Robert J. Ogg

Subtypes of medulloblastoma have distinct developmental origins.

Medulloblastoma encompasses a collection of clinically and molecularly diverse tumour subtypes that together comprise the most common malignant childhood brain tumour. These tumours are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) after aberrant activation of the Sonic Hedgehog pathway (hereafter, SHH subtype). The pathological processes that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development of much needed new therapies. Here we provide evidence that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (hereafter, WNT subtype) arises outside the cerebellum from cells of the dorsal brainstem. We found that genes marking human WNT-subtype medulloblastomas are more frequently expressed in the lower rhombic lip (LRL) and embryonic dorsal brainstem than in the upper rhombic lip (URL) and developing cerebellum. Magnetic resonance imaging (MRI) and intra-operative reports showed that human WNT-subtype tumours infiltrate the dorsal brainstem, whereas SHH-subtype tumours are located within the cerebellar hemispheres. Activating mutations in Ctnnb1 had little impact on progenitor cell populations in the cerebellum, but caused the abnormal accumulation of cells on the embryonic dorsal brainstem which included aberrantly proliferating Zic1+ precursor cells. These lesions persisted in all mutant adult mice; moreover, in 15% of cases in which Tp53 was concurrently deleted, they progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of human WNT-subtype medulloblastoma. We provide the first evidence, to our knowledge, that subtypes of medulloblastoma have distinct cellular origins. Our data provide an explanation for the marked molecular and clinical differences between SHH- and WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer.

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.

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.

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.

Predicting Change in Academic Abilities After Conformal Radiation Therapy for Localized Ependymoma

PURPOSE Conformal radiation therapy (CRT) aims to limit the highest radiation dose to the tissue volume at risk while sparing surrounding normal tissues. This study investigated whether treatment of childhood ependymoma with CRT would preserve cognitive function. Academic competence was chosen as the primary outcome measure given it is a measure of applied cognitive abilities in a childs natural setting. PATIENTS AND METHODS Eighty-seven pediatric patients diagnosed with ependymoma received CRT in which doses ranging from 54.0 to 59.4 Gy were prescribed to the postoperative tumor bed with a 10-mm clinical target volume margin. Cognitive testing was conducted at the start of CRT, 6 months, and annually after the start of CRT. The median length of follow-up was 59.6 months. Academic testing included subtests from the Wechsler Individual Achievement Test (WIAT) and the Achenbach Child Behavior Checklist. RESULTS Linear mixed models with random coefficients revealed a modest but significant decline in reading scores during follow-up (WIAT slope estimate -0.064 +/- 0.028 points/month; P = .026). Math and spelling performance remained stable. Supratentorial tumor location and multiple surgeries were predictive of worse reading performance at CRT baseline. Male sex, longer symptomatic interval, pre-CRT chemotherapy, pre-existing endocrine deficiencies, hydrocephalus, and younger age at CRT (< 5 years) were predictive of a significant decline in reading scores over time. CONCLUSION CRT may result in better long-term cognitive outcomes when compared to conventional radiation therapy approaches. Reading appears more vulnerable than other academic skills and may decline over time despite stable intellectual functioning.

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.

Fractal-based brain tumor detection in multimodal MRI

In this work, we investigate the effectiveness of fusing two novel texture features along with intensity in multimodal magnetic resonance (MR) images for pediatric brain tumor segmentation and classification. One of the two texture features involves our Piecewise-Triangular-Prism-Surface-Area (PTPSA) algorithm for fractal feature extraction. The other texture feature exploits our novel fractional Brownian motion (fBm) framework that combines both fractal and wavelet analyses for fractalwavelet feature extraction. We exploit three MR image modalities such as T1 (gadolinium-enhanced), T2 and FLuid-Attenuated Inversion-Recovery (FLAIR), respectively. The extracted features from these multimodality MR images are fused using Self-Organizing Map (SOM). For a total of 204 T1 contrast-enhanced, T2 and FLAIR MR images obtained from nine different pediatric patients, our successful tumor segmentation is 100%. Our experimental results suggest that the fusion of fractal, fractalwavelet and intensity features in multimodality MR images offers better tumor segmentation results when compared to that of just fractal and intensity features in single modality MR images. Next, we exploit a multi-layer feedforward neural network with automated Bayesian regularization to classify the tumor regions from non-tumor regions. The Receiver Operating Characteristic (ROC) curves are obtained to evaluate tumor classification performance. The ROC suggests that at a threshold value of 0.7, the True Positive Fraction (TPF) values range from 75% to 100% for different patients, with the average value of 90%.

Proximal dentatothalamocortical tract involvement in posterior fossa syndrome

Posterior fossa syndrome is characterized by cerebellar dysfunction, oromotor/oculomotor apraxia, emotional lability and mutism in patients after infratentorial injury. The underlying neuroanatomical substrates of posterior fossa syndrome are unknown, but dentatothalamocortical tracts have been implicated. We used pre- and postoperative neuroimaging to investigate proximal dentatothalamocortical tract involvement in childhood embryonal brain tumour patients who developed posterior fossa syndrome following tumour resection. Diagnostic imaging from a cohort of 26 paediatric patients previously operated on for an embryonal brain tumour (13 patients prospectively diagnosed with posterior fossa syndrome, and 13 non-affected patients) were evaluated. Preoperative magnetic resonance imaging was used to define relevant tumour features, including two potentially predictive measures. Postoperative magnetic resonance and diffusion tensor imaging were used to characterize operative injury and tract-based differences in anisotropy of water diffusion. In patients who developed posterior fossa syndrome, initial tumour resided higher in the 4th ventricle (P = 0.035). Postoperative magnetic resonance signal abnormalities within the superior cerebellar peduncles and midbrain were observed more often in patients with posterior fossa syndrome (P = 0.030 and 0.003, respectively). The fractional anisotropy of water was lower in the bilateral superior cerebellar peduncles, in the bilateral fornices, white matter region proximate to the right angular gyrus (Tailerach coordinates 35, -71, 19) and white matter region proximate to the left superior frontal gyrus (Tailerach coordinates -24, 57, 20). Our findings suggest that multiple bilateral injuries to the proximal dentatothalamocortical pathways may predispose the development of posterior fossa syndrome, that functional disruption of the white matter bundles containing efferent axons within the superior cerebellar peduncles is a critical underlying pathophysiological component of posterior fossa syndrome, and that decreased fractional anisotropy in the fornices and cerebral cortex may be related to the abnormal neurobehavioural symptoms of posterior fossa syndrome.

Functional MRI and Wada Determination of Language Lateralization: A Case of Crossed Dominance

Summary:  The Wada test has historically been the conventional procedure for determining language lateralization before neurosurgery. However, functional magnetic resonance imaging (fMRI) offers a less invasive alternative to the Wada procedure. Research indicates that the two techniques used together may provide comparable, and sometimes complementary, information that results in improved prediction of postsurgical language ability. We present a case in which use of fMRI in conjunction with Wada testing provided complementary information about language lateralization before neurosurgical resection of a mesial temporal subependymoma for seizure control in a patient with schizencephaly.

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.