CNS: Special Report: Parkinson's Disease

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SPECIAL REPORT: PARKINSON'S DISEASE

First described in 1817 by James Parkinson, a London physician, Parkinson's disease affects brain centers involved in the control and regulation of movement. Due to disordered control of movement, rigidity of the muscles develops, accompanied by uncontrollable tremor of the extremities, stooped posture, loss of facial expression, and difficulty in walking, talking, writing or any action requiring a high degree of muscular coordination.

Parkinson's disease is one of the most severely crippling chronic disorders of the nervous system. Estimates of prevalence range from one case per 1,000 to one case per 200 population. The disease most frequently attacks people in their 50's and 60's. Parkinson's disease is rarely a primary cause of death, but often weakens the victim so that he falls prey to other diseases. The National Institutes of Health (NIH) has had a long-standing responsibility for research and research support in parkinsonism, dating from the establishment of the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) in 1950.

Treatment

Research Success Story
Advances in the treatment of parkinsonism have been one of the major neurological research success stories of the decade. For the better part of a century, patients were treated with extracts from the belladonna plant, and, after World War II, a variety of synthetic belladonna-like drugs. These drugs were of some help, but none was truly effective. Then a period of real progress occurred in the 1950's when scientists began experimenting with tranquilizers as a means of controlling high blood pressure. This research produced a large amount of new information on the action of chemical neurotransmitters-substances that transfer information between nerve cells. Contributions came from a number of countries, but some of the most crucial basic research was done at the National Institutes of Health. It was shown that reserpine, a tranquilizing drug, produces symptoms similar to those of parkinsonism when given in large doses. In studying the biochemical effects underlying the symptoms, scientists found that reserpine reduces high concentrations of the neurotransmitter chemical, dopamine, in parts of the brain responsible for motor control. A key finding making these studies relevant to parkinsonism was reported in 1960, when scientists at the University of Vienna found a striking shortage of dopamine in the brains of parkinsonian patients at autopsy. This clearly pointed to the possibility of replacement therapy, and led to immediate efforts to treat Parkinson's disease with dopamine.

The Blood-Brain Barrier
Early attempts to replace dopamine directly (intravenously) were unsuccessful. It would not cross the blood-brain barrier-a protective biochemical mechanism which selectively screens substances passing from the blood into the central nervous system. Then, scientists found that dopamine's metabolic precursor-the preceding link in the chain of chemical reactions leading to its production-would cross the barriers. The precursor, levodopa or L-DOPA, at first was not given in large enough dosage, for a long enough time, or by the best route to build up an effective and stable blood level.

It was subsequently found that by starting on small oral doses and increasing the rate very slowly the majority of patients could tolerate effective amounts of levodopa. After extensive trials in many medical centers, the drug was approved for prescription sale in June 1970.

Side-Effects
The new therapy was not without problems, however. Chief of these were side-effects caused by the extremely large doses necessary to control parkinsonian symptoms. Levodopa is broken down very rapidly in the body, and large doses are necessary to achieve the saturation required for penetration into the brain. In some cases, side-effects were so severe that the drug had to be discontinued. Later, a way was found to reduce the high dose levels-and certain side-effects-by giving levodopa with a decarboxylase inhibitor, a substance which slows its peripheral metabolic breakdown, permitting a reduction in dosage level of approximately 80 percent. And, since use of a decarboxylase inhibitor tended to decrease levodopa-induced nausea and vomiting, more patients were able to tolerate therapy. After extensive trials, a pill combining levodopa and such an inhibitor, alpha methyldopa hydrazine or carbidopa, was approved for prescription sale, and this stands as the most effective anti-parkinsonian treatment currently available. The majority of patients are benefitted in some degree: some moderately, some with striking relief from their symptoms.

However, despite this exciting progress in alleviation of symptoms, the disease progresses, and many patients continue to have severe problems even with the best efforts of their physicians. For example, one of the most serious difficulties facing parkinsonian patients today is abrupt fluctuation from near immobility or involuntary movement to states of normal function. These changes, termed "on-off" reactions, appear to correlate with cumulative, high-dose administration of levodopa. Thus, the obvious need is for, an increasingly intense research effort, so that the fundamental causes of parkinsonism can be discovered, the disease process revealed in molecular detail, and an optimal means of halting progression found.

The Research Program
A major component of the NINCDS program in parkinsonism are studies conducted by the lnstitute's Intramural Research Program in laboratories and clinics at the Bethesda, Maryland campus and on the island of Guam. This program has made very large contributions to the progress described above, and continues to be one of the Nation's chief producers of new knowledge in both basic and clinical research relating to parkinsonism and other extrapyramidal disorders. The NINCDS effort in parkinsonism also includes grant support for interdisciplinary research groups at Mt. Sinai School of Medicine and Cornell University Medical College in New York, and the University of Colorado School of Medicine in Denver, as well as 24 smaller, more circumscribed research projects. In general, researchers are determining which nerve cells and areas of the brain use specific transmitter molecules. Increasingly, there is interest in the study of the peptide transmitters which may be involved in the derangement seen in Parkinson's disease. Work is actively proceeding in several laboratories on the separate categories and distribution of dopamine receptors and on the chemistry of neurotransmitters.

Dopamine Agonist
At NINCDS, scientists are exploring new therapeutic approaches to Parkinson's disease using substances called dopamine receptor agonists. These substances mimic dopamine in that they have a direct effect on receptors for this neurotransmitter. Unlike levodopa, however, they do not depend on enzymatic conversion of a precursor. Thus, dopamine agonists may induce more consistent therapeutic effects, and could continue to operate even if the enzymatic machinery needed to convert levodopa to dopamine is destroyed. And, if an agonist were relatively specific-that is, acting primarily on those receptors defective in parkinsonism-then side effects linked to the more generalized actions of dopamine might possibly be avoided.

NINCDS scientists have reported a statistically significant response in double-blind studies with the agonist bromocriptine. Adverse reactions were dose dependent, reversible, and qualitatively similar to those encountered with levodopa. In one series of patients, many were able to stop levodopa while taking bromocriptine. In another, the drug was added to otherwise optimum therapy, including levodopa. The improvement was measured at about 10 percent in patients with minor disabilities, and at about 20 percent in those with more severe diseases. During the past four years, NINCDS scientists have administered bromocriptine (with or without levodopa) to over 100 research patients. The agonist appears to have a therapeutic profile similar to levodopa, but with evidence of more prolonged action. Although completely successful management of "on-off" reactions has yet to be realized, concomitant administration of bromocriptine with lower doses of levodopa has helped to ameliorate the condition in many patients. A major issue yet to be resolved, however, is whether the efficacy of bromocriptine can be sustained during the long-term therapy without inducing "on-off" or other late adverse reactions. To help answer this question, Intramural scientists are doing careful follow-ups of patients with no previous history of levodopa therapy, who are now taking bromocriptine alone.

Blocking Agents
Paralleling work with bromocriptine and other dopamine agonists are related studies of enzymes which block substances known to destroy dopamine in the brain. Preliminary studies involving use of one such drug, deprenyl, have prolonged the therapeutic effects of levodopa, alleviating mild "on-off" symptoms. Thus, NINCDS scientists are approaching the problem of dopamine depletion from both ends-by finding ways to mimic dopamine or by blocking substances that destroy it.

A rare form of parkinsonism, parkinsonism-dementia, or PD, occurs among the Chamorro people of Guam and the other Mariana Islands at a far greater rate than that of parkinsonism elsewhere in the world. It accounts for 10 percent of adult Chamorro deaths, and is rapidly progressive, leading to death in four to five years. In an attempt to learn why PD is so devastating within this small isolated population, the NINCDS Intramural Research Program operates a permanent clinical research center on Guam. The search has focused on discovering possible genetic or familiar factors, and also on uncovering any possible viral or toxic metal causes. Treatment of these patients with levodopa-carbidopa has been highly successful in alleviating parkinsonian symptoms, although the dementia of PD has not been alleviated.

The scientists expect in the near future to have enough experience to determine whether the drugs alter the natural history of this form of parkinsonism, or produce any changes in morbidity and mortality patterns. Research patients on Guam form an important resource population for basic studies by NIH scientists. The Guam Research Center also serves as the setting for cooperative studies involving researchers from universities and other institutions. In studies both in Bethesda and on Guam, new techniques for measuring the uptake anti activity of neurotransmitters are now being developed. Recently, for example. Oxygen" has buen used instead of radioactive labeling to profile the activity of dopamine and other substances in the human central nervous system. At the same time, computerized techniques are helping to define with greater specificity (he degree of movement disorders in parkinsonian patients. These and other technological advances are greatly helping Intramural scientists in there search for improved therapies, as well as for a better understanding of the pathology of Parkinson's disease.

Mt. Sinai
Mount Sinai School of Medicine in New York City is the site of the largest interdisciplinary research team supported by a grant from the Institute. This group, now in its 14th year, has made major contributions to drug therapy in parkinsonism, and also has served as a leading training center for young scientists interested in this field. During this time, it has operated a clinical center for Parkinson patients, and has conducted hundreds of basic studies in virtually all areas relevant to parkinsonism, including neurochemistry and pharmacology, neurophysiology, ultrastructure and histochemistry, nerve regeneration, and neurovirology.

At present, clinical studies include a long-term effort to determine the effect of levodopa on life expectancy, studies of several untried drugs on disorders different from but similar to parkinsonism, and studies of the "on-off" effect. The investigators in this group have reported an improvement in control of parkinsonian symptoms by combining levodopa with bromocriptine. Studies aimed at alleviating the "on-off" effect have shown that pilocarpine may prevent L-DOPA induced dyskinesia. Also in progress are studies aimed at measuring intellectual deterioration in parkinsonism, and at determining whether levodopa affects the process. In a report published last year, the Center noted a reduced ability in patients to form concepts, and no apparent benefit from the drug in concept formation. However, the scientists did find an improvement in "vigilance" with levodopa.

Other clinical studies at the Center relate to eye movements in parkinsonism as a possible diagnostic aid and means of evaluating the disease state and therapy; the question of whether the dopamine deficiency of parkinsonism also exists in the retina; and studies of the effect of levodopa on carbohydrate metabolism.

The Center has a registry of over 1,500 parkinsonian patients who are followed on a regular basis. The data collected is extensively used for evaluation of the progress of the disease, prognosis, treatment regimens, and education of scientists and clinicians.

The Center has a bank of brains removed at autopsy, and is continuously adding to it. The brains received are from patients who have been thoroughly studied clinically, and samples of tissue are made available to researchers. This is an unusually valuable research resource.

Several examples of the basic research projects at the Center are studies of two newly discovered proteins in nerve cells which may be part of the mechanism of transmitter release; and a long-range study of the exact neuronal morphology, synaptology, and anatomy of the basal ganglia-the brain area most affected in Parkinson's disease.

Cornell
A group at Cornell University Medical College is credited with the original development of levodopa therapy, and is continuing an extensive biochemical and genetic exploration of parkinsonism. First interested in manganese poisoning, whose symptoms are similar to those of parkinsonism, the Cornell scientists are continuing studies of the role of manganese in neurotransmission. By feeding manganese to newborn mice, they have found that cerebral dopamine levels correspond with cerebral manganese. They feel that this provides strong evidence that trace quantities of the metal participate in the development and normal functioning of the dopamine neurochemical system.

Also being conducted by this group are studies of a number of novel antiparkinsonian drugs. One of particular interest is N-propyl norapomorphine, or NPA. An analogue, or close relative of the drug, tried earlier had caused azotemia (urea in the blood) and had to be abandoned. NPA, however, completely circumvents this problem, and appears to have other advantages over prolonged levodopa administration, particularly in that it reduces involuntary movements and the "on-off" phenomenon mentioned earlier. Combined with small doses of levodopa in the form of Sinemet, NPA has been found to be superior to other treatments in that it offers maximum antiparkinsonian effects, maximal diurnal stability of symptoms, and minimal dyskinesia (involuntary movements).

An interesting drug development reported by the Cornell workers during the year concerns diphenylhydantoin (DPH), an anticonvulsant drug widely used in medical practice, and of considerable current interest in clinical research. Whereas it has reportedly improved the symptoms of otherwise untreated Parkinson patients, it was found to block the therapeutic effects of levodopa, both in Parkinson patients and in patients with manganese poisoning. Thinking its use might throw light on the puzzling fact that symptoms 'of Parkinson's disease and Huntington's chorea are affected in opposite directions by some tranquilizers and levodopa, the scientists tried DPH in Huntington's chorea, and found that the patients were made worse.

In a study of long-term experience with levodopa, the Cornell scientists have followed one group of 67 patients very closely for up to 8 years. They have found that 10 percent of the patients continue to improve after the first year of treatment; that 60 percent retain initial improvement for 2 to 7 years, and that in 30 percent, some loss of therapeutic effect or emergence of limiting side-effects becomes evident after the first year.

University of Colorado School of Medicine
At the University of Colorado School of Medicine, a broad clinical and laboratory investigation of levodopa and catecholamine metabolism is in progress. A large group of patients is being studied over a three year period. In these studies the pharmacodynamics of therapeutic agents and their effects on motor functions, as well as psychological and behavioral manifestations are evaluated. Levels of metabolites are being monitored in sequential urine samples, and correlated with therapeutic and side-effects, including psychiatric status. Clinical studies in human patients are supplemented with research in primates. The biochemical, enzymatic and electrophysiological events in response to administration of various anti-parkinsonian drugs are monitored. From these and the human studies it appears that the extrapyramidal side-effects associated with L-DOPA therapy may in some way be related to the metabolism of the drug. This center has a strong psychiatric interest and the role of neurotransmitters in schizophrenia is being studied along with their role in organic brain disease. In untreated Parkinson patients, for example, low urinary dopamine excretion correlates with schizophrenic symptoms as well as with Parkinson symptoms. Just as studies in blood pressure lowering agents led to the most effective antiparkinsonism drug yet found, studies of neurotransmitters in parkinsonism could lead to new ways of treating one of the most baffling of the mental disorders.

Other Research Efforts
A group at New York University has used a monkey model of Parkinson's disease to screen potential therapeutic agents and provide for biochemical and histochemical analyses of the nervous system. Therapeutic trials of dopamine agonists in patients with Parkinson's disease are continuing and expanding. They have been particularly fruitful in advancing our understanding of drug induced involuntary movements. Knowledge gained from these animal studies is applied in the study of parkinsonian patients where the therapeutic effect of drugs and the side effects of these treatments can be evaluated.

Unsolved Problems

"On-Off " Reactions
Management of "on-off" reactions continues to be an overriding problem in parkinsonian therapy. As noted previously, use of bromocriptine in combination with levodopa had often resulted in some improvement of these phenomena. Other alternatives include temporary withdrawal from levodopa or maintenance of total daily intake through administration of smaller, more frequent doses. In an attempt to delay "on-off" reactions, many scientists are now advocating that patients use less potent antiparkinsonian drugs to alleviate early symptoms, while reserving levodopa for later, more severe stages. Of course, therapeutic regimens should be determined on an individual basis to fit each patient's unique needs.

Problems With Animal Models
Another recurring difficulty is that limited correlation may exist between animal and human toxicity. In one study encouraging results were obtained using the dopamine agonist lergotrile. Unfortunately subsequent Intramural trials produced evidence of liver dysfunction in patients, in spite of negative liver toxicity tests in animals. Because of this research, it is doubtful that lergotrile will ever be marketed.

In all pharmacological approaches to Parkinson's disease, human toxicity will continue to be a primary concern. Thus, ways must be found to improve the therapeutic index of drugs; that is, the ratio of wanted to unwanted effects.

Outlook

Although great advances have been made in treatment of symptoms, the causes and methods of prevention and cure of Parkinson's disease remain essentially unknown. However, research is steadily progressing, and should produce answers to these most critical questions. The gains made in the past ten years have justified an optimistic belief among scientists, physicians, and patients that control of this disabling disease can be achieved.