (ASR). The median, 70th percentile and 90th percentile ASR values obtained from neonatal three-directional DWI using nonlinear optimization alone were 2.8%, 4.6% and 9.6%, respectively. Efficacy improved (P<.005), particularly in dealing with the images most difficult to correct, when the phase correction by numerical optimization was combined with segment data swapping (median ASR=1.9%, 70th percentile ASR=2.7%, 90th percentile ASR=4.3%). Similar results were obtained for nine-directional diffusion tensor imaging. Nonlinear optimization alone applied to adult images showed significantly (P<.001) lower ASR values (median ASR=0.9%, 70th percentile ASR=2.1%, 90th percentile ASR=4.1%), demonstrating the greater challenge in DWI of neonates with segmented EPI. In conclusion, phase correction by nonlinear optimization provides effective motion correction for neonatal DW eight-segment EPI, especially when used in conjunction with segment data swapping.

Optimization of 3D MP-RAGE for neonatal brain imaging at 3.0 T.

Three-dimensional (3D) magnetic resonance imaging (MRI) has shown great potential for studying the impact of prematurity and pathology on brain development. We have investigated the potential of optimized T1-weighted 3D magnetization-prepared rapid gradient-echo imaging (MP-RAGE) for obtaining contrast between white matter (WM) and gray matter (GM) in neonates at 3 T. Using numerical simulations, we predicted that the inversion time (TI) for obtaining strongest contrast at 3 T is approximately 2 s for neonates, whereas for adults, this value is approximately 1.3 s. The optimal neonatal TI value was found to be insensitive to reasonable variations of the assumed T1 relaxation times. The maximum theoretical contrast for neonates was found to be approximately one third of that for adults. Using the optimized TI values, MP-RAGE images were obtained from seven neonates and seven adults at 3 T, and the contrast-to-noise ratio (CNR) was measured for WM versus five GM regions. Compared to adults, neonates exhibited lower CNR between cortical GM and WM and showed a different pattern of regional variation in CNR. These results emphasize the importance of sequence optimization specifically for neonates and demonstrate the challenge in obtaining strong contrast in neonatal brain with T1-weighted 3D imaging.

Apparent diffusion coefficient pseudonormalization time in neonatal hypoxic-ischemic encephalopathy.

The apparent diffusion coefficient changes with time after hypoxic-ischemic brain injury. In this study, we quantitatively examined the relationship between the apparent diffusion coefficient and postnatal age for neonates with hypoxic-ischemic encephalopathy and poor outcome, and determined the postnatal age at which these values cannot be distinguished from those of neonates without hypoxic-ischemic encephalopathy (pseudonormalization time). Diffusion-weighted brain images were obtained from clinical scans of term neonates with hypoxic-ischemic encephalopathy and poor outcome (12 neonates, 23 scans) and from control subjects (30 neonates, 31 scans). The correlation between apparent diffusion coefficient and postnatal age was investigated for several brain regions. Pseudonormalization times were determined (1) from the intersection of the regression lines for the hypoxic-ischemic encephalopathy and control groups, as well as (2) from intrasubject apparent diffusion coefficient changes between two scans within a small subgroup. Pseudonormalization times from the regression ranged from 8.3 +/- 1.9 days to 10.1 +/- 2.1 days. Slightly (approximately 1 day) longer values were obtained from the intrasubject analysis. The results suggest that, although abnormally decreased apparent diffusion coefficient values may be evident from approximately 2 days to almost 1 week of postnatal age, abnormally elevated values may not be apparent until late in the second week of life.

The Interface Between Iron Metabolism and Gene-Based Iron Contrast for MRI.

Using a gene-based approach to track cellular and molecular activity with magnetic resonance imaging (MRI) has many advantages. The strong correlation between transverse relaxation rates and total cellular iron content provides a basis for developing sensitive and quantitative detection of MRI reporter gene expression. In addition to biophysical concepts, general features of mammalian iron regulation add valuable context for interpreting molecular MRI predicated on gene-based iron labeling. With particular reference to the potential of magnetotactic bacterial gene expression as a magnetic resonance (MR) contrast agent for mammalian cell tracking, studies in different cell culture models highlight the influence of intrinsic iron regulation on the MRI signal. The interplay between dynamic regulation of mammalian iron metabolism and expression systems designed to sequester iron biominerals for MRI is presented from the perspective of their potential influence on MR image interpretation.

A hybrid strategy for correcting geometric distortion in echo-planar images.

A hybrid strategy for geometric distortion correction of echo-planar images is demonstrated. This procedure utilizes standard field mapping for signal displacement correction and the so-called reverse gradient acquisition for signal intensity correction. (The term reverse gradient refers to an acquisition of two sets of echo-planar images with phase encoding gradients of opposite polarity.) The hybrid strategy is applied to human brain echo-planar images acquired with and without diffusion-weighting. A comparison of the hybrid distortion corrected images to those corrected with standard field mapping only demonstrates much better performance of the hybrid method. A variant of the hybrid method is also demonstrated which requires the acquisition of only one pair of opposite polarity images within a set of images.

Biophysical features of MagA expression in mammalian cells: implications for MRI contrast.

We compared overexpression of the magnetotactic bacterial gene MagA with the modified mammalian ferritin genes HF + LF, in which both heavy and light subunits lack iron response elements. Whereas both expression systems have been proposed for use in non-invasive, magnetic resonance (MR) reporter gene expression, limited information is available regarding their relative potential for providing gene-based contrast. Measurements of MR relaxation rates in these expression systems are important for optimizing cell detection and specificity, for developing quantification methods, and for refinement of gene-based iron contrast using magnetosome associated genes. We measured the total transverse relaxation rate (R2*), its irreversible and reversible components (R2 and R2', respectively) and the longitudinal relaxation rate (R1) in MDA-MB-435 tumor cells. Clonal lines overexpressing MagA and HF + LF were cultured in the presence and absence of iron supplementation, and mounted in a spherical phantom for relaxation mapping at 3 Tesla. In addition to MR measures, cellular changes in iron and zinc were evaluated by inductively coupled plasma mass spectrometry, in ATP by luciferase bioluminescence and in transferrin receptor by Western blot. Only transverse relaxation rates were significantly higher in iron-supplemented, MagA- and HF + LF-expressing cells compared to non-supplemented cells and the parental control. R2* provided the greatest absolute difference and R2' showed the greatest relative difference, consistent with the notion that R2' may be a more specific indicator of iron-based contrast than R2, as observed in brain tissue. Iron supplementation of MagA- and HF + LF-expressing cells increased the iron/zinc ratio approximately 20-fold, while transferrin receptor expression decreased approximately 10-fold. Level of ATP was similar across all cell types and culture conditions. These results highlight the potential of magnetotactic bacterial gene expression for improving MR contrast.

Using the magnetosome to model effective gene-based contrast for magnetic resonance imaging.

Formation of iron biominerals is a naturally occurring phenomenon, particularly among magnetotactic bacteria which produce magnetite (Fe(3) O(4) ) in a subcellular compartment termed the magnetosome. Under the control of numerous genes, the magnetosome serves as a model upon which to (1) develop gene-based contrast in mammalian cells and (2) provide a mechanism for reporter gene expression in magnetic resonance imaging (MRI). There are two main components to the magnetosome: the biomineral and the lipid bilayer that surrounds it. Both are essential for magnetotaxis in a variety of magnetotactic bacteria, but nonessential for cell survival. Through comparative genome analysis, a subset of genes characteristic of the magnetotactic phenotype has been found both within and outside a magnetosome genomic island. The functions of magnetosome-associated proteins reflect the complex nature of this intracellular structure and include vesicle formation, cytoskeletal attachment, iron transport, and crystallization. Examination of magnetosome genes and structure indicates a protein-directed and stepwise assembly of the magnetosome compartment. Attachment of magnetosomes along a cytoskeletal filament aligns the magnetic particles such that the cell may be propelled along an external magnetic field. Interest in this form of magnetotaxis has prompted research in several areas of medicine, including magnetotactic bacterial targeting of tumors, MR-guided movement of magnetosome-bearing cells through vessels and molecular imaging of mammalian cells using MRI, and its hybrid modalities. The potential adaptation of magnetosome genes for noninvasive medical imaging provides new opportunities for development of reporter gene expression for MRI.

Optimization of time-to-peak analysis for differentiating malignant and benign breast lesions with dynamic contrast-enhanced MRI.

RATIONALE AND OBJECTIVES: The aim of this study was to investigate the feasibility of applying measures sensitive to time-to-peak (T(peak)) heterogeneity as indicators for malignancy on breast dynamic contrast-enhanced magnetic resonance imaging. MATERIALS AND METHODS: The study included 39 benign and 97 malignant breast lesions from 103 patients. Lesions were automatically segmented by k-means clustering. Voxel-by-voxel T(peak) values were extracted using an empirical model. The pth percentile values (p = 10, 20…) of the T(peak) distribution within each lesion and the fractional and absolute hot spot volumes were determined, where the hot spot volume is the volume of tissue with T(peak) less than a threshold value. Using the area under the receiver-operating characteristic curve (AUC), these measures were tested as indicators for differentiating fibroadenomas from invasive lesions and from ductal carcinoma in situ, as well as for differentiating nonfibroadenoma benign lesions from these malignant lesions. Region of interest-based T(peak) measurements were also tested. Finally, the relationship between hot spot volume and lesion volume was investigated. RESULTS: For differentiating fibroadenomas from malignant lesions, AUC values increased with decreasing values of p. At the optimal threshold (3 minutes), the hot spot volume provided high diagnostic performance (AUC ≥0.96 ± 0.02 for absolute hot spot volume). However, for differentiating nonfibroadenoma benign lesions from malignant lesions, AUC values were low. A significant correlation between absolute hot spot volume and lesion volume was found for malignant lesions and nonfibroadenoma benign lesions. CONCLUSION: Quantitative analysis of the T(peak) distribution can be optimized for diagnostic performance, providing indicators sensitive to intralesion T(peak) heterogeneity.

High-contrast 3D neonatal brain imaging with combined T1- and T2-weighted MP-RAGE.

Optimization of magnetization-prepared rapid gradient-echo (MP-RAGE) sequence variations for maximum white matter (WM) versus gray matter (GM) contrast in neonates at 3T was investigated. Numerical simulations were applied to optimize and compare three contrast preparation modules and to assess the effect of phase encoding (PE) order on contrast between WM and thin cortical GM layers. Simulations predict that a new sequence, which combines both T(1)- and T(2)-weighting into the contrast preparation and utilizes an interleaved elliptical-spiral PE order, should provide the strongest contrast between neonatal WM and cortical GM. This sequence was compared to a conventional MP-RAGE acquisition (i.e., T(1)-weighted preparation, centric PE order) for in vivo imaging of seven preterm newborn infants. Regional measurements of the contrast-to-noise ratio (CNR) between WM and GM demonstrated an increase of 50-70% (depending on GM region) using the new sequence, in good agreement with theoretical predictions. This improved contrast resulted in superior WM versus GM discrimination in intensity-based brain tissue segmentations.

White matter abnormalities in autism detected through transverse relaxation time imaging.

While neuroimaging studies have reported neurobiological abnormalities in autism, the underlying tissue abnormalities remain unclear. Quantitative transverse relaxation time (T2) imaging permits the examination of tissue abnormalities in vivo, with increased T2 largely reflecting increased tissue water. Blood flow and the presence of tissue iron may also affect T2. In this study, we used voxel-based relaxometry of the cerebrum and global averages to examine T2 abnormalities in autism. Nineteen males with autism (age: 9.2 +/- 3.0 years) and 20 male controls (age: 10.7 +/- 2.9 years) underwent magnetic resonance imaging at 3.0 T. Quantitative T2 maps, generated through gradient echo sampling of the free induction decay and echo, were segmented into gray matter, white matter, and cerebrospinal fluid. Average cerebral gray and white matter T2 were determined and compared between groups. To assess localized T2 differences, the quantitative T2 maps were warped to a template created for this study, smoothed, and compared using statistical parametric mapping. Patients with autism had an increase in average cerebral white matter T2, although no group differences were seen in average cerebral gray matter T2. Patients with autism also had bilateral regional T2 increases in the gray matter and associated white matter of the parietal lobes (primary sensory association areas) and occipital lobes (visual association areas) and in the white matter within the supplementary motor areas in the frontal lobes. The regional and global elevations in white matter T2 suggest abnormalities of white matter tissue water content in autism, which may represent a neurobiological basis for the aberrant cortical connectivity hypothesized to underlie the disorder.