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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 Parkinson’s disease. I want to convey my enthusiasm and optimism. I also want to emphasize that the task before us, conquering Parkinson’s 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 Parkinson’s groups. Finding a cure for Parkinson’s 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.

Parkinson’s disease is a devastating, complex disease. Starkly put, Parkinson’s 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 Parkinson’s 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 Parkinson’s patients from immobility. This drug helps replenish the brain’s 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 Parkinson’s disease.

Years of analysis of the brain circuits that control movement is leading to dramatic advances in surgical repair of Parkinson’s 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 Parkinson’s 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 Parkinson’s and other neurological diseases.

Beyond the impact on Parkinson’s disease itself, Parkinson’s research will certainly lead to insights about many other diseases in which nerve cells die. Neurodegeneration—the death of nerve cells—is a ubiquitous problem. Most notable are the classic chronic neurodegenerative diseases such as Alzheimer’s, Huntington’s, 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 Parkinson’s disease will shed light on all of these disorders, and research on these other disorders may also advance understanding of Parkinson’s disease.

Let me now focus on a a few critical issues that must be resolved as we move forward.

Early detection of Parkinson’s 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 Parkinson’s disease.

We must also follow the genetic trail. Though most people do not inherit Parkinson’s disease, we can learn a great deal by studying the rare families that carry a Parkinson’s disease gene. The first gene defect that causes Parkinson’s disease, a mutation in the protein synculein, was identified just three years ago, and two more Parkinson’s genes have since been discovered. We already have clues that synuclein plays a role not only in familial Parkinson’s disease but also in the more common non-inherited form. Synuclein may also play an important role in the development of Alzheimer’s disease, again demonstrating the close ties among brain diseases.

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 Parkinson’s 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 Parkinson’s 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 Parkinson’s 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 Parkinson’s 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 Parkinson’s disease. Led by NINDS, the Parkinson’s Disease Coordinating Committee has undertaken several initiatives, including a major workshop in 1995 that identified new directions for Parkinson’s disease research and a cooperative program announcement on "Mechanisms of Cell Death and Injury in Neurodegenerative Disorders."

Finally, as you have just heard, the NINDS has now funded 11 Morris K. Udall Parkinson’s Disease Research Centers of Excellence. These centers will play a key role in coordinating and carrying out research efforts in Parkinson’s disease. The centers will explore many aspects of Parkinson’s 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 Parkinson’s 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 Parkinson’s, 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 Parkinson’s 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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