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Statement on Parkinson's Disease by Gerald D. Fischbach, M. D.
Director, National Institute of Neurological Disorders and Stroke
National Institutes of Health
U.S. Department of Health and Human Services
Before the Senate Appropriations Subcommittee on Labor, Health and Human Services, Education and Related Agencies
September 28, 1999
Mr. Chairman and members of the Committee, I am pleased to tell you what NIH is doing
to reduce the burden of Parkinsons disease. I want to convey my enthusiasm and
optimism. I also want to emphasize that the task before us, conquering Parkinsons
disease, will not be easy. The problems ahead will challenge the insight and ingenuity of
scientists and physicians throughout the country and require coordinated effort by several
NIH Institutes working closely with private Parkinsons groups. Finding a cure for
Parkinsons is not like sending a man to the moon or making the atom bomb, where a
resolute effort to apply what is known produced success. We still need to learn a great
deal before we can stop this disease, but I am encouraged that the pace of discovery is
increasing each year, and that we are on the right track.
Parkinsons disease is a devastating, complex disease. Starkly put,
Parkinsons destroys the ability to control movement. It begins with tremor and
difficulty in initiating voluntary movements, and it progresses
relentlessly, with a broad spectrum of symptoms, including depression and dementia in some
patients. Nevertheless, there are several reasons for hope.
· At first, the degeneration of nerve cells is confined to
one region of the brain and one type of nerve cell. These are nerve cells that normally
transmit messages to other cells by releasing a chemical called dopamine. We are rapidly
learning, down to the level of single molecules, how cells make dopamine and respond to
it. Therefore the target early in disease is clear.
· A second reason for optimism is the discovery that nerve
cells often follow a "final common path" to degeneration in Parkinsons
disease and in many other disorders. Apoptosis, this death program, is often called
"cell suicide" because cells participate in their own destruction by activating
a cascade of enzymes that disrupt the integrity of genes and normal cell metabolism. Each
step in the cascade offers new therapeutic targets to halt the progression.
· We have new insights about what damages nerve cells
provoking the cell death pathway. Mechanisms such as free radical damage, malfunction of
mitochondria (the cells energy factories), "excitotoxicity" from excessive
release of neurotransmitters, abnormal protein aggregates, and sudden elevations of
calcium inside cells have been implicated. Again, each event offers opportunities to slow
the damage caused by disease.
· Levodopa, when first introduced, seemed to be a miracle
drug liberating Parkinsons patients from immobility. This drug helps replenish the
brains diminishing supply of dopamine. Unfortunately the effects of levodopa are not
sufficiently lasting, side effects can be serious, and, most importantly, levodopa cannot
halt the underlying death of nerve cells. It is encouraging that as we learn more about
dopamine and other neurotransmitters in the brain, we are learning how to prolong and
enhance the effects of levodopa and develop new drugs.
· Neurotrophic factors, an entirely new class of
therapeutic drugs, were identified as natural brain chemicals that promote the growth and
survival of nerve cells in the development of the nervous system. We are now learning how
neurotrophic factors can be used to protect against neurodegeneration in adult brains,
with promising results in animal models of Parkinsons disease.
· Years of analysis of the brain circuits that control
movement is leading to dramatic advances in surgical repair of Parkinsons disease.
Pallidotomy is a surgical procedure designed to rebalance the normal interplay of brain
circuits that initiate and restrain voluntary movement. The procedure is now carried out
with exquisite precision guided by advanced brain imaging and microelectrode recordings
from single brain cells. An astounding new technology, chronic brain stimulation through
electrodes implanted deep in the brain. Beyond relief of symptoms chronic brain
stimulation may even slow the progression of the disease. We must pursue this possibility
and determine the long term consequences of these surgical procedures.
· Stem cells offer an entirely new therapeutic approach.
Cell implantation offers hope for actually replacing nerve cells lost in Parkinsons
and many other diseases. Clinical trials of fetal tissue transplantation, still underway,
have developed methods for implanting cells into the brain, and demonstrated the viability
of the concept and promising results for at least some patients. Now, neural stem cells,
cells that have the capacity to renew themselves indefinitely and to specialize to form
all cell types of the brain, offer a potentially unlimited supply of dopamine cells. Stem
cell therapy has already produced dramatic success in animal models of Parkinsons
and other neurological diseases.
Beyond the impact on Parkinsons disease itself, Parkinsons research will
certainly lead to insights about many other diseases in which nerve cells die.
Neurodegenerationthe death of nerve cellsis a ubiquitous problem. Most notable
are the classic chronic neurodegenerative diseases such as Alzheimers,
Huntingtons, and ALS. Many devastating neurodegenerative disorders also attack the
brain of infants and children. Nerve cell death is critical in stroke, brain and spinal
cord injury, and in epilepsy. Alchohol and drug abuse can cause neurodegeneration. Even
severe depression, long thought to be related to a chemical imbalance in the brain, is
associated with degeneration of nerve cells. The same destructive processes come into play
and provoke the same cell death programs. Advances in Parkinsons disease will shed
light on all of these disorders, and research on these other disorders may also advance
understanding of Parkinsons disease.
Let me now focus on a a few critical issues that must be resolved as we move forward.
· Early detection of Parkinsons disease is absolutely
crucial. More that 75 percent of the dopamine cells have already died before the first
symptoms are detected. Preventing cells from dying in the first place is the best hope for
effective medical therapy. Extensive efforts to develop early detection of
neurodegenerative diseases, though brain imaging and other approaches, are a major thrust
of programs at the NINDS, the National Institute of Aging, and other components of NIH.
· Thorough epidemiological and environmental studies are
essential to identify factors that set off the disease process. The National Institute of
Environmental Health Sciences is leading a major NIH initiative to detect risk factors in
the environment that may influence the onset or progression of neurodegeneration in
· We must also follow the genetic trail. Though most people
do not inherit Parkinsons disease, we can learn a great deal by studying the rare
families that carry a Parkinsons disease gene. The first gene defect that causes
Parkinsons disease, a mutation in the protein synculein, was identified just three
years ago, and two more Parkinsons genes have since been discovered. We already have
clues that synuclein plays a role not only in familial Parkinsons disease but also
in the more common non-inherited form. Synuclein may also play an important role in the
development of Alzheimers disease, again demonstrating the close ties among brain
· The advent of new surgical therapies, like deep brain
stimulation, reinforces the importance of better understanding the brain circuits that
control movement. If we understand the circuits perhaps we can reactivate them. Likewise,
the more we are learning about dopamine and other neurotransmitters the greater the
options to restore motor control to Parkinsons patients.
· We are expanding our efforts in experimental therapeutics
to keep the pipeline full of potential new treatments. Finding better animal models that
truly mimic the slow neurodegeneration of human Parkinsons disease is critical to
expediently move candidate therapies to human testing. This is one area where genetic
technology may be essential. Other technologies, like high-throughput drug screening and
gene arrays, promise to greatly expedite the search for cures and must be made accessible
to any researcher with a good idea.
· We need to develop methods to deliver drugs to the brain.
Many potentially therapeutic substances, such as neurotrophic factors, do not cross the
blood-brain barrier which excludes substances from the general circulation.
· For no area of medicine is the promise of stem cells
greater than for treating diseases of the human brain. We must learn how to control the
survival, proliferation, and specialization of neural stem cells so we can repair the
damage wrought by Parkinsons disease. The recent startling demonstration that even
60 year old human brains harbor stem cells presents the possibility that we may someday
learn how to empower the Parkinsons ravaged brain to repair itself, if only we can
learn the control signals.
In addition to the National Institute of Neurological Disorders and Stroke (NINDS), the
National Institute of Aging, the National Institute of Mental Health, the National
Institute of Envronmental Health Sciences, the National Human Genome Research Institute,
the National Institute on Drug Abuse, the National Institute of Diabetes and Digestive and
Kidney Diseases, and the National Center for Research Resources all support research on
Parkinsons disease. Led by NINDS, the Parkinsons Disease Coordinating
Committee has undertaken several initiatives, including a major workshop in 1995 that
identified new directions for Parkinsons disease research and a cooperative program
announcement on "Mechanisms of Cell Death and Injury in Neurodegenerative
Finally, as you have just heard, the NINDS has now funded 11 Morris K. Udall
Parkinsons Disease Research Centers of Excellence. These centers will play a key
role in coordinating and carrying out research efforts in Parkinsons disease. The
centers will explore many aspects of Parkinsons disease, from basic science to
clinical applications. They will play a particularly important role in bringing scientists
and clinicians together to move research advance to therapy that can benefit patients.
We believe that current extensive efforts by the NIH in Parkinsons research are
justified by the extraordinary opportunities that neuroscience research now presents for
fighting this disease and the implications for other diseases. Because we know so much
about Parkinsons, this disease can lead the way in confronting the broader problem
of neurodegeneration. What we learn about the broader problem of neurodegeneration will
also the fight against Parkinsons disease. We have an extraordinary opportunity and
a great challenge. Neuroscience has arrived at a state when we can contemplate translating
fundamental discoveries into a cure for seemingly inexorable neurodegenerative disorders.
Thank you Mr. Chairman. I would be happy to answer any questions.
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