Anatomic Neuroimaging Characteristics of Posterior Fossa Type A Ependymoma Subgroups.

BACKGROUND AND PURPOSE: Posterior fossa type A (PFA) ependymomas have 2 molecular subgroups (PFA-1 and PFA-2) and 9 subtypes. Gene expression profiling suggests that PFA-1 and PFA-2 tumors have distinct developmental origins at different rostrocaudal levels of the brainstem. We, therefore, tested the hypothesis that PFA-1 and PFA-2 ependymomas have different anatomic MR imaging characteristics at presentation. MATERIALS AND METHODS: Two neuroradiologists reviewed the preoperative MR imaging examinations of 122 patients with PFA ependymomas and identified several anatomic characteristics, including extension through the fourth ventricular foramina and encasement of major arteries and tumor type (midfloor, roof, or lateral). Deoxyribonucleic acid methylation profiling assigned ependymomas to PFA-1 or PFA-2. Information on PFA subtype from an earlier study was also available for a subset of tumors. Associations between imaging variables and subgroup or subtype were evaluated. RESULTS: No anatomic imaging variable was significantly associated with the PFA subgroup, but 5 PFA-2c subtype ependymomas in the cohort had a more circumscribed appearance and showed less tendency to extend through the fourth ventricular foramina or encase blood vessels, compared with other PFA subtypes. CONCLUSIONS: PFA-1 and PFA-2 ependymomas did not have different anatomic MR imaging characteristics, and these results do not support the hypothesis that they have distinct anatomic origins. PFA-2c ependymomas appear to have a more anatomically circumscribed MR imaging appearance than the other PFA subtypes; however, this needs to be confirmed in a larger study.

The Impact of Persistent Leukoencephalopathy on Brain White Matter Microstructure in Long-Term Survivors of Acute Lymphoblastic Leukemia Treated with Chemotherapy Only.

BACKGROUND AND PURPOSE: Survivors of acute lymphoblastic leukemia are at risk for neurocognitive deficits and leukoencephalopathy. We performed a longitudinal assessment of leukoencephalopathy and its associations with long-term brain microstructural white matter integrity and neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia treated on a modern chemotherapy-only protocol. MATERIALS AND METHODS: One hundred seventy-three survivors of acute lymphoblastic leukemia (49% female), treated on a chemotherapy-only protocol, underwent brain MR imaging during active therapy and repeat imaging and neurocognitive testing at follow-up (median, 13.5 years of age; interquartile range, 10.7-17.6 years; median time since diagnosis, 7.5 years; interquartile range, 6.3-9.1 years). Persistence of leukoencephalopathy was examined in relation to demographic and treatment data and to brain DTI in major fiber tracts and neurocognitive testing at follow-up. RESULTS: Leukoencephalopathy was found in 52 of 173 long-term survivors (30.0%) and persisted in 41 of 52 (78.8%) who developed it during therapy. DTI parameters were associated with leukoencephalopathy in multiple brain regions, including the corona radiata (fractional anisotropy, P = .001; mean diffusivity, P < .001), superior longitudinal fasciculi (fractional anisotropy, P = .02; mean diffusivity, P < .001), and superior fronto-occipital fasciculi (fractional anisotropy, P = .006; mean diffusivity, P < .001). Mean diffusivity was associated with neurocognitive impairment including in the genu of the corpus callosum (P = .04), corona radiata (P = .02), and superior fronto-occipital fasciculi (P = .02). CONCLUSIONS: Leukoencephalopathy during active therapy and neurocognitive impairment at long-term follow-up are associated with microstructural white matter integrity. DTI may be more sensitive than standard MR imaging for detection of clinically consequential white matter abnormalities in childhood acute lymphoblastic leukemia survivors treated with chemotherapy and in children undergoing treatment.

Relative ADC and Location Differ between Posterior Fossa Pilocytic Astrocytomas with and without Gangliocytic Differentiation.

BACKGROUND AND PURPOSE: Pilocytic astrocytomas, the most common posterior fossa tumors in children, are characterized by KIAA1549-BRAF fusions and shows excellent 5-year survival rates. Pilocytic astrocytoma with gangliocytic differentiation, a recently defined pilocytic astrocytoma variant that includes glial and neuronal elements similar to a ganglioglioma, may be distinguished from a classic ganglioglioma by molecular, radiologic, and histopathologic features. This study investigated whether imaging could distinguish posterior fossa pilocytic astrocytoma with and without gangliocytic differentiation. MATERIALS AND METHODS: Preoperative MRIs (± CTs) of 41 children (age range, 7 months to 15 years; mean age, 7.3 ± 3.7 years; 58.5% male) with pilocytic astrocytoma with gangliocytic differentiation (n = 7) or pilocytic astrocytoma (n = 34) were evaluated; differences in tumor location, morphology, and minimum relative ADC between tumor types were compared (Wilcoxon rank sum test, Fisher exact test). Histopathology and BRAF fusion/mutation status were reviewed. Associations of progression-free survival with diagnosis, imaging features, and BRAF status were examined by Cox proportional hazards models. RESULTS: Pilocytic astrocytoma with gangliocytic differentiation appeared similar to pilocytic astrocytoma but had lower minimum relative ADC (mean, 1.01 ± 0.17 compared with 2.01 ± 0.38 for pilocytic astrocytoma; P = .0005) and was more commonly located within midline structures (P = .0034). BRAF status was similar for both groups. Non-total resection (hazard ratio, 52.64; P = .0002), pilocytic astrocytoma with gangliocytic differentiation diagnosis (hazard ratio, 4.66; P = .0104), and midline involvement (hazard ratio, 3.32; P = .0433) were associated with shorter progression-free survival. CONCLUSIONS: Minimum relative ADC and tumor location may be useful adjuncts to histopathology in differentiating pilocytic astrocytoma with gangliocytic differentiation from pilocytic astrocytoma. Shorter progression-free survival in pilocytic astrocytoma with gangliocytic differentiation is likely due to a propensity for involvement of midline structures and poor resectability.

MR Imaging Characteristics of Wingless-Type-Subgroup Pediatric Medulloblastoma.

BACKGROUND AND PURPOSE: "Transcriptionally different" medulloblastoma groups are associated with specific signaling pathway abnormalities; hence, they may present with distinct imaging manifestations. In this study, we sought to describe the MR imaging features of wingless-type-subgroup medulloblastomas with embryologic correlations. MATERIALS AND METHODS: Pre- and postoperative imaging studies of 16 patients with wingless-type-subgroup medulloblastoma were evaluated for tumor location, involvement of surrounding CSF spaces or parenchymal structures, conventional and DWI signal properties, and postsurgical damage patterns. Laterality scores were assigned to tumors at each step in the evaluation process. Continuous variables were summarized by using descriptive statistics. The Wilcoxon signed rank test was performed to compare laterality scores. To determine the interobserver variability, we computed the intraclass correlation and Cohen κ coefficients. RESULTS: Wingless-type-subgroup medulloblastomas in our series were histopathologically "classic." Wingless-type-subgroup medulloblastomas occur in specific sites, with involvement of the foramen of Luschka (75%), the fourth ventricle (68.75%), the cisterna magna (31.25%), and the cerebellopontine angle cistern (18.75%). Laterality scores were low (<2) when preoperative primary and secondary anatomic features were evaluated separately, but they increased (>2) when all pre- and postoperative anatomic features were considered. Results were statistically shown to be reproducible (interclass correlation coefficient, 0.71-0.94; Cohen κ, 0.63-1.00). On the basis of anatomic lesion patterns, 4 location-based subtypes may be distinguished: 1) midline-intraventricular, 2) midline-extraventricular, 3) off-midline-intraventricular, and 4) off-midline-extraventricular, which represent a continuum. CONCLUSIONS: Wingless-type-subgroup medulloblastomas are lateralized tumors arising from the brain stem and cerebellum around the foramen of Luschka. Our current understanding of their embryologic origins is in concordance with the spatial distribution of these tumors.

Ischemic tolerance is associated with VEGF-C and VEGFR-3 signaling in the mouse hippocampus.

The functions of vascular endothelial growth factor C (VEGF-C) and the VEGF receptor 3 (VEGFR-3) in the nervous system are not well known. In this study, we examined the role of VEGF-C and VEGFR-3 in ischemic preconditioning (IPC)-induced tolerance in the mouse hippocampus. Adult male C57BL/6 mice were subjected to either severe ischemia (SI) induced by 40 min of bilateral common carotid artery occlusion (BCCAO) with or without IPC (5-min BCCAO) or IPC only. Cerebral blood flow was measured during ischemic periods using laser Doppler flowmetry. Neuronal damage was assessed histologically, and VEGF-C and VEGFR-3 expression levels were assessed through immunostaining. Fluoro-Jade B-labeled cells were abundant in the CA1 area 7 days after SI without IPC (sham+SI group), whereas cells were rarely labeled in mice subjected to IPC followed by SI (IPC+SI group). Similarly, the number of neuronal nuclei (NeuN)-positive cells in the CA1 area was significantly lower in the sham+SI group than in the IPC+SI group. Interestingly, we found that sublethal IPC treatment induced prominent VEGF-C expression in the CA1 pyramidal neurons and VEGFR-3 expression in the stratum radiatum and stratum lacunosum moleculare after 3 days of reperfusion that were sustained for 7 days. Moreover, VEGF-C immunoreactivity was also markedly increased, whereas VEGFR-3 expression was sustained in tolerance-acquired CA1 neurons after SI. Application of a VEGFR-3 inhibitor, SAR131675, abolished the IPC-induced neuroprotection in a dose-dependent manner in the mouse hippocampus. These results suggest that VEGF-C/VEGFR-3 signaling is associated with IPC-induced hippocampal tolerance to lethal ischemia.

Digital topological analysis of in vivo magnetic resonance microimages of trabecular bone reveals structural implications of osteoporosis.

Osteoporosis is a disease characterized by bone volume loss and architectural deterioration. The majority of work aimed at evaluating the structural implications of the disease has been performed based on stereologic analysis of histomorphometric sections. Only recently noninvasive imaging methods have emerged that provide sufficient resolution to resolve individual trabeculae. In this article, we apply digital topological analysis (DTA) to magnetic resonance microimages (mu-MRI) of the radius obtained at 137 x 137 x 350 microm3 voxel size in a cohort of 79 women of widely varying bone mineral density (BMD) and vertebral deformity status. DTA is a new method that allows unambiguous determination of the three-dimensional (3D) topology of each voxel in a trabecular bone network. The analysis involves generation of a bone volume fraction map, which is subjected to subvoxel processing to alleviate partial volume blurring, followed by thresholding and skeletonization. The skeletonized images contain only surfaces, profiles, curves, and their mutual junctions as the remnants of trabecular plates and rods after skeletonization. DTA parameters were compared with integral BMD in the lumbar spine and femur as well as MR-derived bone volume fraction (BV/TV). Vertebral deformities were determined based on sagittal MRIs of the spine with a semiautomatic method and the number of deformities counted after threshold setting. DTA structural indices were found the strongest discriminators of subjects with deformities from those without deformities. Subjects with deformities (n = 29) had lower topological surface (SURF) density (p < 0.0005) and surface-to-curve ratio (SCR; a measure of the ratio of platelike to rodlike trabeculae; p < 0.0005) than those without. Profile interior (PI) density, a measure of intact trabecular rods, was also lower in the deformity group (p < 0.0001). These data provide the first in vivo evidence for the structural implications inherent in postmenopausal osteoporosis accompanying bone loss, that is, the conversion of trabecular plates to rods and disruption of rods due to repeated osteoclastic resorption.

Origin of a signal intensity loss artifact in fat-saturation MR imaging.

Artifactual water signal intensity loss can be observed on fat-saturation magnetic resonance (MR) images of inhomogeneous regions such as the thorax. Magnetic effects of air inclusions on fat-saturation pulses were investigated as the possible origin of this artifact. Computer simulation results agreed well with observed production of water saturation by means of nominal fat suppression in MR imaging of phantoms and a representative clinical example.

Cross-sectional study of osteopenia with quantitative MR imaging and bone densitometry.

PURPOSE: To evaluation the cancellous bone-induced intravoxel spin dephasing rate (R2') and its relationship to bone mineral density and marrow fat and to examine these parameters as predictors of vertebral fracture status. MATERIALS AND METHODS: R2' and R2, the rate constants for reversible and irreversible spin dephasing, and marrow fat fraction were measured in the lumbar vertebrae and proximal femur. One hundred thirty-nine subjects (mean age, 62.4 years +/- 11.4 [SD]; 33 men, 106 women) had spinal dual-energy x-ray absorptiometric bone mineral density (BMD) T scores ranging from +3 to -5. R2', BMD, and bone marrow composition as determinants of vertebral fracture status were examined. RESULTS: Strongest single predictors of fracture status for BMD and R2' were the Ward triangle (r(2) = 0.48) and trochanter (r(2) = 0.37), respectively. Combined, the two parameters and sites increased fracture prediction (r(2) = 0. 62), whereas the combination of multiple BMD sites did not. Multivariate regression involving marrow fat fraction further improved fracture status prediction. R2' was correlated with BMD at all sites, although slopes differed by a factor of up to 2.5, which reflected differences in trabecular orientation relative to the static field. R2, the true transverse relaxation rate, was negatively correlated with marrow fat fraction. A non-age-related increase in marrow fat fraction in osteoporosis parallels earlier findings in animal models. CONCLUSION: Cancellous bone marrow R2' measured in the proximal femur provides information, which, with BMD, improves prediction of vertebral fracture status.

Topological analysis of trabecular bone MR images.

Recently, imaging techniques have become available which permit nondestructive analysis of the three-dimensional (3-D) architecture of trabecular bone (TB), which forms a network of interconnected plates and rods. Most osteoporotic fractures occur at locations rich in TB, which has spurred the search for architectural parameters as determinants of bone strength. In this paper, we present a new approach to quantitative characterization of the 3-D microarchitecture of TB, based on digital topology. The method classifies each voxel of the 3-D structure based on the connectivity information of neighboring voxels. Following conversion of the 3-D digital image to a skeletonized surface representation containing only one-dimensional (1-D) and two-dimensional (2-D) structures, each voxel is classified as a curve, surface, or junction. The method has been validated by means of synthesized images and has subsequently been applied to TB images from the human wrist. The topological parameters were found to predict Young's modulus (YM) for uniaxial loading, specifically, the surface-to-curve ratio was found to be the single strongest predictor of YM (r2 = 0.69). Finally, the method has been applied to TB images from a group of patients showing very large variations in topological parameters that parallel much smaller changes in bone volume fraction (BVF).

The effects of N-methyl-N-nitrosourea and azoxymethane on focal cerebral infarction and the expression of p53, p21 proteins.

If the activity of pro-apoptotic genes can be down-regulated by certain chemicals, cells may be protected from apoptosis. To test this hypothesis in a cerebral infarction model, we used N-methyl-N-nitrosourea (MNU) and azoxymethane (AOM), which were approved gene-modulating chemicals. A focal cerebral infarction was created by coagulation of the right middle cerebral artery and ipsilateral common carotid artery (CCA) and simultaneous transient occlusion of the contralateral CCA for 30 min in 25 adult Sprague-Dawley rats that were sacrificed 24 h later. In one group (n=7), MNU (5 mg/kg) was injected intravenously 30 min before initiation of ischemia. In another group (n=7), AOM (15 mg/kg) was administered intraperitoneally before 24 h of ischemia. The infarction volumes were checked and the brains were stained for p53 and p21 proteins. The width in micrometers of the peri-infarct area containing p53 or p21 protein-positive cells, and the number of p53 or p21 protein-positive cells (cells/HPF) were measured at an adjacent peri-infarct area. The AOM-treated group showed a significantly reduced infarction volume (by 42.5%, p<0.001), a significantly greater number of p53 positive cells (by 12.0%, p<0. 05), and a significantly wider p53 protein-positive area (by 15.6%, p<0.01) than the untreated group. AOM did not show any influence on the expression pattern of the p21 protein. MNU had no effect in the expression of p53 or p21 proteins. As a result, we concluded that AOM revealed a protective effect in ischemia by suppressing the pro-apoptotic activity of the p53 gene. Safer chemicals that can modulate apoptotic genes, if any, will provide a new therapeutic modality for cerebral infarction.

Relationship between cancellous bone induced magnetic field and ultrastructure in a rat ovariectomy model.

The site-dependent variations in trabecular bone morphology were studied in the rat tibia by magnitude and phase difference three-dimensional nuclear magnetic resonance microscopy and image processing, and the implications of ovariectomy were evaluated. Specimens excised from the proximal tibial metaphysis in ovariectomized (n = 7) and intact control (n = 4) rats were imaged at 9.4T with their anatomic axes parallel to the direction of the magnetic field. An echo-offset 3D rapid spin-echo excitation pulse sequence was used to generate phase difference maps, from which the standard deviation of the phase difference, sigma(delta psi), was calculated. In addition, a fictitious rate constant, R2', was calculated from the slope of the exponential portion of the Fourier transform of the phase difference histogram. Trabecular bone volume fraction was also determined in the same volume of interest. The results show strong correlations between bone volume fraction and both sigma(delta psi) and R2', suggesting that these parameters could be useful for nondestructive assessment of trabecular bone volume.

Experimental evaluation of a surface charge method for computing the induced magnetic field in trabecular bone.

The magnetic field induced in the pores of trabecular bone as a result of the susceptibility difference between bone and bone marrow was computed with the aid of magnetic surface charge models generated from images of trabecular bone specimens acquired at 78 and 63 microm resolution. The predicted field was compared with the values derived from 2D and 3D field maps obtained by echo-offset imaging techniques and excellent agreement was found between the two methods. Finally, from the slopes of regression between the experimental and computed fields, the absolute susceptibility of bone was nondestructively determined as -11.0 x 10(-6) (MKS), which is in close agreement with a reported value of -11.3 x 10(-6) obtained with powdered bone by means of a spectroscopic susceptibility matching technique (J. A. Hopkins and F. W. Wehrli, Magn. Reson. Med. 37, 494-500 (1997)).

Effect of prostaglandin and bisphosphonate on cancellous bone volume and structure in the ovariectomized rat studied by quantitative three-dimensional nuclear magnetic resonance microscopy.

The purpose of this work was to evaluate the potential of nuclear magnetic resonance microscopy (NMRM) in conjunction with a processing technique to monitor the effect of preventive agents in an ovariectomized (OVX) rat. Twenty-five female Sprague-Dawley rats were OVX at 6 months of age (except for the intact control group), allowed to lose bone for 60 days, and then treated for 60 days. During treatment, animals were administered vehicle, prostaglandin E2 (PGE2; 6 mg/kg), or alendronate (3 microg/kg) subcutaneously once a day. Subsequently, tibiae were harvested and the marrow removed. NMRM was carried out at 9.4 T, with the specimens immersed in 1.2 mM diethylenetriaminepentaacetic acid-gadolinium salt (Gd-DTPA) aqueous solution. A three-dimensional (3D) partial flip-angle pulse sequence was used, providing a 1283 array of (46 microm)3 isotropic voxels. Fifty of the 128 axial images in the 3D data set comprising approximately 2.4 mm volume distal to the growth plate were processed from each specimen using a probability-based method for determining bone volume fraction (BVF), tubularity, contiguity, as well as the mean trabecular plate thickness and separation. PGE2 and alendronate altered BVF consistently at all tibial regions. The effect of alendronate was to keep BVF about midway between intact and OVX, whereas PGE2 returned BVF to intact levels. The other parameters showed similar responses to treatment. The strongest discriminator was trabecular BVF, which could obviously differentiate the groups. The study establishes NMRM as a nondestructive histomorphometric method for the quantitative evaluation of drug response in a rat ovariectomy model.

Cancellous bone volume and structure in the forearm: noninvasive assessment with MR microimaging and image processing.

PURPOSE: To develop and apply a method for the derivation of cancellous bone architectural parameters from in vivo magnetic resonance (MR) images of the distal radius and to evaluate these parameters as predictors of vertebral fracture status in osteopenia. MATERIALS AND METHODS: MR images (137 x 137 x 500-micron3 voxel size) were acquired with a three-dimensional partial flip-angle spin-echo pulse sequence in the distal radius of 36 women. Subjects were classified as healthy or with osteoporosis on the basis of vertebral deformity and bone mineral density (BMD). Images rated as of adequate quality in 20 subjects were processed with a method that is applicable in the limited spatial resolution regime. The method relies on histogram deconvolution to obviate binary segmentation. Cancellous bone structure was treated as a quasi-regular lattice and analyzed with spatial autocorrelation, yielding parameters that quantify intertrabecular spacing, contiguity, and a measure of longitudinal alignment called tubularity. RESULTS: Whereas neither BMD nor any of the structural parameters individually correlated significantly with vertebral deformity fraction, a simple function that involved tubularity and longitudinal spacing predicted deformity fraction well (r = .78, P < .005). CONCLUSION: Histomorphometric parameters characterizing cancellous bone in the distal radius can be derived from in vivo MR microimages and are predictive of vertebral deformity.

New architectural parameters derived from micro-MRI for the prediction of trabecular bone strength.

This article reviews recent progress in magnetic resonance microimaging of cancellous bone in vitro and in vivo from the perspective of the authors' laboratory. It is shown that in particular in vivo the key technical prerequisites to satisfy are: (i) achieving sufficient signal-to-noise ratio (SNR) to allow for adequate spatial resolution; (ii) the image processing algorithms have to be robust enough to provide accurate structural information in the limited spatial resolution regime, i.e., in the presence of inevitable partial volume blurring and noise. The practical lower limit of voxel size in vivo was found to be about 6 x 10(-3) mm3 in the radius, and about 10(-4) mm3 for small specimens in vitro with state-of-the-art equipment and scan times of 10 and 30 minutes, resp., and SNR approximately 10. Finally, data are presented highlighting the potential of these methods for predicting the bone's elastic modulus in vitro and fracture risk in vivo.

Probability-based structural parameters from three-dimensional nuclear magnetic resonance images as predictors of trabecular bone strength.

The mechanical competence of trabecular bone is a function of its apparent density and three-dimensional (3D) distribution. Three-dimensional structure is typically inferred from histomorphometry and stereology on a limited number of two-dimensional anatomic sections. In this work 3D nuclear magnetic resonance (NMR) images of anisotropic trabecular bone from the distal radius were analyzed in terms of a series of new structural parameters which are obtainable at relatively crude resolution, i.e., in the presence of substantial partial volume blurring. Unlike typical feature extraction techniques requiring image segmentation, the method relies on spatial autocorrelation analysis, which is based on the probability of finding bone at specified locations. The structural parameters were measured from high-resolution images (78x78x78 microm3 voxels) of 23 trabecular bone specimens from the distal radius. Maximum-likelihood bone volume fractions (BVF) were calculated for each voxel and a resolution achievable in vivo (156x156x391 microm3 voxels) was simulated by averaging BVF's from neighboring voxels. The parameters derived from the low-resolution images were found to account for 91% of the variation in Young's modulus. The results suggest that noninvasive assessment of the mechanical competence of trabecular bone in osteoporotic patients may be feasible.

A single-scan imaging technique for measurement of the relative concentrations of fat and water protons and their transverse relaxation times.

A two-component chemical-shift-imaging technique is described from which fat and water images can be obtained in a single scan and in the presence of an inhomogeneous field. In addition, the method provides transverse relaxation rates R2 and R2' separately for each of the spectral components. The method is a combination and extension of the GESFIDE [gradient echo sampling of FID and echo, J. Ma and F. W. Wehrli, J. Magn. Reson. B 111, 61 (1996)] and the multipoint Dixon techniques. It is based on sampling the descending and ascending portions of a Hahn spin echo with a train of gradient echoes which are spaced at one-half of the chemical-shift modulation period. Processing of the complex echo data, involving an automated phase unwrapping algorithm, affords relative amplitudes and transverse relaxation rates of the two spectral components. An additional benefit of the method is its superior signal-to-noise ratio resulting from echo summation. Applications targeted and illustrated involve MRI osteodensitometry of trabecular bone in the presence of varying fractions of hematopoietic and fatty bone marrow.