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Testimony on National Institute of Neurological Disorders and Stroke's FY 1998 Budget by Dr. Zach W. Hall
Director, National Institute of Neurological Disorders and Stroke
National Institutes of Health

Accompanied by
Dr. Audrey S. Penn, Deputy Director, NINDS
Mr. Richard L. Sherbert, Executive Officer, NINDS
Mr. Andrew C. Baldus, Budget Officer, NINDS
and
Dr. Harold Varmus, Director, NIH
Mr. Dennis P. Williams, Deputy Assistant Secretary, Budget, DHHS

U.S. Department of Health and Human Services

Before the House Appropriations Committee, Subcommittee on Labor, Health and Human Services, Education and Related Agencies
March 5, 1997

Mr. Chairman and Committee Members:

Thank you for the opportunity to appear before this Committee. These appearances are a pleasure for me because we are in an era of unprecedented progress in research on the brain and its diseases, and I appreciate the opportunity to share with you some of the important advances of the last year. There is a growing awareness of the importance of diseases of the brain in our society. In part this arises because our population is aging, and diseases of the brain become more prevalent as one gets older. In part it is also due to the growing awareness of the importance of the nervous system for many problems that have not traditionally been considered as biologically based diseases, conditions such as autism or addiction or Tourette's syndrome. We share responsibility for brain research with a number of other Institutes and Centers at NIH, and we cooperate with them in areas of mutual research interest, including pain, sleep disorders, and neurological aspects of AIDS. Our own Institute has responsibility for more than 600 neurological disorders, ranging from those well-known, such as stroke, Parkinson's disease and epilepsy, affecting millions of Americans, to those less common, such as Batten disease, Friedreich's ataxia and ataxia-telangiectasia, that may affect a only few hundred Americans, but are nevertheless devastating to the patients and their families.

These are exciting times in research on neurological disease, as we stand on the threshold of an era in which the treatment of brain disease will become not just a promise, but a reality. In the past, we have had few treatments to offer patients with brain disease. When I was in medical school and became interested in neurological disease, I was told by my advisors that if I was interested in the intellectual challenge of diagnosis, neurology was a wonderful specialty, but if I wanted to make patients well, I should look for something else. Fortunately, that distressing situation is about to change. As we make progress in understanding the mechanisms at work in brain disease, as we identify genes that cause or predispose to brain disease, as we understand more about how the normal brain works, we are better able to devise treatments to prevent, slow or stop the disease process. Today, I want to tell you about our progress in three important disease areas: stroke, Parkinson's disease and spinal cord injury.

Stroke

Stroke is a major health problem in the United States; 500,000 Americans have a stroke each year; of these approximately 150,000 die. Those who survive are often left with major disability, at great emotional and financial cost to their families and to our society. Last year at this time I reported that NINDS, working with leading investigators across the country, with the private sector, and with the patient community, had organized a clinical trial showing for the first time that prompt administration of a clot-buster to those with the most common form of stroke gives a 30% increase in the chance for full recovery. This finding heralds a new era in stroke medicine, by showing that acute treatment can be effective. Widespread use of the new treatment will not follow automatically, however, because to be effective, therapy must be delivered within three hours after symptoms first appear. To insure such prompt treatment requires that physicians, patients and their families be educated, and that paramedics and hospital personnel be organized to give urgent care. Our clinical trial provided a model for this change by showing that a rapid response could be organized in a variety of health care and emergency settings. To help bring about the change, NINDS convened a major symposium involving doctors, nurses, paramedics, and patient representatives, to provide guidance for health care providers implementing acute stroke therapy. We will continue to work with patient and professional organizations to publicize the results of the symposium, helping public and health care professionals organize acute stroke treatment in a variety of settings.

Parkinson's Disease

Parkinson's disease (PD), which usually strikes in late middle age and affects more than a half million Americans, impairs control of movement, progressing from symptoms such as tremor and muscular rigidity to total disability and death. Parkinson's disease, like Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Huntington's disease, is a neurodegenerative disease with an unknown cause.

• In 1995 NINDS and three other institutes sponsored a Parkinson's Disease Research Planning Workshop to identify new directions of research. A major conclusion of the Workshop was that PD likely has a large genetic component. In response, NINDS initiated a collaboration with the National Human Genome Research Institute and extramural researchers which quickly showed that in a single large family PD was caused by an alteration in a gene on chromosome 4. This discovery was published in last November's issue of the journal, Science. Current investigations are aimed at identifying the gene and determining whether genetic alterations would benefit patients. Most importantly, identification of the genes responsible for familial Parkinson's disease may help solve the mystery of what triggers the degenerative processes in both familial and non-familial Parkinson's disease and provides the tools for testing new treatments. As a result of the 1995 Workshop, NINDS also issued a program announcement calling for applications on the mechanisms of cell death and injury in neurodegenerative disorders including PD, jointly sponsored by the National Institute on Aging, the National Institute of Environmental Health Sciences, and the National Institute of Mental Health.
  
  
• Clinical trials are underway to evaluate a surgical technique called pallidotomy to treat PD. Other trials are investigating the use of nervous system tissue implanted into the brain to halt or delay the process of degeneration, and to evaluate improved drug therapy for people with advanced PD.
  
  
• Trophic, or nurturing, factors are important for the survival of neurons in the growing brain and are essential for a healthy nervous system in adults. Promising results using trophic factors as therapies for PD have now been extended to primate models. Further research is required to overcome obstacles to human administration.

Spinal Cord Injury

One reason trauma to the central nervous system has such severe consequences is that neurons in the brain and spinal cord fail to regenerate after damage. Now we know they make unsuccessful attempts to regenerate, and in some circumstances can be coaxed to regrow. In 1996, NINDS with other NIH components sponsored a major workshop to foster new ideas and collaborations. Following that meeting, NINDS issued a program announcement to encourage research in several areas with potential for success:

• Neuroprosthetic devices connect with the nervous system via electrodes to stimulate muscles or provide sensory input. For example, a neural prosthesis developed with NINDS support and recently recommended for approval by an FDA advisory panel restores significant hand function to quadriplegics. Realistic future targets include a splint-free system to allow a paraplegic person to rise, stand, and sit again without assistance, and technologies to control muscles using direct brain signals.
  
  
• High dose methylprednisolone, the first therapy to improve the outcome of spinal cord injury, is now regularly used in emergency rooms. The effects of longer methyl-prednisolone treatment and of a new class of cortico-steroid drugs are now being studied.
  
  
• Efforts to repair damaged spinal cords in animals are continuing, using grafts, nerve bridges, cell implants, cell survival factors, antibodies, and genetic engineering. An NINDS grantee in Sweden has been able to use nerve grafts successfully in animals to bridge gaps in injured spinal cords. The potential use of newly-discovered neural progenitor cells, nerve cells that may have the capacity to replace cells lost because of trauma, is also under investigation.

Diseases of Childhood

More than a third of all genetic disorders affect the nervous system, and hundreds affect infants and children. In the past several years, research has rapidly progressed in identifying genes for a number of brain disorders. Approximately 50 genes have been identified. Finding the defective gene that causes a disease is only a beginning towards developing a therapy, but it allows scientists to develop diagnostic tests, create animal models, learn how the gene and its protein function to promote health or disease, and pursue a reasoned strategy towards counteracting the defect. Examples of progress in understanding neurogenetic disorders of infancy and childhood include:

• In neurofibromatosis 1, a common hereditary disorder of the nervous system, tumors, called neurofibromas, develop along nerves. Most of these tumors are benign but some become malignant. A defective NF1 gene results in the disease, and the normal gene is thought to be a tumor suppressor. This is an important clue to tumor formation in NF and perhaps will help predict which tumors will progress to malignancy, a valuable tool for planning surgery or other treatments.
  
  
• Recently scientists discovered that a defect in a gene for a previously unknown protein causes Friedreich's ataxia, a neurodegenerative disease of childhood. This should lead to a test for screening carriers of the gene and also to effective treatments.
  
  
• Turner syndrome, a genetic disorder of the X chromosome causing a lack of sexual development and a variety of cognitive and motor deficiencies, occurs in about 1 of every 3000 live-born females. Ongoing clinical trials are examining the effects of estrogen and androgen on cognition and social development. Besides providing information about the effectiveness of hormone replacement therapies for girls with Turner syndrome, these studies present a unique opportunity to study the effects of hormones on brain development and function, with implications for children's and women's health. Last year we reported exciting evidence that the administration of magnesium sulfate to mothers at risk for premature delivery was associated with a reduced risk of cerebral palsy in their infants. Now, NINDS is collaborating with the National Institute of Child Health and Human Development on a prospective clinical trial designed to validate this finding. In another study published in 1996, NINDS-funded researchers linked low levels of the hormone thyroxin in premature infants to cerebral palsy, suggesting another avenue for preventing this disabling illness.

Future Research

Despite the astonishing progress of neuroscience, there is much we do not understand about the brain. Continued support of fundamental neuroscience research will undoubtedly yield important insights. Progress in molecular biology, genetics, imaging, and other areas has accelerated the flow of knowledge between basic and clinical neuroscience. NINDS is taking steps to enhance the Institute's ability to respond to emerging clinical research opportunities. While relying primarily on investigator-initiated ideas and peer review to ensure the best quality science, the Institute uses other important tools for stimulating research. In FY 1996 NINDS solicited new research proposals from extramural investigators in the genetics of Parkinson's disease, mechanisms of cell death and injury in neurodegenerative disorders, Batten disease, immune system mediated diseases, central nervous system injury, and the effect of HIV in the brain. NINDS additionally organizes and funds workshops either directly, as in the case of recent workshops on Parkinson's disease and spinal cord injury, or through grants to investigators or organizations. The Institute will continue to take appropriate active steps to stimulate submission of research ideas in areas identified as high priority and to participate in the NIH special emphasis areas: Biology of Brain Disorders, Preventive Strategies, Therapeutics/Drug Development, and Genetics of Medicine.