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Twenty years ago, striatal cholinergic neurons were central figures in models of basal ganglia function. But since then, they have receded in importance. Recent studies are likely to lead to their re-emergence in our thinking. Cholinergic interneurons have been implicated as key players in the induction of synaptic plasticity and motor learning, as well as in motor dysfunction. In Parkinson's disease and dystonia, diminished striatal dopaminergic signalling leads to increased release of acetylcholine by interneurons, distorting network function and inducing structural changes that undoubtedly contribute to the symptoms. By contrast, in Huntington's disease and progressive supranuclear palsy, there is a fall in striatal cholinergic markers. This review gives an overview of these recent experimental and clinical studies, placing them within the context of the pathogenesis of movement disorders.

The clinical efficacy and safety of bilateral pallidal deep-brain stimulation for severe primary dystonia in a series of 40 patients who participated in a prospective trial of neurostimulation is reported. In this randomized comparison of the effects of neurostimulation and sham stimulation it was found that bilateral high-frequency stimulation of the internal globus pallidus is efficacious in the reduction of movement impairment and disability in patients with primary generalized or segmental dystonia.

It is known that Parkinson's disease may exist for years before the destruction of brain cells in the substantia nigra reaches the point where symptoms become apparent. The incentive for identifying patients in this presymptomatic stage has become much greater in recent years, however. Studies of the drug selegiline (L-deprenyl) indicate that it may slow the progression of Parkinson's disease. Therefore, early, presymptomatic diagnosis of Parkinson's disease may provide the opportunity to greatly extend the useful life of the patient. One method which might prove useful in the early diagnosis of Parkinson's disease is the electrophysiological measurement of movement abnormalities. Long before the tremor and bradykinesia (slow movement) characteristics of Parkinson's disease become apparent to the observer, it may be possible to measure subtle changes. Potential diagnostic electrophysiological tests were evaluated in 10 patients with mild Parkinson's disease of less than three years' duration, on the presumption that tests which clearly indicated the deficit in these patients might also indicate abnormalities in patients who have not yet developed symptoms. Healthy controls matched for age and sex were compared with the Parkinson's disease patients. The results demonstrated that the electrophysiological measurements made on patients as they performed movement tasks were capable of demonstrating subtle defects. The tests of bradykinesia proved to be the most sensitive, that is, they detected abnormalities in the greatest proportion of affected subjects. Tests for the presence of tremor, however, proved to be more specific, meaning that while tremor was less sensitive for identifying affected individuals, those who were found to be abnormal on the tremor test were more likely to actually have Parkinson's disease. (Consumer Summary produced by Reliance Medical Information, Inc.)

The symptoms of Parkinson's disease result from the progressive loss of neurons in a region of the brain called the substantia nigra. Recent evidence suggests that it may be possible to slow the loss of neurons in this area, and as a result there has been increased interest in the identification of 'disease markers' which would indicate the presence of Parkinson's disease before the actual onset of symptoms. However, an ideal marker, which quickly and inexpensively indicates the presence of disease in all cases, may not be found. It may be more practical to use a battery of tests, no one of which is entirely satisfactory as a marker but which, taken together, provide a good indication of the presence of presymptomatic Parkinson's disease. Complex motor plans may play a useful role in the development of such a battery of tests. An example of such a motor plan is the signing of one's signature. The hand movements involved in a signature are complex, but the activity, once learned, is performed fairly automatically. A person's signature might, therefore, provide insight into declining function of the affected brain regions before the typical symptoms of Parkinson's disease become evident. Since many people store cancelled checks, an archive of handwriting samples covering many years is often readily available. A pilot study has indicated that handwriting samples do, indeed, chronicle the development of Parkinson's disease. Similarly, the analysis of speech samples has been shown to indicate the presence of abnormalities in complex learned movement in patients in the early stages of symptomatic Parkinson's disease. These tests are easy to perform and may provide useful information that supplements clinical and laboratory tests. (Consumer Summary produced by Reliance Medical Information, Inc.)

Parkinson's disease is a neurological disease which involves the selective destruction of some brain cells preferentially over others. The brain is able to compensate for considerable damage, and the available evidence suggests that the symptoms of Parkinson's disease appear only after the destruction of neurons (nerve cells) surpasses the brain's ability for compensation. Parkinson's disease largely results from the destruction of special brain cells within a region called the substantia nigra; by some estimates as many as 90 percent of these neurons may be destroyed before the brain can no longer compensate and disease symptoms appear. Therefore, the disease is present, and destroying neurons in the substantia nigra, long before it is recognized by the patient and physician. Evidence is accumulating that the drug selegiline may significantly slow the progression of Parkinson's disease, and so the initiation of treatment prior to the onset of symptoms might provide important clinical benefit. Just how long is Parkinson's disease present before the symptoms actually appear? Since there is no reliable test for the presence of Parkinson's disease, there is no way of answering with certainty. However, estimates may be made on the basis of neuropathological observations of brain tissue specimens obtained at autopsy. The characteristic pathological observation in Parkinson's disease is the Lewy body, which is a structure visible in the cytoplasm of some brain cells under the microscope. Lewy bodies are also found in cells of the substantia nigra of about 10 percent of people over age 60 who do not have symptoms of Parkinson's disease. If the assumption is made that Lewy bodies represent an early stage in the long progression towards brain cell destruction, then calculations suggest that the delay between the appearance of Lewy bodies and the development of the symptoms of Parkinson's disease must be about 30 years. The cells of the substantia nigra may be examined, of course, only at autopsy, and so other means must be found to diagnose Parkinson's disease in its presymptomatic stages. The search is underway to evaluate many techniques of medical imaging, biochemical analysis, and genetic screening for the diagnosis of presymptomatic Parkinson's disease. (Consumer Summary produced by Reliance Medical Information, Inc.)

Dopa-responsive dystonia (DRD) is a genetic disorder that seems to be a variant of childhood-onset idiopathic torsion dystonia (ITD). It involves diminished muscle tone, abnormal gait and, eventually, signs of parkinsonism in most patients. Dopamine-responsive dystonia does not seem to be linked to the locus on the long arm of chromosome 9, 9q32-34, to which ITD is linked. In addition, DRD seems to have limited penetrance, that is, not all people carrying the autosomal dominant gene are affected by the disorder. As its name implies, DRD is distinguished by the dramatic response to treatment with levodopa. The authors review the characteristics of 66 cases of dopamine-responsive dystonia, including key aspects of its diagnosis. Some clinicians have suggested that one diagnostic feature of DRD is diurnal variation, in which the symptoms worsen as the day progresses. However, in the present series of cases, 23 percent did not show diurnal variation. Forty-seven cases occurred within affected families, and it is important to note that even within a family, some affected members may show diurnal variation while others may not. Laboratory tests reveal evidence of a deficiency in dopamine metabolism. Analysis of cerebrospinal fluid shows a reduction in levels of homovanillic acid. Reduced levels of biopterin are also found in DRD, but it is not certain if this represents a primary defect which contributes to the disease or a secondary consequence of the disease process. Biopterin is a cofactor for tyrosine hydroxylase, a critical enzyme in dopamine metabolism. The excellent response of these patients to levodopa suggests that the dopamine neurons in the substantia nigra may be intact. This is not the case in Parkinson's disease, in which the dopamine reduction results from the disappearance of dopamine neurons. Unlike patients with Parkinson's disease, patients with DRD show normal uptake of fluorodopa on positron emission tomography (PET scan), indicating that there is little or no loss of dopaminergic neurons in this area. The authors suggest that PET scanning may be an ideal method for distinguishing among clinically related syndromes resembling dopamine-responsive dystonia. (Consumer Summary produced by Reliance Medical Information, Inc.)

Catechol is a chemical which serves as the basic backbone for a number of different biochemical substances. Included among these are norepinephrine and dopamine, neurotransmitters (chemical messengers) in the brain which are included in the class of neurotransmitters called catecholamines. It is well known that the motor (movement) symptoms of Parkinson's disease result from the progressive destruction of dopamine-containing neurons, or nerve cells, of the substantia nigra in the brain. It may therefore be possible to monitor the progressive destruction of these neurons by measuring the amounts of metabolic by-products of catechol metabolism in the cerebrospinal fluid. Indeed, it may be possible to identify abnormalities specific to Parkinson's disease in individuals who have not yet progressed to the point at which disease symptoms first become apparent. Some of the metabolic by-products of dopamine metabolism are known to be toxic, and some researchers suspect that these may help to bring about the destruction of neurons in the substantia nigra. Unfortunately, these same metabolic by-products are so highly reactive that they only exist for a short time before being converted to other substances, and are therefore impossible to detect in cerebrospinal fluid. It has proved possible, however, to measure a biochemical compound closely related to these short-lived metabolic by-products. This compound, called 5-S-cysteinyl-dopamine, is present in such small quantities in the cerebrospinal fluid that new analytical techniques must be developed to measure it. However, postmortem measurements made on human brains have shown that this substance appears to be formed at an increased rate in patients with greater loss of dopamine-producing neurons. This was determined by measuring the ratio of 5-S-cysteinyl-dopamine to dopamine or to DOPAC (another dopamine metabolite called 3,4, dihydroxyphenylacetic acid). Scientists hope that it will soon be possible to accurately evaluate the amounts of these substances in the cerebrospinal fluid of living patients. (Consumer Summary produced by Reliance Medical Information, Inc.)

The onset of tremor, rigidity, and slow movement marks the beginning of clinical Parkinson's disease. But these symptoms only show up after many of the cells in the substantia nigra, a region of the brain, have already died. Researchers are not certain how long before the appearance of symptoms the disease actually begins, but some feel the delay may be as long as decades. The diagnosis of Parkinson's disease before the actual onset of symptoms would have important consequences for both the basic understanding of the disease process and its treatment. Evidence is accumulating that the drug selegiline, which is an inhibitor of an enzyme called MAO-B, may slow the progression of Parkinson's disease; if treatment can begin before symptoms are apparent, the progression of the disease may be slowed even more. At present, however, there are no completely reliable indicators of the impending onset of Parkinson's disease symptoms. Scientists are actively searching for disease markers; a 'marker' is some physiological change which may be detected prior to the onset of symptoms and which provides a reliable indicator of the underlying disease process. It is known that changes in dopamine uptake in the basal ganglia in the brain are present prior to the onset of Parkinson's disease symptoms, and chemical alterations in the cerebrospinal fluid can be detected. Patients with impending Parkinson's disease may also have alterations in the sense of smell, and small changes in muscle tone. However, none of these changes are 100 percent indicative of Parkinson's disease. At the same time that disease markers are being investigated, disease risk factors are also being evaluated. A risk factor differs from a marker in that it is not indicative of the actual disease process at work, but rather is some behavior or condition which renders a particular individual more susceptible to a disease than the average person. The identification of risk factors for Parkinson's disease may prove, in the long run, to be particularly important, as risk factors might point the way towards effective prevention. (Consumer Summary produced by Reliance Medical Information, Inc.)