close

Вход

Забыли?

вход по аккаунту

?

Career development.

код для вставкиСкачать
AMERICAN NEUROLOGICAL ASSOCIATION 133RD ANNUAL MEETING
SEPTEMBER 21-24, 2008 SALT LAKE CITY, UTAH
CAREER
DEVELOPMENT
Poster # CD-2
Each year, recipients of K-awards are invited to attend that
Career Development Symposium, designed to provide them
with the essential tools to enhance their ability to write successful grant proposals and to obtain grant funding from the
NIH and other institutions. The ANA/NINDS Career Development Symposium was set up to foster the success of
young members of the faculty who had obtained career development awards (K08, K12, or K23) from the NIH. The
following abstracts, submitted by the Career Development
Symposium attendees, were presented at the Career Development Symposium and the Poster Session on Monday, September 22, 2008. The K-awardee participant’s name is in
bold.
Poster # CD-1
Anatomical and Behavioral Evidence that a Triptan
Action in the Amygdala Modulates the Affective
Dimension of Pain
A. H. Ahn1,2 and A. I. Basbaum2,3,4
1
Department of Neurology, University of California San
Francisco, San Francisco, CA 2Department of Anatomy,
University of California San Francisco, San Francisco, CA
3
Department of Physiology, University of California San
Francisco, San Francisco, CA 4W.M.Keck Foundation Center
for Integrative Neuroscience, University of California San
Francisco, San Francisco, CA
The triptans have anti-migraine properties through their selective activation of a subset of serotonin receptors. In order
to identify how these individual receptors contribute to the
potentially diverse actions of triptans in the brain, we used a
receptor-subtype selective antibody to one receptor, the serotonin 1D (5-HT1D) receptor, and immunohistochemistry in
the rat and mouse brain, and found a dense terminal pattern
of immunoreactivity (5HT1D-IR) within the central nucleus
of the amygdale (CeA). Double-label immunohistochemistry
colocalized these 5HT1D-IR terminals extensively with the
peptide neurotransmitter calcitonin-gene related protein
(CGRP), but not with the peptide substance P, nor with the
serotonin vesicular transporter (SERT) or tyrosine hyroxylase
(TH). Treatment of rats and mice with intraventricular colchicine shows that the terminal labeling in CeA arises from a
small population of 5HT1D-IR neurons in the subparafascicular (SPF) region of the thalamus and parabrachial nucleus (PB). We next tested whether sumatriptan administration could alter amygdala function, and indeed found that it
shortens the latency to explore the exposed portions of the
elevated zero/circle maze. Together with recent physiologic
and behavioral evidence that indicates a pain-modulatory
role for CGRP in the central amygdala, we hypothesize that
sumatriptan modulates amygdala function through the inhibition of CGRP release.
Financial Disclosure: Supported by NIH grants NS14627,
NS48499, NS47113.
Evolutionarily Conserved Trafficking Signal within the
Alpha2C Adrenergic Receptor Restricts Plasma
Membrane Expression
C. Hurt1, D. Daunt2, B. Kobilka2, T. Angelotti1
1
Anesthesia/CCM, Stanford University Medical Center,
Stanford, CA 2Molecular and Cellular Physiology, Stanford
University Medical Center, Stanford, CA
Introduction: a2A&C adrenergic receptors (AR) have overlapping but unique physiological roles in neuronal signaling,
possibly due to differences in cellular localization (1,2).
Plasma membrane (PM) expression of polytopic cargo proteins such as G-Protein coupled receptors (GPCRs) is required for their activation by extracellular ligands. For some
GPCRs such as the alpha2C adrenergic receptor (a2C-AR),
their heterologous expression results in limited PM expression and intracellular (IC) retention in the endoplasmic reticulum (ER). To date, the structural determinants within
the a2c-AR that dictate neuron-specific trafficking have yet
to be elucidated.
Methods: Epitope-tagged (HA) cDNA vectors encoding
␣2A&C-ARs, along with ten chimeric swaps (e.g. amino terminal, 3rd intracellular loop) were constructed. In addition,
specific deletions, insertions and point mutations where constructed using standard methodologies (Fig. 1). Membrane
binding to the a2 AR antagonist [3H] RX-821002 was performed for all constructs following expression in HEK cells
to demonstrate proper GPCR folding. Effects of the chimeric
swaps and mutations on cellular localization were determined
by immunofluorescent microscopy following expression in
Rat 1 cells. In addition, quantification of cell surface expression was done by FACS sorting.
Results: Utilizing a chimeric a2A/a2C-AR strategy, we were
able to localize the region responsible for a2CAR peculiar
trafficking to an evolutionarily conserved hydrophobic sequence within the extracellular amino terminus. Deletion of
this trafficking signal in the a2CAR resulted in improved
PM expression and a reduction in IC retention in HEK 293
and Rat1 fibroblast cell lines. Conversely, transplantation of
the a2C-AR trafficking signal into the a2A-AR resulted in
restricted plasma membrane expression and IC retention.
Conclusions: The presence of an evolutionarily conserved
trafficking signal with the a2C-AR suggests a yet to be identified retention protein(s) restricting plasma membrane expression. These results further validate the hypothesis that
a2a and a2C-ARs are evolutionarily distinct GPCRs and are
not interchangeable within the sympathetic nervous system.
Specific neuronal localization may allow them to serve different roles and suggest that the development of subtype specific drugs may be of clinical benefit.
References:
Hein L, Altman JD, Kobilka BK Nature (1999) 402:181-4.
Brum PC, Hurt CM, Kobilka B, Angelotti T. Neuropharm
(2006) 51:397-413.
Financial Disclosure: This work was supported in part by
NINDS K08 NS050654-01A1
© 2008 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
S141
Poster # CD-3
In-Vivo Animation of Event-Related GammaOscillations in Pediatric Brain Surgery
Eishi Asano12
1
Departments of Pediatrics and Neurology, Wayne State
University, Detroit, MI 2Department of
Electroneurodiagnostics, Children’s Hospital of Michigan,
Detroit, MI
Introduction: Previous studies have suggested that augmentation of cortical gamma-oscillations (⬎50 Hz) is tightly linked
with various forms of physiological activity in humans.
Methods: Using the novel technique: “in-vivo animation of
event-related gamma-oscillations”, the dynamic change of
gamma-oscillations induced by physiological tasks was animated on a three-dimensional MR image in epileptic children
who underwent epilepsy surgery in Children’s Hospital of
Michigan between 2006 and 2008.
Results: i) Semantic auditory-language task (Brown et al, NeuroImage 2008): Gamma-augmentation (50-150 Hz) sequentially involved: the posterior superior temporal gyrus when listening to the question, the posterior lateral temporal region
and the posterior frontal region in the time interval between
question completion and the patient’s vocalization, and the
pre- and post-central gyri immediately preceding and during
the patient’s vocalization. ii) Auditory-repetition task: Gammaaugmentation (50-150 Hz) sequentially involved: the posterior
superior temporal gyrus when listening to the auditory stimuli
and the pre- and postcentral gyri immediately preceding and
during the patient’s vocalization. iii) Auditory-motor task:
Gammaaugmentation (50-150 Hz) sequentially involved: the
posterior superior temporal gyrus when listening to the auditory command and the pre- and post-central gyri immediately
preceding and during the motor task. iv) Median-nerve somatosensory stimulus (Fukuda et al, Brain 2008): High-frequency
(100-250 Hz) gamma-oscillations emerged in the post-central
gyrus at 13.6-17.5 ms after median-nerve stimulation, gradually slowed down in frequency around and below 100 Hz, and
progressively involved the neighboring areas. v) Full-field flash
stimulus: Gamma-augmentation (50-150 Hz) sequentially involved: the anterior-medial occipital cortex and the lateraltopolar occipital cortex. vi) Central-field picture stimulus:
Gamma-augmentation (50-150 Hz) sequentially involved: the
lateral-to-polar occipital cortex, the inferior occipitaltemporal
cortex and the posterior frontal cortex.
Conclusion: This novel method can delineate not only where
but also how gamma oscillations were altered by various physiological tasks. Further studies using electrical stimulation and
post-operative behavioral measures are warranted to determine
whether recording of event-related gamma-oscillations can
supplement conventional cortical mapping using electrical
stimulation for presurgical evaluation of children undergoing
brain surgery.
Financial Disclosure: Supported by NINDS NS 47550 to E.
Asano
Poster # CD-4
Mitochondrial Dynamics in Living Neurons
Sarah B. Berman1, Beth A. Arnold1, and
J. Marie Hardwick2
1
Department of Neurology and Pittsburgh Institute for
Neurodegenerative Diseases, University of Pittsburgh,
Pittsburgh, PA 2Department of Molecular Microbiology and
Immunology, Johns Hopkins University Bloomberg School of
Public Health, Baltimore, MD
Mitochondria are dynamic organelles, undergoing frequent
fission and fusion, and these processes are centrally involved
S142
Annals of Neurology
Vol 64 (suppl 6)
in apoptosis and mitochondrial DNA protection. They also
play a critical role in normal synapse formation and function
and mitochondrial distribution in neurons, and specific defects in fusion/fission genes cause neurodegeneration. Recently, mitochondrial fission was implicated in an acute Parkinson’s disease (PD) model (Barsoum et al., 2006). These
important processes, however, have been difficult to study
directly in brain, and little is known about mitochondrial
fission and fusion in healthy neurons, and even less in aging
neurons or chronic models of neurodegenerative diseases. We
developed methodology in which fusion and fission, along
with transport, can be directly and quantitatively imaged in
individual mitochondria in live neurons. Primary rat cortical
neurons were transfected with mitochondrially-targeted RFP
and photoactivatable mitochondrially-targeted GFP. Neuronal processes were imaged live at 37oC, and individual mitochondria were selected and photoactivated. Images were
then taken every 10 sec for 15 min. From this, we can observe individual fusion events by rapid diffusion of GFP
from photoactivated to unactivated mitochondria. Fission
and mitochondrial transport can also be quantified. Mitochondrial fusion is frequently inferred by mitochondrial
morphology. However, we found that in neurons, where mitochondria are transported frequently, this can be misleading. Most often, passing mitochondria do not fuse. In addition, mitochondria can move adjacent to each other and be
transported together without fusing, which has been used to
classify fusion events. We found that fusion occurs at a
slower rate than described in other cell types. At day 7 in
culture, we observe that mitochondria have a 10% probability of undergoing fusion over 15 min, whereas fission occurs
more frequently (21% probability). Fissioning mitochondria
are often rapidly transported along neuronal processes, which
may have implications for synapse function. Mitochondrial
morphology correlates with ratios of fission to fusion, as evidenced by co-expression of fission/fusion regulators, the
dominant-negative form of the fission protein Drp1 and
BclxL, while mitochondrial mobility was unaffected. We
have similarly been able to observe and quantify mitochondrial dynamics in cortical neurons of different ages in culture, and have observed similar processes in a chronic rotenone model of PD in differentiated PC-12 cells. This will
help elucidate the role that mitochondrial dynamics may play
in aging and neurodegenerative disease.
Financial Disclosure: Supported by NIH K08NS059576,
American Parkinson Disease Association (APDA) Research
Grants, and a Pittsburgh Institute for Neurodegenerative
Diseases (PIND) Pilot Seed Grant award.
Poster # CD-5
Brain Structure Change is Associated with Clinical
Decline of Elderly Controls: A Longitudinal Study
Using the ADNI Dataset
James B. Brewer1,2, Dominic Holland1,
Christine Fennema-Notestine1, Anders M. Dale1,2
1
Department of Radiology, University of California San
Diego, La Jolla, CA 2Department of Neurosciences, University
of California San Diego, La Jolla, CA
Introduction: Automated segmentation and measurement of
subregional brain volumes from MRI data has allowed highthroughput quantification of regional brain atrophy. Such
measures predict subsequent clinical decline in patients with
mild cognitive impairment (MCI). Quantitative analysis of
brain structure change over time may be even more sensitive
December 2008
to the earliest effects of neurodegenerative disease, including
that which may be present in elderly controls who have passed
clinical screening.
Methods: We examined whether longitudinal measures of
brain change in healthy elderly controls would be associated
with decline on clinical and neuropsychological measures. We
analyzed longitudinal MRI data from 70 control subjects of
the Alzheimer’s Disease Neuroimaging Initiative (ADNI) who
had 6- and 12-month follow-up imaging at the time of the
analysis. 6- and 12-month subregional change was quantified
using automated anatomical segmentation based upon the
FreeSurfer software package and non-linear image registration.
Subjects were sorted based upon the degree of change in the
temporal horn of the lateral ventricle and dichotomized at the
median, creating a group with a highdegree of anatomical
change and a group with a low-degree of anatomical change.
In addition, atrophy was analyzed as a continuous measure,
plotting change in the temporal horn against 12-month
change in MMSE.
Results: Healthy elderly control subjects showing a high degree of anatomical change in bilateral temporal horn of the
lateral ventricle declined more on MMSE over 12 months.
This effect was significant both for 6-month change and for
12-month change in temporal horn volumes (each p ⬍ .01,
two-tailed). Average age of the high atrophy group (76.6⫾4.9)
did not differ from the age of the low atrophy group
(75.9⫾5.1). Correlation between change in temporal horn
volume and MMSE decline was significant at p⬍.02 for
6-month change and at p⬍.005 for 12-month change.
Conclusions: Change in temporal horn volume is associated
with clinical decline of healthy elderly controls. Such changes
may reflect processes of normal aging, but the rate of atrophy
may rather suggest the presence of subclinical neurodegenerative disease. No patients converted to MCI or Alzheimer’s disease. Continued follow-up of the high atrophy cohort will determine whether such measures predict later clinical
conversion.
Financial Disclosure: JBB is supported by NINDS K23
NS050305. The authors do not have a financial relationship
as described in the ANA Abstract Authors’ Acknowledgement,
Concurrence and Disclosure Statement.
Poster # CD-6
Lean Mass and Brain Volume in Early Alzheimer’s
Disease
Jeffrey M. Burns1, Benjamin B. Cronk1, Russell Swerdlow1,
William Brooks1
1
Department of Neurology, University of Kansas School of
Medicine, Kansas City, KS
Introduction: Alzheimer’s disease (AD) is associated with
unintended weight loss. We examined components of body
composition in relation to cognition and structural brain
changes in early AD and nondemented individuals.
Methods: Brain magnetic resonance imaging (MRI), and
neuropsychological testing were performed on nondemented
(CDR 0, n⫽70) and early-stage AD (CDR 0.5 or 1, n⫽70)
subjects. Dual energy x-ray absorptiometry (DEXA) was used
to determine whole body fat mass and lean (muscle) mass.
Height and weight assessments were used to assess body mass
index (BMI). Partial correlations controlling for age and gender were used to assess the relationship between body composition, cognition, and brain atrophy measures.
Results: Lean mass was reduced in individuals with early AD
compared to nondemented controls (F⫽7.73, p⫽0.006) af-
ter controlling for gender. Lean mass was associated with habitual physical activity (r⫽0.21, p⫽0.02) and peripheral insulin levels (r⫽0.21, p⫽0.02). In the overall group, lean
mass was associated with global cognitive performance (beta⫽0.23, p⬍0.23) and whole brain volume (beta⫽0.54,
p⬍0.001) when controlling for age and gender. In separate
within-group analyses, lean mass in early AD subjects was
associated with whole brain (r⫽0.44, p⬍0.001) and white
matter volume (r⫽0.36, p⫽0.003) after controlling for age
and gender. Lean mass was not associated with brain atrophy
or cognition in nondemented subjects. Measures of adiposity
including BMI, percent body fat, and waist-hip ratio were
not different across groups or related to cognition or brain
atrophy measures in the overall group and within groups.
Conclusion: In Alzheimer’s disease lean (muscle) mass was
positively associated with brain volume. Sarcopenia may be a
direct or indirect consequence of AD pathophysiology or factors that preserve lean muscle may attenuate AD progression.
Financial Disclosure: This study was supported by grants
R03AG026374-01 from the National Institutes of Aging,
K23NS058252 from the National Institute on Neurological
Disorders and Stroke. The University of Kansas General
Clinical Research Center (M01RR023940) provided essential
space, expertise, and nursing support.
Poster # CD-7
Role of the Autism-Linked Neurexin-Neuroligin TransSynaptic Interaction in Learning-Related Synaptic
Plasticity at the Aplysia Sensory to Motor Neuron
Synapse
Yun-Beom Choi 1,2, Stefan R. Kassabov 2, Hsiu-Ling Li 2,3,
Sathya V. Puthenveettil 2, Craig H. Bailey 2,
Eric R. Kandel 2,3
1
Department of Neurology, Columbia University, New York,
NY 2Department of Neuroscience, Columbia University, New
York, NY 3Howard Hughes Medical Institute, Columbia
University, New York, NY
A class of mutations in human neuroligin genes has been
linked to autism. In addition, a recent linkage study has implicated neurexin which undergoes a heterophilic transsynaptic
interaction with neuroligin as another autism risk locus. Previous in vitro studies in mammals have shown that the
neuroligin-neurexin interaction can induce differentiation of
both the pre- and postsynaptic components of a synapse and is
important for de novo synapse formation. By contrast, little is
known about the role of the neurexin-neuroligin interaction in
learning-related changes in synaptic strength and synaptic
structure. This question is of particular interest since autism is
likely to affect synaptic remodeling during maturation of the
nervous system and stabilization of synaptic connections rather
than synaptogenesis. Toward that end, we have studied sensitization of the gill-withdrawal reflex of Aplysia, a model system
that has proven useful for studying activity-dependent and
learning-related synaptic plasticity. The monosynaptic component of this reflex – direct connections between siphon sensory
neurons and gill motor neurons - can be reconstituted in dissociated cell culture and is modulated in culture, as in the
intact animal, by serotonin (5-HT). Thus, five applications of
5-HT produce a long-term increase in synaptic strength lasting several days (long-term facilitation: LTF) as well as the
remodeling and growth of new sensory neuron synapses. We
cloned an Aplysia homolog of neurexin (ApNRX) and an Aplysia homolog of neuroligin (ApNLG). We have found that injection of ApNRX antisense oligonucleotide into the presyn-
Abstracts
S143
aptic sensory neuron to downregulate ApNRX mRNA or
injection of ApNLG antisense oligonucleotide into the
postsynaptic motor neuron to downregulate ApNLG mRNA
blocks LTF. Over-expression of the C-terminal deletion construct of ApNRX, which can act as a dominant negative, also
leads to a significant reduction of LTF. In addition, 5-HT
treatment that induces LTF leads to the enrichment of overexpressed ApNRX in previously existing empty varicosities as
well as newly formed varicosities re-imaged at 24 hrs after
5-HT treatment. In addition to the previously characterized
role in de novo synapse formation, these results suggest that the
neurexin-neuroligin transsynaptic interaction plays a significant role in learning-related synaptic plasticity. Our study also
provides potentially valuable insights into the dysfunction of
synaptic remodeling, maturation, and stabilization that may
represent important, contributing cellular underpinnings of
autism.
Financial Disclosure: Supported by HHMI and
K08NS053415.
Poster # CD-8
Motor Neuron Neuritogenesis and Differentiation is
Accelerated by Nanofibers
JM Corey1, CC Gertz1, LK Birrell1, DC Martin2, and
EL Feldman1
1
Department of Neurology, University of Michigan, Ann
Arbor, MI 2Departments of Materials Science, Engineering
and Biomedical Engineering, University of Michigan, Ann
Arbor, MI
Nanofiber scaffolds provide directional cues to guide regenerating neurites in vitro and in vivo. Since the biochemical composition of extracellular matrix (ECM) influences neuronal
differentiation, we hypothesized that nanofibers in the ECM
would also influence differentiation. Aligned and random
nanofibers of poly-L-lactide were electrospun on substrates and
coated with polylysine. Primary motor neurons (MN) were
isolated from E15 rat spinal cords, grown on nanofiber substrates, then fixed and stained for neurofilament or betatubulin. Neurons grown for 3, 6, 15, 24 hours or longer were
assigned to stages of differentiation based on scoring for the
presence of lamellipodia, neurites, and major neurites. MN
differentiation on nanofibers, both aligned and random, was
accelerated compared to glass substrates. Whereas at 24 hours
only 69% of MN on glass had neurites, 93% on aligned nanofibers and 95% on random nanofibers had neurites. Even by 3
hours, 66% of MN on aligned nanofibers and 45% of MN on
random nanofibers had formed neurites compared to 9% on
glass. Neuritogenesis at 3 hours appears most accelerated on
aligned nanofibers. These studies suggest that nanofiber scaffolds could speed the differentiation of transplanted neurons
into injured nervous tissue.
Financial Disclosure: NIH K08 EB003996, Army
W911NF0610218
Poster # CD-9
Neural Progenitor Cells & Cortical Development:
Genetic Control of Differentiation and Proliferation
Kevin C. Ess1
1
Departments of Neurology and Pediatrics, Vanderbilt
Kennedy Center for Research on Human Development,
Vanderbilt University, Nashville, TN
Tuberous Sclerosis Complex (TSC), one of the most common genetic causes of epilepsy or autism in children, is
S144
Annals of Neurology
Vol 64 (suppl 6)
caused by loss of the TSC1 (encoding hamartin) or the TSC2
genes (encoding tuberin). Brain malformations (tubers) are
seen in virtually all patients with TSC and likely cause the
severe neurologic features (epilepsy, developmental delay,
mental retardation, and autism). Tubers have been identified
in 19 and 20 week human fetuses suggesting that they occur
during early stages of brain development. We have previously
found abnormal expression of neural stem/progenitor cell
markers in TSC-associated tubers and subependymal giant
cell astrocytomas (SEGAs) (Ess et al. 2004, 2005). Such
findings led us to the overall hypothesis that the TSC genes
normally function during the differentiation of neural progenitor cells. The generation of animal models to test this
hypothesis has been challenging. Conventional knockout of
the mouse Tsc1 or Tsc2 genes are embryonic lethal prior to
significant development of the cerebral cortex (Kwiatkowski
et al 2002). A rat model with a mutated Tsc2 gene (Eker rat)
also has a very similar phenotype. To circumvent these issues, a knock-in of the mouse Tsc1 gene to include LoxP
sites has been generated and allows conditional tissue-specific
knockouts using the Cre-LoxP system. We have generated
two complementary mouse models of TSC using this approach. The first targets the Tsc1 gene in dorsal neural progenitor cells. These cells normally give rise to almost all excitatory glutamatergic neurons as well as glia of the cerebral
cortex. These Tsc1Emx1- Cre conditional knockout mice
have profound abnormalities in cortical development and die
by one month of life. The second model inactivates the Tsc1
gene in ventral progenitor cells that generate GABAergic interneurons. The resultant conditional knockout mice
(Tsc1Dlx5/6-Cre) have epilepsy, stunted growth, and behavioral problems. Analyses of their cortex reveal ectopic cell
populations with aberrant differentiation. These two novel
models of TSC will allow us to pursue further studies exploring the mechanism(s) involving the Tsc1 gene during
dorsal and ventral progenitor cell differentiation and the formation of the cerebral cortex.
Financial Disclosure: Supported by grants from: NINDS,
NIH (K08NS050484), the Tuberous Sclerosis Alliance, and
Milken/AES Early Career Award.
Poster # CD-10
Applying of Diffusion Tensor Imaging to Understand
Multiple Sclerosis Pathophysiology and the Impact of
Therapies
Robert J. Fox1, Ken Sakaie2, Jian Lin2, Mark Lowe2,
Michael Phillips2, Jar-Chi Lee2, Elizabeth Fisher2,
Richard Rudick2, Elliot Frohman3, Teresa Frohman3,
Masaya Takahashi3, and Roddy McColl3, Josef Debbins4, and
Yu Liu5
1
Mellen Center for Multiple Sclerosis, Cleveland Clinic,
Cleveland, OH 2Cleveland Clinic, Cleveland, OH 3University
of Texas Southwestern Medical Center, Dallas, TX 4Barrows
Neurological Institute, Phoenix, AZ 5Aurora Healthcare,
Milwaukee, WI
Objective: Apply diffusion tensor imaging (DTI) to multiple
sclerosis to understand disease pathogenesis and the impact
of therapies.
Introduction: Conventional MR imaging detects the occurrence of inflammatory brain injury, but is a poor measure of
the degree of injury and its later recovery. DTI has a broad
dynamic range and good spatial resolution, and so is an attractive imaging metric of tissue injury. We sought to 1) validate DTI as a physiologically relevant measure of tissue in-
December 2008
tegrity, using the internuclear ophthalmoplegia (INO)
model; 2) study tissue recovery and later degeneration using
DTI in patients who start highly-effective anti-inflammatory
therapy (natalizumab); and 3) implement DTI in a multicentered clinical trial, which included validation studies of
feasibility and data comparability.
Methods: Project 1: In a small pilot study, MS patients with
INO and healthy controls were studied with DTI and infrared oculography. DTI measures within the median longitudinal fasciculus were correlated with measures of horizontal
ocular dysmotility. Project 2: MS patients starting natalizumab underwent DTI and conventional imaging monthly
for 2 months, and then semi-annually for two years. DTI
measures within gadolinium-enhancing lesions were evaluated longitudinally using FSL and AFNI co-registration and
visualization software. Project 3: Two healthy volunteers underwent DTI scans on five different 3T magnets, including 2
different manufacturers. Within each subject, 16 ROIs were
placed on a single image set and co-registered to other image
sets. Concordance correlations were evaluated across magnets.
Results: Project 1: Modest correlations were observed between DTI measures and ocular dysmotility, ranging from
0.43-0.65. Project 2: Preliminary data over the first two
months of treatment showed that fractional anisotropy (FA)
increased relative to baseline, which was driven by a decrease
in transverse diffusivity. Project 3: Overall mean correlation
between scanners was 0.96 for FA and 0.88 for ADC. There
was no difference in correlations within scanner types vs.
across scanner types.
Conclusion: DTI provides a physiologically relevant measure
of brain tissue integrity. DTI is a dynamic metric, indicating
repair during the recovery stages of brain inflammation.
Multi-center DTI yields comparable measures from different
scanners, even different manufacturers. Altogether, these
studies support the utility of DTI in measuring tissue injury,
recovery, and later degeneration in MS, including the impact
of MS therapies. Additional studies and analyses within each
Project are underway.
Financial Disclosure: These studies were supported by NIH
K23 NS47211, National MS Society RG3548, the Nancy
Davis Center Without Walls, and Genentech, Inc, all to
RJF.
Poster # CD-11
Causal Prefrontal-Temporoparietal Interactions
Correlate with Word-Rhyming Performance in Reading
Disabilities
Richard E. Frye1, Roger Wu2, George Zouridakis2, and
Jacqueline Liederman3
1
University of Texas Health Science Center, Houston, TX
2
University of Houston, Houston, TX 3Boston University,
Boston, MA
Introduction: Magnetoencephalography (MEG) has demonstrated abnormal early activation of the prefrontal cortex
(PFC) in children with reading disabilities (RD). However, it
is not clear whether this represents bottom-up activation of
the PFC area or top-down influence of the PFC on other
brain areas.
Methods: We measured directional and instantaneous causality between the left PFC and temporoparietal (TP) areas
during an orthographic-to-phonological decoding task using
Dynamic Autoregressive Neuromagnetic Causal Imaging
(DANCI). Low-gamma (30-60 Hz) MEG activity from sen-
sors overlying the left PFC and left TP areas during a 300ms
pre-stimulus period was analyzed. Directional and instantaneous causality between the left TP and left PFC was correlated with the sensitivity measure (d-prime) derived from
performance on a non-word decoding task.
Results: Stronger bottom-up influence from the left TP area
to the left PFC area was correlated with poorer performance
(lower d-prime) for individuals with RD but not TD individuals. Stronger instantaneous causality between the left
PFC and left TP correlated with better performance (higher
d-prime) for the RD, but not the TD, group.
Conclusion: These data help clarify the organization and hierarchical architecture of neural networks responsible for
compensation in RD. Tightly coupled interactions between
the TP and PFC areas appear to be necessary for compensatory processes to work effectively.
Financial Disclosure: This study was supported by
NS046565 to Dr. Richard E. Frye.
Poster # CD-12
Neonatal Seizures Independently Impact Long-Term
Outcome in Infants with Hypoxic-Ischemic Brain
Injury
Hannah C. Glass,1,2 David Glidden,3 Rita J. Jeremy,2
A. James Barkovich,4 Donna M. Ferriero,1, 2
Steven P. Miller5
1
Department of Neurology, University of California, San
Francisco, CA 2Department of Pediatrics, University of
California, San Francisco, CA 3Departments of Epidemiology
& Biostatistics, University of California, San Francisco, CA
4
Department of Radiology, University of California, San
Francisco, CA 5Department of Pediatrics, University of British
Columbia, Vancouver, BC, Canada
Background: Although experimental data suggest that seizures are associated with adverse outcome, it is not known
whether seizures themselves cause injury, or simply mark preexisting brain damage.
Methods: We used multivariate regression to examine the
independent effect of neonatal seizures on neurodevelopmental outcome in 77 term newborns at risk for hypoxicischemic brain injury. Seizures were recorded prospectively,
and state-of-the-art newborn magnetic resonance imaging
(MRI) was used to measure the severity of brain injury. The
primary outcome measures were the full-scale intelligence
quotient (FSIQ) of the Wechsler Preschool and Primary
Scale of Intelligence-Revised and the neuromotor score at
four years.
Findings: After controlling for the severity of injury on
MRI, children with neonatal seizures had worse outcomes
than those without seizures. The magnitude of the effect varied with seizure severity: children with severe seizures had
poorer neurodevelopment than those with mild/moderate seizures. The average FSIQ after adjusting for severity of brain
injury was 29.7 points lower (95% CI -45.2 to -14.2 points)
for children with severe neonatal seizures and 14.2 points
lower (95% CI -26.5 to -1.9 points) for children with mild/
moderate seizures when compared to children without seizures. Similarly, after controlling for the severity of injury on
MRI, the odds of abnormal neuromotor examination were
higher in infants with severe seizures when compared with
children with mild/moderate or no seizures.
Interpretation: Neonatal seizures in the setting of birth asphyxia are associated with worse cognitive and neuromotor
outcome, independent of the severity of hypoxic-ischemic
Abstracts
S145
brain injury. Randomized controlled trials are essential to determine whether treatment of seizures can improve outcome.
Financial Disclosure: Supported by NINDS Neurological
Sciences Academic Award (NS01692)
Poster # CD-13
Experience-Independent Decorrelation of Internally
Generated Network Activity in Developing Neocortex
Peyman Golshani1, Jose Tiago Goncalves1,
Sattar Khoshkhoo1, Ricardo Mostany1, Stelios Smirnakis3, and
Carlos Portera-Cailliau1,2
1
Department of Neurology, David Geffen School of Medicine,
UCLA, Los Angeles, CA 2 Department of Neurobiology,
David Geffen School of Medicine, UCLA, Los Angeles, CA 3
Department of Neurology, Baylor College of Medicine,
Houston, TX
Introduction: After its assembly, the adult neocortex must
generate internal network dynamics that allow its circuits to
perform complex neural computations. When this critical
step is reached during cortical maturation and the mechanisms mediating this transition are still unclear. Furthermore,
the contribution of sensory experience in the establishment
of mature spatiotemporal dynamics of cortical activity is still
controversial.
Methods: We used in vivo two-photon calcium imaging of
large ensembles of layer (L)2/3 neurons in mouse barrel cortex, coupled with in vivo patch-clamp recordings, to examine
whether sensory experience is important for the emergence of
the correlational structure of spontaneous activity during
postnatal development.
Results: We find a rapid decorrelation of network activity at
around postnatal day (P) 12 that coincides with a sharp decrease in the input resistance of L2/3 neurons and an increase in the relative contribution of inhibitory input. Strikingly, removing sensory inputs does not affect the time
course of this transition, suggesting that the decorrelation of
spontaneous cortical network activity is intrinsically generated and possibly genetically hard-wired.
Conclusions: Developmental decorrelation of spontaneous
activity in the neocortex occurs after the second postnatal
week. This decorrelation likely plays an important role in the
efficiency of sensory coding. It also likely plays an important
role in the developmental changes in the susceptibility to seizures. Future studies will address how neonatal seizures affect
the correlational structure of neocortical spontaneous activity
and the role of epigenetic modifications in these changes.
Financial Disclosure: This work was made possible by NIH
KO8 award 5K08NS056210.
Status Epilepticus in the Immature Rat
Hui-Wei Chen1, John Williamson1, and
Howard P. Goodkin1
1
Department of Neurology, University of Virginia,
Charlottesville, VA
Status epilepticus (SE) is most frequent at the extremes of
life; yet, many prior pathophysiological studies of SE were
performed in adult animals. As the pathophysiological process underlying SE in the immature brain may differ from
that in the mature brain, we have characterized SE in the
immature brain using electrographic, immunohistochemical,
and patch clamp electrophysiological techniques. SE was in-
Annals of Neurology
Vol 64 (suppl 6)
Poster # CD-15
Corticospinal Tract-Directed Exercise Training for
Rodent Spinal Cord Injury
Noam Y. Harel1, Xin Tang1, Kang-Ho Song1, and
Stephen M. Strittmatter1
1
Department of Neurology, Yale University School of
Medicine, New Haven, CT
Poster # CD-14
S146
duced in postnatal day 10-12 Sprague Dawley rats via the
subcutaneous injection of kainic acid (KA) 3 mg/kg. Electrographic recordings were obtained from monopolar electrodes
placed in the right and left hippocampi, left frontal cortex,
and right parietal cortex. Standard immunohistochemical
techniques were used to characterize Fos-like immunoreactivity (Fos-LI), an indirect measure of neuronal depolarization
and activity, in the hippocampus in brain slices from SEtreated animals obtained 2 and 4 hours after KA injection
and from salineinjected controls. GABAA receptor
(GABAR)-mediated synaptic currents (sIPSCs) were recorded
using standard whole cell patch clamp techniques from CA1
pyramidal neurons (PN) and dentate granule cells (DGC) in
hippocampal slices from SE-treated animals (SE-treated
slices) and from naı̈ve controls. Following injection of KA,
recurrent behavioral and electrographic seizures were observed. Behavioral changes progressed through a regular sequence of hindpaw scratching, the loss of postural control
and turning on the side with clonic or tonic-clonic movements, and the late onset of wet dog shakes. Electrographically, ictal bursts occurred no sooner than 30 minutes after
KA injection and were 1-3 minutes in duration. Although
the interictal period between bursts decreased during the 4
hours of EEG recording, continuous ictal bursts ε 5 minutes
did not occur. At 2 and 4 hours after KA injection, induction of Fos-LI was observed in the cornus Ammons (CA1
and CA3) but not in the dentate gyrus (DG). As regional
heterogeneity in FOSLI suggests prolonged neuronal depolarization in the CA but not in the DG, we hypothesized
that GABAR-mediated synaptic transmission in the CA but
not the DG would be altered. Compared to controls, sIPSCs
recorded from PNs in SE-treated slices were distinct. At 2
hours after KA injection, amplitude was reduced; and at 4
hours after KA injection, there was a reduction in both amplitude and frequency. In contrast, the amplitude and frequency of sIPSCs recorded from DGCs in SE-treated slices
obtained 2 hours after KA injection were similar to controls.
In the immature brain, SE was characterized by recurrent
seizures resulting in neuronal activation and altered GABARmediated synaptic inhibition in the CA. This finding is in
contrast to the prolonged seizures of SE in the mature brain
that result in reduced GABAergic inhibition in both the CA
and DG. Additional studies are required to further characterize the differences in SE in the immature and mature
brain.
Financial Disclosure: This work was supported by National
Institutes of Health Grant NS-048413 (HPG).
Introduction: One of the major goals of spinal cord injury
(SCI) research is stimulating regrowth of the injured corticospinal tract (CST), the tract mediating fine voluntary
movement in humans. However, in rodent models, CST fibers exhibit the least potential for growth when axonal
growth inhibitors are blocked or eliminated1. Does the selective resistance of CST fibers to growth reflect an intrinsic
incapability, or might it reflect the fact that the CST is a
relatively minor pathway for spontaneous activity and loco-
December 2008
motion in rodents2? If so, exercise stimulating CST function
might improve CST axon growth. We hypothesize that spinal cord-injured mice subjected to CST-targeted training
regimens will demonstrate improvements relative to untrained mice not only in functional measures, but in anatomical CST growth.
Methods: Female C57/Bl6 mice 8-10 weeks of age are acclimated to exercises stimulating CST activity for two weeks
prior to surgery. They are then subjected to right lateral spinal cord hemisections (or sham laminectomies) at the C4
level. Following surgery, half of the mice continue the training regimen for 4 days per week. CST-stimulating exercises
include horizontal ladder walk3; nutating mesh grip; treadmill training with obstacles; and forelimb grip-strength training4. Trained and untrained mice are subjected to weekly
evaluation on these tests as well as the Basso Mouse Scale5.
At four weeks post-surgery, both sensorimotor cortices are
injected with distinguishable dextran tracers to compare anatomical plasticity of both the injured and uninjured CST.
Mice are sacrificed at six weeks post-surgery. Functional and
histopathological comparisons are made between sham and
C4 lateral hemisection mice, and trained versus untrained
mice.
Results: Mice are currently in the pre-surgical acclimation
phase of the experiment. Baseline performance measures on
various tests are consistent across uninjured animals. Results
of functional comparisons between post-surgical trained and
untrained mice will be presented.
Conclusions: One of the reasons for limited CST axonal
growth in rodent models of SCI may be the relative underutilization of the CST in rodents. Exercise training regimens
focused on stimulating use of the CST may increase axonal
growth from this tract, which is critical for human voluntary
behavior. Our future studies will combine CST-directed
training with methods to overcome axon growth inhibitors
to further increase growth after SCI. CST-directed training
regimens could improve the correlation between functional
and anatomical recovery in pre-clinical models of SCI. Not
only would this lead to improved physical rehabilitation regimens for human SCI patients, but it could also improve the
reliability of pre-clinical models in predicting outcomes of
human trials.
References:
Kim, JE, Liu, BP, Park, JH, and Strittmatter, SM. Nogo-66
receptor prevents raphespinal and rubrospinal axon regeneration and limits functional recovery from spinal cord injury.
Neuron 2004;44: 439-51.
Muir, GD, and Whishaw, IQ. Complete locomotor recovery
following corticospinal tract lesions: measurement of ground
reaction forces during overground locomotion in rats. Behav
Brain Res 1999;103: 45-53.
Cummings, BJ, Engesser-Cesar, C, Cadena, G, and Anderson, AJ. Adaptation of a ladder beam walking test to assess
locomotor recovery in mice following spinal cord injury. Behav Brain Res. 2007;177:232-241
Anderson, KD, Abdul, M, and Steward, O. Quantitative assessment of deficits and recovery of forelimb motor function
after cervical spinal cord injury in mice. Exp Neurol 2004;
190:184-91.
Basso, DM, Fisher, LC, Anderson, AJ, et al. Basso Mouse
Scale for locomotion detects differences in recovery after spinal cord injury in five common mouse strains. J Neurotrauma 2006;23: 635-59.
Financial Disclosure: This work is supported by NINDS
grant K08-NS056212 to N.Y.H. and NINDS grants
RO1NS39962, RO1NS42304 and RO1NS56845 to S.M.S.
No conflicts of interest relevant to this research are present.
Poster # CD-16
DJ-1 Knock-Down in Astrocytes Impairs AstrocyteMediated Neuroprotection against Rotenone
Steven J. Mullett1, David A. Hinkle1
1
Department of Neurology and Pittsburgh Institute for
Neurodegenerative Diseases and University of Pittsburgh
School of Medicine, Pittsburgh, PA
Astrocytes, the most abundant cell type in the brain, are
known for their wide array of neuron-supportive functions
and for their propensity to survive and become “reactive” in
chronic neurodegenerative conditions. Previous studies have
shown that a novel protein, DJ-1, is abundantly expressed in
reactive astrocytes in idiopathic Parkinson’s disease (PD),
and that mutations in the DJ-1 gene which eliminate its expression cause an early-onset form of familial PD, PARK7.
Thus, since DJ-1 has anti-oxidative and anti-apoptotic properties, it is plausible that the normal physiological role of
DJ-1 involves neuroprotection, and that its overexpression in
reactive astrocytes represents an attempt by the PD-affected
brain to protect both astrocytes and neurons against disease
progression. We sought to determine experimentally whether
astrocytic DJ-1 contributes to astrocyte-mediated neuroprotection as may occur in the human PD brain. To do this, we
assessed wild-type (WT) neuronal survival after rotenone
treatment in CD1 mouse neuron-astrocyte co-cultures from
the cerebral cortex in which the astrocytes either expressed
normal levels of DJ-1 (WT), reduced levels of DJ-1 (by
siRNA-mediated knockdown), or elevated levels of DJ-1 (by
transfection-mediated over-expression). Our results indicate
that astrocyte presence alone is strongly neuroprotective
against rotenone treatment based on comparisons of neuronastrocyte and neuron-only primary cultures. DJ-1 knockdown in astrocytes to ⬃5% of its baseline level significantly
reduced the capacity of astrocytes to protect co-cultured WT
neurons against rotenone in contact co-cultures, non-contact
cocultures, and by using astrocyte conditioned media on
neuron-only cultures. Conversely, DJ-1 (human or mouse)
over-expression in astrocytes to ⬃2-3 fold baseline levels augmented their neuroprotective capacity against rotenone in all
three types of co-culture. Our results suggest that astrocytederived DJ-1 plays a role in astrocyte-mediated neuroprotection against potentially PD-relevant oxidative stress, and that
astrocyte-released, soluble factors are critical to the mechanism.
Financial Disclosure: This work was supported by NINDS
K08NS055736-01 and Pittsburgh Foundation John F. and
Nancy A. Emmerling Fund for Medical Research grants to
DH.
Poster # CD-17
Impaired Maturation of GABA-A Receptor Expression
and Function in Intractable Pediatric Epilepsy
L.A. Jansen1, 2; L.D. Peugh 1; W.H. Roden1;
J.G. Ojemann3
1
Seattle Children’s Hospital Research Institute, Seattle, WA
2
Division of Pediatric Neurology, University of Washington,
Seattle, WA 3Neurological Surgery, Children’s Hospital and
Regional Medical Center and University of Washington,
Seattle, WA
Rationale: Expression of the protein subunits that make up
the GABAA receptor pentamer is known to change during
brain development. In animal models of epilepsy, both ongoing seizures and antiepileptic medications have been found
Abstracts
S147
to alter GABAA subunit expression and receptor pharmacology. In the present study, analysis of cortical GABAA subunit expression and function was performed in control human tissue obtained from infancy through adolescence, and
was compared to that from similarly aged children with intractable epilepsy.
Methods: Frozen control neocortical specimens were obtained from the NICHD Brain and Tissue Bank for Developmental Disorders. Fresh cortical tissue from children undergoing surgery for intractable epilepsy was frozen in liquid
nitrogen and stored at -80° C. The membrane fraction of the
frozen tissue was isolated and subjected to Western blot analysis using standard techniques and commercially available
antibodies. An additional membrane fraction was injected
into Xenopus oocytes, resulting in incorporation of the brain
membrane vesicles with their associated receptors into the
oocyte cellular membrane. Two-electrode voltage clamp analysis of GABAA receptor currents was performed 18-72 hours
after injection.
Results: In control cortical samples, a1 and a2 GABAA receptor subunits exhibited low expression in infancy which
increased into adolescence. In contrast, a4 subunit expression
was higher in infants than in older children. Expression of
the a5 and a subunits was relatively stable throughout development. Levels of the K⫹/Cl- cotransporter KCC2 increased
markedly with age. These patterns were all absent in the agematched epileptic children, both in those with pathologies of
focal cortical dysplasia and in those with gliosis. Subunit expression in the epileptic samples was not related to the extent
of astrocytosis as assessed by GFAP expression. Functional
studies of GABAA receptor pharmacology from the control
and epileptic specimens were correlated with receptor subunit expression.
Conclusions: Intractable epilepsy in children is associated
with disruption of the normal developmental pattern of cortical GABAA receptor maturation.
Financial Disclosure: NIH NINDS K08 NS052454 to
L.A.J.
Poster # CD-18
LAMA4 and Laminin-a4 Expression in DysferlinDeficient versus Dystrophin-Deficient Human Skeletal
Muscle
P.B. Kang1,2, A.T. Kho3, A.J. White1, I1 Eisenberg,
K.N. North4, M. Zatz5, R.H. Brown Jr.6*, L.M. Kunkel1,7*
1
Program in Genomics, Children’s Hospital, Boston, MA
2
Department of Neurology, Children’s Hospital, Boston, MA
3
Children’s Hospital Informatics Program, Boston, MA
4
Children’s Hospital at Westmead, Sydney, Australia
5
Universidade de São Paulo, São Paulo, Brazil 6Day
Laboratory for Neuromuscular Research, Massachusetts General
Hospital, Boston, MA 7Howard Hughes Medical Institute,
Chevy Chase, MD
*contributed equally
Background: Dysferlin deficiency causes several forms of
muscle disease, most prominently limb-girdle muscular dystrophy type 2B and Miyoshi myopathy. Dystrophin deficiency causes Duchenne muscular dystrophy (DMD) and
Becker muscular dystrophy, the most common forms of the
disease.
Methods: To explore the molecular consequences of dysferlin deficiency in humans, we analyzed gene expression patterns in muscle samples obtained from 7 Miyoshi myopathy
patients and compared them to 4 controls using the Af-
S148
Annals of Neurology
Vol 64 (suppl 6)
fymetrix U133Plus2.0 GeneChip system. We compared
these to existing data on human DMD and mouse dysferlin
deficiency. Further studies were performed using immunohistochemistry. Results: There were similarities between human and mouse data, with dysferlin-deficient mouse quadriceps at 8 months bearing the greatest similarity to human
disease. Geometric fold change analysis demonstrated that
only 35 genes, including LAMA4, are discordantly regulated
between the dysferlin and dystrophin-deficient datasets. The
expression of LAMA4 and its protein product laminin-␣4
was increased in dystrophin deficiency and decreased in dysferlin deficiency, correlating with the gene expression analysis. Laminin-␣4 localizes to muscle capillaries.
Discussion: Gene expression patterns in dysferlin deficiency
and dystrophin deficiency are similar, with only a few exceptions, suggesting that these patterns result from a common
downstream processes, including inflammation and connective tissue infiltration. The differences in LAMA4 and
laminin-a4 expression, along with the localization of
laminin-a4, suggest that vascular proliferation may contribute to the pathogenesis of dystrophin deficiency, but not
dysferlin deficiency.
Financial Disclosure: Nothing to disclose.
Poster # CD-19
Good Outcome After Technically Successful Intraarterial Therapy is Time-Dependent
Pooja Khatri1, T. Abruzzo1, S. Yeatts2,
Joseph P. Broderick1, T. Nichols1, and Thomas A. Tomsick1
1
IMS I and II Trial Investigators, University of Cincinnati
Academic Health Center, Cincinnati, OH 2Medical University
of South Carolina, Charleston, SC
Background: IV thrombolysis trials have taught us that
“time is brain,” specifically the time from stroke onset to the
initiation of therapy. Transcranial doppler and angiographic
studies have addressed vessel status in only a limited manner
to date. Understanding the role of time becomes especially
relevant as recent IA reperfusion studies have initated treatment at later time windows. We sought to determine how
time from stroke onset to technically successful reperfusion
(TReperfuse) affects clinical outcome in the context of intraarterial (IA) treatment and angiographic assessment in the
Interventional Management of Stroke (IMS) I and II trials.
Methods: The IMS trials used low-dose IV rt-PA (0.6 mg/
kg), followed by IA rt-PA (up to 22 mg), for large ischemic
strokes (NIHSSa10) within 3 hours of onset. In IMS II, lowenergy ultrasound via the EKOS MicroLysus® Catheter
was also used whenever possible. To isolate the effect of
TReperfuse, we only analyzed angiographic M1 and ICA-T
occlusions reperfused (TICI 2-3) during the interventional
procedure (a7 hours). TReperfuse was defined as time from
stroke onset to procedure termination. Good clinical outcome was defined as modified Rankin Score 0-2 at 3
months. Adjustments were made for known predictors of
clinical outcome—age, baseline NIHSS score, sex, and baseline glucose—using stepwise logistic regression.
Results: Fifty-four cases were identified with ICA-T (n⫽8)
and M1 (n⫽46) occlusions and reperfusion. TReperfuse
ranged from 208 to 395 minutes. Mean baseline NIHSS
scores were 18.6 (range 10-28) for these 54 cases, compared
to 19.9 (range 10-27) for the 38 cases without reperfusion
(TICI 0-1). Only TReperfuse (OR 0.981; 95% 0.967-0.995)
and age (OR 0.949; 95% CI 0.903-0.998) independently
predicted good clinical outcome after reperfusion. Both ad-
December 2008
justed and unadjusted analyses showed that the probability of
good clinical outcome decreased as TReperfuse increased
(p⫽0.009 and p⫽0.02, respectively). The graph below
shows the probability of a good clinical outcome over time
(with 95% prediction bands) for cases with reperfusion, and
a horizontal line depicting the rate of good clinical outcome
for cases without reperfusion as a reference:
Conclusions: We provide the first angiographic evidence in
a clinical trial that good clinical outcome following reperfusion with IA therapy is strongly time-dependent. Opening an
artery is not enough; time matters. At later times, reperfusion
may be associated with a poor risk-benefit ratio.
Financial Disclosure: Nothing to disclose.
Poster # CD-20
The Number Needed to Treat is the Number Needed to
Know
Maarten G. Lansberg1, Erich Bluhmki2, and
Jeffrey L. Saver3
1
Department of Neurology, Stanford University, Stanford, CA
2
Boehringer Ingelheim GmbH, Ingelheim, Germany 3UCLA
Stroke Program, UCLA, Los Angeles, CA
Introduction: Number needed to treat to benefit (NNTB)
and number needed to treat to harm (NNTH) estimates provide physicians and patients with a statistically valid summary measure that they may use intuitively to determine if a
treatment effect is clinically worthwhile. When NNT estimates are based on a dichotomization of an ordinal outcome
scale, they may underestimate the true treatment effect size.
Objective: To determine, using the entire range of the modified Rankin Scale (mRS) as the outcome variable, NNTB
and NNTH estimates for tPA therapy administered within
90 minutes of symptom onset, between 91-180 minutes, between 181-270 minutes, and between 271 and 360 minutes.
Methods: Data from the pooled analysis of the NINDS Part
1 and 2, ECASS I and II, and ATLANTIS A and B trials
were used. Seven experts generated for each 90-minute treatment time window joint distribution outcome tables in
model samples of 1000 patients assigned to placebo and tPA
therapy.
Results: Average NNTB estimates for patients treated in the
0-90 minute time-window, the 91-180 minute time-window,
the 181-270 time-window, and the 271-360 minute timewindow were 3.6, 4.3, 6.0, and 19.0. NNTH estimates for
these time-windows were 67, 39, 30 and 14. When the mRS
was condensed to six strata (combining mRS scores 5-6) or
five strata (combining mRS scores 4-6) NNTB estimates did
not change, whereas NNTH estimates increased. With the
mRS reduced to five strata the NNTH estimates for the four
90-minute time-windows were 106, 83, 59 and 27 respectively.
Conclusions: When 100 patients are treated with intravenous tPA within 90 minutes of symptom onset 28 experience a treatment benefit and one is harmed. With longer
time-to-treatment windows the benefit gradually declines and
the potential for harm increases. In the 271-360 minute
time-window, out of 100 patients treated with tPA, only five
experience a benefit and seven are harmed.
Financial Disclosure: Nothing to disclose.
Poster # CD-21
Increased Prevalence of Stroke Among Siblings of
Ischemic Stroke and Transient Ischemic Attack Cases
Lynda D. Lisabeth1, Patricia A. Peyser1, Jeffrey C. Long2,
Jennifer J. Majerisk3, Melinda A. Smith3, and
Lewis B. Morgenstern3
1
Department of Epidemilogy, University of Michigan, Ann
Arbor, MI 2Human Genetics Department, University of
Michigan, Ann Arbor, MI 3Department of Neurology, Stroke
Program, University of Michigan, Ann Arbor, MI
Background: Future ischemic stroke genetics studies are
warranted particularly studies which incorporate minority
populations with an increased risk of stroke at younger ages,
such as Hispanics. The aim of this study was to calculate the
sibling recurrence risk ratio and to compare this ratio across
two ethnic groups, Mexican Americans (MA) and nonHispanic whites (NHW).
Methods: Probands with ischemic stroke (IS) or transient
ischemic attack (TIA) between ages 45-64 were identified
through BASIC (Brain Attack Surveillance in Corpus
Christi), a population-based stroke surveillance study in a biethnic community in Nueces County, Texas. A random subset of patients with IS/TIA were interviewed to ascertain
number of biologic siblings and family history of stroke
among siblings. The sibling recurrence risk ratio was calculated overall and by ethnicity as the ratio of the observed
number of strokes among siblings to the expected number of
strokes among siblings using national prevalence data.
Results: One hundred eighty one stroke/TIA cases 45-64
years of age were interviewed. Fifty-nine percent were MA;
49.2% female. Siblings of probands had a relative risk of
stroke of 1.92 (95% CI: 1.39-2.61) compared with what
would be expected based on national prevalence estimates.
The sibling recurrence risk ratio for MAs was 2.0 (95% CI:
1.39-2.81) with the highest risk among MA men (RR⫽2.61;
95% CI: 1.64-3.99) versus MA women (RR⫽1.47; 95% CI:
0.83-2.46). Female NHWs had a sibling recurrence risk ratio
of 2.76 (95% CI: 1.22-5.66). Male NHW and total NHW
sibling recurrence risk ratios were not statistically significant.
Conclusions: Among IS/TIA patients between 45 and 64
years of age in Neuces County, Texas, there is a near doubling of sibling stroke relative risk compared to what is expected based on national prevalence data. This risk is highest
among MAs, suggesting that the genetics of ischemic stroke
may vary by ethnicity. Further genetic studies of ischemic
stroke across ethnicities are warranted.
Financial Disclosure: Nothing to disclose.
Poster # CD-22
Immediate Short-Duration Hypothermia Provides LongTerm Protection in an in Vivo Model of Traumatic
Axonal Injury
Marek Ma1,3, Brian T. Matthews1,3, Joshua W. Lampe1,3,
David F. Meaney2, Robert W. Neumar1,3
1
Department of Emergency Medicine, University of
Pennsylvania, Philadelphia, PA 2Department of
Bioengineering, University of Pennsylvania, Philadelphia, PA
3
Center for Resuscitation Science, University of Pennsylvania,
Philadelphia, PA
Introduction: More than 1.5 million cases of traumatic brain
injury (TBI) occur each year in the U.S., and a significant
component of the morbidity and mortality from TBI has been
attributed to traumatic axonal injury (TAI). Posttraumatic hypothermia has previously been shown to afford short-term ax-
Abstracts
S149
onal protection in models of TAI. However, the long-term
effect of mild hypothermia has not been established.
Methods: To test our hypothesis that hypothermia provides
long-term axonal protection after TAI, we developed an in
vivo rat optic nerve stretch model. Adult male SpragueDawley rats (n⫽6 animals in each group) underwent unilateral optic nerve stretch (8 mm piston displacement) at 37.037.5°C (probe inserted into the temporalis muscle). The
contralateral optic nerves in each animal served as controls. In
the experimental group, hypothermia was induced immediately after stretch, and the animal was maintained at 32°C for
3 hours. Animals were then slowly rewarmed 1°C every 40
minutes to a temperature of 37°C before ending general anesthesia. Normothermic control animals were maintained at
37.5°C and kept anesthetized for the same duration. Two
weeks after injury, animals were perfusion fixed, and the tissue
processed for electron microscopy. The optic nerve crosssectional area was systematically sampled, and a blinded observer counted myelinated axons. Overall and regional axonal
densities were calculated. Statistical analysis was performed using ANOVA in repeated measures.
Results: In normothermic rats, the calculated number of myelinated axons per optic nerve averaged (⫾SD) 89,214⫾3,348
in the uninjured nerve and 56220⫾19090 in the injured contralateral nerve (37.1% decrease, p⫽0.002). In rats treated
with hypothermia, the calculated number of myelinated axons
per optic nerve averaged 86,485⫾4,286 in uninjured nerves
and 68,922⫾20,879 in injured nerves (20.4% decrease,
p⫽0.051). Optic nerve axonal density counts demonstrated a
similar overall decrease after injury (normothermia: 32.6%,
p⫽0.016; hypothermia: 20.5%, p⫽0.102). Regional counts
showed that axonal density decreased by 45.0% (p⫽0.023) in
the central region and 16.6% (p⫽0.154) in the periphery of
the normothermic injured optic nerves. In rats treated with
hypothermia, central axonal density decreased by only 23.7%
(p⫽0.164) after injury. Comparison of central axonal density
between normothermic and hypothermic injured nerves demonstrated statistically significant protection with hypothermia
(p⫽0.027).
Conclusions: These results support further clinical investigation of temporally optimized therapeutic hypothermia after
traumatic brain injury.
Financial Disclosure: Support provided by the Society for
Academic Emergency Medicine Institutional Research Training Grant and NIH NS055880.
Poster # CD-23
Distributed Source Modeling of Language with
Magnetoencephalography: Application to Patients with
Left Temporal Lobe Epilepsy
Carrie R. McDonald1,3, Thomas Thesen2,3,
Donald J. Hagler, Jr.3,4, Chad Carlson2, Orrin Devinksy2,
Rubin Kuzniecky2, William Barr2, Rajan H. Patel3,
Lusineh Gharapetian3, Anders M. Dale3,4,5, and
Eric Halgren3,4,5
1
Department of Psychiatry, University of California, San
Diego, La Jolla, CA 2Comprehensive Epilepsy Center,
Department of Neurology, New York University, NY, NY
3
Multimodal Imaging Laboratory, University of California,
San Diego, La Jolla, CA 4Department of Radiology,
University of California, San Diego, La Jolla, CA
5
Department of Neurosciences, University of California, San
Diego, La Jolla, CA
Introduction: Magnetoencepholography (MEG) is gaining
widespread acceptance as a presurgical language mapping
S150
Annals of Neurology
Vol 64 (suppl 6)
tool in the evaluation of patients with epilepsy [1]. To date,
most studies have focused on late activity (⬎200ms) to auditory or visual word stimuli that are presumed to reflect
sustained N400 effects elicited during lexical-semantic processing [2]. The vast majority of these studies have used an
equivalent current dipole (ECD) or other focal source solutions to lateralize N400 effects and have demonstrated a
strong concordance between MEG language lateralization
and the intracarotid amobarbitol procedure (IAP). When focal source solutions are employed, N400 effects are reliably
localized within left or right perisylvian cortex, centered on
the superior and middle temporal gyri, supramarginal gyrus,
or within the superior temporal sulcus [3]. Although each
region is undoubtedly critical to language, it is well known
that language processing is distributed in nature, simultaneously and sequentially recruiting multiple areas within
temporal, frontal, and parietal cortex [4]. In this study, we
used distributed source modeling to evaluate the cortical dynamics of language processing in healthy controls and patients with left TLE.
Methods: MEG was obtained in 10 healthy controls and
modeled using an anatomically-constrained, noisenormalized
distributed source solution (dSPM) [5]. Distributed source
modeling of language was then applied to three patients with
left TLE and compared to results obtained from equivalent
current dipole (ECD) modeling.
Results: In healthy controls, dSPM revealed activity in visual
cortex bilaterally from ⬃80-120ms in response to novel
words and sensory control stimuli (i.e., false fonts). Activity
then spread to fusiform cortex ⬃160-200ms, and was dominated by left hemisphere activity in response to novel words.
From ⬃240-450ms, novel words produced activity that was
strongly left-lateralized in frontal and temporal lobe regions,
including anterior temporal, inferior temporal, temporal
pole, and pars opercularis, as well as bilaterally in posterior
superior temporal cortex. Analysis of patient data with dSPM
and ECD modeling suggested left hemisphere language dominance in two patients and right hemisphere dominance in
one patient. Lateralization of language using dSPM and
ECD source modeling agreed in all three left TLE patients.
As expected, results from dSPM revealed a spatially distributed network of regions involved in language processing,
whereas ECD modeling detected only a subset of regions.
Conclusion: Our results reveal that MEG can unveil the dynamic and distributed nature of language processing in
healthy controls and demonstrate the potential application of
dSPM to presurgical language mapping in patients with epilepsy.
References:
Papanicolaou, A.C., et al., Magnetoencephalographic mapping
of the language- specific cortex. J Neurosurg, 1999. 90(1): p.
85-93.
Salmelin, R., Clinical neurophysiology of language: the MEG
approach.Clin Neurophysiol, 2007. 118(2): p. 237-54.
Lee, D., et al., Reliability of language mapping with magnetic
source imaging in epilepsy surgery candidates. Epilepsy Behav,
2006. 8(4): p. 742-9.
Geschwind, N., The organization of language and the brain.
Science, 1970. 170(961): p. 940-4.
Dale, A.M., et al., Dynamic statistical parametric mapping:
combining fMRI and MEG for high-resolution imaging of cortical activity. Neuron, 2000. 26(1): p. 55-67.
Financial Disclosure: K23NS056091 and GE Healthcare
December 2008
Poster # CD-24
Poster # CD-25
Gene-Environment Interactions in the Epigenetic
Regulation of Brain Function in Neurological Disorders
B. Meyers1, R. Wilson-Sheffield1, R. Teague2, C. Pedroza3,
Paolo Moretti1,2
1
Department of Neurology, Baylor College of Medicine,
Houston, TX 2Department of Molecular and Human
Genetics, Baylor College of Medicine, Houston, TX 3University
of Texas School of Public Health, Houston, TX
Fluvastatin Demonstrates Toxicity for Sensory and
Motor Neurons: Results of an in Vitro Model Study of
Statin-Induced Peripheral Neuropathy
Beth B. Murinson1, Zachary Senders1, Amy Kerman1,
Nicholas Maragakis1, and Ahmet Hoke1
1
Department of Neurology, Johns Hopkins School of Medicine,
Baltimore, MD
Introduction: Epigenetics refers to the regulation of gene expression that takes place in the absence of DNA sequence
changes. Examples of epigenetic regulation include
X-chromosome inactivation, genomic imprinting, tissuespecific gene expression, and silencing of repetitive/ transposable elements. DNA methylation, histone modifications, histone variants, chromatin remodeling complexes, non-coding
RNAs, and higher-order topological organization of nuclear
structures (nuclear architecture) are known epigenetic mechanisms. Both genetic and environmental factors regulate
DNA methylation, including DNA methyltrasferases,
methyl-CpG binding proteins such as Mecp2, and methyl
donors such as folate. Dysfunction of Mecp2, a methyl-CpG
DNA binding protein and regulator of gene expression,
causes Rett syndrome an autism spectrum disorder. Abnormalities of epigenetic regulation are found in several additional human diseases including neurodevelopmental disorders with autism spectrum manifestations, neurodegenerative
disorders, and cancer.
Hypothesis: We hypothesize that the interaction of genetic
and environmental factors regulating DNA methylation plays
an important role in the modulation of cell function and
gene expression in the brain.
Design/Methods: We exposed wild-type and Mecp2 mutant
mice to low or high dietary methyl donors at levels within
the physiological range for a rodent’s healthy diet. We characterized the phenotype and gene expression of these mice.
Results: The health and behavior of wild-type mice were not
significantly influenced by manipulation of dietary methyl
donors. In contrast, methyl donor levels modified growth,
motor function and survival in Mecp2 mutant mice. We
identified gene expression changes in the hypothalamus of
wild-type or Mecp2 mutant mice in response to (1) changes
in dietary methyl donors, (2) mutation of Mecp2, or (3) an
interaction between these genetic and dietary factors. These
expression changes include genes known to play key roles in
the regulation of energy homeostasis, pain, anxiety, seizures,
and social behavior. The human orthologs of 14% of these
genes are known to contain mutations causing mendelian
disorders.
Conclusions: These data indicate that methyl donor levels
modulate neuronal gene expression and modify the neurologic deficits of Mecp2 mutant mice. The results raise important questions about the influence of the environment on
the epigenetic regulation of neuronal function and gene expression. Neuronal genes whose expression is modified by
methyl donor levels and/or Mecp2 function are relevant to
our understanding of the role of DNA methylation in brain
function. These genes identify epigenetic pathways sensitive
to environmental cues and may be important candidates for
epigenetic therapeutic interventions in genetic and epigenetic
neurologic disorders.
Financial Disclosure: K08 - NS049181, March of Dimes
#6-FY2007-364.
Introduction: It is estimated that 250 million people worldwide are treated with statins for the prevention of ischemic
heart disease, stroke and death. Statins are highly effective at
reducing cholesterol in humans and it is likely that millions
of cardiovascular events have been prevented by statins. Very
few pharmacological alternatives exist. Although the most
common side effect of statin treatment is diffuse muscle
pains, peripheral neuropathy is a potentially serious side effect of statin treatment for which no effective treatment,
other than statin cessation, exists. The incidence of statininduced peripheral neuropathy (SI-PN), while less than that
of statin-induced muscle aches, is thought to equal or exceed
that of statin-induced myopathy. Clinical and epidemiological studies have been confounded by the co-occurrence of
other causes for peripheral neuropathy, in particular, patients
with hypercholesterolemia are more likely to have impaired
glucose tolerance (metabolic syndrome) when compared with
controls. The mechanisms by which statins may induce peripheral neuropathy are not known. The goal of this study
was to determine experimentally the extent to which statins
are toxic to peripheral nerves in in vitro model systems and
to identify safe and effective potential remedies for this problem.
Methods: Cultures consisting of immortalized DRG-derived
cells (50B11 cells), DRG explants and primary motor neurons in organotypic spinal cord cultures were established as
previously described1,2,3. Treatment with various statins
suspended in growth medium with DMSO was compared
with vehicle control responses. For 50B11 cells outcome
measures included ATP levels determined using a ViaLight
assay system at 24 hours confirmed with trypan blue exclusion for viability at 48 hours. DRG explants were treated for
48-96 hours and neurite extension and integrity was assayed
using immunostaining for ␤3-tubulin. Motor neurons were
treated for 96 hours and assayed for motor neuron number
using SMI-32 staining.
Findings: Most statins were not highly toxic to neurons in
culture, however fluvastatin exhibited a dose-dependent toxicity for cultured sensory neurons as well as primary motor
neuron cultures. In cultured sensory neurons (DRG explants) and immortalized sensory neuron-derived cells in culture, this toxicity is fully reversed with mevalonate. Statin
toxicity in immortalized sensory neuron cultures did not respond to supplementation with CoEnzymeQ10 or CoQ9.
Preliminary data have implicated intracellular signaling pathways as important to this toxicity.
Conclusions: We conclude that in vitro evidence does not
support toxicity of most statins for peripheral nerves, however fluvastatin was toxic to motor and sensory neurons at
low micromolar concentrations, this toxicity exhibited mevalonate dependence.
References:
Chen W, Mi R, Haughey N et al. Immortalization and characterization of a nociceptive dorsal root ganglion sensory
neuronal line. J.Peripher. Nerv.Syst. 2007;12:121-130.
Wang MS, Wu Y, Culver DG et al. Pathogenesis of axonal
degeneration: parallels between Wallerian degeneration and
Abstracts
S151
vincristine neuropathy. J.Neuropathol.Exp.Neurol. 2000;59:
599-606.
Maragakis NJ, Jackson M, Ganel R et al. Topiramate protects against motor neuron degeneration in organotypic spinal cord cultures but not in G93A SOD1 transgenic mice.
Neurosci.Lett. 2003;338: 107-110.
Financial Disclosure: This work is supported in part by a
K08 career development grant to Dr. Murinson
Poster # CD-26
Persistent Hyperexcitability in Developing
Hippocampus with Co-existent Compensatory and
Pathogenic Changes in GABA-Mediated Inhibition
James Owens1,2, Kevin Winoske1, John Swann1,3
1
Department of Pediatrics, Baylor College of Medicine,
Houston, TX 2Department of Neurology, Baylor College of
Medicine, Houston, TX 3Department of Neuroscience, Baylor
College of Medicine, Houston, TX
Objective: These experiments were designed to assess physiological effects of prolonged hyperexcitability on the developing nervous system.
Background: Brain insults such as ischemia or infection produce excess excitation and neurotransmitter release and may
result in subsequent epilepsy (Koura, 1998; Kurtz, 1998).
4-aminopyridine (4-AP), a potassium channel antagonist,
causes hyperexcitability as well as elevated transmitter release
(Rutecki, 1987). I therefore investigated the effects of growing hippocampal slice cultures in media containing 4-AP.
Design/Methods: Organotypic hippocampal slice cultures
were prepared from postnatal day 6 C57/B6 mice and grown
in standard media with or without 200 micromolar 4-AP.
After 5 to 11 days in vitro (DIV), extracellular CA1 field
recordings were obtained while perfused with artificial CSF.
In “washout” experiments, cultures were grown in media
with 4-AP for 6 DIV then in normal media for another 1 to
5 days.
Results: Prolonged repetitive epileptiform discharges were recorded in area CA1 from 19 of 20 cultures grown in 4-AP
(4-AP cultures) but in only 1 of 20 grown in normal media
(control cultures). Washout experiments showed persistence
of the hyperexcitability for up to 5 days. Quantitative immunoblots revealed significant increases in glutamic acid decarboxylase (GAD) and vesicular GABA transporter (vGAT)
expression levels in slice cultures grown in 4-AP. Although
such a change appears compensatory, the slice cultures grown
in 4-AP also demonstrated a relative decrease in expression of
the KCC2 chloride cotransporter and a relative increase in
expression of the NKCC1 chloride cotransporter as compared to cultures grown in control media. Such a change
would tend to prolong the time period during which
GABA-A responses are depolarizing (Dzhala, 2005).
Conclusions: Growing hippocampal slice cultures in media
containing 4-AP produces persistent hyperexcitability which
is associated with increased expression of GABA synthetic
and vesicular packaging proteins as well as maintenance of an
immature chloride cotransporter phenotype. These findings
suggests that compensatory upregulation of inhibition may
exacerbate hyperexcitability in the immature brain. Such
findings illustrate potential pathogenic mechanisms in developmental epilepsy as well as possible targets for pharmacologic intervention.
References:
Koura, S.S., et al., Relationship between excitatory amino
acid release and outcome after severe human head injury.
S152
Annals of Neurology
Vol 64 (suppl 6)
Acta Neurochir Suppl, 1998. 71: p. 244-6.
Kurtz, Z., P. Tookey, and E. Ross, Epilepsy in young people:
23 year follow up of the british national child development
study. BMJ, 1998. 316(7128): p. 339-342.
Rutecki, P.A., F.J. Lebeda, and D. Johnston,
4-Aminopyridine produces epileptiform activity in hippocampus and enhances synaptic excitation and inhibition. J
Neurophysiol, 1987. 57(6): p. 1911-1924.
Dzhala VI, et al., NKCC1 transporter facilitates seizures in
the developing brain. Nat. Med. 2005. 11(11):1205-13.
Financial Disclosure: Supported by NIH NINDS
NS18309, NS37171, NS43124, and K08NS054882.
Poster # CD-27
Epidemiology of Pediatric Central Nervous System
Germ Cell Tumors: A California Cancer Registry Study
Sonia Partap1, J. Von Behren1, J. MacLean1, PG Fisher1,
PR Reynolds1
1
Departments of Neurology and Pediatrics, Stanford University
School of Medicine, Palo Alto, CA, and Northern California
Cancer Center, Berkeley, CA
Background: Pediatric central nervous system (CNS) germ
cell tumors (GCTs) are reported to comprise 2 to 4% of
childhood brain tumors, with an even greater prevalence in
Asians. In the United States GCTs have historically been
separated from other brain tumors, when sorted by the International Classification of Childhood Cancer, and thus, are
often neglected in analyses. Past Western studies of GCTs
have also been limited by small sample sizes.
Methods: We aimed to perform a rigorous, descriptive analysis of childhood CNS GCTs, using data from the
population-based California Cancer Registry.
Results: We obtained data on 4,070 CNS cancers, diagnosed
from 1988 through 2004 in children ages 0-14 years. 214
(5.3% of sample) primary intracranial and intraspinal germ
cell tumors were identified. Mean age at diagnosis was 9.1
years, and 68% of tumors occurred in males. The most common tumor location was the pineal gland (93 cases, 43%)
with 7.5% of cases in the sellar region. 43% of the cases
were Hispanic children, 35% white, 16% Asian, and 6%
African-American, compared to general California childhood
population ethnic frequencies of approximately 42% Hispanic, 37% white, 10% Asian, and 7% African-American.
Histologically, 131 cases (61%) were reported as germinomas, with the remainder distributed among various pathologic classifications. The overall frequency of CNS GCTs in
our cohort was 5.3%, with 11% of cases occurring between
ages 0-1 years and 62% between ages 10-14. Children ⬍1
year most often had malignant teratomas, with more females
than males (16 vs. 7, p ⬍.001, chi-square test). GCT incidence increased starting at age 7 and continued to rise at age
14. The proportion seen in males was greater than two fold
that in females (p ⬍ .05).
Conclusion: With the largest pediatric intracranial and intraspinal germ cell tumor series in the United States to date,
our study reveals that CNS GCTs may be more prevalent
among Western pediatric brain tumors than initially reported. Overall these tumors were more common among
males; however, female infants were affected more than
males, a difference that has not been previously reported.
While our sample might be influenced by a high proportion
of Asian-Americans, the patterns observed differ from Asian
series.
Financial Disclosure: Nothing to disclose.
December 2008
Poster #CD-28
Autonomic Function in Obstructive Sleep Apnea: The
Role of Impaired Glucose Regulation
Amanda Peltier1, David Robertson1,2, Stephen Davis3, and
Beth Malow1
1
Department of Neurology, Vanderbilt University, Nashville,
TN 2 Department of Pharmacology, Vanderbilt University,
Nashville, TN 3 Department of Medicine, Vanderbilt
University, Nashville, TN
Both diabetes mellitus (DM) and obstructive sleep apnea
(OSA) are associated with autonomic dysfunction, increasing
the risk of sudden death and cardiovascular disease in these
disorders. The aims of the study are to determine whether
autonomic dysfunction occurs in OSA independently of impaired glucose regulation (undiagnosed diabetes, impaired
glucose tolerance or impaired fasting glucose collectively
called IGR in this study) and if autonomic function and glucose improves after continuous positive airway pressure
(CPAP) treatment. Nineteen subjects were screened, with
fourteen subjects enrolled (three men, eleven women). Five
subjects dropped out due to poor compliance with CPAP (all
women). Subjects enrolled had a mean age of 49 (32-63),
body mass index 33 (25-40), apnea hypopnea index of 17
(5-50), fasting glucose of 97 (81-115), 2 hour glucose of 126
(60-162). Thirteen subjects have undergone autonomic testing, nine had abnormal glucoses. Mean sweat volume was
0.705 uL in normoglycemic (NG), 0.437 uL in IGR patients. Change in norepinephrine from supine to standing
was 274 pg/dL in NG, 300 pg/dL in IGR patients. E:I ratio
1.2 in both groups. Sural amplitude was 13.9 uV in NG, 9.8
uV in IGR. Further data collection will determine whether a
definitive difference in peripheral and autonomic nervous
system function exists in OSA patients with IGR.
Financial Disclosure: Nothing to disclose.
Poster # CD-29
Markers Which Precede Clinical Features of PD in the
Unaffected Side in LRRK2 Early Asymmetric Parkinson
Disease
Kaili M. Stanley1, Johannes Hagenah2, Monica Kurtis3,
Kathrin Reetz2, David Eidelberg4, Seth Pullman3, and
Rachel Saunders-Pullman5
1
Beth Israel Medical Center, New York, NY 2University of
Luebeck, Lubeck, Germany 3Columbia University, New York,
NY 4North Shore, Manhasset, NY 5Beth Israel Medical
Center/ Albert Einstein College of Medicine, New York, NY
Introduction: FDG-PET has been established as an early
marker in PD. Transcranial ultrasound has also been proposed
as a pre-clinical marker. Spiral analysis indices have been
shown to correlate with UPDRS motor scores in mild PD
patients, but their utility in discriminating early PD has not
been reported. Markers for early PD should be able to discern
asymptomatic PD on the clinically unaffected side. The objective is to measure the utility of spiral analysis and imaging
markers in detecting early Parkinsons Disease (PD) associated
with LRRK2 mutation.
Methods: Digitized spiral analysis, transcranial ultrasound and
FDG PET were evaluated for a 62 year old right-handed man
with the G2019S LRRK2 mutation and symptomatic tremor
of the left leg. Spiral values, previously associated with detection or progression of PD, were compared to those of 26 age
matched controls. Clinical FDG-PET was compared to 12
healthy controls using single case SPM (threshold: p⫽0.05).
Results: Exam was notable for mild left arm and leg rigidity,
rest tremor in the left leg, trace bilateral action tremor and
left-sided bradykinesia. FDG-PET revealed increased metabolism in the thalamus, pons, motor cortex/supplementary motor area and anterior cingulate, consistent with idiopathic PD.
One year later, signs remained limited to the left side except,
as at baseline, trace action tremor on the right. In the dominant (unaffected) arm, spiral analysis showed abnormal
pressure-frequency (p⬍0.001), speed slope ratio (p⬍0.001),
tightness (p⬍0.0054), first order z-crossing(p⬍0.001) but degree of severity (p⫽0.058), and second order smoothness
(p⫽0.9391) were not significant. Ultrasound demonstrated increased echogenicity of the substantia nigra (0.293cm(2)left,
0.328cm(2) right).
Conclusions/Relevance: Consistent with their promise as
early clinical markers, both spiral analysis and transcranial ultrasound showed abnormalities on the side clinically unaffected by PD, suggesting they should be further explored.
These changes are consistent with those observed in FDGPET.
Financial Disclosure: Supported by Thomas J. Hartman
Foundation and NIH-K23-NS047256
Poster # CD-30
Dok-7 Myasthenia: Phenotypic and Molecular Genetic
Studies in 16 Patients
Duygu Selcen,1 Margherita Milone1 Xin-Ming Shen1
C. Michel Harper,1 Anthony A. Stans,2 Eric D. Wieben,3
and Andrew G. Engel1
1
Department of Neurology and Neuromuscular Research
Laboratory, Mayo Clinic, Rochester, MN 2Department of
Orthopedic Surgery, Mayo Clinic, Rochester, MN 3Department
of Biochemistry and Molecular Biology, Mayo Clinic,
Rochester, MN
Objective: Detailed analysis of phenotypic and molecular genetic aspects of Dok-7 myasthenia in 16 patients.
Methods: We assessed our patients by clinical and EMG
studies, by intercostal muscle biopsies for in vitro microelectrode analysis of neuromuscular transmission and quantitative EM of 409 endplates (EPs), and by mutation analysis,
and expression studies of the mutants.
Results: The clinical spectrum varied from mild-static limbgirdle weakness to severe generalized progressive disease. The
synaptic contacts were single or multiple and some but not
all were small in size. In vitro microelectrode studies indicated variable decreases of the number of released quanta and
of the synaptic response to acetylcholine (ACh); AChR channel kinetics were normal. EM analysis revealed widespread
and previously unrecognized destruction and remodeling of
the EPs. Each patient carries two or more heteroallelic mutations: 11 in genomic DNA, 7 of which are novel, and 6
identifiable only in cDNA, cloned cDNA or single allele
analysis of genomic DNA, 3 of which are novel. The pathogenicity of the mutations was confirmed by expression studies. Although the functions of Dok-7 include AChR
␤-subunit phosphorylation and maintaining AChR sitedensity, patient EPs showed normal AChR ␤–subunit phosphorylation and the AChR density on the remaining junctional folds appeared normal.
Interpretation: (1) The clinical features of Dok-7 myasthenia are highly variable. (2) Some mutations are complex and
identifiable only by cDNA analysis. (3) Dok-7 is essential for
maintaining not only the size but also the structural integrity
of the EP. (4) The profound structural alterations at the EPs
likely contribute importantly to the reduced safety margin of
neuromuscular transmission.
Abstracts
S153
Financial Disclosure: This work is supported by K08 grant
from NIH to DS and NS6277 and research grant from the
MDA to AGE.
Poster # CD-31
Sonic Hedgehog Regulates Ischemia/Hypoxia-induced
Neural Progenitor Proliferation
John R. Sims12, Sae-Won Lee1, Kamil Topalkara1,
Jianhua Qiu1, and Michael A. Moskowitz1
1
Department of Radiology and Neuroscience Center, Harvard
Medical School, Massachusetts General Hospital, Stroke and
Neurovascular Regulation Laboratory, Charlestown, MA
2
Department of Neurology, Harvard Medical School,
Massachusetts General Hospital, Stroke and Neurovascular
Regulation Laboratory, Charlestown, MA
Introduction: Brain ischemia causes increased proliferation of
hippocampal neural progenitor cells (NPCs). In the embryonic
and adult hippocampus, Sonic Hedgehog (Shh) protein is required for the maintenance of NPCs. We therefore examined
whether Shh regulates the increase in proliferation of NPCs
after ischemia/hypoxia.
Methods: Male SV129 mice were exposed to 20-minute middle cerebral artery occlusion (MCAO). Bilateral hippocampi
were collected at 0.5, 2.5, 7 and 10 days later and analyzed by
for Shh mRNA and protein expression by real-time PCR, immunoblot and immunohistochemistry. To determine the cell
type expressing Shh, primary cell cultures of neurons, astrocytes and NPCs were exposed to 16 hours of hypoxia (1%
O2) and analyzed by real-time PCR and immunoblot. Proliferation of NPCs, in vivo and in vitro, was measured by bromodeoxyuridine incorporation.
Results: MCAO was associated with a transient, 2-fold increase in the mRNA encoding both Shh and its transcription
factor Gli1 0.5 days after ischemia. At 3 and 7 days, Shh protein was increased approximately 3-fold and was observed predominantly within cells in the CA3 and subgranular regions
by 3 days. Among the cell types examined in vitro, only NPC
and neurons increased Shh mRNA under hypoxic conditions.
Furthermore, hypoxia increased proliferation of NPCs and this
proliferation was enhanced by the addition of recombinant
Shh or blocked by the pathway specific inhibitor, cyclopamine. In vivo, cyclopamine also suppressed ischemia-induced
proliferation of subgranular NPCs.
Conclusion: The Shh pathway regulates the proliferation of
NPCs induced by ischemia/hypoxia and might participate in
injury remodeling.
Financial Disclosure: Supported by NIH K08 NS049241
grant
decoding them, and using them to control the desired output, e.g., a computer cursor, a prosthetic limb, or the patient’s plegic limb via functional electrical stimulation. Thus
far, most efforts to develop such an interface have used either
noninvasive EEG or highly invasive intracortical electrodes to
obtain control signals for BMIs. However, scalp signals offer
limited bandwidth, and intracortical electrodes have limited
longevity when recording spikes (usually no more than 1-2
years), in addition to their increased invasiveness. Therefore,
a few groups (Leuthardt et al., 2004, Felton, et al., 2007)
have begun to investigate the use of subdurally recorded field
potentials (electrocorticogram, ECoG) for BMIs. It has been
postulated, but not yet shown, that epidural field potentials
(EFPs) would offer an even less-invasive, yet similar quality
alternative to ECoG. The optimal electrode spacing for such
arrays has not yet been determined. We used spatial spectral
analysis (Freeman and Baird 1987) to investigate the optimal
spatial resolution of scalp, epidural and subdural electrode
arrays.
Methods: Electrodes spaced 0.5 mm apart in a 16X1 arrangement were implanted epidurally over sensorimotor cortex and used to record from both anesthetized and behaving
rats. The same type of array was also used to record sequentially from scalp, epidural and subdural locations in anesthetized rats. The spatial frequency bandwidth was indicated by
the maximum frequency at which the power varied with frequency (i.e., the point at which the spectrum devolved into
white noise). We used this frequency to determine the spacing which would capture the most spatial information.
Results: The optimal interelectrode distances for epidural
and subdural arrays were very similar (⬍1 mm), while that
for scalp electrodes was much larger (⬎3 mm). Moreover,
these results were consistent for neural activity from both
anesthetized and awake, moving rats.
Conclusion: These results suggest that epidural field potentials may provide nearly as much spatial information as
ECoG. This information is currently being used to design
electrode arrays for recording EFPs from behaving rats. Rats
have been trained to move a joystick using their forelimb to
control a sipper tube in a 2-D, modified center-out task. We
are using EFPs to predict the direction of movement during
this task. This suggests that EFPs may be a viable control
signal for BMIs.
References:
E.A. Felton, J.A. Wilson, J.C. Williams, and P.C. Garell,
J Neurosurg 106, 495-500 (2007)
W.J. Freeman and B. Baird, Behav Neurosci 101 (3), 393
(1987)
E.C. Leuthardt, G. Schalk, J.R. Wolpaw, J.G. Ojemann, and
D.W. Moran, J Neural Eng 1 63-71 (2004)
Financial Disclosure: This work was supported by NINDS
grants K08NS60223 and R01NS048845.
Poster # CD-32
Spatial Design of Surface Electrode Arrays for BrainMachine Interfaces
Marc W. Slutzky1, Luke R. Jordan2, and Lee E. Miller2
1
Departments of Neurology and Physical Medicine and
Rehabilitation, Northwestern University, Feinberg School of
Medicine, Chicago, IL 2Department of Physiology, Northwestern
University, Feinberg School of Medicine, Chicago, IL
Introduction: Brain-machine interfaces (BMIs) have the potential to help thousands of movement-impaired individuals
(such as those who are tetraplegic or lockedin from spinal
cord injury or stroke) by improving their ability to interact
with their environment. BMIs aim to achieve this goal by
recording movement-related signals from the cerebral cortex,
S154
Annals of Neurology
Vol 64 (suppl 6)
Poster # CD-33
Petit-mal Sonata: Predominant EEG Seizure Patterns in
Childhood Absence Epilepsy (CAE)
Yoshimi Sogawa1, Solomon L Moshe1, Shlomo Shinnar1,
Dennis Dlugos2, Joan Conry3, Avital Cnaan2,
Tracy A Glauser4
1
Albert Einstein College of Medicine, Bronx, NY 2Children’s
Hospital of Philadelphia, Philadelphia, PA 3Children’s
National Health Center, Washington, DC 4Cincinnati
Children’s Hospital Medical Center, Cincinnati, OH
Objective: To identify the predominance of various features
of 3Hz spike-and-wave discharges in children enrolled in the
December 2008
NIH Childhood Absence Epilepsy (CAE) trial.
Method: We analyzed unprovoked ictal spike-wave discharges in children ages 3-12 years with CAE during wakefulness. The following montage was used: F3-A1, F7-A1,
O1-A1, F4-A2, F8-A2, O2-A2, Cz-A1, Pz-A2.
Results: To date, 376 discharges from 103 children were analyzed. Within a burst there are five electrographic components: Introduction is the initial change from baseline. Exposition is the characteristic 3Hz spike-wave discharge.
Development is the variation on the 3Hz pattern. Recapitulation is the reemergence of the Exposition-like pattern.
Coda is the change prior to return to baseline. The morphology, distribution and combination of components were consistent in all bursts within an individual in 82% but showed
burst-to-burst variability in the combination of the components in 18%. There are 3 predominant patterns of expression. The classic (textbook) pattern occurred in only 13.6%
of individuals.
Conclusion: The expression of 3Hz spike-wave discharges in
absence epilepsy is not uniform. The existence of various
electrographic patterns may reflect genetic variability and
may be associated with different outcomes.
References:
Electroclinical features of absence seizures in childhood absence epilepsy. Sadleir LG, Farrell K, et al. Neurology
2006(67)413-418
Epidemiology of Absence Epilepsy: EEG findings and Their
Predictive Value. Hedstrom A, Olsson I. Pediatr Neurol
1991(7)100-104
The morphology of the spike-wave complex. Weir B. Electroencephalogr Clin neurophysiol 1965(19) 284-290
Financial Disclosure: Supported by grants NS 045911, NS
045803 and NS 048856 from NINDS
Poster # CD-34
Structural Brain Differences Between Autistic Children
and Their Typically-Developing Siblings: a Voxel-Based
Morphometry Analysis
Kyle Steinman1, Linda Lotspeich2, Sweta Patnaik3,
Fumiko Hoeft3, Allan Reiss3
1
Child Neurology, University of California, San Francisco,
San Francisco, CA 2Psychiatry & Behavioral Sciences,
Stanford University, Stanford, CA 3Center for
Interdisciplinary Brain Sciences Research, Psychiatry and
Behavioral Sciences, Stanford University, Stanford, CA
Background: Morphologic brain differences have been identified between children with autism and typically-developing
children, though findings have been inconsistent across studies. One potential cause is the variability in brain morphology resulting from the influence of multiple genetic and environmental factors on brain development. A strategy to
control for such factors is to compare brain structure between siblings discordant for autism.
Objectives: To assess the relationship between brain morphology and autism using voxel-based morphometry to examine siblings discordant for autism.
Methods: Participants included 27 same-gender sibships
consisting of one child with autistic disorder (AU; confirmed
with ADI-R and ADOS-G) and one typically-developing sibling (TD). Subjects were between 6-13 years old (AU
9.7⫾1.7; TD 9.1⫾1.9), and all pairs were less than 4 years
apart. High-resolution structural magnetic resonance images
were pre-processed (including modulation) and analyzed
(paired t-test covarying for age, gender, and total gray/white
matter volume) using SPM5 and VBM5.1 (p⫽0.01 corrected).
Results: AU had greater grey matter volume than TD in the
right superior temporal gyrus and surrounding posterior perisylvian region and the left insula parahippocampal gyrus. AU
had greater white matter volume in the right inferior temporal lobe. AU had less grey matter volume than TD in right
postcentral gyrus, and less white matter volume in bilateral
cingulate, posterior corpus callosum, and left superior parietal lobe.
Conclusions: Grey and white matter volume differences
found in temporal lobes and perisylvian structures, as well as
insular cortex and parahippocampal gyrus, correspond to areas involved in language and social behaviors known to be
abnormal in autism. Posterior corpus callosum and parietal
lobe differences correspond to previously reported abnormalities, and may relate to abnormal inter-hemispheric connectivity thought to exist in autism. The use of discordant siblings to study brain morphology provides better confidence
about controlling for environmental and non-autism–causing
genetic factors, likely resulting in more robust findings. We
recommend this strategy in future neuroimaging studies in
autism.
Financial Disclosure: Research supported by NIMH K01
MH001832. KJS is supported by the NINDS Neurological
Sciences Academic Development Award (NS01692).
Poster # CD-35
Development of a Cost Effective System with High
Frequency Response to Monitor Video-EEG in a Rat
Model of Temporal Lobe Epilepsy
Andrew M. White1, D. Shmueli, L. Frey, S. Waldbaum,
and M. Patel
1
Department of Neurology, University of Colorado, Denver,
Denver, CO
Rationale: Animal models of status epilepticus, traumatic
brain injury, and neonatal hypoxia-ischemia have been developed to study the process of epileptogenesis. To investigate
this process, it is necessary to monitor both the behavior and
the EEG of animals. While seizure detection systems have
been developed to monitor chronic seizures their cost is often
prohibitive for routine use and they often can only be used
intermittently. Therefore, we developed a cost-effective
video-EEG system. To validate the system we investigated
seizure activity in the rat model of kainate-induced epileptogenesis.
Methods: The system was composed of four main parts: (1)
video collection, (2) EEG collection, (3) data storage, and,
(4) data analysis. The first of these was composed of a 4
camera system (Q-See) whose signal was fed into a video
capture card. Real time acquisition software was then used to
compress the signal using the MPEG4 format and the output was stored on a hard drive. EEG collection was performed using a Pinnacle Technology system composed of a
preamplifier on the rats head (reducing noise), a commutator, an amplifier and the necessary cables. The data was
stored on an off-the-shelf computer hard drive, with back-up
external drives and DVDs. A data analysis code (SVERAT)
was written using Visual Basic 2008 routines that displayed
the video-EEG data simultaneously for 4 rats. It also allowed
for analysis of the data (FFTs, seizure detection). To validate
the utility of the system we used the rat kainate model of
epilepsy. Adult rats were implanted with two hippocampal
electrodes and a single dural electrode using stereotaxic place-
Abstracts
S155
ment and audiometric evaluation. After a recovery period of
one to seven days), the rats underwent video-EEG monitoring. The sampling frequency was 400 Hz. The rats (n⫽10)
were subsequently injected with one or more doses of kainate
to achieve at least 10 convulsive seizures for 3 consecutive
hours. Controls included a group of rats that underwent
video monitoring after kainate injection without implantation (n⫽4) or implantation without kainate treatment
(n⫽3). The study endpoint was the time at which the first
chronic seizure (not associated directly with the kainate treatment) occurred.
Results: The system, with a cost of about $3,000 per rat,
provides high quality EEG while recording at up to 1000Hz.
Seizures and interictal spikes were easily identifiable. Our
benchmarking study confirmed our suspicion that the implantation of electrodes did decrease the time to first chronic
seizure, but not significantly. Also, implantation in the absence of kainate injection did not result in chronic seizures.
The time to first chronic seizure in implanted rats injected
with kainate was 293 ⫹/- 134 hours. In comparison, unimplanted kainite injected rats monitored for behavior by video
displayed seizures 204 ⫹/- 50 hours after kainate injection.
Although many of the chronic seizures did not have a behavioral correlate, the initial electrographic seizure had a behavioral correlate in 7 of the 10 implanted rats that were
treated with kainate.
Conclusions: Our preliminary results suggest that a less expensive video-EEG system can be utilized to detect chronic
seizures in a rat status epilepticus model of epilepsy.
Financial Disclosure: Funding was provided through NIH
grants KO8 NS053610-03(AW) and RO1NS039587 (MP).
Poster # CD-36
Intracranial Atherosclerosis in a Type 2 Diabetes Swine
Model
Bradford B Worrall1, Tirtha R Koirala2,
Stephen R Williams1, Jerry L Nadler2, Ross G. Gerrity3
1
University of Virginia, Charlottesville, VA 2UVA Health
System, Charlottesville, VA 3Medical College of Georgia,
Augusta, GA
Introduction: Intracranial atherosclerosis accounts for
⬃10% of all ischemic strokes [1] and is a major cause of
recurrent stroke and death [2]. Data from the WarfarinAspirin Symptomatic Intracranial Disease (WASID) study
underscores the tremendous burden of intracranial disease
with stroke rates of ⬃20% in both treatment arms [3]. Patients with this disease are at extremely high risk and the lack
of a good animal model has severely impeded efforts to better understand the pathophysiology, to develop treatments
for this disease and to conduct preclinical assessment of such
treatments. The NINDS Stroke progress review group
(PRG) cited establishment of better large animal models as
essential to realize all 5 of their research priorities for the
21st century [4]. Diabetes appears to preferentially increase
risk for large artery atherosclerotic stroke involving both intracranial and extracranial vessels [5].
The Type 1 Model: Gerrity and colleagues developed a
model using diet induced hyperlipemia in animals treated
with streptozotocin (STZ). This type 1 diabetic/hyperlipemic
(Type 1 model) swine and have accelerated development of
coronary (Figure 1) and aortic atherosclerosis compared to
non-diabetic/hyperlipemic control swine [6]. The accumulation of atherosclerotic burden is markedly accelerated and
demonstrably greater in the type 1 animals than in controls
S156
Annals of Neurology
Vol 64 (suppl 6)
from as early as 12-weeks of diabetes and hyperlipemia [6].
These animals develop symptomatic and fatal coronary disease, accompanied by lipid profiles similar to human diabetics, including hypertriglyceridemia. We have previously has
demonstrated significant extra- and intracranial atherosclerosis in the type 1 model (Figures 2 and 3) [7, 8].
The Type 2 Model: More recently, we have used dietary
manipulation alone to create an insulin-resistant, type 2
model of diabetes. These animals develop atheromata in abdominal and coronary vascular beds comparable to that seen
in the type 1 model. We have used two dietary formulations
including a commercially available high carbohydrate diet
and a diet supplemented with sucrose to see if similar results
can be obtained.
Methods: At 8-12 weeks of age (15-20 kg body weight), the
experimental animals were placed on a high carbohydrate
and high fat diet. The carbohydrate content was either commercially prepared high carbohydrate chow (N⫽6 ) or sucrolose (N⫽6). All animals are also placed on a high fat diet
(1.5% cholesterol and 15% lard) to induce hyperlipemia and
hypertriglyceridemia. This high fat diet is identical that used
in the Type 1 DM model (N⫽16). Control animals (N⫽6)
were fed normal chow. At necropsy (⬃30 wk), serum samples were taken for terminal readings of serum profiles, and
cerebral and precerebral arteries were harvested for quantitative en face and histological analysis of lesion extent and severity. The carotid and circle of Willis vessels collected at
necropsy were divided for flash freezing and fixation in formalin for histology. Lesions were graded using a standard
0-6 scale.
Results: More than half of the type 2 DM animals had
grossly visible intracranial lesions at necropsy, whereas none
of the controls did. Fifty percent of the type 1 DM animals
had grossly evident intracranial lesions. Microscopically,
atheromata were present extracranially in all 12 of the type 2
DM animals (Figures 4 and 5), 15/16 1 DM animals did
(Figure 6) whereas none of the controls did (Figure 7). Intracranially, 9/12 type 2 DM animals had plaques. The basilar artery was especially severely involved with grade 4-6 lesions in 5/12 animals (Figures 8 and 9). The high
carbohydrate show fed animals more frequently had lesions
but the two most severe lesions ccured in the high sucrose
fed animals. None of the controls showed any lesions. In the
concurrently studied type 1 DM model animals, 12/16 had
intracranial atherosclerotic leasions. Again the basilar was
most severely affected with 5/16 having grade 4-6 lesions.
(Figures 10).
Discussion: Thus, diet induced type 2 DM in swine results
in significant intracranial and extracranial cerebrovascular
atherosclerosis comparable to that previously seen in a type 1
swine model. These lesions, in both models have humanoid
characteristics histologically and with respect to their distribution and severity. These animals develop mature lesions by
30 weeks of induced diabetes (⬃40 weeks of age).
Conclusions: These data suggest that this type 2 DM pig is
viable as a model for intracranial cerebrovascular atherosclerosis. We are now examining inflammatory mediator express
in these models. This animal may prove useful for investigating pathogenesis and testing novel therapies for this frequently aggressive cerebrovascular disease. We are exploring
the extent to which the effects of the commercial high carbohydrate diet can be reproduced with sucrose supplementation.
References:
Sacco, R.L., et al., Race-ethnicity and determinants of intracranial atherosclerotic cerebral infarction. The Northern
Manhattan Stroke Study. Stroke, 1995. 26(1): p. 14-20.
December 2008
Williams, J.E., et al., Gender differences in outcomes among
patients with symptomatic intracranial arterial stenosis.
Stroke, 2007. 38(7): p. 2055-62.
Chimowitz, M., et al., Comparison of warfarin and aspirin
for symptomatic intracranial arterial stenosis. N Engl J Med.,
2005. 352(13):p. 1305-16.
NINDS-Stroke-PRG. (2002). Report of the Stroke Progress
Reivew Group. Bethesda: National Institute of Neurological
Disorders and Stroke.
Matsumoto, K., et al., Insulin resistance and classic risk factors in type 2 diabetic patients with different subtypes of
ischemic stroke. Diabetes Care, 1999. 22(7): p. 1191-5.
Gerrity, R.G., et al., Diabetes-induced accelerated atherosclerosis in swine. Diabetes, 2001. 50(7): p. 1654-65.
Worrall, B.B., et al., Carotid atherosclerosis in a pig model.
Stroke, 2003. 34(1): p. 349 [ABSTRACT].
Worrall, B.B., et al., Intracranial Disease in a Pig Model of
Atherosclerosis. Stroke, 2004. 35(1): p. 303 [ABSTRACT].
Financial Disclosure: Dr. Worrall is funded by NINDS
K08-NS045802 and was previously funded by a pilot and
feasibility grant under P50 DK 0636091 (Eugene Barrett–
PI). Dr. Nadler and Dr. Gerrity collaborated as part of a
diabetes Program Project Grant titled “Glucose, Insulin in
Diabetic Vascular Disease” which supported some of the earlier pig work (P01HL055798 – Jerry Nadler-PI)).
Poster # CD-37
Imatinib Attenuates Skeletal Muscle Dystrophy in mdx
Mice
Ping Huang1, Sherry X Zhao1, Matthew Fields1,
Richard Ransohoff1, Lan Zhou1
1
Departments of Neurology and Neurosciences, Lerner Research
Institute, Cleveland Clinic, Cleveland, OH
Introduction: Duchenne muscular dystrophy (DMD) is the
most common, lethal, and currently untreatable muscle disease. Muscle necrosis, inflammation, and fibrosis are prominent pathological features, which lead to muscle weakness.
Pharmacotherapy to ameliorate these pathological changes
represents an important therapeutic approach to improve
phenotype of DMD. Imatinib is an anti-neoplastic therapy
that selectively inhibits the tyrosine kinase activity of c-abl,
c-kit, and PDGF receptors (PDGFRs). It is also a promising
anti-inflammatory and anti-fibrotic therapy as demonstrated
by its substantial inhibition of inflammation and fibrosis of
liver, kidney, lung, or skin in various animal models of disease. Therefore, we have hypothesized that imatinib can inhibit skeletal muscle inflammation and fibrosis associated
with dystrophin deficiency to improve muscle function.
Methods: We tested our hypothesis by treating mdx mice, a
Duchenne mouse model, with intraperitoneal injection of
imatinib at the peak of limb muscle inflammation and at
onset of diaphragm fibrosis; controls received PBS vehicle or
were left untreated. Muscle necrosis and inflammation were
quantified by measuring serum CK activity and percentage
of CD45 immunoreactive area, respectively. Muscle fibrosis
was evaluated by collagen III immunostaining. Muscle function was assessed by measuring hindlimb grip strength. Phosphorylation of the tyrosine kinase targets of imatinib was
studied by Western blot.
Results: Compared with control mdx mice, imatinibtreated
mdx mice showed striking pathological and functional benefit. Serum CK level, diaphragm and quadriceps inflammation
areas, and diaphragm fibrosis were markedly reduced. Hindlimb grip strength was significantly improved. Reduced clin-
ical disease was accompanied by suppression of TNF-alpha
and IL-1beta mRNA expression, and inhibition of c-abl and
PDGFR phosphorylation.
Conclusions: 1) Imatinib therapy for DMD may hold
promise for ameliorating muscle necrosis, inflammation, and
fibrosis. 2) Imatinib likely exerts its therapeutic effects on
mdx mice by inhibiting c-abl and PDGFR signaling and
downstream inflammatory cytokine and fibrotic gene expression.
Financial Disclosure: Work supported by the NIH/NINDS
1K08 NS049346 grant.
Poster # CD-38
Foxc1, a Transcription Factor Expressed in the
Meninges and not the Neocortex, Is Required for
Normal Neocortical Development
Jonathan H Hecht1, Julie A Siegenthaler2,
Konstantinos Zarbalis2, and Samuel J Pleasure2
1
Departments of Neurology and Pediatrics, University of
California, San Francisco, San Francisco, CA 2Department of
Neurology, University of California, San Francisco, San
Francisco, CA
The meninges are understudied regulators of neocortical development. We recently identified a mutant in the meningeal
transcription factor Foxc1, hith, that reduces protein stability. Hith mutants develop neocortical heterotopias and basement membrane (BM) defects resembling Type II lissencephaly in humans. Determining the embryonic progression
of brain malformations is critical for understanding the developmental role of Foxc1.
We obtained E12.5-E18.5 embryos carrying combinations
of hith and null alleles of Foxc1. We then studied the expression of BM components and the effect on Cajal-Retzius
(CR) cells. Abnormalities of the BM worsened throughout
gestation, and as Foxc1 dosage decreased. Interestingly, we
also observed striking defects in CR cell development.
Our data indicate that meningeal Foxc1 is required for
normal cerebral BM formation. Foxc1 is also required for
CR cell development. The gene dosage of Foxc1 has significant effects on the phenotype. We hypothesize that Foxc1
influences brain development in a cell non-autonomous fashion, by controlling important signals originating from the
meninges. Therefore, the meninges may be involved in the
pathogenesis of Type II lissencephaly.
Financial Disclosure: Nothing to disclose.
JUNIOR ACADEMIC
NEUROLOGIST
ABSTRACTS
In addition to K-awardees, the American Neurological Association invites 10 Junior Academic Neurologists to attend
the Career Development Symposium. Many of the topics
and discussions are of interest to junior faculty who may not
have obtained K awards, who are within 4 years of completing residency or fellowship training, and are committed to
Abstracts
S157
careers in academic neurology. The following abstracts have
been submitted by the Junior Academic Neurologist Attendees and were presented at the Poster Session on Monday,
September 22, 2008. The Junior Academic Neurologist’s
name is in bold.
Poster # JAN-1
Coagulopathy is an Independent Predictor of Inhospital
Mortality in Patients with Acute Subdural Hematoma
Eric M Bershad1, Saeid Farhadi2, Mohammed F Suri3,
Eli S Feen4, Olga H Hernandez5, Warren R Selman2,
Jose I Suarez1
1
Section of Vascular Neurology and Neurocritical Care,
Departments of Neurology and Neurosurgery, Baylor College of
Medicine & St. Luke’s Episcopal Hospital Neuroscience
Center, Houston, TX 2Neurological Institute, Department of
Neurosurgery, University Hospitals Case Medical Center,
Cleveland, OH 3Department of Neurology, University of
Minnesota, Minneapolis, MN 4Division of Neurocritical Care,
Department of Neurology, St Louis University, St Louis, MO
5
Division of Neurocritical Care, Instituto Neurologico de
Antioquia, Medellin, Colombia
Introduction: Acute subdural hematoma (ASDH) is a lethal
form of intracranial injury. Early time to surgery is associated
with reduced mortality. Coagulopathy may be present in
some patients with ASDH and could delay surgical evacuation of the hematoma. Furthermore, coagulopathy could foster expansion of the hematoma. It is known that coagulopathy is associated with poor outcome in patients with
intracerebral hemorrhage and trauma; however, this association has not been definitely proven in patients with ASDH.
We investigated the association between coagulopathy and
inhospital mortality in patients with acute subdural hematoma (ASDH).
Methods: We investigated all patients admitted to our
Neuro-ICU with ASDH between 06/1999 – 06/2001. We
recorded demographic, APACHE III score on admission,
laboratory values, admission source, prior functional status,
comorbid disease, treatments received, and discharge disposition. Coagulopathy was defined as an INR ⬎ 1.2 seconds.
A multivariate logistic regression model was used to investigate independent predictors of inhospital mortality (significance P⬍0.05).
Results: We found 244 patients. Most were male (61%)
with mean age 71.3 ⫹/- 15 years. Fifty-three patients had
coagulopathy. The median APACHE III score was 43 (range
11 – 119). Twenty-nine patients died in the hospital (12%).
Independent predictors of inhospital mortality were the
APACHE III score (OR 4.4, 95% CI 1.4-13.4, p⫽0.011),
and coagulopathy (OR 2.7, 95% CI 1.1-7.1, p⫽0.037).
Mean time to correction of coagulopathy with fresh frozen
plasma and vitamin K was 29 hours (range 7-72 hours) Surgical evacuation of ASDH was associated with significantly
decreased in-hospital mortality (OR 0.2, 95% CI 0.1-0.6,
p⫽0.003).
Conclusions: Coagulopathy is an independent predictor of
inhospital mortality in patients with ASDH. Treatment of
coagulopathy with traditional medical treatment using fresh
frozen plasma and vitamin K required an excessive length of
time. Other modalities for rapid correction of coagulopathy
in ASDH patients should be explored.
References:
Seelig JM, Becker DP, Miller JD, Greenberg RP, Ward JD,
Choi SC. Traumatic acute subdural hematoma: major mor-
S158
Annals of Neurology
Vol 64 (suppl 6)
tality reduction in comatose patients treated within four
hours. N Engl J Med. 1981 Jun 18; 304(25):1511-8
Depreitere B, van Calenbergh F, van Loon J. A clinical comparison of non-traumatic acute subdural haematomas either
related to coagulopathy or of arterial origin without coagulopathy. Acta Neurochir (Wien) 2003; 145:541-6
Konig SA, Schick U, Dohnert J, Goldammer A, Vitzthum
HE. Coagulopathy and outcome in patients with chronic
subdural hematoma. Acta Neurol Scand 2003; 107:110-6
Mayer SA, Brun NC, Begtrup K, Broderick J, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2005 Feb 24; 352(8):777-85.
Financial Disclosure: None
Poster # JAN-2
Prophylactic Statin Use and Physiologic Markers of
Delayed Cerebral Vasospasm following Aneurysmal
Subarachnoid Hemorrhage
Sherry (Hsiang-Yi) Chou1, Eric E. Smith2,
Neeraj Badjatia4, Raul G. Nogueira5, John II Sims5,
Christopher C. Ogilvy6, Guy Rordorf2, Cenk Ayata5,
MingMing Ning3, Eng H. Lo7, Steven K. Feske1
1
Department of Neurology, Brigham and Women’s Hospital
Harvard Medical School 2Department of Neurology,
Massachusetts General Hospital Harvard Medical School
3
Clinical Proteomics Research Center, Department of
Neurology, Massachusetts General Hospital Harvard Medical
School 4Department of Neurology and Neurosurgery, Columbia
University College of Physicians and Surgeons 5Departments of
Neurology and Radiology, Massachusetts General Hospital
Harvard Medical School 6Department of Neurosurgery,
Massachusetts General Hospital Harvard Medical School
7
Neuroprotection Research Laboratory, Departments of
Neurology and Radiology, Massachusetts General Hospital
Harvard Medical School
Introduction: Aneurysmal subarachnoid hemorrhage (SAH)
affects over 30,000 patients yearly in the US and is responsible for 27 percent of all stroke-related years of potential life
lost before age 65. Up to 20% of SAH patients with symptomatic vasospasm develop ischemic stroke or die from vasospasm despite supportive therapy. There are limited therapeutic options for vasospasm at this time. Animal and pilot
human studies suggest statins have pleotropic effects targeting many processes in the pathogenesis of vasospasm and
ameliorate SAH-induced vasospasm and reduce cerebral ischemic complications1, 2. We tested whether 80 mg/day simvastatin is safe and feasible for vasospasm prevention in critically ill SAH patients.
Pathogenesis of delayed cerebral vasospasm following SAH
remains poorly understood. Tissue biomarkers have been associated with prognosis3 after SAH and may suggest novel
hypothesis for vasospasm pathogenesis. We have established a
prospective SAH clinical database and tissue bank to study
physiologic markers of vasospasm following SAH.
Methods: After endovascular or surgical treatment of their
aneurysms, 39 patients with Fisher grade 3 SAH and no
prior statin exposure were double-blind randomized to receive simvastatin 80 mg once a day (n⫽19) or placebo
(n⫽20). Study drug was started within 96 hours after SAH
and discontinued at intensive care unit discharge. We examined mortality, drug morbidity, and incidence of clinical and
angiographic vasospasm.
In addition, we prospectively enroll control subjects and
SAH patients within 96 hours of aneurysm rupture who are
December 2008
not receiving statin/placebo study drug into a clinical database. We serially collect and store serum and cerebrospinal
fluid samples. We obtain brain MRI at 14 days post SAH
and follow subjects for long-term functional outcome at 3
month intervals.
Results: Subjects randomized to simvastatin versus placebo
had comparable baseline characteristics. Mortality was 3/20
in placebo and 0/19 in simvastatin group. Study drug was
withdrawn in 1 patient in the simvastatin group and 1 in the
placebo group for reversible liver enzyme or creatine phosphokinase elevation. Angiographically-confirmed vasospasm
occurred in 8/20 placebo and 5/19 simvastatin patients.
Vasospasm-related ischemic infarcts developed in 5/20 placebo and 2/19 simvastatin patients. TCD indices of vasospasm did not differ between study groups.
Prospective SAH cohort currently has 14 SAH (10 female,
4 male) subjects and 23 control subjects. 4/14 developed
moderate to severe angiographic vasospasm and 3 of these
subjects had MRI at day 14. 0/3 had new restricted diffusion
following vasospasm.
Conclusions: Simvastatin for the prevention of delayed cerebral ischemia is safe and feasible after SAH. Ongoing prospective SAH clinical data base and tissue bank will allow
investigation of biomarkers of vasospasm and SAH outcome
which may guide future therapy. A larger randomized study
with biomarker sampling is necessary to determine the mechanisms of action and effects of statin on cerebral vasospasm
and SAH outcome.
References:
Lynch JR, Wang H, McGirt MJ, Floyd J, Friedman AH,
Coon AL, Blessing R, Alexander MJ, Graffagnino C, Warner
DS, Laskowitz DT. Simvastatin reduces vasospasm after aneurysmal subarachnoid hemorrhage: Results of a pilot randomized clinical trial. Stroke. 2005; 36:2024-2026
Tseng MY, Czosnyka M, Richards H, Pickard JD, Kirkpatrick PJ. Effects of acute treatment with pravastatin on cerebral vasospasm, autoregulation, and delayed ischemic deficits after aneurysmal subarachnoid hemorrhage: A phase ii
randomized placebo-controlled trial. Stroke. 2005; 36:16271632
Petzold A. Csf biomarkers for improved prognostic accuracy
in acute cns disease. Neurol Res. 2007; 29:691-708
Financial Disclosure: Dr. Sherry (Hsiang-Yi) Chou receives
support from NIH K30 (RR022292-07), Dr. MingMing
Ning receives support from NINDS (NS051588), and Dr.
MingMing Ning and Dr. Eng Lo receive support from
NINDS (NS052498).
Poster # JAN-3
Evaluation of the Six-Minute Walk in Multiple
Sclerosis Subjects and Healthy Controls
Myla D Goldman1, Ruth Ann Marrie2, Jeffrey A Cohen3
1
Department of Neurology, University of Virginia,
Charlottesville, VA 2Section of Neurology, Health Sciences
Centre, Winnipeg, MB, Canada 3Mellen Center for Multiple
Sclerosis Treatment and Research, Cleveland Clinic
Foundation, Cleveland, OH
Objective: 1) Assess characteristics of the 6MW in multiple
sclerosis (MS) and control subjects. 2) Assess 6MW performance within MS subjects of varied disability. 3) Assess correlation of 6MW to subjective measures of health status
(SF-36 Health Status Questionnaire, PCS), ambulation (MS
Walking Scale-12, MSWS), and physical fatigue (physical
subset of the Modified Fatigue Impact Scale, MFISphy).
Background: 60-90% of MS patients report fatigue. Subjective fatigue measures poorly correlate with disease classification or EDSS. Evaluation of gait, including speed and stride
length have also failed to correlate with subjective fatigue.
Motor fatigue, defined as loss of maximal capacity to generate force during exercise, may be more quantitative. A standardized, reproducible, validated measure of motor fatigue is
needed. The 6MW is a good candidate measure of motor
fatigue in MS patients.
Design/Methods: 40 MS (EDSS 0-6.5) and 20 control subjects were recruited from a MS outpatient clinic. All subjects
completed three 6MW tests with 1-hr interval rest and survey material (MSWS, SF-36 PCS and MFIS) in a single
visit. MFISphy was calculated based on previously published
equations.
Results: There is no learning effect or fatigability with repeat
6MW tests when 1-hr of rest is required. The 6MW has
excellent intra (ICC⫽0.95) and inter-rater (ICC⫽0.91) reliability. MS subjects demonstrate reduced 6MW distance and
speed compared to controls (p⬍0.0001). Moderate-severely
disabled MS subjects have reduced 6MW distance and speed
compared to mildly disabled MS subjects (p⬍0.0001). The
6MW strongly correlates to subjective measures of ambulation (MSWS r ⫽ -0.81), health status (SF-36 PCS, r ⫽
0.69), and physical fatigue (MFISphy, r ⫽ 0.66)
Conclusions/Relevance: The 6MW is a feasible, reproducible, and reliable measure in MS. MS subjects demonstrate
motor fatigue in both 6MW distance and speed compared to
controls. Within MS subjects there is an inverse relationship
between 6MW and disability. 6MW strongly correlates to
subjective measures of ambulation, health status, and physical fatigue.
Financial Disclosure: Dr. Myla Goldman was supported by
the NMSS Sylvia Lawry Physician Fellowship Award while
performing this research.
Poster # JAN-4
Detection of Nonconvulsive Seizures in the Intensive
Care Unit: Does it make a Difference?
Niranjan N. Singh, John Chibnall, Kitti Kaiboriboon
Department of Neurology & Psychiatry, Saint Louis University
School of Medicine, St. Louis, MO
Introduction: Nonconvulsive seizures (NCS) are common in
patients with acute brain injury. The clinical diagnosis of
NCS is often challenging especially in comatose patients.
Most NCS are unrecognized at bedside and usually require
EEG for diagnosis. Although prolonged EEG monitoring is
essential in the diagnosis of NCS, it is time consuming, labor
intensive, expensive and technically challenging. In addition,
it is still unclear whether treating subclinical seizures will improve the outcome.
Methods: To determine the clinical utility and prognostic
importance of prolonged EEG monitoring in identifying
NCS in the intensive care unit, we reviewed 831 bedside
routine and prolonged EEG recordings performed between
January 1, 2000 and September 30, 2007. The indications
for these EEGs were generalized convulsive status epilepticus
and persisting encephalopathy with or without seizures. For
this study, only patients who had prolonged EEG monitoring for at least 72 hours were evaluated. Patients who required prolonged EEG monitoring for titration of antiepileptic medications or pentobarbital were excluded. We used
multivariate logistic regression to identify factors that are associated with NCS documented on prolonged EEG moni-
Abstracts
S159
toring. Multinomial logistic regression was used to determine
the association between the variables and the outcome.
Results: One hundred and thirty-eight patients were identified. The mean age was 56 years. Eighty-nine patients (64%)
did not have NCS on routine EEGs or prolonged EEG
monitoring. NCS were detected by routine EEG recordings
in 42 patients (30%). Only seven patients (5%) had unremarkable routine EEGs but developed NCS during prolonged EEG monitoring. Six of these patients had NCS
within the first 12 hours of recording. The other patient developed NCS within the first 24 hours. Among patients with
NCS, the history of epilepsy was associated with electrographic seizures (OR 7.4, 95% CI 2.2 to 25.0). Level of
consciousness and age were poor predictors of NCS on prolonged EEG monitoring (P⬎0.05). The outcome was identified in 115 patients. Among these, there were death in 62
patients, vegetative state in 4 patients, severe disability in 21
patients, moderate disability in 17 patients and mild disability in 11 patients. We found that only coma was associated
with death (OR 11.2, 95% CI 3.7-34.2). The presence of
NCS, number of antiepileptic medications administered, age,
underlying medical conditions and duration of illness were
not of prognostic importance (P⬎0.05).
Conclusion: At least 12 hours of prolonged EEG monitoring is essential in the diagnosis of NCS in the intensive care
unit. Patients with a history of epilepsy have a higher risk of
developing NCS. Although it seems reasonable to detect subclinical seizures, treatment of EEG identified NCS in comatose patients does not appear to improve clinical outcome.
More definitive prospective studies are needed to assess the
clinical utility and cost effectiveness of prolonged EEG monitoring for NCS.
Financial Disclosure: None
Poster # JAN-5
Recanalization Rates and Outcomes for MMRT (Multi
Modality Reperfusion Therapy) in Patients with Severe
Acute Ischemic Strokes
Jawad Kirmani, Akram Shhadeh, Ameer Hassan,
Aavik Sarkar, Bahareh Hassanzadeh, Oriana Cornett,
Steven Hoover
UMDNJ, Newark, NJ
Background and Purpose: Endovascular therapies using
mechanical and pharmacological modalities for large vessel
occlusions in acute stroke are rapidly evolving. Our aim was
to determine whether one modality is associated with higher
recanalization rates and better outcomes.
Methods: We retrospectively reviewed 96 consecutive patients treated with intra-arterial (IA) therapy for acute ischemic stroke between July 2005 and June of 2008. Demographic, clinical, radiographic, angiographic, and procedural
notes were reviewed. Recanalization was defined as achieving
Qureshi flow grading scales of 0 to 2 after intervention. A
logistic regression model was constructed to determine independent predictors of successful recanalization using SPSS 15
software.
Results: A total of 96 patients were reviewed with a mean
age of 62⫾16 years and mean National Institutes of Health
Stroke Scale of 17⫾7.6. Recanalization was achieved in 79
(82%) patients. The mean modified Rankin Scale (mRS) was
3.5⫾1.8. The use of MERCI retrieval device was an independent predictor of recanalization and good outcome
(p⫽0.03). Extracranial stenting is an independent predictor
for good outcome but not for recanalization as defined in
S160
Annals of Neurology
Vol 64 (suppl 6)
our study (p⫽0.033). Snare device showed a trend toward
effect on both mRS (p⫽0.076) and recanalization
(p⫽0.058). IA Reteplase alone given through a microcatheter showed a trend toward effect on mRS (p⫽0.058). Aside
from MERCI and extracranial stenting, there is no difference
in recanalization rate when using one or more methods in
any combination of treatment (p⬎0.05).
Conclusions: Both MERCI retrieval device and extracranial
stenting are associated with better outcomes for large vessel
occlusions in acute stroke. MERCI retrieval device was associated with better recanalization rates in patients treated with
multimodal endovascular reperfusion therapy for acute ischemic stroke.
Financial Disclosure: Nothing to disclose
Poster # JAN-6
Clinical and Electrophysiologic Findings in Cryptogenic
Sensorimotor Polyneuropathy Compared to Diabetic
Polyneuropathy and Normal Controls
Mamatha Pasnoor, Anh Pham, Laura Herbelin,
Richard Barohn
The University of Kansas Medical Center, Kansas City, KS
Objective: To assess the clinical and electrophysiologic features in patients with CSPN and compare these with diabetic
and healthy normal subjects
Background: Peripheral neuropathy is a frequent complication of diabetes. However, even with the modern diagnostic
approaches, many polyneuropathies remain unclassified.
Slowly progressive neuropathy that begins in late adulthood
with predominant sensory symptoms and signs, limited motor impairment and no identifiable cause is classified as cryptogenic sensory polyneuropathy(CSPN).
Design/Methods: We initiated a prospective study to assess
and compare clinical and electrophysiologic findings in
CSPN with diabetic polyneuropathy (DPN) and healthy
normal subjects. All patients received clinical examination,
Michigan Neuropathy Screening Instrument, which includes
the Michigan Patient Questionnaire (MNSIPQ) and Michigan Neuropathy Physical Assessment Scale (MNSIPA), and
Michigan Diabetic Neuropathy Scale (MDNS). All patients
also received nerve conduction studies and quantitative sensory testing
Results: Nine CSPN patients, sixteen diabetic and eight
healthy volunteers were enrolled in this study. The mean age
of CSPN patients was 63(13), DPN 59(14) and normal subjects was 34(10). The mean duration of symptoms from onset to this evaluation was 6.6 years in CSPN and 4.5 years in
DPN. Mean MNSIPQ score for CSPN: 6.1(2.6) and DPN:
3.3(2.9); mean MNSIPA for CSPN: 3.6(2.1) and DPN:
4.6(2.9); mean MDNS for CSPN: 9.8(6.7) and DPN:
7.1(8.2). Vibration testing using Rydel-Seiffer vibration tuning fork and standard tuning fork were abnormal in 8/
9(89%) CSPN and 11/16 (69%) DPN subjects. EMG results were abnormal in 7/9(78%) CSPN and 9/16
(56%)DPN subjects. QST heat pain thresholds were higher
than normal in 6/9 (67%)CSPN, 13/16(81%) DPN. Cold
thresholds were abnormal in 4/9 (44%)CSPN, 4/16
(25%)DPN. Vibratory threshold was abnormal in 4/9
(44%)CSPN and 9/16(56%) DPN subjects
Conclusions/Relevance: The MNSIPQ scores were higher
in CSPN compared to DPN. CSPN and DPN groups did
not show significant differences in electrophysiologic parameters.
December 2008
References:
Wolfe GI, Barohn RJ. Cryptogenic Sensory and Sensorimotor Polyneuropathies. Seminars in Neurology 1998; 18(1):
105-111.
Dyck PJ. 1999. Cryptogenic sensory polyneuropathy. Archives of Neurology. 56(5):519-520.
Wolfe GI, Baker NS, Amato AA, Jackson CE, Nations SP,
Saperstein DS, Cha C, Bryan WW, Barohn RJ. Cryptogenic
sensory polyneuropathy: clinical and electrophysiologic characteristics. Arch Neurol 1999; 56:540-547.2
Financial Disclosure: Supported by General Clinical Research Grant.
Poster # JAN-7
Snoring, Insomnia and Sub-clinical Atherosclerosis in
the Northern Manhattan Study (NOMAS)
Alberto Ramos-Sepulveda1, William Wohlgemuth1,
Hannah Gardener1, Dalia Lorenzo1, Salim Dib1,
Douglas M. Wallace1, Bruce Nolan1,
Bernadette Boden-Albala2, Mitchell S.V. Elkind2,
Ralph L. Sacco1, Tatjana Rundek1
1
Sleep Disorders Center, Department of Neurology, Miller
School of Medicine, University of Miami, Miami, FL
2
Division of Stroke, Department of Neurology, Columbia
University, New York, NY
Background and Purpose: Sleep disordered breathing is an
independent risk factor for stroke, but its association with
sub-clinical atherosclerosis remains controversial. Snoring
and insomnia may contribute to stroke and cardiovascular
disease risk and are frequently co morbid with sleep disordered breathing. Data on the relationship between snoring
and insomnia with atherosclerotic disease is sparse. We therefore investigated the relationship between carotid intimamedia thickness (IMT), a marker of subclinical atherosclerosis, insomnia complaints and habitual snoring in the
population-based Northern Manhattan Study (NOMAS) cohort of stroke-free individuals enrolled to investigate an incident stroke risk in a multi- ethnic population.
Methods: A group of 1,605 participants (mean age 65 ⫾ 8
years; 40% men; 61% Hispanic, 19% black, 20% white)
who had carotid IMT measurements performed was assessed
for self-reported sleep habits. Habitual snoring was defined as
self-reported snoring ⬎ 4 times per week. Insomnia information was based on the three items extracted from the
Hamilton rating scale for depression and defined as a total
sum greater than 2. Carotid IMT was expressed as a composite measure of IMT in the carotid bifurcation, common
and internal carotid artery. Multivariate linear regression
models were used to identify relations between snoring, insomnia and carotid IMT.
Results: Habitual snoring was present in 29% of the subjects
and insomnia in 31%. There was a higher prevalence of self
reported snoring (84%) and insomnia (66%) among Hispanics. In men insomnia was reported in 33.3% (n⫽129) and
habitual snoring in 42% (n⫽137). The mean total carotid
IMT was 0.95⫾ 0.09 mm. Prevalence of carotid plaque was
66% (N⫽1062). After controlling for age, gender, race, ethnicity, BMI, hypertension, diabetes, smoking, LDL, HDL
and presence of cardiac disease, snoring (parameter estimate ⫽ 0.00009, p⫽ 0.986) and insomnia (parameter estimate ⫽ -0.0012, p⫽ 0.829) were not independently associated with increased carotid IMT or presence of plaque.
Conclusion: In this cross-sectional study, self-reported snoring and insomnia were not observed to be significantly asso-
ciated with subclinical atherosclerosis. Alternative mechanistic linking pathways between sleep complaints and risk of
stroke and other vascular may be considered.
References:
Wattnakit K, et al., Relation of sleep-disordered breathing to
carotid plaque and intima-media thickness, Atherosclerosis
(2007), doi: 10.1016/j.atherosclerosis.2007.02.029
Boden-Albala, B, Bazil C, Moon Y, De Rosa J, Elkind MS,
Paik MC, Sacco RL. Daytime Sleepiness and Risk of Stroke
and Vascular Disease: Findings from the Northern Manhattan Study (NOMAS). Stroke (2008); Vol 39, No 2 (94).
Silvestrini M, et al. Carotid artery wall thickness in patients
with obstructive sleep apnea syndrome. Stroke 2002; 33:
1782-5.
Yaggi HK, et al. Obstructive sleep apnea as a risk Factor for
stroke and death. N Engl J Med. 2005; 353(19):2034-41.
Phillips B, Mannino D. Do insomnia complaints cause hypertension or cardiovascular disease? J Clin Sleep Med 2007;
3(5):489-494.
Financial Disclosure: National Institute of Neurological
Disorders and Stroke grant R01 NS 29993.
Poster # JAN-8
Acute Confusional Migraine may be the Presenting
Feature of CADASIL
Swati Sathe, Edgar Deperalta, Edwin H. Kolodny
Division of Neurogenetics, NYU School of Medicine, New
York, NY
Objective: Characterize the phenomenon of acute confusional state associated with migraine among CADASIL patients as well as to emphasize the diagnostic possibility of
CADASIL in adults with acute confusional migraine.
Background: Acute confusional migraine (ACM) has been
well described in children (1, 2); however, confusional state
in adults with migraine has rarely been reported. Although
30-60 % of CADASIL patients are known to have migraine,
the development of acute confusional state during migraine
episode has not been reported (3). The most recent version
of International Classification of Headache Disorders does
not include acute confusional state with migraine as a subtype in adults (4). We describe seven adults with ACM that
complicated up to 50% of the migraine episodes. Although
earlier brain MRI had shown white matter changes in these
patients, the diagnosis of CADASIL had not been considered.
Design/ Methods: Detailed neurologic evaluation was performed in 20 CADASIL patients; ICHD2 criteria were used
to diagnose migraine.
Results: The patients’ mean age was 51 years (range 42 to
59 years). 14 of 20 patients reported headache; 11 met the
criteria for migraine (mean age of onset 25 years). These 11
patients reported visual, sensory or speech aura and eight had
atypical migraine. Seven patients experienced concomitant
confusion during the migraine episode, usually within three
years of migraine onset. The confusional state occurred either
abruptly or insidiously, at the onset of aura or headache; lasting for two- 48 hours, and usually, ending abruptly. These
episodes were stereotypic, characterized by disorientation
with agitation, and some degree of retrograde amnesia. Only
one patient reported complete amnesia for the event. Patients
reported the following situations: inability to recognize
friends or family members, inability to find directions in familiar neighborhood, fear of getting lost, inability to dial
numbers on the telephone, inability to interpret traffic lights
Abstracts
S161
or tell the time. Patients reliably predicted these episodes,
and felt the need to seek a safe place for protection. Severity
of the episodes progressed, but striking improvement occurred after the first stroke.
Conclusion: ACM may be a presenting feature and important clue, enabling CADASIL to be recognized up to a decade or earlier than at present. Therefore, a brain MRI and
/or testing for Notch3 mutations should be considered in
adult patients with ACM. Understanding the pathophysiology of CADASIL may provide a unifying explanation for the
overlap among migraine, acute confusional migraine, TGA
and stroke.
S162
Annals of Neurology
Vol 64 (suppl 6)
References:
Gascon G, Barlow C. Juvenile Migraine, Presenting As Acute
Confusional State. Pediatrics 1970; 45:628-635.
Ehyai A, Fenichel GM. The Natural History of Acute Confusional Migraine. Arch Neurol 1978; 35:368-370.
Vahedi K, Chabriat H, Levy C, Joutel A, Tournier-Lasserve
E, Bousser M. Migraine With Aura and Brain Magnetic Resonance Imaging Abnormalities in Patients With CADASIL.
Arch Neurol 2004; 61:1237-1240.
The International Classification of Headache Disorders
Cephalgia 2004; 24: Supplement 1
Financial Disclosure: Nothing to disclose
December 2008
Документ
Категория
Без категории
Просмотров
0
Размер файла
222 Кб
Теги
development, careers
1/--страниц
Пожаловаться на содержимое документа