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Tuesday, October 10, 2006
doses, thereby reducing side effects. Study supported by
Pfizer, Inc.; Co-authors Philip Iredale and Frank Menniti
have financial relationship with the supporting entity.
T-1. Trophic Factor Gene Transfer in Parkinson’s
Disease: Preliminary Outcomes from the Phase I
CERE-120 Study
William J. Marks, Jr., Leo Verhagen Metman,
Philip A. Starr, Paul S. Larson, Roy A. Bakay, Robin Taylor,
Daniel R. Lee, Deborah Cahn-Weiner, Raymond T.
Bartus, and Jill L. Ostrem; San Francisco, CA; Chicago, IL
and San Diego, CA
Objective: We sought to evaluate the safety, tolerability, and
potential efficacy of CERE-120 in Parkinson’s disease. Background: Neurturin and GDNF are closely-related neurotrophic factors that prevent degeneration of dopaminergic nigrostriatal neurons and improve motor function in animal
models of PD. CERE-120 is an adeno-associated viral vector
encoding human neurturin cDNA. CERE-120 has been
shown to provide steady, long-term, safe, and biologically active expression of neurturin in animal studies, including PD
models. Design/Methods: PD patients (H&Y Stage 3-4) received one of two dose levels (N⫽6 each) of CERE-120 via
bilateral intraputaminal injections. Multiple measures at
baseline and post-treatment evaluated safety and clinical response. Results: Dosing was completed in March 2006. No
serious adverse events have occurred. At both 3 and 6
months, the low-dose cohort showed a 25% improvement in
off-medication UPDRS motor scores, a 50% reduction in off
time, and increased on time without dyskinesia. Similar
trends appear to be emerging in the high-dose cohort. Conclusions: Intraputaminal administration of CERE-120 is safe
and well tolerated. Initial efficacy outcomes are encouraging.
Detailed six-month follow-up data on both cohorts will be
presented. Study supported by Ceregene, Inc.; Lee: Employee. Bartus: Employee and officer.
T-2. A Selective Cannabinoid CB1 Antagonist
Increases Levodopa Responses in Parkinsonian Monkeys
Xuebing Cao, Philip A. Iredale, Frank S. Menniti,
John T. Greenamyre, and Stella M. Papa; Atlanta, GA and
New York, NY
The modulating action of presynaptic cannabinoid receptors
on neurotransmission particularly at terminals in globus pallidus seems to affect motor behavior in the parkinsonian setting. We tested a cannabinoid CB1 antagonist, CE, in
treatment-naı̈ve parkinsonian monkeys as monotherapy and
in co-administration with levodopa. CE was also tested in
dyskinetic monkeys. CE doses were 0.03-1 mg/kg s.c., and
levodopa methyl ester doses (s.c.) were selected as optimal
and suboptimal doses (maximal and 50% maximal response).
Motor disability was scored at regular intervals after drug administration with a standardized scale. CE had no effects per
se on motor behavior in treatment naı̈ve or levodopa-primed
parkinsonian monkeys. CE (0.3-1 mg/kg) increased suboptimal responses to levodopa predominantly by producing a
30% longer ‘on’ state (p ⬍ 0.01). Lower disability scores
were also demonstrated since the onset of the ‘on’ state. Optimal responses to levodopa were unchanged by CE coadministration. CE had no effects on levodopa-induced dyskinesias. These results suggest that selective cannabinoid CB1
antagonists may enhance the antiparkinsonian action of dopaminomimetics, and possibly facilitate the use of lower
T-3. Effects of STN-DBS Surgery on Sensorimotor
Integration in Brain – A Longitudinal TMS Study
Aparna Wagle Shukla, Elena Moro, Carolyn Gunraj,
Andres M. Lozano, Anthony E. Lang, and Robert Chen;
Toronto, ON, Canada
Deficient sensorimotor integration in Parkinson’s Disease(PD) was investigated in a previous Transcranial Magnetic Stimulation(TMS) study. They found reduced short latency afferent inhibition(SAI) to be reflective of
dopaminergic medications side-effects & reduced long latency afferent inhibition(LAI) to be independent of medications suggesting non-dopaminergic manifestations. Effects of
subthalamic nucleus-deep brain stimulation(STN-DBS) surgery on SAI and LAI in PD are unknown and were evaluated
in the present study. Eleven patients were compared with 10
age-matched normals. Patients were assessed one(acute) and
six(5 patients-chronic effect) months post-surgery. Each assessment included study in four conditions: (MED-OFF &
ON and both with STIM-OFF & ON). SAI and LAI were
studied with median nerve stimulation at wrist preceding the
TMS pulse(20 & 200 ms respectively), applied to contralateral motorcortex and recording EMG response from ipsilateral first Dorsal Interosseous muscle. One-month postoperatively, there was no significant effect of medication and/or
stimulation on SAI or LAI. At six-months, SAI reduced in
presence of medications and LAI reduced independent of
medications, normalizing in MED-ON/STIM-ON condition. These results suggest, chronic STN stimulation positively affects both dopaminergic side-effects(SAI) and nondopaminergic PD manifestations(LAI) presumably due to
long-term plastic changes in brain. Study supported by the
Michael J. Fox Foundation (MJFF) for Parkinson’s Research
& Canadian Institutes of Health Research.
T-4. Parkinson’s Disease and Melanoma: An
Epidemiologic Evaluation
John M. Bertoni, John P. Arlette, Hubert H. Fernandez,
Karen Frei, Mark F. Gordon, Mohamed N. Hassan,
Stuart H. Isaacson, Mark F. Lew, Eric Molho,
William G. Ondo, Tania J. Phillips, Carlos Singer,
James P. Sutton, and John E. Wolf, Jr.; Omaha, NE;
Fountain Valley, CA; Great Neck, NY; Houston, TX;
Albany, NY; Los Angeles, CA; Oxnard, CA;
Calgary, AB, Canada; Boston, MA; Hartford, CT;
Boca Raton, FL; Gainesville, FL and Miami, FL
Neurologists from 31 North American movement disorder
centers enrolled 2106 patients with idiopathic Parkinson’s
disease (PD), confirmed by medical history and examination,
in a survey to evaluate the possible association between PD
and melanoma. Dermatologists then collected melanoma risk
factor information, performed whole-body examinations, and
biopsied suspicious lesions. Mean patient age was 68.6 ⫾
10.6 years, mean PD duration 7.1 ⫾ 5.7 years, and mean
H&Y score 2.2 ⫾ 0.7. Most patients (84.8%) were taking
levodopa. Dermatologists identified 346 patients with suspicious pigmented lesions; dermatopathology confirmed 20 in
situ melanomas (0.95%) and 4 invasive melanomas (0.19%).
Patient histories recorded 72 prior melanomas. No relationship between occurrence of melanoma (prior or at examination) and levodopa usage was observed. Prevalence (5-year
© 2006 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
limited-duration) of invasive melanoma in US PD patients
(n⫽1692) was 2.2-fold higher (95% CI 1.21-4.17) than expected in age- and sex-matched populations in the national
SEER database. Compared with American Academy of Dermatology screening programs, age- or sex-adjusted relative
risk of any melanoma at screening was ⬎8 for US patients.
These data support existing evidence of an association between melanoma and PD. Increased dermatologic screening
may be warranted for PD patients. Study supported by Teva
Pharmaceutical Industries, Ltd., Petach Tikva, Israel; Dr.
Lew is a consultant, researcher and has received honoraria for
speaking for Teva. Dr. Gordon has received an honorarium
for speaking for Teva. Pacific Neuroscience Medical Group
has received financial compensation for other work performed as part of TEVA’s clinical drug development program; Dr. Sutton is the sole shareholder of Pacific Neuroscience Medical Group. The other authors have no
substantial personal finanacial relationship to disclose.
T-5. Mutation Analysis of the PINK1 Gene in 642
Patients with Parkinson Disease
Ryuya Kumazawa, Hiroyuki Tomiyama, Manabu Funayama,
Hiroyo Yoshino, Hirohide Takahashi, Fumihito Yoshii,
Yoshikuni Mizuno, and Nobutaka Hattori;
Tokyo, Bunkyo, Japan and Isehara, Kanagawa, Japan
Objective: To determine the frequency, distribution, and
clinical features of Parkinson disease (PD) with PINK1 mutations. Methods: We performed extended mutation analyses
in 642 parkin-negative PD patients from13 countries using
sequencing of PCR or quantitative analysis with TaqMan assay. Results: We found 11 PINK1 mutations including 7
novel mutations (homozygote ⫽ c.889del G: p.318X and
W437R; heterozygote ⫽ A78V, c.585del C: p.220X,
M342V, W437R, V482M, and N542S). We found no compound heterozygous missense mutation. The frequency of
homozygous mutations was 5.88% in autosomal recesive PD
(ARPD) families and 0.21% in sporadic PD patients. The
frequency of heterozygous mutations was 3.74% in autosomal dominant PD (ADPD) families and 0.42% in sporadic
PD patients. At age of PD onset, patients with single heterozygous mutations (51 ⫾ 11.6, ⫾ SD, range, 39-69 yrs)
were older than those with homozygous mutations (34 ⫾
20.3, 10-55 yrs). Myocardial MIBG uptake was low in patients with heterozygous but not homozygous mutations.
Conclusions: Our results suggest that homozygous PINK1
mutations tend to asssociated with early-onset ARPD, while
single heterozygous mutations associate with late-onset
ADPD and sporadic PD.
T-6. Prevalence and Risk Factors for Reward-Based
Behaviors in Parkinson’s Disease
Jennifer S. Hui, Gail Murdock, David Fly, Megan Gomez,
Jessica Moon, Megan Langille, and Mickie D. Welsh;
Los Angeles, CA
Objective: To estimate the prevalence of reward-based behaviors (RBBs) using standardized clinical criteria, and to
identify possible risk factors for the expression of RBBs in
Parkinson’s disease (PD). Methods: 39 consecutive PD patients were interviewed by a clinical psychologist and completed the Tridimensional Personality Questionnaire (TPQR). RBBs were diagnosed using empirically-based clinical
criteria, and correlated with demographic characteristics and
DSM-IV criteria. Results: 12/39 (31%) subjects demonstrated probable, possible or definite RBBs. All patients with
Annals of Neurology
Vol 60 (suppl 3)
behaviors meeting “definite” criteria (n⫽4) also met criteria
for DSM-IV diagnoses. Subjects manifesting RBBs were
younger (p⬍0.003), had longer disease duration (p⬍0.030),
and scored significantly higher on the Novelty Seeking dimension of the TPQ-R (p⬍0.012) compared to those without RBBs, but did not differ with respect to medication
class. Conclusions: The prevalence of RBBs in PD is higher
than previously expected when behaviors are screened for
collectively using empirically-based clinical criteria. Although
dopaminergic medication has been implicated in the development of RBBs, underlying personality traits such as Novelty Seeking may be significant risk factors for the development of these behaviors.
T-7. Contribution of Parkin to Familial Aggregation
of Early-Onset PD
Karen Marder, Yuanjia Wang, Lorraine N. Clark,
Helen Mejia-Santana, Juliette Harris, Elan D. Louis,
Lucien Cote, Stanley Fahn, Howard Andrews, Cheryl Waters,
Blair Ford, Steven Frucht, and Ruth Ottman; New York, NY
Objective: To evaluate the contribution of parkin mutations
to familial aggregation of early-onset PD.
Methods: The parkin gene was screened for sequence variants, exon deletions and duplications in 211 PD probands
with AAOⱕ50 and 105 controls. The probability that each
first-degree relative carried a mutation was based on the proband’s carrier status and relative’s relationship to proband.
Penetrance was computed based on diagnoses of PD in relatives and their estimated carrier distribution. Results: 25 PD
probands (11.8%) (5 homozygotes, 3 compound heterozygotes, 17 heterozygotes) and no controls carried parkin mutations. Prevalence of a history of PD was 2.4% (95%CI
0.7-6.1) in 165 relatives of cases with mutations, 1.5%
(95%CI 0.8-2.4) in 1093 relatives of cases without mutations, and 0.9% (95% CI 0.3-2.0) in 650 relatives of controls. Cumulative incidence of PD to age 70 was 5.3% in
relatives predicted to be carriers, 2.2% in relatives predicted
to be non-carriers (p⫽0.60), and 1.0% in relatives of controls. Conclusions: Cumulative incidence of PD was similar
in non-carrier relatives and relatives of controls, suggesting
that increased risk of PD in relatives of PD cases with AAO
ⱕ50 is due in large part to parkin. Study supported by
NS36630, Parkinson Disease Foundation.
T-8. Novel Mutations of the GTP-Cyclohydrolase I
Gene and Their Clinical Consequences of Chinese
Patients with Dopa-Responsive Dystonia
Ning Wang, Wan-Jin Chen, Hui Xie, Shenxing Murong, and
Zhi-Ying Wu; Fuzhou, Fujian, China
Most dopa-responsive dystonia (DRD) is autosomal dominantly inherited with reduced penetrance and caused by mutations in the GTP-cyclohydrolase I gene (GCH-I). The
spectrum of mutations and their clinical consequences have
been investigated in patients with DRD in different ethnic
populations. Up to date, 91 mutations have been reported,
however none of them is of the Chinese origin. Here we
screened the mutations of GCH-I gene by direct sequencing
in 120 unrelated healthy Chinese and 9 unrelated Chinese
DRD families, including 11 patients and 19 relatives. 7 out
of 9 families were identified to have GCH-I mutations, representing mutation rate of 77.8%. Four mutations are novel
including Glu61Lys, Gln161Pro, 628delC and 753⫹12t3c,
further broadening the mutational spectrum of GCH-I gene.
Also the mutation analysis is helpful to diagnose the atypical
cases then facilitates causal therapy with levodopa. The
Gln48Term mutation might be the specific mutation of
Asian descent. However, it is difficult to establish a correlation between GCH-I mutations and phenotypes of DRD because of a rather variable phenotype and a limited number of
same mutations. Study supported by a grant (2002Y001)
from Fujian Provincial Science and Technology Foundation
and a grant (FJGXQ04002) from Fujian Medical University,
Fuzhou, People’s Republic of China. The authors thank the
people with DRD for their participation.
T-9. Catechol-O-Methytransferase Enzyme Gene
Polymorphism (COMT RS 6267) Play a Role in
Susceptibility in Parkinson’s Disease and Levodopa
Induced Dyskinesia: Genetic Predictors in Parkinson’s
Disease Progression (GEPIP) Chort Study
Sea-Mi Park, A-hyun Cho, Myoung-Chong Lee, Jiyoung Lim,
and Kyuyoung Song; Seoul, Korea
Background: levodopa induced dyskinesia (LID) is a characteristic complication in Parkinson’s disease (PD) with
chronic levodopa therapy. The genetic differences may determine heterogeneous COMT activity effect on the susceptibility to PD and the levodopa response. We hypothesized the
individual genetic factors correlated particular COMT alleles
could play a role in susceptibility to PD and early occurrence
of LID. Method: We consecutively recruited 179 typical PD
patients with regular levodopa therapy for at least 4-years in
GEPIP chort and compaired with 429 matched controls. At
first visit, we genotyped COMT RS 6267 and after 4 years,
we evaluated LID. We performed subgroup analysis. PD
group was more associated with the COMT G/T , T/T genotypes than controls (G/T and T/T - 21.8% in PD Vs 14.5%
in controls, P⫽0.027). In subgroup analysis, early LID was
weakly associated COMT G/T , T/T genotypes than the late
LID (G/T and T/T - 33.3% in early LID Vs 11.9% in late
LID, P⫽0.131). Conclusion: In Korean population,
COMT RS6267 play a role in susceptibility to PD and LID.
T-10. The 3-Year Course of Schizophrenia among
Persons with Tardive Dyskinesia and Persons without
Haya Ascher-Svanum, Baojin Zhu, Douglas Faries,
Bruce Kinon, and Mauricio Tohen; Indianapolis, IN
Objective: To compare the 3-year course of schizophrenia between persons with tardive dyskinesia (TD) and persons without. Methods: Data were drawn from a large, nonrandomized
naturalistic study of persons treated for schizophrenia. Treatment outcomes were assessed at 12-month intervals using
standard psychiatric measures and medical record abstraction.
Using repeated measures analyses, participants with probable
TD at enrollment (fulfilling Schooler-Kane criteria, N⫽621,
29.5%) were compared with participants who did not
(N⫽1482), on clinical and functional measures across the
3-year study. Results: Participants with TD had, across the
3-year study, significantly more severe psychopathology, were
less likely to experience symptom remission, had more severe
EPS, and poorer level of functioning. Results were essentially
unchanged following adjustments for known correlates of TD
and when using a subgroup of participants with persistent TD
(at enrollment and at 1 year). Conclusions: In the long-term
treatment of schizophrenia, persons with TD have a significantly more severe and more refractory course of illness than
persons without TD, suggesting poorer prognosis and need for
specialized interventions. Study supported by Eli Lilly and
Company; employees of Eli Lilly and Company.
T-11. Rasagiline Improves Quality of Life (QoL) in
Early Parkinson’s Disease (PD): Symptomatic Effects
and Measures of Global Improvement
John M. Bertoni, and Phyllis M. Salzman; Omaha, NE and
Horsham, PA
Non-motor aspects of PD are often more troublesome than
motor symptoms. Rasagiline (N-propargyl-1[R]-aminoindan)
mesylate, a novel, potent, second-generation, selective, irreversible MAO-B inhibitor, improved total (p⬍0.0001) and motor
(pⱕ0.005) UPDRS scores (TEMPO;PSG,Arch.Neurol.2002;
59:1937-1943) in PD patients not yet requiring dopaminergic
therapy. We now report pre-specified secondary and exploratory non-motor endpoints that capture global aspects of patient improvement and treatment response for the 404 early
PD patients randomized (rasagiline 1mg or 2mg, or placebo)
for 26 weeks in TEMPO. Pre-defined global measures were
number of responders (total UPDRS change from baseline ⬍3
points), Clinical Global Impression of Change (including
physician-rated Global Improvement and Severity of Illness),
QoL using the PD-QUALIF, and adverse event frequency.
Rasagiline-treated patients maintained QoL scores while placebo group patients deteriorated (pⱕ0.02; Biglan et al.
Mov.Disord;2006(31 Jan)Epub. Two-thirds of patients receiving rasagiline were “responders” compared to half the patients
receiving placebo (p⬍0.004). Rasagiline-treated patients experienced more global improvement (1mg, p⬍0.015; 2mg, ns)
and severity of illness deteriorated less (p⬍0.01). Adverse
event frequencies were similar in all groups. Once-daily rasagiline provides statistically significant benefits in global improvement and QoL for patients with early PD. Study supported by TEVA Pharmaceutical Industries Ltd, H. Lundbeck
A/S, Teva Neuroscience Inc, and Esai Inc.; Phyllis Salzman is
employed by TEVA Neuroscience as Director, Medical Research.
T-12. Efficacy and Safety of Topiramate in Restless
Legs Syndrome
Bethany Quinn, and Michael P. Biber; Newton, MA
Restless legs syndrome (RLS) is a neurological disorder characterized by unpleasant sensations in the legs, causing delayed sleep onset and sleep interruptions. Preliminary data
suggest that topiramate (TPM), a neurostabilizer used for the
treatment of epilepsy and migraine prevention, may reduce
RLS symptoms due to its multiple modes of action. This
placebo-controlled, double-blind, 8-week study evaluated
TPM (25 mg, titrated up to 150 mg qhs by week 5) in
patients with RLS. The primary endpoint was the difference
in the average number of periodic leg movements (PLM)
over 3 consecutive nights of actigraphy. Secondary assessments included sleep efficiency, time in sleep stages, Epworth
Sleepiness Scale and a modified RLS Rating Scale. Of 44
patients randomized, 33 completed the study. At study end,
there was no significant difference between topiramate- and
placebo-treated patients in the mean ⫾ SD PLM rate
(53.5⫾74.8 vs 41.3⫾41.5) or in any of the secondary endpoints, except for quality of sleep. Adverse events reported
with TPM included fatigue, pharyngitis, paresthesia, insomnia, viral infection, and coughing. Topiramate was not better
than placebo in relieving RLS symptoms. Study supported
by Ortho-McNeil Neurologics, Inc., Titusville, NJ.
Program and Abstracts, American Neurological Association
T-13. Tolerability of Switching from an Oral
Dopamine Agonist to Transdermal Rotigotine in
Parkinson’s Disease
Paul A. Nausidea, Steven Neilson, and Babak Boroojerdi;
Milwaukee, WI and Research Triangle Park, NC
In this Phase IIIb, open-label trial, subjects with idiopathic
Parkinson’s disease (PD) were switched overnight from ropinirole, pramipexole or cabergoline to rotigotine, a D3/D2/D1
dopamine agonist delivered via a transdermal system. Effects
on PD symptoms were assessed by the UPDRS and sleep
scales. Ninety percent of subjects who switched to rotigotine
completed the Treatment period. Eighty percent of subjects
did not require dose adjustment following the switch to
rotigotine, and 9.5% had a single dose adjustment. Twelve
subjects withdrew early, 5 due to AEs (2 from the ropinirole
group, 3 from the pramipexole group). For all subjects completing the Treatment period, mean changes in UPDRS II
and III were -1.4 and -2.5, respectively. Most AEs reported
during rotigotine treatment were consistent with stimulation
of dopamine receptors or use of a transdermal patch. Application site reaction (8.6%) was most frequently reported followed by nausea (6.0%), somnolence (6.0%), and headache
(4.3%). In this trial, overnight switch from ropinirole,
pramipexole or cabergoline to rotigotine was well tolerated
without exacerbating PD symptoms and resulted in an overall symptomatic improvement. Study supported by
SCHWARZ PHARMA; Dr. Babak Boroojerdi is an employee of SCHWARZ PHARMA.
T-14. Restless Legs Syndrome (RLS) Is Twice as
Common in Women Regardless of Family History
Laura A. Brown, Jill A. Searcy, Siong-Chi Lin, Ryan J. Uitti,
and Zbigniew K. Wszolek; Jacksonville, FL
Several studies have demonstrated the prevalence of RLS in
women is nearly twice that of men. Prevalence of familial
RLS in kindreds with a history of parkinsonism remains unknown. Medical and genealogical records of patients with familial RLS alone and familial RLS with a history of parkinsonism were analyzed (n⫽181). Male to female ratio of
patients affected with familial RLS alone (n⫽131) was 42:
89. Familial RLS in combination with a history of parkinsonism was present in 51 patients from 7 kindreds; male to
female ratio of patients with RLS alone was 7:17. Male to
female ratio of those affected with both RLS and parkinsonism was 2:4. These findings confirm previous studies of
higher prevalence of RLS in females regardless of family history of RLS, parkinsonism, or both. The gender ratio in parkinsonism patients in the families studied was reversed with
higher prevalence in males, as seen in sporadic Parkinson’s
disease. Gene interactions may play a role in gender preferences in familial RLS associated with parkinsonism. Further
studies are needed to determine the role of gender in heritability of RLS. Study supported by NIH/NINDS Morris K.
Udall Center for Excellence in Parkinson’s Disease Research.
T-15. Genetic Analysis of the SLITRK1 Gene in
Caucasian Patients with Tourette Syndrome
Hao Deng, Weidong Le, Wenjie Xie, and Joseph Jankovic;
Houston, TX
To determine whether variants in the Slit and Trk-like 1
gene (SLITRK1) are present in American Caucasian population of patients with Tourette syndrome (TS). We sequenced
the 3’-untranslated region for var321, the whole coding re-
Annals of Neurology
Vol 60 (suppl 3)
gion and intron/exon boundaries in the SLITRK1 gene in 82
Caucasian patients with TS from North America. None of
the 82 samples from patients with TS showed the noncoding
sequence variant (var321) and mutation(s) in the coding region of the SLITRK1 gene. In 32 probands from familial TS,
only one patient with TS is heterozygous for a novel
708C⬎T (Ile236Ile) nucleotide variant. Our results indicate
that the var321 and mutation(s) in the coding region of the
SLITRK1 gene probably are rare cause of TS in Caucasian
population; therefore, genetic heterogeneity of TS should be
considered. Tests designed to detect variant(s) in the
SLITRK1 gene probably will not have a diagnostic utility in
clinical practice.
T-16. LRRK2 R1441C/G/H and G2019S Mutations in
Patients with Parkinson’s Disease
Hao Deng, Weidong Le, Yi Guo, Christine B. Hunter,
Wenjie Xie, Maosheng Huang, and Joseph Jankovic;
Houston, TX
In addition to the G2019S mutation in the leucine-rich repeat kinase 2 gene (LRRK2), which is particularly frequent in
patients of Ashkenazi Jewish and Northern African origin,
three amino acid substitutions (R1441C, R1441G, and
R1441H), all at the same residue (R1441), have been identified as important genetic causes of Parkinson’s disease
(PD). To evaluate the frequency of R1441C/G/H and
G2019S mutations in the LRRK2 gene in North American
patients with PD, we screened 496 PD patients from North
America. One Hispanic female was heterozygous for the
LRRK2 R1441G mutation, and six other cases including 2
non-Jewish/non-Hispanic whites, 3 Jews, and 1 Hispanic,
were found to be heterozygous for the LRRK2 G2019S mutation. G2019S mutation in the LRRK2 gene is a common
mutation associated with PD, especially in Jewish PD patients (10.7%), while the R1441C/G/H mutation occurs at a
relatively low frequency in North Americans except possibly
in Hispanics for R1441G. The clinical features of all seven
cases with LRRK2 mutation were quite broad and included
early and late disease onset. These finding may provide new
insights into the cause and diagnosis of PD and have implications for genetic counseling.
T-17. Rasagiline Is Effective and Well Tolerated in
Parkinson’s Disease (PD) Patients with LevodopaRelated Motor Fluctuations Receiving Entacapone
Lawrence W. Elmer, and the Parkinson Study Group;
Toledo, OH and Rochester, NY
Background: Rasagiline, a novel, irreversible MAO-B inhibitor, is efficacious in PD patients with levodopa-related motor fluctuations (PRESTO and LARGO studies). We examined subsets of PRESTO patients taking concomitant
COMT inhibitors (COMT-I) and those not taking
COMT-I. Methods: The PRESTO study examined the effects of once-daily rasagiline 0.5 mg/day, 1 mg/day, or placebo in 472 PD patients with motor fluctuations. Prior to
baseline, all patients were judged by investigators to be taking optimal levodopa/carbidopa (LD/CD); 165 (35%) were
also taking COMT-I, with or without concomitant dopamine agonists. Results: The treatment effect of rasagiline 1.0
mg/day compared to placebo was statistically significant in
the primary endpoint of change in total daily ‘off’ time assessed by patient home diaries and in the secondary endpoint
of global improvement, regardless of concomitant COMT-I
use. UPDRS mental subscores in subjects receiving rasagiline
with adjunctive COMT-I therapy were not significantly
changed. Conclusion: Adjunct rasagiline produced additional
symptomatic benefits in patients taking LD/CD therapy and
COMT-I. Adverse effects, including mental dysfunction,
were not increased when rasagiline was added to multiple
dopaminergic adjunctive agents. Study supported by Teva
Pharmaceutical Industries, Ltd. (Netanya, Israel) and H.
Lundbeck A/S (Copenhagen, Denmark).
T-18. Drug-Induced Parkinsonism: Still Common,
Under-Recognized, and Treatable
Christine D. Esper, and Stewart A. Factor; Atlanta, GA
to assess levodopa responsiveness and diagnosis of PD. Study
supported by Beijing Tiantan Hospital.
T-20. Dopamine Receptor Agonists and Levodopa
Have Similar Propensity To Induce Psychosis-Like
Behaviour in the MPTP-Lesioned Primate Model of
Parkinson’s Disease
Susan H. Fox, Naomi P. Visanji, Tom H. Johnston,
Valerie Voon, and Jonathan M. Brotchie;
Toronto, ON, Canada and Washington, DC
Background: Drug-induced parkinsonism (DIP) is classically
associated with typical neuroleptics. The recent use of atypical antipsychotics (AA) suggests that DIP may occur less frequently, but may also be less recognized. Objective: To examine the frequency, causative agents, and diagnostic
accuracy of DIP patients seen in a movement disorders
clinic, 2004-2005. Methods: Retrospective database and
record review. Results: Of 304 consecutive new parkinsonian patients seen, 8% had DIP. Symptom onset to clinic
presentation averaged 1.6 years. Average age of onset was 71
years and 73% were female. 50% had concomitant tardive
dyskinesia and 83% had tremor. 82% were not diagnosed
with DIP at presentation, and of those cases, 80% were previously evaluated by a neurologist. 46% were diagnosed with
Parkinson’s Disease and started on dopaminergic medication.
55% were due to AA including risperidone, olanzapine, ziprasidone, and aripiprazole; other causative agents were metoclopramide and typical neuroleptics. Of 13 patients followed, 11 improved or remitted 3 months after withdrawal
of medication. Conclusion: DIP remains a common, often
under-recognized cause of parkinsonism, even by neurologists. A high index of suspicion, including risks related to
AA, is warranted. Cessation of the offending agent results in
improvement of symptoms.
The relative ability of dopaminergic drugs to induce neuropsychiatric problems in Parkinson’s disease is controversial.
Recently the dopamine D3-preferring agonist, pramipexole
has been suggested to cause impulsive behaviours. Determining the propensity of dopaminergic drugs to induce such behaviors is difficult clinically due to confounding factors To
investigate these issues, we used the recently described animal
model of psychosis-like behaviours in parkinsonism where
agitation, steretypies, hallucinatory-like and obsessivecompulsive behaviours are seen in MPTP-lesioned primates
after long term levodopa therapy. Levodopa (12.5. mg/kg),
pergolide (0.01 mg/kg), ropinirole (0.16 mg/kg) and
pramipexole (0.06 mg/kg) p.o, were administered and parkinsonism, dyskinesia and psychosis-like behaviours scored
with described rating scales, using post hoc video analysis
blinded to the treatments. There was no significant difference in peak-dose anti-parkinsonian action between levodopa, pramipexole, ropinirole or pergolide (Dunn’s Multiple
Comparison Test P⬎0.05, n ⫽ 6/7). All drugs induced
psychosis-like behaviours; there was no significant difference
in peak-dose psychosis-like behaviours between levodopa,
pramipexole, ropinirole or pergolide (P⬎0.05). Dopamine
D3-preferring agonists are no more likely to cause psychosislike behaviours than levodopa or D2-preferring agonists in
PD. Study supported by Parkinson Society Canada; Krembil
Neuroscience Foundation.
T-19. The Receiver Operating Characteristic Curve of
Acute Consecutive Levodopa Challenge Test in
Parkinson’s Disease
Tao Feng, Yong Jun Wang, and Jian Guo Zhang;
Beijing, China
T-21. Prospective Study of Dietary Pattern and Risk
of Parkinson’s Disease
Xiang Gao, Honglei Chen, Teresa T. Fung, Frank B. Hu,
and Alberto Ascherio; Boston, MA and
Research Triangle Park, NC
Objective: To establish receiver operating characteristic curve
and cutoff of acute consecutive levodopa challenge test.
Methods: The levodopa responsiveness was analyzed in 151
parkinsonian patients, including 102 with clinical diagnosis
of PD and 49 with non-PD parkinsonian syndrome. All patients received consecutive dosage of oral levodopa/benserazide (50/12.5mg, 100/25mg, 150/37.5mg, 200/50mg, 300/
75mg) every morning in five days. The UPDRS part III
scores were evaluated every 30 minutes until 6 hours after
administration. The maximum improvement of UPDRS part
III scores was compared between PD and non-PD. The receiver operating characteristic curves were plotted comparing
PD with non-PD. The cutoff of improvement was defined
according to the curve. Results: The improvement of UPDRS part III scores in PD was higher than that in non-PD
at consecutive dosage (levodopa/benserazide 100/25mg:
29.5% vs. 7.5%; 150/37.5mg: 38.2% vs. 12.4%; 200/50mg:
39.1% vs. 15.8%; 300/75mg: 46.5% vs. 19.9%; p ⬍ 0.01).
When PD was compared with non-PD, the test had 85.9%
sensitivity and 90.9% specificity with cutoff of improvement
at 25.5% for levodopa/benserazide 200/50mg. Conclusion:
The acute consecutive levodopa challenge test should be used
Objectives: To examine associations between dietary patterns
and risk of Parkinson’s Disease (PD) in the Health Professionals Fellow-up Study and the Nurses’ Health Study.
Methods: 47,408 men and 66,819 women free of PD,
stroke, and cancer at baseline were included in the study. We
used factor analysis to identify dietary patterns, and the Alternate Healthy Eating Index (AHEI), and the alternate
Mediterranean Diet Score (aMED) to assess diet quality.
Relative risks (RR) were computed using Cox proportional
hazards models within each cohort, and pooled using a
random-effects model. Results: We documented 254 cases of
PD in men and 166 in women. A prudent dietary pattern,
characterized by high intakes of fruit, vegetables, legumes,
and fish, was inversely associated with PD risk. The pooled,
multivariate-adjusted RR for the top versus the bottom quintiles of the score was 0.71(95% CI: 0.50-1.03;
P-trend⫽0.04). For the AHEI, the pooled, multivariateadjusted RR for the top versus the bottom quintile was
0.68(95% CI: 0.49-0.94; P-trend⫽0.04), and for aMED,
0.71(95% CI: 0.52-0.98; P-trend⫽0.04). Conclusion: Dietary patterns high in fruit, vegetables, legume, and fish may
protect against PD. Benefits of plant-based dietary patterns
Program and Abstracts, American Neurological Association
to PD merit further investigation. Study supported by research grants NS48468, CA87969, and NS35624 from the
National Institutes of Health, Bethesda, Maryland.
T-22. Rotigotine as Adjunctive Therapy to Levodopa
in Advanced-Stage Parkinson’s Disease
Werner Poewe, Nir Giladi, Bernard Boothman,
Diane Maguire, and Babak Boroojerdi; Innsbruck, Austria;
Tel-Aviv, Israel; Blackpool, Lancashire, United Kingdom;
Chesham, Germany and Monheim, Germany
The efficacy and safety of transdermal rotigotine, a D3/
D2/D1 dopamine agonist, was compared to placebo and
pramipexole in patients with advanced PD inadequately controlled with levodopa. The primary efficacy measurement
was reduced “off” time. Compared to baseline, mean daily
decreases in “off” time were: 2.44 hours (rotigotine), 2.82
hours (pramipexole), 0.88 hours (placebo; P⬍.001 rotigotine
vs. placebo). Rotigotine was non-inferior to pramipexole. Additionally, a greater reduction in the proportion of patients
in “off” after waking was observed with rotigotine compared
to placebo. Application site reactions, nausea, and vomiting
were the most common adverse events (AEs). The incidence
of psychiatric AEs was similar between rotigotine and placebo, but higher with pramipexole. The frequency of AEs
leading to trial discontinuation was similar among all groups
(5.4%-7%). Within the pramipexole group, AEs leading to
the highest withdrawal incidence were psychiatric disorders;
none were reported in the placebo and rotigotine groups.
Transdermal rotigotine in this trial showed clinically relevant
and statistically significant reductions in “off” time versus
placebo and a similar effect as pramipexole. Study supported
by SCHWARZ PHARMA; Dr. Babak Boroojerdi is an employee of SCHWARZ PHARMA.
T-23. Medication Effects on Psychosis and Motor
Function in Dementia with Lewy Bodies (DLB)
Jennifer G. Goldman, Christopher G. Goetz,
Melanie Brandabur, Michelle Sanfilippo, Sue E. Leurgans,
and Wenqing Fan; Chicago, IL and Schaumburg, IL
Objective: To assess medication effects in DLB Background:
Pharmacological treatment in DLB carries risk of worsened
psychosis or motor function and neuroleptic sensitivity.
Methods: Probable/possible DLB (McKeith criteria) subjects
were assessed before and after changes in dopaminergic, neuroleptic, and cognitive-enhancing medications with standard
clinical measures. Wilcoxon signed rank tests compared baseline with follow-up. Statistical significance was p⬍0.1. Results: We identified 32 subjects, mean age 74 years (S.D.
5.1), baseline mean UPDRS motor score 37.6 (10.5),
MMSE 20.7 (6.4), and Hoehn-Yahr 3.6 (range 2-5), and
baseline mean levodopa dose 332.2 mg/day (220.7).
Follow-up assessments with either increased (21) or decreased dopaminergics (12), initiation of neuroleptics (14) or
cognitive-enhancers (12) occurred at mean 3.6 months (S.D.
2.5). Thought disorder (TD), UPDRS motor, and HY score
changes were not significant with any medication intervention. However, TD scores worsened with dopaminergic increases (4/20) and improved with dopaminergic decreases (2/
11); cognitive-enhancers improved TD scores (3/11), but
neuroleptics worsened them (4/13) and improved none.
Conclusion: Medications for parkinsonism, psychosis, or
cognition did not significantly affect psychosis or motor
function in DLB. Dopaminergic agents had limited motor
Annals of Neurology
Vol 60 (suppl 3)
benefit but did not clearly worsen psychosis. Study supported by Parkinson’s disease foundation.
T-24. Structural White Matter Abnormalities in
Patients with Idiopathic Dystonia
Leonardo Bonilha, Diana J. Vincent, Chris Rhorden,
Paul S. Morgan, Mark W. Hurd, Paulien M. deVries,
Nada Besenski, Kenneth J. Bergmann, and
Vanessa K. Hinson; Columbia, SC; Charleston, SC;
Nottingham, United Kingdom and Groningen, Netherlands
Purpose: We investigated whether structural white matter
abnormalities, in the form of disruption of axonal coherence
and integrity (measured with Diffusion Tensor Imaging
(DTI)), constitute an underlying mechanism of idiopathic
dystonia (ID). Methods: We studied 7 subjects with ID: six
with cervical dystonia (one with concurrent spasmodic dysphonia), and two with generalized dystonia (both DYT1
negative). We compared DTI MRI images of patients with 7
matched controls, evaluating differences in mean diffusivity
(MD) and fractional anisotropy (FA). Results: ID was associated with larger FA values in close proximity to the insula,
putamen, claustrum, precentral gyrus, cingulate and superior
frontal gyrus. Smaller FA values in patients with ID were
observed in the pallidum, parahippocampal areas, thalamus,
precentral and postcentral gyri, medial and middle frontal
gyri, cingulate gyrus, precuneus, cuneus, and superior temporal sulcus. ID was also associated with increase in MD in
adjacent white matter to the pallidum and putamen bilaterally, left caudate, and in subcortical hemispheric regions including the postcentral gyrus. Conclusion: Patients with ID
show abnormal cortico-subcortical axonal coherence and integrity. Impaired connectivity and disrupted flow of information may contribute to the impairment of motor planning
and regulation in dystonia. Study supported by the study was
partially funded by the Murray Center for Research on Parkinson’s Disease and Related Disorders.
T-25. Medications Associated with the Onset of
Tardive Dyskinesia
Christine Hunter, and Joseph Jankovic; Houston, TX
Tardive dyskinesia (TD), has been causally related to exposure to dopamine receptor blocking drugs (DRBD). With
increasing use of atypical antipsychotics, particularly at high
doses and for extended periods, we may see a rise in the
causality of TD due to these compounds. Other DRBD’s
used to treat a wide array of medical, chiefly gastrointestinal,
conditions are also suspect. These are commonly used in the
elderly and caution should be used in this population. We
report data obtained on retrospective chart review for 262
subjects, 77% female, a mean age of 62.2 years in whom
causal DRBD were identified in 94.3%. The most common
agents associated with onset of TD were metoclopramide
29%, haloperidol 21%, perphenazine 7%, prochlorperazine
6%, risperidone 5%, and olanzapine 4.2%. Common movements seen are stereotypies, oro-lingual dyskinesias, dystonia,
parkinsonism, akathisia and tremor. 41% presented with
mixed symptomatology. TD, a feared and common side effect of DRBD treatment, may be caused by multiple drugs
including antipsychotic and anti-emetic medications. Metoclopramide was the most frequent cause of TD in this series.
In addition to the classic DRBD, atypical antipsychotics are
emerging as a potentially important cause of TD. Study supported by BCM Movement Disorders Clinic.
T-26. MRI and Brainstem Atrophy in Progressive
Supranuclear Palsy (PSP)
Jerzy Slowinski, Akiko Imamura, Ryan J. Uitti,
Audrey J. Strongosky, Robert A. Pooley, Dennis W. Dickson,
Daniel F. Broderick, and Zbigniew K. Wszolek;
Jacksonville, FL
We examined the brainstem atrophy in five pathologically
confirmed PSP patients (three men, mean age at death 77
years, range 64-84 years). Time interval between MRI and
death ranged from 33 to 52 months. Only one patient had
clinical diagnosis of PSP at the time of MRI. Control group
consisted of 19 age and gender-matched healthy subjects.
Seventeen morphometric parameters of the midbrain and
pons were measured on T1 midsagittal and T2-weighted axial MRI scans with Image Analyzer. Measurements of superior cerebellar peduncle (SCP) width were performed on PSP
autopsy specimens. Mean SCP width on MRI in PSP was
2.7 ⫾ 0.8 mm, and was smaller than in controls (3.7 ⫾ 0.5
mm, p ⬍0.001). Mean SCP width at autopsy was 8%
smaller than mean SCP width on MRI. Midsagittal midbrain
area was 99.1 ⫾ 6.9 in PSP and 141.0 ⫾ 18.1 in controls. Midbrain:pons area ratio in PSP was 1:5
and in controls was 1:4. Repeat MRI study 17 months later
in one PSP case revealed 30% decrease of SCP width. Midbrain atrophy measurement on routine MRI study can assist
in making diagnosis of early PSP. Study supported by Jerzy
Slowinski is a recipient of Smith Fellowship at the Mayo
T-27. Deep Brain Stimulation of the Subthalamic
Nucleus on Parkinsons Disease: Effects on Quality of
Alan L. Diamond, Kevin Dat Voung, and Joseph Jankovic;
Houston, TX
Introduction: Advanced Parkinson disease (PD) is associated
with deterioration in health related quality of life (HRQol).
Deep brain stimulation of the subthalamic nucleus (STNDBS) is associated with improvements in motor symptoms
of PD. Methods: A retrospective analysis of the impact of
STN-DBS on HRQol was performed in 40 consecutive patients utilizing the PD Quality of Life scale (PDQUALIF).
Primary outcome was improvement in PDQUALIF total
score. Multiple regression model and Spearman correlation
analysis were used to determine the impact of pre-DBS UPDRS items on HRQol outcomes. Wilcoxin signed rank test
was used to determine the change in HRQol and UPDRS
scores. Results: There were significant improvements in UPDRS III, UPDRS subscales and dyskinesias. There were non
significant improvements in total PDQUALIF score. Only
improvement in PDQUALIF sleep subscale reached significance. More severe tremor, dyskinesias, akinesia and gait/
postural instability items of the UPDRS at baseline strongly
predicted HRQol in PD patients. Conclusion: Although
STN-DBS significantly improved motor function the effects
on HRQol did not reach statistical significance, partly because of retrospective nature. Our findings suggest that many
measures of baseline impairment are predictive of HRQol
outcome. Study supported by Study supported in part
funded by Medtronic.
T-28. Effects of Adenosine A2A Antagonist,
Istradefylline on Motor Response Complications in
MPTP-Treated Monkeys
Tomoyuki Kanda, Shin-Ichi Uchida, Tomomi Tashiro, and
Shizuo Shiozaki; Shizuoka, Japan
Limitations of dopaminergic therapies for Parkinson’s disease
(PD) include the development of motor response complications over long term. Adenosine A2A receptors are a promising non-dopaminergic target. We examined the dyskinetic
potential of istradefylline in 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP)-treated marmosets, a frequently
used model of PD, that were primed to exhibit dyskinesia
through previous exposure to levodopa. Three sets of experiments were conducted in the levodopa-primed MPTPtreated marmosets. (1) Istradefylline (10 mg/kg PO) was
acutely given with or without levodopa (2.5 and 5.0 mg/kg
PO). (2) Istradefylline alone was administered for 21 consecutive days. (3) Istradefylline was also administered in conjunction with levodopa (2.5 mg/kg PO) for 21 days. Istradefylline enhanced and prolonged the antiparkinsonian
activity of levodopa in the levodopa-primed MPTP-treated
marmosets. Administration of istradefylline for 21 days induced no dyskinesia. The coadministration of istradefylline
and levodopa significantly reduced the amplitude of involuntary movements on day 21, compared with treatment with
levodopa alone. The results of this study demonstrate that
Istradefylline 1) does not induce dyskinesia, 2) reduces the
severity of dyskinesia caused by levodopa, and 3) augments
the anti-parkinsonian activity of levodopa in this levodopaprimed animal model of PD.
T-29. Rotigotine Transdermal Patch Improves Quality
of Life in Restless Leg Syndrome
Stiasny-Kolster Karin, Garcia-Borreguero Diego, Saletu Bernd,
Schollmayer Erwin, and Oertel H. Wolfgang;
Marburg, Germany; Madrid, Spain and Monheim, Germany
Rotigotine, a dopamine agonist delivered via transdermal
patch, was evaluated in a 7-week double-blind, placebocontrolled study in moderate to severe idiopathic Restless
Leg Syndrome (RLS). Patients (N⫽340) were randomized to
placebo or one of five rotigotine doses: 1.125mg, 2.25mg,
4.5mg, 6.75mg, and 9.0mg (corresponding to 2.5cm2, 5cm2,
10cm2, 15cm2 and 20cm2 patch sizes). Quality of Life was
measured using the QoL-RLS score. Safety and tolerability
were evaluated by AEs, SAEs, laboratory values, ECG, and
vital signs. A statistically significant treatment difference was
observed for 2.25mg-9mg rotigotine versus placebo, with the
greatest difference (6.8 points on QoL-RLS total score) occurring in the 6.75mg rotigotine group. No clinicallyrelevant changes in vital signs, clinical chemistry, hematology, endocrine parameters or urinalysis were recorded. The
most common AEs (ⱖ5%) were consistent with stimulation
of dopamine receptors or transdermal delivery systems: nausea, application site reaction, fatigue, and headache. In this
trial, rotigotine improved moderate to severe Restless Legs
Syndrome compared with placebo on the QoL-RLS total
score. The quality of live improved consistently on all parameters tested, demonstrating that rotigotine is efficacious,
well tolerated and safe. Study supported by SCHWARZ
Program and Abstracts, American Neurological Association
T-30. Short-Term Effects of Tetrabenazine in Chorea
Associated with Huntington Disease
Christopher Kenney, Christine Hunter, Anthony Davidson,
and Joseph Jankovic; Houston, TX
Objective: To assess the short-term clinical effects of tetrabenazine (TBZ) on choreiform movements in Huntington
disease patients. Design/Methods: A total of 10 patients on
stable doses of TBZ were enrolled in this observation study.
After maintaining a diary of choreiform movements for three
days, patients took their evening dose of TBZ and presented
the next day without taking the usual morning dose. Each
patient’s baseline was assessed using the Unified Huntington
Disease Rating Scale (UHDRS) motor assessment and Beck
Depression Inventory (BDI). The morning dose of TBZ was
then administered and patients were followed with serial
UHDRS motor examinations every 2 hours until choreiform
movements subsided and then returned. Results: TBZ decreased the UHDRS chorea score on average 42.4 ⫾17.8%
(range: 10.0-63.6%). The duration of effect varied from a
minimum of 190 minutes to a maximum of 485 minutes
(mean⫽324 ⫾ 79). No patient experienced an adverse event
related to TBZ or its withdrawal. Conclusion: During shortterm follow up after a single dose, TBZ improves chorea for
about 5 hours. Study supported by Prestwick Pharmaceuticals.
T-31. The Natural History of Spinocerebellar Ataxias
(SCA): The EUROSCA Clinical Project
Thomas Klockgether, Tanja Schmitz-Hübsch,
Sofie Tezenas du Montcel, and
EUROSCA Clinical Study Group; Bonn, Germany and
Paris, France
The EUROSCA Clinical Study Group is a consortium of
ataxia experts from 10 European countries dedicated to clinical research in spinocerebellar ataxias (SCA). To facilitate
clinical trials and genetic research we established a registry
that contains data of more than 2000 European SCA patients. As standardized evaluation methods for ataxia were
lacking, we devised a novel clinical scale, Scale for the Assessment and Rating of Ataxia (SARA), and validated it in
two trials of 167 and 119 SCA patients. In June 2005, a
natural history study of 400 SCA patients (100 patients with
SCA1, SCA2, SCA3 and SCA6) was initiated. Primary outcome measure of this study is SARA. Non-ataxia symptoms
are assessed in a standardized manner, and functional capacity is evaluated with a set of quantitative functional tests. In
addition, a number of clinical scales that measure activities of
daily living, quality of life and depression are applied. We
here present the data of the baseline evaluation of the entire
study population. Study supported by European Union
(EUROSCA/LSHM-CT-2004-503304 ) and the German
Ministery of Education and Research (GeneMove/01 GM
T-32. Effects of Varying Repetitve Transcranial
Magnetic Stimulation (rTMS) in PD
Jau-Shin Lou, Diana Dimitrova, Ryan Eaton, Melanie Davis,
Kevin Blaine, and John Nutt; Portland, OR
Background: Studies have shown that rTMS has inconsistent
effects in PD. Methods: Thirteen subjects were tested before
and after rTMS while off medication. An 800-rTMS stimuli
train was delivered at three intensities/frequencies (1 Hz,90%
of resting motor threshold (RMT); 10 Hz, 90% RMT; and
Annals of Neurology
Vol 60 (suppl 3)
1 Hz,120% RMT) in three visits. We used silent period
(SP), intracortical inhibition (ICI) and facilitation (ICF) to
evaluate cortical excitability. We measured frequency, dwell
time (DT), and movement time (MT) during FT. Results:
rTMS of 1 Hz and 90% RMT tended to increase frequency
and shorten MT but not DT, SP, ICI or ICF. rTMS of 10
Hz and 90% RMT decreased frequency with prolonged DT
but not MT. The ICF tended to be higher but SP and ICI
were not altered. rTMS of 1 Hz and 120% RMT tended to
decrease frequency associated with increased DT and MT
while the SP, ICI and ICF remained unchanged. Conclusion: Subthreshold low frequency rTMS tends to improve
FT. Suprathreshold or high frequency rTMS tends to worsen
FT. Changes in FT were not associated with changes in SP,
ICI or ICF. Study supported by NIH, Michael J Fox Foundation.
T-33. Microglial Activation May Mediate the Toxic
Effects of Haloperidol on Midbrain Dopamine Neurons
Michael F. Mazurek, Catherine Krasnik, Lisa Lagrou,
Vanessa Bell, and Patricia I. Rosebush;
Hamilton, ON, Canada
We have previously shown that antipsychotic drugs (APDs)
induce apoptotic cell death in dopaminergic neurons of the
substantia nigra (SN). We studied whether microglial activation might play a role in this phenomenon. Rats received a
single injection of either saline (n⫽9) or the APD haloperidol (HAL; n⫽72). Sections of SN were tripled-stained using
fluorescence immunohistochemistry for tyrosine hydroxylase
(TH), OX42 (a marker for activated microglia) and propidium iodide. Within 10 minutes of HAL administration,
OX42 cell counts in SN were 202% of control values, rising
to 249% of control by 1 hour, then persisting at this level
for three days before falling towards control values by 7 and
21 days. TH-positive cell counts in SN followed a reverse
pattern, with a 38% decrease at 10 minutes post-HAL, progressing to a 58% reduction after one hour, then stabilizing
at this level for three days. Triple-stained sections and ultrastructural analysis showed the activated microglial cells to be
in close approximation to the TH-stained dopaminergic neurons. These results suggest that microglial activation may
mediate the APD-induced apoptotic changes that we have
previously documented. Study supported by Ontario Mental
Health Foundation and the Natural Sciences and Engineering Research Council of Canada (NSERC).
T-34. Do Alpha-Synuclein Aggregates (ASA) in
Peripheral Autonomic Neurons Precede Development of
Diseases with Lewy Bodies (DisLB)? A Cohort Study
Adolfo Minguez-Castellanos, Francisco Escamilla-Sevilla,
Clara E. Chamorro, Carlos Arnaiz,
Antonio Rodriguez-Fernandez, Angel C. Rebollo,
Manuel Gomez-Rio, Angel Ortega-Moreno, Angel Concha,
and David G. Munoz; Granada, Spain and
Toronto, ON, Canada
Objective: To determine the prevalence of ASA in
abdomino-pelvic autonomic plexuses in the general population and to evaluate the relationship between this finding
and the subsequent development of neurological dysfunction.
Methods: First, surgical specimens from 100 subjects (44-84
years) who underwent a wide resection of an abdominopelvic organ were examined by anti-AS immunostaining.
Second, 16 subjects (6 ASA⫹, and 10 randomly selected
ASA-) participated in yearly double-blinded neurological as-
sessments. Results: The prevalence of ASA was 9% (95% CI:
3.4-14.6%). Sixteen months after the biopsy no prevalent
cases of Parkinson’s disease (PD), dementia or autonomic
failure were diagnosed. A trend for lower blood pressure
overshoot during phase IV of Valsalva maneuver was identified in the ASA⫹ group. Cardiac 123I-MIBG uptake was significantly reduced in the ASA⫹ group (p⫽0.03), and striatal
I-FP-CIT uptake was abnormally low in one ASA⫹ subject. Thirty months after the biopsy, lower cardiac and striatal uptake values tended to correlate with higher UPDRSIII scores (p⫽0.07). Conclusion: The common presence of
ASA in peripheral autonomic neurons may represent an
early, presymptomatic phase in the development of PD or
other DisLB. Study supported by grants from Consejeria de
Salud of the Andalusian Government and Instituto Carlos
III of the Spanish Government.
T-35. Leber’s Hereditary Optic Neuropathy with
Dystonia in a Japanese Family
Shuji Mita, Masaki Watanabe, Tomohiro Takita,
Yu-ichi Goto, Makoto Uchino Uchino, and
Shigehiro Imamura; Koshi, Kumamoto, Japan;
Kumamoto, Japan and Kodaira, Tokyo, Japan
Leber’s hereditary optic neuropathy (LHON) is a maternally
inherited disease causing acute or subacute bilateral blindness, and occurs predominantly in young males. An association between LHON and various neurologic diseases has
been suggested and referred to as a Leber’s plus. We investigated two sisters in a Japanese family with generalized dystonia attributed to striatal degeneration, which occurred in
childhood, and late-onset optic neuropathy. We determined
the entire nucleotide sequence of mitochondrial DNA
(mtDNA) from the proband, and compared our findings
with the 2001 Revised Cambridge Reference Sequence. The
mtDNA of the proband showed a total of 42 nucleotide
changes. We identified two A3203G and G14459A mutations, which were completely absent in a population of 200
healthy Japanese, by estimating the frequency of each nucleotide change. The nucleotide G14459A mutation occurs in
NADH dehydrogenase subunit 6, and has been suggested
previously as the disease–causing mutation in Hispanic,
African-American and Caucasian families of LHON and/or
dystonia. The significance of the A3203G mutation remains
unknown. To our knowledge, this is the first case of LHON
with dystonia that revealed a mtDNA mutation in a Japanese
T-36. Deep Brain Stimulation Mechanisms of Action
and Basal Ganglia-Thalamic-Cortical Systems
Erwin B. Montgomery, Jr.; Madison, WI
Current concepts of basal ganglia-thalamic-cortical (BG-ThCtx) neurophysiology suggest hierarchical schemes with sequential processing. Theories of deep brain stimulation
(DBS) mechanisms emphasize local effects. Non-human primate neurophysiological studies and computational simulations suggest neither theory is correct. Microelectrode recordings during subthalamic nucleus (STN) DBS demonstrate
excitation propagated throughout the BG-Th-Ctx. No differences in the direct DBS responses are seen with different
frequencies. Paired-pulse DBS demonstrates resonance corresponding to high frequency DBS. Such resonance effects are
consistent with a new theory of the BG-Th-Ctx as sets of
loosely-coupled non-linear reentrant oscillators (Montgom-
ery, Non-linear Studies, 2004) further supported by direct
demonstrations of high frequency periodic activity throughout the BG-Th-Ctx system. Extensions of the new theory
posit fundamental high frequency oligosynaptic oscillators
modulated by longer loop oscillators to generate dynamic
modulation of activity appropriate to behavior. Computer
simulations demonstrate that modulated activity corrupted
by “noise” can be recovered with application of unmodulated
constant amplitude activity at the fundamental frequency.
This may account for the normalization of behavior with
high frequency and regular DBS. Preliminary studies in nonhuman primates demonstrated neurons that modulate activity with behavior only in the presence of DBS. Study supported by Univesity of Wisconsin - Madison, American
Parkinson Disease Association.
T-37. MRI-Induced DBS Electrode Heating:
Important Laboratory Variables
Jules M. Nazzaro, and Slawomir Daniluk; Boston, MA
Introduction: The safety of MRI in the setting of DBS
hardware is a very important subject requiring further investigation. Methods: Important experimental variables in laboratory investigations of the interaction between MRI scanning and DBS lead heating utilizng fiber optic temperature
probes are addressed. Results: Varying results of electrode
heating during MRI scanning may be obtained dependant
upon temperature probe specific orientation to- and distance
from- a DBS contact when tested within gel-filled phantoms,
which in turn are dependant upon the specific temperature
probe utilized. Manufacturer production tolerances vary regarding the specific location of the thermo-sensitive phosphorescent sensor within temperature probes. Different models of temperature probes vary in resposne to a sudden
temperature rise as well as data sampling and collection characteristics. These important variables most often are not accounted for in publications reporting laboratory data addressing MRI safety and DBS hardware using fiber optic
temperature probes. Conclusions: Subtle differences in experimental variables may significantly affect the recorded
temperatures of DBS electrode contacts during MRI scanning. Examples of these important experimental variables
and their influence on results obtained will be presented.
T-38. Avoidance of Intracerebral Hemorrhage in
Microelectrode-Guided Movement Disorders Surgery
Jules M. Nazzaro, Dwight A. Bramble, Peter Novak,
Samuel A. Ellias, and Daniluk Slawomir; Boston, MA
Introduction: There is debate whether microelectrode brain
mapping for movement disorders surgery is associated with
an increased incidence of clinically significant intracerebral
hemorrhage. Methods: Microelectrode-associated hemorrhagic complications in 133 consecutive movement disorders
operations directed to the subthalamic nucleus (STN) or globus pallidus internus (GPi) in an IRB-approved prospective
series of parkinsonian surgical patients was studied. Results:
Basal ganglia targets were localized utilizing an average of 1.5
microelectrode runs/target. There was no case of short- or
long-term clinically significant intracerebral hemorrhage. To
avoid brain hemorrhage, microelectrodes are inspected with
microscope to insure the tips (2-3 microns) are without
bend, brain cannula are also inspected to insure no rough
edges, electrode impedance is checked to insure proper functioning, trajectory avoids cortical sulci, thalmostriate and related veins, and if possible the ventricles, microelectrode ar-
Program and Abstracts, American Neurological Association
rays are not used, blood pressure is continuously monitored,
and for patient anxiety a light propathol drip is used routinely. Conclusions: Microelectrode recording is not associated with symptomatic intracerebral hemorrhage provided
several precautions are taken. As only one DBS lead required
revision due to suboptimal efficacy, we view microelectrode
recordings to be very important in basal ganglia target localization.
T-39. A 3-Year Open-Label, Follow-Up Study To
Evaluate the Efficacy and Tolerability of Sarizotan in
Parkinson’s Disease Patients
C. Warren Olanow,
on behalf of the SPLENDID-O Study Group; New York, NY
This study evaluated the long-term efficacy and safety of sarizotan in an open-label follow-up study. Participants of
SPLENDID could continue sarizotan treatment for up to 36
months. Patients received sarizotan HCl 2, 5, 7 or 10 mg
bid. Efficacy was assessed by patient diary, UPDRS, AIMS
and Rush Dyskinesia Scale. Safety assessments included adverse events (AEs), serious AEs and clinical laboratory values.
Forty-six patients entered the study, 16 remained after 156
weeks. Throughout the observation period, sarizotan tended
to increase time spent ‘ON without dyskinesia’, reduce the
severity, duration and disability caused by dyskinesa and decreased AIMS score at rest (-4.5) and provoked (-4.3). Fortythree patients reported 340 AEs; most were mild or moderate in intensity. The most frequent AE was worsening of
Parkinson’s disease. Fifty-three serious AEs were reported; 18
of these were considered to be related to sarizotan. No
changes of clinical significance were observed in vital signs or
laboratory values. These results suggest that sarizotan reduced
the severity and duration of dyskinesia and disability caused
by dyskinesia throughout the study. Long-term use of sarizotan was generally well-tolerated. Study supported by Merck
KGaA, Darmstadt, Germany.
T-40. Identification of Novel Biomarkers of
Amyotrophic Lateral Sclerosis Clinical Progression
Giulio M. Pasinetti, Dale Lange, Merit Cudkowicz,
Robert Brown, Elaine Peskind, and Lap Ho; Bronx, NY;
New York, NY; Bostom, MA and Seattle, WA
The goal of this study was to determine if there is a specific
protein profile in the CSF and in serum that predict ALS
and eventually its clinical progression. In this study CSF obtained from patients with ALS, disease controls (patients
with other neurologic disorders), and normal controls were
analyzed using the surface-enhanced laser desorption/ ionization time-of-flight mass spectrometry proteomics technique.
Biomarker sensitivity and specificity was calculated with receiver operating characteristic curve methodology. In initial
proteomic discovery studies, three protein species (4.8-, 6.7-,
and 13.4-kDa) that were significantly lower in concentration
in the CSF from patients with ALS (n - 36) than in normal
controls (n - 21) were identified. A combination of three
protein species (the “three-protein” model) correctly identified patients with ALS with 95% accuracy, 91% sensitivity,
and 97% specificity from the controls. Ongoing quantitative
analysis of the sequence identified biomarkers by ELISA and
RIA assays in CSF and in serum will provide an objective
diagnostic test to help identify prospectively patients with
ALS and eventually to monitor ALS clinical progression by
functional rating scale (ALS-FRS). Study supported by VA/
NIH research grant in ALS, and MDA to GMP.
Annals of Neurology
Vol 60 (suppl 3)
T-41. Functional Decline Correlates with Cognitive
Impairment in AD and PD
Marwan N. Sabbagh, Tyson Lahti, Donald J. Connor,
John N. Caviness, Holly A. Shill, Padma Mahant,
Johan Samanta, Richard S. Burns, Virgilio G. Evidente,
Erica Driver-Dunckley, Lauren T. Bonner, Barry Reisberg,
Sorin Bircea, and Charles H. Adler; Sun City, AZ;
Scottsdale, AZ; Phoenix, AZ and New York, NY
To determine the correlation between cognitive decline and
functional decline in PD and AD. Functional decline is related to global measures of cognitive change in PD and AD.
93 PD and 124 AD/MCI subjects were evaluated. Functional and global decline was measured using the Functional
Assessment Staging (FAST) and the Global Deterioration
Scale (GDS). Cognitive measures included the Auditory Verbal Learning Test (AVLT), WAIS-III Digit Span, Controlled
Oral Word Association (COWA), Animal Fluency (AF),
Clock Draw, Stroop, and Judgement Line Orientation
(JLO). In PD, the FAST significantly correlated with AVLT,
Digit Span, COWA, AF and Stroop but not with Clock
Draw or JLO. GDS correlated with AVLT, Stroop, COWA,
AF but not with digit span, clock draw, or JLO. In AD/MCI
subjects, FAST correlated with AVLT, Digit Span, Clock
Draw, COWA, AF, and JLO but not with Stroop. GDS
correlated with AVLT, Digit Span, Clock Draw, COWA,
AF, and JLO but did not correlate with Stroop. Functional
declines in PD and AD correlate with cognitive decline. Differences between PD and AD may be explained by the influence of motor disability on some of the measures in PD.
Study supported by the Arizona Parkinson’s Disease Center,
NIA ADCC AG019610. and the Sun Health Research Institute.
T-42. Cortical C-11-␤CFT Dopamine Transporter
Activity Is Asymmetrically Reduced and Lateralizes to
the Clinically Most Affected Body Side in Parkinson’s
Kurt Schimmel, Priyantha Herath, Scott Ziolko,
Brian Lopresti, Chet Mathis, Robert Moore, and
Nicolaas Bohnen; Pittsburgh, PA and Ann Arbor, MI
To investigate the relationship between hemispheric cortical
dopamine transporter (DAT) activity and the clinically most
affected body side in patients with Parkinson’s disease (PD),
19 PD patients (H&Y I-III) underwent a standardized clinical assessment and C-11␤CFT DAT positron emission tomography (PET). Clinical examination and the Unified Parkinson’s Disease Rating Scale (UPDRS) were performed to
determine the clinically most affected body side. Patients on
dopaminergic drugs were studied in the clinically defined
‘off’ state. Fourteen patients were found to have predominant left-body side involvement and five patients had predominant right body side involvement on the UPDRS motor
examination. There was a significant correlation between the
degrees of clinical asymmetry on the UPDRS motor examination and asymmetric striatal DAT activity (R2⫽-0.62,
P⬍0.005). Comparison of the cerebral hemisphere corresponding to the clinically most affected body side to the contralateral hemisphere demonstrated significant reductions of
DAT in the hemisphere corresponding to the most affected
body side (whole brain F⫽6.04; P⬍0.01 ). Reductions were
more prominent in the temporal and frontal cortex. Asymmetric cortical dopaminergic denervation may contribute to
the clinical parkinsonian syndrome. Study supported by
NIH 2 P01 NS019608.
T-43. Rasagiline Is Beneficial as Adjunct Therapy in
Patients with Moderate Parkinson’s Disease: Subgroup
Steven R. Schwid, and PRESTO and LARGO Investigators;
Rochester, NY
Background: Rasagiline has demonstrated efficacy as adjunct
to levodopa in the PRESTO (n⫽472) and LARGO studies
(n⫽687), significantly reducing OFF time and improving
UPDRS-Motor scores during ON. This, along with a favorable safety profile and ease of dosing, prompted our analysis
of rasagiline in moderate patient subgroups. Methods: Data
were pooled from patients receiving rasagiline 1 mg/day as
adjunct to levodopa. Moderate PD patients were defined by
two criteria: patients receiving only levodopa at baseline (no
concomitant treatment with COMT inhibitors/dopamine
agonists, n⫽253), and patients with relatively ‘mild fluctuations’ (baseline daily OFF time ⬍ 4hr, n⫽217). Together
these subgroups included 383 patients. Results: In the levodopa only subgroup, addition of rasagiline significantly reduced OFF time (treatment effect: -0.78hr; p⫽0.0048), and
improved the clinician’s global impression (p⬍0.0001),
UPDRS-Motor when ON (p⫽0.0007), and UPDRS-ADL
when OFF (p⫽0.0067). Results from the mild fluctuator
subgroup were similar, with rasagiline significantly reducing
OFF time (treatment effect: -0.98hr; p⬍0.0001), and improving the clinician’s global impression versus placebo
(p⫽0.0003). Conclusions: Rasagiline can offer efficacy as
first adjunct to levodopa and provide benefits to patients
over a range of baseline motor fluctuation severity. Study
supported by Teva Pharmaceuticals
T-44. Weight Change in Parkinson’s Disease Patients
Taking Atypical Antipsychotics
Oraporn Sitburana, and William G. Ondo; Houston, TX
Background: Weight loss is common in Parkinson’s disease
(PD). Atypical antipsychotics (AA), which are commonly
used to treat psychosis in PD, are strongly associated with
weight gain. Objective: To determine the AA effect on body
mass index (BMI) when used in PD Methods: We included
patients started on AA who had accurate weights for more
than 6 months prior to initiate AA and more than 6 months
after. We tabulated demographic information and created a
linear regression model to compare BMI trends before and
after 6 months the initiation of AA. Result: 55 PD data (54
subjects), 33 male, mean age of 71.2 ⫾ 8.9 years, PD duration of 11.4 years, Hoehn & Yahr 2.9 ⫾0.7 were prescribed
either quetiapine (87.2%) or clozapine (12.7%). The mean
BMI loss for 2 years before starting AA was 0.6 kg/m2/year
(1.8 kg/year) and for 2 years after starting AA was 0.4 kg/
m2/year (1.2 kg/year). There was no significant difference in
BMI loss after initiating AA. Conclusion: AA did not cause
weight gain in this population. This should not be a concern
in administering these medications.
T-45. Therapeutic Disposition of Patients Presenting
for Initial Treatment of Parkinson’s Disease
Shilpa Tilwalli, Kathleen Shannon, Sue Leurgans, and
Wenqing Fan; Chicago, IL
Background/Objective: The initial treatment of Parkinson’s
Disease (PD) is tailored to the individual patient. We reviewed charts of 116 subjects with untreated PD to determine the factors associated with the choice of initial PD
therapy in a subspecialty Movement Disorders Clinic. Meth-
ods: We reviewed outpatient charts of 116 subjects with untreated PD looking at 5 possible outcomes: enrollment in
clinical trial, no medication, minor agent (selegiline, anticholinergic, amantadine), dopamine agonist and levodopa. We
used ordinal logistic regression to analyze variables associated
with patient disposition and separately for enrollment in trials. Results: Subjects who entered clinical trials were younger
(p⫽0.0061) and had lower HY scores (p⫽0.033), but the
latter was no longer significant when adjusted for age. Age
(p⫽0.0056), UPDRS motor score (p⬍0.0001), and HY
scores (p⬍0.0001) were associated with disposition; older,
more advanced subjects were more likely to receive levodopa.
When adjusted for HY stage, age and motor severity were no
longer associated with medication choice. The association of
HY and initial therapy remains significant if adjusted for age
and UPDRSm (p⬍0.0001). Conclusions: Younger PD patients are more likely to enter clinical trials. Illness severity
determines initial therapy choice. Study supported by Department of Neurology, Rush University Medical Center;
Dr. Kathleen Shannon has received personal compensation
from Mylan Bertek and research funding from Teva,
Schwarz, Titan, Schering, Cephalon, Prestwick, NINDS. Dr.
Sue Leurgans and Wenqing Fan have received funding from
the NIH. Dr. Shilpa Tilwalli has nothing to disclose.
T-46. Behavioral Testing of Saccadic Eye Movements
in Huntington’s Disease
Travis H. Turner, Jody L. Goldstein, Joanne M. Hamilton,
Mark W. Jacobson, Eva Pirogovsky, and Jody Corey-Bloom;
San Diego, CA and La Jolla, CA
Abnormal saccadic eye movements are well-documented in
persons with Huntington’s Disease (HD). These abnormalities increase with disease progression and may be useful for
tracking change with therapeutic intervention. However, the
expense and expertise associated with traditional eye-tracking
equipment preclude its use in clinical assessments or drug
treatment trials. Using a recently validated battery of portable computerized behavioral oculomotor tests, we examined
samples of patients with HD (n⫽11) and age-matched
healthy controls (n⫽12). The battery is hierarchical with respect to demand, providing measures of visuoperceptual ability without eye movement (Fixation), latency for eye movements towards visual targets (Reflexive), and saccade
inhibition (Anti-Saccade). As expected, no significant group
differences were observed on the Fixation test; however, HD
patients performed significantly worse than controls on the
Reflexive (t(21)⫽2.957, p⫽0.013) and Anti-Saccade
(t(21)⫽4.544, p⬍.0005) tests. The group difference on the
Anti-Saccade test remained after controlling for differences
on the Reflexive task (⌬R2⫽.191, t(20)⫽3.011, p⫽0.007),
suggesting that impaired Anti-Saccade performance in HD
reflects saccadic disinhibition independent of reduced oculomotor efficiency. These results support the utility of the behavioral oculomotor battery for assessing saccadic eye movements in subjects with manifest HD and those at risk for
phenoconversion. Study supported by U.C.S.D. Huntington’s Disease Society of America Center of Excellence,
U.C.S.D. Alzheimer’s Disease Research Center, NIH P5
0AG 005131.
Program and Abstracts, American Neurological Association
T-47. Long-Term Safety and Efficacy of the
Rotigotine Transdermal Patch in Early-Stage
Parkinson’s Disease
Ray L. Watts, Rajesh Pahwa, Kelly E. Lyons, and
Babak Boroojerdi; Birmingham, AL; Kansas City, KS and
Monheim, Germany
In a previously conducted multi-center, double-blind,
placebo-controlled trial, Parkinson’s disease (PD) patients
treated with rotigotine, a D3/D2/D1 dopamine agonist delivered via a transdermal patch, showed statistically significant
improvement in UPDRS scores. Interim results of an ongoing, open-label extension to this double-blind phase are reported. Early-stage PD patients were titrated over a 3-week
period before entering the open-label phase and were evaluated every 3 months using the UPDRS (II⫹III). Scores were
compared to baseline values from the double-blind trial. Adverse events also were assessed. The most common adverse
events included somnolence, application site reactions
(ASRs), nausea and dizziness. Most ASRs were mild in severity and accounted for only 6 AE-related discontinuations.
Upon reintroduction of rotigotine during the titration phase,
patients’ UPDRS (II⫹III) scores showed improvement. On
average, the UPDRS (II⫹III) score remained below the
double-blind baseline score indicating that patients maintained benefit throughout the duration of the study. Transdermal rotigotine was well tolerated and patients showed
continued improvement after 85 weeks of rotigotine treatment in this long-term study. Study supported by
SCHWARZ PHARMA; Dr. Babak Boroojerdi is an employee of SCHWARZ PHARMA.
T-48. Safety and Tolerability of Transdermal
Rotigotine in Early-Stage Parkinson’s Disease
Ray L. Watts, James M. Patton, Werner Poewe, and
Babak Boroojerdi; Birmingham, AL; Asheville, NC;
Innsbruck, Austria and Monheim, Germany
Safety and tolerability data from three clinical trials of
rotigotine, a D3/D2/D1 dopamine agonist delivered via a
transdermal system, in early-stage PD were pooled. Adverse
events (AEs) were compared between treatment groups: 289
placebo, 649 rotigotine (titration phase); and, 250 placebo
and 604 rotigotine (maintenance phase). The overall incidence of AEs in the titration phase was 74% rotigotine, 64%
placebo; the overall incidence of AEs in the maintenance
phase was 62% rotigotine, 64% placebo. A total of 13% of
rotigotine-treated patients discontinued due to an AE versus
6% of placebo patients. The most common AEs in the titration phase versus placebo were: nausea (35% vs. 12%), application site reaction (ASR; 23% vs. 9%), dizziness (14% vs.
6%), vomiting (10% vs. 1%) and insomnia (6% vs. 3%). In
the maintenance phase, the incidences of these AEs were reduced: nausea (8% vs. 4%), ASR (19% vs. 6%), dizziness
(6% vs. 5%), vomiting (4% vs. ⬍1%) and insomnia (4% vs.
2%). ASRs were mostly mild or moderate in severity.
Rotigotine was generally safe and well tolerated in this
pooled early-stage PD population. Study supported by
SCHWARZ PHARMA; Dr. Babak Boroojerdi is an employee of SCHWARZ PHARMA.
Annals of Neurology
Vol 60 (suppl 3)
T-49. The Effect of SSRI’s on Hallucinations in
Parkinson’s Disease Patients with Depression
Craig A. Wlodarek, Joanne Wuu, and Christopher G. Goetz;
Chicago, IL
OBJECTIVE: Serotonin may be involved in the pathogenesis
of hallucinations in Parkinson’s disease (PD), and serotonin
reuptake inhibitors (SSRIs) increase central serotonin. We
investigated whether SSRIs induce or exacerbate hallucinations in PD patients with depression. METHODS: Depressed PD patients were identified by the computerized
Rush Movement Disorders Repository database between
1998 and 2005. Baseline data on hallucinations (Thought
Disorder Item on the Unified Parkinson’s Disease Rating
Scale) were collected from the first visit with documented
depression. Subjects who did not change their PD medications on the baseline visit fell into two groups: those starting
SSRI (N⫽20) and those pharmacologically untreated for depression (N⫽20). We followed TD scores at the subsequent
visits on all subjects for between 5 weeks and 1 year. RESULTS: The groups were comparable in PD duration and
age. One SSRI patient developed hallucinations within 6
weeks of treatment, with resolution after SSRI discontinuation. Hallucinations developed or worsened in 3 untreated
patients (SSRI vs. untreated, p⫽0.60). CONCLUSIONS: Although SSRIs alter serotonergic pharmacology, the addition
of this drug class does not exacerbate the risk of hallucinations in depressed PD patients.
T-50. A Ketogenic Diet as a Potential Novel
Therapeutic Intervention in Amyotrophic Lateral
Zhong Zhao, Dale Lange, Lap Ho, and
Giulio Maria Pasinetti; New York, NY
The cause of neuronal death in amyotrophic lateral sclerosis
(ALS) is uncertain but mitochondrial dysfunction may play
an important role. Ketones promote mitochondrial energy
production and membrane stabilization. SOD1-G93A transgenic ALS mice were fed a ketogenic diet (KD) based on
known formulations for humans. Blood ketone levels (D-␤-3
hydroxybutyrate (DBH)) were ⬎ 3.5 times higher in KD fed
animals compared to controls. KD fed mice lost 50% of
baseline motor performance 25 days later than disease controls. In spinal cord sections obtained at the study endpoint,
there were more motor neurons in KD fed animals
(p⫽0.030). DBH prevented rotenone mediated inhibition of
mitochondrial complex I but not malonate inhibition of
complex II. Rotenone neurotoxicity in SMI-32 immunopositive motor neurons was also inhibited by DBH. This is the
first study showing that diet, specifically a KD, alters the
progression of the clinical and biological manifestations of
the G93A SOD1 transgenic mouse model of ALS. These effects may be due to the ability of ketone bodies to promote
ATP synthesis and bypass inhibition of complex I in the mitochondrial respiratory chain. Study supported by VA/NIH
research grant in ALS, and MDA to GMP.
T-51. Gender, Intelligence, and Medication Cost in
Parkinson’s Disease Treated with Deep Brain
Courtney R. Schadt, Daniel W. Byrne, and P. David Charles;
Nashville, TN
Parkinson’s disease (PD) patients require significantly less
medication following treatment with bilateral subthalamic
nucleus deep brain stimulation (DBS). We investigated the
relationship between gender, intelligence, and medication
cost following DBS. Twenty-one PD patients (7W, 14M,
ages 49-75) treated with DBS completed the Wechsler Adult
Intelligence Scale (WAIS-III). Antiparkinson medication
costs were calculated in a standardized fashion utilizing
wholesale prices from the 2005 volume of the Drug Topics
Red Book. The average daily cost pre-operatively was $18.42
⫹/- 8.72 and post-operatively $14.51 ⫹/- 7.85 per patient, a
21% reduction (95% boostrap CI⫽-2.3% to 40.3%). The
change in medication costs significantly correlated with gender (rs⫽0.50, P⫽0.021). Men had a significant reduction
post-operatively of $7.06 per day (CI⫽0.26 to 13.84,
P⫽0.043). Women had increased medication costs per day
by $2.39 (CI⫽-5.02 to 0.25, P⫽0.068). The women’s preand post-operative daily medication costs correlated with
WAIS-III scores (rs⫽0.56, rs⫽0.62). Medication cost reduction following DBS differs by gender with men saving significantly more than women. Women with higher intelligence scores have significantly higher pre- and post-operative
medication costs. More studies are needed to better understand gender differences in PD patients treated with DBS.
Dr. Charles has received honoraria, and Vanderbilt has received grants in excess of $10,000 from Medtronic, Inc.,
Minneapolis, Minnesota.
T-52. The Change of Levodopa Responsiveness and
Levodopa-Equivalent Dose in Parkinsonian Patients
with Bilateral Subthalamic Nucleus Stimulation
Tao Feng, Jian Guo Zhang, Yong Jun Wang, and Wei Li;
Beijing, China
Objective: To investigate the effect of bilateral subthalamic
nucleus stimulation on the levodopa responsiveness and the
levodopa-equivalent dose. Methods: 58 patients with PD
who undergone bilaterally STN-DBS were assessed before
and after 12 months of stimulation. The levodopa challenge
tests were performed with the stimulator on or off. The maximal improvement of UPDRS motor scores, the latency and
duration of effect after stimulation were compared with those
before stimulation. The levodopa-equivalent dose that can
achieved the same baseline of UPDRS motor scores before
stimulation were tested with stimulator on or off after 12
months of stimulation. Results:The STN-DBS increase the
magnitude of the levodopa responsiveness significantly with
the increasing of duration and decreasing of latency of effect
with stimulator on. But with stimulator off there were no
significant difference between the responsiveness before implantation and that after it. With stimulator on the
levodopa-equivalent dose that met the baseline of UPDRS
motor scores were decreased compared with that before implantation. With stimulator off levodopa-equivalent dose
didn’t increased significantly. Conclusion: The continuous
STN-DBS may not change the levodopa responsiveness after
one year of stimulation. Study supported by Beijing Tiantan
T-53. XP13512 Improves Restless Legs Syndrome
(RLS) Patient Sleep and Symptoms in Two DoubleBlind, Randomized, Placebo-Controlled Studies
Arthur S. Walters, Clete A. Kushida, Philip M. Becker,
Aaron L. Ellenbogen, and Daniel M. Canafax; Edison, NJ;
Stanford, CA; Dallas, TX; Bingham Farms, MI and
Santa Clara, CA
XP13512 (XP, gabapentin prodrug) was assessed in RLS.
Study #1: 36 patients treated in 2-week crossover study with
XP (600 mg at 5PM; 1200 mg 1 hr before bed) or placebo
with sleep, Polysomnography (PSG), IRLS score, and CGI
assessed. Results: XP vs. placebo improved quality of sleep;
reduced awakenings and hrs awake from RLS (all
p⬍0.0001). XP increased PSG-determined total sleep time
(⫹25.2 min; p⫽0.0317), Stage 3/4 sleep (⫹21.3 min;
p⫽0.0002), and reduced time awake after persistent sleep
onset (-28.2 min; p⫽0.0009), and reduced PLMs with
arousals (46.3 for placebo; 29.3 for XP; p⫽0.0082) and
PLM-awakenings (p⫽0.0172). XP vs. placebo reduced IRLS
scores at 2 weeks (-12.1 vs. -1.9), 1 week (-11.7 vs. 3.7), and
CGI (all p⬍0.0001). Study #2: 95 patients randomized to
placebo, XP 600 mg or 1200 mg @ 5PM daily with sleep,
IRLS score, and CGI assessed. Results: XP improved sleep
quality (p⬍0.005), and nights with RLS, IRLS score at 2
weeks (-16.1 vs. -8.9), 1 week (-14.2 vs. -7.8) and CGI (all
p⬍0.0001). Side effects were somnolence and dizziness.
XP13512 reduced sleep disturbance and symptoms in RLS
patients. Study supported by XenoPort, Inc.; Dr. Walters &
Dr. Ellenbogen received personal compensation for consulting with XenoPort, Inc. Dr. Canafax is an employee of XenoPort, Inc.
T-54. Gender Differences in Echocardiographic
Variables Associated with Acute Ischemic Stroke
Anjali Bhagra, Rachel Gilmore, Bellolio, M. Fernanda,
Lekshmi Vaidyanathan, Allan S. Jaffe, Wyatt W. Decker,
Robert D. Brown, and Latha G. Stead; Rochester, MN
Objective: To determine differences in echocardiographic
parameters between men and women with acute ischemic
stroke (AIS). Methods: The study population consisted of
292 consecutive patients who presented to the Emergency
Department at the Mayo Clinic with acute ischemic stroke
(AIS) in whom echocardiograms were performed during a 27
month period. Results: There were 128 women and 164
men, with a median age of 75 years. Women were older
(median, 72.6 vs 69.4 years, pⴝ0.007). The Median NIHSS
was 4 overall and similar between genders (5 and 4). Fewer
women had ejection fractions ⬍ 35% compared to men (4%
compared to 8%, Wilcoxon rank sum test, pⴝ0.002). However, of those with MVR, women were likely to have moderate/severe mitral valve regurgitation (MVR) (69.2% vs.
30.8%; pⴝ0.006) and there was a non significant trend towards more left atrial thrombus in women. Conclusion: In
the setting of AIS, women have a different echocardiographic
substrate than those of men which may well contribute to
the differences observed in survival and functional outcomes
after AIS.
T-55. Comparison of Cerebral Infarct Volume on
Diffusion Weighted MR Imaging with Functional
Outcome after Acute Ischemic Stroke
Anjali Bhagra, Reordan DeJesus, Vaidyanathan Lekshmi,
Bellolio, M. Fernanda, Gilmore Rachel, John Huston,
Robert D. Brown, and Latha G. Stead; Rochester, MN
Objective: To compare the extent of cerebral infarct on diffusion weighted MR imaging (DWI) with functional outcome in patients with acute ischemic stroke (AIS). Methods:
The study cohort had 216 patients with onset of AIS within
24 hours of presentation and brain MRI done within index
hospitalization. Infarct volumes were calculated on DWI by
mapping out the exact extent of infarcts. Stroke severity was
Program and Abstracts, American Neurological Association
determined using the NIHSS. Functional outcome was assessed via the modified Rankin score (mRs) at 90-days and
dichotomized into a good outcome (mRS 0,1,2, or 3) versus
a poor outcome (mRs 4,5, or 6). Results: Mean and median
infarct volumes were significantly higher in the poor rankin (
53826, 20443) versus the good rankin ( 12130, 4113)
group, p<0.001. Logistic regression adjusting for age and
LN(NIHSS) yielded a statistically significant relationship between larger MRI volume and poor Rankin (OR 1.3, 95%
CI, 1.1-1.6; p⫽0.013). This represents a 30% increase in
risk of poor outcome per a doubling in MRI volume. Conclusion: Larger infarct volume on initial MRI scan is associated with a poor functional outcome at 90-days even after
adjusting for age and stroke severity.
T-56. Chronic Neuronal Adaptation to Physiological
Hypoxia Reduces Acute Ischemia-Reperfusion Injury
Dongdong Li, Zuohui Shao, Terry L. Vanden Hoek, and
James R. Brorson; Chicago, IL
Measurements of oxygen tensions in mammalian brain reveal
physiological pO2 values ranging widely from 6% O2 down
to 1% O2, substantially less than ambient pO2 in usual culture conditions (20% O2). In cultured murine cortical neurons, chronic exposure to 1% O2 has a trophic effect, associated with upregulation of hypoxia-inducible factor-1␣. We
asked whether chronic moderate hypoxia might also alter the
vulnerability of neurons to ischemia-reperfusion. Utilizing
real-time monitoring of cell morphology and viability, we
observed effects of in vitro ischemia-reperfusion (60 min
simulated ischemia including anoxia, glucose deprivation, acidosis, hyperkalemia, and 30␮M glutamate) in cortical neurons. Neurons cultured for 10 days in 20% O2 displayed
cytoplasmic swelling and neuritic beading during ischemia,
followed by cytolytic death during reperfusion, with 51 ⫾
12 % (n⫽5, mean ⫾ S.D.) of neurons dead within 2 hours
of reperfusion. In contrast, neurons cultured from time of
plating in 1% O2 failed to exhibit morphological signs of
injury during identical ischemia, and showed only 4 ⫾ 2%
(n⫽4) death during 2 hours of reperfusion. We conclude
that neuronal adaptation to chronic moderate hypoxia produces relative resistance to ischemia-reperfusion injury in
vitro. Study supported by American Heart Association.
T-57. Diabetes Is a Predictor of Carotid Stenosis in
African Americans with Ischemic Heart Disease
Greg Norris, Sunitha Santhakumar, Elizabeth Berlow,
James D. Marsh, Marvin W. Kronenberg, Steven R. Levine,
and Seemant Chaturvedi; Detroit, MI; Little Rock, AK;
Nashville, TN and New York, NY
Background: African Americans (AA) are thought to have
more intracranial stenosis but existing ischemic heart disease
(IHD) increases the likelihood of extracranial carotid stenosis
(CS). Objective: To examine the impact of diabetes mellitus
(DM) on CS in AA with IHD. Methods: 101 AA subjects
with documented IHD were enrolled in a prospective study.
Medical history was obtained and carotid duplex exams were
performed. Medication use was evaluated and the frequency
of CS was determined. Results: Overall, the mean age of the
subjects was 59.6 years and 51% were male. 36% of patients
had DM. There was no difference in the use of statins, ACE
inhibitors, or beta blockers among diabetics and nondiabetics. CS of ⬎50% was found in 22% of diabetics compared
to 5% of nondiabetics (p⬍0.001, chi square test). Among
diabetics, ⬎50% CS was present in 37% of patients age 60
Annals of Neurology
Vol 60 (suppl 3)
or greater compared to 6% of patients below 60 years
(p⫽0.04). DM remained a predictor of CS on multivariate
testing. Conclusions: Diabetes is a predictor of clinically relevant CS in AA subjects with IHD. Screening older AA diabetics for CS may be cost-effective if confirmed in larger
studies. Study supported by Blue Cross Blue Shield of Michigan Foundation.
T-58. Preoperative Quality of Care Indices for Carotid
Endarterectomy at an Academic vs. Community
Ramesh Madhavan, Sunitha Santhakumar, Maysaa Merhi,
Kumar Rajamani, and Seemant Chaturvedi; Detroit, MI
Background: Previous studies have shown a benefit for aspirin, statins, and beta blockers (BB) for patients undergoing
carotid endarterectomy (CE) or other forms of vascular surgery. Objective: To examine preoperative use of these medications. Methods: Retrospective review of CE subjects
(2003-04) from an academic (A) and community (C) hospital. Medical history and hospital complications were recorded. Results: 99 and 51 patients were evaluated at the A
and C hospital, respectively. There was no difference in the
preoperative use of statins (54% A vs. 53% C, chi square),
ACE/ARB (47% A vs. 47% C), or BB (55% A vs. 47% C,
p⫽0.39). There was a trend for greater aspirin use at the A
hospital (75% A vs. 63% C, p⫽0.12). The rate of perioperative stroke/MI was 7.1% (A) and 17.6% (C)(p⫽0.06).
There was a trend for reduced rate of stroke or MI at the C
hospital for patients on statins (7% vs. 25%, p⫽0.13). Conclusions: The preoperative use of vascular medications was
suboptimal but not significantly different between an academic and community urban hospital. The trend for reduced
complications in patients receiving statins preoperatively
should be evaluated in a randomized trial.
T-59. Prognostic Significance of Continuous EEG
Monitoring in Poor-Grade Subarachnoid Hemorrhage
Jan Claassen, Lawrence J. Hirsch, Jennifer A. Frontera,
Andres Fernandez, Michael Schmidt, E. Sander Connolly,
Ronald G. Emerson, and Stephan A. Mayer; New York, NY
Introduction. Predicting outcome of subarachnoid hemorrhage (SAH) patients may help guide therapy and assist in
family discussions. We studied if continuous EEG (cEEG)
monitoring is predictive of three-month outcome in poorgrade SAH patients. Methods. Among 756 prospectively
studied SAH patients, 116 (88% of these were Hunt-Hessgrade 3-5) underwent cEEG monitoring. Functional outcome was assessed at 3 months with the modified Rankin
Scale (mRS). Using multivariate analysis we identified EEG
findings associated with poor outcome (mRS 4-6). Results.
After controlling for age, Hunt-Hess-grade, and admission
CT scan findings, poor outcome was associated with the absence of sleep architecture (OR 4.3, 95%-CI 1.1-17.2) and
the presence of periodic lateralized epileptiform discharges
(PLEDS; OR 18.8, 95%-CI 1.6-214.6). In addition, outcome was poor in all patients with absent EEG reactivity
(N⫽8), generalized periodic epileptiform discharges (N⫽12)
or bilateral independent PLEDs (N⫽5), and in 92% (11 of
12) of patients with nonconvulsive status epilepticus. Conclusions. CEEG monitoring provides independent prognostic information in poor-grade SAH patients, even after controlling
for clinical and radiologic findings. Unfavorable findings include periodic epileptiform discharges, electrographic status
epilepticus, and the absence of sleep architecture. Study supported by a Grant-in-Aid from the American Heart Association to Dr. Mayer (#9750432N).
T-60. The SPARCL Trial: Effect on Statins on Stroke
Larry B. Goldstein, and SPARCL Investigators; Durham, NC
Background: Laboratory experiments suggest statins may
improve poststroke recovery. Only limited data are available
to determine whether a similar effect occurs in humans, and
if so, whether that effect varies by sex. Methods: The Stroke
Prevention with Aggressive Reduction in Cholesterol Levels
(SPARCL) trial was a prospective, placebo-controlled randomized clinical trial designed to determine whether treatment with atorvastatin (80 mg/d) reduces the occurrence of
stroke in patients with recent stroke or TIA. Stroke severity
was assessed with the NIH-SS, Barthel Index and Rankin
Index at enrollment (1-6 months after the index event) and
90 days post-stroke in patients having a stroke during the
trial. Results: 4731 subjects were randomized (mean age 63
years, 60% men, 93% Caucasian; mean LDL-C 73 mg/dL
with atorvastatin vs. 129 mg/dL with placebo). Over 4.9
years, strokes occurred in 576 subjects. At the time of abstract submission, the relationship between statin treatment
and outcome, and the interaction between treatment and sex,
are being analyzed. Conclusion: As the only prospective,
placebo-controlled trial of a statin for secondary stroke prevention with baseline and follow-up measures of stroke severity, SPARCL provides unique data addressing the impact
of statins on stroke severity. Study supported by Pfizer; Dr.
Goldstein was a member of the SPARCL Steering Committee and has served as a consultant for Pfizer.
T-61. Conderation of Unknown Variables When
Dosing Warfarin
Cathy M. Helgason, and Thomas H. Jobe; Chicago, IL
Warfarin dosing requires repeated measurement of warfarin
effect (INR) to direct dosing. When goal INR is achieved,
the dosage is maintained assuming their linear relation.
Known unmeasurable and unknown variables in patient context give suboptimal or supratherapeutic INR. Methods:
Contour plotting of the fuzzy causation measure K is performed at each moment of measured INR and warfarin dosing ( initial condition) using the program MATHEMATICA
to give warfarin dosage to maintain INR at goal while keeping unknown variables constant. Results: Causal contour
plots change with initial condition. The contour plot is non
linear and offers a choice of two warfarin doses to maintain
goal INR.Conclusion: Consideration of causation is part of
the medical decision process. Causal contour plotting may
help the physician use the non-linear relation between dose
and INR when known but unmeasured factors such as diet,
and other context elements are considered. This may avoid
bleeding and thrombosis while on warfarin.The hypothesis
that causal contour mapping is effective in maintaining goal
INR can be tested first by retrospective review of data from
patients receiving warfarin to see if the dosage choice by contour plot is safe, and then by prospectively.
T-62. Coated-Platelet Levels Are Decreased in AfricanAmerican Patients with Stroke or TIA
Preeti M. Joseph, George L. Dale, and Calin I. Prodan;
Oklahoma City, OK
Objective: To explore the relationship between coatedplatelet levels and stroke in the general population and in
different racial groups. Background: Coated-platelets are a
subset of platelets produced by dual-agonist activation with
collagen and thrombin(Nature 415:175, 2002).Unlike
single-agonist activated platelets, these platelets express procoagulant proteins, including factor V and fibrinogen, on
their surface.Because of the pro-thrombotic profile of coatedplatelets, we investigated their role in strokes.We also investigated potential racial differences, given the increased incidence and mortality of stroke in African-Americans
compared to the general population. Methods: Platelets from
25 controls and 35 patients with stroke/TIA (20 whites,14
African-Americans, and 1 Native-American) were assayed for
coated-platelets.Control subjects with stroke/TIA over the
preceding year were excluded.Results are reported as the percent of cells converted into coated-platelets(mean⫾1SD).
Results: Patients with stroke/TIA had significantly lower
coated-platelet levels than controls(23.96⫾11% versus
32⫾12.9%,p⫽0.01). Within the stroke/TIA group, there
was significant difference(p⫽0.002)between African-American(17.38⫾9.25%;n⫽14)and white patients(28.78⫾10%;
n⫽20). Conclusions: Our pilot data indicates a significant
decrease in coated-platelet levels in patients with stroke/TIA
compared to controls. This decrease is most significant in
African-Americans. Explanation for this finding is possibly
that thrombotic consumption of coated-platelets has occurred. Further investigation of the coated-platelets’ role in
stroke, especially in African-Americans, is warranted.
T-63. Right-Hemispheric Extensive Hypometabolism
Is Associated with Persistent Severe Unilateral Spatial
Neglect Due to Cerebral Infarction
Haruhisa Kato, Ken Nagata, Hirohiko Saito, Tetsuya Maeda,
and Hiroya Utsumi; Akita, Japan and Tokyo, Japan
To elucidate the mechanisms underlying the evolution of
unilateral spatial neglect (USN) due to cerebral infarction,
cerebral metabolic rate of oxygen (CMRO2) was measured
quantitatively with positron emission tomography (PET),
and the regional CMRO2 was analyzed statistically by region
of interest (ROI) basis. Out of 189 consecutive patients with
cerebral infarction in the right hemisphere who underwent
PET, we recruited 6 patients (USN-1) who exhibited persistent severe USN, 7 patients (USN-2) with mild USN, 11
patients (USN-3) who had recovered from USN at the timing of PET, and 27 patients (DC) who did not present USN
throughout. Eight normal volunteers (NV) served as control.
As compared with DC and NV, regional CMRO2 decreased
significantly in right temporal, parietal and occipital cortices
in USN-1, whereas that decreased only in the right frontal
cortex in USN-2. As compared with DC and NV, the rightleft asymmetry index of CMRO2 was significantly greater in
temporal, parietal and occipital cortices in USN-1, but only
in the frontal cortex in USN-2. These results suggest that
right-hemispheric extensive hypometabolism accompanying
with a pronounced asymmetrical distribution is associated
with persistent severe USN. Study supported by Akita prefecture government.
Program and Abstracts, American Neurological Association
T-64. eNOS T-786C SNP Predicts Susceptibility for
Vasospasm after Subarachnoid Hemorrhage
Nerissa U. Ko, Pam Rajendren, Martin Rutkowski,
Ludmila Pawlikowski, Jonathan Zaroff, Pui L. Kwock, and
William L. Young; San Franciso, CA
T-66. MIRROR ANEURYSMS – The International
Study of Unruptured Intracranial Aneurysms
Irene Meissner, David Wiebers, James Torner, Robert Brown,
John Huston, Lyell Jones, Michelle Rajput; Rochester, MN
and Iowa City, IA
Vasospasm following subarachnoid hemorrhage (SAH) is the
leading cause of death and disability after aneurysm rupture,
yet the mechanism of vasospasm remains poorly understood.
Evidence suggests that decreased availability of the vasodilator molecule nitric oxide may be crucial in the pathogenesis.The endothelial nitric oxide synthase (eNOS) gene harbors
three well-characterized genetic variants. We hypothesize that
the eNOS gene promoter T-786C single nucleotide polymorphism (eNOS T-786C SNP) predicts susceptibility to
vasospasm after SAH. METHODS: We conducted a prospective cohort study to determine clinical and radiographic
evidence of vasospasm using cerebral angiography as the gold
standard. We collected genomic DNA from blood samples
and genotyped the eNOS gene polymorphisms. Using multivariable logistic regression, we quantified the effect of the
eNOS polymorphism on subjects with and without vasospasm. RESULTS: We genotyped 256 subjects with SAH.
Similar to other studies, 43% of patients had vasospasm on
angiography. The eNOS T-786C SNP was significantly associated with vasospasm (OR 2.60, p⫽0.047). CONCLUSIONS: Patients with the eNOS T-786C SNP had a greater
than two-fold increase in vasospasm. These findings suggest
that genetic factors involved in regulation of nitric oxide may
determine risk for vasospasm in patients with SAH.
The NIH sponsored International Study of Unruptured Intracranial Aneurysms evaluates predictors of future hemorrhage in patients with unruptured aneurysms. The natural
history of mirror aneurysms (MA), paired aneurysms in bilateral “mirror” arterial positions, is unknown. In 60 centers,
376 of 3120 patients (12%) had MA. More MA patients
were female, 82% vs 73% (p⫽.0001 and reported a family
history of aneurysm or SAH (p⫽.0001). More MA patients
had larger aneurysms (⬎10mm), (mean maximum diameter
11.7 vs 10.4, respectively, (p⫽.0009). Distribution was middle cerebral (4%), non-cavernous internal carotid (IC)
(32%), posterior communicating (16%), cavernous IC
(13%), anterior cerebral (3%) and vertebrobasilar (2%).
Compared with non MA patients, there was no statistical
difference in age (mean, 54 years), blood pressure, smoking
history, or cardiac disease. Rupture rates were similar (3.5%,
MA vs 3.8%, non-MA). Overall, mirror aneurysm patients
were more likely to be female, report a family history of aneurysmal SAH and have larger aneurysms. Presence of a mirror aneurysm was not an independent predictor of future
T-65. The Low-Affinity NMDA Antagonists,
Memantine and 3-〈-Ol-5-〉-Pregnan-20-One
Hemisuccinate Improve Clinical Rating Scores in
Rabbits Following Multiple Infarct Embolic Strokes
Paul A. Lapchak, and Justin A. Zivin; La Jolla, CA and
San Diego, CA
Plasmatic B-type-natriuretic peptide (NT-PBNP) and
C-reactive protein (CRP) have been reportedly elevated in
stroke patients, however their clinical significance remains
uncertain. The purpose of this work is to investigate whether
elevation of these proteins at baseline predicts CT-evidence
of brain edema. We recruited 41 consecutive patients with
stroke and determined NT-PBNP and CRP at baseline, after
48-72 hours, and at discharge. We also carried out brain CT
at admittance and after 48 hours. On delayed CT scan 14
patients showed brain edema. Baseline levels of NT-PBNP
did not predict CT-evidence of edema but CRP levels did so
significantly (0.7 mg/dl in patients without edema versus 4.7
mg in patients with edema; p⫽0.005). Both NT-PBNP and
PC levels correlated poorly to NIHSS score and increased
markedly from baseline to the second determination in patients with edema. For these patients the NT-PBNP increase
was 114 pmol/l in comparison to 2.7 pmol/l in patients
without edema (p⫽0.008). We conclude that CRP at baseline but not NT-PBNP predicts CT evidence of brain edema
in stroke patients and that NT-PBNP levels elevated markedly in response to edema.
The progression of behavioral deficits associated with acute
ischemic stroke (AIS) is related to initial rapid excitotoxic
events. In this study, we determined if either the uncompetitive open-channel NMDA antagonist memantine or the neurosteroid NMDA modulator/antagonist 3-␣-ol-5-␤-pregnan20-one hemisuccinate (ABHS) would improve the behavior
of rabbits using a multiple infarct AIS model. Rabbits were
embolized with small-sized blood clots via an indwelling carotid artery catheter. Memantine (25 mg/kg) was infused intravenously over 60 minutes. The P50 of the control group
measured 24 hours after embolization was 1.08⫾0.23mg.
Memantine significantly (p⬍0.05) increased the P50 to
2.31⫾0.48mg and 3.13⫾1.13mg when given 5 or 60 minutes following embolization. When ABHS was given intravenously as a bolus injection (over 1 minute) at a dose of
25mg/kg, there was a significant (p⬍0.05) increase in the
P50 value to 2.60⫾0.69 mg when given 5 minutes following
embolization, but not at 60 minutes following embolization.
Both drugs caused sedation with loss or righting reflex.
These results suggest that low-affinity NMDA receptor antagonists may have substantial therapeutic benefit for the
treatment of AIS-induced behavioral deficits and should be
developed. Study supported by NIH and VA Merit Review
grants to PAL and JAZ.
Annals of Neurology
Vol 60 (suppl 3)
T-67. B-Type Natriuretic Peptide and C-Reactive
Protein as Markers of CT Evidence of Brain Edema in
Hyperacute Stroke
Pedro J. Modrego, Beatriz Boned, Juan J. Berlanga,
Mercedes Serrano, Jose A. Olivan, and Miguel A. Pina;
Zaragoza, Spain and Alcañiz, Teruel, Spain
T-68. Fabry Disease – A Patient and Murine Model
Study Utilizing a Systems Biology Approach
David F. Moore, Oleg V. Krokhin, John A. Wilkins,
Monique P. Gelderman, Ehud Goldin, and
Raphael Schiffmann; Winnipeg, MB, Canada; Bethesda, MD
and Rockville, MD
Fabry disease is secondary to the cellular deficiency of the
lysosomal enzyme ␣-galactosidase A. This results in multi-
organ dysfunction with neurological disease resulting from
Fabry vasculopathy and stroke. A knock-out (KO) mouse
model is available for Fabry disease. Using a combination of
gene expression arrays and tandem mass spectrometry (MSMS) in the KO model and in patient PBMCs and serum we
identified a series of Fabry disease markers including neuronal apoptosis inhibitory protein (NAIP) and ␣-2 antiplasmin. The KO model was treated with and without enzyme
replacement therapy followed by examination of gene expression in the heart, aorta and liver. From significantly expressed and multiple comparison corrected (false discovery
rate) genes, correlational expression networks were derived
followed by structural equation modeling (SEM) analysis.
This allowed examination of ‘a priori’ hypotheses concerning
the cellular basis of Fabry glycolipidopathy. Such data indicated extensive cellular pathway dysregulation in Fabry. Selected genes were confirmed as protein products on Western
blots including pituitary tumor-tranforming 1, a cellular oncogene. Utilizing a system biology approach we demonstrate
enhanced understanding of Fabry pathophysiology together
with a basis for directed therapeutic target selection. Study
supported by the Intra-mural Program of The National Institute of Neurological Disorders and Stroke.
T-69. Neuronal Apoptosis after Cerebral Ischemia in
the TNF␣-Transgenic Rat
Luther C. Pettigrew, Xiao-Hong Song, Susan D. Craddock,
and Joe E. Springer; Lexington, KY
Tumor necrosis factor-alpha (TNF␣) is an inflammatory cytokine that activates receptor-mediated apoptosis in acute
neuronal degeneration. Employing a unique transgenic (Tg)
rat over-expressing TNF␣ in brain, we tested the hypothesis
that elevated levels of this cytokine are associated with
caspase-3 activation and apoptotic neuronal death in cerebral
ischemia. TNF␣-Tg rats expressing the mouse TNF␣ promoter and gene were subjected to middle cerebral artery occlusion (MCAO). We measured TNF␣ and caspase-3 activation in the infarct core (IC) and peri-infarct (PI) zone
approximating the ischemic penumbra 24 hrs after MCAO.
The highest TNF␣ levels were in PI (169⫾45 pg/100␮g
protein) and IC (138⫾11) of ischemic TNF␣-Tg rats, compared to PI (119⫾8) and IC (116⫾34) of wild type (WT)
littermates or naive TNF␣-Tg (43⫾8) and WT (21⫾2) rats
(n⫽3-4 per group; pⱕ0.01; ANOVA/Fisher’s test).
Caspase-3 was activated more intensely in IC of TNF␣-Tg
rats (24⫾11 ⌬fluorescence units/min/100mg protein), compared to WT (17⫾6; pⱕ0.05). Co-localization by fluorescence immunohistochemistry showed prevalence of cytoplasmic caspase-3 activation in apoptotic neurons within
ischemic striatum in TNF␣-Tg rats. We conclude that increased synthesis of TNF␣ is associated with caspase-3 activation and apoptotic neuronal death after cerebral ischemia.
Study supported by NIH/NINDS R01 NS047395.
T-70. Reduced CDK5 Activity Prevents HypoxiaInduced Ischemic Tolerance
Svetlana Pundik, Jose Valerio, Jorge Gamboa, Karl Herrup,
and W. David Lust; Cleveland, OH
Ischemic tolerance is induced in animal stroke models by
pre-exposure to hypoxia. We have previously shown that one
novel mechanism of hypoxia-induced neuroprotection is mediated by cyclin dependent kinase 5 (CDK5). CDK5 is a
regulator of neuronal development and differentiation and
paradoxically has been implicated in neuronal death. We hy-
pothesized that inhibition of CDK5 activity with its inhibitor, roscovitine, will reduce hypoxia-induced preconditioning. Intraventricular infusion with an Alzet pump of
Roscovitine (40 nmole/day) or vehicle (25% DMSO) was
initiated 1 day before the Wistar rats were exposed to 10%
of normobaric hypoxia for two hours. Two days after H,
MCA was occluded for 2 hours using the monofilament
technique. Rats were sacrificed at 1 day of reperfusion and
infarct volume determined on thionin-stained coronal sections. Pretreatment with Roscovitine, reversed the neuroprotective effects of hypoxic preconditioning. Infarct volumes of
Roscovitine and vehicle treated animals were 0.41⫾0.15 and
0.24⫾0.1 (mean ⫾ SD), respectively (p⫽0.032). In summary, the results indicate that CDK5 activity is an important
permissive mediator of ischemic tolerance and has be present
prior and during the preconditioning paradigm.
T-71. Matrix Metalloproteinase Inhibition Blocks
Proteolysis of Tight Junction Proteins in Focal
Ischemia in Rat Brain
Yi Yang, Eduardo Y. Estrada, Jeffrey F. Thompson,
Wenlan Liu, and Gary A. Rosenberg; Albuquerque, NM
Matrix metalloproteinases (MMPs) disrupt the blood-brain
barrier (BBB) early in acute focal ischemia with reperfusion.
MMP inhibitors block the early BBB damage. We hypothesized that tight junction proteins (TJPs), occludin and claudin, which form the BBB, are attacked by MMPs. Adult
SHR had a 90 min middle cerebral artery occlusion with
reperfusion for 2 or 3 hrs. We measured expression of
mRNA and proteins for gelatinases A and B (MMP-2 and
-9, respectively), membrane-type MMP (MT-MMP), furin,
occludin and claudin-5. After 2 hrs of reperfusion, real-time
PCR showed significant increases in mRNA for MMP-2 and
-9, furin, MT-MMP, and decreased occludin and claudin-5.
At 3 hrs of reperfusion, there was opening of the BBB to
C-sucrose, and the opening was significantly reduced by a
MMP inhibitor, BB-1101. In situ zymography showed gelatinase activity, which by gel zymography was due to MMP-2.
Immunohistochemistry and confocal microscopy showed
fragmentation of the TJPs in the ischemic cerebral vessels.
On western blots, cleavage products of TJPs were seen,
which were significantly reduced by BB-1101. We conclude
that inhibition of MMP-2 protects the BBB by blocking proteolysis of TJPs. Study supported by NIH RO1 NS45847
and AHA Grant-in-Aid.
T-72. 1H MRS Study of Cerebral Metabolism in
Patients with Stenosis or Occlusion of the Internal
Carotid Artery
Vladimir A. Rogozhyn, Zina Z. Rozhkova,
Victor I. Shcheglov, Dmitry V. Shcheglov, and
Andrei V. Barkanov; Kiev, Ukraine
We propose the indicators for the characteristics of regional
distributions of Cho, Cr, and NAA in patients with stenosis
or occlusion of the internal carotid artery (ICA) and without
overt infarction of the brain tissue. Two groups of subjects
are examined by 1H MRS using 1.5T Magnetom Vision
(SIEMENS). The 1st group (VG) consists of 75 volunteers.
The 2nd group (PG) includes 112 patients with transient cerebral ischemia. In all patients and controls 2DCSI 1H spectra in the centrum semiovale in both hemispheres are obtained. In the PG in subjects with unilateral stenosis of the
ICA in symptomatic side the metabolites ratios are: NAA/
Cr⫽3.51, NAA/Cho⫽2.23; in asymptomatic side: NAA/
Program and Abstracts, American Neurological Association
Cr⫽4.27, NAA/Cho⫽3.1. In subjects with unilateral occlusion of the ICA in symptomatic side: NAA/Cr⫽3.69, NAA/
Cho⫽1.98; in asymptomatic side: NAA/Cr⫽3.42, NAA/
Cho⫽2.94. In subjects with bilateral stenosis of ICA in
symptomatic side:NAA/Cr⫽3.38, NAA/Cho⫽2.27; in
asymptomatic side:NAA/Cr⫽3.82, NAA/Cho⫽2.15. In
comparison, in the VG: NAA/Cr⫽3.64, NAA/Cho⫽3.13.
Our approach gives us a way for the estimation of cerebral
abnormalities in regions that are not infarcted, but are at risk
for infarction.
T-73. Stroke Subtype May Influence the Relationship
between Subacute Neurologic Impairment and
Cognitive Status: The Ischemic Stroke Genetics Study
Beth K. Rush, James F. Meschia, L. D. Case, and
Thomas G. Brott; Jacksonville, FL and Winston-Salem, NC
At least 30% of patients demonstrate post-stroke cognitive
impairment. Cases (n ⫽ 43) are assessed within 30 days of
first-ever ischemic stroke onset using the National Institutes
of Health Stroke Scale (NIHSS) and Mini-Mental State Examination (MMSE). Stroke subtype is classified using criteria
of the Oxfordshire Community Stroke Project (OCSP) and
the Trial of Org 10172 in Acute Stroke Treatment
(TOAST). Overall correlation between NIHSS and MMSE
was modest (r ⫽ -.63, p ⬍ .001). The correlation between
NIHSS and MMSE was greatest for posterior and partial anterior circulation infarct subtypes of OCSP (r ⫽ -.77, p
⬍.13, r ⫽ -.69, p ⬍ .01, respectively), and cardioembolic
and undetermined subtypes of TOAST (r ⫽ -.85, p ⬍ .01;
r ⫽ -.68, p ⬍ .01, respectively). The correlation between
NIHSS and MMSE was higher for non-lacunar than lacunar
strokes (OCSP: non-lacunar r ⫽ -.64, p ⬍ .001 vs. lacunar
r ⫽.37; TOAST: non-lacunar r ⫽ -.63, p ⬍ .001 vs. lacunar
r ⫽ -.54). Neurological impairment from lacunar strokes
may have less of an influence on subacute cognitive status
than non-lacunar strokes. Study supported by NIH/
NINDS#: R01NS42733, The Ischemic Stroke Genetics
T-74. The Epidemiology of Generalized Convulsive
Status Epilepticus in Acute Hemorrhagic and Ischemic
Brian T. Bateman, Jan Claassen, Joshua T. Wiley,
Lawrence J. Hirsch, Stephan A. Mayer, Ralph L. Sacco, and
H. Christian Schumacher; New York, NY
Objective: Generalized convulsive status epilepticus (GCSE)
is a complication of acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH). We examined the frequency and
impact of GCSE in AIS and ICH. METHODS: Patients
with AIS or ICH were extracted from the Nationwide Inpatient Sample (years 1994-2002) and those coded as developing GCSE were identified. Multivariate logistic regression
was performed to identify predictors of GCSE and outcome.
RESULTS: 0.2% of 718,531 AIS patients and 0.3% of
102,763 ICH patients developed GCSE. For AIS patients,
female sex, African-American race, renal disease, alcohol
abuse, sodium imbalance, and hemorrhagic transformation
were independently associated with an increased risk, while
increasing age, hypertension, and diabetes mellitus were associated with a decreased risk for GCSE. For ICH patients,
African-American and Hispanic race, renal disease, coagulopathy, brain tumor, alcohol abuse, and sodium imbalance
were associated with an increased risk, while increasing age
and hypertension were associated with a decreased risk for
Annals of Neurology
Vol 60 (suppl 3)
GCSE. GCSE was associated with a higher in-hospital mortality for AIS but not ICH. CONCLUSIONS: GCSE is a
rare but serious complication of AIS and ICH with multiple
specific associated factors identified. Study supported by
B.T.B. was supported by the Doris Duke Charitable Foundation. R.L.S. is supported by grants from NINDS (Specialized Program on Translational Research in Acute Stroke,
P50 049060).
T-75. Adipose Stromal Cells Have Direct
Neuroprotective Effect in In Vitro Ischemia
Eun-Cheol Song, Kon Chu, Keun-Hwa Jung, Eun-Hee Kim,
Dong-In Sinn, Manho Kim, and Jae-Kyu Roh;
Seoul, Republic of Korea
Adipose stromal cells (ASCs) secrete multiple angiogenic and
anti-apoptotic growth factors. In this study, ASCs were isolated from subcutaneous adipose tissue of Sprague-Dawley
rats. By culturing ASCs for 72 hours, conditioned media obtained from ASCs (ACM). In 15 hours of OGD-induced cell
death of rat PC 12 cells, the neuroprotective effect of serially
diluted (1/2, 1/4, 1/8, 1/16, 1/32) ACM was examined using
MTS assay. Compared with control group, viability index
(%) of OGD without ACM was 48 ⫾ 3%, but those with
serially diluted ACM were 103 ⫾ 3% (1/2), 94 ⫾ 9% (1/4),
100 ⫾ 1% (1/8), 84 ⫾ 4% (1/16), and 71 ⫾ 5% (1/32).
Nuclear staining of Hoechst 33342 and annexin/PI FACS
analysis were done for evaluation of apoptotic and necrotic
cell death. Caspase-3 immunoreactivity was also reduced in
ACM-treated OGD-exposed PC12 cells. In our experiments,
OGD-induced cellular toxicity in PC12 cells was dosedependently prevented by ACM treatment, which suggests a
neuroprotective ability of secreted molecules by ASCs. We
conclude that in addition to its known role as a proangiogenic factor, ASCs may exert a direct neuroprotective
effect in hypoxic-ischemic injury.
T-76. Combination Aspirin/Dipyridamole Therapy
Given at Onset of Acute Cerebrovascular Event
Improves Short-Term Clinical Outcome
Syed F. Zaidi, Tanvir Syed, and Efrain Salgado; Weston, FL
Introduction: We assessed the hypothesis that combination
aspirin/dipyridamole therapy administered at the time of
acute-cerebrovascular-event predicts improved short-term clinical outcome. Methods: We prospectively collected data on
patients evaluated for acute- cerebrovascular-event at a stroke
center. Stroke-specific, patient-specific, and managementrelated data were assessed. Clinical outcome was defined as
“improved” if either NIHSS score decreased from admission to
discharge or a diagnosis of TIA was made. To overcome the
inherent limitations of standard statistical methods we incorporated artificial-intelligence models into the analysis. Bivariate
predictors( p⬍0.20:chi-squared,t-test) were used to build both
a logistic-regression-model and an artificial-neuralnetwork(ANN), the former only retaining predictors with
p⬍0.05. Sensitivity-analysis was used to include/exclude predictors in the final ANN-model. Results: Of 356 consecutive
patients, the LR-model identified age⬍80(OR⫽4.6,[1.8,11.8]),
evaluation-within-3-hours (OR⫽2.6,[1.16,7.05]), and carotid
stenosis(OR⫽4.2,[1.3,20.2]) as predictors of improvement.
Hemorrhage(OR⫽-19.3,[-111.5,-3.4]), cryptogenicity(OR⫽3.2,[-9.8,-1.0]), and 24-hr-Tmax ⬎99.9(OR⫽-5.0,[-9.5,-1.0])
were identified as predictors of worsening. Additionally, the
ANN-model retained combination aspirin/dipyridamole
administered in the initial 72 hours as a predictor of
clinical improvement (160 patients). The sensitivity,
specificity, and positive-predictive-value of the ANNmodel(88.1%,83.7%,90.1%) were greater than those of the
LR-model(84.4%,57.1%,79.4%). Conclusions: Combination aspirin/dipyridamole therapy given at the onset of
acute cerebrovascular event improves short-term clinical
outcome. Study supported by the author.
T-77. Increased Common Carotid Artery IntimaMedia Thickness in Takayasu’s Arteritis
Sanjeev Sivakumar, and Sivakumar M. Rajappa;
Chennai, Tamil Nadu, India
Background: The intima-media thickness (IMT) of the
common carotid artery (CCA) is well correlated with the degree of arteriosclerosis and is an independent predictor of
vascular morbidity and mortality. Takayasu’s Arteritis (TA)
is a primary systemic vasculitis. Aim: To compare the values
of CCA IMT with regard to the incidence of stroke, myocardial infarction (MI), and death in patients with TA when
compared with normal healthy controls. Methods: IMT
from CCA and Internal Carotid arteries were estimated by
Duplex sonography in 46 TA patients without cardiovascular
risk factors or established arteriosclerosis and 46 age and sex
matched healthy controls. During follow-up for a median of
30 months, the occurrence of vascular events was assessed.
Results: There were 6 cases of MI, 8 strokes, and 4 deaths.
The relative risk for a vascular event per increase of the IMT
by 1 SD (0.16 mm) was 1.52 (95% CI). The event rate was
more with IMT ⬎0.79 mm (mean). Log rank analysis
showed a continuous increase in the risk of vascular event
with increasing range of the IMT (P⫽0.028).Conclusions:
Carotid IMT is increased in Taksyasu’s Arteritis and it independently predicts future vascular events.
complicates NT-SAH and is associated with increased mortality, length of hospital stay and cost. Study supported by
B.T.B. was supported by the Doris Duke Charitable Foundation. R.L.S. is supported by grants from NINDS (Specialized Program on Translational Research in Acute Stroke,
P50 049060).
T-79. Self-Sustaining Neural System Models: Critical
Homeostasis and Implications for Epileptogenesis
David Hsu, Aonan Tang, Murielle Hsu, and John M. Beggs;
Madison, WI and Bloomington, IN
We explore the minimal requirements of a computational
neural system model that is both self-sustaining and capable
of learning. Such a model must incorporate firing rate homeostasis, critical homeostasis, Hebbian learning, and a
distance-dependent connectivity cost function. Criticality
maintains an optimal connectivity for system learning. As a
direct consequence of these minimal requirements, we find
that critical homeostasis must drive dynamical scaling of connection strengths; firing rate homeostasis drives dynamical
scaling of the spontaneous firing probabilities; most connections are very weak; the connectivity pattern corresponds to a
small world distribution; and the activation pattern is scalefree. We argue that a neural system that is persistently supercritical will be more prone to seizures. Further, we predict
that post-seizural interventions that either boost spontaneous
activity or that inhibit connectivity-dependent activity will
decrease the tendency towards supercriticality, and thus be
protective against epileptogenesis. Study supported by American Epilepsy Society.
T-78. Generalized Convulsive Satus Epilepticus after
Nontraumatic Subarachnoid Hemorrhage
Jan Claassen, Brian T. Bateman, Joshua Z. Wiley,
Sarah Inati, Lawrence J. Hirsch, Stephan A. Mayer,
Ralph L. Sacco, and H. Christian Schumacher;
New York, NY
Objective. To identify the frequency and impact on outcome
of generalized convulsive status epilepticus (GCSE) among
patients with nontraumatic subarachnoid hemorrhage (NTSAH). Methods. We identified all adult NT-SAH patients included in the Nationwide Inpatient Sample (NIS) - an administrative database - between 1994 and 2002. Independent
predictors of GCSE and mortality were identified using multivariate logistic regression analysis. Multivariate linear regression analysis was used to determine if GCSE was independently associated with increased cost and duration of
hospitalization. Results. Seventy-three (0.2%) of 29,998 patients admitted with NT-SAH developed GCSE. GCSE was
more frequent among those with renal disease (OR 4.5,
95%-CI 2.5-8.3), Asian/Pacific Islanders (OR 2.9, 95%-CI
1.2-7.2), those younger than 40 years old (OR 2.8, 95%-CI
1.7-4.6), with a history of alcohol abuse (OR 2.3, 95%-CI
1.0-5.0), and those who did not undergo a neurosurgical
procedure involving a craniotomy (OR 2.0, 95%-CI 1.33.3). GCSE was associated with higher in-hospital mortality
(48% vs. 33%; OR 2.1; 95%-CI 1.3-3.4; P⫽0.002), longer
(9 vs. 7 days, P⫽0.016) and more expensive hospitalizations
($39,677 vs. $26,686; P⫽0.007). Conclusion. GCSE rarely
T-80. A Robust Increase of Neural Progenitor Cells
and Microglia in Extrahippocampal Areas of Adult
Rodents Following Pilocarpine-Induced Status
Keun-Hwa Jung, Kon Chu, Jeong-Min Kim, Doing-In Sinn,
Eun-Chol Song, Manho Kim, Sang Kun Lee, and
Jae-Kyu Roh; Seoul, Korea
Recent evidences suggest critical roles of aberrant neuro/gliogenesis or inflammation in the epileptogenesis. Although the
patterns of cell genesis or microglial activation have been described in the hippocampus after seizures, little data so far
ascertained those in extrahippocampal regions. In this study,
we attempted to examine the histological changes in the
whole brain regions of epileptic rats, in terms of cell genesis
and inflammation. Experimental status epilepticus was induced by pilocarpine injection. Neuronal death was evident
in the hilus, CA1 and CA3 subfields of the hippocampus
and piriform cortex. Microglial activation was found in more
extended limbic areas, such as the hilus, CA1 and CA3 of
the hippocampus, entorhinal, perirhinal and piriform cortex,
amygdala, thalamus, and hypothalamus. BrdU-positive proliferating cells were distributed robustly in these areas. Most
BrdU⫹ cells were initially co-labeled with Nestin, and differentiated to neurons or glia. These findings raise the evidence of neuronal death, inflammation, and cellular genesis
to be substantially linked together in other brain areas as well
as in hippocampus, and to act importantly on epileptogenesis.
Program and Abstracts, American Neurological Association
T-81. Erythropoietin Attenuates Epileptogenic
Processes in the Adult Rodent Hippocampus with
Pilocarpine-Induced Status Epilepticus
Jeong-Min Kim, Keun-Hwa Jung, Kon Chu, Dong-In Sinn,
Eun-Chol Song, Song-Yi Ko, Manho Kim, Sang Kun Lee,
and Jae-Kyu Roh; Seoul, Korea
Erythropoietin (EPO) and EPOR are essential for early embryonic neural development. EPO treatment has also shown
neuroprotective effects in a variety of neurological diseases.
The effects of EPO underlie the neuroprotection, astrogial
cytoprotection, and reduction of tissue-injuring molecules
such as reactive oxygen species, glutamate and inflammatory
cytokines. Although EPO may constitute an effective therapeutic modality in cases of epileptic insult, there is no study
for the effects of exogenous EPO on the epileptogenic process. In this study, we attempted to examine the histological
changes in the hippocampus of epileptic rats. EPO receptor
was increased in the epileptogenic hippocampus. During the
latent period after pilocarpine-induced status epilepticus,
EPO treatment prevented neuronal death and microglial activation in the dentate hilus, CA1 and CA3, and inhibited
the generation of ectopic granule cells in the hilus and new
glia in CA1. These findings suggest a potential therapeutic
role for EPO in the process of epileptogenesis.
T-82. JME: Novel Mutations in Myoclonin1/EFHC1
Marco T. Medina, Toshimitsu Suzuki, Reyna M. Duron,
Maria E. Alonso, Julia N. Bailey, Iris E. Martinez-Juarez,
Dongsheng Bai, Yushi Inoue, Ihoko Yoshimura,
Sunao Kaneko, Maria C. Montoya, Astrid Rasmussen,
Adriana Ochoa, Aurelio Jara-Prado, Miyabi Tanaka,
Jesus Machado-Salas, Kazuhiro Yamakawa, and
Antonio V. Delgado-Escueta; Tegucigalpa, Honduras;
Saitama, Japan; Mexico City, Mexico; Los Angeles, CA;
Shizuoka, Japan and Aomari, Japan
Juvenile myoclonic epilepsy (JME) is a lifelong epilepsy responsible for 3 to 12% of all epilepsies. In 2004, our GENESS Consortium demonstrated 4 missense mutations in
Myoclonin1/EFHC1 of chromosome 6p12.1 segregating in
21 epilepsy and polyspike affected members of six unrelated
JME Hispanic families. Here, we report two new JME cohorts (44 from Mexico and Honduras, 47 from Japan) that
were screened for mutations by heteroduplex analysis followed by direct sequencing. We detected two novel heterozygous missense mutations (c.755C⬎A and c.1523C⬎G) in
isoform A of a singleton from Mexico and in another singleton from Japan. We found in a mother and daughter from
Mexico, C.789del.AV264fsx280, a dinucleotide deletion/
frameshift in isoform B. We also observed a non-sense mutation (c.829C⬎T) in isoform B in 2 clinically and 7
epileptiform-EEG affected members of a 4-generation family
from Honduras. The same non-sense mutation (c.829C⬎T)
occurred as a de novo mutation in a sporadic from Honduras. In conclusion, our results demonstrate that 9% of consecutive JME cases from Mexico and Honduras clinics carry
mutations in myoclonin1/EFHC1. These represent the highest percentage of JME patients carrying mutations for any
population group. Such mutations are rarely found in JME
patients from Japan. Study supported by National Institutes
of Health.
Annals of Neurology
Vol 60 (suppl 3)
T-83. Predictors of Response of Intractable Epilespy
to Intravenous Gammaglobulin Therapy
Rana Kurdi, Ziad El Khoury, Amal Rahi, Wissam Raad, and
Mohamad Mikati; Beirut, Lebanon
Background: Several studies documented the usefulness of
intravenous immunoglobulin (IVIG) in treating intractable
epilepsy. However the predictors of response to IVIG are unknown. Goals: Determine factors associated with response of
intractable epilepsy to IVIG. Methods: 37 patients with intractable epilepsy participated in a prospective open-label uncontrolled study. 2g/kg of IVIG were given in divided doses
over four days followed by 1g/kg/day every 4 weeks for six
months. Data were analyzed using the t-test, Chi-square test,
Kruskal-Wallis and Wilcoxon signed rank sum test. Binary
logistic regression for “response” (defined as ⬎50% drop in
seizure frequency during the one-month period after IVIG as
compared to the one-month baseline before IVIG) was performed. Results: Seizure frequencies dropped (before
229.30⫾351.74, after 88.30⫾173.79, p⫽0.01). Bivariate
analysis showed that males responded to the treatment more
than females (p⫽0.01). In the binary stepwise logistic regression, 3 variables were predictors of response to IVIG; sex
(male⬎female, p⫽0.01), seizure type (generalized⬎partial,
p⫽0.06), and age (⬍9 years, p⫽0.10). Log odds of response
versus no response ⫽-1.91-2.87sex ⫹1.86type⫹0.15age,
Sensitivity⫽66.67%, Specificity⫽76.19%, Positive Predictive Value⫽66.67%, Negative Predictive Value⫽76.19%.
Conclusion: Male sex, generalized seizures and age ⬍9 years
were associated with a better response to IVIG.
T-84. Metabotropic Glutamate Receptor 3
Alison Berent-Spillson, and James W. Russell; Ann Arbor, MI
High glucose concentrations cause oxidative injury and programmed cell death in neurons, a process that underlies diabetic neural complications. Activating the type 3 metabotropic glutamate receptor prevents glucose-induced oxidative
injury in dorsal root ganglion neurons co-cultured with
Schwann cells. To determine the mechanisms of protection,
studies were performed in rat dorsal root ganglion neuronSchwann cell co-cultures. The metabotropic glutamate receptor 3 agonist 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate
prevented glucose-induced inner mitochondrial membrane
depolarization, reactive oxygen species accumulation, and
programmed cell death in co-cultured neurons. Activating
metabotropic glutamate receptor 3 increased reduced glutathione concentration in co-cultured neurons and Schwann
cells, but not in neurons cultured without Schwann cells.
Protection was diminished in neurons treated with the glutathione synthesis inhibitor L-buthionine-sulfoximine, suggesting that metabotropic glutamate receptor-mediated protection requires glutathione synthesis. Glutathione precursors
and the glutathione analogue glutathione-ethyl-ester also
protected neurons from glucose-induced injury, indicating
that glutathione synthesis in Schwann cells, and transport of
reaction precursors to neurons, may underlie metabotropic
glutamate receptor-mediated neuroprotection. These results
support the conclusions that activating glial metabotropic
glutamate receptor 3 protects neurons from glucose-induced
oxidative injury, by increasing free radical scavenging and
stabilizing mitochondrial function, through increased glutathione antioxidant defense. Study supported by NIH
NS42056, (JDRF), Office of Research Development (Medi-
cal Research Service), VA (JWR), NIDDK #5P60DK20572, Michigan Diabetes Research and Training Center
(MDRTC), and the Michigan Imaging Laboratory.
T-85. MEG Evidence for Apraxia as a Mechanism of
Disability in ALS
Robert A. Boyajian, Carlos Amo, Shirley M. Otis,
John S. Romine, and Richard A. Smith; La Jolla, CA
Background/Objective There may be instances when motor
disabilities in ALS are more severe than the degree of muscle
denervation and atrophy. This study looks for cortical motor
network dysfunction in ALS, and whether any identified deficits relate to abnormal slow wave discharges we recently described in ALS using MEG. Methods 148 channel whole
brain MEG signal-averaged fields were obtained during cued
motor task (repeated brisk dorsiflexion then extension of
each wrist) performed by upper limb-onset ALS patient complaining of “useless hands” and exhibiting slow wave discharges on MEG. The topography of cortical activations is
mapped onto patient MRI with “slow wave” frontal areas
compared to contralateral “control” areas, and model topography from healthy subject. Results No motor activations
were detectable in right frontal motor areas corresponding to
generator sites of slow wave discharges. An anomalous spatiotemporal organization of activations in left hemisphere corresponded to generator sites of slow wave discharges. Conclusions Abnormal slow wave discharges involving
supplementary motor and premotor areas appear to impede
cortical motor network function in a patient with ALS.
Apraxia should be considered a possible mechanism contributing to severity of motor disabilities in selected patients
with ALS.
T-86. A Double-Blind, Placebo-Controlled Study of
Rituximab in Patients with Anti-MAG AntibodyDemyelinating Polyneuropathy (A-MAG-DP)
Marinos C. Dalakas, Goran Rakocevic, Kian Salajegheh,
James Dambrosia, Raghavan Raju, and Beverly McElroy;
Bethesda, MD
A-MAG-DP causes sensory ataxia and distal weakness. In
spite of a causative link between IgM-MAG and neuropathy,
the disease is resistant to immunotherapies. Rituximab, a chimeric monoclonal antibody against the CD20 B-cell antigen,
causes B cell depletion. Because anectodal reports have
shown effectiveness of Rituximab in some A-MAG-DP, we
conducted a placebo-controlled study. Sample size was calculated to detect ⬎20% change on the INCAT disability
scores. 26 patients were randomized to 4 weekly infusions of
375 mg/m2 Rituximab or placebo. Randomiztion was balanced for age, disability and QoL. Clinical and laboratory
data were collected bi-monthly up to a year. The INCAT
scores of patients with baseline disability ⬎ 1, significantly
improved (p ⬍0.05) 8 months after Rituximab compared to
placebo. Changes in B cell subsets, plasma cells, regulatory T
cells, APC’s, immunoglobulins and anti-MAG antibodies
were serially monitored as reported in an accompanied abstract. Induction of regulatory CD25⫹CD4⫹T cells and
CD62L⫹CD4⫹ cells appear associated with clinical improvement at month 8. We conclude that Rituximab is an
effective treatment in 75% of patients with A-MAG-DP with
disability ⬎1 INCAT scores. Study supported by NINDS.
T-87. Altered Zinc Binding in Cu, Zn SOD1 Mutants
That Cause Amyotrophic Lateral Sclerosis
Ashutosh Tiwari, and Lawrence J. Hayward; Worcester, MA
More than 100 different mutant forms of the antioxidant
enzyme Cu,Zn-superoxide dismutase (SOD1) cause preferential motor neuron degeneration in familial amyotrophic lateral sclerosis (ALS). SOD1 misfolding is thought to render
the mutants toxic to motor neurons by a non-cellautonomous mechanism, but the target(s) of mutant SOD1
toxicity remain unclear. Our laboratory has purified 14 representative SOD1 mutants and compared measures of protein stability, conformation, and metal ion binding between
normal and mutant SOD1 variants. In this study, we sought
to characterize the interaction of zinc ions with normal and
mutant SOD1s, using isothermal titration calorimetry.
SOD1 mutants exhibited lower zinc binding affinity compared to the normal enzyme. A subset of these mutants
(D124V, D125H, and S134N) showed an initial weak exothermic zinc binding during titration and a second endothermic event, suggesting an aberrant interaction of zinc with the
protein. G85R SOD1 exhibited very little detectable zinc
binding. We hypothesize that weaker or abnormal zinc interactions contribute to mutant SOD1 misfolding, which
may facilitate aberrant interactions of the protein with other
cellular constituents to produce motor neuron toxicity. Study
supported by NIH-NINDS, ALS Association, ALS Therapy
T-88. Reversible Splenial Lesion with Restricted
Diffusion in a Wide Spectrum of Diseases and
Osamu Igarashi, Yasuo Iwasaki, Masayuki Maeda,
Hirokazu Tsukahara, Hitoshi Terada, Shunsuke Nakaji,
Hisao Nakamura, Hiroshi Oba, Keisuke Arasaki,
Toru Machida, Kan Takeda, and Jun-ichi Takanashi;
Tokyo, Japan, Mie, Japan, Fukui, Japan, Kanagawa, Japan
and, Chiba, Japan
Reversible lesion in the central area of the splenium of the
corpus callosum (SCC) is a unique phenomenon occurring
particularly in patients with encephalitis or encephalopathy
and in patients receiving antiepileptic drugs (AED). We report MR imaging findings, clinical courses, and outcomes
in eight patients with various diseases and conditions.
Seven patients had isolated SCC lesions; one patient with
osmotic myelinolysis showed additional parenchymal lesions. The reversible SCC lesion shape was oval (n⫽6) or
extended (n⫽2). The mean apparent diffusion coefficient
value of the splenial lesion was 0.40 ⫾ 0.16 ⫻ 10-3 mm2/s,
ranging from 0.22 to 0.64 ⫻ 10-3 mm2/s. In a patient with
osmotic myelinolysis, additional white matter lesions,
shown as restricted diffusion, were revealed as not reversible
on follow-up MR imaging. Neurological courses and outcomes were good in seven patients with isolated SCC lesions, but poor in one with osmotic myelinolysis. Reversible SCC lesion with restricted diffusion is apparent in a
wide spectrum of diseases and conditions. Knowledge of
MR imaging findings and the associated spectrum of diseases and conditions might prevent unnecessary invasive examinations and treatments.
Program and Abstracts, American Neurological Association
T-89. Proteins Relating to Quality Control Are UpRegulated in Denervated Skeletal Muscle
Takahiro Jimi, Yoshihiro Wakayama, Yoko Matsuzaki,
Seiji Shibuya, and Hajime Hara; Yokohama, Japan
Neural factors are important in maintaining the function of
skeletal muscle. To examine gene expression change of denervated skeletal muscle, we performed differential gene analysis between normally innervated and denervated skeletal
muscles. We isolated differentially up-regulated genes in the
denervated skeletal muscle by using ready-made DNA microbead analysis (129th ANA meeting, Toronto, 2004). Using the differentially up-regulated genes in denervated skeletal muscle, we made a DNA chip and carried out a semiquantitative analysis. Both normally innervated and
denervated skeletal muscle cDNA were labeled with cy3 and
cy5, respectively, and were applied to the DNA chip. Signals
of fluorescence were measured, and a signal ratio of the denervated muscle per normal muscle was calculated. High signal ratios were shown in alpha B crystalline, cathepsin B,
heat shock protein 27, thioredoxin, and cyclophilin A. Most
of these genes were classified into molecular chaperone, lysosome, or anti-oxidative proteins. According to these results,
we speculated that denervation causes some stress, such as
oxidative stress, on skeletal muscle, and the proteins relating
to quality control are induced to protect against these
stresses. Study supported by Grant-in-Aid for Scientific Research (C-2-14570619) from Ministry of Education, Culture, Sports, Sciences, and Technology, Japan.
T-90. The Chemokine Receptor 2 Gene
Polymorphism V64I (CCR2-64I) and the Chemokine
Receptor 5 del32 Allele (CCR5D32) in Patients with
Myasthenia Gravis
Hyun Sook Kim, Dae-Seong Kim, Eun Young Lee,
Il-Nam Sunwoo, and Young-Chul Choi;
Bundang-gu, Seongnam-Si, Republic of Korea;
Pusan, Republic of Korea and Seoul, Republic of Korea
Objectives: Chemokines and their receptors are considered
to be the couriers of inflammation and tissue damage in autoimmune disorders. Recently, the importance of chemokine
receptor genetic polymorphisms in some autoimmune and
infectious disorders have been demonstrated. To define the
role of the chemokine receptor polymorphisms in myasthenia
gravis (MG), we studied the genotypes in MG cases and controls and investigated the clinical features associated with
these genotypes. Methods: 115 normal controls (51 men
and 64 women) and 109 MG patients (44 men and 65
women) were included. Clinical features including electrophysiology tests, laboratory tests, and thymic pathology and
genotyping of the CCR2-64I and CCR5D32 polymorphisms
were studied. Results: For the CCR2-64I polymorphism, we
detected no differences between MG patients and healthy
controls. For the CCR5 genotype, all of the MG patients
and the case controls were homozygous for the wild type
genotype. The results of electrophysiological tests and thymic
pathologies were not influenced by the CCR2-64I polymorphisms. Conclusions: We found no evidence of increased
risk for myasthenia gravis associated with the chemokine receptor gene polymorphisms CCR2-64I and CCR5D32.
Annals of Neurology
Vol 60 (suppl 3)
T-91. Neuromyotonia Sera Target Kv1.6 Shaker-Type
Potassium Channels Expressed in Motor Axon
Kleopas A. Kleopa, Steven S. Scherer, and Angela Vincent;
Nicosia, Cyprus; Philadelphia, PA and
Oxford, United Kingdom
Neuromyotonia and Morvan’s syndrome are characterized by
peripheral nerve hyperexcitability that often originates distally close to the neuromuscular junction. Both disorders are
associated with antibodies to Shaker-type potassium channels
Kv1.1, Kv1.2, and Kv1.6. While Kv1.1 and Kv1.2 are clustered at the juxtaparanodes of myelinated axons, the expression pattern of Kv1.6 in the peripheral nerves and its role in
neuromyotonia remain unclear. Using immunostaining and
immunoblotting we show that Kv1.6 is not clustered at the
juxtaparanodes, but instead it is strongly expressed in the intramuscular axons close to the neuromuscular junction. Labeling with sera from 11 patients with neuromyotonia and 2
patients with Morvan’s syndrome combined with commercial antibodies revealed that 6 of 13 sera colocalized with
these Kv1.6 channels at axon terminals. Expression of mature
Kv1.6 channels in transfected HeLa cells and testing of the
same sera confirmed their specific reactivity to Kv1.6, although most of these sera were also reactive against Kv1.2.
This study demonstrates for the first time the expression of
Kv1.6 in distal peripheral axons, where it might control excitability and constitute an important target for pathogenic
antibodies in neuromyotonia and Morvan’s syndrome. Study
supported by National Multiple Sclerosis Society (USA) and
T-92. Charcot-Marie-Tooth Type 4A and 4F Diseases
Caused by Mutations in the GDAP1 and PRX Genes
Andrzej Kochanski, Dagmara Kabzinska, Hanna Drac,
Katarzyna Rowiñska-Marciñska, Anna Kostera-Pruszczyk,
Peter Brophy, Francesc Palau, Laia Pedrola, Mustafa Saifi,
Diane Sherman, James R. Lupski, and
Irena Hausmanowa-Petrusewicz; Warsaw, Poland;
Edinburgh, United Kingdom; Valencia, Spain and Texas, TX
Charcot-Marie-Tooth type 4A and 4F diseases (CMT4A and
F) belong to a heterogenous group of autosomal recessive
neuropathies. Only 23 mutations in the GDAP1(CMT4A)
gene and 7 mutations in the PRX (CMT4F) gene have been
reported. Sural nerve biopsy was reported only in a few patients. Given the small size of the group of CMT4A and
CMT4F patients, the delineation of the CMT4A and
CMT4F phenotypes is required. The aim of this study is to
present characteristics of five mutations in the GDAP1 gene
and one mutation in the PRX gene detected by us in a group
consisting of 60 CMT patients. Clinical examination, electrophysiological study, sural nerve biopsy, genetic and functional studies were performed. CMT 4A disease caused by
Leu239Phe, Pro153Leu, Met116Thr and Ser130Cys/3111G⬎A mutations and CMT4F disease caused by
Ser399fsx410 mutation belong to a group of early onset neuropathy with variable clinical phenotype with axonaldemyelinating features (CMT4A) and broad spectrum of
morphologic changes (CMT4F). The presence of the broad
spectrum of morphologic changes (CMT4F) and axonaldemyelinating changes (CMT4A) may be used as differentiating criteria.
T-93. Anti-DAF Antibody Administration Augments
the Development of Ocular Myasthenia Gravis in HLADQ8 Transgenic Mice
Jing Li, Erdem Tuzun, Shamsher S. Saini, Andrey Bednov,
Claire L. Harris, and Premkumar Christadoss; Galveston, TX
and Heath Park, Cardiff, United Kingdom
We have recently developed a new ocular MG (oMG) model
by immunizing HLA-DQ8 transgenic mice with human
AChR subunits. Decay-accelerating factor (Daf) is a complement regulator and inhibits the formation of C5b-C9. To
study the role of Daf in the development of oMG in mice,
we treated HLA-DQ8 mice with anti-Daf (40ug/mice) or
control antibody (IgG1) following immunization with human AChR ␥ subunit. Mice were screened for the development of oMG and limb muscle weakness. Serum was collected to measure anti-AChR antibodies. 75% of anti-Daf
antibody injected mice developed oMG compared to 62.5%
IgG1 injected mice. Anti-Daf antibody administration also
induced severe ocular symptoms (ptosis) compared to isotype
control (p⫽0.04). Interestingly, sera anti-AChR IgG2b was
significantly (p⫽0.02) elevated in anti-DAF antibody treated
mice. However, there was no significant difference in the serum level of anti-AChR IgG, IgG1, IgM, complement C3
and immune complex. Further immunopathology studies
will be performed and reported. Anti-Daf antibody administration augments oMG susceptibility in HLA-DQ8 mice.
This augmentation of clinical oMG is associated with increased production of complement binding IgG2b. Thus Daf
directly or indirectly influences the production of IgG2b isotype. Study supported by Myasthenia Gravis Foundation of
America Osserman/Slosin/McClure Fellowship.
T-94. Detection of Demyelinating Neuropathy Using
Cauda Equina Nerve Conduction Studies
Paul J. Maccabee, Ian A. G. Stein, Larry P. Eberle,
Justin A. Willer, and Vahe E. Amassian; Brooklyn, NY
Background: Segmental conduction time analysis of the entire peripheral motor axis may provide fundamental and diagnostic information in demyelinating neuropathies. Methods: Neuromagnetic stimulation of cauda equina, and
conventional electric stimulation more distally, elicited responses in abductor hallucis and vastus medialis. The limit of
normal was defined at 3 SD from the mean in healthy controls. Demyelination was defined by strict latency and/or CV
criteria; ie 125%-150% upper limit and/or 70-80% lower
limit of normal, respectively, given preserved distal amplitude. Demyelinating criteria for CMAP durations were also
established. Findings: (1) Cauda equina conduction time
(CECT) may be prolonged into the demyelinating range in
both AIDP and CIDP. (2) Distal cauda equina - popliteal
fossa (DCE - PF) conduction time ( posterior-tibial nerve) is
rarely demyelinated in AIDP, and frequently demyelinated in
CIDP. (3) In an IVIG responsive CIDP patient seen 9 days
after onset, demyelination was demonstrated in the DCE PF segment; but not in the CECT segment until six months
later. (4) Demyelinative slowing may also be observed in
CECT and especially DCE-PF segments in anti-MAG polyneuropathy. Conclusions: Cauda equina conduction studies
may be uniquely informative in peripheral neuropathy.
T-95. Strength, Physical Activity, and Fasciculations in
Patients with ALS
Farrah Mateen, Eric Sorenson, and Jasper Daube;
Rochester, MN
The source of the variation in number of fasciculations in
patients with amyotrophic lateral sclerosis (ALS) remains uncertain. The effects of physical activity, weakness, atrophy,
and disease duration on fasciculation frequency were tested.
The months since onset of disease and symptoms in the
arm, level of arm physical activity, weakness and atrophy in
the arm and hand were determined in twenty-four patients
(20 male; 4 female) who met El Escorial criteria for ALS
(mean age 64 years). The number of fasciculations in the
forearm flexor and extensor muscles over 3 minutes was determined by observation and surface electromyography
(sEMG). The variables were compared by multiple linear regression. Fasciculation frequency by sEMG in the flexors
(226⫹200;6-226) and extensors (209⫹215;23-815) and by
observation (98⫹114;0-421) and (68⫹68;0-285), correlated
with arm strength and arm use (p⫽0.04 and p⫽0.02); for
maintained physical activity and loss of strength together p⫽
0.06. In the tested muscles fasciculation frequency was independent of degree of atrophy, of overall disease duration and
of disease duration in the tested limb. Fasciculations in ALS
may have a similar mechanism to those in normal subjects
after exercise, especially of poorly conditioned muscles.
T-97. Modulation of Protective Autoimmunity
Improves NSC Treatment of ALS
Gustavo A. Moviglia, Gabriela S. Varela, Jose A. Brizuela,
Carlos A. Gaeta, Pablo Farina, Hernan Costanzo,
Fabiana Bastos, and Maria E. Pes; Buenos Aires, Argentina
Schwartz proved Cop-I elicits Protective Autoimmunity (PA)
improving evolution of ALS rodents. We found anti motor
neuron T cells (AMT) in ALS patients. 7/9 patients responded to T Cell Vaccination (TCV). 2/7 responders are
alive and neurologically stable after 9 years. To improve
these results, we associated TCV and AMT to NSC. Methods and results: 4 ALS patients have been recruited. AMT
are selected from apheresed lymphocytes and divided into 2
aliquots. The first is used for TCV. The second is kept frozen. TCV is IV infused once a month. At second month,
bone marrow MSC are isolated and cocultured with frozen
AMT. NSC transdifferentiation is assessed using Nestin and
Tubulin III immunostain Remaining AMT are IV administered. 48 hours later NSC are IV infused. Neurological evaluations were performed following ALS FRS-R. Hand force
and respiratory function were assessed. 3/4 patients stopped
disease progression, 2/4 improved gait, hand force and respiratory capacity. Toxic effects were minimal. Conclusion:
Modulation of AMT cells seems to achieve sustained results
of NSC treated ALS patients. Study supported by Regina
Mater Foundation.
T-98. VEGF Electro-Gene Therapy for Mouse Model
of Diabetic Neuropathy and ALS
Tatsufumi Murakami, Yuki Shimada, Yoshimi Imada,
Akihiro Nakamura, and Yoshihide Sunada; Kurashiki, Japan
and Fukuyama, Japan
Vascular endothelial growth factor (VEGF) is an essential
mediator of angiogenesis and has neurotrophic activities.
Program and Abstracts, American Neurological Association
Electroporation in vivo promotes gene transfer in skeletal
muscles. We have previously shown that intramuscular
vegf164 gene transfer by electroporation markedly restore
sensory disturbances in diabetic mice. In these mice, mild
but significant increase of plasma VEGF level was observed.
To examine the efficiency of electro-gene therapy for ALS,
VEGF165 plasmid was injected into the bilateral tibial anterior muscles of female G93A SOD1 transgenic mouse model
of ALS at age 11 with electroporation. Mice were monitored
for their motor functions and survival. There was no significant increase in survival of treated SOD1 mice (140.1 ⫾
5.1 days, n ⫽ 7) compared with control SOD1 mice
(134.1 ⫾ 8.0 days, n ⫽ 7) (p ⫽ 0.275 by log-rank test),
although a trend toward an increase in survival was observed
in treated SOD1 mice. VEGF delivery at high levels or earlier introduction of VEGF plasmid may be necessary to improve motor functions and survival of SOD1 mice. Study
supported by JSPS KAKENHI (13670679, 17590906).
T-99. Multiple Myeloma (MM) Polyneuropathy before
and after Initial Chemotherapy with Single-Agent
Anne Louise Oaklander, Paul G. Richardson,
Hannah Briemberg, Kenneth C. Anderson, Patrick Wen,
Asher A. Chan-Khan, Robert L. Schlossman,
Nikhil C. Munshi, L. Thompson Heffner, Hani Hassoun,
David E. Avigan, and Anthony Amato; Boston, MA;
Buffalo, NY; Atlanta, GA and New York, NY
Polyneuropathy can complicate MM and its-treatment. A
multi-center, phase II, single-agent trial of bortezomib (VELCADE) studied neuropathy prevalence, severity and effects
of dose modification. Patients received 1.3mg/m2 (d1, 4, 8,
11 every 21d) for 8 cycles. Sixty-six were enrolled; 34 underwent pre- and post-treatment neurologic examination,
quantitative sensory and autonomic testing, electrophysiology, and distal-leg skin biopsy. At baseline, reduced or absent
sural-SNAP identified large-fiber axonopathy (LFA) in 9%
(3/34); 62% (21/34 including all with LFA) had small fiber
neuropathy (SFA) based on abnormal thermal thresholds or
dysautonomia. Ten had QST abnormalities, four had
QSART abnormalities, six had both, and one only abnormal
HR variability. Mean epidermal innervation was 26% of predicted norms; 24% (8/33) had densities ⱕ 5th predicted centile. During treatment, new neuropathy symptoms developed
in 43% of subjects, but symptoms improved or resolved in
75% after dose reduction. Physiological testing revealed new
LFA in 6 patients and SFA in 4. SFA worsened physiologically in 67% (13/21) with baseline SFA. SFA appears more
common in untreated MM than previously appreciated.
Bortezomib therapy can cause new large- and small-fiber axonopathy, but dose modification usually improves symptoms. Study supported by Study supported in part by Millennium Pharmaceuticals, Inc., Johnson and Johnson
Pharmaceuticals Research & Development L.L.C. and by
NIH P30 EY 12196; Dr Richardson has received research
grant support, Speaker Bureau honoraria and is on the advisory board for Millennium Pharmaceuticals, Inc. Dr Anderson has received research grant support, Speaker Bureau honoraria
Pharmaceuticals, Inc. Dr Schlossman has received honoraria
from Millennium Pharmaceuticals, Inc and Celgene Corporation. Dr Munshi has received honoraria from Millennium
Pharmaceuticals, Inc, Celgene Corporation, and Novartis.
Dr Amato has received honoraria and consultancy fees from
Annals of Neurology
Vol 60 (suppl 3)
Millennium Pharmaceuticals, Inc. Dr Oaklander has received
honoraria from Millennium Pharmaceuticals, Inc.
T-100. Pathological Correlates of Neuralgia after
Minor Distal Nerve Injuries (MDNI)
Jeung Woon Lee, Sandra M. Siegel, Heather M. Downs, and
Anne Louise Oaklander; Boston, MA
Most MDNI cause no long-lasting harm, but rare patients
are left with neuralgia and sometimes dysautonomia, for unknown reasons. Adult rats were perfused 14 days after single
18G-needlestick of one tibial nerve, and pathologic data were
compared between rats with profound versus no mechanical
allodynia (n⫽5/group). Unoperated rats provided controls.
Toluidine-blue-stained tibial-nerve cross-sections (4mm distal to MDNI) were morphometrically analyzed. Endoneurial
area increased more (33%) in allodynic than in nonallodynic rats (14%) (P⬍0.01). Endoneurial vessel diameter
may have been larger (P⬍0.1). Post-MDNI abnormalities
that were pain-independent included myelinated-fiber losses
(30%), increased vessel-wall thickness (35%), increased mast
cells (311%), and hindpaw epidermal neurite losses (27%).
Numbers of endoneurial vessels were unchanged by MDNI.
Nerves contralesional to MDNI lacked edema and
myelinated-fiber loss, but had 264% more mast cells than
controls. Contralesionally, vessel-lumen areas decreased by
31% in allodynic rats but increased by 11% in non-allodynic
rats (P⬍0.0001). Contralesional epidermal neurite losses
(11%) seemed pain-independent. Development of neuralgia
after MDNI thus appears independent of the severity of axonal injury, but may correlate with the severity of endoneurial neurogenic edema. MDNI may also cause contralesional
mastocytosis, and endoneurial vasoconstriction restricted to
neuralgic rats. Study supported by National Institutes of
Health (R01-NS042866), Reflex Sympathetic Dystrophy Society of America, National Organization for Rare Diseases,
and the Beatrice and Roy Backus Foundation.
T-101. Clinical and Electrophysiological Studies in
Survivors of Paralytic Poliomyelitis
Olavo M. Vasconcelos, Olga A. Prokhorenko, Vitalie Lupu,
Karen E. Livornese, Mary K. Floeter, Bahman Jabbari, and
William W. Campbell; Bethesda, MD and New Haven, CT
Although poliomyelitis is a motor neuronopathy, there is evidence supporting involvement of sensory pathways, including sensory loss during the acute infection, abnormal lower
extremity sensory evoked responses in convalescents, and
damaged thalamus and dorsal ganglia in autopsies. In a prospective study, we assessed the integrity of sensory and motor
pathways in aging polio survivors. After consent, participants
underwent clinical evaluation followed by 4-limb motor and
sensory evoked potentials (SEPs and MEPs). Subjects with
abnormal responses were further evaluated with brain and
spine MRIs. Twenty-one polio survivors were studied (mean
age: 66 years, interval: 57-82 years). MEPs and upper limbs
SEPs were normal. Lower limbs SEPs demonstrated delayed
cortical responses (P37) in 15 of 21 patients. Four of these
15 patients had impaired sensation to light touch, vibration
and proprioception. Of the six MRIs obtained, one showed
encephalomalacia and hemosiderosis in occipital lobe and
cerebellum, four showed foci of white matter hyperintensity,
and one exhibited focal cord atrophy. Abnormal SEP responses from lower extremities, often associated with deficits
in deep sensory modalities, may represent sequelae of poliomyelitis infection. Further analysis and correlations with
MRI will help anatomically localize and explain these findings. Study supported by a grant from the Department of
T-102. Cortical Alterations in Early Stages of
Amyotrophic Lateral Sclerosis (ALS) Using Magnetic
Resonance Imaging (MRI)
M. Muddasir Qureshi, Merit E. Cudkowicz,
Bruce Jenkins, Jonathan Kaiser, Megan Dieterich,
Dianne Mckenna-Yasek, Steve Hodge, Lena Tang,
David N. Kennedy, Verne S. Caviness, Jean P. Vonsattel,
Robert H. Brown, Jr., and Nikos Makris; Boston, MA and
New York, NY
Background: The pathogenesis of ALS involves cortical motor neuron atrophy however the location that contributes to
start of the neurodegenerative process remains obscure. Objective: To study the pattern of atrophy as well as degenerative loci in the brain of ALS subjects by using structural
T1-weighted Magnetic Resonance Imaging (MRI) in subjects
with ALS. Methods: Four subjects with ALS underwent T1MRI in two time points (baseline and after one year). Two
groups of datasets were created (time point 2 vs time point
1) and compared using the FreeSurfer software to obtain cortical thickness difference measurements. MRI-based morphometry was performed for structural volumetric analysis.
Results: Cortical thinning was encountered as a function of
time in a bilateral localized fashion at the temporooccipital,
mesial frontal and parietal areas of both hemispheres. Cortical volume decreases showed an analogous profile particularly
at the mesial frontal regions. Cortical thickness increase was
localized at the hand area of the left postcentral gyrus. Conclusion: In four ALS subjects, degenerative loci were seen at
the cortical regions of the paralimbic system within the frontal and temporal lobes beyond the brain regions related to
motor control.
T-103. Search for the Therapeutic Enzyme: Tales of
Mistargeting and Autophagy in Pompe Disease
Tokiko Fukuda, Maria Gabriela Pittis, Bruno Bembi,
Robert Mattaliano, Paul Plotz, and Nina Raben;
Bethesda, MD; Trieste, Italy and Framingham, MA
Enzyme replacement therapy will soon become available for
patients with acid alpha-glucosidase deficiency, the lysosomal
glycogen storage disease. Based on clinical and pre-clinical
studies, the effective clearance of skeletal muscle glycogen appears to be significantly more difficult than anticipated. We
have shown a dramatic induction of autophagy in therapyresistant myofibers from KO mice, and we asked whether the
autophagic build-up affected the M6P receptor-mediated endocytosis/trafficking of the drug. Labeled enzyme was
tracked in live cultured single KO myofibers by confocal microscopy: most of the enzyme was trapped in the autophagic
areas. Similarly, labeled dextran, which enters the cell
through fluid phase endocytosis, accumulated in vesicular
structures in the autophagic regions. Furthermore, partially
processed enzyme was the predominant form in single fibers
from ERT-treated KO. Also, we looked at the extent of autophagy in muscles from several late-onset Pompe patients.
As in the KO, there was a significant increase in autophagy
in the affected fibers. However, unlike the KO, in the human samples some fibers contained huge glycogen-filled areas
devoid of M6P receptor, which may further impair enzyme
delivery to the lysosomes in these fibers.
T-104. The Clinical Response of Rituximab in
Patients with Anti-MAG Antibody-Demyelinating
Polyneuropathy (A-MAG-DP) Is Associated with
Alteration of Lymphocyte Homing and Induction of
Regulatory T Cells
Raghavan Raju, Wei Shi, and Marinos Dalakas;
Bethesda, MD
A controlled trial of 26 patients with A-MAG-DP demonstrated improvement in 75% of Rituximab treated group
with disability ⬎1 INCAT score (submitted to this meeting).
To further understand the immunological alterations associated with improvement, we examined the effect of Rituximab on immunoglobulin levels and lymphocyte phenotypes
before and after therapy. The IgM level, but not the MAG/
SGPG titers, declined by 30-40%. CD20⫹ cells were depleted within a week of the first infusion and began to reappear after eight months. The newly emerging B cells were
CD20⫹CD19⫹CD22⫹, and negative for the CD27 memory phenotype. CD4⫹CD25⫹ regulatory T cells, were significantly elevated soon after the first infusion (p⬍0.0005)
and remained high up to the eight month coinciding with
the peak of clinical response. An increase of CD62L⫹ cells
associated with lymphocyte homing to high endothelial
venules was noted. Changes in antigen presenting cells are
being investigated. We conclude that Rituximab treatment in
A-MAG-DP patients increases the regulatory T cells and
lymphocyte homing and has an immunoregulatory effect beyond B cell depletion. Study supported by NINDS intramural research program.
T-105. Neuronal Mitochondrial Degeneration in
Diabetic Rats and Ameliorative Effects of Pioglitazone
James W. Russell, Tatsuya Inoue, and Edward K. Kim;
Ann Arbor, MI
Mitochondrial degeneration seems to be involved in the progression of diabetic neuropathy. Neuronal gene expression
changes regulating mitochondrial number/proteins and effects of pioglitazone, a PPAR␥ agonist were investigated using STZ-diabetic rat model of 1 and 3 month-diabetes.
Nerve conduction deficit was seen after 1 month of diabetes
whereas tactile allodynia was seen after 2 months. Mitochondrial DNA was decreased and loss was greater at 3 month as
neuropathy got severer. PGC1a was increased at 3 month by
11% associated with upregulation of Nrf1 and Tfam. Mitochondrial fission proteins, Drp1 was high after 1 month
whereas Fis1 was so only at 3 month. Mitochondrial fusion
proteins, Mfn2 and Opa2, were high at 3 month. Pioglitazone (20 mg/kg) improved neuropathy and prevented the
loss in mitochondrial DNA. Pioglitazone also reduced gene
expression changes controlling mitochondrial homeostasis. In
conclusion, there is loss of mitochondrial DNA in DRG
from rodents with chronic diabetes. In response, there is altered gene expression regulating Mt number and proteins.
Pioglitazone prevents mitochondrial DNA loss and normalizes gene expression changes suggesting protection against
mitochondrial degeneration. Study supported by Study supported in part by NIH NS42056, JDRF, Office of Research
Development (Medical Research Service), Department of
Veterans Affairs.
Program and Abstracts, American Neurological Association
T-106. Effects on Pioglitazone on Mitochondrial
Degeneration in Animals with Diabetic Neuropathy
Tatsuya Inoue, Edward K. Kim, Kay Cherian, and
James W. Russell; Ann Arbor, MI
Mitochondrial (Mt) degeneration plays a role in diabetic
complications. Under such conditions, there may be a
change in gene expression regulating Mt number and Mt
proteins. Regulation could be done by Mt biogenesis proteins, PGC1␣, Nrf1 and Tfam or Mt fission/fusion proteins.
The aim of this study was to investigate 1) gene expression
changes regulating Mt dynamics in diabetic neurons and 2)
the effects of pioglitazone, in normalizing these changes. Rats
were made diabetic with streptozotocin. Pioglitazone (20
mg/kg) was administered once daily by gastric gavage. Nerve
conductions were slowed at 1 and 3 months by diabetes. In
diabetic dorsal root ganglions, PGC1␣ expression was increased at 3 month by 11% associated with upregulation of
Nrf1 (23%) and Tfam (26%). Mt fission genes, Drp1 was
elevated at 1 month (16%) and 3 month (15%) and Fis1 at
3 month (31%). Mt fusion genes of Mfn2 (10%) and Opa2
(21%) were elevated at 3 month. Pioglitazone treatment improved neuropathy and maintained gene expression changes.
In conclusion, in diabetic neurons, there is altered gene expression regulating Mt dynamics. Pioglitazone ameliorates
neuropathy and normalizes gene expression leading to balanced Mt fission/fusion dynamics. Study supported by Study
supported in part by NIH NS42056, JDRF, Office of Research Development (Medical Research Service), Department
of Veterans Affairs.
T-107. Characteristics of Cardiac Involvement in
Genetically-Confirmed Danon Disease and Related
Autophagic Vacuolar Myopathies
Kazuma Sugie, Ayaka Yamamoto-Koide, Kumiko Murayama,
Chuanzhu Yan, May Christine V. Malicdan, Satoshi Ueno,
Ikuya Nonaka, and Ichizo Nishino; Kashihara, Nara, Japan
and Kodaira, Tokyo, Japan
Danon disease (DD), an X-linked dominant cardiomyopathy
and myopathy, is caused by primary LAMP-2 deficiency.
DD and related autophagic vacuolar myopathies (AVM) are
pathologically characterized by autophagic vacuoles with sarcolemmal features. To characterize cardiac involvement in
AVM, we reviewed 51 DD patients (27 men and 24
women), one X-linked myopathy with excessive autophagy
(XMEA) patient, two infantile AVM patients, one patient
with adult-onset AVM with multi-organ involvement, and
seven patients with X-linked congenital AVM. In DD, cardiomyopathy were evident in all patients. Hypertrophic cardiomyopathy (HCM) was documented in most men, while
dilated cardiomyopathy was more predominant among
women. WPW syndrome was noted at 33%. Pacemakers
and/or heart transplantation were performed in some patients. In XMEA, no cardiac involvement was noted. Both
infantile AVM patients had mild cardiomegaly. An adult
AVM patient developed HCM with arrhythmia. In congenital AVM, only one showed HCM among seven patients. In
conclusion, cardiomyopathy is the most important prognostic factor and the main cause of death among DD patients.
Although infantile AVM and adult AVM are pathologically
more similar to XMEA, the presence of cardiac involvement
may suggest a different pathomechanism from XMEA.
Annals of Neurology
Vol 60 (suppl 3)
T-108. Trichostatin A Increases Survival of Mice with
Spinal Muscular Atrophy
Charlotte J. Sumner, Amy M. Avila, Melanie A. Knight,
Barrington G. Burnett, Addis A. Taye, and
Kenneth H. Fischbeck; Bethesda, MD
Spinal muscular atrophy (SMA) is caused by mutation of the
survival motor neuron 1 (SMN1) gene and retention of the
SMN2 gene. One promising therapeutic strategy for SMA is
to increase SMN2 gene expression. Histone deacetylase
(HDAC) inhibitors have been shown to increase SMN levels
in vitro and are being evaluated in early clinical trials in SMA
patients. In this study, we treated 22 SMA model mice beginning at post-natal day 5 with daily 10mg/kg doses of the
potent HDAC inhibitor, trichostatin A (TSA) and 21 SMA
mice with vehicle. The median survival for TSA-treated mice
was 19.5 days (range 10-32) as compared to 16 days (range
10-18) for vehicle-treated mice. A 71% decreased hazards of
death was seen in the TSA-treated mice compared to vehicle
control mice (hazard ratio 0.29, 95% CI 0.13-0.65,
p⫽0.0015). This treatment also resulted in decreased weight
loss and improved motor behavior compared to vehicletreated mice. Biochemical analysis of tissues showed that
TSA treatment was associated with increased gene expression
of SMN2 and brain derived neurotrophic factor (BDNF),
particularly in muscle. HDAC inhibitors deserve further
study in SMA and other neurodegenerative disorders.
T-109. Intraneural Lymphoma
Vahid Taghavi, Peter James B. Dyck, and Peter James Dyck;
Rochester, MN
Objective: To describe the clinical, and pathological features
of patients with direct invasion of peripheral nerves by lymphoma. Methods: We reviewed the clinical charts and biopsies of the patients with biopsy proven lymphoma of periheral nerves . Results: There were 13 patients with the mean
age of 62.3 years. The clinical presentations were 5 brachial
plexopathies, 1 sciatic neuropathy, 1 lumbosacral plexopathy,
2 cauda equina syndrome, 3 polyradiculoneuropathy and 1
polyradiculopathy. All patients presented with weakness and
11 had pain . The pain was sharp stabbing (6), aching (3),
allodynia (1) and burning (1). Six patients had prior known
lymphoma.The pathology showed an increased rate of segmental demyelination .The lymphoma cells were identified
in the epineurium (6) and in the endoneurium (11).Two patients were treated with radiation, 8 with chemotherapy and
3 with with stem cell rescue. Nine patients had a good outcome with remission of lymphoma.Twelve cases were B cell
and one was T cell lymphoma. Conclusion: 1) Intraneural
lymphoma is a cause of neuropathy presenting with
weakness, pain and numbness with the majority of cases
being of B cell type 2) The prognosis may be poor but
some of our patients did well, especially with stem cell
T-110. Safety Concerns in Amyotrophic Lateral
Sclerosis [ALS] Patients Who Are on Riluzole and Bu
Nao Gao [BNG] Chinese Herbal Medication – Rapid
Worsening of ALS Clinimetrics and Deep Vein
Andrew J. Waclawik, Benjamin Rix Brooks, Shirley M. Peper,
and Ann M. Houdek; Madison, WI
Objective: Report observations of subacute onset of weakness or rapid deterioration of ALS when riluzole and BNG
treatments were combined. Background: BNG, in Chinese,
“tincture or solution to revive the brain”, contains 14 herbs.
Western literature has no clinical descriptions of observed
side effects of BNG alone or in combination with riluzole.
Design/Methods: Observational study. Results: Four arm
onset ALS patients were self-treated with BNG either before[n⫽2] or after[n⫽2] initiation of riluzole treatment.
These patients noted increased asthenia, weakness, loss of appetite, weight loss[10-22 pounds] and decreased ALS FRS-R.
Two patients rechallenged with riluzole worsened and discontinued this medication. One patient was rechallenged
twice with development of weakness and asthenia each time.
Another patient added BNG to riluzole with consequential
weakness that improved with cessation but returned when
rechallenged with BNG. Deep vein thrombosis developed in
one of four patients on BNG. Conclusions/Relevance:
BNG may be associated with subacute onset of asthenia,
worsening of ALS clinimetrics, anorexia and weight loss. ALS
patients on riluzole may be at risk when starting BNG.
Study supported by MDA/ALS Clinical Center is supported
in part by the Muscular Dystrophy Association - ALS Division.
T-111. Altered Expression of Sarcospan in Skeletal
Myofibers of Fukuyama Type Congenital Muscular
Yoshihiro Wakayama, Hiroko Kojima, Sumimasa Yamashita,
Masahiko Inoue, Seiji Shibuya, Takahiro Jimi, Hajime Hara,
and Hiroaki Oniki; Yokohama, Kanagawa, Japan
Expression profile of sarcospan in muscles with muscular
dystrophies is scarcely reported. To examine this, we studied immunohistochemically the muscles from 5 Fukuyama
type congenital muscular dystrophy (FCMD) children, 10
disease control muscles from 4 Duchenne dystrophy (DD)
boys, 2 boys with Becker dystrophy, 2 myotonic dystrophy
patients, 2 facioscapulohumeral dystrophy patients, and 5
normal control muscles. The primary antibodies for immunofluorescent staining included anti-sarcospan, anti-␤ spectrin and anti-neonatal myosin antibodies. The FCMD muscles showed that most of the large diameter myofibers
expressed sarcospan discontinuously at their surface membranes. The small diameter FCMD myofibers usually did
not express sarcospan at their surface membranes, most of
which were ␤-spectrin immunopositive. Moreover these
small diameter myofibers contained the myosin with the
positive anti-neonatal myosin antibody reactivity and therefore were thought to be immature. Although the DD myofibers showed the reduced expression of sarcospan, other
disease control muscles revealed almost the same expression
of sarcospan as seen in normal control muscles. Finally the
FCMD muscles contained the small number of the large
diameter sarcospan positive myofibers and the remaining
large number of the immature small diameter sarcospan
negative myofibers.
T-112. Proteomic Analysis of Sequential Solubilization
of Muscle Proteins in Inclusion Body Myositis
Ronan J. Walsh, Ken Parker, Anthony A. Amato,
Bryan Krastins, David Sarracino, and Steven A. Greenberg;
Boston, MA
Introduction Inclusion body myositis (IBM) is characterized pathologically by endomysial inflammation, rimmed
vacuoles and inclusion bodies. We used a proteomic approach to analyze the proteins of the insoluble fraction of
muscle in IBM. Methods Muscle biopsies from patients
with IBM (N⫽2), polymyositis (N⫽1), and a patient without neuromuscular disease were compared. Each cell lysate
was sequentially solubilized with first a physiological buffer,
a non-ionic detergent buffer, and finally a buffer containing
urea and 2% SDS. Following SDS gel electrophoresis, appropriate slices were trypsin digested, extracted, and injected into an ion trap mass spectrometer. Preliminary results From the 82 slices, 850 proteins have been identified.
Identifications were confirmed semi-automatically or manually. Five proteins were more abundant in IBM samples: a
myosin heavy chain, a myosin light chain, glycogen phosphorylase, myoglobin, and lamin A-C. Disussion Lamin
A-C is a nuclear protein, and is of particular interest as the
inclusions in IBM tissue may be related to degenerated nuclei. The other four proteins may indicate that much of the
inclusion bodies consist of major muscle proteins. Future
work will test additional samples, and follow up proposed
enriched proteins with Western blots. Study supported by
grants to R.J.W. from the Muscular Dystrophy Association
and to S.A.G. from the Muscular Dystrophy Association
(MDA3878), the National Institute of Neurological Disorders and Stroke (NINDS) of the NIH (R01NS043471),
and the Foundation for Sporadic Inclusion Body Myositis
T-113. A Novel PMP-22 Gene Mutation in a Family
with Roussy-Levy Syndrome
Salman Zubair, Neil R. Holland, Brent Beson, and
Calin I. Prodan; Oklahoma City, OK and
West Long Branch, NJ
Roussy-Levy syndrome was described in 1926 as an inherited
disorder characterized by pes cavus, areflexia, distal muscle
atrophy, gait ataxia, kyphoscoliosis, postural tremor and sensory loss. The original family was found to have a point mutation in the MPZ gene, suggesting hereditary demyelinating
neuropathy belonging to the CMT-1B subgroup. We present
a 58-year-old man with the above-mentioned symptoms
since childhood. Neurophysiologic evaluation showed severe
sensorimotor demyelinating polyneuropathy and the diagnosis of Roussy-Levy syndrome was made. Out of four siblings,
he was the only one affected . The patient’s daughters, age
20 and 22, had similar symptoms, signs and electrodiagnostic findings. All three affected patients were found to
have a point mutation in PMP-22 allele 1 with T-to-C translocation at nucleotide position 195509 and codon position
108 (amino acid change leucine to proline) which has never
been related with this syndrome before. One of the patient’s
asymptomatic siblings had normal neurological examination
and electro-diagnostic studies. No alteration was found in
the asymptomatic relative. The clinical phenotype of RoussyLevy syndrome does not correlate with a specific mutation.
With the advent of genetic testing, genotyping may not always match previous clinical classifications.
T-114. Dynamic Responses of the Glutathione System
to Acute Oxidative Stress in Dystrophic Mouse (mdx)
Roy W. R. Dudley, Maya Krairallah, Shawn Mohammed,
Larry Lands, Christine Des Rosiers, and Basil J. Petrof;
Montreal, QC, Canada
Functional ischemia/reperfusion (I/R) and oxidative-stress
have been implicated in the pathogenesis of skeletal muscle
damage in Duchenne muscular dystrophy (DMD). There-
Program and Abstracts, American Neurological Association
fore, we applied a model of acute hindlimb I/R in mdx mice
(a genetic homologue of DMD) to evaluate dynamic in vivo
responses of dystrophic muscles to this form of oxidative
stress. Prior to the application of I/R, mdx muscles showed:
(i) decreased levels of total glutathione with an increased
GSSG/GSH ratio; (ii) greater activity of the GSHmetabolizing enzymes, glutathion peroxidase (GPx) and glutathione reductase (GR); and (iii) lower activity levels of
NAPD-linked isocitrate dehydrogenase (ICDH) and aconitase, two metabolic enzymes which are sensitive to inactivation by oxidative stress and also implicated in GSH regeneration. Interestingly, non-dystrophic muscles subjected to I/R
Annals of Neurology
Vol 60 (suppl 3)
exhibited similar changes in total glutathione, GSSG/GSH,
GPx, ICDH, and aconitase. In contrast, all of the above remained stable in mdx muscles subjected to I/R. Taken together, these results suggest that mdx muscles are chronically
subjected to increased oxidative stress, leading to adaptive
changes that act to protect (although only in part) the dystrophic muscles from acute I/R-induced oxidative stress.
Study supported by Canadian Institutes of Health Research,
Canadian Lung Association, Muscular Dystrophy Association
DOI: 10.1002/ana.11491
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