Novel MYC-driven medulloblastoma models from multiple embryonic cerebellar cells.

Group3 medulloblastoma (MBG3) that predominantly occur in young children are usually associated with MYC amplification and/or overexpression, frequent metastasis and a dismal prognosis. Physiologically relevant MBG3 models are currently lacking, making inferences related to their cellular origin thus far limited. Using in utero electroporation, we here report that MBG3 mouse models can be developed in situ from different multipotent embryonic cerebellar progenitor cells via conditional expression of Myc and loss of Trp53 function in several Cre driver mouse lines. The Blbp-Cre driver that targets embryonic neural progenitors induced tumors exhibiting a large-cell/anaplastic histopathology adjacent to the fourth ventricle, recapitulating human MBG3. Enforced co-expression of luciferase together with Myc and a dominant-negative form of Trp53 revealed that GABAergic neuronal progenitors as well as cerebellar granule cells give rise to MBG3 with their distinct growth kinetics. Cross-species gene expression analysis revealed that these novel MBG3 models shared molecular characteristics with human MBG3, irrespective of their cellular origin. We here developed MBG3 mouse models in their physiological environment and we show that oncogenic insults drive this MB subgroup in different cerebellar lineages rather than in a specific cell of origin.

Evaluation of SWI in children with sickle cell disease.

BACKGROUND AND PURPOSE: SWI is a powerful tool for imaging of the cerebral venous system. The SWI venous contrast is affected by blood flow, which may be altered in sickle cell disease. In this study, we characterized SWI venous contrast in patients with sickle cell disease and healthy control participants and examined the relationships among SWI venous contrast, and hematologic variables in the group with sickle cell disease. MATERIALS AND METHODS: A retrospective review of MR imaging and hematologic variables from 21 patients with sickle cell disease and age- and sex-matched healthy control participants was performed. A Frangi vesselness filter was used to quantify the attenuation of visible veins from the SWI. The normalized visible venous volume was calculated for quantitative analysis of venous vessel conspicuity. RESULTS: The normalized visible venous volume was significantly lower in the group with sickle cell disease vs the control group (P < .001). Normalized visible venous volume was not associated with hemoglobin, percent hemoglobin F, percent hemoglobin S, absolute reticulocyte count, or white blood cell count. A hypointense arterial signal on SWI was observed in 18 of the 21 patients with sickle cell disease and none of the 21 healthy control participants. CONCLUSIONS: This study demonstrates the variable and significantly lower normalized visible venous volume in patients with sickle cell disease compared with healthy control participants. Decreased venous contrast in sickle cell disease may reflect abnormal cerebral blood flow, volume, velocity, or oxygenation. Quantitative analysis of SWI contrast may be useful for investigation of cerebrovascular pathology in patients with sickle cell disease, and as a tool to monitor therapies. However, future studies are needed to elucidate physiologic mechanisms of decreased venous conspicuity in sickle cell disease.

Diffusion tensor imaging of tract involvement in children with pontine tumors.

BACKGROUND AND PURPOSE: Conventional MR imaging permits subcategorization of brain stem tumors by location and focality; however, assessment of white matter tract involvement by tumor is limited. Diffusion tensor imaging (DTI) is a promising method for visualizing white matter tract tumor involvement supratentorially. We investigated the ability of DTI to visualize and quantify white matter tract involvement in pontine tumors. METHODS AND MATERIALS: DTI data (echo-planar, 1.5T) were retrospectively analyzed in 7 patients with pontine tumors (6 diffuse, 1 focal), 4 patient controls, and 5 normal volunteers. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were calculated from the diffusion tensor in 6 regions of interest: bilateral corticospinal tracts, transverse pontine fibers, and medial lemnisci. Relationships between FA and ADC values and results of the neurologic examinations were evaluated. RESULTS: The corticospinal tracts and transverse pontine fibers were affected more often than the medial lemnisci. The DTI parameters (FA and ADC) were significantly altered in all tracts of patients with pontine tumors (P < .05), compared with those values in the control groups. A marginally significant (P = .057) association was seen between the severity of cranial nerve deficit and decreased FA. CONCLUSION: DTI provided superior visualization and quantification of tumor involvement in motor, sensory, and transverse pontine tracts, compared with information provided by conventional MR imaging. Thus, DTI may be a sensitive measure of tract invasion. Further prospective studies are warranted to assess the ability of DTI to delineate tumor focality and improve risk stratification in children with pontine tumors.

More than meets the eye: significant regional heterogeneity in human cortical T1.

Segmented k-space acquisition of data was used to decrease the acquisition time and to increase the imaging resolution of the precise and accurate inversion recovery (PAIR) method of measuring T(1). We validated the new TurboPAIR method by measuring T(1) in 158 regions of interest in 12 volunteers, using both PAIR and TurboPAIR. We found a 3% difference between methods, which could be corrected by linear regression. After validation, the TurboPAIR method was used to test a hypothesis that there is significant regional heterogeneity in cortical T(1). We measured cortical gray matter T(1) in 11 right-handed volunteers, in 48 regions of interest scattered over frontal and parietal cortex, and in 46 ROIs along the central sulcus (CS). We found that T(1) in the CS is less than T(1) elsewhere in the cortex (p<0.001), and that there is considerable hemispheric asymmetry in T(1) in gray matter, but not in white matter. In central gray structures (caudate, thalamus, nucleus pulvinarus), and in the posterior CS (sensory cortex), right hemisphere T(1) was significantly greater than left hemisphere T(1) (p< or =0.004). In cortical gray matter of the frontal lobe and anterior CS (motor cortex), left hemisphere T(1) was significantly greater than right hemisphere T(1) (p< or =0.003). These findings demonstrate that there is considerable regional heterogeneity in human cortical T(1) that is unexplained by differences in tissue iron content, but may be evidence of an inherent anatomic asymmetry of the brain.

The correlation between phase shifts in gradient-echo MR images and regional brain iron concentration.

The purpose of this study was to investigate the relationship between the magnetic susceptibility of brain tissue and iron concentration. Phase shifts in gradient-echo images (TE = 60 ms) were measured in 21 human subjects, (age 0.7-45 years) and compared with published values of regional brain iron concentration. Phase was correlated with brain iron concentration in putamen (R2 = 0.76), caudate (0.72), motor cortex (0.68), globus pallidus (0.59) (all p < 0.001), and frontal cortex (R2 = 0.19, p = 0.05), but not in white matter (R2 = 0.05,p = 0.34). The slope of the regression (degrees/mg iron/g tissue wet weight) varied over a narrow range from -1.2 in the globus pallidus and frontal cortex to -2.1 in the caudate. These results suggest that magnetic resonance phase reflects iron-induced differences in brain tissue susceptibility in gray matter. The lack of correlation in white matter may reflect important differences between gray and white matter in the cellular distribution and the metabolic functions of iron. Magnetic resonance phase images provide insight into the magnetic state of brain tissue and may prove to be useful in elucidating the relationship between brain iron and tissue relaxation properties.

Diffuse T1 reduction in gray matter of sickle cell disease patients: evidence of selective vulnerability to damage?

The objective of our study was to test the hypothesis that subtle brain abnormality can be present in pediatric sickle cell disease (SCD) patients normal by conventional MR imaging (cMRI). We examined 50 SCD patients to identify those patients who were normal by cMRI. Quantitative MR imaging (qMRI) was then used to map spin-lattice relaxation time (T1) in a single slice in brain tissue of all 50 patients and in 52 healthy age-similar controls. We also used a radiofrequency (RF) pulse to saturate blood spins flowing into the T1 map slice, to characterize the effect of blood flow on brain T1. Abnormalities were noted by cMRI in 42% (21/50) of patients, with lacunae in 32%, and encephalo malacia in 20%. Brain T1 in patients normal by cMRI was significantly lower than controls, in caudate, thalamus, and cortex (p < or =0.007), and regression showed that gray matter T1 abnormality was present in caudate and cortex by age 4 (p < or =0.002). In patients abnormal by cMRI, T1 reductions in gray matter were larger and more significant. White matter T1 was not significantly increased except in patients abnormal by cMRI. RF saturation in a slab below the T1 map produced no significant change in T1, compared to RF saturation in a slab above the T1 map, suggesting that inflow of untipped spins in blood does not cause an artifactual shortening of T1. Gray matter T1 abnormality was present in patients normal by cMRI, while white matter T1 abnormality was present only in patients also abnormal by cMRI. These findings suggest that gray matter is selectively vulnerable to damage in pediatric SCD patients and that white matter damage occurs later in the disease process. Our inability to find an effect from saturation of inflowing blood implies that rapid perfusion cannot account for T1 reduction in gray matter.

Effect of a gadodiamide contrast agent on the reliability of brain tissue T1 measurements.

To determine whether brain spin-lattice relaxation time (T1) can routinely be measured after contrast-agent injection, we measured T1 by a precise and accurate inversion-recovery (PAIR) method in five brain tumor patients, before and again after contrast-agent injection. The T1 in at least 20 regions of interest (ROIs) was measured in each patient, avoiding areas of contrast enhancement visible by conventional MR imaging. Contrast-agent injection reduced T1 in 51 regions of interest in white matter by less than 1% (not significant), and in 50 regions of interest in gray matter by less than 2% (p = 0.001). Pixel-by-pixel plots demonstrate that T1 is reduced substantially in extra-parenchymal tissues, but not in brain tissues. Therefore, T1 mapping with the precise and accurate inversion-recovery method can routinely be done after contrast injection. Our results suggest that the precise and accurate inversion-recovery method is not sensitive to the T1 of blood in the presence of an intact blood-brain barrier, although a substantial T1 reduction does occur in the absence of a blood-brain barrier.

Correction of errors caused by imperfect inversion pulses in MR imaging measurement of T1 relaxation times.

Spin-lattice (T1) relaxation times were measured by an inversion-recovery magnetic resonance imaging method with a slice-selective inversion pulse (SIP), a non-selective rectangular inversion pulse (RIP), or a B1-insensitive adiabatic inversion pulse (AIP). Data analysis either assumed perfect inversion (two-parameter fit) or allowed for imperfect inversion (three-parameter fit). Imperfect inversion pulses caused low T1 values in phantoms with a two-parameter fit, while three-parameter T1 estimates were accurate over the range 430-2670 ms. A difference of approximately 10% between two-parameter and three-parameter T1 values in normal human brain tissue was attributed to B1 inhomogeneity with the slice-selective inversion pulse and rectangular inversion pulse, to the slice profile with the slice-selective inversion pulse, and to T2 effects for the adiabatic inversion pulse. Any T1 method that relies on accurate flip angles may have a significant systematic error in vivo. Phantom accuracy does not ensure accuracy in vivo, because phantoms may have a more homogeneous B1 field and a longer T2 than do biological samples.

Age-related changes in brain T1 are correlated with iron concentration.

Age-related changes in brain T1 from 115 healthy subjects (range, 4.5-71.9 yr) were analyzed in relation to published regional brain iron concentration in cortex, caudate, putamen, and frontal white matter. The relaxation rate in these structures was linear with respect to iron concentration (P < 0.001). The iron relaxivity, k1 (s(-1)/mg iron/g wet weight), was much higher in cortex (5.5) and white matter (6.1) than in caudate (1.7) and putamen (1.0). These results are consistent with evidence that iron is an important factor in determining the relaxation properties of brain tissue. Iron relaxivity may reflect regional differences in the physical state of brain iron or in the interaction of brain iron with tissue water.

Proton MR spectroscopy of pediatric brain tumors.

Primary central nervous system tumors are the most common solid tumors in children. Their overall frequency is second only to that of leukemia. Many brain tumors in children are relatively benign and can be successfully treated with surgery or radiation therapy, but progress in treating the malignant forms of these neoplasms lags behind that for leukemias and other solid tumors. This article discusses how MR spectroscopy is used to manage the individualized treatment of children with brain tumors.

Quantitative MRI of the brain in children with sickle cell disease reveals abnormalities unseen by conventional MRI.

Conventional MRI (cMRI) has shown that brain abnormalities without clinical stroke can manifest in patients with sickle cell disease (SCD). We used quantitative MRI (qMRI) and psychometric testing to determine whether brain abnormalities can also be present in patients with SCD who appear normal on cMRI. Patients 4 years of age and older with no clinical evidence of stroke were stratified by cMRI as normal (n = 17) or abnormal (n = 13). Spin-lattice relaxation time (T1) of gray and white matter structures was measured by the precise and accurate inversion recovery (PAIR) qMRI method. Patient cognitive ability was assessed with a standard psychometric instrument (WISC-III or WISC-R). In all 30 patients with SCD, qMRI T1 was lower than in 24 age- and race-matched controls, in cortical gray matter (P < .0006) and caudate (P < .0009), as well as in the ratio of gray-to-white matter T1 (P < .008). In the 17 patients who were shown to be normal by cMRI, qMRI T1 was still lower than in controls, in both cortical gray matter (P < .02) and caudate (P < .004). Histograms of voxel T1 show that the proportion of voxels with T1 values intermediate between gray and white matter (ie, consistent with encephalomalacia) was 9% higher than controls in patients shown to be normal by cMRI (P < .05) and 15% higher than controls in patients shown to be abnormal by cMRI (P < .0005). The full scale intelligence quotient (FSIQ) of all patients with SCD was 75, compared to the FSIQ of 88 in a historical control group of patient siblings (P < .001). The FSIQ of patients shown to be normal by cMRI was 79, significantly lower than the FSIQ of patient siblings (P < .04). The FSIQ of 71 in patients shown to be abnormal by cMRI was significantly lower than both the patient siblings (P < .005) and the patients shown to be normal by cMRI (P < .04). Patients shown to be abnormal by cMRI scored lower than patients shown to be normal by cMRI, specifically on the subtests of vocabulary (P = .003) and information (P = .03). Cognitive impairment is thus significant, even in patients with SCD who were shown to be normal by cMRI, suggesting that cMRI may be insensitive to subtle neurologic damage that can be detected by qMRI. Because cognitive impairment can occur in children normal by cMRI, our findings imply that prophylactic therapy may be needed earlier in the course of SCD to mitigate neurologic damage.

Ectasia of the basilar artery in children with sickle cell disease: relationship to hematocrit and psychometric measures.

GOAL: To determine whether children with sickle cell disease (SCD), but without clinical evidence of cerebrovascular disease, have vasculopathy shown by quantitative magnetic resonance angiography (MRA). METHODS: In a retrospective review of MRA films, we compared 47 SCD patients with 49 control patients. Time-of-flight three-dimensional T1-weighted gradient-echo images were reconstructed, by maximum-intensity projection, to show the basilar artery in coronal view, and basilar volume was calculated from measurements made on films. Basilar volume was correlated with hematocrit and with results of cognitive testing. FINDINGS: Mean basilar artery volume was 74% larger in SCD patients than in controls (P<.001). If the upper limit of normal is defined as mean adult volume +2 SD (< or =427 mm(3)), 2% (1 of 43) of controls but 37% (17 of 46) of SCD patients exceed this value (chi(2)=19.0; P<.001). Basilar volume correlated inversely with hematocrit (r=-.60; P<.0001), with full-scale IQ (r=-.62; P<.005), and with freedom from distractability (r=-.61; P<.006) in SCD patients. Analysis of basilar artery tissue from a 5-year-old SCD patient showed that basilar dilatation can be associated with pathological changes typical of hypertension. CONCLUSIONS: Approximately 37% of a heterogenous group of pediatric SCD patients had ectasia of the basilar artery. Quantitative MRA is sensitive to subtle vasculopathy that can go undetected in the qualitative analysis more commonly done. Data suggest that there is a substantial elevation of arteriolar blood volume in pediatric SCD patients, and that such patients may share disease features in common with adult hypertension.

Age-related changes in the pediatric brain: quantitative MR evidence of maturational changes during adolescence.

PURPOSE: To determine whether a quantitative MR imaging method to map spin-lattice relaxation time (T1) can be used to characterize maturational changes in the normal human brain. METHODS: An inversion-recovery technique was used to map T1 transversely at the level of the basal ganglia in a study population of 19 healthy children (4 to 10 years old) and 31 healthy adolescents (10 to 20 years old), and in a normative population of 20 healthy adults (20 to 30 years old). RESULTS: Nonparametric analysis of variance showed that T1 decreases with age in the genu, frontal white matter, caudate, putamen, anterior thalamus, pulvinar nucleus, optic radiation, cortical gray matter (all P < .0001), and occipital white matter. There was a significant reduction in T1 between childhood (mean age, 7.1 +/- 1.4) and adolescence (mean age, 13.5 +/- 2.6) in all brain structures, but there was also a significant reduction in T1 between adolescence (mean age, 13.5 +/- 2.6) and adulthood (mean age, 26.5 +/- 3.4) in all brain structures except occipital white matter. Regression shows that T1 declines to within the range (mean +/- 2 SD) of young adult T1 values by about 2 years in the occipital white matter, by about 4 years in the genu, by 11 years in the cortical gray matter, by 11 years in the frontal white matter, and by 13 years in the thalamus. CONCLUSION: Brain structures mature at strikingly different rates, yet the ratio of gray matter T1 to white matter T1 does not change significantly with age. Thus, conventional MR imaging methods based on inherent contrast are insensitive to these changes. Age-related changes tend to reach completion sooner in white matter than in gray matter tracts. Such normative data are essential for studies of specific pediatric disorders and may be useful for assessing brain maturation in cases of developmental delay.

Establishing norms for age-related changes in proton T1 of human brain tissue in vivo.

The goal of this study was to determine the expected normal range of variation in spin-lattice relaxation time (T1) of brain tissue in vivo, as a function of age. A previously validated precise and accurate inversion recovery method was used to map T1 transversely, at the level of the basal ganglia, in a study population of 115 healthy subjects (ages 4 to 72; 57 male and 58 female). Least-squares regression analysis shows that T1 varied as a function of age in pulvinar nucleus (R2 = 56%), anterior thalamus (R2 = 51%), caudate (R2 = 50%), frontal white matter (R2 = 47%), optic radiation (R2 = 39%), putamen (R2 = 36%), genu (R2 = 22%), occipital white matter (R2 = 20%) (all p < 0.0001), and cortical gray matter (R2 = 53%) (p < 0.001). There were no significant differences in T1 between men and women. T1 declines throughout adolescence and early adulthood, to achieve a minimum value in the fourth to sixth decade of life, then T1 begins to increase. Quantitative magnetic resonance imaging provides evidence that brain tissue continues to change throughout the lifespan among healthy subjects with no neurologic deficits. Age-related changes follow a strikingly different schedule in different brain tissues; white matter tracts tend to reach a minimum T1 value, and to increase again, sooner than do gray matter tracts. Such normative data may prove useful for the early detection of brain pathology in patients.

Clinical value of proton magnetic resonance spectroscopy for differentiating recurrent or residual brain tumor from delayed cerebral necrosis.

PURPOSE: Delayed cerebral necrosis (DN) is a significant risk for brain tumor patients treated with high-dose irradiation. Although differentiating DN from tumor progression is an important clinical question, the distinction cannot be made reliably by conventional imaging techniques. We undertook a pilot study to assess the ability of proton magnetic resonance spectroscopy (1H MRS) to differentiate prospectively between DN or recurrent/residual tumor in a series of children treated for primary brain tumors with high-dose irradiation. METHODS AND MATERIALS: Twelve children (ages 3-16 years), who had clinical and MR imaging (MRI) changes that suggested a diagnosis of either DN or progressive/recurrent brain tumor, underwent localized 1H MRS prior to planned biopsy, resection, or other confirmatory histological procedure. Prospective 1H MRS interpretations were based on comparison of spectral peak patterns and quantitative peak area values from normalized spectra: a marked depression of the intracellular metabolite peaks from choline, creatine, and N-acetyl compounds was hypothesized to indicate DN, and median-to-high choline with easily visible creatine metabolite peaks was labeled progressive/recurrent tumor. Subsequent histological studies identified the brain lesion as DN or recurrent/residual tumor. RESULTS: The patient series included five cases of DN and seven recurrent/residual tumor cases, based on histology. The MRS criteria prospectively identified five out of seven patients with active tumor, and four out of five patients with histologically proven DN correctly. Discriminant analysis suggested that the primary diagnostic information for differentiating DN from tumor lay in the normalized MRS peak areas for choline and creatine compounds. CONCLUSIONS: Magnetic resonance spectroscopy shows promising sensitivity and selectivity for differentiating DN from recurrent/progressive brain tumor. A novel diagnostic index based on peak areas for choline and creatine compounds may provide a simple discriminant for differentiating DN from recurrent or residual primary brain tumors.

Statistical error mapping for reliable quantitative T1 imaging.

We developed a statistically based error image for rapid appreciation of unreliable regions in quantitative water proton T1 images. The chi-squared error and co-efficient of variation of the fitted parameter were used to estimate uncertainties in the goodness-of-fit to mono-exponential T1 relaxation and the reliability of the calculated T1, respectively, for each pixel. Errors exceeding a statistical threshold based on a .1 acceptance criterion were displayed as a color-coded overlay on the T1 image. Error maps of quantitative T1 images from 31 healthy volunteers showed a characteristic error structure; few pixels within the parenchyma had excessive errors. Clinical cases with stroke and sickle cell disease showed deviations from the normal pattern in the spatial distribution and magnitude of chi-squared errors. Disease states may deviate from mono-exponential T1 relaxation more than normal brain does. The color-coded error map is a valuable tool for investigators using quantitative MR imaging to determine tissue relaxation parameters.

WET, a T1- and B1-insensitive water-suppression method for in vivo localized 1H NMR spectroscopy.

Suppression of the water signal during 1H magnetic resonance spectroscopy by repeated sequences of a frequency-selective radiofrequency pulse and a gradient dephasing pulse requires nulling of the longitudinal component of the water magnetization and is therefore affected by T1 relaxation, RF-pulse flip angles (which depend on B1), and sequence timing. In in vivo applications, T1 and B1 inhomogeneity within the sample may cause spatially inhomogeneous water suppression. An improved water-suppression technique called WET (water suppression enhanced through T1 effects), developed from a Bloch equation analysis of the longitudinal magnetization over the T1 and B1 ranges of interest, achieves T1- and B1-insensitive suppression with four RF pulses, each having a numerically optimized flip angle. Once flip angles have been optimized for a given sequence, time-consuming flip-angle adjustments during clinical examinations are eliminated. This water-suppression technique was characterized with respect to T1 variations, B1 variations, off-resonance effects, and partial saturation effects and was compared to similar techniques. Effective water suppression has been achieved with this new technique in single-voxel spectroscopy examinations of more than 50 brain tumor patients at 1.5 T.