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Platform Session 1 (1Ц9).

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Malformation and Tumors of
the Developing Nervous
Thursday, October 19, 2006
3:30 – 5:45 pm
1. Abnormal Brain Development in Newborns with
Congenital Heart Disease Prior to Cardiac Surgery.
Miller SP, McQuillen P, Xu D, Charlton N, Glidden D,
Hamrick S, Karl T, Barkovich AJ, Vigneron D
(San Francisco, CA and Vancouver, BC, Canada)
Background: Term newborns with congenital heart disease
(CHD) have an unusual predilection to white matter injury,
a pattern of injury more typical of premature newborns. Objective: To characterize brain microstructure and metabolism, as measures of brain development, in term newborns
with CHD prior to heart surgery relative to normal controls.
Methods: Term newborns with TGA (n⫽29) and single
ventricle physiology (SV) (n⫽12), were studied with MRI,
including 3D MR spectroscopic imaging (MRSI) and diffusion tensor imaging (DTI), before cardiac surgery. Normal
term controls (n⫽16) were studied at similar postmenstrual
age. MRSI: N-acetylaspartate (NAA)/choline and lactate/choline were derived from 7 regions: Basal Ganglia, Thalamus,
Calcarine Region, Optic Radiations, Perirolandic, Parietal
and Frontal White Matter. DTI: Average diffusivity (Dav) in
these regions and fractional anisotropy (FA) in white matter
regions were quantified as measures of brain microstructure.
Results: Relative to controls, newborns with CHD had
lower NAA/choline, independent of brain region (-11%,
P⬍0.0001), with a trend for higher lactate/choline (⫹11%,
P⫽0.1). Relative to controls, Dav was higher with CHD
(⫹3.4%, P⫽0.04) and white matter FA was lower (-11%,
P⬍0.0001). These results are similar to those found in premature neonates. The differences in MRSI and DTI measures were not associated with the type of heart lesion or the
presence of brain injury on preoperative MRI. Conclusions:
Term newborns with TGA and SV physiology have abnormalities of brain structure and metabolism prior to cardiac
surgery. Impaired metabolism and delayed development may
predispose these newborns to a white matter vulnerability
more typical of premature newborns.
2. Nischarin Provides a Stop Signal for Glial-Guided
CNS Neuronal Migration
Fryer, R, Hatten ME (New York, NY)
Correct positioning of neurons in the mammalian neocortex
requires the combined effects of signals that promote migration as well as signals that stop migration. While many genes
have been identified that promote neuronal migration, genes
that lead to a cessation of neuronal migration have not been
identified. Nischarin, an intracellular protein identified in fibroblasts, forms a complex with alpha 5 integrin and modulates actin dynamics at the leading edge of migrating fibroblasts. Nischarin overexpression inhibits cerebellar granule
neuron migration in both in vitro migration assays and in organotypic slice cultures. To determine the mechanism behind
nischarin’s ability to inhibit neuronal migration, we synthe-
sized nischarin constructs lacking several putative domains and
have determined that a domain near the N-terminus of nischarin is obligatory for nischarin’s inhibitory effect on migration. Biochemical assays were performed using full length nischarin as well as a nischarin construct lacking this N-terminal
domain to determine the mechanism of nischarin’s inhibitory
effect on migration. Our results show a strong correlation between the ability of these nischarin constructs to inhibit migration with their ability to inhibit pak kinase activity. We
also report that inhibiting pak kinase using a kinase-dead pak
mutant similarly inhibits neuronal migration, while overexpressing wild type pak enhances migration, supporting a crucial and previously unknown role for pak in stimulating neuronal migration. Lastly, we also report that nischarin inhibits
pak from forming a complex with the dynein motor. We hypothesize that this is the mechanism behind nischarin’s ability
to inhibit neuronal migration.
3. Childhood Medulloblastoma (MB): Incidence and
Significance of Anaplasia
Packer RJ, Jakacki R, Zhou T, Rorke-Adams LB, Sposto R,
Burger PC (Washington, DC; Pittsburgh, PA; Arcadia, CA;
Philadelphia, PA; Los Angeles, CA; Baltimore, MD)
Although survival rates have risen for children with MB,
30% or more of patients fail present treatments. Identification of those at highest risk of relapse is mandatory. Between
1996 and 2002, the COG entered 472 children between 3
and 21 years of age with MB on two prospective trials.
Event-free survival (EFS) was 81 ⫾ 2% (at 5 years) for
average-risk and 81 ⫾ 5% (at 3 years) for high-risk patients.
On central review, anaplasia was found in 74 of 403 (18%)
including 19 (32%) of high-risk and 55 (15.5%) of averagerisk patients. Five-year EFS was 68 ⫾ 6% for those with
anaplasia vs. 80 ⫾ 2% for those without ( p ⫽ .02). Overall
survival was even more impacted by anaplasia (5 year, 76 ⫾
6% vs. 47 ⫾ 17%, p ⫽ .003). The effect of anaplasia on
survival was not affected by the risk group or the treatment
received. In those with metastatic disease, 5-year survival was
47 ⫾ 17% for those with anaplasia and 86 ⫾ 5% for those
without ( p ⫽ .009). We conclude that anaplasia is a predictor of poor outcome for children with MB, detrimentally
affecting survival in those with average and poor-risk disease.
Occurring more frequently in those with disseminated disease at diagnosis, anaplasia remains an independent predictor
of poor outcome, including in those with metastatic disease.
It should be incorporated into patient stratification schema,
and those with anaplastic non-disseminated, totally resected
tumors (otherwise average-risk) should be considered to have
high-risk disease.
4. The MRI Study of Normal Brain Development:
Neurobehavioral Evaluation and Magnetic Resonance
Rivkin MJ, Lange N, and the Brain Development
Cooperative Group (Boston, MA)
The MRI Study of Normal Brain Development comprises
the largest neuroimaging database to characterize typical development from newborns to young adults. Participants were
recruited so the study sample would proportionally represent
socioeconomic and racial/ethnic features of U.S. children according to Census 2000. Candidates and first degree relatives
were extensively screened for medical, psychiatric, neurologic
and genetic conditions that could affect typical brain development. Participants attend three or more study sessions re-
© 2006 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
ceiving standardized neurologic, comprehensive neurobehavioral and brain MRI evaluation at each visit. The MRI
protocol includes 3D-volumetric T1-weighted and dual-echo
T2-weighted acquisitions for neuroanatomic data. Singlevoxel proton magnetic resonance spectroscopy is obtained at
frontal and parietal white matter, thalamus and bi-occipital
cortex. Echo-planar diffusion tensor images obtained in six
directions at a b-value⫽1000sec/mm2 (plus b⫽0) characterize white matter microstructure. Recruitment of 521 children
to date will produce cross-sectional and longitudinal MRI
and neurobehavioral data. Preliminary cross-sectional data
yields growth curves for several brain volumes between ages
4.5 and 18 years of age. Both sexes demonstrated similar
patterns of age-dependent volume change. Lobar volumes declined with age. Frontal lobe demonstrated a quadratic pattern of decline; other lobes demonstrated a linear pattern.
Lobar gray matter volume and white matter volume declined
and increased, respectively, with age. Caudate, putaminal
and pallidal volumes declined with age for both sexes. Thalamic and brainstem volumes increased with age. The complete data of this project will be available to investigators for
use in their own research. The first public release of data is
planned for Summer 2006.
5. Early Detection of Focal Cortical Gyration
Anomalies: Prenatal MR Imaging
Righini A, Parazzini C, Triulzi F (Milan, Italy)
Purpose: to highlight the magnetic resonance imaging
(MRI) patterns of focal cortical gyration anomalies, as they
appear at very early stage of the sulcation process. Methods:
we reviewed 780 fetal MRI studies performed at our Institution between 2000 and 2006. The cases showing focal
anomalies of the cortical rim before the 25th week of gestation were selected and classified according to the type of cortical ribbon distortion. Results: among eight selected cases,
we identified three basic patterns of cortical rim anomaly:
“wart-like”, “saw-tooth”, and major aberrant invaginating
sulci. All anomalies were already detectable when the brain
was still smooth (“physiological lyssencephaly”). The “wartlike” and “saw-tooth” patterns were confirmed to be focal
polymicrogyria at follow-up. In one “wart-like” case and in
aberrant sulci cases the anomaly became more complex along
with gyration process. Four cases were associated with additional brain anomalies: callosal partial agenesis, septum pellucidum agenesis, periventricular nodular heterotopias, focal
thinning of migrating glia band, germinal matrix-ganglionic
eminence hypertrophy. Four cases were probably on genetic
basis, while the others were very probably of clastic origin.
Conclusions: the present cohort shows how focal cortical gyration anomalies can be detected even at a very early sulcation process stage. Moreover, it shows how polymicrogyria
and aberrant sulci grow along with normal brain maturation.
The detection of migrating cells focal alterations suggests a
migratory defect playing a role in the genesis of some focal
gyration anomalies.
6. Detection of Human Herpesvirus 6 (HHV6) in
Childhood Central Nervous System Glioma
Crawford J, Thorarinsdottir H, Santi MR, MacDonald T
(Washington D.C.)
Purpose: To determine whether Human Herpesvirus 6
(HHV6) is present in childhood central nervous system
(CNS) gliomas. Materials/Methods: Tissue microarrays
(TMA) consisting of 88 pediatric patients diagnosed with gli-
omas of varying grades (WHO I-IV) were probed with antiHHV6 monoclonal antibody. Brain biopsy from a known
HHV6 encephalitis patient served as positive control. For confirmation of IHC findings, nested PCR using primers for
HHV6 major capsid protein (MCP) was run on corresponding DNA samples extracted from paraffin embedded slides.
DNA from both positive and negative non-brain tumor specimens served as controls. Results: 25% of the pediatric gliomas in the tissue microarray were positive using anti-HHV6
monoclonal antibodies. While expressed in all grades of gliomas, 45% of low grade tumors were HHV6⫹ compared with
only 15% of high grade tumors (p⫽0.037). DNA was extracted from a subset of IHC positive/negative glioma and
control brain samples to confirm immunohistochemistry
(IHC) results by HHV6 MCP nested PCR. HHV6 was not
detected by IHC or PCR in 30 control pediatric brain samples. There was no statistical significance between HHV6⫹
tumors and outcome based on the limited number of patients
studied. Conclusion: HHV6 is present in pediatric gliomas
with an increased frequency in lower grade tumor type, especially juvenile pilocytic astrocytoma. Our results suggest that
HHV6 may play a role in transformation or tumor progression of childhood gliomas. Studies are underway to determine
whether the HHV6 is isoform specific (A or B) and whether
infectivity alters gene/protein expression of growth promoting
signal transduction pathways.
7. Fetal MRI Diagnosis of Agenesis of the Corpus
Callosum: A Valuable Predictor of Early Development
Khwaja O, Robson C, Barnewolt C, Estroff J, Soul J,
Condie L, du Plessis A (Boston, MA)
Background: Agenesis of the corpus callosum (ACC) is one
of the most common CNS abnormalities, and is associated
with impaired neurodevelopmental outcome but with considerable phenotypic heterogeneity. Our goal was to determine the prognostic value of fetal diagnosis of ACC. Methods: We identified 67 cases of ACC diagnosed by fetal MRI
at our center between 1998 and 2005. Genetic/syndromic
diagnoses and epilepsy were noted. Based on fetal MRI we
dichotomized ACC as “Isolated” (ACC ⫹/- interhemispheric cysts only) or “Complex” (ACC ⫹ other parenchymal malformation). We compared ACC categorization,
based on fetal and. postnatal MRI, with early neurodevelopmental testing (12-36 mo) scores between the two groups.
Developmental quotients (DQ- language, motor and global)
were based on standardized testing including Bayley Scales of
Infant Development (II). Results: Fetal MRI showed isolated ACC in 36 (53%) and complex ACC in 31 (47%)
cases. Live births resulted in 43 (69%) cases. Postnatal MRI
confirmed fetal categories in all cases. 17 children had other
abnormalities and 12 had a syndromic diagnosis. Mean
global DQ was 91 (⫾ 21) in isolated ACC; 79 (⫾11) in
complex ACC. There was significant variation in scores
across domains for language and motor skills by subtype of
ACC. Syndromic diagnoses and epilepsy correlated with
worse outcome. Conclusions: ACC diagnosed by fetal MRI
has significantly worse outcome when associated with other
parenchymal malformations. Significant neurodevelopmental
differences are detectable prior to 36 months age. Fetal MRI
reliably distinguishes these two major ACC groups, and is a
valuable tool for antenatal counseling.
Program and Abstracts, Child Neurology Society
8. Medulloblastoma Incidence has not Changed Over
Time: A Cbtrus Study
Curran EK, Gem ML, Propp JM, Cobb KL, Fisher PG
(Palo Alto, CA; Fremont, CA; Chicago, IL)
Background: Previous medulloblastoma (MB) studies
present conflicting claims about declines and rises in MB incidence, possibly due to misclassification. By using a strict
classification and a rigorous analysis, we aimed to determine
the incidence trends of MB over the last two decades. Methods: 441 MB patients diagnosed between 1985 and 2002
were identified from the Central Brain Tumor Registry of
the United States (CBTRUS), representing approximately
5% of the U.S. population (6 registries). MB was strictly
defined and non-cerebellar embryonal tumors (primitive
neuro-ectodermal tumors [PNETs]) excluded, using histology and site codes. The estimated average annual percentage
change (EAPC) and sharp changes in incidence were determined using multiplicative Poisson regression and joinpoint
regression (Joinpoint Regression Program, version 3.0), respectively. Results: A slight but nonsignificant (p⫽.18) increase in medulloblastoma was demonstrated (EAPC ⫽ 1.1),
with no sharp changes in incidence (joinpoints ⫽ 0). A repeat analysis, with a less strict MB definition (including noncerebellar PNETs), identified 559 patients. Using this
broader classification scheme, there was a statistically significant increase in incidence (p⫽.02, EAPC ⫽ 1.6), but no
sharp changes in incidence (joinpoints ⫽ 0). Conclusion:
MB incidence does not appear to have changed since the
1980s. Incidence increased only when MB was not strictly
defined and misclassified by including non-cerebellar PNETs
in the analysis. The observed increase in the combined MB/
PNET classification may relate to the PNET hypothesis—a
proposal that all brain tumors of apparently undifferentiated
cells be considered a unique diagnostic group—popularized
in the 1980s and early 1990s.
DOI: 10.1002/ana.11472
9. A Dual PI3-kinase/mTOR Inhibitor Reveals
Emergent Efficacy in Glioma
Fan, QiWen, Knight ZA, Goldenberg DD, Wei Y,
Mostov KE, Stokoe D, Shokat KM, Weiss WA.
(San Francisco, CA)
The PI3-kinase family of lipid kinases promotes cell growth
and survival by generating the second messenger
phosphatidylinositol-3,4,5-trisphosphate (PIP3). The frequent activation of this pathway in glioma has focused intense interest on PI3-kinases as drug targets. Yet it remains
unclear which kinases in this family should be targeted in
glioma, in large part because the first selective inhibitors of
these enzymes have only recently been reported. We report a
novel strategy for pharmacological target validation, based on
screening an array of chemically diverse inhibitors that potently target the PI3-kinase family. To define targets critical
for cancers driven by activation of PI3-kinase, we screened a
biochemically-characterized and structurally diverse set of
drug-like molecules that target this entire family. These compounds include representatives from the majority of chemotypes and target selectivities currently in preclinical development by the pharmaceutical industry, and therefore preview
the biological activities of compounds that will ultimately enter clinical development. Surprisingly, we show here that a
single agent (PI-103) effected proliferative arrest in glioma
cells, despite the fact that many compounds were able to
Annals of Neurology
Vol 60 (suppl 3)
block PI3-kinase signaling through its downstream effecter,
Akt. The unique cellular activity of PI-103 was traced directly to its ability to inhibit both a growth-factor dependent
pathway (PI3-kinase alpha) and a nutrient-sensing pathway
(mTOR). PI-103 showed significant activity in xenografted
tumors with no observable toxicity. These data confirm the
importance of PI3-kinase alpha in cancer and demonstrate
an emergent efficacy due to combinatorial inhibition of
mTOR and PI3-kinase alpha in malignant glioma.
Injury and Repair of the
Developing Nervous System
Thursday, October 19, 2006
3:30 – 5:30 pm
10. Use of Magnetic Resonance Imaging in Rat Pups
to Monitor Iron-Labelled Neural Stem Cell Homing
After Hypoxia-Ischemia
Ashwal S, Obenaus A, Digicaylioglu M, Tone B, Robbins M,
Wang A, Tian H, Snyder E (Loma Linda, CA and
La Jolla, CA)
Neural stem cells (NSCs) have attracted increasing attention
as a potential treatment for neonatal hypoxic ischemic injury
(HII) and several studies have demonstrated a reparative effect on brain injury in rats after unilateral carotid ligation/8% hypoxia (Rice-Vannucci model, RVM). Although
multiple mechanisms, aside from neural replacement, have
been proposed to explain this reparative effect, it is realized
that developing non-invasive means to monitor NSC migration and homing to the site of injury would be extremely
helpful in understanding injury repair mechanisms. We have
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