ORGANIZED CLINICAL AND RESEARCH CENTERS
The Baird Multiple Sclerosis Center
The Baird Multiple Sclerosis Center, directed by Dr. Lawrence Jacobs, is a prime example of
networking across the various geographic units within the Department. This is an integral
component of the UB MS Center, a consortium designed to maximize the effectiveness and
efficiency of health care related services to 2,000 MS patients in Western New York. The Baird
personnel facilitate access to Neurology, Rehabilitation, Home Care counseling, support group,
and other needed services on a daily basis. Staff participate in a variety of educational programs
such as the Research Teleconference sponsored by the National MS Society. The Baird Center
operates several clinics a week with over 800 annual visits for neurologic diagnosis and care. In
addition to the clinical activity, scientific activity of the Baird includes IM recombinant beta
interferon as a treatment for MS, lymphocytic phenotyping for relapsing MS, the Baird tissue
repository, familial MS studies, studies of optic neuritis, and a dream study. This section will
highlight various activities of the Baird Multiple Sclerosis Center.
The New York State Multiple Sclerosis (MS) Consortium
The Department of Neurology at The Buffalo General Hospital is the coordinating center for the
New York State Multiple Sclerosis Consortium. The consortium brings together the research and
clinical expertise of fifteen major medical centers in New York State in an effort to further define
the MS population in terms of demographic, clinical, functional, quality of life and treatment
parameters. The consortium also represents a cooperative alliance for competitive research
funding.
Lawrence Jacobs, M.D. is Project Director. Collaborators include Carol Brownscheidle, Ph.D.,
Principal Research Scientist, SUNY Research Foundation and Administrative Director of the
BGH Department of Neurology and Baird Multiple Sclerosis Research Center; Carl V. Granger,
M.D., Professor of Rehabilitation Medicine and Director of the Center for Functional
Assessment Research, University at Buffalo; Steven Greenberg, M.D., Chief of Neurology at
Roswell Park Cancer Institute (RPCI) and Director of the Baird Multiple Sclerosis and
Neuroimmunology Tissue Repository at RPCI; Karl Wende, Ph.D., Director of the Data
Management Center, BGH Department of Neurology; Brian Apatoff, M.D., Ph.D., Cornell
Medical Center; Patricia Coyle, M.D., SUNY Stony Brook; Andrew Goodman, M.D., University
of Rochester Medical Center; Malcolm Gottesman, M.D., Winthrop University Hospital; Joseph
Herbert, M.D., New York University School of Medicine; Neil Lava, M.D., Albany Medical
College; Cheryl Maize, M.D., Helen Hayes Hospital; Cornelia Mihai, M.D., SUNY Syracuse;
Aaron Miller, M.D., Maimonides Medical Center; James Miller, M.D., Columbia Presbyterian
Medical Center; Allen Perel, M.D., Staten Island University Hospital; Charles Smith, M.D., St.
Agnes Hospital; and David Snyder, M.D., New York Hospital Medical Center of Queens.
The current research efforts of the Consortium involve the development of an MS patient registry
and centralized uniform database of MS patient information, and specimens (tissue, blood,
cerebrospinal fluid) for member Centers. Over 1600 patients have been enrolled in the registry
since April, 1996. This project was awarded a $265,000 grant from the New York State
Department of Health for the period March 1, 1995-February 15, 1997. A continuation award of
$200,000 has been granted for the period February 16, 1997 - February 15, 1999. Biogen, Inc.
(Cambridge, Mass.) will contribute $75,000 toward the Consortium in 1997. The Consortium
permits access to sufficiently large patient populations, not available at any single Center, for
future MS research. This will have a significant impact on the ability of the Consortium to be
more competitive in relation to extramural funding and to increase research dollars designated for
New York State medical schools.
A Central New York office of the Consortium was opened in March, 1997 to facilitate
enrollment of patients at the SUNY Health Science Center, Syracuse and to encourage
participation of community-based physicians. There are an estimated 2000 MS patients in the 16
county region extending from Binghamton to Massena.
Several substudies of the Consortium have been undertaken within the last year. Drs. Jacobs and
Brownscheidle collaborated with Dr. Joseph Herbert, Hospital for Joint Diseases, in a
reproductive health survey of over 70 MS patients. Dr. Jacobs and Dr. Goodman, University of
Rochester, are studying predictors of MS outcome with specific emphasis on timed ambulation
and correlation with Expanded Disability Status Scale (EDSS) score.
Open Label Study of Interferon Beta-1a in Relapsing MS
In May 1995, an open label safety study of interferon beta-la in patients who had participated in
the Phase III clinical trial was opened. The original duration of the study was two years. Biogen,
Inc. recently announced an extension of the study for an additional two years. This research
focuses on safety monitoring of over 85 patients at the Baird MS Center who are receiving
weekly IM injections of Avonex. Study participants also include patients who had previously
received Betaseron as well as those who had never been treated with recombinant beta interferon.
Dr. Jacobs is site Principal Investigator for this study.
CHAMPS
Dr. Jacobs is Study Project Director for the clinical trial of interferon beta-1a in individuals at
high risk for the development of multiple sclerosis. In April 1996, the CHAMPS trial began to
enroll individuals who had experienced a single, isolated neurological event suggesting
demyelination and who were at high risk for developing clinically definite MS. This four-year
trial, funded by Biogen, Inc. will include 380 individuals at 55 clinical centers in the United
States and Canada. The specific objective of the study is to determine if Avonex is beneficial in
delaying or preventing the onset of clinically definite MS in individuals who have experienced a
first demyelinating event and who, based on MRI findings, are at high risk for developing MS.
Linomide in Relapsing-Remitting and Secondary Progressive Multiple Sclerosis
The Buffalo General Hospital Department of Neurology is one of 30 clinical Centers
participating in a randomized, parallel group, double-blind, placebo-controlled Phase III study of
roquinimex (Linomide®) in the treatment of patients with relapsing-remitting and secondary
progressive multiple sclerosis. The primary objective of this research is to determine if linomide
is effective in delaying the time to development of confirmed clinical worsening. Twenty-seven
patients had been enrolled when the study was terminated by the Sponsor, Pharmacia-Upjohn,
due to concerns regarding cardiac toxicity. Patients at the Buffalo General Hospital will be
followed for 6 months off drug. The study will be closed out the end of 1997.
Baird Multiple Sclerosis and Neuroimmunology Tissue Repository
The Baird Multiple Sclerosis and Neuroimmunology Tissue Repository was established in the
Fall of 1991 via a grant from the Baird Foundation to the Millard Fillmore Health, Education and
Research Foundation. During the six years since its inception, the Repository has collected and
stored over 1,000 tissues or fluids from MS patients on whom we have detailed demographic and
neurologic data. We also have serial samples of blood and cerebrospinal fluid for the 86 MS
patients who were included in the Buffalo arm of the phase III interferon beta-1a clinical trial.
Familial MS Studies
Since 1988, we have examined and collected demographic data on over 120 different proband
MS patients who have at least one other family member with MS. Seven of these cases include
monozygotic twins who are discordant for MS. Dr. Greenberg has been conducting
immunogenetic studies on blood samples from these families and an extensive DNA bank has
been developed. Various genes from the Class III MHC region are being evaluated by analysis of
microsatellite polymorphisms to determine if they may be potential susceptibility genes.
Several members of the New York State Multiple Sclerosis Consortium have also expressed
interest in our immunogenetic studies and will collaborate by forwarding samples for analysis to
Dr. Greenberg's laboratory.
Avonex Tolerability Study
Biogen, Inc. has funded a tolerability study of interferon beta-1a (Avonex) in the treatment of
subjects with relapsing and secondary progressive multiple sclerosis. Dr. Jacobs is site Principal
Investigator for this multicenter study which began in May, 1997. The primary objective of this
research is to determine the maximum tolerated dose (MTD) of Avonex, within 30 to 90 mcg,
that can be administered by weekly IM injection to subjects with relapsing and secondary
progressive MS and who have moderate to severe disability. Adjuvants administered at the time
of injection will also be evaluated for their effectiveness in reducing any side effects.
Cytokines and MS
A new liaison has developed with Dr. Murali Ramanathan of the SUNY Department of
Pharmaceutics regarding the mechanism of action of interferon gamma, a project funded by both
the NIH and the National MS Society.
Chronic Progressive MS
Dr. Jacobs is site Principal Investigator for a new clinical trial beginning June, 1997, "A
double-blind, dose escalation study to evaluate the safety, tolerability, and biological activity of
3-every other day intravenous doses of placebo or AG284 in patients with secondary, chronic,
progressive multiple sclerosis". This research is funded by Anergen, Inc., Redwood City, CA.
The investigational drug AG284 is a complex composed of human glycoprotein HLA-DR2
complexed to the synthetic peptide based on the amino acid sequence 84-102 of human myelin
basic protein. The trial is expected to be completed by Spring, 1998.
Viagra Study
We recently agreed to participate in a clinical trial to determine the efficacy, safety, and toleration
of Viagra (sildenafil) in the treatment of erectile dysfunction in MS. This study, sponsored by
Pfizer, will be conducted at 20 sites (10 U.S.; 10 European). Dr. Jacobs, site Principal
Investigator, will begin patient enrollment (n = 12-15) Fall-Winter 1997.
Optic Neuritis
We have followed over 90 patients in a longitudinal study designed to identify the relationships
between isolated monosymptomatic optic neuritis (ON) and the potential for eventual conversion
of some cases to multiple sclerosis. The occurrence of brain lesions as identified by serial MRI
has been analyzed in relation to ON and the development of disseminated MS. The results of
this study were published in Annals of Neurology, Spring, 1997.
Dream Study
We interviewed 70 MS patients from the BGH Department of Neurology and the Baird MS
Center regarding their dreams. The patients had Kurtzke Expanded Disability Status Scale
scores (EDSS) of 6.0 or greater, at least requiring a unilateral assistive device to walk. Those
with higher EDSS scores were generally dependent on wheelchairs for motility most of the day.
Marge Umhauer, Nurse Practitioner at the Baird, continues to coordinate this project in
collaboration with Dr. Jacobs and Dr. Manning of the Sleep Disorders Center at Millard Fillmore
Hospital. The majority of patients who recalled their dreams had dreams of walking unassisted
or even running. These dreams of regained functions may relate to psychological wish
fulfillment or the variable physiological impact of deafferentation on body image perception. A
manuscript is in preparation for submission Fall, 1997.
Division of Developmental and Behavioral Neurosciences
The Division of Developmental and Behavioral Neurosciences under the direction of Dr. David
Shucard has two arms: The research laboratory and the neurodiagnostic laboratory. The research
laboratory has as its major focus brain - behavioral relationships, and in particular cognitive
neurosciences. The major methodological approach used in the laboratory is a combination of
electrophysiological, neuropsychological and other behavioral methods. Populations studied
include infants, children and adults, as well as animals. Multiple studies are being conducted that
focus on such topics as the role of early hormone exposure on brain organization and cognition,
the relationship between neurophysiology and linguistic development in infants, brain
organization and attentional systems in infants and adults, cortical evoked potential variability as
an index of neural efficiency and information processing in animals and humans, and attentional
systems in animals. In addition to normal populations, clinical populations are also investigated.
These studies rely on techniques developed with normal populations and include investigations
of attentional systems in Posttraumatic Stress Disorder, Autism and Tourette's Syndrome.
Projects also are underway with Dr. Alan Lockwood and the PET Center. These projects
combine electrophysiology, neuropsychology and neuroimaging. Animal investigations using
chronically implanted electrodes allow for further probing of the relationship between attention,
learning and the functional organization of the brain. These studies parallel and enhance the
human investigations.
During the 1996-1997 year, the research laboratory of the Division of Developmental and
Behavioral Neurosciences was comprised of seven permanent staff members, ten graduate
students (including three at ECMC), two fellows and one visiting faculty member. There was
also one undergraduate honors student who did his honors project in our laboratory.
Teaching is an important part of the Division's activities. During the 1996-1997 year members of
the Division have presented individual lectures to various classes and groups at the University.
Aside from formal courses, the training of graduate and undergraduate students through an
apprenticeship methodology is an ongoing activity of the Division. Drs. David Shucard, Janet
Shucard and Ralph Benedict have supervised both graduate and undergraduate students in the
laboratory.
The Neurodiagnostic Laboratory is the clinical arm of the Division. Although, the primary focus
of this laboratory is clinical service, the merging of clinical service and clinical research is an
important goal of the Division. There are currently four full time faculty in this laboratory and
three other faculty members from Neurology (2) and Medicine (1) involved with our clinical
service. There are 15 additional laboratory members that constitute technical and secretarial
staff. The Neurodiagnostic Laboratory offers service in the following areas: Neuropsychology,
Electroencephalography and Clinical Neurophysiology, Intraoperative Neurophysiology and
Sleep.
The Clinical Neurodiagnostic Laboratory has expanded three of its services: The sleep program
has doubled in number of beds and number of patients evaluated and we have also expanded our
capabilities with the computerized sleep system used in the data collection and scoring of sleep
studies. In addition, because of increasing demand the center has expanded its
neuropsychological services. In October of 1996 a Neuropsychology Laboratory was opened at
Amherst General. A comprehensive intraoperative neurophysiology program has been
established and has enjoyed rapid growth since its development last year. Growth has been seen,
both on the preoperative and intraoperative side.
This year Dr. Janet Shucard joined the Department as a Research Assistant Professor of
Neurology. Her research has been in the neuropsychologic and electrophysiologic indices of
cognitive sex differences in preadolescent children. She also has an ongoing interest in
neurocognitive indices of attention in posttraumatic stress syndrome. This has led to recent
receipt of a National Institutes of Health grant.
The future goal for our research laboratory is to interface more closely with the clinical side of
the Department. This interfacing has been particularly fruitful through collaborative studies
between Neuropsychology and Neurology as noted in the publications of Drs. Benedict, Jackson
and Capruso. Further plans are being made to relate more closely to the multiple sclerosis work
being done in the Department. Techniques developed in the laboratory may provide useful
information about cognitive functioning in MS. The clinical laboratory is moving forward in
providing quality evaluations across the various areas. We have enjoyed substantial growth over
the past year and have had problems with expansion of services largely due to space issues.
Although space remains an issue, we have expanded the Neuropsychological service to Amherst
General where we now have a permanent office. Dr. Lisa Jackson is located at that facility
(starting October, 1996). Dr. Mark Gunther has joined the BGH location. Because of the
demand, intraoperative monitoring has shown a significant increase in service. In addition, the
clinical neurophysiology service is upgrading its equipment through the purchase of a digital
EEG system that will allow multichannel EEG monitoring of surgical cases as well as 24-hour
monitoring of patients while they are in the hospital. The sleep program has also received
increasing demand. There are plans to enlarge the service to 12-14 patients per week
(approximately double what we anticipated) and increase our beds from two to four.
Neuroimmunology and Molecular Genetics
The Laboratories of Neuroimmunology and Neurovirology, Department of Neurology, RPCI,
support an array of research activities whose central themes include: (1) mechanisms of T-cell
receptor and B-cell immunoglobulin gene rearrangements with regard to lymphocyte maturation,
recruitment in autoimmune diseases, and clonal expression in leukemia and lymphoma; (2)
development of new recombinant viral technologies to transfer and express genetic material into
human cells and tissue: (3) development of strategies for gene therapies in cancer that target
lymphoid-specific leukemia and lymphoma genes and angiogenic dependent astroglioma cancer
cell genes; (4) studies involving putative disease susceptibility genes using various polymorphic
genetic markers; and (5) application of molecular biological techniques for the rapid and
sensitive detection of infectious agents and B-cell and T-cell repertoires in heme-oncologic
disease.
A primary focus of the Laboratory of Neuroimmunology and Neurovirology is the study of
unique genetic recombinatorial events that orchestrate T-cells receptor and B-cell
immunoglobulin expression. As uncommitted bone marrow stem cells or thymic T-cells
differentiate, a series of gene rearrangements occur producing a vast array of diverse,
combinatorial juxtaposed variable, diversity and joining gene products. Rearrangement of
immunoglobulin and T-cell receptor genes is principally mediated by lymphoid-specific and
developmental stage-specific expression of recombinase activation genes 1 and 2 (RAG-1,
RAG-2). As one of its goals in attempting to exploit the transcriptional differences between
lymphoid and non-lymphoid-derived tissues to develop gene therapies, the Laboratory of
Neuroimmunology and Neurovirology achieved a research first in the successful cloning and
sequencing of the human RAG-1 and RAG-2 promoter regions.
The gene therapy program spear-headed by the Department of Neurology is a multidisciplinary
research project that combines the talents and resources of the Departments of Neurology,
Neurosurgery, Pathology, Microbiology and Immunology, and Biochemistry in an attempt to
develop and test a novel form of molecular chemotherapy that ultimately will be used to treat
leukemias and lymphomas invading the central nervous system (CNS) and in the treatment of
primary CNS tumors, including astroglioma. To accomplish this, artificial chimeric genes are
engineered to possess DNA motifs that encode for transcriptional regulatory sequences of either
lymphocyte-specific or glioma-specific proteins adjacent to the structural protein coding domain
of a suicide enzyme. These chimeric gene constructs are inserted into retroviral expression
vectors and have been packaged into recombinant retroviruses. The infectious recombinant
retroviruses have proven to be a highly efficient mechanism for delivery and expression of
genetic material in eukaryotic cells. A novel experimental animal model of human leukemic
meningitis in the nude rat, recently developed in collaboration with Dr. Robert Plunkett's
Laboratory, has served as an in vivo model to assess promoter-controlled drug activation efficacy
and targeted killing of human leukemias that invade the meninges of the brain and spinal cord.
The Laboratory is also investigating the inter-relationships of certain angiogenic growth factors,
especially endothelin-1 (ET-1) and transforming growth factor 1 (TGF-1), and the evolution of
astroglial tumors. Exciting preliminary data from our laboratory suggests that the malignant
phenotype of astroglial tumors can be significantly genetically altered by the engineered
expression of ET-1 and TGF-1 in vivo.
One of the largest collections of familial multiple sclerosis patient groups has been assembled
and an extensive DNA bank developed. Using analysis of microsatellite polymorphisms, various
genes from the class III MHC region (tumor necrosis factor/ lymphotoxin, heat shock protein-70)
and gamma-interferon are being studied as potential susceptibility genes. These studies are
underway in collaboration with Dr. Lawrence Jacobs, Buffalo General Hospital, and the Baird
MS Center, Millard Fillmore Hospital. Other genetic studies underway involve the ACE gene
insertion/deletion polymorphism, angiotensinogen microsatellite polymorphism, and
polymorphisms of the cyclo-oxygenase enzyme, as potential markers for cerebrovascular disease.
These studies are underway in collaboration with Dr. Patrick Pullicino, Buffalo General Hospital.
Novel molecular detection methodologies have been developed that identify, with exquisite
specificity and sensitivity, unique lymphocyte clonotypes. The new gene amplification technique
is being applied to study a variety of heme-oncologic states, including adult T-cell leukemia,
Sezary and mycosis fungoides, T-cell and B-cell ALL and CLL, primary CNS lymphoma and
leukemic and lymphomatous meningitis. Studies have included the characterization of active
disease, detection of minimal residual disease post systemic chemotherapy or bone marrow
purging, and early detection of relapse. Also, the methodology is being used to assess the
efficacy of experimental gene therapies in animal models. Finally, the strategy forms the basis of
our ability to study the clonal evolution and specific repertoire recruitment in normal cellular
immune system maturation and in infectious and autoimmune disease states.
The Neuroimmunochemistry Unit, under the direction of Dr. Philip Hohmann, focuses on the
development of therapeutic DNA analogues and molecular gene constructs to treat primary brain
and spinal cord astroglial tumors and leukemias and lymphomas that invade the central nervous
system. In addition, the Neuroimmunochemistry Unit supports the molecular genetic detection,
identification, and sequence characterization of unique T-cell and B-cell clonotypes from
the lymphoid repertoires of patients with leukemias and lymphomas. In this regard, the Unit has
been instrumental in helping to develop and validate several experimental animal models of
leukemia and human leukemic meningitis to evaluate new modalities of immunotherapy and
gene therapy. Finally, several neurological disorders, including cerebrovascular disease and
multiple sclerosis, are under current investigation in search of disease susceptibility genes.
Specific candidate genes are being screened for polymorphic linkage disequilibrium and potential
disease association also is being assessed by chromosomal saturation using microsatellite
markers.
Neuropharmacology Division
The Neuropharmacology Division, under the direction of Francis Gengo, Associate Professor of
Neurology and Pharmacy at the Dent, is a joint collaboration between the School of Pharmacy
and the School of Medicine. This Division is involved in an Acute Stroke Program and a
Comprehensive Epilepsy Program. The aims of this program are to evaluate comprehensive and
optimal drug treatments for patients with cerebrovascular disease and seizure disorders, and to
develop a research outcomes program that focuses on the cost effectiveness ratio of drug
treatment strategies in stroke and epilepsy. Lastly the program is designed to enhance the ability
to conduct clinical pharmacokinetic and pharmacodynamic research in the current health care
environment.
In addition, University teaching activities have expanded two-fold and clinical involvement has
increased. Accomplishments of the Neuropharmacology Division include a stroke research team,
a clinical research program for epilepsy, an antiplatelet pharmacokinetic and pharmacodynamic
program in investigating migraine headache.
Graduate students in the Pharm.D. program of the University continue to complete their
doctorate degree research requirements in the Neuropharmacology Division at the Dent. It is
anticipated that this program, under the supervision of neuropharmacology staff members, will
continue and that the postdoctorate fellowship will increase over the next several years.
Dr. Alan Lockwood serves as the Operations Director of the PET Center which is
administratively housed in the Department of Nuclear Medicine. The PET Center is a result of
shared facilities with the Department of Veterans Affairs and the State University of New York
at Buffalo. The center is supported, in part, with a major grant from the Cummings Foundation.
The center began its operations in October 1991. The cyclotron was installed and the
radiochemistry laboratories were completed during the Summer and Fall of 1992. After a period
of testing, the first flurodeoxyglucose was produced in this facility was performed in April 1993.
The volume of clinical and research studies to date has steadily grown.
In addition to the Cummings Foundation, the Mabie family has provided an endowment for the
William and Grace Mabie Laboratory for Behavioral Neurosciences in the PET Center at the VA.
Clinical activities in the center are reviewed monthly by the PET Operations Council. This
committee was established to link the activity of the center with the medical community and the
insurance industry. Current procedures require review and approval of all clinical protypes by
the committee prior to offering specific imaging services to referring physicians. The process
was designed to ensure responsibility for the use of scarce medical and financial resources.
Center personnel are conducting follow-up studies to determine how the data from specific scans
are used to enhance patient care and minimize cost.
The research activities of the PET Center are truly cross-departmental and involve faculty from
the Departments of Gynecology and Obstetrics, Internal Medicine (Cardiology, Oncology, and
Gastroenterology), Neurology, Nuclear Medicine, Otolaryngology, Psychiatry, Rehabilitation
Medicine, and Surgery. In addition, the PET Center interacts with faculty from the Social
Sciences and Communicative Disorders, Linguistics, and faculty in the School of Pharmacy and
the Graduate School of Education. There have been also some interactions with Neurology
faculty and Otolaryngology faculty at the University of Rochester.
Research Activities
A. Neuroscience
With the maturation of the Center, support from the University at Buffalo through the pilot
project program, support from the Center for Hearing and Deafness, and additional grant support
from the American Tinnitus Association, the center has been able to develop sufficient
preliminary data to apply for major extramural funding from the National Institutes of Health.
The expectation, based on recent practices at NIH, is that grants will require multiple
submissions before they receive priority scores that are in the fundable range. Thus, these efforts
are part of a longer-range, strategic plan. Two major applications have been made. The first,
Functional Imaging of Tinnitus and Hearing Loss, was originally submitted for the June 1, 1996
deadline, revised and resubmitted for the February 1, 1997 deadline. The largest effort was
directed toward assembly and submission of a program project grant titled Functional Imaging of
the Auditory System for the October 1, 1996 deadline. Plans for revision and resubmission are
being developed. We have received preliminary word that the priority score for this grant was in
the 5th percentile and in all probability will be funded. Several other applications as projects or
portions of projects for other program project grants were made.
In response to a Department of Veterans Affairs request for applications to establish a
Rehabilitation Research and Development Center a multidisciplinary group was formed to
develop and submit an application titled "Recovery After Acquired Brain Injury." Dr. Lockwood
will be the director of the center, if funded, and Drs. Linda Hershey (Neurology) and John
Naughton (Rehabilitation Medicine) will be associate directors. The focus of the research will be
recovery from aphasia, recovery after traumatic brain injury, and epidemiological studies of
rehabilitation outcome in collaboration with the Uniform Data Systems for Medical
Rehabilitation. Substantial input in the preparation of the application was provided by Dr.
Richard Linn (Rehabilitation Medicine).
With support from the American Tinnitus Association, Drs. Richard Salvi, Robert Burkard
(Communicative Disorders and Sciences) and Lockwood are investigating patients who are able
to exert substantial voluntary control over the loudness of tinnitus. In addition, we have initiated
studies designed to determine fundamental relationships between stimulus loudness and pitch of
pure tones and cerebral activation.
Studies of the effects of mild traumatic brain injury (MTBI) on cerebral function continue under
the direction of Dr. Richard Linn, Rehab Medicine. Most recent studies have focused on
functional anatomy of the Paced Serial Addition Test (PASAT) in normal subjects and patients
with MTBI. Patients show more activity in retrosplenial cortical areas than controls. Since this
brain region mediates formation of auditory episodic memory, the results suggest impairment of
this element of the PASAT task.
Studies of auditory attention using a continuous performance task (CPT) under conditions of
sustained, focused, and divided attention continue under the direction of Dr. Ralph Benedict.
The results of this study suggest similarities and differences in auditory versus visual attention.
The anterior attention system, particularly the anterior cingulate gyrus appears to be a mediating
structure in auditory as well as visual attention. Unlike divided visual attention tasks (monitoring
speed, shape, and color) which activate multiple discrete brain regions, divided and focused
auditory attention appear to be mediated by the same brain regions.
The James H. Cummings Foundation has continued to be generous in its support of the Center.
They have recently awarded the center a three-year grant which will enable the development of
techniques for the co-registration of MRI and PET images.
B. Cardiovascular Research
Studies of myocardial ischemia and hibernating myocardium have continued under the direction
of Drs. James Fallavollita and John Canty (Medicine). They have developed a porcine model of
hibernating myocardium by chronic placement of a snare around the proximal left anterior
descending coronary artery. The affected myocardium is characterized by relative reductions in
resting function and perfusion and an increase in the uptake of FDG in the fasting state. The
transmural variations in flow and FDG uptake that suggest that hibernation changes are most
prominent in subendocardial regions and vary in relation to local coronary flow reserve. These
studies suggest that fasting FDG studies may be the method of choice for the detection of
hibernating myocardium that will respond favorably to revascularization. This work is supported
by grants from the American Heart Association, the NIH Heart Lung and Blood Institute, and the
Department of Veterans Affairs.
C. Pharmacological Research
Studies of cerebral blood flow and metabolism in patients with migraine in acute headache, after
treatment with sumatriptan, and in headache-free phase continue under the direction of Edward
Bednarczyk (Nuclear Medicine) with support from the Department of Defense. Findings of this
work have been presented at the American Society for Clinical Pharmacology and Therapeutics,
1997 annual meeting. He anticipates support from American Headache Foundation to support
studies of model of nitroglycerine-precipitated migraine.
This site has become a part of a lipid-lowering drug trial that uses FDG PET scans of the heart as
a clinical indicator.
D. Oncological Research
Dr. Nabi (Nuclear Medicine) and Dr. Grant from the Department of Internal Medicine
(Pulmonology) in cooperation with thoracic surgery are responding to Health Systems Research
and Development requests for applications with a protocol designed to identify the role of FDG
PET in the evaluation of patients with non-small cell carcinoma of the lung. Even after the
diagnosis is established by other criteria, projections based on costs of thoracotomy, avoidance of
thoracotomy that would not benefit the patient, and other factors suggest strongly that PET will
prevent surgical morbidity and mortality by avoiding operative intervention when other therapies
are more appropriate and result in substantial cost savings.
Studies of patients with head and neck tumors using FDG PET demonstrate a clear role for this
procedure in these patients in studies directed by Drs. Nabi and Meyers (Head and Neck
Surgery). A manuscript describing these findings is in press in Laryngoscope.
E. Radiochemistry Research
Perhaps the most promising program in the PET Center is that developed between Drs.
Lockwood and Benedict from our faculty, Dr. Salvi from Hearing and Speech, and Drs. Frisina
and Jaeger from the Department of Linguistics to study mechanisms of auditory reception,
language acquisition and localization in the central nervous system using PET methodology.
All told, this has been an active year in the PET Center. It is hoped that some of the current
grants that are under review will be funded and that the PET Center will move into another phase
of its research activity. Clinical activity in the PET Center primarily is generated by physicians
in Nuclear Medicine while the research activity, specifically in the areas of cognitive
neurosciences has been the focus of the neurologic commitment to the PET Center.
Lucy Dent Imaging Center
The Lucy Dent Imaging Center at the Dent Neurologic Institute supports an array of techniques
in neuroimaging. Research takes the form of technical contributions such as the development of
MRI techniques and coordination of clinical and neuroimaging studies. Educational pursuits
involve the development of neuroimaging fellowship programs, a lecture series, and case review
presentations. In the neuroimaging center, a computer imaging network has been developed
which permits access to imaging studies performed in the neuroimaging center.
The Neuroimaging Research Center is composed of several fellows, two research Ph.D. scientists
and engineers, and several secretaries. The investigative endeavors are supported by annual
grants from Picker International and private donations from the Millard Fillmore Research
Foundation.
Neuroimaging Research
Researchers acquire high resolution, cross-sectional, multispectral images of the human carotid
artery to characterize plaque composition and, in particular, to assess their embolic potential and
suitability for treatment with angioplasty techniques. Angioplasty has been performed for several
years, but has only more recently been applied to the treatment of carotid stenosis. Although the
surgical risks may be lower with angioplasty, depending upon the composition of the plaque,
emboli may be caused by the procedure or the vessel may restenose. Restenosis has been
associated with plaque calcification. Imaging studies help determine the spontaneous risk of an
embolic stroke by better characterizing the plaque. Thus, restenosis rates can be predicted and
alternative therapies suggested.
Individually, existing non-invasive technologies have shortcomings with respect to assessing plaque. Calcium can cause streaking artifacts in CT and shadowing in carotid ultrasound. Its lack of proton content renders it hypointensive on MRI, which can be confused with blood flow signal voids. DSA images blood flow as opposed to vessel wall pathology; unsubtracted x-ray angiograms provide only limited view projection images. The synthesis of these methods should permit more accurate classification. An algorithm based on combined methodology should more accurately characterize the plaque of a given individual.
Functional imaging methods are under investigation which assess damage, potential salvageability, and treatment monitoring of patients with acute stroke. Examples include: magnetic resonance diffusion to assess cell damage; magnetic resonance perfusion and angiography to non-invasively assess the degree of blood flow to areas of the brain damaged by stroke, location of clots impeding blood flow; MR spectroscopy to assess chemical and metabolic changes caused by stroke or treatment; multi-modal imaging to optimally combine or fuse data from several imaging techniques (nuclear, MR, CT, angiography), thereby providing more information than any one alone; and development of a database to help define standards for observing and treating stroke victims with newly emerging agents.