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changing during the earliest stages of Alzheimer's disease and relating these findings to ongoing genetic, metabolic, and cellular studies.
The National Institute on Aging research efforts emphasize diagnosis, developing treatment and management strategies, and educating the lay and professional audience with regard to the disease.
I understand that a relatively new discovery in the field of Multiple Sclerosis (MS) is that the disease results in the failure of the blood/brain barrier.
Please discuss these findings. What implications does it have for additional MS research?
Answer. Magnetic resonance imaging (MRI) studies of multiple sclerosis (MS) patients provide evidence that the blood/brain barrier is disturbed in MS. During the scans, a contrast agent used to enhance the images was able to cross the blood/brain barrier and highlight lesions in the brain. At this point, we don't know if the breakdown in the barrier is a primary effect or even a causative factor in MS or whether it is secondary to some other process. The same studies demonstrate that the disease can be progressing even if, outwardly, the patient's symptoms appear stable. These findings have vital implications for MS research. Scientists now have a tool, MRI, to monitor both the disease process and the effects of treatments.
Question. While we have 40 percent fewer stroke cases than we did 10 years ago, we still have 500,000 cases a year and more than 2 million people are living with the disabilities caused by stroke.
Please tell the Committee about the progress made in the field of stroke research.
Answer. Over the past year, NINDS-supported clinical trials have demonstrated the efficacy of two strategies to prevent stroke. The first trial showed that treatment with either aspirin or warfarin for patients with a specific heart condition (atrial fibrillation) greatly reduced the risk of stroke. Most recently, we have found that a surgical procedure on the large arteries in the neck, carotid endarterectomy, can prevent stroke in many patients who have severe blockage of the carotid artery and have already · shown warning signs of stroke. We are continuing to study this procedure in patients with less severe blockage and patients who are asymptomatic.
Stroke research shows that, although the major brain damage occurs within the first few hours of stroke, injury to certain cell groups continues to progress for as long as 2 days. Several causes have been found, including the entry of toxic levels of calcium and other molecules into the nerve cell and an abnormal release of neurotransmitters. We are pursuing clinical studies of several promising therapeutic agents. A major research priority for the
next decade lies in further identifying and learning how to prevent the cellular and molecular processes of ischemic nerve cell injury and death.
The importance of identifying and characterizing specific risk factors for stroke continues. An ongoing study has related ethnic differences in risk factors to differences in stroke type and outcome.
GRANT COST CONTROL
Question. This year NINDS has, for the first time, a $750,000 cap on program project grants.
Are you satisfied that the institute can continue an effective research program with the cap in place?
Answer. The NINDS established the $750,000 direct cost cap on new and competing centers and program projects in FY 1990. NINDS center and program projects are strong overall and we continue to support excellent research. The assumption can be made that without a cap, undertaken in part as a cost control measure, productivity of the centers and program projects would be higher due to greater breadth and depth of research.
Question. Dr. Goldstein, last year when additional funds were needed for an important clinical trial for Gaucher's Disease the Senate Appropriations Committee agreed to redirecting funds from a clinical trial in Multiple Sclerosis but instructed you to direct an additional $1 million towards MS research in this fiscal year. Could you please tell us what you have done to date to meet the Senate's direction and where you stand now?
Answer. The multiple sclerosis studies that were delayed were funded in FY 1991. We have a number of competitive and meritorious applications for multiple sclerosis research, and expect the continued receipt of good applications that will compete well within the payline. Additional projects, totaling in excess of $1 million, will be funded in FY 1991.
Question. Last year the Senate indicated that they were interested in NINDS directing more MS research in the area of genetics. What has been done to achieve this aim?
Answer. The NINDS supports and conducts a vigorous research agenda to understand the cause of multiple sclerosis, including genetic factors. More women than men develop MS, and relatives of MS patients are more likely to develop MS than individuals from the general population. Persons with certain genetically determined histocompatibility antigens also have a higher risk of developing
Thus, the accumulating data implicate a genetic contribution in susceptibility to the development of MS, but we still do not know the scope and magnitude of that factor. Ongoing research on refining, sequencing, and cloning of T cell receptors should help to pinpoint a particular subclass of cells causing or perpetuating the disease. Research on the genetic basis of multiple sclerosis will
also benefit from the cloning of the human myelin basic protein gene.
Question. We are in the second year of the Decade of the Brain. What have you done to accomplish the goals in MS research to date, and what do you plan for the next few years?
Answer. The recent finding that multiple sclerosis (MS) can progressively attack the nervous system even in the absence of clinical symptoms, sheds a new light on the disease process and has important implications for treatment and future research. We will follow up on this discovery with continued intramural studies and new extramural studies using magnetic resonance imaging (MRI), the technique that made this finding possible.
A central question in MS concerns myelin, the insulating covering of the brain and spinal cord that is damaged by the disease. The possible roles of viral, genetic, and immune system factors in the disease process are active areas of study. There appear to be specific, but currently unidentified, cellular and subcellular targets of immune attack on the brain and spinal cord. Once these targets are defined, new methods for halting or reversing and repairing the destruction of myelin that results in the symptoms of MS may be developed.
QUESTION SUBMITTTED BY SENATOR ARLEN SPECTER
Question. Dr. Goldstein, are funds included in the President's FY 1992 budget to expand the Gaucher's Disease research effort? If not, how much would it cost to fully implement the trials necessary to complete the minimum dosage studies and the study of Type III treatment?
Answer. We plan to start enrolling patients in April 1991 for a study to determine the minimum dose of enzyme necessary to yield a therapeutic response in Type I Gaucher's disease. In addition, NINDS scientists are in the final phases of developing the protocol to study the maintenance dose needed to keep Type I Gaucher' S patients healthy after they have been treated with enzyme replacement therapy. The FY 1992 President's Budget includes funds to continue the present work on the Type I studies, but not to conduct the full-scale trials. The additional costs to complete the Type I studies, over a three year period, are $200,000 in FY 1991; $1,340,000 in FY 1992; and $645,000 in FY 1993.
At the time the FY 1992 budget was developed, the main priority in Gaucher's disease research was expansion of the Type I studies. At this point, it is clear that planning for the Type III study is sufficiently advanced that we can move ahead this year to expedite the conduct of the trial, probably by July. Initial investigations needed to develop a human study protocol for Type III are under way. If a protocol is scientifically approved, NINDS will initiate a pilot investigation this year by transferring funds from other research areas ($565,000). The costs for this trial, over a 4 year period, are an estimated $5,535,000. Funds for the Type III trial, $1,680,000, were not included in the President's FY 1992 budget.
QUESTIONS SUBMITTTED BY SENATOR MARK O. HATFIELD
SLEEP DISORDERS AND NARCOLEPSY
Question. Dr. Goldstein, would you summarize for the Subcommittee research being supported by the NINDS research on sleep disorders such as narcolepsy?
Answer. NINDS-supported sleep research includes investigation of how the brain controls the normal sleep-wake cycle and what occurs in disorders of this cycle, such as narcolepsy. A clinical research center supported by NINDS is conducting collaborative basic science and clinical research exploring molecular genetic, immunologic, and neurophysiologic hypotheses for the pathogenesis of sleep disorders. Other clinical investigators are developing improved drug therapy for narcolepsy, studying the mechanisms for "rebound insomnia" following discontinuation of sleep-promoting medications, and evaluating techniques to improve the sleep patterns of shift workers with rotating day and night schedules.
Linkage markers for the autosomal recessive gene responsible for canine narcolepsy have been identified and researchers are working to isolate and sequence the gene. When this is accomplished, the abnormal gene product can be identified and strategies developed to counter the activity of the abnormal gene product. This research with dogs should have important implications for human narcolepsy.
Question. Dr. Goldstein, it is my understanding that years ago many believed that because narcolepsy and epilepsy patients displayed similar symptoms, that a link existed between the two disorders. What is the present understanding today?
Answer. Years ago a number of neurological disorders, such as tics, muscle jerks, and narcolepsy were misclassified as epilepsy. It is fairly common for two disorders to have similar symptoms but entirely different causes, prognoses, and treatments. Narcolepsy and epilepsy are similar in that they are both episodic, or "paroxysmal" disorders of the brain, and in the case of most epilepsy and all narcolepsy, there is little anatomical change in the brain that can explain the disorder. Electrophysiologically and behaviorally there is overlap between epilepsy and sleep disorders, in that seizures can affect sleep, and sleep has a strong impact on the occurrence of seizures. However, testing with modern electrophysiological techniques has shown that the characteristic brain electrical features of narcolepsy and epilepsy are quite distinct.
Question. Is it still prudent for research on narcolepsy to be conducted through the epilepsy branch or should a separate branch on sleep be established?
Answer. The Institute provides research support for a large number of neurological disorders. Each scientific division or branch of the NINDS is assigned responsibility for a variety of disorders not necessarily reflected in the name of that unit. Epilepsy Branch presently has responsibility for the support of essentially all clinical and basic electrophysiological research related to a variety of paroxysmal or episodic disorders such as epilepsy, myoclonus, narcolepsy, and circadian rhythms. Because of similarities in the technical expertise needed to diagnose and manage these disorders, it is more efficient for the research support to be within the same unit. Creation of separate branches for sleep and other neurological disorders would fragment the research effort, and require extensive duplication of scarce scientific resources.