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National Parkinson Foundation, Inc. Written Testimony of Muhammad Ali and Abraham Lieberman, M.D. before the House of Representatives Commerce Committee Subcommittee on Health and Environment "New Developments in Medical Research" 2123 Rayburn House Office Building March 26, 1998 Mr. Chairman and distinguished members of this Subcommittee, my name is Abraham Lieberman. I am Medical Director of the National Parkinson Foundation and Executive Director of the Muhammad Ali Parkinson's Institute in Phoenix, Arizona. I am accompanied today by my friend and patient, Muhammad Ali who, of course, needs no introduction, and Mr. Nathan Slewett, volunteer Chairman of the Board of the National Parkinson Foundation, whose worldwide headquarters are located in Miami, Florida. We are here at the invitation of Chairman Bilirakis whom I want to personally thank and commend for holding these hearings on "New Developments in Medical Research." Muhammad has assured me that he would have preferred to speak directly to you today, but his Parkinson's disease has robbed him of what was one of his most prized assets....the ability to speak with resonance. I can assure you, however, that his thoughts and muted speech remain as eloquent as ever. We are here today for two principal reasons. First to enlighten this committee and thereby the United States Congress, on the pathology of Parkinson's disease, at least what we currently know about its causes, course and treatment. Also, we would be remiss if we failed to use this opportunity to demonstrate once again, why more research resources are needed NOW to take advantage of some of the fantastic scientific breakthroughs that are at our door step. Parkinson's disease (PD) affects more than a million Americans, and costs the United States more than five billion dollars a year in Medicare, Medicaid and nursing home outlays. In addition it costs each patient five thousand dollars a year for medications, doctor's visits and hospital stays. As a society we spend ten billion dollars a year for PD, without considering the indirect costs of lost income, missed opportunities and family disruptions. The ten billion dollars results in treatments that provide only temporary relief because there is no cure. No Parkinson's patient, no care giver, no doctor is happy, nor considers the ten billion dollars well spent. At the time of diagnosis, every patient had probably had Parkinson's disease for at least four years. Based on the time between disease onset and diagnosis, it's estimated there is at least one person who is undiagnosed, for each patient who is diagnosed. In other words, there are probably two million Americans with PD: 2% of the population over age 60, and 4% over age 70. The degeneration of nerve cells in Parkinson's disease is associated with a particular particle, called a Lewy body, in each dying cell. Based on the observation that the Lewy body is a marker for PD, and that 10% of the population over age 60 years have Lewy bodies without symptoms of PD, it's estimated that at least ten million Americans may develop PD, if they live long enough. Lest the young be sanguine, and relegate PD to senescence, 15% of all patients who develop PD are less than 50 years of age. And the disease appears in adolescence. Given the increased chance of developing PD with increased life, what is the point of conquering cancer, heart disease, stroke, and diabetes if the end result is a population, 10% of whom have PD and 10% of whom must care for the afflicted or live in dread of being afflicted? Public health, preventive medicine, and environmental safety are laudable goals only if the resultant increased life span is satisfying and free of the plague of Parkinson's disease. Parkinson's disease results from the death of pigmented nerve cells in the substantia nigra, part of the basal ganglia, the region of the brain between the hemispheres, the creators and initiators of thought and movement, and the brainstem and spinal cord, the executioners of movement. In the past ten years, as a result of developments in molecular biology, genetics, neurophysiology, and computer science, the mystery of cell death is being unraveled. It's known that some neurons are more susceptible to dying than others, that their death is associated with both external (to the cell) and an internal (within the cell) generation of free radicals and this, in turn, may be associated with the deposition of iron. Sadly, the end result of Parkinson's disease is that the human brain, the highest expression of creativity--rusts. Whether the cause of Parkinson's disease is an externally produced toxin, AN internally generated poison, a defect in the cell itself, or an abnormal gene is the now the subject of intense thought, debate, study, and experimentation. A debate that, as recently as ten years ago, was conceptually impossible and scientifically unprovable. Unraveling the mechanism of cell death in PD, will increase our understanding of the more complicated, disintegrative mechanisms in Alzheimer's disease and the aging process itself. Since the introduction of levodopa in 1967 it has been the mainstay of treatment for PD. Levodopa is combined with a dopa decarboxylase inhibitor, to facilitate its passage from the gut. There are several drugs including MAO-B inhibitors, COMT-inhibitors, and controlled-release levodopa preparations that enhance levodopa's activity. There are several other drugs, dopamine agonists, bromocriptine, pergolide, ropinerole and pramipexole, that activate the dopamine receptors. Recent discoveries have shown that nerve cells, heretofore considered incapable of regenerating themselves, are able to do so. This regeneration occurs under the influence of trophic, or growth factors, small molecules, poly-peptides, produced in the brain. There may be hundreds of trophic factors, each one specific for one or two nerve cells, so as to limit uncontrolled growth, and its resultant tumor induction. Several factors have been identified, characterized, engineered and tested in animal models of PD. One of them glial derived neurotrophic factor (GDNF) is undergoing clinical trials for Parkinson's disease. Knowledge of the mechanism of action of trophic factors will increase our understanding of cell death and aging and will lead to treatments heretofore thought possible only through immersion in the legendary and elusive, "Fountain of Youth." The challenge is to determine which trophic factors are relevant to which nerve cell, and which disease, to deliver the factors into the nervous system and target them to the relevant cells. These are complex engineering problems, but ones, as with the World War II Manhattan Project which produced the atomic bomb, are within the realm of being solved with our present technology. Within the past ten years neuroanatomists, neurophysiologists and neuropathologists have distinguished differences between the caudate nucleus and the putamen, the two components of the striatum. They have separated the ventral from the dorsal caudate, and ventral from the dorsal putamen, and have identified several cell types within the striatum. Meanwhile the neurochemists and molecular biologists have further characterized the striatum's nerve cells by co-localizing them with one or more of several neurotransmitters. The significance of the striatum's newly discovered external geography, and internal architecture is being scrutinized in PD and heretofore unknown relationships are emerging. While the external characteristics of the striatum were being studied, the more important and challenging task of understanding the internal biology of the individual cells has proceeded simultaneously. Specific proteins, and poly-peptides are produced in specific cells, and the ability of a cell to produce a specific protein defines the individuality of the cell. The ability to replicate, amplify or inhibit these interactions will have consequences for our health and our civilization as profound, and as monumental as splitting the atom. Thirty percent of Parkinson's disease patients develop a dementia which has many similarities to Alzheimer's disease. A smaller portion of PD patients develop a dementia, at an earlier age, called Lewy-body dementia. Whether the dementia of Parkinson's disease and Alzheimer's disease are different, or the same is now under intense investigation. Approximately 50% of Parkinson's disease patients become depressed during the course of the illness and require counseling and/or anti-depressant medication. In some patients the depression is a reaction to the PD, but in most, depression is an intrinsic component of PD. Unraveling Parkinson's disease will lead to a better understanding of the affective disorder. At the level of the human brain, as distinct from the human spirit, the formulation, initiation and execution of a thought, is conceptually similar to that of a movement. An idea recognized in the Bible by the sages who described the consequences of a stroke by saying, "If I forgot you, Jerusalem, let my right hand lose (not its strength or power) but its cunning." We are in the midst of a revolution in understanding the brain. The centerpiece of this is Parkinson's disease. With increased financial support from the government, foundations and private donors, the scientific community will unlock the mother-lode of information contained within the Parkinson brain that will banish these diseases and ameliorate the aging process itself. Mr. Chairman, as I am certain you have witnessed, the Parkinson's community has mounted one of the most visible and effective grassroots campaigns in history to secure additional needed funding for Parkinson's research. The culmination of this monumental effort was last November's passage of the Morris K. Udall Parkinson's Research and Education Act of 1997. When the Udall Bill was signed into law, both the President and Vice President specifically recognized its intent as a very essential part of the Labor/HHS appropriations Bill in which it was included as an amendment. Also recognized by the President was the bill's principal sponsor, and your colleague, Congressman Fred Upton who was on hand to witness its signing. It was truly a great moment. I am proud to say that the National Parkinson Foundation regarded the passage of the Udall bill as its highest legislative priority and lobbied aggressively for more than two years in favor of its enactment. Muhammad appeared last April on behalf of the NPF before the House Appropriations Committee to urge the Udall bill's passage and requested that that committee appropriate the funding called for in the Udall Bill after its enactment. That has not yet happened. The Morris K. Udall Parkinson's Research and Education Act is authorizing legislation. It does not provide for the funding that the entire Parkinson's community has worked tirelessly for, and fully expects will hasten the cure for this dreaded disease. Today, the Congress has before it the responsibility to fund the Udall legislation making this victory a full one rather than a hollow one. Some have said that the Udall legislation provides for up to $100 million for Parkinson's research. The National Institutes of Health have recently released numbers attributed to Parkinson's disease research that will soon exceed the $100 million provided for in the Udall legislation. This makes it appear that additional funding for Parkinson's research is not necessary. This conclusion is UNACCEPTABLE! Whatever the National Institutes of Health claims to be spending on Parkinson's disease is based upon an analysis that I am personally not in a position to challenge. However, the entire Parkinson's community believed that the Udall Bill would authorize at least $65 million additional dollars for Parkinson's disease research. This figure is based upon the funds leading Parkinson researchers tell us are needed to dramatically advance our finding a cure or significantly improved treatments for Parkinson's disease. The Parkinson's community has sought, and believes it has found a sympathetic and supportive ear in Congress. Parkinson's activists nationwide have sacrificed some of the best remaining years of their lives advocating a substantially increased federal investment in Parkinson research so that a cure may be found in their lifetime. To say to them now that there is no new money for Parkinson's disease is also unacceptable. If Congress is to honor the intent of the Udall Bill it must appropriate $100 million of additional funds for Parkinson's research for each of the next three fiscal years. The NPF recognizes that federal funding is one of several ways to support medical research. Therefore we have taken unprecedented steps to increase the role of the private sector in finding a cure for Parkinson's disease. The National Parkinson Foundation is the largest voluntary health agency representing the interests of people with Parkinson's disease. It supports 51 NPF Centers of Excellence worldwide. The research conducted by these centers is cutting edge and the grants it awards are subjected to a peer review process similar to that of the National Institutes of Health. It also provides a myriad of patient services including physical therapy, occupational therapy and speech therapy to persons suffering from Parkinson's disease. Furthermore, the NPF works closely with NIH in three ways. First, we provided needed additional funding to the National Center for Human Genone Research when they were looking for the gene that was believed to cause a form of Parkinson's disease. Within a short time, that gene was indeed located as highlighted in the President's State of the Union Address. Secondly, we are cooperating with NIH in providing "bridge" grants to those researchers whose grant applications were of high scientific merit, but fell just below the funding level. And finally, the National Parkinson Foundation has just designated the Parkinson intramural research facility at NIH as a NPF Center of Research Excellence. Thank you, Mr. Chairman and members of this distinguished committee for the opportunity to appear before to talk about Parkinson's disease. Muhammad and I have dedicated our lives to finding a cure for this disease and seek your help. I will be happy to answer any questions that you may have for either Muhammad or me.