Spring 2012 - The Feinstein Institute for Medical Research

focus ON
INSIDE
New Lupus Drug +
Mesenchymal Stem Cell Research + Tourette Syndrome
Research
A Member of the North Shore-LIJ Health System + northshorelij.com
Scientists Study Brain Development
P
Spring 2012
sychiatric researchers at The Zucker
Hillside Hospital are tracking brain
development in normal children and
adolescents with hopes that someday it
will yield keys to mental illness. So far,
100 people ages 8 to 21 have offered up
their brains for scanning and their saliva
for genotyping. They have also agreed to
undergo neurocognitive tests to measure
the way their brains learn. Researchers
used the information to create a neurotrajectory of the developing brain.
The study is named CANDY, for
Comprehensive Assessment of
Neurodevelopment in Youth.
Researchers learned that the brain’s
white matter volume
increases throughout
adolescence and into
early adulthood, especially in an area
involved in learning
and memory called
the superior longitudinal fasciculus (SLF). Anil Malhotra, MD
The thalamus, which
acts as a relay center for information, was
also growing throughout adolescence.
Researchers used several types of brain
imaging scans.
“This will be an invaluable resource,”
said Anil Malhotra, MD, director of the
Laboratory of Molecular Psychiatry. The
study was led by Bart Peters, MD, PhD, a
postdoctoral research fellow in the laboratory.
“Diffusion tensor imaging has provided valuable insights into healthy white matter development in adolescence,” said Dr. Peters. “The
increasing connectivity in the SLF during this
period implicates the region as a specific
target for neurodevelopmental disorders that
involve language dysfunction.”
Dr. Malhotra wants to recruit another
400 young people, and the hope is to follow up with additional scans. Researchers
will have genetic information matched
with brain, cognitive and behavioral information and, should any of the young people develop a mental illness, researchers
will be able to go back to the data to
see whether there were any hints in the
developing brain that could have predicted mental illness years later.
The study is supported by a grant
from the National Institutes of Health.
Potential participants should call
Kimberly Cameron at 718-470-4656. 
Clinical Testing of a New Lupus Drug
N
othing is more satisfying in science
than studying a medication that
makes its way through the experimental pipeline and ends up approved
for use by the US Food and Drug
Administration (FDA). When the FDA
approved Benlysta, a treatment for lupus,
in March 2011, Richard Furie, MD, chief
of the Division of Rheumatology, Allergy
and Clinical Immunology at the North
Shore-LIJ Health System and director of
the Systemic Lupus Erythematosus (SLE)
and Autoimmune Disease Treatment
Center, quickly penned a note to his
patients. After all, more than 50 people
had been willing to sign on at different
phases in the clinical testing of the drug.
Dr. Furie is the first author of a study
published in December 2011 in Arthritis
and Rheumatism. The paper outlines the
results from the phase III testing of the
drug Benlysta. The drug is a monoclonal
antibody that binds a protein known as
BLyS (B lymphocyte stimulator). BLyS
was discovered in the late 1990’s and
was found to be crucial for B-lymphocyte
survival, growth and differentiation.
Preclinical work in animals, along with
observational studies in humans that
demonstrated increased levels of BLyS in
lupus, fueled interest in developing inhibitors of BLyS as a treatment for SLE. The
strategy was to create a monoclonal antibody to BLyS and use it to subdue the
overactive B-lymphocyte compartment
seen in patients with lupus. A phase I
study demonstrated safety and tolerability
in patients, and that study served as the
foundation for a phase II study performed
to determine whether Benlysta could
reduce disease activity in lupus patients.
The phase II study included 400
patients, and more than a dozen of them
are patients followed in the Division of
Rheumatology. While the study did not
reach its primary endpoint, many favorable signals were observed. The most
important post-hoc analysis led to the
creation of a novel composite responder
index, which was used as the primary
endpoint in the two pivotal phase III
trials. The two phase III studies were
designed to determine whether Benlysta
could reduce lupus disease activity. One
study was known as BLISS-52 and the
other BLISS-76. Both studies were successful in achieving their endpoints.
The former was conducted outside the US
and was reported in
The Lancet. The latter
was done primarily in
North America and
Europe. Eleven patients
followed by Division
members were also
enrolled in the phase III
study. Other lupus clinicians at The Feinstein
Institute for Medical
Research also enrolled
patients into the
studies.
Patients enrolled in
the study had a certain level of disease
activity, as determined
by a commonly used
instrument known as
the SELENA SLEDAI.
The drug was administered intravenously
once a month.
Assessments were perRichard Furie, MD
formed monthly, and
the activity at one
year was compared with baseline values.
There was a statistically significant reduction in disease activity in the group that
received the higher of the two doses.
Since Benlysta was approved, six more
patients have signed up to receive the new
treatment. It is the first new lupus drug
approved in 50 years. 
Advancing Women in Science and medicine (AWSM)
AWSM was created to advance the
career opportunities and career
satisfaction of women scientists at The
Feinstein Institute for Medical
Research, and to enhance the visibility
of the Institute through the scientific
productivity and excellence of its
women scientists. The group organizes
events and lectures for leadership
development and to showcase the
2
FOCUS ON RESEARCH I Spring 2012
outstanding basic and clinical research
led by female scientists across the
country.
For more information, please visit
www.feinsteininstitute.org/Feinstein/
AWSM, or contact AWSM President
Christine Metz, PhD, at cmetz@nshs.
edu or AWSM Vice President Nadeen
Chahine, PhD, at nchahine@nshs.edu.
Christine Metz, PhD
Nadeen Chahine, PhD
Lengthening Kidney Dialysis
Treatments Could Reduce Mortality
K
idney dialysis is a lifesaving treatment, but doctors have been frustrated by the high death rate among
people who spend as much as a dozen
hours a week hooked to machines that
help flush fluid out of the body. Despite
40 years of experience with dialysis, the
death rate in American dialysis centers is
higher than in some countries in Europe
and Asia, and a new study suggests one
possible explanation: the treatment seems
to thicken the blood, which in turn puts
stress on blood vessels and could increase
the risks for cardiovascular death. Two of
the most common reasons that kidneys
fail are hypertension and diabetes.
Steven Fishbane, MD, vice president
of Network Dialysis Services for North
Shore-LIJ Health System and director of
clinical research for the Department of
Medicine at North Shore University
Hospital and LIJ Medical Center, and his
colleagues started looking at a variety of
factors to explain the high death rate.
With a pilot grant and a new device that
measures blood viscosity, the researchers
scanned blood vessels before, during and
after kidney dialysis. They were surprised
to find that there was a surge in thickness
of the blood — in both large and small
vessels — that occurs
during dialysis. The
thickness was observed
more often in patients
who retained a lot of
fluid between treatments.
It is not clear what
causes this thickening.
Steven Fishbane, MD
Dr. Fishbane has his
suspicions. The average life span for a dialysis patient in the US is significantly
shorter than in European and Asian countries. One possible explanation is the use
of shorter dialysis sessions. Extending the
treatment over a longer period of time
could be less stressful to the blood vessels,
researchers say. Dr. Fishbane and his colleagues are collaborating with a team in
France to test blood thickness in
European patients.
Dr. Fishbane presented his findings at
the American Society of Nephrology annual
meeting in Philadelphia last November.
“We may be delivering dialysis the
wrong way,” said Dr. Fishbane. There are
about 300,000 people in the US on dialysis, and the numbers are expected to rises
to 500,000 in the next 20 years as rates of
diabetes and obesity continue to climb. 
The Zucker
Hillside Hospital
to Host Chinese
Psychiatrist
Xin Yu, MD, a
clinical professor
of psychiatry at
the Institute of
Mental Health in
Beijing who has
served as
president of
John Kane, MD
the Chinese
Psychiatrist
Association, will be a visiting
scientist at The Zucker Hillside
Hospital. During his three-month
tenure, Dr. Yu, one of the leading
psychiatrists in China, will learn
about services offered to people
with schizophrenia and other
serious mental illnesses, as well as
the research being conducted by
our investigators. Following medical
school in Beijing, he completed
fellowships at the University of
Melbourne, Johns Hopkins
University and Harvard University.
But no matter how much Dr. Yu
understands the biology of mental
illness, he works in a country with
very limited psychiatric resources.
Even 35 years after the end of the
Cultural Revolution, some estimates
suggest that there is one psychiatrist
for every 83,000 people. With few
alternatives, families have been
known to lock their loved ones
away to keep them from harming
other people.
John Kane, MD, chairman of
psychiatry at Zucker Hillside, and
Dr. Yu are proposing to study
treatment options in rural
communities of China. They want
to test a long-acting injectable
antipsychotic to see if it can
improve outcomes for patients
with schizophrenia treated in
regions with few healthcare
resources. “This could have a
dramatic impact,” said Dr. Kane.
SETTING NEW STANDARDS IN HEALTHCARE I feinsteininstitute.org
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d iscovery zone
Making Sense
of Perfect Pitch
Mesenchymal Stem Cell Research
S
cientists are testing whether stem cells
from bone marrow can help repair
damaged intervertebral discs in the
spine. The idea made perfect sense to
Nadeen Chahine, PhD, as assistant
investigator in the Biomechanics and
Bioengineering Laboratory at The Feinstein
Institute for Medical Research. But the
question that had never been asked is
whether delivering the stem cells into the
disc early in the injury process, or a month
later, will make a difference in the level of
repair. Would the timing of stem cell treatment affect the strength of the disc and
correct the damage?
Dr. Chahine used a laboratory model
of disc injury and injected a million stem
cells isolated from bone marrow into the
injured disc. The cells were delivered at
day 3, or during the second and fourth
week postinjury. Dr. Chahine thought
that the stem cells administered during
the initial days of the injury would not
work as well because the environment
was flooded with inflammatory molecules
sent in to help repair the tissue. But they
found quite the opposite. The disc was
stronger when treated
only a few days after
the injury when there
were higher inflammatory changes in
the tissue. And the
tissue repaired after
a month’s delay was
Nadeen Chahine, PhD
more damaged.
This might not be
great news for disc
repair. Many patients see their doctor
after the injury has set in and it would be
challenging to get people in within days
of the acute injury. Still, the scientists will
now repeat the study using anti-inflammatory medication before and right after
the injury to confirm the role of inflammation in therapeutic response of stem
cells. “We need to understand how to
optimize the conditions under which we
can expect a beneficial therapy for stem
cell repair,” said Dr. Chahine.
The study was selected for the Best
Abstracts session at the Global Spine
Congress in March 2011 in Barcelona,
Spain. 
Peter K.
Gregersen, MD,
is a geneticist
and musician
who has been
using his skills in
the laboratory
to identify
Peter K. Gregersen, MD
genes for
perfect pitch,
an uncommon
ability to recognize a musical note
without relying on a reference
note. People with perfect pitch
can spot a B-flat or a C-sharp
within a second of hearing the
note. Researchers suspect there
are genes that confer the ability
to have perfect pitch.
Dr. Gregersen, chair of the
Robert S. Boas Center for Genomics
and Human Genetics, and his
colleagues have set up a Webbased study to assess perfect pitch,
also called absolute pitch, and they
are collecting DNA samples to hunt
for perfect pitch genes. People
who join the study will be able to
take a seven-minute test that will
determine whether they have
absolute pitch. Until recently,
researchers relied on self-reports
of perfect pitch to identify and test
people. Now they are testing a
new tool that allows them to move
into the general population to find
people with perfect pitch who may
never have had musical training,
but have an uncanny ability to
label all sorts of notes in real time.
The scientists are also working with
colleagues in China to collaborate
on a study of absolute pitch using
the new testing format.
For more information, contact
study coordinator Elena Kowalsky
at elenak@nshs.edu, visit
absolutepitchstudy.com or call
1-888-897-3098.
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Arou n d t h e ins titute
Better Management of Tourette Syndrome
Cathy Budman, MD, an internationally renowned expert in
the treatment of Tourette syndrome, has been director of the
Movement Disorders Program in Psychiatry at North Shore
University Hospital since 1990. She is a primary investigator for
a number of clinical treatment trials to help reduce the disruptive
symptoms of this debilitating neuropsychiatric disorder.
Tourette syndrome is marked by multiple sudden movements or
vocalizations that can include repetitive eye blinking, facial twitching, shoulder shrugging, throat clearing, coughing or grunting.
Much less commonly, Tourette syndrome may involve more complex behaviors including blurting out inappropriate or vulgar words.
Last summer, Dr. Budman helped organize a training workshop on Comprehensive Behavioral Interventions for Tics (CBIT)
by Douglas Woods, PhD, of the University of Wisconsin in
Milwaukee, to teach a new type of behavioral intervention to therapists. The idea behind CBIT is to teach patients how to manage and
better inhibit their tics by learning how to recognize and regulate
the urges that precede tic symptoms. While many children and
adults with tic disorders could potentially benefit from this nonmedication treatment, few professionals have adequate training to deliver
CBIT. Now more than 42 staff members from North Shore-LIJ
Health System have received training in this cutting-edge therapy.
Dr. Budman is a pioneer in the study of explosive outbursts
in Tourette syndrome. She is also part of a team of investigators
studying the treatment of Tourette syndrome and Attention Deficit
Hyperactivity Disorder (ADHD), which commonly occur together.
She and her coinvestigators showed that the use of psychostimulants to treat ADHD does not worsen tics, as had been previously
thought. Dr. Budman was also an investigator in the EPI-PANDAS
study, a multisite epidemiological study investigating the link
between Group A beta hemolytic streptococcal infection and tics.
She was involved in a study group that tested atomoxetine for treatment of ADHD in children with tic disorders.
Dr. Budman’s clinic is one of only three sites in the US now
conducting a phase II study of a novel agent for treatment of tics in
adults. Two additional studies of investigational agents for treatment of tics in adults are
planned in 2012. Dr. Budman is conducting a
multicenter, randomized, double-blind, placebo-controlled study with a follow-up openlabel multicenter study that will evaluate safety
Cathy Budman, MD
and efficacy of flexible-dose, once-weekly oral
aripriprazole in children and adolescents with
Tourette syndrome. Dr. Budman is also a member of the
International Genetics Consortium for Tourette syndrome and is
currently recruiting subjects for participation in genetic studies of
Tourette syndrome.
If you are interested in learning more about treatment of
Tourette syndrome and its associated disorders or if you are
interested in participating in existing research studies of Tourette
syndrome at North Shore-LIJ Health System, contact Cathy
Budman, MD, at 516-562-3223. 
ABAI Honors Vincent Bonagura
for MOC Reciprocity Milestone
At their annual October meeting in Nashville, Tenn., the
board of directors of the American Board of Allergy and
Immunology (ABAI) honored Vincent Bonagura, MD, for
his work in establishing Maintenance of Certification
(MOC) reciprocity between ABAI and the American Board
of Pediatrics (ABP). Dr. Bonagura, who served as an ABAI
director from 2002 to 2007, and ABAI representative
to ABP from 2005 to 2010, was presented with an award
for the integral role he played in shaping the mutual
relationship between the boards. As a result of his work,
diplomates of ABAI and ABP are now able to participate in
and complete interchangeable aspects
of their respective MOC programs
more efficiently without duplicating
efforts.
Dr. Bonagura is the associate
chair, Department of Pediatrics for
Vincent Bonagura, MD
Academic Affairs; chief, Division of
Allergy/Immunology; Jack Hausman
Professor of Pediatrics; professor of molecular medicine,
Hofstra North Shore-LIJ School of Medicine; and an
investigator at The Feinstein Institute for Medical Research.
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5
Michael Dowling
President and CEO
North Shore-LIJ Health System
Kevin J. Tracey, MD
focus on
Research
President
The Feinstein Institute for Medical Research
Terry Lynam
Vice President, Public Relations
Jamie Talan
Science Writer
NORTH SHORE-LONG ISLAND JEWISH
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Focus on Research is published by The Feinstein Institute for
Medical Research in conjunction with the Public Relations
Department of the North Shore-LIJ Health System. The information provided in this publication is intended to educate and
inform readers about biomedical research that may be pertinent
to their health and is not a substitute for consultation with a
personal physician. For more information about this publication,
call 516-465-8314. Produced by Krames StayWell, Evanston, IL.
© 2012. Printed in USA.
Need to find a doctor? 1-888-321-DOCS • North Shore-LIJ Health System
Unraveling the Web of Alzheimer’s Disease
A
few years ago, scientists at the
Litwin-Zucker Research Center for
the Study of Alzheimer’s Disease
at The Feinstein Institute for Medical
Research identified a genetic variant that
increases the risk for Alzheimer’s disease by
about 11 percent. The gene is called calcium homeostasis modulator 1 (CALHM1),
and it makes a protein that helps regulate
the brain’ s calcium channels. Calcium is
critical to the health of cells. CALHM1
also seems to help control the metabolism
of a protein called amyloid-beta that builds
up in the brains of Alzheimer’s patients.
The specific variant of CALHM1 that the
scientists are interested in is thought to
functionally impair CALHM1 and lead
to an increase in the accumulation of
amyloid-beta in the brain.
CALHM1 P86L is a common genetic
variant. About 45 percent of the population has at least one copy, and eight or nine
percent have two copies. While there is
ample research being done to understand
the role this gene has in Alzheimer’s, there
is evidence that people with the CALHM1
P86L risk allele may naturally make more
amyloid beta, which means that more of it
has to be cleared out of the brain into the
cerebrospinal fluid.
The work will be performed by
Philippe Marambaud, PhD, Jeremy
Koppel, MD, and their colleagues in the
Alzheimer’s research center.
Exactly how CALHM11 leads to
Alzheimer’s was the next step. The scientists analyzed the CALHM1 P86L gene in
203 Alzheimer’s patients (in collaboration
with German colleagues), and 46 young,
healthy and cognitively fit people with at
least one family member with Alzheimer’s.
The two groups, one healthy and one with
Alzheimer’s, would allow the researchers to
test the power of the variant in the disease
process.
In a study published in Molecular
Medicine, the scientists reported that
there was not an association between the
cerebrospinal fluid amyloid-beta levels in
the Alzheimer’s patient sample but there
was a significant association with the risk
allele in the healthy younger people at
risk for Alzheimer’s.
“These tests indicated that in the cognitively healthy cohort, CALHM1 genotype
had a significant effect on amyloid-beta
levels,” said Dr. Marambaud. It is still not
clear how this affects the development of
Alzheimer’s. Researchers will continue to
follow the young, healthy volunteers to
see who develops Alzheimer’s and whether
there are any changes in the CSF amyloid-
beta levels that precede
the development of
symptoms.
Other studies
have shown that the
CALHM1 P86L polymorphism seems to
influence the timing of
Philippe Marambaud, PhD
the disease onset and
not the disease itself.
There is evidence that these types of protein
changes in the blood or cerebrospinal fluid
could be used to predict Alzheimer’s disease
a decade or more before the first signs of
memory loss appear. 
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