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Tuesday, October 9, 2007
ported by Grant #AG16335 from the National Institute on
T-3. Neuroligin Deletion Results in Autism & Mental
Retardation-Related Behavioral Abnormalities
Jacqueline Blundell, Katsuhiko Tabuchi, Marc Bolliger,
Nils Brose, Thomas C. Sudhof, and Craig M. Powell;
Dallas, TX; and Gottingen, Germany
T-1. 3D Analysis of Hippocampal Atrophy
Progression in MCI Subjects
Liana G. Apostolova, Paul M. Thompson, Amity H. Green,
Clifford R. Jack, Danielle Harvey, Ronald C. Petersen,
Leon J. Thal, Jeffrey L. Cummings, Charlie DeCarli, and
for the ADCS Group; Los Angeles, CA; Rochester, CA;
Sacramento, CA; Rochester, MN; and San Diego, CA
Objective: To investigate the progression of hippocampal atrophy in mild cognitive impairment (MCI) subjects rated
with the visual quantitative medial temporal atrophy rating
scale (range 0 – no to 4 – severe atrophy).
Methods: We used the baseline and follow-up MRI data of
110 amnestic MCI (mean age 72.4⫾6.5, mean MMSE⫽
27.7⫾1.8) participants with medial temporal atrophy scale
rating of ⬍2 from the imaging part of the ADCS Donepezil/
Vitamin E trial. 40.1% of these patients converted to Alzheimer’s disease later in the trial. Using the radial distance
atrophy mapping approach we developed 3D hippocampal
mesh models. We mapped the radial distance from the medial core to each surface point, computed baseline and
follow-up group average maps and subjected them to statistical comparisons.
Results: The 3D statistical maps revealed more pronounced
right-sided interim hippocampal changes (right p⫽0.011,
left p⫽0.11, corrected for multiple comparisons). The most
significant areas exhibited over 5% greater atrophy in
follow-up relative to baseline. Atrophy progression was seen
in all hippocampal subfields.
Conclusion: Hippocampal atrophy in amnestic MCI is progressive, asymmetric process affecting all hippocampal subfields. Study supported by Alzheimer’s Disease Cooperative
Study Group and NIA K23 AG026803.
T-2. A Longitudinal Study of Drivers with Dementia
Brian R. Ott, William C. Heindel, George D. Papandonatos,
Elena K. Festa, Jennifer D. Davis, Lori A. Daiello, and
John C. Morris; Providence, RI; and St. Louis, MO
Objective: To define the natural progression of driving impairment in persons with very mild to mild dementia.
Subjects: 128 older drivers, including 84 with dementia, and
44 age-matched controls.
Methods: All subjects underwent a detailed clinical assessment every six months over a period of up to three years.
Within two weeks of the office evaluation, subjects were examined by a professional driving instructor on a standardized
road test.
Results: Over time both groups declined in driving performance on the road test. More severe dementia was associated
with higher rates of failure and marginal performance on the
road test; however, the majority of subjects with mild dementia were able to pass the examination at baseline. Control subjects were involved in more motor vehicle accidents
during the course of the study than the dementia subjects.
Conclusions: This study confirms previous reports of potentially hazardous driving in persons with early dementia.
The finding that dementia subjects were involved in fewer
accidents than control subjects during the study suggests that
repeated assessments of driving in this at-risk group may reduce the frequency of motor vehicle accidents. Study sup-
Annals of Neurology
Vol 62 (suppl 11)
Recently, loss-of-function mutations in neuroligin 3 (NL3)
and NL4 have been identifiedin autism spectrum disorder
and mental retardation. We have begun a systematic analysis
of NL function in vivo using NL KO mice. Our hypothesis
is that deletion of NLs will lead to deficits in behavioral tasks
relevant to autism/mental retardation, thereby creating novel
animal models of these enigmatic disorders.
NL1 KOs and NL3 disease-linked point mutants, but not
NL2 KOs, show a decrease in social interaction. These findings support the idea that NL3 mutant mice exhibit behavioral features relevant to the core features of autism.
Consistent with the role of NLs in mental retardation, NL1
and NL2 KOs exhibit deficits in learning and memory. NL1
KOs have deficits in both spatial and social learning while
learning and memory in NL3 mutants is underway.
Consistent with their role at inhibitory synapses, NL2 KOs
exhibit increased anxiety-like behavior in multiple behavioral
tasks. NL1 KOs, however, show no anxiety phenotype.
These experiments are the first to describe the role of the NL
family in cognitive behaviors, and suggest that NL mutant
mice provide rational models of autism. Study supported by
Autism Speaks (CMP), NIMH (CMP), HHMI (TCS).
T-4. Tau Reduction Increases Resistance to
Excitotoxins and Network Dysfunction
Erik D. Roberson, Kimberly Scearce-Levie, Jorge J. Palop,
Fengrong Yan, Irene H. Cheng, Tiffany Wu, Hilary Gerstein,
Gui-Qiu Yu, and Lennart Mucke; San Francisco, CA
The microtubule-associated protein tau is implicated in the
etiology of several neurodegenerative diseases by both genetic
association and its presence in inclusions such as neurofibrillary tangles, but the mechanism by which tau contributes to
these diseases remains uncertain. We investigated the role of
tau in an animal model of Alzheimer’s disease in which tau
does not aggregate into tangles or contain disease-associated
mutations. We found that reducing endogenous, wild-type
tau protected human amyloid precursor protein (hAPP)
transgenic mice from behavioral and cognitive deficits induced by A␤. These mice are more prone than nontransgenic mice to seizures after challenge with excitotoxins such
as glutamate agonists or GABA blockers, suggesting that
neuronal network dysfunction is an important aspect of their
pathophysiology. We found that tau reduction blocked this
A␤-induced susceptibility to aberrant neuronal activity.
Moreover, even in hAPP-nontransgenic mice, reducing tau
gene expression increased resistance to seizures and death induced by glutamate agonists or GABA blockers. These results point to a novel role for tau in regulating neuronal excitability, and suggest that tau reduction could be an
effective therapeutic strategy for prevention or treatment of
neurological diseases associated with excitotoxicity. Study
supported by National Institutes of Health grants AG011385
and AG022074 (L.M.), MH070588 (K.S.L), and NS054811
(E.D.R), the Giannini Foundation (E.D.R.), the S.D. Bechtel, Jr. Young Investigator Award (E.D.R.), and the NIH
National Center for Research Resources grant RR18928-01.
T-5. Distinct Biochemical Pools of A␤ in Alzheimer’s
Disease Brain: A Clinical-Pathological Study
Joshua R. Steinerman, Michael Irizarry, Nikolaos Scarmeas,
Susan Raju, Jason Brandt, Marilyn Albert, Deborah Blacker,
Bradley Hyman, and Yaakov Stern; New York, NY;
Boston, MA; and Baltimore, MD
We hypothesized that A␤ quantified in distinct biochemical
compartments from AD brain would be differentially associated with clinical features. 27 subjects from the Predictors
Study AD cohort and 13 controls were analyzed. Temporal
and cingulate neocortex were sequentially extracted in solutions containing Tris (hypothesized to represent extracellular
A␤), Triton (intracellular), SDS (membrane-associated), and
formic acid (extracellular-insoluble). A␤40 and A␤42 were
quantitated in each biochemical compartment using ELISA.
Compared to controls, AD brains had significantly higher
mean concentrations of formic acid (FA) and Tris A␤42 and
A␤40. Mean Triton and SDS A␤42, but not A␤40, were
higher in AD. Among AD cases, APOE-ε4 subjects had increased FA and Tris A␤40. A␤42 in the Triton and SDS
compartments from temporal cortex correlated with functional impairment proximate to death. More rapid cognitive
decline was observed in cases with elevated SDS A␤42 and
lower Triton A␤40 in temporal cortex, as well as elevated
SDS A␤40, lower SDS A␤42, and lower FA A␤42 in cingulate cortex. Exploratory analysis of between-compartment
correlations suggested a loss of A␤ compartmentalization in
AD compared with control brains. Study supported by
R01AG07370, P50AG05134; Dr. Steinerman has nothing
to disclose. Dr. Irizarry has received personal compensation
from GlaxoSmithKline, Inc. Dr. Scarmeas has nothing to
disclose. Dr. Brandt has received royalty payments from Psychological Assessment Resources, Inc. Dr. Albert has nothing
to disclose. Dr. Blacker has nothing to disclose. Dr. Raju has
nothing to disclose. Dr. Hyman has received personal compensation from Pfizer, Inc., and research support from Elan
Corporation. Dr. Stern received personal compensation from
Eisai for scientific consultation.
T-6. White Matter Hyperintensities and Subclinical
Infarction: Associations with Psychomotor Speed and
Cognitive Flexibility
Clinton B. Wright, Joanne R. Festa, Myunghee C. Paik,
Alexis Schmiedigen, Truman R. Brown, Mitsuhiro Yoshita,
Charles DeCarli, Yaakov Stern, and Ralph L. Sacco;
New York, NY; and Sacramento, CA
Background: We examined white matter hyperintensity volume (WMHV) and subclinical infarction (no history of clinical stroke; SI) in relation to performance on tests of sequencing, cognitive flexibility, and sensorimotor ability.
Methods: The Northern Manhattan Study includes a strokefree community-based sample of Hispanic, black, and white
participants. A subsample (N⫽656) has undergone measurement of WMHV, SI, and neuropsychological testing. Linear
regression was used to examine WMHV and SI in relation to
performance on tests of sequencing, cognitive flexibility, and
sensorimotor ability using generalized estimating equations
(GEE) to account for the correlation among the cognitive
tests and other covariates. Results: Both WMHV
(P⫽0.0006) and subclinical infarction (P⫽0.003) were each
associated with worse cognitive performance. Those with
WMHV in the upper quartile performed significantly worse
on the tests of cognitive flexibility and sensorimotor ability.
Those with frontal SI performed worse on the test of cognitive flexibility and those with SI in the deep gray matter
worse on the test of sequencing. Conclusions: Both SI and
WMHV were associated with worse cognitive performance.
The effects of SI on cognitive performance varied by location. Study supported by grants from the National Institute
of Neurological Disorders and Stroke (R01 NS 29993) and
the Irving General Clinical Research Center (M01
RR00645); Dr. Sacco is a consultant for Boehringer Ingelheim for a clinical trial.
T-7. Predictors of Subjective Memory Complaints
(SMCs) and Cognitive Impairment in a Clinical Sample
Laura Bracco, Carolina Piccini, Valentina Bessi,
Federica Biancucci, Sonia Padiglioni, Guia Martinenghi,
Benedetta Nacmias, and Sandro Sorbi; Florence, Italy
Population studies suggest that SMCs are common in older
people, inconsistently related to current cognitive impairment and associated to depression and neuroticism. We evaluated demographic characteristics, premorbid intelligence,
personality traits, depression, functional-neuropsychological
profile and APOE genotype in 41 M and 97 F (mean age
63.5 ⫾ 8.3yrs, MMSE 27.9⫾2.0) complaining for mild
memory deficit and 9M and 13F controls (mean age
67.7⫾6.6 yrs, MMSE 28.7 ⫾ 1.9).The SMCs severity was
graded by a semi-structured interview (MAC-Q). Forty-nine
cases (mean age 68.7 ⫾ 6.6yrs, MMSE 27.2 ⫾ 2.0) were
diagnosed as Mild Cognitive Impairment (MCI). Linear and
logistic regression models were applied to verify if age, gender, pre-morbid intelligence, depression, neuroticism and
APOE genotype predicts MAC-Q scores, neuropsychological
performance or MCI diagnosis. Only female gender was significantly associated to higher MAC-Q score (p⬍0.007),
even when considering neuroticism, depression or objective
memory performance. Premorbid intelligence and age were
associated to episodic and prospective memory performance
(p ⬍0.01) and to the diagnosis of MCI (p⫽0.000). Our
findings show that in subjects spontaneously self-referring to
a memory clinic only gender is related to SMCs severity.
Older age and lower premorbid-intelligence appear the best
predictors of memory impairment and MCI. Study supported by Regione Toscana grants (n. 139, 1107, 6086, 921,
831 and 694).
T-8. Influence of Silent and Symptomatic Infarcts on
Cognitive Testing Profile in Patients with Alzheimer’s
Soo Jin Cho, Nikolaos Scarmeas, Karen Marder, and
Lawrence S. Honig; New York, NY; and
Seoul, Republic of Korea
About a third of patients with Alzheimer disease (AD) have
evidence of a cerebral infarct at autopsy. Using logistic regression, we evaluated the association between silent infarcts
(no clinical history of stroke but present on neuroimaging)
and symptomatic infarcts (presence of both clinical history
and neuroimaging evidence) and cognitive performance in
1001 patients clinically diagnosed with AD in an Alzheimer
Disease Research Center. Inclusion criteria for this study are
presence of information about stroke history and a brain
neuroimaging study encoded in the database. The models
were adjusted for age, gender, education, vascular risk factors, baseline modified mini Mental Status examination
[0-57], clinical dementia rating, and function (BDRS). Silent
infarcts were present in 24% and symptomatic infarcts in
Program and Abstracts, American Neurological Association
6.8%. Better scores on memory function (delayed recall of
selective reminding test) were related to higher odds of silent
infarcts (OR 1.2, 95% CI 1.05-1.44). Poorer scores on
language-speed function (categorical fluency test) were related to higher odds for symptomatic infarcts (OR 1.25,
95% CI 1.04-1.40). We conclude that presence of cerebrovascular disease in AD is associated with relatively less impaired memory but worse language-speed performance.
Study supported by Taub Institute for Research, and NIH
T-9. Molecular Classification of Disease Based on
Peripheral Gene Expression Profiles in FTD and AD
Giovanni Coppola, Anna Karydas, Matthew N. Suberlak,
Bruce L. Miller, and Daniel H. Geschwind; Los Angeles, CA;
and San Francisco, CA
Background and Objective: Microarray studies in pathological conditions are useful in identifying genes involved in disease pathogenesis. We aimed at identifying a molecular fingerprint or biomarkers in peripheral blood samples from
patients with dementia.
Patients and Methods: We studied 35 controls and 109 patients with AD (no⫽46), FTD (no⫽43), CBD (no⫽13),
and other diseases (no⫽7). Total RNA was extracted from
peripheral blood and hybridized on Illumina microarrays.
Results: We identified 483 differentially expressed genes,
whose expression partially clustered the samples according to
clinical diagnosis. We built a molecular classifier, which is
able to correctly label blood samples with clinical diagnosis
with an overall error rate of 37%, using a subset of genes.
We detected 50% reduced levels of progranulin in three patients, one of them clinically unaffected, and we are confirming this finding by direct sequencing. Remarkably, most
genes involved in inherited neurodegenerative dementias are
also expressed in peripheral blood.
Conclusions: Microarray studies from peripheral blood samples show potential applications in dementia patients, identifying candidate genes with pathogenic role and possible peripheral biomarkers. A molecular classifier is a potentially
valuable tool in diagnosis and clinical trials. Study supported
by NIA (R01 AG 026938).
T-10. Genetic Investigation in Frontotemporal
Dementia and Alzheimer’s Disease: The GIFT Study
Giovanni Coppola, Bruce L. Miller, Helena Chui,
Arousak Varpetian, Allan Levey, Carl W. Cotman,
Charles DeCarli, Mario F. Mendez, George Bartzokis,
Walter A. Kukull, Tatiana Foroud, and
Daniel H. Geschwind; Los Angeles, CA; San Francisco, CA;
Atlanta, GA; Seattle, WA; Indianapolis, IN; Irvine, CA; and
Sacramento, CA
Background and Objective: Genes involved in modifying
tau are candidates for contributing to the genetic risk for
FTD and AD. We aim at identifying and confirming these
novel genetic risk factors, using a novel re-sequencing approach.
Patients and Methods: We are collecting blood samples
from AD/FTD patients and controls (including ethnic minorities) enrolled in 6 ADRC in California and Atlanta, GA.
Cell lines are being stored at the National Cell Repository
for Alzheimer’s Disease, and clinical data at the National
Alzheimer’s Coordinating Center. Target genes are involved
in tau modification, ubiquitin pathways, and in AD/FTDrelated neurodegeneration. We designed an Affymetrix Cus-
Annals of Neurology
Vol 62 (suppl 11)
tomSeq array, able to test 80 genes from a total of 469 amplicons, covering a total of 280,398 bases. Currently we are
able to sequence more than 75% of the targeted sequences at
⬎85% call rate in a single hybridization step. We are optimizing both the platform protocol and the base-calling algorithm. We have been able to identify known mutations (eg.
in MAPT, PSEN1, GRN) and we are beginning to sequence
patients and develop a database of mutation and polymorphisms, which will include valuable genetic information on
understudied ethnic minorities. Study supported by NIA
(R01 AG 026938).
T-11. Boomers and Younger: The Economic Price of
Caregiving – A Canadian Alzheimer’s Dementia Survey
Serge Gauthier, Sandra Black, William Dalziel, Ron Keren,
Jane Correia, Huong Hew, and Carin Binder;
Verdun, QC, Canada; Toronto, ON, Canada; and
Ottawa, ON, Canada
Introduction: As the baby-boomer(BB) population ages,care
for aging family members becomes a concern.The long-term
course of Alzheimer’s Disease(AD)and/or related dementias
will have an effect on BB’s as many assume the caregiving
role.This abstract highlights the financial/workplace impact
that caring for a person with AD/related dementias may represent.
Methods: DecimaResearch together with an expert panel developed this web-based survey.330 of the 398 respondents
were non-spousal BB(⬍65 years)caregivers.
Results: Caregivers reported spending an average of 4yrs/17
hours/wk providing care;35% experienced disruption to their
work,with 3% either retiring early or resigning.An average of
6.4 lost work days/year were reported.23% used vacation
time and 22% reported time conflicts between working and
providing care.10% felt less effective at their jobs;9% took a
leave of absence.5% changed employment to a less demanding job.3% changed from a full-time to a part-time position;7% reported not accepting/losing a promotion. Caregivers assumed an additional average cost of $501/month as a
result of caregiving.
Conclusion: Caregiving carries an economic cost to families
and society.This economic burden is seen as many BB’s are
forced to decrease their working hours,decline promotions,limit career choices and resign from paying jobs in order to
assume the unpaid job of caring. Study supported by
Janssen-Orth Inc.; Authors 1,2,3 and 4 have been on Advisory Boards, received honoraria and participated in clinical
trials for Janssen-Ortho Inc. Authors 5,6, and 7 are employees of Janssen-Ortho Inc.
T-12. Variability of Normal Cerebral Glucose
Metabolism from the Alzheimer’s Disease Neuroimaging
Initiative (ADNI): Implications for Clinical Trials
P. Thomas Fletcher, Angela Y. Wang, Tolga Tasdizen,
Kewei Chen, William J. Jagust, Robert A. Koeppe,
Eric M. Reiman, Michael W. Weiner, Satoshi Minoshima,
and Norman L. Foster; Salt Lake City, UT; Los Angeles, CA;
Berkeley, CA; Ann Arbor, MI; Phoenix, AZ;
San Francisco, CA; and Seattle, WA
3D-Stereotactic Surface Projection (3D-SSP) generates statistical maps of individual metabolism compared to a normal
database and has been used extensively in dementia research.
The method relies on an accurate quantification of the mean
and standard deviation (SD) of normal metabolism. We
wished to determine the number of subjects required to fully
define normal metabolism. Baseline FDG-PET images of 95
ADNI normal volunteers (57 males, 38 females, ages 60 –
89) were used for bootstrap analysis of groups composed of 1
to 95 scans with 10,000 resamples. For each pixel we calculated the standard error (SE) of both the mean and SD of
metabolic rates relative to pons, and displayed the results as
3D-SSP maps. We found that at least 30 subjects are required to reduce the maximal SE of both mean and SD to
below 1% relative to pons. A sample of 95 further reduced
the SE of the mean and SD to 0.095% and 0.28%, respectively. These results provide a guide for determining the sample size needed to construct comparative normal imaging databases for explanatory studies of dementia and clinical trials
in Alzheimer’s disease. Study supported by University of
Utah Center for Alzheimer’s Disease Care, Imaging and Research, NA-MIC, NIH U54-EB005149, ADNI, NIH U01AG024904.
T-13. Progranulin and ␤-Amyloid in Alzheimer’s
Gediminas Gliebus, Andrea Rosso, and Carol F. Lippa;
Philadelphia, PA
Objective: To compare progranulin (PGRN) and ␤-amyloid
(A␤) deposition in Alzheimer’s disease (AD), mild cognitive
impairment (MCI), pathologic aging (PA) and preclinical
PS-1 AD.
Background: PGRN is a growth factor that aggregates in association with A␤ plaques in AD. The reason for this is unknown.
Design/methods: To begin to understand the relationship
between A␤ and PGRN, we used immunohistochemistry on
sections of medial temporal lobe (MTL) and middle frontal
gyrus (MFG) from AD, MCI, PA (n ⫽ 6, 1 and 6, respectively) and a preclinical PS-1 AD case. Multiple other regions were examined in the PS-1 case. A semiquantitative (0
to 3 point) scale was used to compare PGRN and A␤ immunoexpression.
Results: PGRN aggregates were more abundant than A␤ in
PS-1 AD (3:1 [MTL]; 2.5:2.5 [MFG]) and PA (1.5:0.5
[MTL]; 2.5:0.5 [MFG]). The ratio was similar in MCI.
PGRN was less abundant in AD (2.5:3.0 [MTL]; 1.5:2.5
Conclusion: PGRN plaque-like aggregates were more numerous than A␤ plaques in preclinical AD and PA. This ratio
equalized in MCI, and A␤ plaques predominate in clinically
overt AD. This evolution may be related either to compensatory mechanism failure or a decrease in PGRN expression.
T-14. Comparison of Soluble Progranulin and A␤ in
Aging and Alzheimer’s Disease
Gediminas Gliebus, Gonzalo Revuelta, Yuesong Gong,
Richard Nowak, and Carol F. Lippa; Philadelphia, PA
Objective: We determined whether progranulin (PGRN) and
soluble A␤ oligomer (SAO) concentrations are linked in the
normal control and AD brain.
Background: Insoluble PGRN colocalizes in aggregates with
A␤ in AD brains raising the possibility that they are biologically related. Increased PGRN may be a response to tissue
damage by SAO. Alternatively, PGRN and SAO may increase together in response to other factors.
Methods: We used Western blot analysis for soluble forms of
PGRN (A&G) and Dot blot for SAO (anti-6E10) in temporal lobe tissue of AD (n⫽5) and cognitively normal control postmortem tissue lacking overt AD pathology (n⫽5).
Results: SAO and PGRN were both increased in AD tissue.
Two elderly control brains showed significantly elevated
PGRN and SAO; the other three had low levels of both.
Conclusion: Since SAO and soluble PGRN remain low or
increased proportionately in aging and AD these two substances may be linked biologically. Early molecular changes
in aging might be associated with increased SAO and soluble
PGRN before insoluble A␤ or PGRN deposits occur. Further research is needed to further clarify the relationship between A␤ and PGRN.
T-15. Spinal Pseudomeningocele as a Cause of
Superficial Siderosis
Ahed Hanna, Bruno Policeni, Edip Gurol, and
Robert Rodnitzky; Iowa City, IA
Superficial siderosis (SS) of the Central Nervous System
(CNS) is caused by deposition of hemosiderin in the superficial layers of the brain and the spinal cord. A potential
source of hemorrhage was identified in only half of the cases
reported to date. We present two patients with a diagnosis of
SS based on clinical and MRI findings. As brain imaging did
not reveal a source of bleeding, we performed an extensive
etiological workup. Patient #1: Cerebral angiography was
negative in a 68 year-old-woman with SS. Spinal MRI revealed subtle displacement of the spinal cord at T6-T7. CT
myelogram confirmed a spinal pseudomeningocele (SP) with
an extradural fluid collection from T4-T12. Patient #2: Spinal MRI showed a large anterior SP from C5 to T2 and a
cystic epidural lesion in a 42 year-old woman with a remote
history of head and spine trauma. CT myelogram confirmed
both findings. SP is an extension of the subarachnoid space
into the soft tissue surrounding the spinal cord and can be
the source of indolent venous bleeding in rare cases. Detailed
imaging targeting the spine including CT myelogram may
help identify this otherwise occult cause of SS.
T-16. Predicting Time to Nursing Home Placement
Based on Activities of Daily Living (ADL) Scores
Hind T. Hatoum, Simu K. Thomas, S. Lin, Roger Lane, and
Roger Bullock; Chicago, IL; East Hanover, NJ; and
Swindon, United Kingdom
Background: There is an increased recognition that cognitive deterioration of patients with Alzheimer’s disease (AD) is
not always sufficient to reflect disease progression necessitating nursing home placement (NHP).
Objective: To quantify the impact of baseline ADL scores
(and subsequent changes) on NHP risk for AD patients.
Methods: EXCEED was a 2-year, multinational, randomized, double-blind trial with rivastigmine and donepezil. Total ADCS-ADL (T-ADL) was assessed, and NHP was documented at Week 104. Cox regression models based on data
collected from all patients (irrespective of cholinesterase
treatment) were used to predict the risk of NHP based on
changes in ADL scores.
Results: Approximately 800 patients (mean age 75.44⫾6.9)
had a mean T-ADL score of 48.39⫾16.64 at baseline, and
exhibited a -15.14⫾16.85 point change by Week 104. Cox
regression models indicated that older age ( p⫽0.013), female
gender ( p⫽0.042), worse T-ADL at baseline ( p⫽0.001),
and deterioration in T-ADL ( p⬍0.001) all increased risk of
NHP. The risk of NHP was shown to increase 3% for each
1-point deterioration in ADL score.
Conclusions: Analyses from this long-term clinical trial established that patient functioning is an important predictor
Program and Abstracts, American Neurological Association
of time to NHP. Study supported by Novartis Pharmaceuticals; H Hatoum, S Lin - Consultants; R Bullock - Consultant / Speaker honoraria, Clinical Investigator; S Tekin, R
Lane - Novartis Employees.
T-17. Baby-Boomers as Caregivers in the Canadian
Alzheimer’s Disease Survey (CADS)
Sandra Black, Serge Gauthier, Ron Keren, William Dalziel,
Huong Hew, Jane Correia, and Carin Binder;
Toronto, ON, Canada; Montreal, QC, Canada; and
Ottawa, ON, Canada
Introduction: Demographic realities mean that many elders
with dementia are being cared for by the baby boomer generation.
Methods: A steering committee of clinical dementia experts
developed an online survey with Decima Research. Of the
398 caregiver respondants,221 were non-spousal BabyBoomers(BBs) defined as 44-64years.
Results: The 3 most commonly reported symptoms were
constant forgetfulness(82%),constant repetition(67%) and
loss of concentration(70%), with forgetfulness and repetition most often being the triggers for physician consultation. Dementia symptoms were present for a mean of 4
years. The average age was 81years and co-morbidities included high blood pressure (37%), heart disease (23%),
high cholesterol (19%), diabetes (23%) and stroke (12%).
91% of the BB caregivers were unpaid;68% were caring for
a parent/parent-in-law and 11% lived with the care recipient. In a typical week,BBs spent 18 hours providing
care,51% doing so out of a sense of responsibility. 35% of
the BBs felt their general health had worsened since becoming a caregiver and reported feelings of tiredness, stress,
helplessness and depression.
Conclusions: This online survey suggests that BBs are playing a significant role in dementia care and experience the
emotional and social consequences.Their own aging brings
a double jeopardy - providing dementia care and potentially
needing care themselves. Study supported by Janssen-Ortho
Inc., Canada; Authors 1-4 have participated in advisory
boards, received honoraria and/or participated in clinical
trials with Janssen-Ortho Inc. Authors 5-7 are employees of
Janssen-Ortho Inc.
T-18. Medical Comorbidity and Cognitive Domain
Involvement at the Transition from Normal Cognition
to Mild Cognitive Impairment (MCI)
Gregory A. Jicha, Gregory E. Cooper, Frederick A. Schmitt,
Nancy Stiles, Robin Hamon, Charles D. Smith, and
William R. Markesbery; Lexington, KY
BACKGROUND: Limited data exist providing insight into
the critical transition from normal cognition to MCI.
OBJECTIVE: To evaluate medical causes for cognitive decline and domain involvement at the earliest identifiable
stage of MCI.
METHODS: Forty-eight subjects transitioning from normal
cognition to MCI are presented.
RESULTS: Memory impairment was the most prevalent
cognitive deficit (n⫽41; 85%). MCI classification identified
amnestic MCI (single domain, n⫽28), amnestic MCI with
multiple domain involvement (n⫽13), nonamnestic MCI
(single domain involvement, n⫽6), and nonamnestic MCI
with multiple domain involvement (n⫽1). Subjects were encouraged to undergo medical workup for reversible causes of
Annals of Neurology
Vol 62 (suppl 11)
MCI. Eleven subjects (23%), including 10 with prominent
memory deficits (91%), exhibited anosognosia/denial and refused further evaluation. Medically-reversible or nondegenerative causes of MCI were found in 12 cases (25%)
including vitamin B12 deficiency, thyroid abnormalities, cerebrovascular disease, subdural hematoma, and normal pressure hydrocephalus.
CONCLUSIONS: These data demonstrate that: 1) “early”
MCI is characterized by single domain involvement, most
frequently amnesia, 2) anosognosia, mediated by memory
deficits, appears early in the course of MCI, and 3)
medically-reversible causes of MCI are common in a naive
population and should be evaluated. Study supported by
NIH/NIA 1 P30 AG028383.
T-19. Prodromal Clinical Manifestations of
Neuropathologically-Confirmed Neocortical Lewy Body
Gregory A. Jicha, Frederick A. Schmitt, Gregory E. Cooper,
Charles D. Smith, and William R. Markesbery;
Lexington, KY
BACKGROUND: MCI as a prodromal stage of dementia
with Lewy bodies (MCI-DLB) has not yet been defined but
is likely to differ from that seen in the MCI stage of Alzheimer’s disease (MCI-AD).
OBJECTIVE: To determine whether clinical features distinguish MCI-DLB and MCI-AD.
METHODS: The clinical features of 9 cases of
neuropathologically-confirmed MCI-DLB and 12 cases of
MCI-AD were compared.
RESULTS: No significant differences were found between
MCI-DLB and MCI-AD cases in age at death, gender, education, time followed while clinically normal, or duration of
MCI. MCI-DLB and MCI-AD cases differed clinically in
the expression of Parkinsonism (p⫽0.006), fluctuations
(p⫽0.01), and prodromal delirium precipitated by hospitalization (p⫽0.02). Neuropsychometric test performance did
not differ between MCI-DLB and MCI-AD in MMSE, category fluency, Boston Naming Test, CERAD word list
memory, or Trailmaking. In contrast, phonemic fluency
(p⫽0.003) was significantly lower and Logical Memory I
(p⫽0.01) were significantly higher in MCI-DLB compared
to MCI-AD cases.
CONCLUSIONS: These data demonstrate the feasibility of
differentiating underlying pathologic processes responsible
for cognitive decline in the preclinical disease state and suggest that further refinement in diagnostic criteria may allow
for more accurate early detection of prodromal DLB and
AD. Study supported by NIH/NIA 1 P30 AG028383.
T-20. MEM 1003, a Novel Dihydropyridine L-Type
Ca2ⴙ Channel Modulator, Is a Potential Therapeutic
Drug for Alzheimer’s Disease
David A. Lowe, Wayne B. Rowe, Crista Tripodi-Murphy,
Jing Yang, Rosemary Ahrens, Rachael DiSomma,
Cathleen Hsu, Jeff Kogan, Daguang Wang, Marc Dizon,
Voon Ong, Michael Murray, Paul Fraser, David Westaway,
and Michael DeVivo; Montvale, NJ; Edmonton, AB, Canada;
and Toronto, ON, Canada
Abnormal Ca2⫹ signaling has been implicated in a number
of neurological and psychiatric illnesses, including Alzheimer’s disease(AD). Familial presenilin mutations are known
to cause increases in cytosolic Ca2⫹. MEM1003 is a L-type
Ca2⫹ channel modulator that is being developed for AD.
MEM1003 is distinguished by its preferential CNS activity
and superior cardiovascular safety profile compared to other
DHP drugs, including nimodipine. MEM1003 was effective
in mediating a reduction in the slow afterhypolarization
which is enlarged in hippocampal CA1 neurons from aged,
cognitively-impaired rats and mice. In preclinical models of
cognition, MEM1003 was effective in restoring cognitive
deficits in aged rodents. These models include both
hippocampus-dependent spatial memory, fear conditioning
and PFC-dependent set-shifting models. We will also be presenting data on MEM1003 that was tested in a transgenic
mouse model of AD, the TgCRND8 mouse. The pharmacokinetic and safety profiles of MEM1003 were recently
studied in double-blind, randomized, placebo-controlled
Phase 1A and Phase 1B clinical trials. MEM1003 was well
tolerated up to the highest dose tested of 180 mg twice daily.
MEM1003 is currently in a Phase 2A clinical trial for AD.
Study supported by Memory Pharmaceuticals.
T-21. Dual Effects of Amyloid-Beta (A␤) and Amyloid
Precursor Protein (APP) in the Pathogenesis of
Alzheimer’s Disease
Jin-Jun Luo, John Kusiak, Matthew Wallace, and
William C. Wallace; Baltimore, MD; Philadelphia, PA; and
Washington, DC
Transgenic mouse models over-expressing A␤ peptide exhibit
no significant neuronal death. These observations are inconsistent with cell culture studies, which warrant a reconsideration
of the role of A␤ in causing neuronal death. To test this hypothesis, we constructed and tested adenoviral constructs containing cDNAs of human APP695V642F, APP695V642I, and
APP695wt, that significantly increased APP expression and apoptosis in rat cortical and chick sympathetic ganglionic neuronal cultures, as determined by Western blot and TUNEL,
when compared to cultures treated with null adenovirus. Cortical neurons treated with purified secreted APP␣ exhibited
more neurite outgrowth and cell viability as measured by morphology and MTT. Depletion of endogenous APP by antisense decreased neurite outgrowth from differentiated PC12
cells. Genetically modified (truncated) APP with C-terminal
22 amino acids removed from sAPP␣ not only lost the trophic
effect but produced neurotoxicity. A␤25-35, an active fragment
of A␤ caused significant hippocampal neuron, but not astrocyte, death. However, A␤1-42 partially prevented differentiated
PC12 neurons from death caused by high calcium in culture.
Our results suggest distinct dual roles of A␤ and APP relating
to neuronal viability implicated in the pathogenesis of AD.
Study supported by the Intramural Program, NIA, NIH, and
a National Research Council-NIA/NIH award to JJL.
T-22. Exposure to Antidementia Drugs Slows Clinical
Progression of Alzheimer’s Disease (AD)
Susan D. Rountree, Wenyaw Chan, Rachelle S. Doody,
Valory Pavlik, Eveleen J. Darby, Samina Siddiqui, and
Alexandra Gulley; Houston, TX; and Queens Village, NY
There are no current guidelines for duration of therapy with
donepezil, galantamine, rivastigmine, and memantine. We
prospectively evaluated 643 probable AD patients and evaluated cumulative drug exposure as calculated by a persistency
index (PI): years drug use/years disease duration. Neuropsychological testing at baseline and annually included MiniMental State exam (MMSE), Alzheimer’s Disease Assessment Scale-Cognitive Subscale(ADAS-Cog), Baylor
Profound MSE (BPMSE), Clinical Dementia Rating Scale
Sum of Boxes (CDR-SB), Physical Self-Maintenance Scale(PSMS), and Independent Activities Daily Living (IADL).
Random effects linear regression modeling examined impact of PI on change in slope for neuropsychological tests.
The primary model included time from the first visit, PI,
interaction of these two terms and symptom duration. We
then adjusted for baseline age, sex, education, severity,
symptom duration, and drug exposure prior to initial visit.
Patients with greater cumulative exposure to the drugs had
slower cognitive and functional loss (with, without) adjustment: MMSE (p⬍0.001, p⬍0.05), ADAS-Cog (p⬍0.05,
p⬍0.05), BPMSE (p⬍0.05, p⬍0.05), and PSMS
(p⬍0.001, p⬍0.05). No significant effects were found for
the IADL and CDR-SB. Persistent treatment with antidementia drugs had a positive impact on disease progression
even in those with advanced stage disease. Study supported
by Forest Pharmaceuticals, Inc. and the Cynthia Woods
Mitchell Endowed Research Fund; Dr. Rountree received
financial support for research activities from Forest Pharmaceuticals, Inc.; Dr Doody has received consulting honoraria from Forest Pharmaceuticals, Inc. in the past.
T-23. Achieving Optimal Therapeutic Doses –
Rivastigmine (Exelon®) Patch and Capsule
Carl Sadowsky, Jeffrey Cummings, Sibel Tekin, and
Roger Lane; Fort Lauderdale, FL; Los Angeles, CA; and
East Hanover, NJ
Background: Patches offer many advantages over oral formulations. Exelon Patch is the first patch developed for Alzheimer’s disease (AD). Target-dose Patch 10 provides exposure approaching that of highest doses of capsules (12mg/
Objective: To compare efficacy, tolerability and treatment
duration with target doses of Exelon Patch and capsules.
Methods: IDEAL was a 24-week, double-blind, doubledummy, placebo- and active-controlled study of Exelon
Patch and capsule versus placebo. Doses were titrated at
4-week intervals. Primary evaluations included assessments of
cognition and global functioning. Dosing information and
safety/tolerability assessments were prospectively recorded.
Results: 1195 AD patients entered the study. Exelon Patch
10 provided equivalent efficacy to highest doses of capsules
with three times fewer reports of nausea and vomiting. Patients receiving Patch 10 spent 1.5-times longer on target
dose versus capsules (75.5 versus 48.9 days; maintenance
phase) and 1.5-times more patients reached target dose
(96.2% versus 63.3%).
Conclusion: Patients maintain target doses more frequently
and for longer with Exelon Patch 10 versus capsules. This
reflects the more favorable tolerability of Patch, and suggests
greater likelihood that patients will access therapeutic doses,
potentially increasing efficacy. This effect may be more pronounced in routine clinical practice. Study supported by Novartis Pharmaceuticals; C Sadowsky - Speaking honorarium
from Novartis; J Cummings - Consultant/Speaker bureau
(Novartis); S Tekin - Employee of Novartis; R Lane - Employee of Novartis.
T-24. Lewy Body Pathology and Cerebral
Nikolaos Scarmeas, Karen Marder, Jean Paul G. Vonsattel,
and Lawrence S. Honig; New York, NY
While studies have demonstrated an association between cerebral atherosclerosis (CATH) and Alzheimer’s disease
Program and Abstracts, American Neurological Association
changes, the relation between CATH and Lewy body (LB)
burden has not been adequately investigated. Thus, we explored this association in a series of 403 brains of the Columbia University Medical Center data bank, obtained between 1990 and 2007. LBs were present in 106 (26%)
brains. CATH was absent in 124 (31%), mild in 147 (37%)
and moderate-severe in 132 (33%) brains. LBs were detected
in 19% of brains with absent CATH, in 23% with mild and
in 36% of brains with moderate-severe CATH (p ⫽ 0.005).
In logistic regression models that adjusted for age, gender
and the presence of Alzheimer’s disease changes, as compared
to absence of CATH, mild CATH was related to higher
odds of presence of LBs (OR: 1.07; 95% CI 0.56 – 2.02),
while moderate-severe CATH was related to even higher
odds 2.20 [1.15-4.24]: p for trend 0.01. We conclude that
LB burden seems to be associated with increased severity of
CATH. Study supported by Henry Panasci Fund, Taub Institute, and NIH P50AG08702.
T-25. Cerebral Ischemia Mediates the Serum Uric
Acid and Cognition Association
Tracy D. Vannorsdall, H. A. Jinnah, Barry Gordon,
Michael Kraut, David J. Schretlen, and Anjeli B. Inscore;
Baltimore, MD
High normal concentrations of serum uric acid (UA) are associated with mild cognitive dysfunction and greater cerebral
ischemia as indexed by white matter hyperintensity volumes
on brain magnetic resonance imaging (MRI). In this crosssectional, observational study we hypothesized that individual differences in cerebral ischemic burden mediate the association between UA and mild cognitive dysfunction.
Participants included 180 community-dwelling adults aged
20 to 96 years who completed comprehensive neuropsychological testing, laboratory blood studies, and brain MRI.
High normal UA was associated (p⬍0.05) with greater cerebral ischemia and poorer performance on tests of working
memory, processing speed, fluency, and verbal memory. In
hierarchical multiple regression models, these associations remained even after controlling for age, sex, race, education,
hypertension, diabetes, history of alcohol abuse, smoking status, and body mass index. However, adding a term for cerebral ischemic burden to the model attenuated the association
between UA and cognitive functioning, such that UA no
longer predicted cognitive performance. These findings suggest that severity of cerebral ischemia might mediate the association between UA and cognitive dysfunction. They also
suggest that even normal elevations in UA contribute to
structural and functional brain changes. Study supported by
NIH/NIMH Grants: MH60504, MH43775, MH52886, &
MH068522; the Therapeutic Neurosciences Fund; and the
Benjamin and Adith Miller Family Endowment on Aging,
Alzheimer’s and Autism Research.
T-26. Tissue Microstructural Changes Are
Independently Associated with Pre-Index Cognitive
Impairment in Survivors of Lobar Intracerebral
Anand Viswanathan, Pratik Patel, Rosanna Rahman,
Kaveer Nandigam, Catherine Kinnecom, Chahin Pachai,
Jonathan Rosand, Hugues Chabriat, Steven M. Greenberg,
and Eric Smith; Boston, MA; Paris, France; and
Lyon, France
Objective:Cerebral amyloid angiopathy(CAA) is a major
cause of lobar intracerebral hemorrhage(ICH) and cognitive
Annals of Neurology
Vol 62 (suppl 11)
impairment and is associated with white matter hyperintensities(WMH) and cortical microbleeds(MB). MRI diffusion
tensor imaging detects microstructural tissue damage in advanced CAA even in areas that appear normal on conventional MRI. We hypothesized that higher global mean apparent diffusion coefficient(mean-ADC) would be associated
with CAA-related cognitive impairment.
Methods: Pre-ICH cognitive impairment(PICI) was systematically assessed using a standardized questionnaire(IQCODE)
in 49 patients. Volume of WMH,number of MB and meanADC were determined from MRIs obtained within
14.0⫾22.5 days of ICH. WMH and mean-ADC were measured in the hemisphere uninvolved by ICH to avoid confounding.
Results: PICI was identified in 10/49 subjects. Mean-ADC
was the only variable associated with PICI. Mean-ADC positively correlated with age but not WMH or number of
MB.In logistic regression controlling for age, mean-ADC was
independently associated with PICI(p⫽0.036;OR(per 1x102
4mm /s increase)⫽2.45[95%CI 1.11 5.40]).
Conclusions: Mean-ADC is independently associated with
pre-ICH cognitive impairment in CAA. These results suggest
that global MRI diffusion changes are sensitive to clinicallyrelevant microstructural alterations, and may be a useful
marker of CAA severity. Study supported by K23 NS046327.
T-27. Discourse Impairment in Corticobasal
Rachel Goldmann Gross, Sharon Ash, Chivon Anderson,
Peachie Moore, and Murray Grossman; Philadelphia, PA
Corticobasal degeneration (CBD) is an akinetic-rigid syndrome associated with cognitive impairment. Clinically, patients with CBD show marked conversational difficulties. In
this study, we evaluated discourse—how a sequence of utterances is organized—in patients with CBD. Patients with
CBD (n⫽17) and healthy seniors (n⫽10) reviewed and then
narrated a wordless picture story. Narratives were recorded
digitally and coded by two investigators for speech rate, accuracy, and measures of story organization (connectedness of
events, maintenance of the narrative theme). For patients
with CBD, we correlated narrative measures with cognitive
tasks and with cortical atrophy as identified by MRI voxelbased morphometry. T-tests showed significant narrative impairment in CBD relative to controls (p⬍0.05 for all measures). Patients’ ability to maintain the story theme
throughout their narratives correlated with geometric design
copy and pictorial semantic memory tasks (p⬍0.05), but not
with lower-level visuoperceptual tasks. This measure of story
organization correlated with atrophy of frontal and parietal
regions (p⬍0.01). We conclude that organization of verbal
and visual material is impaired in CBD and may be related
to frontoparietal disease. Difficulty processing narrative information in CBD may represent a ‘conceptual simultagnosia’ that limits the ability to tell a story. Study supported by
National Institutes of Health (NS44266, AG17586,
T-28. A Reward Signal in Motor Cortex
Dimitrios Kapogiannis, Paul I. Campion, and
Eric M. Wassermann; Bethesda, MD
Dopaminergic drugs alter the motor cortex (M1) response to
transcranial magnetic stimulation (TMS). M1 receives pro-
jections from Dopaminergic midbrain neurons, whose firing
rate is modulated by reward prediction error defined as the
discrepancy between received and predicted rewards. We
used TMS of M1 to study healthy men during a three-barrel
slot machine simulation that required no motor output. Subjects won monetary rewards on 50% of the trials resulting in
3 – way matches. To maximize dopaminergic activation,
there were multiple reward values, no losses, and rare unexpected rewards. We delivered single and paired TMS (subthreshold conditioning and suprathreshold test pulses; 2 and
10 ms interstimulus intervals) at varying latencies after trial
outcome. We recorded motor evoked potentials (MEPs)
from resting dominant finger flexors and calculated the ratios
of conditioned to unconditioned MEPs. Reward/ Expectation condition significantly affected the response to TMS
(F⫽7.171; p⫽0.006). Unexpected reward decreased both
unconditioned MEP amplitude and intracortical inhibition
(increased conditioned/unconditioned MEP) relative to other
conditions. This is the first evidence of a reward signal in the
motor cortex and raises the possibility of an online, physiological measure of reward in humans. Study supported by
Intramural Program, NINDS/NIH.
T-29. Memory and Executive Skills Are Impaired in
Relapsing-Remitting MS
Theodora Panou, Panagiotis Simos, Chrisoula Fassaraki, and
Andreas Plaitakis; Heraklion, Crete, Greece; and
Rethymnon, Crete, Greece
We assess verbal learning and retention in patients with relapsing remitting MS in relation to long term episodic memory and executive skills. Thirty-three patients were tested 8.1
years after diagnosis. Patients and controls (n⫽30) were
matched on IQ, age and education. The ability to encode
and maintain new episodic information was assessed with
CVLT and narrative memory with WMS; retrieval of verbal
representations from long term memory using COWAT;
dexterity and visuomotor coordination with Grooved Pegboard and Trail Making Test Part A, respectively; the ability
to adopt and maintain a simple visuomotor strategy using
Part B of the TMT; symptoms of depression and daily functioning using CES-D-20 and Kurtze’s scales, respectively.
We found differences between groups on immediate and delayed narrative memory (p⬍0.001). Performance of patients
was lower than controls on both immediate and delayed
word list recall in the cued-recall condition (p⬍0.002), indicating impaired ability to take advantage of semantic properties of the word stimuli to support retention and/or retrieval. This notion is corroborated by the fact that
performance of patients on semantic scale of COWAT was
decreased. In addition, disease duration correlated strongly
with performance on these measures.
although approximately 40 miles distant. He thought the
lay-out and furnishings were identical. Otherwise, his initial
mental status testing was normal. Neuropsychologic testing
disclosed isolated executive dysfunction. He had diffuse
myokymia and myoclonic movements of the limbs. CSF
showed 475 WBC/uL (37% neutrophils, 42% lymphocytes,
21% monocytes), 700 RBC/uL without xanthochromia, and
normal protein and glucose. Serum CPK was 319 IU/L and
VGKC antibody was 0.38 nmol/L (⬍0.02). Brain MRI had
subtle increased T2/FLAIR signal in the medial temporal regions. EMG showed diffuse myokymia. An extensive infectious, neoplastic, and rheumatologic workup was negative.
He was treated with IVIG (0.4 g/kg for five days) and steroids with resolution of his reduplicative paramnesia and myoclonus. To our knowledge, this is the only reported case of
treatment responsive reduplicative paramnesia associated
with VGKC antibodies.
T-31. The Relationship between Cognitive Impairment
and Behavioral Performance in Amyotrophic Lateral
Alicia R. Salamone, Mariana Witgert, Adriana Macias, and
Paul E. Schulz; Houston, TX
The relationship between behavioral and cognitive changes
in Amyotrophic Lateral Sclerosis (ALS) remains to be elucidated. 225 ALS patients were given neuropsychological testing, including a measure of frontal-mediated behavioral
change, the FrSBe (Frontal Systems Behavior Scale). Behavioral impairment was found in 24.4% of patients. Apathy
was the prevalent impairment, surpassing executive dysfunction and disinhibition. Correlations were found between cognitive measures and FrSBe Apathy, Dysexecutive, and Total
scores. FrSBe Total score was correlated with category fluency and visuoconstruction (p⬍0.01), attention and delayed
memory (p⬍0.05). Apathy was correlated with category fluency, visuoconstruction, attention (p⬍0.01), set-shifting and
depression (p⬍0.05). Executive Dysfunction was correlated
with attention, visuoconstruction, delayed learning, memory
(p⬍0.05) and category fluency (p⬍0.01). Category fluency
was able to predict FrSBe behavioral performance (p⫽0.04
Total; p⫽0.002 Apathy; p⫽0.02 Dysexecutive). Patients
with behavioral impairment tended to have increased cognitive impairment. Interestingly, 16.1% of patients with intact
cognition were behaviorally impaired, with the most problems in Apathy. 56.8% of patients with intact behavior were
cognitively impaired. Results suggest that even if a patient
appears to be cognitively or behaviorally intact, caregivers
should be aware that impairment may exist and should be
T-30. Reduplicative Paramnesia, Myoclonus, and
Myokymia Associated with Voltage Gated Potassium
Channel Antibodies
Yvonne D. Rollins, Lynsee A. Hudson, Clark A. Anderson,
Kenneth L. Tyler, and Christopher M. Filley; Denver, CO
Syndromes associated with voltage gated potassium channel
(VGKC) antibodies include limbic encephalitis, amnesia,
myokymia, neuromyotonia, and seizures. We present a 64
year old right-handed man who developed reduplicative paramnesia, myoclonus, and myokymia over several months.
On admission, he described making several trips with his
wife to a house which was a duplicate of their own home
T-32. Whole-Genome Association for Late-Onset
Alzheimer Disease (LOAD)
Gary W. Beecham, Eden R. Martin, Yi-Ju Li, Carol Haynes,
Regina M. Carney, Michael A. Slifer, John R. Gilbert,
Jonathan L. Haines, and Margaret A. Pericak-Vance;
Durham, NC; Miami, FL; and Nashville, TN
Genetic studies have estimated that the heritability of lateonset Alzheimer disease (LOAD) is at 80%. Despite its
strong genetic component, only apolipoprotein E (APOE)
has been consistently associated with LOAD. While APOE
has a strong effect on LOAD, the risk allele is neither necessary nor sufficient for LOAD. At most, APOE accounts for
Program and Abstracts, American Neurological Association
half of the genetic component of LOAD and the risk allele is
not even present in a third of LOAD cases. We now report
the results of a whole-genome association (WGA) study for
LOAD. We used the Illumina Infinium platform to perform
WGA on 1049 individuals at 550,000 markers. We implemented numerous quality control (QC) tests to ensure the
integrity of the data, and tested for association using Armitage’s Trend test. Three APOE markers were significantly associated at the 0.05 level (Bonferroni corrected); these serve
as positive controls. One marker on Chromosome 12 was
significant at the FDRBum corrected level of 0.05. The
marker was located at the FAM113B gene, and is under previously reported linkage peaks. Additionally, there were
markers on chromosomes 1, 2, 12, 13, 14, and 19 with
p-values less than 0.00001, uncorrected.
T-33. Mitochondrial Changes in Patients with Optic
Thomas M. Bosley, Cris S. Constantinescu,
Christopher R. Tench, and Khaled K. Abu-Amero;
Camden, NJ; Nottingham, United Kingdom; and
Doha, Qatar
We evaluated 26 patients with optic neuritis (ON) affecting
one or both eyes (11 male and 15 female; average age at
onset 23.4 ⫾ 8.1 years) for evidence of systemic mitochondrial abnormalities. We performed clinical examinations and
neuroimaging; sequenced the entire mitochondrial DNA
(mtDNA) coding region in blood of all patients; assessed relative mtDNA content; measured mitochondrial respiratory
function in 15 patients; and sequenced OPA1 and OPA3
genes associated with dominant and recessive optic atrophy,
respectively. Eleven patients had neuroimaging evidence of
disseminated demyelination, and six had clinically definite
multiple sclerosis. No patient had a primary LHON mutation or a pathologic sequence change in OPA1 or OPA3
genes. Sixteen patients had potentially pathologic mtDNA
changes, and these patients had worse visual acuity (p ⫽
0.002) and color vision (p ⫽ 0.009) after recovery than
other patients. Mean relative mtDNA content was significantly increased in ON patients compared to controls (2.39
v 1.03; p ⬍ 0.001), while Mitochondrial Respiratory Activity was decreased (16.78 v. 22.53; p ⬍ 0.001). Mitochondrial abnormalities in blood were associated with the occurrence and severity of optic nerve injury, suggesting that
mitochondrial abnormalities may constitute a risk factor for
ON. Study supported by Prince Salman Center for Disability Research, Riyadh, Saudi Arabia; and the King Abdulaziz
City for Science and Technology, Riyadh, Saudi Arabia.
The gene for the novel CLN9 NCL variant is unknown.
CLN9-deficient fibroblasts demonstrate rapid growth, increased apoptosis and diminished ceramide/dihydroceramide/
sphingomyelin levels. CLN9 positively modulates dihydroceramide synthase. Transfecting CLN9-deficient fibroblasts
with LASS1 corrects ceramide, growth and apoptosis. Proteomic and genomic approaches will identify the CLN9
gene. In families with affected and unaffected offspring, regions of homozygosity are random between family members,
but identical in affected siblings. Genotypes using 100,000
Annals of Neurology
Vol 62 (suppl 11)
T-35. Identification of Genetic Interactors of the LIS1 Disease Gene
Edgar A. Buttner, Anandita K. Rajpurohit, Nikki D. Patel,
Erica L. Farber, Aleksandra J. Gil-Krzewska, and
Craig P. Hunter; Cambridge, MA; and Belmont, MA
Lissencephaly is a pediatric neurological disorder characterized by mental retardation and epilepsy. Partial loss-offunction of lis-1 produces neuronal defects, while deletion
results in embryonic lethality. To understand the earliest defects associated with lis-1(lf) we are investigating its role in
C. elegans germline development. We demonstrated that deletion of lis-1 causes spindle checkpoint-mediated mitotic arrest followed by ced-3-dependent programmed cell death of
germ cells. To identify genes that couple spindle checkpoint
activation to programmed cell death we have carried out forward mutagenesis and RNAi screens to identify mutants and
genes that, when depleted, suppress lis-1(lf)-induced germline apoptosis. Our RNAi screen identified five genes that
suppress lis-1(lf)-induced apoptosis but do not interfere with
lis-1(lf)-induced mitotic arrest. We are also characterizing the
genetic interaction between lis-1 and the dynein heavy chain
homolog dhc-1. Severe loss-of-function of lis-1 or dhc-1 produces lethality in C. elegans. Surprisingly, we have found
that double mutant animals produce viable progeny. Using
an RNAi-based screening appoach, we have identified other
genes that suppress dhc-1(lf)-induced lethality and that likely
encode interactors of the LIS-1/DHC-1 protein complex.
Study supported by NINDS, Bernhard Foundation.
T-36. HMSN Type VI with a Leber’s Hereditary
Optic Neuropathy Phenotype and Mild Neuropathy
Due to New Mutation in Mitofusin 2
Desmond P. Kidd, Pauline Wilson, Bronia Unwin,
Mushriq Al Khayatt, Mary Davis, and Tony H. V. Schapira;
London, United Kingdom
T-34. In Search of the CLN9 Gene and Protein
Defective in a Novel Batten Disease Variant
Talal Mousallem, Angela Schulz, Ryan Kennedy,
Lauren Smith, Kevin Shianna, and Rose-Mary Boustany;
Durham, NC; and Beirut, Lebanon
single nucleotide polymorphism (SNP) loci were generated
for parents/siblings and affecteds. Homozygosity mapping allowed localization of homozygous regions in chromosomes
2/8/11/13/15/17, spanning 550 genes. 73 candidate genes
were chosen according to function, of which NME2/ALG9/
DGKE/LOH11CR2A have been excluded. LASS1p, a human homologue of lag1/dihydroceramide synthase, corrects
the CLN9 phenotype. CLN9p may bind to LASS1p. Protein
fractionation (2D-gel electrophoresis) of normal/CLN9deficient cells after immunoprecipitation with LASS1 antibody yielded one spot, the ␥-Actin (ACTG1) protein.
ACTG1 is normal in CLN9. CLN9p may bind to ACTG1p.
An ACTG1 antibody to immunoprecipitate proteins from
normal/CLN9-deficient cells shows ACTG1-bound protein
differences between normal and CLN9-deficient cells. The
convergence of both proteomic and genomic approaches will
undoubtedly yield the CLN9 protein and gene.
We report a family in which a subacute bilateral visual loss
developed and subsequently improved similar to that seen in
Leber’s hereditary optic neuropathy. Axonal sensory neuropathy was found to coexist which was mild and even asymptomatic in most cases but was disabling in two. The pattern
of inheritance was autosomal dominant.
All affected persons showed signs of a moderate or severe
bilateral optic neuropathy at onset which improved slowly
over several years back to reasonable visual function. The
neuropathy was asymptomatic in three, symptomatic in two
and associated with difficulty walking in two, one of whom
had symptoms and EMG signs of a superimposed severe
A new mutation of mitofusin 2 was found in all patients.
Mutations in this gene have recently been shown to be associated with HMSN type II, including patients with a progressive optic neuropathy conforming to HMSN type VI.
Mitofusin 2 is a mitochondrial membrane GTPase responsible for the integrity of the mitochondrial membrane. This
explains why a Leber’s phenotype may arise in patients with
inherited motor and sensory neuropathies associated with optic neuropathy.
T-37. MRI and SPECT Findings in a Patient with
Megalencephalic Leukoencephalopathy with Aubcortical
Takao Kiriyama, Makito Hirano, Tanizawa Emi,
Takayuki Shinkai, Hirohide Asai, Yoshiko Furiya, and
Satoshi Ueno; Kashihara, Nara, Japan
Megalencephalic leukoencephalopathy with subcortical cysts
(MLC) is a rare autosomal recessive disorder characterized by
megalencephaly and cerebral leukoencephalopathy with
slowly progressive neurologic symptoms, including epilepsy,
ataxia, spasticity, and mild cognitive impairment. MLC is
caused by mutations in the gene encoding MLC1. We show
findings on magnetic resonance imaging (MRI), magnetic
resonance spectroscopy (MRS), and single photon emission
computed tomography (SPECT) in a patient with homozygous S93L mutation in the MLC1 gene. Furthermore, we
summarized clinical and MRI findings in 10 previous MLC
patients with genetically definite disease. Technetium-99methyl cysteinate dimer SPECT revealed hypoperfusion in the
cerebral white matter, which had shown high signal intensity
on MRI T2 images. Hypoperfusion was also found in the
frontal cortices, which showed no abnormalities on MRI.
This frontal abnormality corresponded clinically to a low
score on the frontal assessment battery. Decreased GABA receptor density as suggested by 123I-Iomazenil SPECT provided further evidence of cortical neuron dysfunction. Our
findings raise the possibility that SPECT can be used to noninvasively monitor in vivo cortical functions in this disease.
T-38. Atlastin Is a Novel ER Protein Involved in
Golgi-ER Transport
Genny Orso, Jessica Tosetto, Diana Pendin, Andrea Daga,
and Andrea Martinuzzi; Dublin, Ireland;
Conegliano, TV, Italy; Padova, PD, Italy; and Padova, Italy
The SPG3A gene encoding atlastin is associated with early
onset hereditary spastic paraplegia. Atlastin shows homology
to large GTPases of the dynamin superfamily, but its function is unknown. We have identified and cloned the fly homologue (D-atlastin) of human Atlastin. We carried out a
detailed analysis of the embryonic and larval expression patterns, and studied the subcellular localization of D-atlastin.
D-atlastin is ubiquitously expressed during all stages of fly
development. D-atlastin is highly enriched in and colocalizes with Endoplasmic Reticulum (ER) markers. A small
amount of signal is also detected in the Golgi suggesting its
involvement in vesicular trafficking between ER and Golgi.
We generated transgenic flies for its overexpression and
knockdown. Ubiquitous overexpression of D-atlastin causes
death at embryonic stage 13. Tissues overexpressing
D-atlastin show morphological alterations of the Golgi which
disassembles and colocalizes with markers for ER. Loss of
D-atlastin allows survival of few escapers with most individ-
uals dying at pupal stage. Eclosed adults have a short lifespan
and an obvious reduction of size. We show that Atlastin is
important for vesicular transport between ER and Golgi and
necessary for proper development. Study supported by Telethon Italy, The Ministry of Health, Italy.
T-39. Gene-Environment Interaction in PD: Joint
Analysis of Four Genes and Two Exposures
Colin McCulloch, Denise Kay, Stewart Factor, Ali Samii,
John Nutt, Donald Higgins, John Roberts,
Jennifer Montimurro, Cyrus Zabetian, and Haydeh Payami;
Albany; Niskayuna; Atlanta; Seattle; Portland; and Seattle
Idiopathic Parkinson’s disease (PD) is thought to result from
interaction between genes and environment, although studies
to support this notion have been few, often small and examined only two factors at a time. We analyzed the joint effects
of smoking, coffee, and genetic polymorphisms in the SNCA
(alpha-synuclein) promoter (REP1), MAPT (H1/H2 haplotypes), APOE (e2/e3/e4) and UCHL1 (S18Y), in 932 PD
and 664 control subjects from the NeuroGenetics Research
Consortium, using stepwise logistic regression while controlling for sex, age and data collection site. We detected a significant main effect for MAPT-H1H1 diplotype (OR⫽1.54,
p⫽.0001) and significant interactions between SNCA-REP1
and smoking, APOE and coffee, and UCHL1 and coffee.
These data suggest that the inverse associations of coffee and
smoking with PD risk are genotype-specific. When considering the six factors simultaneously, the effect on risk was
ten-fold stronger than the strongest individual association
(OR⫽ 14.7, 95% CI ⫽ 6.3-34.3). This study demonstrates
the power of interaction studies for identifying risk factors
with modest individual effects, and presents strong evidence
in support of the long-held notion that PD risk is modulated
by cumulative and interactive effects of genes and environment. Study supported by National Institutes of Health and
Michael J Fox Foundation for Parkinson Research.
T-40. Identification of Changes in Dorsal Root
Ganglia Gene Expression in Cisplatin-Induced
Armin Alaedini, Hesed S. Kim, Zhaoying Xiang, and
Norman Latov; New York, NY
Cisplatin is an effective anti-neoplastic drug, but its use is
dose-limited due to severe peripheral neurotoxicity. The neurotoxic effect of cisplatin is believed to result from its accumulation in the dorsal root ganglia (DRG), although the
mechanism is not completely understood. We used a previously developed animal model, in which cisplatin-treated rats
exhibit reduced sensory nerve conduction velocity and nociceptive signs, to examine changes in gene expression in the
rat DRG in response to cisplatin. Six Sprague Dawley rats
were treated with cisplatin, 4 mg/kg/week, for 4 weeks, while
6 control rats were treated with vehicle. We found that cisplatin significantly affects the expression of several genes associated with apoptosis (Cdkn1a, Ckap2, Bid3), inflammation (S100a8, S100a9, Clecsf2, Cd163), and nerve growth
and regeneration (Mmp9, Gfap, Fabp7). The differential
regulation of some of these genes may directly contribute to
the neurotoxic effect of cisplatin, while others may be representative of the subsequent cellular response to contain damage and initiate peripheral nerve regeneration. As such, the
identified genes may represent candidate processes and path-
Program and Abstracts, American Neurological Association
ways that should be considered as targets for therapeutic intervention in cisplatin-induced neuropathy. Study supported
by a generous gift from Wade F. B. Thompson.
T-41. Sports and Trauma in Amyotrophic Lateral
Sclerosis Revisited
Carmel Armon; Boston, MA; and Springfield, MA
OBJECTIVE: Review the literature from 2003 to 2006 to
determine if new data change the conclusions of a previous
review (Neuroepidemiology 2003; 22:217-228) that sports
and trauma are probably (“more likely than not”) not risk
factors for developing ALS.
BACKGROUND: Reported apparent excess occurrence of
ALS in professional Italian soccer players has rekindled the
discussion, whether sports or trauma are risk factors for ALS.
METHODS: A Medline search was conducted for the years
2002 – 2006. Original articles were classified using evidencebased methods. The expected number of cases of ALS in the
Italian soccer player cohorts was re-calculated independently,
assuming complete case finding in the reference cohort. Previous evidence was considered in updating conclusions.
RESULTS: Two reports showed that physical activities and
sports were associated with reduced risk of, or not associated
with, ALS (Class III). A third concluded that varsity athletics
and low BMI were risk factors for ALS (Class IV). There was
no excess of ALS in Italian soccer players (two articles, Class
CONCLUSIONS: 1. Trauma and physical activity are probably not risk factors for ALS (Level B, unchanged). 2.There
is possibly no excess of ALS in professional Italian soccer
players (Level C). Dr. Armon has provided expert opinion in
cases in which trauma was alleged to have caused ALS.
T-42. Treatment with Rasagiline in Patients with
Amyotrophic Lateral Sclerosis
Beatrice Nefussy, Irena Artmonov, and Vivian E. Drory;
Tel-Aviv, Israel
Rasagiline is a new antiparkinsonian agent with neuroprotective properties, which increased survival in SOD1 transgenic
Eighteen patients (13 males) aged 56⫾14.3 years, with clinically definite or probable amyotrophic lateral sclerosis (ALS)
were treated off-label with rasagiline 2 mg as add-on to riluzole. Patients were evaluated every 3 months using the
ALSFRS-R scale. For 9 patients clinical evaluations were
available for 9-14 months before start of rasagiline. The rate
of deterioration of ALSFRS-R in rasagiline-treated patients
was compared to that of 25 randomly chosen patients,
treated with riluzole only.
Mean time on rasagiline was 9.5⫾5.8 months (range 2.2324.94). The mean slope of ALSFRS-R deterioration for
rasagiline-treated patients was 0.68⫾0.37/month, compared
to –1.02⫾0.60 in the riluzole-only group, and a slope of
⬃–1 reported in the literature. In patients with pretreatment data, the mean deterioration slope was
–1.11⫾0.27/month before rasagiline onset and 0.62⫾0.27
thereafter. No significant side effects of rasagiline were reported.
Despite limitations of this small, non-blinded, retrospective
analysis, it appears that rasagiline has positive effects on the
rate of ALS deterioration. Further investigation of this drug
as a potential treatment for ALS is warranted.
Annals of Neurology
Vol 62 (suppl 11)
T-43. Biopsy of the Median Motor Nerve: Description
of Technique and Complications
Nora Chan, Jess Ting, and Dale J. Lange; New York, NY
There is no failsafe method to separate multifocal motor
neuropathy (MMN) without conduction block from motor
neuron disease except for atypical progression. IVIG is an
effective treatment for MMN but failure to treat early may
lead to irreversible loss of strength. Biopsy of motor nerves
may assist in diagnosis. Since arms are the most frequent site
of onset, a safe and easily accessible motor nerve to biopsy is
required. We performed 39 median nerve and pronator muscle biopsies between 2002 and 2006. A small branch to the
pronator muscle is identified after intraoperative stimulation
of one of the identifiable branches by eliciting an evoked
response recorded by a concentric needle placed in the pronator muscle. Simultaneous biopsy of the pronator muscle is
performed for correlation of nerve and muscle pathology.
Wound infection occurred in two patients (5%), hematoma
in one patient required repeat surgery for evacuation (2.5%)
and persistent pain with numbness occurred in one patient
(2.5%). No patient developed new weakness. Median nerve/
pronator muscle biopsy is safe and is able to provide important information to assist in the diagnosis of disorders characterized by weakness without sensory loss.
T-44. Long-Term Alpha-Glucosidase Therapy in a
Case of Juvenile-Adult Form Pompe Disease
Shun-Sheng Chen, Shon-Long Lai, and Tsu-Cheng Hwang;
Kaohsiung County, Taiwan
The 21 year-old male patient suffered from insidious onset
of progressive weakness of bilateral lower limbs since17 years
old. He complained of difficulty in running and climb the
stair since that time. Difficult swallowing and periodic attack
of respiratory failure were found since 20 years old. The patient had several episode of pneumonia followed episodic respiratory failure. Intubation was done twice for improving
conscious disturbance due to hypoxia. He was usually waken
up by breathless sensation, and the condition improved after
BiPAP use at night. Pompes disease was diagnosed after muscle biopsy. Lymphocyte alpha-glucosidase enzyme assay
showed 1.73 (normal ⬎ 60) nmol/mg/Prot/hr. GAA gene
DNA analysis (exon2-20) showed heterozygous mutation at
exon 14 codon [GAC3 GAA, Asp3 Glu]. Pompe disease of
juvenile-adult form was confirmed. Alglucosidase was prescribed since Sep 2006. After six months treatment every two
weeks (20 mg/Kg/IV q2wk), the lower limbs weakness was
improving and now he can walk without support. Lower serum CK and improved respiratory function were noticed.
Follow up muscle biopsy showed dramatic improvement in
terms of less autophagic, necrotized and glycogen containing
vacuolar fibers. This patient still keeps infusional therapy of
alpha-glucosidase every two weeks and his condition is getting better which will be present detailedly.
T-45. Alemtuzumab (CAMPATH 1-H) Therapy in
Sporadic Inclusion Body Myositis (sIBM) Alters Disease
Progression and Suppresses Endomysial Inflammation
Marinos C. Dalakas, Goran Rakocevic, Beverly McElroy,
Mohammad K. Salajegheh, Jens Schmidt,
Michael Harris-Love, Joseph Shrader, Ellen Levy, and
Allen D. Kirk; Bethesda, MD
In this study we examined the effectiveness of Alemtuzumab
in suppressing endomysial inflammation and arresting sIBM
progression. Alemtuzumab is a humanized monoclonal antibody against CD52 that causes severe PBL reduction up to 6
months. Thirteen sIBM patients with a 12 – month natural
history were treated with 0.3 mg/kg/day Alemtuzumab for 4
days. Primary end-points were the disease stabilization or increased strength 6 months after treatment. During a 12 –
month observation, patients’ total strength had declined by a
mean of 14.9% on QMT, while six months after therapy,
only by 1.9 % (p⬍0.002). Six of 13 patients improved by
15.7% (4 – 35%); the other 7 declined by 6% (-1.5 – 15%).
Total MRC scores declined during observation by 13.8%
but improved after 6 months by 11.4 % (p⬍0.001). PBL
depletion persisted for 6 months after treatment, with naive
CD45RA⫹ CD62L⫹, but not effector CD45RA⫹CD62L-,
cells affected. Repeated muscle biopsies showed CD3 lymphocyte depletion by a mean of 50 % (p⬍0.008). Only
mRNA of Fas, Mipa and ␣B-crystallin, were significantly reduced in muscle. In sIBM, Alemtuzumab causes peripheral
and endomysial lymphocyte reduction and halts disease progression up to 6 months.
T-46. Comparison of Thymectomy with Conservative
Treatment in Autoimmune Non-Thymomatous
Myasthenia Gravis
Srikanth Reddy Emani, Anisya Vasanth Taly, Arun B. Taly,
S. K. Shankar, and P. N. JayaKumar;
Nellore, Andhrapradesh, India; and
Bangalore, Karnataka, India
Background: There is lack of consensus on the role of thyectomy in the management of myasthenia gravis.
Aim: To evaluate the benefit of thymectomy over conservative treatment in non-thymomatous Myasthenia Gravis
(MG), in a matched study.
Patients & Methods: Over a period of 32 years (1969-2000),
375 Patients of MG were evaluated. All the patients were
sorted out with a computer as per the age, gender and duration of illness and severity of illness. Thirty-two thymectomized non-thymomatous MG patients were compared with
their controls who were matching for the prognostic variables.
Results: The best response(modified Keyne’s clasiification)
was seen in 13 thymectomized patients and 14 nonthymectomized patients. Both groups were not having any
statistically significant differences in the multiple prognostic
variables, including the immunomodulation.There were 4
patients in each group, with a drug free remission period of
one year. In the non-thymectomy group additional 4 asymptomatic patients, were not receiving AchEI for a period of
one year, but they were on immuno modulators.
Conclusion: Thymectomy did not offer any distinct advantage over conservative treatment in inducing remission or
improvement of myasthenia.
T-47. HyperIgEaemia-Atopy Associated CIDP
(Chronic Immune Dysschwannian Polyneuropathy) Can
Have Excellent Benefit from Intravenous
Immunoglobulin (IVIG)
Daniel P. Hexter, and W. King Engel; Los Angeles, CA
Elevated serum IgE, often accompanied by multi-tissue evidence of atopy, can be associated with neuromuscular disease. A. Kimura (2005) described a patient having CIDP
with elevated total IgE (850 IU/mL), who responded to
IVIG treatment. We present three men with markedly elevated IgE levels of 2332-11,606 IU/ml (normal 0-165), and
several aspects of the Hyper-IgE Syndrome (HIES); none has
blood or muscle-biopsy eosinophilia. Two have CIDP and
one has CIDP plus slight non-inflammatory myopathy. Each
patient’s extensive workup established the diagnosis of a dysimmune dyschwannian neuropathy. With IVIG treatment,
the improvement of one CIDP patient (age 55, IgE 2332)
began rapidly and continues to increment. The
CIDP⫹myopathy patient (age 48, IgE 6739) had no benefit
from IVIG (nor from other immune-modulations). For the
third patient (age 23, IgE 11,606), IVIG results will be presented. Serum IgE levels and features of atopy, including
atopic dermatitis, chronic infections, and other aspects of the
rare HIES, can help categorize CIDP patients, although a
putative pathogenic role of the hyper-IgE/atopy remains unclarified. We emphasize that this neuropathy can respond to
IVIG, and suggest it is a subtype of CIDP.
T-48. Atorvastatin Protects Spinal Motor Neuron
Death from Axotomy Induced Neuronal Death
Yasuo Iwasaki, Ken Ikeda, Osamu Kano, Kiyokazu Kawabe,
and Kiyoko Murata; Tokyo, Japan
In the recent years, several studies have demonstrated that
statins, in addition to their lipid-lowering effects, have neuroprotective properties. These properties of statins have suggested they have beneficial effects in neurological disorders.
To examine the neuroprotective effect of atorvastatin in vivo,
we examined the ability of atorvastation on axotomized spinal motor neuron death in the rat spinal cord. After the
postnatal unilateral section of sciatic nerve, there was approximately a 50% survival of motor neurons in the fourth lumbar segment. In comparison with vehicle, intraperitoneal injection of atorvastation for 14 dayas rescued spinal motor
neurons. There was no significant relationship between rescue of spinal motor neuron numbers and dose of atorvastation. Our results indicated that atorvastatin plays an important role in the survival and maintenance of spinal motor
neurons in their neuroprotection against axotomy induced
neuronal death. This finding indicates a potential therapeutic
use of atorvastation in treating neuronal death that kill the
spinal motor neurons, such as amyotrophic lateral sclerosis
and motor neuropathies.
T-49. Metabolic Proteins Are Down-Regulated in
Denervated Skeletal Muscle
Takahiro Jimi, Yoshihiro Wakayama, Yoko Matsuzaki,
Seiji Shibuya, and Hajime Hara; Yokohama, Japan
Nerve supply is very important in maintaining the function
of skeletal muscle. To study the effects of denervation on
skeletal muscle, we made experimentally denervated rat muscles by removal of unilateral sciatic nerves. Then we excised
denervated and ipsilateral innervated skeletal muscles. We extracted the RNA and isolated differentially down-regulated
genes from the denervated skeletal muscle by using readymade DNA microbead analysis (130th ANA meeting, San
Diego, 2005). Using the differentially down-regulated genes
from denervated skeletal muscle, we made a DNA chip and
carried out semi-quantitative analysis. Then, cDNA from
both normally innervated and denervated skeletal muscle was
labeled with cy3 and cy5, respectively, and was applied to
the DNA chip. Signals of fluorescence were measured, and
signal ratios of the denervated muscle to normal muscle were
calculated. Low signal ratios were shown in phosphoglycerate
mutase, protein kinase inhibitor, and glycerol-3-phosphate
dehydrogenase. Most of these proteins were metabolic en-
Program and Abstracts, American Neurological Association
zymes or proteins relating to normal metabolic processes. We
concluded that denervation causes disturbance of the metabolic processes in skeletal muscle and down-regulates metabolic proteins, which induces muscle weakness and atrophy.
Study supported by Grant-in-Aid for Scientific Research (C2-14570619) from Ministry of Education, Culture, Sports,
Sciences, and Technology, Japan.
T-50. Anti-Ganglioside Complex Antibodies in Miller
Fisher Syndrome and Guillain-Barré Syndrome with
Ken-ichi Kaida, Mami Kanzaki, Masami Sada,
Kazuo Motoyoshi, Keiko Kamakura, and Susumu Kusunoki;
Tokorozawa, Saitama, Japan; and
Osaka-Sayama, Osaka, Japan
Some patients with Miller Fisher syndrome (MFS) have antibodies to ganglioside complexes (GSCs) containing GQ1b
or GT1a, and anti-GQ1b antibody is associated with ophthalmoplegia in Guillain-Barré syndrome (GBS). To determine clinical significance of antibodies to GSCs containing
GQ1b or GT1a, we investigated such anti-GSC antibodies
and clinical features in 64 patients MFS, 53 GBS with ophthalmoplegia (GBS-OP(⫹)), and 53 GBS without ophthalmoplegia (GBS-OP(-)). Thirty patients with MFS, 25 with
GBS-OP(⫹) and none with GBS-OP(-) had the antibodies
to GSCs containing GQ1b or GT1a. MFS-associated antibodies were subdivided into three groups: reactive specifically
to GQ1b or GT1a (group 1), to a total of two sialic acids in
terminal residues in GSCs such as GQ1b/GM1 (group 2),
and to a total of three sialic acids in GSCs such as GQ1b/
GD1a (group 3). Sensory disturbances were significantly infrequent in group 2 patients with MFS (p ⬍ 0.001). IgG
antibodies to GSCs containing GQ1b or GT1a were closely
associated with development of MFS and ophthalmoplegia in
GBS. The number of sialic acids in the terminal residues of
the gangliosides may be important for the affinity of each
anti-GSC antibody.
T-51. Connexin32 Mutations with CNS Phenotype
Impair the Expression of Connexin47
Kleopas A. Kleopa, Jennifer L. Orthmann-Murphy,
Xenia Alevra, Irene Sargiannidou, and Steven S. Scherer;
Nicosia, Cyprus; and Philadelphia, PA
X-linked Charcot-Marie-Tooth disease (CMTX) is an inherited peripheral neuropathy caused by mutations affecting the
gap junction (GJ) protein connexin32 (Cx32). Several Cx32
mutations also cause transient or chronic CNS phenotypes
and white matter lesions. Since Cx32 is expressed by
Schwann cells and oligodendrocytes we examined whether
trans-dominant interactions between mutant Cx32 and
Cx47, another major oligodendrocytic GJ protein, may account for the CNS phenotypes in CMTX. In postmortem
human brain, Cx47 was expressed in cortical and subcortical
oligodendrocytes forming GJ plaques at the cell bodies and
proximal processes. Oligodendrocytes in the subcortical
white matter co-expressed Cx32 in the surrounding large
myelinated fibers. Cx47 and wild type Cx32 expressed in
transfected HeLa cells formed functional GJs whereas Cx32
mutants were retained intracellularly, in the endoplasmic reticulum or in the Golgi. Coexpressing Cx32 mutants with
CNS manifestations with Cx47 resulted in reduction or loss
of Cx47 positive GJs at the cell membrane and caused retention of Cx47 intracellularly colocalizing with Cx32 immunoreactivity. Thus, the CNS manifestations of certain
Annals of Neurology
Vol 62 (suppl 11)
Cx32 mutations may arise from trans-dominant negative effects on Cx47 in oligodendrocytes. Study supported by National Multiple Sclerosis Society (Grant RG3457A2/1 to
KAK) and the NIH (RO1 NS43560 and NS42878 to SSS).
T-52. Gene Expression of AIF1 and XLKD1/LVYE-1
in Chronic Inflammatory Demyelinating
Polyneuropathy (CIDP) Skin Biopsies
Grace Lee, Russell L. Chin, Thomas H. Brannagan,
Howard W. Sander, and Norman Latov; New York, NY
Gene expression analysis previously identified molecular
markers that are upregulated in CIDP sural nerves. Using
quantitative real-time PCR (RT-PCR), we analyzed the expression of some of the same markers in forearm skin. Samples from patients with CIDP, obtained by punch biopsy,
were compared to those from Charcot Marie Tooth (CMT)
disease, diabetic neuropathy, or normal controls. Two genes,
AIF1 and XLKD1/LVYE-1, both involved in inflammatory
processes, were most consistently elevated in CIDP relative
to the other groups. Expression of both was significantly increased in the CIDP group as compared to CMT (p ⬍
0.05). AIF1 was increased over normal controls in 5 of 6
CIDPs (2.0 – 7.7 fold), compared to 1 of 7 CMTs. Similarly, XLDK1/LVYE-1 was elevated in the same 5 of 6 CIDPs (2.5 – 2.9 fold) but in none of the CMTs or 5 diabetic
neuropathy samples examined. These preliminary results suggest that determination of expression of AIF1 and XLKD1/
LVYE-1 in punch skin biopsies might help distinguish patients with CIDP from those with non-inflammatory
neuropathies. Study supported by Talecris Biotherapeutics,
T-53. Rapid Removal of Nodal Nav during
Mechanically Induced CB
Yunhong Bai, and Jun Li; Detroit, MI
Conduction block (CB) results in focal neurological deficits
and its molecular basis is not well understood. We mechanically induced CB by compressing rat sciatic nerves, which
showed nodal invagination, reminiscent of what were described by Gilliatt et al. The CB recovered by 92% within
18 hours, whereas nodal invagination is irreversible for
weeks. Thus, this rapid recovery is incompatible with nodal
invagination as a major cause of CB. We next quantitatively
examined the molecular architecture of compressed myelinated nerve fibers by immunohistochemistry. The paranodal
protein Caspr and Kv1.2 were unchanged. In contrast, nodes
with positive Nav were significantly reduced in both the
compressed nerve segments (23.8⫾4.9 Nav/␮m2; p⬍0.05)
and in the nerve segment immediately distal to the compression site (16.9⫾5.9 Nav/␮m2; p⬍0.01), comparing to that
in nerve segments proximal to the compression (34.7⫾8.1
Nav/␮m2). Because Nav are necessary to propagate AP, reduced nodal Nav would contribute to cause CB. Our results
suggest that in addition to the classical gaiting mechanism by
dynamic opening and closing ion channels, axonal excitability may be regulated by a novel molecular mechanism, rapid
removal of nodal Nav which may also have implication in
many demyelinating diseases. Study supported by NINDS
K08 NS048204.
T-54. Double-Blind, Placebo Controlled Safety Study
of Ritonavir and Hydroxyurea in Patients with ALS
Catherine Lomen-Hoerth, Sean Scott, Jeyanthi Ramasubbu,
Fernando Vieira, and Richard K. Olney; San Francisco, CA;
and Boston, MA
To date riluzole is the only FDA drug approved to treat
ALS. Hydroxyurea halts cell cycle transition via ribonucleotide reductase inhibition. Ritonavir reduces the levels of the
inducible proteasome subunits, which are observed to be upregulated in ALS. Based on initial efficacy studies in G93A
SOD-1 mice, a safety trial was initiated. Patients were enrolled with ALS using El Escorial Revised Criteria with a
forced vital capacity (FVC)⬎50% and disease duration⬍5
years. Patients were randomized to low dose ritonavir at
200mg BID, high dose ritonavir at 400mg BID, Hydoxyurea
at 1000mg qd, or placebo. Patients were followed monthly
for 6 months. FVC, ALSFRS-R, manual muscle testing
(MMT) and weight were measured. After enrollment of 24
patients, an interim safety analysis was performed. Patients in
the high dose ritonavir arm compared to placebo had a 5
fold decline in FVC (p⬍0.0001), a 19 fold decline in weight
(p⬍0.0001), a 3 fold decline in MMT (p⬍0.0001), and the
decline in ALSFRS was unchanged. Study supported by ALS
therapy development foundation.
T-55. Pseudobulbar Affect Is Prevalent in a Sample of
Patients with Amyotrophic Lateral Sclerosis
Jennifer M. Murphy, Yessinia Ruiz, and
Catherine Lomen-Hoerth; San Francisco, CA
Pseudobulbar Affect (PBA) is a neurologically-based affective
disorder marked by involuntary and excessive displays of
laughing or crying. PBA prevalence rates are highest among
CVA, multiple sclerosis and Amyotrophic Lateral Sclerosis
(ALS) patients. The Center for Neurologic Study-Lability
Scale (CNS-LS), a 7-item self-report measure of PBA, is a
commonly used instrument to measure PBA, but it is limited
in scope and depth. Of 29 ALS patients enrolled from a
multidisciplinary clinic, 34% (n⫽10) had clinical levels of
PBA, as indicated by CNS-LS scores of 13 or above. Patients
with clinical PBA were administered a more in depth questionnaire developed by this lab. Patients reported more crying than laughing episodes, occurring weekly. Patients could
“almost always” identify a specific trigger for episodes, and
they had “somewhat” control over episodes once they began.
When they experienced crying, they reported feeling the actual emotion 100%, but felt less of the humor when laughing. Episodes tended to last “a few minutes” in length. There
was no statistical association between PBA and level of depression, sex, education level, age, length of illness, illness
severity, or breathing capacity. Study supported by Amyotrophic Lateral Sclerosis Association.
T-56. Genome-Wide Expression Profiling of A3243G
MELAS Patients — In Quest for Potential DiseaseModifying Target Genes
Susanne Mende, Alexander Herr, Janet Schmiedel,
Marcus Deschauer, Thomas Klopstock, Vladimir S. Kostic,
Heinz Reichmann, and Alexander Storch; Dresden, Germany;
Halle/Saale, Germany; Munich, Germany; and
Belgrade, Serbia
The heteroplasmic A3243G mtDNA mutation in the
tRNALeu(UUR) gene gives rise to one of the most frequent
mitochondriopathies, the MELAS syndrome (mitochondrial
encephalomyopathy, lactic acidosis and stroke-like episodes).
As the percentage of mutant mtDNAs did not prove to be
directly correlated to the course and phenotype of disease,
other yet unknown factors must be involved. Recent studies
indicated that eukaryotic cells are able to reconfigure their
nuclear gene expression profile to accommodate various cellular processes to the functional status of mitochondria. This
process might be a key to MELAS disease manifestation. We
used Affymetrix microarrays to analyze gene expression
changes in blood samples of ten MELAS patients compared
to controls. Acquired data were then subjected to hierarchical
clustering in order to match clinical/genetical data with expression patterns. We thereby elucidated that the abundance
of mutant mtDNA molecules influences the nuclear gene expression profile. Within this context, we identified potential
disease-modifying nuclear target genes and clarified how
their expression correlates with the patient’s profile and the
clinical outcome of the disease. In conclusion, we elucidated
first biomarkers for MELAS syndrome, thereby pioneering
towards potential therapeutic targets. Study supported by In
part by DFG-GRK 864 and the Medical Faculty of the
Technical University of Dresden.
T-57. Muscleblind-Like Protein (MBNL1) as Marker
of Molecular Pathology of the Myotonic Dystrophies
Giovanni Meola, and Rosanna Cardani;
San Donato Milanese, Milan, Italy; and Milan, Italy
Myotonic dystrophies (DMs) are dominantly inherited multisystemic disorders caused by two similar noncoding repeats
expansion. DM1 is caused by a CTG expansion in the 3’
untranslated region of the DMPK gene, whereas DM2 is
caused by a CCTG expansion in intron 1 of the ZNF9 gene.
The immunohistochemical staining of fast or slow myosin
has shown very small type 2 fibers (diameter ⱕ 20 ␮m) in
DM2 muscle not discernible with ATPase histochemical
staining. The molecular pathogenesis of DMs is the nuclear
accumulation of mutant mRNA containing CUG/CCUG repeats as ribonuclear inclusions (RIs). In a study on 17 DM2
patients we have demonstrated that a biomolecular diagnosis
between DM1 and DM2 can be performed by FISH on
muscle sections using the specific (CAGG)5 probe which reveals the presence of RIs in DM2 but not in DM1 patients.
RIs interact with specific RNA-binding proteins, such as
MBNL1, that regulate alternative splicing. An immunofluorescence study from 7 DM1 and 8 DM2 muscle biopsies has
revealed the presence of nuclear accumulations of MBNL1 as
protein foci which colocalize precisely with RIs. MBNL1
could represent an histopathological marker of the DMs.
T-58. Differential Regulation of TGF␤ Is Associated
with Diabetic Neuropathy
Anjaneyulu Muragundla, Alison Berent-Spillson,
Tatsuya Inoue, and James W. Russell; Baltimore, MD; and
Ann Arbor, MI
The mechanism/s leading to diabetic neuropathy are complex. In this study, the role of TGF-␤ in its various isoforms
was examined in diabetic peripheral neuropathy. Diabetes
was induced with streptozotocin (STZ). After diabetic neuropathy was confirmed at an early time point (4 weeks,
n⫽10/group) and a later time point (12 weeks, n⫽8/group),
TGF-␤ gene isoforms (TGF-␤1, -␤2 & - ␤3) were measured
in both dorsal root ganglia (DRG) and sciatic nerve using
quantitative real-time PCR. In diabetic DRG, TGF-␤1 and
TGF-␤2 mRNA, but not TGF-␤3, was increased at 4 and
Program and Abstracts, American Neurological Association
12 weeks. In sciatic nerve, only TGF-␤3 was increased in
STZ rats. Similar results were found using TGF-␤ immunohistochemistry. In vitro, TGF-␤ is increased in western blots
of DRG treated with added glucose, cellular injury is increased 6 fold when glucose and TGF-␤2 are combined, and
TGF-␤ neutralizing antibody inhibits cellular injury.
TGF-␤2 and -␤3 most severely reduce neurite outgrowth in
vitro. These findings indicate a novel mechanism of cellular
injury in diabetic neuropathy, implicate injury by different
isoforms in peripheral nerve cells, and suggest a possible new
target for treatment of diabetic peripheral neuropathy. Study
supported in part by NIH NS42056, The Juvenile Diabetes
Research Foundation Center for the Study of Complications
in Diabetes (JDRF), Office of Research Development (Medical Research Service), Department of Veterans Affairs.
T-59. Analysis of Alpha-Enolase Expression in Muscle
from Patients with Inflammatory Myopathy
Ken-ya Murata, Ai Suzuki, Tameko Kihira, Hideto Miwa,
Makoto Matsui, and Tomoyoshi Kondo; Wakayama, Japan;
and Uchinada, Ishikawa, Japan
We examined the expression of alpha-enolase (ENO-1) in
muscles of patients with polymyositis (PM) and dermatomyositis (DM). Muscle specimens were obtained from 10 patients with PM, 4 patients with PM associated with Hashimoto thyroiditis (PM-Hashimoto), 10 patients with DM, 10
patients with ALS and 5 normal controls. Serial frozen sections were examined by immunocytochemistry using antibodies against ENO-1, neural cell adhesion molecule
(NCAM) and myosin-heavy chain developmental (MHC-d).
ENO-1 expression in Type II muscle fibers in patients with
ALS and normal controls was very weak. Atrophic round
muscle fibers from inflammatory myopathy showed strong
immunoreactivity for ENO-1 at the cell surface and in the
cytoplasm. ENO-1-expressing muscle fibers were mainly located in the area of lymphocyte infiltration, and some muscle
fibers were NCAM- and/or MHC-d-positive. ENO-1 positive muscle fibers were more prominent in PM and PMHashimoto than DM. ENO-1 constitutes receptors for plasminogen, and localization of plasmin activity on the cell
surface plays a critical role in extracellular matrix remodeling.
Since myoblasts express ENO-1 during the fusion process in
vitro, we conclude that the plasminogen activating system is
important in muscle fiber regeneration with lymphocyte accumulation in inflammatory myopathies.
T-60. The Role of Autophagy in Pathogenesis of
Pompe Disease
Nina Raben, Moris J. Danon, Shoichi Takikita,
Evelyn Ralston, and Paul H. Plotz; Bethesda, MD; and
New York, NY
Autophagy, a major pathway for delivery of proteins and organelles to lysosomes, has been implicated in various diseases,
including Pompe disease, a glycogen storage disorder caused
by deficiency of lysosomal acid alpha-glucosidase. The enzyme deficiency results in expansion of glycogen-filled lysosomes in multiple tissues, with cardiac and skeletal muscle
being the most severely affected clinically. We have demonstrated a failure of productive autophagy in skeletal muscle of
a knockout mouse model of the disease. Massive autophagic
buildup, rather than the buildup of lysosomal glycogen, appears to cause muscle destruction. Furthermore, excessive autophagic accumulation in muscle fibers is associated with
their resistance to enzyme replacement therapy. A profound
Annals of Neurology
Vol 62 (suppl 11)
abnormality in the autophagic pathway - the presumed route
of glycogen delivery to lysosomes - also occurs in skeletal
muscle in humans with the disease, which can no longer be
viewed as simply a lysosomal storage disorder. In patients, as
in the mouse model, the enormous autophagic buildup
causes greater skeletal muscle damage than the enlarged lysosomes outside the autophagic regions. These data point to
a central role of autophagic failure in the pathophysiology of
the disease, and to the need for autophagy-targeted therapy.
T-61. Development of Adenocarcinoma in Stiff Person
Syndrome (SPS) Patients with Anti-GAD Antibodies:
Report of 2 Cases with SPS-Specific Antigens in Their
Goran Rakocevic, Cristina Semino-Mora, and
Marinos C. Dalakas; Bethesda, MD
We describe two SPS patients with high anti-GAD antibodies
who developed cancer after mean period of 9 years (6 – 12).
One patient, a 42 year-old woman, developed breast adenocarcinoma, and the other, a 47year-old woman, lung adenocarcinoma. To investigate presence of cross-reacting antibodies
to antigens shared by GAD and tumors, we applied patients’
sera to paraffin tumor sections and searched for presence of
GAD and amphiphysin antigens in double immunohistochemistry experiments. As controls we used sera from 2 SPS
patients without cancers and 4 healthy persons. Tumors contained both GAD and amphiphysin antigens that cross-reacted
with patients’ own sera; SPS sera from patients without cancer
recognized only GAD but not amphiphysin. Staining for amphiphysin was epitope-specific because it was recognized only
by the patients’ own serum. SPS symptoms of patient with
lung cancer improved after tumor treatment; the other patient
died before cancer therapy. Clinical manifestations of SPS can
rarely precede development of adenocarcinoma. In these patients, adenocarcinomas contain GAD and amphiphysin antigens which may trigger SPS by cross-reacting with neuronal
antigens in a phenomenon of molecular mimicry.
T-62. Metabotropic Glutamate Receptor Agonists
Prevent Early Neuropathy in Diabetic Animals
Anjaneyulu Muragundla, Alison Berent-Spillson, and
James W. Russell; Baltimore, MD; and Ann Arbor, MI
Group II metabotropic glutamate receptor agonists have
been implicated in neuronal protection. The selective
mGluR2/3) agonist, LY379268 was evaluated in animals
with diabetic neuropathy. Diabetes was induced with STZ
and an 8 week primary medication intervention study was
performed. The experimental groups (n⫽8 per group) were
(1) non-diabetic controls (2) diabetic (3) diabetic treated
with LY 379268 (3 mg/kg/day) (4) diabetic treated with LY
379268 (10 mg/kg/day) (5) control rats treated with LY
379268 (10 mg/kg/day). LY379268 maintained normal sensory thresholds in diabetic animals measured with dynamic
Von-Frey testing (p⬍0.01), normal nerve conduction studies
(p⬍0.05), and skin intraepidermal nerve fiber density
(p⬍0.05). mGluR2/3 did not significantly alter glucose or
glycosylated hemoglobin levels in diabetic animals. In tissue
culture with high glucose conditions, mGluR2/3 agonists
stabilize the inner mitochondrial membrane and prevent reactive oxygen species accumulation, and increase glutathione
concentration in neurons co-cultured with Schwann cells.
Overall, these findings indicate that mGluR2/3 agonists
show promise in the treatment of early diabetic neuropathy
and that activating glial mGluR3 protects from glucose-
induced oxidative injury by increasing free radical scavenging
and stabilizing mitochondrial function, through increased
glutathione antioxidant defense. Study supported in part by
NIH NS42056, The Juvenile Diabetes Research Foundation
Center for the Study of Complications in Diabetes (JDRF),
Office of Research Development (Medical Research Service),
Department of Veterans Affairs.
T-63. Experimental Diabetic Autonomic Neuropathy
Herbert Schaumburg, Elena Zotova, Cedric Raine,
Barbara Cannella, Joseph Arezzo, Moses Tar, and
Arnold Melman; Bronx, NY; Bronx; and Bronx
The present study explored the pathophysiology of sympathetic/parasympathetic fibers of cavernous nerves (CN) of
streptozotocin (STZ)-diabetic rats with erectile failure. Electrophysiology and ultrastructure were performed in CN and
in the dorsal nerve of the penis (DNP) (Schaumburg et al,
2007). Nerve conduction velocities in unmyelinated CN fibers ranged from 1-2.5 m/sec; up to 50 m/sec in DNP. In
STZ rats, initial slowing was detected in both CN and
DNP after 2 months of hyperglycemia, progressing with a
mean slowing of greater than 20% in both nerves by
month 4, and virtually absent responses in CN by month
7. Ultrastructure disclosed dystrophic changes in unmyelinated fibers only. No consistent changes were present in
CN proximal to the crus or distally at earlier timepoints.
Main pelvic ganglia and DNP did not differ from agematched controls in either nNOS activity or upon ultrastructural examination. Two cardinal conclusions emerge:
1) the CN is a valid instrument for study of unmyelinated
axons in autonomic neuropathies, and 2) electrophysiology
provides the most sensitive measure of autonomic neuropathy. Study supported by NIDDKD P01-DK060037;
NINDS NS041194, NS11920 and NS08952.
T-64. Thymectomy for Myasthenia Gravis
H. Christian Schumacher, Holly Graves, Brian T. Bateman,
Jan Claassen, Joshua Z. Willey, and Olajide Williams;
New York, NY; and Boston, MA
Objective: To compare inhospital morbidity/mortality in patients (pts.) with myasthenia gravis (MG) and controls who
underwent thymectomy in order to identify perioperative
risks unique to MG.
Methods: We utilized the Nationwide Inpatient Sample for
the years 1988 to 2004 for patients ageⱖ18 years who had
undergone thymectomy. In-hospital morbidity/mortality in
MG (n⫽2,976) was compared to controls (n⫽4,847). Binary logistic regression analysis adjusted for age, gender, race,
and Charlson comorbidity index was used to determine
whether MG was associated with increased risk for predefined outcome events.
Results: MG pts. had increased risk for respiratory failure
(OR⫽3.84, CI⫽3.03 – 4.86), aspiration pneumonia
(OR⫽3.50, CI⫽1.80 – 6.78), ARDS (OR⫽2.22, CI⫽1.61
– 3.06), and atelectasis (OR⫽1.35, CI⫽1.14 – 1.59) but
similar risk for bacterial pneumonia, pneumothorax, pulmonary edema and non-pulmonary complications compared to
controls. MG pts. had lower inhospital mortality (0.5% vs
1.1%, p⫽0.006), longer length of hospital stay (8.14⫾12.3
vs 6.2⫾7.4 days, p⬍0.001) and higher hospital charges in
US$ (29,919⫾47,292 vs. 27,929⫾47,292, p⫽0.012) compared to controls.
Conclusions/Relevance: Thymectomy in MG is associated
with a higher risk for pulmonary complications related to
neuromuscular weakness compared to controls. Prospective
studies need to confirm these findings and to determine
whether specific interventions tailored to the MG population
might reduce these complications. Study supported by NIH
training grant PHS 5-T32- NS007155-26 (HCS).
T-65. Advantages of Automated Serious Adverse
Events Management (SAEM) in Multi-Site Clinical
Trials in ALS
Alexander V. Sherman, April F. Opoliner, Hong Yu,
Mabel Chan, Patricia L. Andres, and Merit E. Cudkowicz;
Charlestown, MA; and Brookline, MA
Background: MGH’s Neurology Clinical Trials Unit, serving as Coordination Center for multi-site clinical trials in
ALS, uses both paper-based reporting (PBR) and automated
computer-based reporting (ACBR) of SAEs. SAEM is a crucial aspect of clinical trials that ensures subjects’ safety.
Methods and Results: Comparison of two ALS studies demonstrates the advantages of ACBR over PBR. ACBR provides
quicker SAE finalization, SAE standardization and transparency, and fewer follow-up reports due to following features:
–Identifying life-cycle stages for SAE reports (SAER)
– Defining user roles involved in SAEM process and what
actions each role may perform[– Recognizing ALS-specific
– Improving communications with automated e-mail notification
– Limiting interactions with SAER based on its status and
user role
– Changing the paradigm of PBR’s linear flow into SAERcentric process allowing simultaneous user roles-specific actions (reviewing, signing, requesting information)
– Eliminating potential confusion stemming from illegibility
of study personnel’s handwriting
– Providing audit trails including users, times and actions
– Requiring electronic signatures compliant with federal
– Grouping initial and follow-up reports based on underlying SAE
– Generating real-time study summary reports.
Conclusion: Automating SAEM streamlines processes, improves subjects’ safety and simplifies ALS trials coordination. Study supported by National Institute of Neuromuscular Disorders and Stroke.
T-66. Peripheral Blood Mononuclear Cell (PBMC)
Cytokine Expression in Diabetic Polyneuropathy
Jayashri Srinivasan, Stephanie Scala, Sarada Sivaraman, and
Gyorgy Abel; Burlington, MA
Background: Inflammation may be important in the development of diabetic microvascular complications. We evaluated basal cytokine expression in PBMC and plasma RAGE
levels in diabetic polyneuropathy (DNP).
Methods: Three groups were studied: 14 diabetic patients
without neuropathy (DM); 16 patients with diabetic polyneuropathy (DNP); 10 healthy subjects (HC). PBMC were
harvested, RNA extracted and basal expression of TNF-␣,
IL-1␤, IL-6, and IL-10 quantified. Plasma soluble RAGE
was also measured. Groups were compared using a nonparametric Kruskal-Wallis or for multiple comparisons Bonferroni tests.
Results: There were significant differences in IL-1␤ and
TNF-␣ expression among the 3 groups (P⫽0.02 and 0.03,
respectively). IL-1␤ expression (median; range, in attomoles)
Program and Abstracts, American Neurological Association
was lowest among DNP (5.3; 4.6 – 8.5) compared to DM
(6.3; 4.9 – 14.1) and HC (6.0; 4.5 – 74.8) (P⫽0.007 and
0.06 respectively). Pairwise comparisons showed that TNF-␣
expression was lowest among DNP (2.7; 2.3 – 6.2) compared to DM (2.8; 2.5 – 4.0) (P⫽0.01) or HC (3.1; 2.5 –
9.0). There were no significant differences in IL-6 or IL-10
expression or plasma RAGE.
Conclusion: Basal PBMC expression of Th-1 cytokines,
IL-1␤ and TNF-␣ is low in DNP. This may reflect greater
impairment of host-defense mechanisms, which may play a
role in the pathogenesis of DNP. Study supported by Robert
Wise Foundation Grant.
T-67. A Mutation Linked to Hypokalemic Periodic
Paralysis Causes an Aberrant Transmembrane Proton
Arie F. Struyk, and Stephen C. Cannon; Dallas, TX
Hypokalemic periodic paralysis (HypoPP) is caused by mutations in the voltage-sensing domains (VSDs) of skeletal
muscle Ca2⫹ (CaV1.1) or Na⫹ (NaV1.4) channels. The
functional impairments in channel gating resulting from
these mutations are insufficient to explain the sarcolemmal
depolarization during HypoPP attacks. We found that the
NaV1.4 mutation R669H causes a structural defect in the
VSD, exposing a separate ionic conduction pathway
(“gating-pore”), distinct from the central Na⫹-conducting
pore. The R669H gating-pore allows protons to cross the
membrane but not other physiologically abundant ions.
Muscle expressing the NaV1.4-R669H mutant is thus subject to a sustained, inwardly-directed proton flow. This proton current is likely to be too small to cause the massive
sarcolemmal depolarization underlying a paralytic attack.
However, it is sufficiently large to potentiate the “paradoxical” membrane depolarization muscle fibers undergo when
extracellular K⫹ is reduced, possibly explaining a characteristic feature of HypoPP. Alternatively, myoplasmic proton
accumulation may indirectly impair mechanisms maintaining
the resting potential. The speculation that gating-pore conductances might be a shared consequence of all HypoPP mutations offers a plausible explanation for how mutations in
different channels might converge on a common phenotype.
Study supported by Muscular Dystrophy Association
T-68. Analyses of Unique Auophagic Vacuoles and
Autophagic/Lysosomal Pathway in GeneticallyConfirmed Danon Disease
Kazuma Sugie, Satoru Noguchi, Satoshi Ueno, Ikuya Nonaka,
and Ichizo Nishino; Nara, Japan; and Tokyo, Japan
Danon disease (DD) is a rare cardiomyopathy and myopathy
with X-linked dominant inheritance, caused by primary
lysosome-associated membrane protein-2 (LAMP-2) deficiency. DD is pathologically characterized by unusual autophagic vacuoles with sarcolemmal features (AVSF). To gain
insights into the pathomechanism that remains unestablished, we studied pathologically about the autophagic vacuoles and autophagic pathway in skeletal muscle on DD patients. Unique autophagic vacuoles consisted of clusters of
autolysosomes by electron microscopy. Some autolysosomes
were surrounded by membranes with sarcolemmal proteins.
In muscle fibers, there were absence of LAMP-2 and accumulations of LAMP-1, lysosomal integral membrane
protein-1 (LIMP-1), and LIMP-2. The vacuolated fibers
contained deposits immunoreactive for endosomal proteins:
Annals of Neurology
Vol 62 (suppl 11)
Rab5, transferring receptor, and LDL receptor. Another endosomal protein: VAMP-7 was increased in nonvacuolated
fibers without autolysosomal accumulations, suggesting that
maturations to late endosomes could prevent the formation
of the unique vacuolar membranes. These results indicated
that in addition to autophagic/lysosomal pathway, endosomal pathway was also activated. Therefore, we considered
that these both pathways may be associated with the degenerative process of muscle fibers in DD.
T-69. Early Administration of HDAC Inhibition
Prolongs Survival of SMA Mice
Heather L. Narver, Barrington G. Burnett, Dong W. Choe,
Kenneth H. Fischbeck, and Charlotte J. Sumner;
Bethesda, MD; and Baltimore, MD
We have previously shown that post-symptomatic delivery of
the histone deacetylase inhibitor, trichostatin A (TSA), to
SMA mice extends survival by 19%. Now we have found
that earlier intervention is more efficacious. The median extension of survival when drug was delivered at P1 or P2 until
P20 was 40%; however, 2 of 28 treated mice showed a
marked extension of survival of 300% and 430%. After
weaning, these mice had relatively stable motor function, but
developed progressive necrosis of the tail, ears, and feet that
contributed to their ultimate decline. TSA combined with
nutritional support more reproducibly caused a marked extension of survival as well as enhanced weight gain and improved motor function. Pathological studies at different ages
indicated that there is widespread hypotrophy of muscle fibers that predates denervation at the neuromuscular junction
and biochemical analysis of SMA muscle showed an immature pattern of myosin heavy chain expression that is improved after TSA treatment. These studies suggest that there
is an abnormality of maturation of muscle in SMA and that
therapy delivered during a critical developmental window
can result in a prolonged amelioration of the SMA disease
T-70. Effects of Hyperbaric Oxygen on Levels of
Tissue Citrate Synthase and Mitochondrial Enzyme
Complex Activities
Turgut Topal, Emin Ozgur Akgul, Bulent Kurt,
Yasemin Kurt, and Ahmet Korkmaz; Ankara, Turkey
Hyperbaric Oxygen (HBO) is a treatment modality by
breathing 100% oxygen at higher than atmospheric pressure.
In several pathologic circumstances, there is evidence showing increased tissue ATP level when HBO administered. Today, several papers regarding HBO may be beneficial in
mithochondrial disorders have been published. However, the
mechanisms how HBO increases tissue ATP levels are unknown. In this work, effects of HBO on tissue citrate synthase and mitochondrial complex activities were investigated.
Sixteen Sprague-Dawley rats were separated into two groups
each of 8 animals as control and HBO group. Before HBO
administration, biopsies were taken from right vastus lateralis
muscle and from left vastus lateralis muscle of rats at the end
of the study. Tissue citrate synthase and mitochondrial complex activities were measured in biopsy specimens. All measured parameters in HBO group were found to be increased
as compared with control measurements. This increment was
statistically significant (p⬍0.05). Supporting tissue ATP levels by HBO may be mediated by increasing tissue mitochondria load and mitochondrial complex activities. Study sup-
ported by Gulhane Military Medical Academy, Research
sarcoglycan and finally sarcospan at the FCMD myofiber
T-71. A Risk-Index for the Clinical Assessment of
Post-Polio Syndrome
Olavo M. Vasconcelos, Olga H. Prokhorenko, Cara H. Olsen,
Lauro S. Halstead, Bahman Jabbari, and
William W. Campbell; Bethesda, MD; and Washington, DC
T-73. Glutamate Receptor Activation on Motor
Neurons (MN) Contributes to Astrocytic Glutamate
Transporter Loss in SOD1 Mutant Rats
John H. Weiss, and Hong Z. Yin; Irvine, CA
Reported risk factors for post-polio syndrome (PPS) are hospitalization during polio, involvement of ⱖ5 muscles, polio
as an adult, elapsed time to diagnosis of polio, permanent
impairment, and increase in weight or activity. Here we examined the predictive value of PPS risk factors. Using published criteria for the diagnosis of PPS we classified survivors
as definite PPS (n⫽20), probable PPS (n⫽20), or possible
PPS/SP (stable polio, n⫽20). Cross tabulations were used to
examine relationships between diagnostic categories and predictors. Sixty patients were studied (men: 31, mean: 62.8
years). Definite and probable PPS were statistically associated
with ⱖ5 muscles involved, permanent impairment, and polio at adult age, only. After combining predictors into a composite index a significant association was found between
higher index values and categories of definite and probable
PPS (Spearman rank correlation of 0.421, p ⫽ 0.001). Also,
the index performed better than chance for distinguishing
between definite PPS and probable or possible PPS/SP
(AUC ⫽ 0.682, 95% CI ⫽ 0.544 – 0.820), and between
definite/probable PPS and possible PPS/SP (AUC ⫽ 0.739,
95% CI ⫽ 0.607 – 0.871). The PPS risk-index may be a
helpful tool for the assessment of aging polio survivors.
Study supported by Department of Defense (Health Affairs,
Grant MDA 905-01-007).
The cause of astrocytic glutamate transport dsyfunction in
ALS is unexplained. Our recent culture studies support an
hypothesis that ROS, produced within MNs in response to
activation of Ca2⫹ permeable AMPA (Ca-A/K) channels,
can exit MNs and disrupt glutamate transport in surrounding astrocytes. We now use mutant SOD1 (G93A) rat
models of ALS to examine effects of a Ca-A/K channel
blocker (naphthylacetylspermine, NAS) on development of
pathology. NAS or saline was infused intrathecally for 30
days to late presymptomatic stage animals, followed by
pathological examination. With saline infusion, there was
substantial MN damage, marked loss of the astrocytic glutamate transporter, GLT-1, in ventral horn, and increased
labeling for nitrotyrosine, often evident surrounding MNs.
NAS infusion markedly diminished the loss of both MNs
and of GLT-1. Loss of astrocytic glutamate transporter
likely contributes to excitotoxic MN damage in ALS.
Present findings support the converse, that MN glutamate
receptor activation contributes to transporter loss. These reciprocal interactions could provide the foundation for a
feed forward mechanism which may be integral to MN degeneration in ALS. Study supported by NIH (R01
NS36548). Muscular Dystrophy Association.
T-72. Altered Sarcoglycan-Sarcospan Expression in
Muscles of Fukuyama Congenital Muscular Dystrophy
Yoshihiro Wakayama, Masahiko Inoue, Hiroko Kojima,
Sumimasa Yamashita, Yoko Matsuzaki, Seiji Shibuya,
Takahiro Jimi, Hajime Hara, and Hiroaki Oniki;
Yokohama, Kanagawa, Japan
T-74. Functional Assessment of Rat Forelimb Function
Following Nerve Injury
Huan Wang, Eric J. Sorenson, Godard de Ruiter,
Robert J. Spinner, and Anthony J. Windebank;
Rochester, MN
The expression of dystroglycan, sarcoglycan-sarcospan complex in muscles of Fukuyama congenital muscular dystrophy (FCMD) was examined immunohistochemically, and
the content of sarcospan mRNA in FCMD and normal
muscles was estimated by real time RT-PCR. We studied 5
FCMD, 5 disease control (3 myotonic and 2 facioscapulohumeral dystrophies) and 5 normal control muscles. The
indirect immunofluorescent staining was done with the antibodies of anti ␣-dystroglycan, dystrophin, ␤-spectrin, ␣-,
␤-, ␥-, ␦-sarcoglycan and sarcospan antibodies. The immunohistochemical studies of FCMD muscles showed the
markedly reduced expression of ␣-dystroglycan, ␣-, ␤-, ␥-,
␦-sarcoglycan and sarcospan at the myofiber surfaces; while
the expression of dystrophin and ␤-spectrin was nearly normal. Those of disease control muscles revealed almost the
same expression patterns as those of normal control muscles. The group mean ratio of sarcospan mRNA copy number versus G3PDH mRNA copy number was 1.86⫾2.27 in
FCMD muscles in comparison with 1.62⫾0.79 in normal
control muscles (P⬎0.1). Thus, the results of present studies implied that the markedly reduced expression of
␣-dystroglycan due to impaired glycosylation in FCMD
muscles may, in turn, lead to the decreased expression of
Our aim was to develop reproducible evaluation methods
for forelimb nerve injury models. Six rats per group underwent median, ulnar, radial, or combined median and ulnar
nerve transection. Measurements included compound muscle action potential (CMAP), somatosensory evoked potential (SEP) and grip strength. Gait was analyzed using video
recording of wrist and metacarpophalangeal (MP) joint
movement and toe spread. All measurements were conducted preoperatively and 1, 3, 4, 6, 8 10, 12 and 16 weeks
postoperatively and compared with sham and non-operated
controls. CMAPs were reproducibly measured after proximal stimulation with needle electrodes in the fore-paw.
Grip strength was not impaired by radial nerve injury.
Combined median and ulnar nerve injury led to the largest
reduction in grip strength which didn’t recover until 12
weeks postoperatively. Motion analysis quantified changes
in wrist and MP joint extension following all types of nerve
injury. Decreased toe spread was only observed after combined median and ulnar nerve or after radial nerve injury.
Nerve injuries of the upper limb in rats can be reliably
evaluated by combining electrophysiology, behavioral tests
and motion analysis. Selection of the most appropriate test
depends on the type of nerve injury. Study supported by
Program and Abstracts, American Neurological Association
T-75. Evaluation of the Accuracy of Motor Axon
Regeneration after Sciatic Nerve Injury
Godard C. W. de Ruiter, Martijn J. S. Malessy,
Robert J. Spinner, Awad Alaid, JaNean K. Engelstad,
Eric J. Sorenson, Kenton R. Kaufman, Peter J. Dyck, and
Anthony J. Windebank; Rochester, MN; and
Leiden, Netherlands
Misrouting of regenerating axons contributes to poor results
after nerve repair. We investigated regeneration after crush
injury, direct suture, and autograft of rat sciatic nerve using
sequential retrograde tracing of peroneal motoneurons before
and 8 weeks after nerve injury. Ankle angle measurements
were used to investigate the impact of misrouting on recovery of ankle plantar and dorsiflexion. Compound muscle action potentials were recorded biweekly, as well as nerve and
muscle morphometry at 8 weeks. Eight weeks after injury
71.4% (⫾ 4.9%), 42.0% (⫾ 4.2%) and 25.1% (⫾ 6.6%) of
peroneal motoneurons were correctly routed after crush, direct repair and autograft respectively. Functional recovery after all injuries was incomplete as a result of the disturbed
balance between ankle plantar and dorsiflexion. Reinnervation was faster after sciatic crush than after direct coaptation
or autograft repair. Mean muscle fiber size was larger after
crush injury. Number of regenerated motoneurons after all
types of repair was not significantly different from normal,
but the number of myelinated axons was significantly increased distal to the site of injury. We found that accuracy of
regeneration after different types of nerve repair was limited.
Study supported by NIH.
T-76. Treatment of Spinal and Bulbar Muscular
Atrophy with Leuprorelin Acetate
Tomotaka Yamamoto, Hiroshi Ohtsu, and Shoji Tsuji;
Tokyo, Japan
Design: open-label, single-center, prospective.
Method: Ten patients exhibiting clinical symptoms of spinal
and bulbar muscular atrophy confirmed by molecular diagnosis were injected with sustained-release leuprorelin acetate
once a month (3.75 mg) or once every three months
(11.25mg), and followed for two years. Chlormadinone acetate was coadministered to prevent the initial testosterone
(TST) surge. The strengths of isokinetic-/isometric-knee extension were measured by CYBEX NORM®. The strengths
were normalized by the body weight as weight-bearing index
(WBI), and averaged for both legs (WBIavg).
Results: TST was maintained at castration level (⬍1 ng/ml)
by this treatment. The means of IK-WBIavg were as follows:
0.289 (range⫽ 0.095 – 0.560) before the treatment; 0.273
(0.094 – 0.501) at two years after the initial injection. The
difference between the means were not significant
(P⫽0.7836, paired-t test). The mean of IM-WBIavg tended
to decline from 0.415 (0.037 – 0.827) to 0.366 (0.084 –
0.777) in the two years. However, the difference between the
means were not significant (P⫽0.5909, paired-t test).
Conclusion: A Longer observation period is necessary to verify the effectiveness of pharmacological castration in preventing disease progression and a larger sample size is required to
examine the existence of a subgroup that responds to this
Annals of Neurology
Vol 62 (suppl 11)
T-77. High Dose Cyclophosphamide Preferentially
Targets Naive T (CD45/CD4/RAⴙ) Cells in Chronic
Inflammatory Demyelinating Polyneuropathy (CIDP)
and Multiple Sclerosis (MS) Patients
Thomas H. Brannagan, Marc G. Golightly, and
Douglas E. Gladstone; New York, NY; Stony Brook, NY; and
Bay Shore, NY
Introduction: T-cells have a central role in MS and CIDP
pathogenesis. High dose cyclophosphamide’s in-vivo
cytotoxic-effect on circulating memory and naive T cells is
Methods: Three MS and five CIDP patients received cyclophosphamide (200mg/kg) for refractory disease. Before and
after chemotherapy, peripheral blood T-cell subsets were determined, for naive T cells (CD45RA⫹/ RO-) and memory
T cells (CD45 RA-/RO⫹). Patients underwent serial neurologic evaluations. MS patients were assessed with MRI and
EDSS; CIDP patients were assessed by MRC strength,
Rankin score and nerve conductions.
Results: Cyclophosphamide decreased clinical disease activity. The baseline median percentage of circulating CD4RA⫹
lymphocytes was 27.0% (2 – 44%). The baseline median
percentage of circulating CD4RO⫹ lymphocytes was 56%
(35 – 86%). At follow-up the median circulating CD4RA⫹
lymphocytes percentage decreased to 2.0% (1 – 11%) and
the median circulating CD4⫹RO lymphocytes percentage
increased to 84% (70 – 93%). The median percentage of
circulating CD26⫹CD4⫹RA⫹ lymphocytes decreased from
45% to 7.5%. Compared to memory T cells, naive T cells
were preferentially eradicated.
Discussion: Cyclophosphamide effectiveness in autoimmune
illness may result from naive T cell destruction, as this compartment may be the source of autoreactive lymphocytes.
T-78. Influence of Ethnicity on Pediatric MS
Dorothee Chabas, and Emmanuelle Waubant;
San Francisco, CA
Background: The proportion of non-Caucasians in pediatric
MS may be higher than in adults. There is a notion that
non-Caucasian adults who develop MS have a more severe
Objective: To explore the influence of ethnicity on pediatric
MS phenotype.
Methods: We report patients with MS onset or clinically isolated syndrome under the age of 18, seen at the UCSF regional pediatric MS center.
Results: 39 patients were identified (56% females; 46% Caucasians, 28% Hispanics, 13% Asians, 5% African-Americans,
3% Native Americans, and 5% mixed background). In the
non-Caucasian group, there were less females (48 vs 67%),
onset was earlier (12 vs 14y, p⫽0.059), elevated IgG index
and/or oligoclonal bands were more frequent (69% vs 33%,
p⫽0.05), brainstem/cerebellar onset was more frequent (58
vs 40%), and recovery was less often complete (57 vs 73%)
compared with Caucasians. Polyregional presentations occurred equally in both groups (18%).
Conclusion: Brainstem/cerebellar onset is twice as common
in children as in adults seen at the same center. NonCaucasian pediatric MS patients seem to have a distinct phenotype. Study supported by National Multiple Sclerosis Society.
T-79. MS-Related Changes in Functional Connectivity
between Working Memory and Long-Term Memory
Neural Systems
Seema Sayala, and Susan M. Courtney; Baltimore, MD
Cognitive deficits are common in multiple sclerosis (MS),
often involving working memory. fMRI studies of cognitive
performance in MS have found compensatory reorganization
underlying better performance, both regarding magnitude of
activation within brain regions and functional coupling between regions. We investigated differences in functional connectivity between MS patients and controls in both spatial
and nonspatial working memory tasks. We tested whether
regions within the working memory network had altered
connectivity with other brain regions, regardless of whether
the subsequently tested region showed task-related changes in
overall activation magnitude. Controls showed greater connectivity between left parahippocampal gyrus and left inferior frontal gyrus. The parahippocampal gyrus has been implicated in long-term memory encoding of associations
among objects and locations. The current results suggest a
stronger relationship between working memory and longterm memory in controls than in MS patients. MS-related
impairment on working memory tasks might be due not
only to altered function within the working memory network itself, but also to its interactions with other neural systems. Study supported by NMSS Grant PP0937 and NIH
Grant RO1 MH61625.
Abstract Withdrawn
T-81. The ICE Study: Immune Globulin Intravenous,
10% Caprylate/Chromatography Purified (IGIV-C) for
the Treatment of Chronic Inflammatory Demyelinating
Polyneuropathy (CIDP) Efficacy Study
Marinos Dalakas, Vera Bril, Peter Donofrio,
Hans-Peter Hartung, Richard Hughes, Norman Latov,
Ingemar Merkies, Pieter van Doorn, Chunqin Deng,
Kim Hanna, Bernd Sommerauer, and The ICE Study Group;
Bethesda, MD; Toronto, ON, Canada; Nashville, TN;
Dusseldorf, Germany; London, United Kingdom;
New York, NY; Rotterdam, Netherlands;
Research Triangle Park, NC; and Puteaux Cedex, France
Background: Large, randomized, long-term trials of CIDP
therapy are lacking, but small studies support IGIV efficacy.
This abstract discusses the largest randomized IGIV phase 3
efficacy trial to date.
Methods: Adults with CIDP (INCAT disability score, 2-9)
received IGIV-C (n⫽59) or placebo (n⫽58) every 3 weeks.
Patients crossed over to other treatment if their INCAT
score worsened from baseline by ⱖ1 point between day 16
to month 6 or was unchanged at week 6. The primary endpoint was the percentage of responders (ⱖ1-point improvement from baseline in INCAT score at month 6) with
IGIV-C versus placebo. Patients who crossed over were considered nonresponders. Responders who completed 6-month
treatment were re-randomized to a blinded 6-month extension phase.
Results: The mean baseline INCAT disability score was similar between both groups. A significantly larger percentage of
CIDP patients treated with IGIV-C (32/59 [54%]) responded versus placebo (12/58 [21%]; P⬍0.001). IGIV-C
was safe and well tolerated.
Conclusion: This CIDP study, the largest IGIV trial conducted to date, demonstrated the long-term efficacy and
safety of IGIV-C, 10% and supports IGIV-C as first-line
therapy. Study supported by Talecris Biotherapeutics, Inc.;
Dr. Dalakas is a consultant for Talecris Biotherapeutics, Inc.
T-82. Occupational Categories at Risk for Multiple
Sclerosis: A Case-Control Study
Joseph Finkelstein, Fang Liu, Walter Royal, and
Mitchell Wallin; Baltimore, MD
Background. The etiology of Multiple Sclerosis (MS) is believed to have a strong environment component, but limited
number of studies was devoted to the potential association
between occupation and the disease.
Methods. National Health Interview Survey (NHIS) adult
sample from years 1983-1996 and 2002 was used in the
analysis. The sample consisted of 290,877 subjects including
431 MS patients. A case-control design was employed to examine association between MS and a particular occupation
or industry category. For each MS case, 5 controls matched
on age, gender and race were randomly selected. Conditional
logistic regression was used to estimate odds ratios (OR) and
95% confidence intervals (CI).
Results. Automotive dealers and gasoline station workers
(OR⫽2.69, CI⫽1.13-6.36) and health service employees
(OR⫽1.58, CI⫽1.06-2.36) were at higher risk of having
MS. Occupations requiring manual labor such as machine
operators (OR⫽0.51, CI⫽ 0.26-0.98) and textile mill workers (OR⫽0.21, CI⫽0.05-0.88) had a protective effect
against MS. Those involved mostly in mental labor with
minimal physical activity such as administrators (OR⫽1.44,
CI⫽1.05-1.99), supervisors (OR⫽1.80, CI⫽1.04-3.10),
mathematicians (OR⫽2.55, CI⫽1.22-5.30) had higher risk
of having MS.
Conclusion. Certain occupations may potentially be a risk
factor for MS.
T-83. Impact of Switching First-Line DiseaseModifying Therapy (flDMT) after Failure in RelapsingRemitting (RR) MS
Alberto Gajofatto, Andrew High, and Emmanuelle Waubant;
San Francisco, CA
Objective: Determine whether flDMT switch after failure influences RRMS course.
Background: flDMTs have limited efficacy in some patients.
Methods: RRMS patients who received interferon-beta
(IFNB) or glatiramer acetate (GA), failed therapy and
switched to another flDMT were identified in UCSF MS
database. The impact was measured comparing annualized
relapse rates (ARR) before and after switch.
Results: 30% of IFNB (n⫽315) and GA (n⫽52) recipients
failed therapy based on relapse frequency, disability progression or MRI activity. 44 IFNB non-responders switched to
another IFNB (IFNB/IFNB’) and 15 to GA (IFNB/GA); 12
GA non-responders switched to IFNB (GA/IFNB). Ethnicity, age (36 years), disease duration (4 years), EDSS score
(1.5), pre-treatment ARR, and duration of first and second
(1059 and 1169 days) treatment periods were similar across
groups. Respective F/M ratio were 1.1, 2.0 and 5.0 for
IFNB/IFNB’, IFNB/GA and GA/IFNB groups (p⫽0.09).
Non-responder ARR before (0.68) and on first DMT (0.56)
were not significantly different. After switching, mean ARR
decreased in all groups (IFNB/IFNB’: 0.56 to 0.20,
p⫽0.002; IFNB/GA: 0.62 to 0.34, p⫽0.18; GA/IFNB: 0.50
to 0.11, p⫽0.01).
Conclusions: Switching flDMT in non-responders is a valid
Program and Abstracts, American Neurological Association
strategy to impact RRMS course. Response predictors are being analyzed. Study supported by Nancy Davis Foundation.
T-84. Phase IIb Trial of BHT-3009 for the Treatment
of Relapsing-Remitting Multiple Sclerosis
Hideki Garren, Jill Gianettoni, William Robinson,
Karen Tersini, Frank Valone, Lawrence Steinman, and
BHT3009 Study Group; Palo Alto, CA; and Stanford, CA
an advisory board for Genentech and received speaker honoraria from Biogen Idec and Teva Neurosciences.
T-86. Cerebellar Ataxia as an Organ Specific
Autoimmune Disease
Marios Hadjivassiliou, Richard A. Grunewald,
David S. Sanders, Basil Sharrack, and
Aelwyn G. B. Davies-Jones; Sheffield, United Kingdom
Objective: To assess the efficacy of BHT-3009 in RRMS.
Background: BHT-3009 is a MBP-encoding DNA plasmid
being developed for RRMS immunotherapy. Design/methods: This is a randomized, double-blind, placebo-controlled
trial in 289 RRMS patients. Randomization was 1:1:1
(0.5mg BHT-3009, 1.5mg BHT-3009, placebo). BHT-3009
is injected intramuscularly in weeks 0, 2, 4, and then every 4
weeks thorough week 44. The primary endpoint is new
gadolinium-enhancing lesions on brain MRI from weeks 28
through 48. Secondary endpoints include new T2 lesions,
relapses and disability scores. Changes in peripheral T-cell
(ELISpot) and CSF antibody (protein-array) responses to
myelin-antigens are being assessed in 93 patients. Results:
Safety data to date show 10 serious adverse events (AE) (2
possibly treatment-related). Only 5% of AEs are grade 3.
These were largely MS-related. Baseline T-cell assays in 77
patients revealed positive responses to MBP in 63, to PLP in
58 and to MOG in 53.
Conclusion: Blinded safety data confirm phase I/II data that
BHT-3009 is well-tolerated. Phase I/II data demonstrated
that BHT-3009 induced antigen-specific immune tolerance.
The phase IIb clinical efficacy data will be available before
October 2007. Study supported by Bayhill Therapeutics; All
authors have received salary, stock options, and/or financial
support from Bayhill Therapeutics.
There is evidence to suggest that the cerebellum can often be
the sole target of autoimmunity (eg paraneoplastic cerebellar
degeneration, post-infective cerebellitis). We prospectively investigated 400 patients with progressive ataxia to identify patients with truly idiopathic sporadic ataxia. A comparison of
the prevalence of autoimmune diseases and of the autoimmunity linked HLA DQ2 was made between the group of
patients with idiopathic sporadic ataxia and those with genetically characterised ataxia. 99/400 patients with progressive ataxia were labelled as having idiopathic sporadic ataxia
after extensive investigations excluded all other causes of
ataxia. The prevalence of autoimmune diseases in this group
of patients was 44% as compared to 5% in the group of
patients with genetic ataxias and the figure of 3% in the
general population (p⬍0.0001 Chi squared test). The HLA
DQ2 was found in 73% of patients with sporadic ataxia as
compared to 36% in patients with genetic ataxia and 36% in
the healthy local population (p⫽0.0005 Chi squared test).
The significantly higher prevalence of autoimmune diseases
and of the HLA DQ2 in patients with idiopathic sporadic
ataxia provides evidence in support of cerebellar ataxia sometimes being an organ specific autoimmune disease.
T-85. T Cell Suppression Following Treatment with
Rituximab in Neuromyelitis Optica
Claude P. Genain, Janeen Islar, Jennifer Gardell,
Aracely Delgadillo, Michael Ross, and Bruce C. Cree;
San Francisco, CA
T-87. Tetrathiomolybdate Inhibits Experimental
Autoimmune Encephalomyelitis by Balancing Th2/Th1
Guoqing Hou, Chunhua Zeng, Robort Dick, and
George J. Brewer; Ann Arbor, MI; and Ann Arbor, MI
B cell depletion with rituximab (RTX) may improve clinical
outcomes in neuromyelitis optica (NMO). The immunological effects of RTX in NMO were studied in 8 subjects
(RTX 1000mg ⫹ 10 mg dexamethasone X 2 infusions).
Lymphocyte subsets counts, T cell proliferation assays and
cytokine production (TNF-a, IFN-g, IL-2, IL-12, IL-4, IL10) in response to lectins, OKT3, and MOG were analyzed
at baseline and at regular intervals post-RTX. B cell depletion was achieved in all patients by the second infusion. A
4-week long, 75% depletion of CD3⫹ cells was apparent 2
weeks post-RTX (P⫽0.029). At 24 weeks, T cell proliferation in response to lectins was suppressed by 94%
(P⫽0.017), to OKT3 by 78% (P⫽0.028), cytokine secretion
was abolished and baseline reactivity against MOG was suppressed by 92% (P⫽0.03). Similar patterns of reactivity were
found after re-treatment. The unexpected finding that RTX
reduces T cell reactivity against MOG suggests inhibition of
antigen presentation by B cells as a possible mechanism of
efficacy. Furthermore, the apparent transient suppression of
CD3 cells may have implications for monitoring immune
function in NMO patients in the context of long-term B cell
depletion with concomitant glucocorticoid administration.
Study supported by Genentech, NIH, Lunardi Foundation;
Dr. Genain received personal compensation for serving on
Experimental autoimmune encephalomyelitis (EAE) is an inflammatory autoimmune disease model of human demyelinating disease multiple sclerosis (MS). Tetrathiomolybdate
(TM), an anticopper drug primarily used for Wilson disease,
has been proven to inhibit the inflammation process by affecting the expression of several cytotoxic inflammatory cytokines. The aim of this study was to investigate whether
TM can affect the immun response in EAE, and improve the
disease development.
In this report, we used proteolipid protein (PLP) 139-151
peptide to induce EAE model in SJL mice, and demonstrated that TM pre-treatment successfully reduced the severity of EAE as measured by clinical scores, and this suppression was consistent with a pronounced decrease of central
nervous system inflammatory cellular infiltrates. The expression of cytokines was also associated with the disease severity
findings, in which we found the increase level of Th2 cytokines and decrease of Th1 cytokines, as measeused by either
cytometric bead array or RNA microarray.
These data strongly indicate that TM offer an efficient
therapy to prevent and ameliorate MS. The mechanism of
these effects might involve TM’s possible immunomodulation in improving the imbalance immune response between
Th1 and Th2 cells in EAE.
Annals of Neurology
Vol 62 (suppl 11)
T-88. Whole Genome Association Study for
Susceptibility to Multiple Sclerosis
International Multiple Sclerosis Genetics Consortium
(IMSGC); Boston, MA
Recent advances in genotyping technology and in our understanding of the structure of the human genome have enabled
the execution of whole genome association scans for the first
time. The IMSGC has used these resources to explore the
genetic architecture of multiple sclerosis (MS) on a genomewide scale. Using the Affymetrix 500,000 Single Nucleotide
Polymorphism (SNP) platform, we have assayed approximately 70% of common genetic variation for their role in
MS susceptibiliy. The analysis of our screening sample set of
931 trio families, each consisting of a subject with MS and
her biological parents, confirmed the association of the
MHC with MS (P⬍10^-30) and identified many other possible susceptibility loci in the genome. Replication is under
way in an additional 655 MS trios as well as 2217 cases of
MS and 4967 healthy control subjects. Amongst the first 50/
170 SNPs undergoing replication, one chromosome 21 SNP
demonstrates greatly enhanced evidence of association to
MS: the evidence of association is P⫽2.2x10^-4 in our
screen and P⫽7.7x10^-8 in an extension analysis including
both the screening and replication data. This locus and others that emerge from our replication effort will be discussed.
T-89. Risk Factors of Multiple Sclerosis Varies by
HLA-DR2 Status
Talat Islam, Wendy Cozen, and Thomas Mack;
Los Angeles, CA
Objective: We investigateed the risk factors for multiple sclerosis(MS) by HLA-DR2 haplotype.
Method: The North American Twin registry consists of
1154 twin pairs with at least one case. DNA samples were
collected from 415 twins with MS and 575 of their sib(cotwin for DZs). Twins born in Canada or adjacent US states,
ⱖ41-420N, were considered “northern”. Ancestry was dichotomized as Celtic/Scandinavian and other. Diagnosis before 29.3(median age) was considered “early”. Data were analyzed using conditional logistic model.
Result: HLA-DR2 haplotype was a risk factor for MS
among females(odds ratio(OR)⫽2.18,95%CI: 1.31-3.64)
but not among males. Furthermore, HLA-DR2 was associated with a 2-fold (95%CI: 1.09-3.94) increase in concordance rate among females but with a reduction among
males(OR⫽0.21,95%CI: 0.05-0.92). HLA-DR2 haplotype
also increased the risk of concordance among twins with
high-risk ancestry(OR⫽3.5, 95%CI:1.07-11.50). Female sex,
early age of diagnosis, northern birthplace and high-risk ancestry were associated with increased risk of concordance
only among HLA-DR2 positive MZ twins. Furthermore, the
interval between diagnosis for concordant pairs was shorter
by 4.8 years among female twin pairs who were HLA-DR2
carriers compared to non-carriers(p-value⫽0.04).
Summary: Genetic and environmental risk factors of MS
vary by HLA-DR2 status.
T-90. Interferon-␤1b Induces ILT3 Expression in
Multiple Sclerosis (MS) and Control Myeloid Dendritic
Cells (mDCs)
Mark A. Jensen, David M. White, and
Barry G. W. Arnason; Chicago, IL
Immunoglobulin like transcripts (ILTs), members of the immunoglobulin superfamily, comprise a family of inhibitory
and activatory surface receptors expressed by leukocytes and
myeloid cells. ILT2, ILT3 and ILT4 are inhibitory, are expressed by mDCs and contain immunoreceptor tyrosinebased inhibitory motifs. Tolerogenic mDCs express higher
levels of ILT3 and ILT4 than immature DCs, are less immunogenic, and induce CD4⫹Treg cell differentiation. We
examined the effect of IFN-␤1b on ILT expression by
mDCs from MS patients and normal controls after 6 days in
culture with GM-CSF and IL-4. Immature mDCs express
low ILT2 levels and moderate ILT3 and ILT4 levels in both
MS and controls. Adding IFN-␤1b from days 6 to 8 markedly increases ILT3 expression and to a lesser extent ILT2
and ILT4 expression. Geometric mean fluorescence intensity
levels of ILT3 rise 3 fold after incubation with IFN-␤1b in
both MS and control DCs. Induction of inhibitory ILT3
expression on mDCs by IFN-␤1b may contribute to the
therapeutic efficiency of IFN-␤1b in MS. Whether, IFN␤1b-induced, increased ILT3 expression by mDCs affects T
cell function is being studied currently and will be presented.
Study supported by Grant RG3563A22/1 from the National
Multiple Sclerosis Society.
T-91. Conversion of Opticospinal Multiple Sclerosis
with Anti-Aquaporin 4 Antibodies to Conventional
Multiple Sclerosis after Interferon〉-1b Treatment
Keiko Kamakura, Mami Kanzaki, Goh Ogawa,
Kazunari Monma, Manabu Araki, Ken-ichi Kaida, and
Keiko Tanaka; Tokorozawa, Saitama, Japan; and
Niigata, Japan
We have been treating eight Japanese patients with opticospinal multiple sclerosis (OSMS) for more than ten years.
Five of them have longitudinal syrinx-like lesions in the spinal cord, decreased deep tendon reflexes and vibration sense
in lower extremities and anti-aquaporin 4 (anti-AQP4) antibodies. Cerebrospinal fluid exhibited marked pleocytosis during relapse. Three were treated with interferon␤ -1b, and
experienced a marked decrease in number of lymphocytes,
but two of them converted to conventional MS (CMS), and
also lost visual acuity unilaterally. MRI showed new longitudinal lesions in the pyramidal tracts in the brainstem in addition to periventricular white matter lesions. As two patients
refused interferon␤-1b treatment, they were treated with
pulse methylprednisolone (mPSL) and plasmapheresis during
relapses and with low dose PSL and azathioprine during remission. They remain ambulatory. The three patients who
lacked anti-AQP4 antibodies had optic neuritis and typical
signs of myelitis with short lesions in the spinal cord and not
syrinx-like lesions. Two were treated successfully with
interferon␤-1b. The findings suggest that treatment of antiAQP4 antibody-positive patients with interferon␤-1b may be
deleterious. Study supported by Grant-in-Aid for Scientific
Research from the Ministry of Health,.Welfare and Labor.
Grant-in-Aid for Scientific Medical Research in the National
Defense Medical College from the Ministry of National Defense.
T-92. Neuroprogenitor Cell Detection in Patients with
Multiple Sclerosis
Mirjana Savatic, Haifang Li, Yao Li, Petar Djuric, and
Lauren Krupp; Stony Brook, NY
The objective of our study is to investigate the role that neural stem and progenitor cells (NSC/NPC) play in the course
of multiple sclerosis (MS). Using proton MRI spectroscopy
(MRS), we have discovered a metabolite that is present in
Program and Abstracts, American Neurological Association
NSC/NPC only, and not in any other cell type present in
the brain tissue. Furthermore, we have developed new signal
processing methodologies that enable detection of NSC/
NPC in the human brain. We have applied our methodology
to imaging of NSC/NPC in MS patients with varying disease
courses. EAE models of MS have shown that there is mobilization of NSC/NPC associated with active disease. Herein,
we measured NSC/NPC density using MRS in normal appearing white matter, non-enhancing lesions, and enhancing
lesions in patients with relapsing (n ⫽ 7) and secondary progressive MS (n⫽3). We have shown a two-three fold increase
in NSC/NPC density in the MS lesions compared to normal
appearing white matter. Our pilot data demonstrate the first
example in which NSC/NPC can be detected in MS patients. In summary, NSC/NPC mobilization occurs within
the MS lesion, and may play a role in clinical recovery.
Study supported by NIH; NMSS.
T-93. The Ganglionic Acetylcholine Receptor
Antibody (␣3-AChR Ab): Oncological, Neurological and
Autoantibody Accompaniments
Andrew McKeon, Vanda A. Lennon, Robert D. Fealey, and
Sean J. Pittock; Rochester, MN
Amongst sera from ⬃18,000 patients undergoing service
paraneoplastic Ab evaluation (2005 – 2007), 156 (mean age
62 years:M:F 1.2:1) were seropositive for ␣3-AChR-Ab (median 0.12 nM, range 0.03 – 18.8, normal ⱕ0.02). Of 12
patients with high Ab values (⬎1.00 nM), neoplasm was detected in 3 (25%, 2 breast, 1 hematopoietic) and autoimmune autonomic ganglionopathies (AAG) predominated
(75%). Of 86 patients with intermediate values (0.10 – 1.00
nM), neoplasm was detected in 16 (19%): 11 adenocarcinomas (breast ⫽ prostate ⬎ GI ⬎ thyroid), 3 hematopoietic,1
urothelial and 1 tonsillar malignancy. Neurological manifestations included: peripheral neuropathies (PN, 37%), AAG
(20%, mostly restricted-enteric ⬎ orthostatic ⬎ anhidrosis),
neuropsychiatric (13%), demyelinating disorders (3%), ataxia
(3%), parkinsonism (2%), myasthenia gravis (MG, 1%) and
stiff-man syndrome (1%). Neoplasm was detected in 6
(10%, 2 melanoma, 1 breast, 3 other) of 58 patients with
low values (0.03 – 0.09 nM). Of these 50% were considered
to have a non-autoimmune disorder but an extensive cancer
search was not undertaken in most. The remaining 50% had
PN (25%), AAG (10%, panautonomic ⫽ restricted), neuropsychiatric disorders (5%), MG (5%), demyelinating disorders (3%), hemichorea (2%). Coexisting neuronal or muscle
Abs were identified in 26% of the entire group. The broader
oncologic profile, particularly adenocarcinoma, distinguishes
␣3-AChR-Ab from other known paraneoplastic Abs. Study
supported by Mayo Foundation.
T-94. Seizures Associated with Acetylcholinesterase
Inhibitor Use in Multiple Sclerosis
Lahar R. Mehta, Andrew D. Goodman, and
Steven R. Schwid; Rochester, NY
Acetylcholinesterase inhibitors (AChEIs) improved cognitive
impairment in patients with multiple sclerosis in a randomized placebo-controlled trial. Seizures have been reported in a
few patients taking AChEIs for Alzheimer’s disease, but the
observed incidence of seizures is not increased by AChEIs in
controlled trials. We report four patients with MS with new
onset seizures during AChEI treatment. All of the patients
had a secondary progressive course with an age range of
42-50 years and disease duration of 18-21 years. Two were
Annals of Neurology
Vol 62 (suppl 11)
treated with donepezil and two with galantamine at FDA
approved dosages. Seizures began 5 days to 13 months after
AChEI initiation. None of the patients had prior episodes
suspicious for seizures, and investigations failed to identify
any other provocation of the seizures. Seizures are more common in MS patients compared to healthy controls, suggesting that the seizure threshold can be reduced by ongoing
inflammation, demyelination, and axonal damage. These
cases suggest that AChEIs may further reduce the seizure
threshold. These medications should be used with caution in
MS patients, especially if they have a history of seizures or
are taking other medications known to increase seizure risk.
Study supported by National Multiple Sclerosis Society.
T-95. Mapping and Modeling MHC-Mediated Genetic
Susceptibility in Multiple Sclerosis
Jorge R. Oksenberg, and for the International Multiple
Sclerosis Genetics Consortium; San Francisco, CA
The association between susceptibility to MS and genes
within the MHC is a consistent finding across populations.
However, the identification of the true predisposing gene or
genes has been held back by the extensive linkage disequilibrium across this region. Progress in developing highthroughput genotyping methods and a better understanding
of the complex functional structure embedded in this superlocus suggest that the tools may be at hand to achieve the
elusive goal of disease-gene identification in the HLA. The
IMSGC and IMAGEN consortia developed a family-based
study allowing fine-scale genetic analysis. Genotyping has
been performed using 1500 SNPs in 1000 MS families. Additional genotyping was performed in an MS AfricanAmerican dataset. The data provide strong evidence for 1)
the direct involvement of the HLA-DRB1 gene, 2) significant DRB1 allelic heterogeneity, 3) a dose effect of DRB1
on disease risk, 4) complex trans allelic interactions determine the balance between susceptibility and resistance, 5) an
effect on early MRI phenotypes, and 6) an independent
HLA class I-associated gene effect on susceptibility. The data
underscore the power of using large and ethnically diverse
cohorts to identify disease genes in complex disorders. Study
supported by NIH, NMSS.
T-96. Dysmyelinated Axons Are More Vulnerable to
Glutamate Excitotoxicity Than Myelinated Axons:
Implications for Multiple Sclerosis (MS)
David Pitt, Anne H. Cross, and Mark P. Goldberg;
St. Louis, MO
Glutamate receptor overactivation (or excitotoxicity) contributes to white matter (WM) injury. While both axons and
oligodendrocytes are vulnerable to excitotoxic insults, it is
not clear whether glutamate damages axons directly, or indirectly through actions on glial cells or myelin.
We examined excitotoxic vulnerability of shiverer (shi)
mutant mice, which lack normal myelin. Mice received stereotaxic injections of the glutamate agonist, S-AMPA, in the
lumbar spinal cord WM and axonal injury was assessed 24
hours later in transgenic mice expressing fluorescent protein
in axons. The average axon injury score was 1.19⫾0.18
(n⫽3) in shi mice and 0.61⫾0.06 (n⫽4) in control mice
(p⬍0.05). Similarly, motor impairment was increased in shi
mice compared to controls (p⬍0.001). In addition, expression of the glutamate receptor subunit, GluR1, but not other
subunits, was higher in WM of shi mice than controls.
These results suggest that dysmyelinated axons are exquis-
itely sensitive to excitotoxicity. This might be relevant to MS
where glutamate homeostasis is permanently disrupted and
glutamate overload could damage chronically demyelinated axons. Preventing glutamate toxicity in MS might thus protect
against progressive axonal loss. Study supported by NMSS FG
1666-A-1 (DP), NMSS PP1222 (AHC), NIH P01
NS032636 (MPG), R01 NS36265 (MPG), P30 NS057105
(MPG), DP is a fellow of the National MS society.
T-97. Neuromyelitis Optica-IgG in Childhood
Inflammatory Demyelinating CNS Disorders
Sean J. Pittock, Silvia Tenembaum, Vanda A. Lennon,
Emily Ursell, Julia Kennedy, Amit Bar-Or,
Brian G. Weinshenker, Claudia F. Lucchinetti, and
Brenda Banwell; Rochester; Buenos Aires, Argentina;
Toronto, Canada; and Montreal, Canada
We analyzed in blinded fashion, serum NMO-IgG status for
87 children with CNS demyelinating disorders: 41 relapsingremitting MS (RRMS), 17 neuromyelitis optica (NMO), 13
monophasic/recurrent optic neuritis (ON), 13 transverse myelitis (TM), of whom 10 were longitudinally extensive
(LETM), and another 3 with LETM in the context of acute
disseminated encephalomyelitis (ADEM). Ten of the 87 children (11%) were seropositive: 8 of 17 (47%) with NMO (7 of
9 with relapsing NMO [78%], 1 of 8 with monophasic NMO
[12.5%]), 1 of 5 with recurrent ON and a single child with
recurrent LETM. No seropositive case was identified among
41 with RRMS (14% of whom had LETM at some point in
their clinical course), 8 with monophasic ON, 9 with
monophasic LETM or 3 with LETM in the context of
ADEM. In children, NMO-IgG is associated with NMO or a
high risk disorder (relapsing ON/LETM). LETM does not appear to be as predictive of an NMO spectrum disorder in children as it is in adults. Longitudinal studies of larger pediatric
LETM cohorts are required to ascertain whether the absence
of NMO-IgG is a negative predictor for relapse in this population. Study supported in part by the Mayo Foundation, the
Ralph Wilson Medical Research Foundation, The Wadsworth
Foundation and the Canadian Multiple Sclerosis Scientific Research Foundation. Don Paty Career Development Award
from the Multiple Sclerosis Society of Canada; The authors
disclose that, in accordance with the Bayh-Dole Act of 1980
and Mayo Foundation policy, Drs. Lennon, Lucchinetti and
Weinshenker stand to receive royalties for the discovery related
to AQP4 autoantigen. This intellectual property is licensed to
a commercial entity for development of a simple antigenspecific assay to be made available world wide for patient care.
The test will not be exclusive to Mayo Clinic. To date the
authors have received a total of ⬍$10,000 in royalties. Mayo
Clinic offers the test as an indirect immunofluorescence assay
to aid the diagnosis of NMO, but the authors do not benefit
personally from the performance of the test.
T-98. A Community-Based Study of MS: Natural
History and Prognostic Factors
Dimitra Kotzamani, Theodora Panou, Vasileios Mastorodemos,
Helen Nikolakaki, Minas Tzagournissakis, Georgios Klados,
Martha Spilioti, Michalis Mavrides, Aikaterini Kalamafkianaki,
Nikolaos Kouroumalos, Thomas Maris, Eleytheria Kontolaimaki,
Kalliopi Psaroudaki, Stella Perisynaki, Cleanthie Spanaki,
Georgios Georgakakis, and Andreas Plaitakis;
Heraklion, Crete, Greece; and Chania, Crete, Greece
We performed a community – based study of MS on Crete
(population 0.6 millions) spanning 20 years (1986-2006). As
of December 2006, we diagnosed 539 patients (330 females;
61.2%, 209 males; 38.8%, F/M ratio: 1.58). Of these, 404
(74.9%) had RRMS, 56 (10.4%) and 79 (14.6%) a CIS.
⌻heir mean current age was 40.1⫾12.1 years and their mean
age at onset 31.1⫾10.3 years. The mean survival time from
onset was 39.7 years (95% CI: 38 to 41). About 70% and
87% of cases relapsed within 5 and 10 years, respectively,
after onset. The overall prevalence was of 83.7x105. In 170
patients with disease duration ⱖ 10 years, 28 (16.5%) had
essentially no disability (EDSSⱕ1.5), whereas 72 (42.4%)
had mild neurological impairment (EDSS 2-4). Analysis of
prognostic factors revealed that disease duration (R2: 0.252)
and current age (R2: 0.234) correlated with EDSS. Male
gender (p⬍0.004) and progressive course from onset
(p⬍0.000) were associated with less favourable prognosis.
Type of presentation affected prognosis, with optic neuritis
predicting a more benign course than spinal involvement. In
conclusion, about 60% of MS patients had little or no disability 10 or more years after onset.
T-99. Mechanisms of Neuroaxonal Injury in Multiple
Sclerosis: Involvement of Glycolytic Enzyme
Reng-Rong Da, Stanley van den Noort, Raymond A. Sobel,
Wallace W. Tourtellotte, Yiping Zhang, Johanna Kolln, and
Yufen Qin; Irvine, CA; Stanford, CA; and Los Angeles, CA
To investigate pathogenetic mechanisms underlying neuroaxonal injury in multiple sclerosis (MS), we analyzed plasma cell
infiltration, antibody (Ab) localization in lesions, normal appearing white matter (NAWM) and normal appearing gray
matter (NAGM) of MS brains (N⫽10) and white matter controls (N⫽10) using immunohistochemistry and immunoelectron microscopy (IEM). Plasma cells and macrophage/microglia were the most numerous inflammatory cells in active
lesions and NAWM. Igs were localized on axons in lesions and
NAWM. Single chain Ab generated by immunoglobulin variable genes of heavy and light chains expressed by CSF and MS
tissue clonal B cells reacted to the glycolytic and microtubule
binding proteins glyceraldehyde-3 phosphate dehydrogenase
(GAPDH) and/or triosephosphate isomerase (TPI). By IEM,
single chain Abs and Igs in lesion were localized on GAPDH
and TPI of axonal microtubule network and mitochondria.
Myelin-reactive IgG was also seen in some MS brains. Neuron
chromatolysis and apoptosis suggested by DNA condensation
were associated with Ab and complement deposition in
NAGM. Ig-positive axons showed ovoids and transection in
active lesions and NAWM and were decreased in inactive
plaques. Our findings implicate the involvement of glycolytic
enzyme autoimmunity in neuroaxonal degeneration in MS.
Study supported by NIH and NMSS.
T-100. Trans-Synaptic Correlations in the Visual
System in Multiple Sclerosis
Daniel S. Reich, Eliza M. Gordon-Lipkin, Mathew Pulicken,
Laura J. Balcer, and Peter A. Calabresi; Baltimore, MD; and
Philadelphia, PA
Background: Although anterior visual pathway dysfunction
commonly causes visual disability in MS, the disease also affects the posterior pathway, where MRI abnormalities reflect
low contrast visual acuity (Wu et al. 2007, submitted). To
assess the link between the two pathways, which are connected via a synapse in the lateral geniculate nucleus, we correlated retinal thickness (anterior) with quantitative MRI of
the optic radiations (posterior).
Program and Abstracts, American Neurological Association
Methods: We used diffusion tensor imaging at 3T to reconstruct paths of the optic radiations and corticospinal tracts.
We correlated median MRI indices along those pathways
with retinal nerve fiber layer thickness measured by optical
coherence tomography in 41 patients and 15 controls.
Results: In MS optic radiations, retinal thickness correlates
with fractional anisotropy (r⫽0.47, p⫽0.002), mean diffusivity (r⫽ - 0.42, p ⫽ 0.006), and T2 (r ⫽ -0.34, p ⫽ 0.04),
but not with magnetization transfer ratio. Correlations are
stronger in relapsing MS (mean diffusivity vs. retinal thickness: r ⫽ 0.60, p ⫽ 0.004, n ⫽ 21) but are not significant
in progressive MS or controls. Weaker correlations of retinal
thickness with corticospinal tract MRI indices are explained
by MRI correlations across the two tracts.
Conclusion: Significant trans-synaptic correlations in the
MS visual system are not fully explained by multifocal disease activity. Study supported by National Multiple Sclerosis
Society Center Award and Tissue Repair Grants; NIH
RR15241, AG20012, and EB000991; and the Nancy Davis
Center without Walls.
T-101. Fetuin-A Is a Possible Biomarker of Disease
Activity in Multiple Sclerosis
Mustapha Rammal, Qijiang Yan, Jacqueline Dinzey,
Nicola R. Donelan, and Saud A. Sadiq; New York, NY
Background: Previously, cerebrospinal fluid (CSF) proteomic analysis revealed elevation of Fetuin-A (Alpha2Hermans-Schmid glycoprotein) in patients with MS. We investigated whether CSF Fetuin levels increased with disease
activity, and if this correlated with neuropatholological findings in MS brains and EAE.
Methods: CSF Fetuin-A levels were determined by ELISA in
40 patients with active MS and 37 patients with stable disease. Disease activity was determined by clinical and MRI
findings. By immunohistochemistry, we compared protein
expression of Fetuin-A in 22 MS plaques with areas of normal appearing white and grey matter in the same brains. In
addition, control brains were immunostained for Fetuin-A
protein expression. These studies were extended to EAE.
Results: CSF levels of Fetuin-A in patients with active disease were significantly eleveated in comparison to patients
with stable disease (mean 1669 ng/ml vs mean 1129 ng/ml
respectively, p⬍0.0003). Fetuin-A levels were markedly elevated uniformly in all active MS plaques by comparison to
other brain regions in the same brains and by comparison to
controls. Identical results were seen in EAE.
Conclusions: Fetuin-A, a protein known to activate matrix
metalloproteinases appears to be a marker of disease activity
in MS. Study supported by Advisory Board of MSRCNY.
T-102. Rituximab Therapy Markedly Reduces CSF T
and B Cell Populations in MS
Niamh B. O’Hara, Jacqueline Dinzey, Jessie Kerr,
Nicola R. Donelan, and Saud A. Sadiq; New York, NY
Background: Recent work has shown that intravenous Rituximab, a monoclonal antibody directed against CD20⫹
B-cells, significantly reduces disease activity in MS as indicated by brain MRI gadolinium scans. This degree of efficacy
is difficult to explain on the basis of isolated B-cell antagonism.
Methods: Five patients with severe multiple sclerosis were
treated with IV Rituximab at a dose of 375mg/m2 on day 1
and day 8. Peripheral blood lymphocyte counts and cerebrospinal fluid (CSF) B and T cell counts were determined by
Annals of Neurology
Vol 62 (suppl 11)
FACS analysis prior to treatment and at 2, 4, 8, and 12
weeks post-treatment.
Results: All 5 patients showed a marked sustained reduction
in peripheral B-cell counts post-treatment. Absolute peripheral
lymphocyte counts and CD3 (T-cell)levels were unaffected
whereas B-cell counts were 1 or less (normal 110 – 660 and were consistently ⬍1% of total cell population
(normal 6 – 29%). By contrast, in CSF, both T and B-cell
populations were markedly decreased post-treatment.
Conclusion: This pilot study suggests that the efficacy of Rituximab in MS may not be a pure B-cell phenomenom.
Whether the observed CSF T-cell reduction is a result of decreased antigen presentation by B-cells needs to be further investigated. Study supported by Advisory Board of MSRCNY.
T-103. Chronic Inflammatory Demyelinating
Polyradiculoneuropathy Associated with Multiple
Khema Ram Sharma, Daniela Saadia, Alicia G. Facca,
Rita Bhatia, Ram D. Ayyar, and William Sheremata;
Miami, FL
Objective: To describe temporal profile of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in patients with definite, relapsing multiple sclerosis (MS).
Background: Peripheral demyelinating neuropathy has been
rarely reported in association with central nervous system demyelinating disorder indistinguishable from MS.
Methods: In addition to usual diagnostic studies for CIDP
and MS in all 5 patients, we studied proximal segments of
nerves using deep tendon reflex latency (DTR) measurements of biceps reflex (BR), patellar reflex (PR), and ankle
reflex (AR).
Results: All patients with MS subsequently (4-22yrs) developed definite CIDP. Two of these patients, developed multiple cranial nerve and spinal root enhancement on subsequent imaging without new intraparenchymal enhancement
after a diagnosis of CIDP. The DTR latencies were prolonged at more than 2 sites in all patients. CSF protein increased (70 ⫾19 mg/dl to 144.8 ⫾17.4, p ⫽ 0.0001) at
time of diagnosis of CIDP. Clinical improvement was observed in all patients following intravenous immunoglobulin
(IVIG) therapy.
Conclusion: When patients with MS develop CIDP, manifestations of central and peripheral disease involvement appears to respond to IVIG. These cases suggest that there may
be common antigenic targets in central and peripheral nervous system in this subset of patients.
T-104. Frequent MRI Study of a Novel CCR2
Antagonist in Relapsing-Remitting Multiple Sclerosis
Basil Sharrack, Timothy Leach, Eric Jacobson,
Debra D. Donaldson, Xing Xu, and Ming Hu;
Sheffield, United Kingdom; and Cambridge, MA
Background: The CC chemokine receptor 2 (CCR2) expressed on monocytes and its ligand, MCP-1 (CCL2), may
be critical in monocyte recruitment and activation.
MLN1202 is a humanized monoclonal antibody to CCR2
which interrupts MCP-1 binding to CCR2 and is being developed for the treatment of multiple sclerosis (MS).
Objective: To evaluate whether MLN1202 significantly affects MS disease activity as measured by reduction from baseline in number of new gadolinium-enhancing lesions on
monthly MRIs.
Trial Design: Fifty patients with relapsing remitting MS
(RRMS) and at least 2 new gadolinium-enhanced lesions detected in three monthly pretreatment scans were randomized
to receive 4.0 mg/kg (n⫽25) or 8.0 mg/kg (n⫽25) MLN1202
and monthly MRIs during the 4 month treatment period.
Results: Patients were recruited from 18 centers in Europe
and Canada. Baseline clinical parameters were similar for 4.0
and 8.0 mg/kg groups and MRI from all intention to treat
subjects completing the four month treatment period have
been obtained.
Conclusion: Data on the efficacy of MLN1202 will provide
valuable information for the first time on the effect of CCR2
blockade with a monoclonal antibody directed specifically to
CCR2 in patients with RRMS. Study supported by Millennium Pharmaceuticals.
T-105. Neuroprotection in CNS Demyelinating
Disease by SIRT1 Activators: A Potential Oral Therapy
Kenneth S. Shindler, Elvira Ventura, Peter Elliott, and
A. M. Rostami; Philadelphia, PA; and Cambridge, MA
Objective: Neuronal loss in the CNS demyelinating disease
multiple sclerosis (MS) and its animal model, experimental
autoimmune encephalomyelitis (EAE), correlates with permanent neurological dysfunction. Activators of SIRT1, an
NAD⫹-dependent deacetylase involved in cellular stress resistance and survival, attenuate retinal ganglion cell (RGC)
loss during acute optic neuritis in EAE mice when given intravitreally. We examined whether oral SRT501, a SIRT1
activator, attenuates neuronal loss in EAE. Methods: RGCs
were retrogradely labeled by Fluorogold injection into the
superior colliculi. EAE was induced in SJL/J mice by immunization with proteolipid protein peptide. Mice were treated
daily with SRT501 or placebo by oral galvage. Following sacrifice, RGCs were counted, and optic nerves and spinal cords
were examined histologically. Results: Oral SRT501 attenuated RGC loss in EAE eyes with optic neuritis in a dosedependent manner. SRT501 penetrated eyes, with effects
similar to that produced by intravitreal injection. Interpretation: The SIRT1 activator SRT501 attenuates RGC loss during acute optic neuritis in EAE mice following oral administration, with similar efficacy to intravitreal injections.
SRT501 is a potential oral therapy to prevent neurodegeneration in MS. Study supported by NIH Grant EY015098, a
Career Development Award from Research to Prevent Blindness, Sirtris Pharmaceuticals, the Paul and Evanina Mackall
Foundation Trust, and the F. M. Kirby Foundation; The
drug examined in these studies, SRT501, is the proprietary
property of Sirtris Pharmaceuticals. Sirtris Pharmaceuticals
provided the compound and a portion of the funding for the
studies as unrestricted research gifts for the research program
of A. M. Rostami at Thomas Jefferson University. One of
the authors, Peter Elliott, is employed full time by Sirtris and
is a company shareholder.
T-106. High Dose Cyclophosphamide in the
Treatment of Multiple Sclerosis
Robert Schwartzman, Nicole Simpkins, Guillermo Alexander,
Kristine Ward, and Isadore Brodsky; Philadelphia, PA
Multiple Sclerosis is often a progessive, disabling disease with
a possible autoimmune etiology. Immunomodulators, disease
modifying agents, are used for disease duration. High dose
cyclophosphamide (HDC), administered over four days, is
an alkylating agent used to treat malignancies and other autoimmune disorders. In this study we evaluated the efficacy
of HDC in multiple sclerosis subgroups. METHODS:
Twenty-three patients underwent treatment; nine patients
had relapsing remitting MS (RRMS), eleven patients had
secondary progressive MS (SPMS), and three patients had
primary progressive MS (PPMS). The primary endpoint was
reduction in EDSS of ⱖ1 points for 6 months or longer.
RESULTS: Nine patients in all subgroups reached the primary endpoint (39%). Seven of nine RRMS patients (78%),
two of eleven SPMS (18%) and no PPMS patients met the
primary endpoint. Five of nine RRMS patients (56%) have
had no progression in EDSS to date, three years posttreatment (three are normal). Two RRMS patients who progressed shortly after treatment are now normal. Eight RRMS
patients (89%) had substantial reductions in number of flares
per year. CONCLUSION: In patients with RRMS, HDC
appears to be well tolerated and effective as a disease modifying agent.
T-107. Correlation of Macular and Retinal Nerve
Fiber Layer (RNFL) Parameters with Disease Duration
in Untreated MS
Rebecca I. Spain, Robert C. Sergott, and Thomas P. Leist;
Philadelphia, PA
OBJECTIVE: Visual measures are being considered as outcomes in MS trials and as monitoring tools in practice. Optical coherence tomography (OCT) has been validated in
ophthalmologic conditions and holds promise for use in MS.
We report the correlation of the RNFL including macula
with disease duration and disability in MS.
METHODS: Untreated patients with MS or isolated syndromes were enrolled into predetermined disease duration
windows. RNFL thickness was assessed using a Stratus OCT
– 3. Expanded Disability Status Score (EDSS) was determined using Neurostatus.
RESULTS: 41 patients (82 eyes, age 45 ⫾ 11 years, disease
duration 0.2 – 35 years) were evaluated. Disease duration
correlated with decline in RNFL thickness (p⫽0.004), total
macular volume (p⬍0.001), and EDSS (p⫽0.04). Correlation between EDSS and RNFL thickness trended toward significance. (p⫽0.06).
INTERPRETATION: RNFL thicknesses and macular volumes showed disease duration-dependent decrements, with a
trend toward significance between disability and RNFL
thickness. Previous studies of OCT in MS employed crosssectional or short-term follow-up designs. To our knowledge,
this is the first study using a longitudinal design to establish
the natural history of the RNFL in untreated MS. Our results support use of OCT in MS trials.
T-108. Voltage-Gated Potassium Channel (VGKC)
K. Meng Tan, Vanda A. Lennon, and Sean J. Pittock;
Rochester, MN
Amongst sera from ⬃100,000 patients evaluated on a service
basis for paraneoplastic autoantibodies (2002 – 2007), indirect immunofluorescence screening identified 66 (56% female) whose IgG bound selectively to CNS synapses in a
pattern consistent with VGKC, and for whom clinical information was available. Specificity was confirmed in all cases
by immunoprecipitation of detergent-solubilized brain synaptic proteins complexed with 125I-alpha-dendrotoxin (median value 0.97 nmol/L; range 0.04-93.3; normal ⱕ0.02).
Neurologic symptoms (median age of onset 65 years) were
multifocal in 48%; median follow-up was 15 months (range
1 – 154). Presentations included: cognitive impairment
Program and Abstracts, American Neurological Association
(71%; frontotemporal ⬎limbic), seizures (58%; mostly temporal origin), autonomic dysfunction (33%; enteric ⬎genitourinary ⬎other), myoclonus (29%), peripheral nerve disorders (23%; hyperexcitability ⬎small-fiber ⬎large-fiber),
brainstem/cranial nerve dysfunction (21%), other movement
disorders (17%; tremor ⬎parkinsonism ⬎stiff-man phenomena), sleep disturbance (17%; insomnia ⬎hypersomnolence)
and Morvan’s syndrome (3%). Neoplasia was diagnosed in
30%, including 12 carcinoma (small-cell lung, 5; prostate, 3;
breast, 2; tongue, 1; skin, 1), 4 thymoma and 2 hematologic.
33% had documented hyponatremia; 41% had additional
neuronal or muscle autoantibodies and 29% had co-existing
autoimmunity (thyroid ⬎diabetes). Of 33 patients receiving
immunotherapy (steroid ⬎ intravenous immunoglobulin ⬎
plasmapheresis), 29 appeared to benefit; 16 (most treated
early) improved markedly.
T-109. A Recombinant Human IgM Promotes Myelin
Repair after a Single Very Low Dose
Arthur E. Warrington, and Moses Rodriguez; Rochester, MN
An important therapeutic goal in the treatment of central
nervous system (CNS) demyelinating disease and injury is
promoting remyelination. Remyelination offers neuroprotection and may limit permanent disability. rHIgM22, a recombinant human IgM, promotes remyelination in several models of demyelination. rHIgM22 binds to myelin and the
surface of oligodendrocytes, and targets to CNS lesions in
vivo. A dose ranging study using rHIgM22 was performed in
mice with chronic virus-induced demyelination, a model of
chronic progressive MS. The median effective dose of
rHIgM22 required to promote remyelination was a single 23
␮g/kg intraperitoneal injection. A time course study of repair
revealed that remyelination plateaued by five weeks following
treatment with rHIgM22. The half life of rHIgM22 in the
mouse systemic circulation was determined to be 15 hr. We
propose that the stage is set within chronic CNS lesions for
remyelination to occur, but the process is blocked by the
balance of agents that injure versus those that promote repair. Treatment with rHIgM22 shifts the evolution of CNS
lesions toward remyelination. Repair of chronic spinal cord
injury is seldom modeled, but is an important reality for the
treatment of humans. Study supported by National Institutes
of Health, The National Multiple Sclerosis Society, The
Multiple Sclerosis Society of Canada, Mr and Mrs Eugene
T-110. Anti-CD20 B-Cell Depletion Reverses EAE
Induced by MOG Protein, but Exacerbates Disease
Induced by Its Sncephalitogenic Peptide
Martin S. Weber, Thomas Prod’homme, Tara Karnezis,
Juan C. Patarroyo, Cynthia D. Rundle,
Christopher Linington, Claude C. Bernard, Flavius Martin,
and Scott S. Zamvil; San Francisco, CA;
Melbourne, Australia; Aberdeen, United Kingdom; and
South San Francisco
Objective: To investigate anti-CD20 mediated B-cell depletion in experimental autoimmune encephalomyelitis (EAE).
Background: B-cells and myelin-specific antibodies (Ab) play
a pathogenic role in CNS autoimmune disease. Recent studies
indicate that B-cells may also have a regulatory function. We
evaluated anti-CD20 mediated B-cell depletion, a candidate
therapy for multiple sclerosis, in EAE induced by either MOG
p35-55 or recombinant mouse MOG 1-125 (rMOG).
Annals of Neurology
Vol 62 (suppl 11)
Results: B-cell depletion was effective within the CNS and
reversed paralysis in rMOG-induced EAE. Depleted mice revealed decreased anti-rMOG Ab titers and attenuated encephalitogenic T cell responses. In contrast, B-cell depletion exacerbated MOG p35-55-induced EAE with enhanced CNSinfiltration, -demyelination and pronounced Th1 responses.
Antigen-specific B-cells from rMOG-immunized mice released
TNF-a, IL12 and promoted Th1/Th17 development of naive
T-cells, whereas B-cells from MOG p35-55-immunized mice
remained naive and released more IL-10.
Conclusion: Our data indicate that anti-CD20 B-cell depletion has differential effects on MOG-protein and MOGpeptide-induced EAE. The beneficial effect in rMOG-induced
EAE reflects decreased antigen-presentation by proinflammatory B-cells to encephalitogenic T-cells and reduced myelinspecific Ab titers, whereas exacerbation of MOG peptideinduced EAE may relate to a regulatory function of naive
T-111. Intra and Extracranial Venous Haemodynamics
in Multiple Sclerosis
Paolo Zamboni, Erica Menegatti, Enrico Fainardi,
Roberto Galeotti, Sergio Gianesini, Enrico Granieri, and
Maria R. Tola; Ferrara, Italy
In multiple sclerosis (MS) no information on cerebral venous
haemodynamics are available. 60 consecutive MS patients
subdivided in 42 relapsing-remitting (RR), and 18 secondary
progressive cases (SP) matched with 60 controls underwent
to combined extra-cranial/trans-cranial- color-Doppler investigation (ECD-TCSS). We assessed the difference of crosssectional areas (⌬CSA) of the internal jugular vein (IJV) respectively measured in supine and sitting position, the
direction of flow in different phases of activation of the thoracic pump in the IJV, vertebral vein (VV), deep middle cerebral veins (dMCVs), and transverse sinus (TS).
⌬CSA assessed in controls was similar to that reported in
physiology, 10.8⫾1.6 mm2, whereas in the entire MS group
was significantly reduced to 1.5⫾2.4 (p⬍ 0.0001); moreover, in SP was quite negative – 8.9⫾6,4 mm2 (p⬍ 0.0001).
The rate of reflux flow in the insonated venous segments was
significantly higher in the MS group, and reflux in at least
one of the dMCVs was detected in 45% of MS vs. 0% in
controls (p⬍0.0001).
In MS, combined ECD-TCSS demonstrate significant alterations in cerebral venous haemodynamics, whose role in the
inflammatory cascade and in iron depositions in MS lesions,
merit further investigations. Study supported by Italian Goverment; Foundation Cassa di Risparmio di Ferrara, Italy.
Abstract Withdrawn
T-113. Chemotherapy with Deferred Radiotherapy for
Newly Diagnosed Anaplastic Oligodendroglial Tumors
Andrew B. Lassman, Timothy F. Cloughesy, Lynn S. Ashby,
Lisa M. DeAngelis, and Lauren E. Abrey; New York, NY;
Los Angeles, CA; and Phoenix, AZ
Management of newly diagnosed anaplastic oligodendroglial
tumors is controversial. We compared outcomes following
various initial treatment strategies by retrospectively reviewing records at several medical centers, identifying 302 patients (170 men, 132 women; median age 42 years, range
18-81) with treatment naive anaplastic oligodendroglial tumors. Median time to progression (TTP) and overall survival
were 2.5 years (range, 0-16) and 7.1 years (range, 0-17), respectively, with median follow-up of 3.6 years for surviving
patients (n⫽175, 58%). Combining radiotherapy and chemotherapy in either order or concurrently (n⫽158) may prolong TTP relative to chemotherapy alone (n⫽45) with median TTP 2.8 vs. 1.9 years (p⫽0.07). However, there was no
overall survival benefit (median 7.3 years vs. not-reached,
p⫽0.90). As many patients survive long enough to experience potential cognitive impairment from brain radiation,
our results suggest that deferring radiotherapy until tumor
progression may be reasonable in patients responding favorably to chemotherapy. We are collecting data from additional Oligodendroglioma Study Group institutions to increase statistical power and assess the impact of different
chemotherapy regimens (PCV vs. temozolomide), 1p/19q
loss of heterozygosity, and histologic subtype on both TTP
and overall survival. Updated results will be presented. Study
supported by Schering Plough and Sigma Tau; Consulting
fees and research support from Schering Plough and Sigma
Tau Pharmaceuticals.
T-114. Acute and Chronic HIV Reduce the BOLD
Signal Magnitude
Beau Ances, Joanna Perthen, Christine Liang, Oleg Leontiev,
Davey Smith, Susan Little, Douglas Richman, Scott Letendre,
Richard Buxton, Ronald Ellis, and HNRC; La Jolla, CA
Objective: Evaluate the effects of HIV infection in the brain
using blood oxygen level dependent functional magnetic resonance imaging (BOLD fMRI).
Background: BOLD fMRI has typically mapped brain activation in seronegative controls (SNC) and HIV⫹ subjects for
attention and memory tasks. Increased recruitment of additional brain regions occurred for HIV⫹ subjects compared to
Design/Methods: 17 SNC (9 male, ages 23-60 years old) and
20 HIV⫹ (12 male, ages 21-52 years old) were studied at 3T.
HIV⫹ subjects were classified into either acute (⬍ 1 year after
seroconversion, n⫽7) or chronic (⬎1 year after seroconversion, n⫽13) groups. BOLD changes were obtained for an 8
Hz flashing black and white checkerboard stimulus alternating
with an isoluminant gray screen. An ANOVA of Group
(SNC, acute, and chronic HIV) was performed on the magnitude of BOLD signal.
Results: The magnitude of the BOLD response was significantly reduced in HIV⫹ subjects compared to SNC. Within
HIV⫹ subgroups a similar reduction was seen for acute and
chronic HIV subjects.
Conclusions: Our results suggest that acute HIV infection affects the BOLD responses. BOLD fMRI may act as a noninvasive surrogate biomarker for assessing effects of HIV in the
brain. Study supported by Universitywide AIDS Research Program Grant (CF05-SD-301) (BA) and an American Federation of AIDS Research (amFAR) (106729-40-RFRL).
T-115. Detection of Tat and Anti-Tat Antibodies in
Cerebrospinal Fluid of Patients with HIV Infection:
Correlation with HIV Dementia, Viral Load, and CD4
Lymphocyte Count
Muznabanu Bachani, Avindra Nath, and Jeffrey Rumbaugh;
Baltimore, MD
Once the HIV genome is integrated into astrocytes of the
brain, large amounts of cytokines, chemokines, and neuro-
toxic viral proteins are produced, triggering neuropathological pathways. The viral protein, Tat, has been strongly implicated as a neurotoxic agent. Sandwich and indirect
enzyme-linked immunosorbent assays were developed to
evaluate the levels of Tat and anti-Tat antibodies in the cerebrospinal fluid (CSF) of HIV infected patients. The antiTat antibody levels were higher in patients without dementia
compared to patients with dementia, and in patients with
CD4 cell counts below 250 cells/␮l or with serum or CSF
viral loads greater than 400 copies/ml. On the other hand,
CSF Tat levels did not differ significantly based on these
variables. Relative Tat and anti-Tat levels varied directly with
each other, suggesting that the development of anti-Tat antibodies is an adaptive immune response to the presence of
Tat. These results suggest that anti-Tat antibodies serve an
important protective role against development of HIV dementia. The ability to detect anti-Tat antibodies in CSF may
have important diagnostic, prognostic, and therapeutic purposes. Study supported by NIH grants to JAR and AN.
T-116. Development of Peripheral Neuropathy after
Stavudine-Based Antiretroviral Therapy in HIV Positive
(HIVⴙ) Patients in Sub-Saharan Africa
Katherine B. Peters, Noeline Nakasujja, Kevin R. Robertson,
Jeff Liner, Richard L. Skolasky, Apollo Basenero,
Andrew Kambugu, Elly Katabira, Seggane Musisi,
Allan Ronald, David Clifford, and Ned Sacktor;
Baltimore, MD; Kampala, Uganda; Chapel Hill, NC;
Winnipeg, MB, Canada; and Saint Louis, MO
Recipients of highly active antiretroviral therapy (HAART)
that includes d-drug nucleoside reverse transcriptase inhibitors such as stavudine are at risk for development of a toxic
neuropathy. Frequency of toxic neuropathy in sub-Saharan
Africa is largely unknown. We examined frequency of toxic
neuropathy and HIV-associated sensory neuropathy in a cohort of HIV⫹ individuals on d-drug based HAART in
Uganda. 102 HIV⫹ patients were started on Triommune
(stavudine/lamivudine/nevirapine) and were assessed for
symptoms and signs of neuropathy at baseline, and 3 and 6
months after therapy initiation. Baseline symptoms of neuropathy were present in 27% of HIV⫹ patients and signs of
neuropathy were present in 43% of HIV⫹ patients. Symptoms of neuropathy occurred in 38%(p⫽0.13) of asymptomatic HIV⫹ patients after Triommune. Signs of neuropathy
were seen in 31%(p⫽0.03) of those who did not have signs
of neuropathy at baseline after Triommune. This suggests
that toxic neuropathy is a significant complication of d-drug
based HAART regimens in HIV⫹ individuals in Uganda.
Further study is needed to evaluate impact that neuropathy
may have on quality of life, and risks and benefits of d-drug
based HAART in sub-Saharan Africa. Study supported by
NS32228, which is the NINDS funding of the Neurological
AIDS Research Consortium.
T-117. Matrix Metalloproteinase Protects Against
HIV-1 Tat-Induced Neurotoxicity by Decreasing
Nitrosative and Oxidative Stress and by Inhibiting HIV
Jeffrey A. Rumbaugh, Muznabanu Bachani, Guanhan Li,
Wenxue Li, and Avindra Nath; Baltimore, MD
Tat is critical for HIV replication and is also implicated in
the pathogenesis of HIV dementia. Matrix metalloproteinases (MMPs) are elevated in CSF of patients with HIV dementia, but their role is not well understood. No treatment
Program and Abstracts, American Neurological Association
is currently available for HIV dementia. To determine potential interactions between Tat and MMPs, rat neuronal
cultures were treated with 200nM Tat and/or 20ng/ul
MMP-1 for 15-24 hours. Tat increased (p⬍0.01) levels of
nitric oxide and inducible nitric oxide synthase, while
MMP-1 increased oxidized protein carbonyls. Both effects
were attenuated (p⬍0.05) by the combination of Tat and
MMP-1. Since Tat itself may get nitrosylated at cysteine residues, the effect of MMP-1 on nitrosylated Tat was determined. MMP-1 cleaved both nitrosylated and nonnitrosylated Tat, but not HIV-p24 or gp120. MMP-1 also
inhibited (p⬍0.05) Tat-mediated HIV-long terminal repeat
transactivation in SVGA cells and replication of HIV-1 JRCSF, in a dose dependent manner, in TZM-bl cells. This
study elucidates a unique viral-host interaction, in which
MMPs may serve as an innate host defense mechanism. Optimization of MMP activity may be a novel therapeutic strategy for HIV dementia. Study supported by NIH grants to
JAR and AN.
T-118. Optical Coherence Tomography as a Possible
Diagnostic Tool in HIV Associated Neurocognitive
Jason Lee, Jason Creighton, Justin McArthur,
Mathew Pulicken, Richard Skolasky, and Nicoline Schiess;
Baltimore, MD
Background: HIV associated neurocognitive disorders
(HAND) are recognized as a frequent complication of the
AIDS pandemic as improved testing measures become available. HIV⫹ patients have sub-clinical axonal changes in the
optic nerves. Optical Coherence Tomography (OCT) is able
to quantify retinal nerve fiber layer (RNFL) thickness.
Objective: HIV causes progressive neurodegeneration, and
we hypothesized that RNFL could serve as a biomarker of
neuronal damage.
Methods: 31 HIV⫹ individuals were studied: 27 had some
degree of HAND. We measured the RNFL thickness in 62
HIV⫹ eyes and in 72 HIV-seronegative controls and performed multiple cognitive tests on the HIV⫹ patients and
CD4 and plasma HIV RNA levels.
Results: There was no significant correlation between dementia scores and RNFL thickness. There was also no significant
correlation between the stage of HIV disease and RNFL.
Conclusions: We show novel data using OCT in an HIVdemented population. Although the initial findings do not
show any correlation, the limits of this study include small
sample size, a highly selected population and lack of available
CSF HIV RNA levels. More studies are needed to establish
OCT as a possible tool for HAND. Study supported by
NINDS NS049465 (JCM).
T-119. Impairment of Adult Hippocampal
Neurogenesis by the HIV Envelope Protein gp120
Arun Venkatesan, Myounghwa Lee, Hongjun Song, and
Avindra Nath; Baltimore, MD
Background and Hypothesis: Despite therapy, human immunodeficiency virus (HIV) infection leads to cognitive impairment in a substantial proportion of individuals. Current
strategies do not adequately treat HIV-induced cognitive
dysfunction. Recent neuropathologic and neuroimaging
studies suggest that hippocampal impairment may play a role
in HIV-induced cognitive dysfunction.
Formation of new hippocampal neurons from progenitor
cells, termed neurogenesis, continues through adulthood.
Annals of Neurology
Vol 62 (suppl 11)
Adult hippocampal neurogenesis may play an important role
in maintenance of cognitive function. We hypothesize that
HIV disrupts adult neurogenesis and interferes with incorporation of new neurons into the hippocampus, contributing to
cognitive impairment.
Methods and Results: Using transgenic mice that express the
HIV envelope protein gp120 in the brain, we have found
that adult neurogenesis is markedly decreased in the adult
hippocampus (40% decrease in proliferation, p⬍0.01; 50%
decrease in newly generated neurons, p⬍0.05; no change in
astrocytic differentiation). This decrease in neurogenesis is
accompanied by decreased expression of brain-derived neurotrophic factor. Current approaches include the use of a cell
co-culture system to identify mechanisms by which gp120
impairs neurogenesis.
Conclusions: We conclude that HIV gp120 markedly impairs adult hippocampal neurogenesis, potentially contributing to cognitive dysfunction in infected individuals. Study
supported by National Institute of Drug Abuse, National Institute of Mental Health.
T-120. Evaluation of the Dentatothalamocortical
Tracts by Diffusion-Tensor Imaging in Children with
Posterior Fossa Syndrome
Brannon Morris, Nicholas S. Phillips, Fred H. Laningham,
Amar Gajjar, and Robert J. Ogg; Memphis, TN
Background: Posterior fossa syndrome (PFS) is a postoperative complication characterized by mutism, oromotor/
oculomotor apraxia, apathy, and cerebellar dysfunction; recovery is often incomplete. Etiology is unknown, but,
involvement of the dentatothalamocortical (DTC) pathways
is posited.
Purpose: To evaluate anatomical differences within the DTC
pathways by diffusion tensor imaging (DTI) in patients with
and without PFS.
Methods: Sixty-two children with posterior fossa tumors underwent surgical resection and DTI. All 13 patients diagnosed with PFS were compared to 13 matched patients (by
age, MRI timing) without PFS. Two DTI parameters- apparent diffusion coefficient (ADC) and fractional anisotropy
(FA) - were measured bilaterally in 3 regions of the DTC
(cerebellar peduncle, thalamus, corona radiata).
Results: In the patients with PFS, significant left-right asymmetry of diffusion properties in the thalami was detected:
ADC higher (p ⫽ 0.002) and FA lower (p ⫽ 0.002) on the
left as compared with the right.
Conclusions: Disruption of the DTC at the level of the left
thalamus may underlie some cases of PFS. Although the thalami subserve both complex motor and behavioral mechanisms, the relative importance of the left thalamus in PFS is
not well understood.
T-121. Tic Severity in Tourette Syndrome (TS):
Relationship to Co-Morbid Attention Deficit
Hyperactivity Disorder (ADHD) and Obsessive
Compulsive Disorder (OCD)
Tamara M. Pringsheim, Michelle Pearce, Anthony E. Lang,
Roger Kurlan, and Sandor Paul; Toronto, ON, Canada; and
Rochester, NY
This cross-sectional, descriptive study was performed to assess if tic severity is affected by co-morbid ADHD and
OCD. Patients 7 to 17 years were evaluated using the Yale
Global Tic Severity Scale (YGTSS) as a measure of tic severity. Baseline characteristics collected included age, gender, diagnosis of ADHD, OCD and other medical/psychiatric disorders, and treatment status for tics, ADHD and OCD. 67
children have been assessed to date; 20 with TS only, 26
with TS⫹ADHD and 21 with TS⫹ADHD⫹OCD. Average
age of the sample was 11 years and 81% were male. The
mean YGTSS score (tic only) was significantly greater in the
TS⫹ADHD⫹OCD group, 22.1 (p⬍0.05), compared to the
TS only (16.1) and TS⫹ADHD (16.5) groups. YGTSS
scores of tic severity plus impairment were also significantly
higher in the TS⫹ADHD⫹OCD group. The odds ratio for
treatment of tics was 9.6 in the TS⫹ADHD⫹OCD group
relative to the TS only group. An explanatory model for tic
severity was created using multiple linear regression. Comorbid diagnoses, treatment for ADHD and TS and gender
were all significant explanatory variables of tic severity.
T-122. Progressive Myoclonic Epilepsy and AlphaDystroglycan Deficit: An Emerging Phenotype?
Giuseppina Pustorino, Maria Spano, Maria Bonsignore,
Domenica L. Sgro, Gabriella Di Rosa, Debora Tripodi,
Antonella Cuzzola, Francesca Lagana, Marilena Briguglio,
and Gaetano Tortorella; Messina, Italy
Progressive myoclonic epilepsies (PMEs) are a group of familial neurodegenerative disorders characterized by intractable myoclonic seizures, generalized tonic-clonic seizures,
myoclonic jerks, progressive neurological deterioration,
mainly cognitive and cerebellar. There are five main causes of
PMEs: Unverricht-Lundborg disease, MERRF, Lafora disease, neuronal ceroid lipofuscinosis, sialidoses. We describe
two females presenting with a clinical phenotype identifiable
as PME, with onset within the first year of life and quickly
progressive neurocognitive deterioration. Both showed progressive cortical and cerebellar atrophy documented by MRI.
Interictal EEG was characterized by a progressive disorganization of background rhythm together with multifocal paroxysmal discharges and a peculiar alpha-like pattern. Once
we excluded the main known genetic causes of PMEs, we
performed muscular biopsy, which allowed us to find alphadystroglycan deficit by means of hymmunohistochemistry
techniques. A diagnosis of congenital muscular dystrophy
(CMD) due to dystroglycanopathy was, thus, made. The
three main genetic causes of dystroglycanopathy were excluded. The overlapping clinical, electroencephalographic
and neuroimaging phenotype in our two patients allows us
to hypothesize an underlying common genetic cause, still unknown. Dystroglycanopathies should be added to the group
of diseases responsible for PMEs.
T-123. Intracerebral Hemorrhage Volume Predicts
Poor Outcome in Children
Lori C. Jordan, Jonathan T. Kleinman, and Argye E. Hillis;
Baltimore, MD
Stroke is among the top ten causes of death in children. Half
of strokes in childhood are hemorrhagic. We hypothesized
that neurologic outcome would be worse in children with
larger hemorrhages. Cases were ascertained by discharge
ICD-9 code. Charts were reviewed. ImageJ software was used
to compute hemorrhage size on CT. From 2001-2006, 30
children with spontaneous ICH met inclusion criteria. Median
ICH volume was 20.4cc. Median brain volume was 1145.9cc.
Hemorrhage size as a percentage of brain volume ranged from
0.004 –11.56% (median 1.92%). 30-day mortality was 16.7%
with all deaths related to ICH. There was no gender difference
in 30-day mortality. African American children had a higher
mortality than white children (33% vs. 5%)(p⫽0.014). Hemorrhage size as a percentage of brain volume was categorized
into two groups: ⬍75th percentile versus ⱖ75th percentile. In
the small hemorrhage group, 4/22 (18%) had poor outcomes
(death or vegetative state). In the large hemorrhage group, 5/8
(62.5%) had poor outcomes (p⫽0.03). ICH volume significantly predicted mortality at 30 days (p⫽0.006). Odds of
death after ICH increased 1.8 for every additional 10cc of
hemorrhage volume (95% CI:1.07-3.06). Large hemorrhage
volume predicted poor outcome in this sample. Study supported by NIH K12 RR017627 (LJ).
T-124. Temporal Profile of Quantitative Brain
Diffusion-Weighted MRI after Cardiac Arrest
Dennis M. Campbell, Michael Mlynash, Eric Leproust,
Anna Finley Caulfield, A. Hsia, and
Christine A. C. Wijman; Palo Alto, CA
We determined the temporal profile of brain diffusionweighted MRI (DWI) values in the first week after cardiac
arrest to identify the optimal time window for prognostication.
Methods: Consecutive comatose cardiac arrest patients were
prospectively enrolled. Quantitative DWI measurements
were performed by two independent investigators. The moving average of the mean absolute diffusion coefficient (ADC)
values of individual brain structures in survivors vs. poor outcome patients (death or persistent vegetative state) were compared with controls.
Results: 35 patients with 42 MRI’s were included. Interand intra-rater reliability was excellent. When compared to
controls, survivors displayed a pattern of facilitated diffusion
whereas patients with poor outcome (death or persistent vegetative state) developed restricted diffusion. Cortical structures showed the earliest and most marked deviation from
controls that started 24 hours following the arrest; deep gray
matter structures displayed a more gradual and less severe
change whereas very mild and even more delayed changes
were noted in the white matter structures.
Conclusion: Quantitative brain DWI differentiates patients
with poor outcome from survivors between 24 hours and up
to 5 days after the arrest. DWI changes occur earliest and are
most pronounced in cortical structures. Study supported by
American Heart Association grant# 0430275N.
T-125. Lack of Uniformity in Hospital Brain Death
Guidelines in Renowned U.S. Medical Institutions
David M. Greer, Panayiotis Varelas, Shamael Haque, and
Eelco F. Wijdicks; Boston, MA; Detroit, MI; and
Rochester, MN
Introduction: In accordance with the Uniform Determination of Death Act, guidelines for brain death determination
are developed at an institutional level, potentially leading to
variability of practice. We evaluated the differences in brain
death guidelines in major U.S. hospitals with a strong presence of neurology and neurosurgery.
Methods: We reviewed the U.S. News and World Report
top 50 neurology/neurosurgery institutions’ guidelines for
brain death determination for 5 categories of data: guideline
performance, pre-clinical testing, clinical examination, apnea
testing and ancillary tests.
Program and Abstracts, American Neurological Association
Results: There was an 82% response rate to requests. Major
discrepancies were present among institutions for all 5 categories. Significant variability existed for performance of the
evaluation, pre-requisites prior to testing, specifics of the
brainstem examination and apnea testing, and what types of
ancillary tests could be performed, including what pitfalls or
limitations might exist.
Summary: Major differences exist in brain death guidelines
among the leading neurological hospitals in the U.S. Adherence to the AAN guidelines published in 1995 is quite variable, leading to significant differences in practice which may
have consequences for the determination of death and initiation of transplant procedures.
T-126. Cholinergic Brainstem Nuclei Involved in
Sleep Regulation Imaged by PET
Wolf-Dieter Heiss, Carsten Eggers, Brigitte Szelies,
Bernd Bauer, Klaus Wienhard, Hansjoerg Schroeder, and
Karl Herholz; Cologne, Germany; and
Manchester, United Kingdom
A complex neuronal network participates in regulation of
sleep. A major activating source is a pair of acetylcholine producing cell groups, the pedunculo-pontine and laterodorsal
tegmental nuclei (PPT / LDT).
PET with 11C-N-methyl-4-piperidyl-acetate (MP4A, 550 –
740 MBq) was applied in 9 healthy volunteers and 2 patients
with mild AD to assess acetylcholine esterase (AChE) activity
in MRI-identified brainstem nuclei. AChE activity was also
measured in the cerebral cortex.
Uptake ratios in LDT and PPT nuclei relative to cerebellum
yielded reproducible values for apparent AChE activity in
controls and reduced values in AD, especially in disturbed
sleep. Cortical AChE activity in the 2 AD patients was markedly below the value in healthy volunteers. AChE activity
was different between the 2 patients: the patient with sleep
disturbance had a slightly better MMSE and a slightly higher
k3 than the patient without.
This is the first report of imaging AChE activity in small
brainstem nuclei, indicating decreased cholinergic activity in
AD, especially with sleep disturbance. The application of
MRI guided high resolution PET of targeted tracers might
permit to investigate the interaction of various nuclei in the
complex network regulating sleep and wakefulness.
T-127. Modafinil Improves Behavioral Alertness in
Patients with Obstructive Sleep Apnea (OSA) Treated
with Nasal Continuous Positive Airway Pressure
(nCPAP) with Residual Excessive Sleepiness (ES)
Max Hirshkowitz, David F. Dinges, and Jed E. Black;
Houston, TX; Philadelphia, PA; and Stanford, CA
Objective: Modafinil significantly improves wakefulness in
nCPAP-treated OSA patients with residual ES. This analysis
determined modafinil’s effect on behavioral alertness.
Methods: A multicenter, double-blind, placebo-controlled,
3-month study randomized patients to modafinil (200 or
400 mg) or placebo. Behavioral alertness was assessed with
the Psychomotor Vigilance Test (PVT). We evaluated
changes from baseline in speed of reaction times (RT), the
ability to sustain attention without lapses, the stability of
alertness, and the number of response errors (index of impulsivity).
Results: Unless otherwise noted, values are expressed as
mean changes from baseline. Modafinil significantly decreased mean RT versus placebo (-14.4 vs ⫹1.3 msec,
Annals of Neurology
Vol 62 (suppl 11)
P⬍.0001). Modafinil significantly improved ability to sustain attention without lapses (-1.8 for modafinil vs -0.24 for
placebo, P⫽.0006). Wake-state stability was improved by
modafinil; mean SD of correct RTs was -30.4 for modafinil
vs ⫹45.5 for placebo (P⫽.0001). No difference was found
between groups in percentage of incorrect RTs. Most commonly reported adverse events were headache, infection, and
Conclusions: Modafinil is well tolerated and improves behavioral alertness in nCPAP-treated OSA patients with residual ES. Study supported by Cephalon, Inc.; Dr. Hirshkowitz
has served as a consultant and speaker for, and received
grant-research support from Cephalon, Inc. Dr. Dinges has
served as a consultant for, and received honoraria and grants
from Cephalon, Inc. Dr. Black has served as a consultant for
and received research support from Cephalon, Inc.
T-128. Modafinil Improves Performance Requiring
Sustained Attention in Patients with Narcolepsy
Andrew D. Krystal, and David F. Dinges; Durham, NC; and
Philadelphia, PA
Background: Narcolepsy is associated with impaired performance and lapses of attention. In this analysis modafinil was
compared with placebo in patients with narcolepsy completing a task requiring sustained attention.
Methods: More than 500 patients with narcolepsy were enrolled in a 9-week, multicenter, randomized, double-blind,
placebo-controlled trial. In addition to safety and efficacy,
the patients’ ability to avoid hitting obstacles was assessed
during a 30-minute driving-like sustained attention test
called Steer Clear.
Results: Modafinil significantly improved performance compared to placebo at all evaluated time points (3, 6, and 9
weeks). At baseline, the mean percentage of obstacles hit by
patients on modafinil 200 mg was 8.2% vs 7.8% for placebo. Patients on modafinil 200 mg showed a decrease in
obstacles hit vs placebo: at week 3, 6.2 vs 8.2 (P⫽.002); at
week 6, 5.7 vs 7.9 (P ⫽ .004); at week 9, 5.9 vs. 8.7
(P⫽.004). Significant decreases in obstacles hit were also
seen at all weeks evaluated for patients given modafinil 400
Conclusion: Modafinil treatment significantly improves performance on a driving-like task requiring sustained attention
in patients with narcolepsy, which was consistent with results
in other patient populations. Study supported by Cephalon,
Inc; Dr. Krystal is a consultant and receives grant support
from Cephalon, Inc. Dr. Dinges is a consultant, and has received honoraria, and grants from Cephalon, Inc.
T-129. Zolpidem Induced Arousal by Paradoxical
GABAnergic Stimulation – Case Report with F-18
Flumazenil & F-18 FDG PET Study
Bum S. Kwon, Jeong Yeo, and Kwang-Ki S. Kim;
Koyang, Kyungki, Korea
Zolpidem is a non-benzodiazepine drug belonging to the
imidazopiridine class. It has a selectivity for stimulating the
effect of gamma amiobutyric acid (GABA) and is used for
therapy of insomnia. We experienced paradoxical effect of
zolpidem by 48 year-old male who had hypoxic brain damage after cardiac arrest. He was confused and could not communicate with his family. His Glasgow coma scale (GCS)
was E2M5V2 and his cognition was grade III by Rancho Los
Amigos (RLA). We tried zolpidem for induction of sleep,
but he became alert (GCS 15, RLA VII) and communicable
30 minute after administration of zolpidem. This arousal
lasted 3 hours and repeated every time of medication. EEG
showed the reversal of slow wave into beta range fast activity.
F-18 Flumazenil PET showed increased GABAnergic receptor activity in both frontoparietotemporal cortex after zolpidem administration compared to baseline status (zolpidem
off). F-18 FDG PET did not show any glucose metabolic
difference between baseline and zolpidem trial status. Our
hypothesis is abnormal GABA receptor after brain ischemia
induced the arousal by stimulation of zolpidem.
T-130. Epidemiology of Hypersomnolence in the
American General Population
Maurice M. Ohayon; Palo Alto, CA
Epidemiological studies on hypersomnolence have assessed
two aspects: excessive sleep quantity and sleep propensity
during wakefulness (excessive sleepiness). Unfortunately, differences in definition and variance in results do not make it
possible to reach any definite conclusions. This study aims to
assess hypersomnolence in the general population. The population was non-institutionalized individuals aged 18 or over
living in Texas, New York and California states. A representative sample of 8,937 individuals was interviewed by telephone using the Sleep-EVAL system. Interviews included a
questionnaire on hypersomnolence, sleeping habits, sleep disorders and mental disorders. Sleeping too much was reported
by 3.5% of the sample; less than 30% of these individuals
slept nine hours or more per 24-hour period. Individuals
with bipolar disorder (OR:2.2), generalized anxiety disorder
(OR: 2.4), obsessive-compulsive disorder (OR:1.6), panic
(OR:1.5) or posttraumatic stress disorder (OR: 2.1) were
more likely to report too much sleep. As many as 11.1% of
the population reported being severely sleepy and 19.5%
moderately sleepy during wakefulness. The different measures of sleepiness had moderate correlations between them
(r between 0.22 and 0.35). A strict definition of hypersomnolence is important for comparison between studies and
identification of its risk factors. Study supported by Cephalon Inc.
T-131. Modafinil Improves Wakefulness in Patients
with Chronic Shift Work Sleep Disorders (SWSD)
Thomas Roth, Kenneth P. Wright, Jonathan R. L. Schwartz,
Charles A. Czeisler, and David F. Dinges; Detroit, MI;
Boulder, CO; Oklahoma City, OK; Boston, MA; and
Philadelphia, PA
Background: This study evaluated modafinil in improving
wakefulness in patients with SWSD as assessed by the objective Multiple Sleep Latency Test (MSLT) and the subjective
Karolinska Sleepiness Scale (KSS).
Methods: In this 3-month, double-blind, placebo-controlled
study, nightshift workers with excessive sleepiness for ⱖ3
months were randomized to modafinil 200 mg or placebo.
Patients who were symptomatic at baseline and became more
alert by final visit were assessed with the MSLT and KSS.
Results: Of patients given modafinil, 20% showed improved
wakefulness (MSLT ⬎6 minutes) by final visit compared to
14% given placebo. Patients were 1.6 times more likely to
have improved objective wakefulness after modafinil than
placebo (OR: 1.6; 95% CI, 0.71-3.46). As determined by
the KSS, 35% of patients given modafinil were less sleepy
compared to 14% given placebo. Patients were 3.2 times
more likely to be less subjectively sleepy after receiving
modafinil than placebo (OR: 3.2, 95% CI, 1.55-6.52). Even
after modafinil administration, patients had excessive sleepiness at night. Seven patients withdrew because of adverse
events (modafinil, n⫽3; placebo, n⫽4).
Conclusion: Modafinil is well tolerated and improves wakefulness compared with placebo in patients with SWSD.
Study supported by Cephalon, Inc; Dr. Roth has served as a
consultant for Cephalon, Inc. Dr. Wright has served as a
consultant for and has been on the speakers’ bureau of and
received grant-research support from Cephalon, Inc. Dr.
Schwartz has served as a consultant for and has received
grant-research support from Cephalon. Dr Czeisler has
served as a consultant and speaker for, and received unrestricted research and education funds from Cephalon Inc. Dr
Czeisler is also the incumbent of an endowed professorship
provided to Harvard University by Cephalon Inc. Dr.
Dinges has served as a consultant for, received honoraria and
grants from Cephalon, Inc.
T-132. Modafinil Improves Behavioral Alertness in
Shift-Work Sleep Disorder (SWSD)
James K. Walsh, David F. Dinges, Thomas Roth,
Kenneth P. Wright, Jonathan R. L. Schwartz, and
Charles A. Czeisler; St. Louis, MO; Philadelphia, PA;
Detroit, MI; Boulder, CO; Oklahoma City, OK; and
Boston, MA
Objective: Assess whether modafinil improves behavioral
alertness in patients with SWSD by testing reaction to stimuli with the Psychomotor Vigilance Test (PVT).
Methods: In this 3-month, double-blind, placebo-controlled
study, nightshift workers with excessive sleepiness and daytime insomnia for ⱖ3 months were randomized to modafinil
200mg or placebo. The PVT assessed the ability to sustain
attention without lapses, and to maintain wake-state stability
and speed of reaction times (RT), without increases in response errors (index of impulsivity).
Results: The difference from baseline in mean number of
attention lapses revealed that modafinil significantly improved patients’ ability to sustain attention (modafinil -3.8 vs
placebo ⫹7.2, P⬍.01). Modafinil significantly improved
wake-state instability as evident in the difference in mean SD
of correct RTs (modafinil 173.4msec vs placebo 441.8msec,
P⬍.05). Nether median RT at final visit nor response errors
were differentially affected by modafinil relative to placebo
(P⬎.05). The most common adverse events with modafinil
(vs placebo) were headache (26% vs 19%) and nausea (9%
vs 3%).
Conclusion: Although patients with SWSD continued to
show evidence of excessive sleepiness during the nightshift,
results from the PVT showed that modafinil significantly improved behavioral alertness compared with placebo. Study
supported by Cephalon, Inc; Dr. Walsh has served as a consultant for and received grant-research support from Cephalon, Inc. Dr. Dinges has served as a consultant for, and received honoraria and grants from Cephalon, Inc. Dr. Roth
has served as a consultant for Cephalon, Inc. Dr. Wright has
served as a consultant for and has been on the speakers’ bureau of and received grant-research support from Cephalon,
Inc. Dr. Schwartz has served as a consultant for and has received grant-research support from Cephalon. Dr Czeisler
has served as a consultant and speaker for, and received unrestricted research and education funds from Cephalon Inc.
Dr Czeisler is also the incumbent of an endowed professorship provided to Harvard University by Cephalon Inc.
Program and Abstracts, American Neurological Association
T-133. How Much of the Brain Is Dead in Brain
Death? A Neuropathological Study in the Modern
Transplant Era
Eelco F. M. Wijdicks, and Eric A. Pfeiffer; Rochester, MN
Introduction: The neuropathological characteristics of brain
death are known as “respirator brain.” The degree of neuronal destruction in patients with brain death has not been
reported in the transplant era.
Methods: We reviewed brain pathology in 43 brain dead
patients Brain tissue slides were retrieved and wet tissue was
taken to complete a series of samples for each patient.
Results: 35 brains were obtained between 12 and 30 hours
and 9 brains between 0 to 12 hours. The causes of brain
death were MVA (n⫽33), stroke (N⫽6), cardiac arrest
(N⫽2), encephalitis (N⫽1), and brain edema (n⫽1). Cerebral edema was found in all patients and autolysis of the
cerebellum was present in 36 of 43 (84%) patients. Complete neuronal loss was variable and present in 53- 69 % of
the hemispheres. Complete neuronal loss was less common
in the thalamus (34%), midbrain (37%), pons (41%) and
medulla (40%).
Conclusions: Sampling of the brain and brainstem shows
variable neuronal loss in Brain Death. Cerebellum autolysis
common. Total brain necrosis is rarely observed due to earlier preservation of the brain and more efficient organ harvesting programs.
T-134. Influence of Circadian Timing in Shift-Work
Sleep Disorder (SWSD)
Kenneth P. Wright, David F. Dinges, Thomas Roth,
James K. Walsh, and Charles A. Czeisler; Boulder, CO;
Philadelphia, PA; Detroit, MI; Chesterfield, MO; and
Boston, MO
Introduction: Failure of the circadian timekeeping system to
adapt to shift work may be a primary factor in impaired
nighttime alertness and disrupted daytime sleep. This analysis evaluated the influence of circadian phase on sleepiness
and alertness in SWSD patients during a simulated nightshift.
Methods: The timing of 3 pg/mL dim light (⬍50 lux) melatonin onset (DLMO) or offset (DLMOff) in saliva collected
hourly from 2000-0800h was used as a circadian phase
marker in patients assessed after 3 consecutive nightshifts.
Sleepiness and alertness were assessed every 2h; daytime sleep
from 1000-1800h.
Results: Of 204 patients, high melatonin levels in 45%
(DLMO) indicated minimal circadian adaptation and 14%
(DLMOff) indicated circadian phase advance. Differences in
circadian phase had no significant effect on objective MSLT
sleepiness scores (P⫽.66). However, patients with phaseadvanced DLMOff showed improved subjective sleepiness
(KSS, P⫽.0554) and significantly improved behavioral alertness (PVT, P⫽.0209) compared to DLMO. Both groups
showed clinically significant disruption in daytime sleep;
however, sleep efficiency was significantly worse in DLMOff
Conclusions: Physiologic sleepiness is similar for SWSD patients regardless of circadian phase. However, differences in
circadian timing appear to influence subjective sleepiness, behavioral alertness, and daytime sleep. Study supported by
Cephalon, Inc.; Dr. Wright has served as a consultant for,
Annals of Neurology
Vol 62 (suppl 11)
has been on the speakers’ bureau of, and received grantresearch support from Cephalon, Inc. Dr. Dinges has served
as a consultant for and received honoraria and grants from
Cephalon, Inc. Dr. Roth has served as a consultant for
Cephalon, Inc. Dr. Walsh has served as a consultant for and
received grant-research support from Cephalon, Inc. Dr
Czeisler has served as a consultant and speaker for, and received unrestricted research and education funds from
Cephalon Inc. Dr Czeisler is also the incumbent of an endowed professorship provided to Harvard University by
Cephalon Inc.
T-135. Modulating Microglial Activity and
Neuroprotection: New Experimental Approaches
Alan I. Faden, Kimberly R. Byrnes, and Bogdan S. Stoica;
Washington, DC
Microglial associated inflammation is implicated in acute and
chronic neurodegeneration. Using microarrays, we found upregulation of numerous microglial inflammatory factors after
spinal cord injury (SCI); some are chronically increased and
are associated with cell death in vitro. We show that metabotropic glutamate receptor 5 (mGluR5), normally found in
neurons and able to inhibit caspase dependent neuronal apoptosis, is highly expressed in microglial cultures after lipopolysaccharide (LPS) stimulation. Pre-treatment with the
mGluR5 agonist CHPG or apocynin, an inhibitor of microglial factor p22phox, strongly inhibit LPS-induced microglial
activation as reflected by decreased proliferation, nitric oxide
production, and TNF_ secretion. Co-culturing LPS-activated
microglia with neurons causes neurotoxicity; pre-treatment
of microglia with CHPG or apocynin before LPS blocked
neuronal death. In parallel studies, CHPG or vehicle were
infused intrathecally after moderate impact SCI in rats.
CHPG treatment markedly reduced markers of microglial
inflammation, including ED1 and p22phox, and significantly improved chronic behavioral recovery. In this SCI
model, apocynin significantly reduced lesion volume. Collectively, these studies indicate that mGluR5 and p22phox represent potential targets for attenuating microglial-related inflammation and associated neurotoxicity. Study supported by
T-136. Neuroprotective Activity of Urea and
Dexamethasone in the Osmotic Demyelination
Syndrome in Laboratory Rats
Helard A. Miranda, and Rosa G. Reymundo;
Cincinnati, OH; and Lima, Peru
OBJECTIVE: To determine if Urea (UR) or Dexamethasone (DX) have neuroprotective activity in preventing the
osmotic demyelination syndrome (ODS) in laboratory rats,
administering these before correct improperly severe hyponatremia.
BACKGROUND: DX and UR have shown in previous
studies diminish the clinical effects of ODS. Rat is an accepted animal model for the study of CPM. Rat anterior
cerebral commissure (ACC) is a structure preferably involved in ODS.
METHODS: We reproduce ODS respecting the protocol
sketched for Kleinschmidt and Norenberg; in a 45 Sprague
Dawley rats divided in 3 experimental groups; 15 for control
group, 15 who received DX before inadequate hyponatremia
correction; then 15 who received UR before equal procedure.
Serum Na was measured 3 times during protocol.
We measured demyelination in medial para sagytal sections of
ACC, previously dyed using histochaemic technique for myelin, Luxol fast blue. We used computerized morfometric measures of previously digitized microscopic images.
RESULTS: Significance statistic difference was found using
ANOVA (p⬍0.005) between experimental groups. Then us-
ing Mann Whitney statistic test we found superiority in DX
versus UR (p⫽0.001) and UR versus Control group
CONCLUSIONS: Probably DX first, then UR has neuroprotective effects in ODS.
DOI: 10.1002/ana.11641
Program and Abstracts, American Neurological Association
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