The Dopamine Connection Workshop

The Dopamine Connection Workshop

November 10-11 , 1999

Working Group Presentations and Roundtable

 

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Working Group Presentations

I. Genetics Working Group

Chair: Guy A. Rouleau, M.D., Ph.D. (Dept. of Neurology, Montreal General Hospital, McGill University, Montreal, Quebec, Canada)

Research Directions and Priorities

The group noted 3 general areas to identify the genes: animal models; genetic epidemiology; and biological markers. Then the group made special recommendations directed to advancing research in the area, but not directed to specific research issues.

A. Animal models can be useful for learning more about a disease and for identifying genes predisposing to disease. Animal models can be developed in mice and rats, and possible in other species. Research directions and applications of animal models include the following:

1. Develop methods for phenotype recognition. This is probably more relevant for restless legs syndrome (RLS) and periodic limb movement disorder (PLMD). Developing a new technology might be necessary, and should be encouraged. Mouse, rat, or any other animal model could be used in studies of phenotype recognition.

2. Screen relevant transgenic animals for the phenotypes that resemble RLS or PLMD. Examples include transgenic animals containing knockouts of transferrin gene, or manipulations of dopamine system genes. Screening for phenotypes that might resemble RLS or PLMS might lead to useful findings fairly quickly.

3. Study differences among established inbred strains (such as C57BL or A/J mice). This approach could be used to study recombinant inbred animals for mapping to identify genes that affect traits. Quantitative trait loci should be looked at.

4. Study animals exposed to precipitants of RLS, such as pregnancy, uremia, iron depletion, to see if these phenotypes respond to classical RLS treatments.

B. Genetic epidemiologic studies of sleep disorders in general are needed to identify the genes. Approaches and applications of genetic epidemiology studies are as follows:

1. Do population-based studies. Population-based studies are needed. A population-based study would answer questions about prevalence and age-distribution. Also, if a population-based study shows high disease burden (such as high need for treatment), then pharmaceutical companies might become more interested. Population-based studies would also help confirm or deny suggestions that prevalence is lower in some populations, such as African-Americans.

An approach to population-based studies is to append a sleep component to ongoing large studies, such as studies of Parkinson's disease (PD). This approach is potentially inexpensive, which might allay concerns in the public and in study sections about the high expense of population-based studies.

2. Do family-based studies. Family-based studies would validate diagnostic categories in subgroups. A problem is in defining and distinguishing familial forms and non-familial forms. How can cases with greater genetic component be identified? Note that interpretation of family studies would be difficult without basic epidemiologic information. Also, although large twin-registries exist, no twin studies of RLS have been published. Twin-studies should be inexpensive.

C. Biological markers needed to identify the genes can be developed. Approaches and applications of developing biological markers are as follows:

1. Identify biological markers that would facilitate logical stratification of cases. Markers could be iron, response to therapy, and imaging.

2. Associate studies of biological markers with other entities to define candidate genes and candidate mechanisms. For example, associate studies of biological markers with genetic entities such as spinocerebellar ataxia type 3, and with other entities such as uremia.

D. Special recommendations can be directed to advancing research in the area.

1. Major points (higher priority) include the following.

a. Create special centers for RLS/PLMS and for narcolepsy.

b. Develop a stream in the review process to favor funding of studies for collection of clinical/genetic information and material, once the entire human genome has been sequenced.

c. Convene a conference to define genetic and non-genetic RLS, and to consider exclusion criteria.

d. Increase funding caps on program projects.

e. Apply evolving technologies; for example, prepare chips specific to various problems, such a "sleep chip". (This is for the future.)

2. Other ideas: (lower priority) include the following.

a. Include sleep components in other ongoing studies (already mentioned).

b. Find special populations that have high rate of illness.

c. Study special forms of the disease.

d. Study small populations that had a bottleneck. (If other efforts at finding genes failed, then study smaller population that had a bottleneck in which the genetic complexity has been reduced. This is a strategy of last resort.)

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II. Basic Central/Peripheral Mechanisms Working Group

Chair: Mark Hallett, M.D., NINDS

Research Directions and Priorities

The group summarized general areas for research directions and priorities: anatomy; oscillations; RLS pathophysiology; RLS epidemiology; RLS animal models; PLMD; opiate sensitivity; iron; muscle tone; nerve tissue banks; and the dopamine connection.

A. Anatomy

Dopamine pathways need to be re-explored because previous studies did not necessarily use good methods. Good methods, which use the dopamine transporter to label the pathways, are now available. Both surveys and focal studies should be done. Surveys have trouble being funded, even though they are probably useful. The brain and the spinal cord, especially descending dopamine pathways, should be explored. All pathways into and out of the hypothalamus should explored, because these are important regions for sleep disorders. Particular attention should be paid to dopamine pathways, but opiate and orexin pathways should also be considered. Neuroanatomic studies should be functional, not merely tract-tracing. Receptors need to be considered.

B. Oscillations

Circadian rhythms are clearly relevant, particularly with the 24-hour periodicity of dopamine. PET scans and lumbar puncture are methods that could be used. Such studies are difficult and costly to do because they take place during the middle of the night, but would be particularly valuable. Iron and opiates should be studied as circadian markers.

Ultradian rhythms and sleep-wake rhythms are part of understanding oscillations. The anatomy and functional pathways of ultradian rhythms and sleep-wake rhythms should be studied.

A 20-second oscillation occurs in the firing rates in dopamine-sensitive neurons in basal ganglia. With increased dopamine concentration, these oscillations increase in frequency. This might have something in common with 20-second periodicity in PLMD. The 20-second periodicity is also noted in isolated spinal cord, so an oscillator must be present in the spinal cord. It would be valuable to find the 20-second oscillator.

Oscillations in sensory pathways such as sensory feelings experienced by RLS patients, have not yet been examined.

For all oscillations, basic mechanisms (cellular events) should be studied.

C. RLS pathophysiology

RLS's major feature is the sensory symptoms. These should be better characterized, especially in relation to their circadian modulation. There is probably an additional oscillation of these sensory symptoms on the 20-second oscillation thought of in RLS. It appears that limb movement eases symptoms, which then worsen before the next movement. This suggests 2 different oscillations for the sensory symptoms: gross circadian oscillation, plus a superimposed 20-second oscillation related to movement. The following questions should be answered: What is the effect of movement on sensory symptoms? Is oscillation of sensory symptoms due to movement (involuntary, voluntary)? What is the relationship of akathisia to RLS sensory symptoms? Where is the locus of the urge to move? Is it coming through the spinal cord?

D. RLS epidemiology

More comprehensive studies of RLS epidemiology are needed. The relationship between RLS and attention deficit hyperactivity disorder should be studied. The responsiveness of RLS to opiates and to dopamine agonists should be compared.

E. RLS animal models

Animal models of RLS should be developed. It is hoped that a genetic model RLS could be developed, similar to what has been developed in narcolepsy. Iron deficiency might create an animal model. Finally, a spinal-cord transection model of periodic limb movements (PLMs) could be developed, although this is not necessarily a model of RLS.

F. PLMD

A dissociation clearly exists between RLS and PLMD. Not every patient with RLS has PLMD, and PLMD occurs in many other disorders. This leads to the following questions:

(1) Are PLMs the same in RLS as in other disorders, such as apnea, narcolepsy, uremia, and peripheral neuropathy? Current relevant results suggest that they are. The relationship between these other disorders and PLMs is not clear. Dyskinesias while awake do seem to be slight different compared with PLMs while sleeping, at least in duration of the electromyographic recording, which is longer while awake.

(2) How often do PLMs manifest as symptoms? Patients are clearly symptomatic from RLS. But are patients symptomatic from PLMs? Even if arousals occur during PLMs, it is not clear if PLMs are actually symptomatic. It is important to determine how often PLMs manifest as symptoms, separate from RLS.

(3)Why aren't PLMs completely suppressed during rapid eye movement (REM) sleep?

G. Opiate sensitivity

The relationship between opiate sensitivity and sensory symptoms should be studied. Spinal opiate effects should also be studied. Are subtypes of opiates better than others, and can this help in understanding RLS symptoms?

H. Iron

Studies of iron should include anatomy of iron/dopamine; iron availability; iron transport; MRIs; and role of iron in other dopamine disorders.

I. Muscle tone

Muscle tone is relevant for many movement disorders. A lot more needs to be learned in the following categories: anatomy, physiology, spinal pathways; regulation; spinal pathways; cataplexy, compared with REM sleep; PD; and RLS and, PLMD. Other questions are as follows: Why is tone not suppressed in REM behavior disorder? During REM, how can there be movements occur when a -motor neurons are supposed to be suppressed? What is the possible relevance of muscle tone to sleep apnea? Can REM without atonia in animals (cats, rats) be corrected with same drugs used for REM behavior disorders, such as dopamine agonists?

J. Nerve tissue banks

Nerve tissue banks, which would include brain, spinal cord, peripheral nerve from patients with RLS and narcolepsy, would be extremely valuable. Brain banks already operate at the University of Maryland and at University of Miami. The International RLS Study Group started a brain bank. Issues of ownership need clarification.

K. The dopamine connection

What is the extent to which the dopamine connection is in common among the disorders? So far, the only thing in common is that the patients respond to drugs that act on dopamine. What else is in common: Drugs; time course; receptor agonists; targets; sensitization and desensitization? The role of dopamine should be studied in sleep, wakefulness, and alertness in RLS, PD, and narcolepsy.

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Roundtable discussion

Co-chairs: Jaques Montplaisir, M.D., Ph.D. (Sleep Disorders Center, Sacré-Coeur Hospital, University of Montreal, Quebec, Canada); and Mahlon R. DeLong, M.D. (Dept. of Neurology, Emory University School of Medicine, Atlanta, Georgia)

Dr. Montplaisir commented that research on RLS and PLMD started after PD and narcolepsy, and needs to catch up. RLS and PLMD are also more recent topics in sleep research. For RLS, a consensus conference is needed to review RLS diagnostic criteria and genetic and non-genetic RLS. For narcolepsy, however, the issue is different. The next step is to discover the human gene for narcolepsy.

One approach, Dr. Montplaisir noted, is to create centers to study movement disorders, sleep, and the interaction between them. Collaborations among researchers in different fields need to be emphasized, Dr. Montplaisir added. For example, narcolepsy researchers, who have studied the control of vigilance, can aid researchers in other fields. Developments in some areas, such as PD research, benefit other areas, such as RLS research. Among patients who have the disorders discussed at this workshop, those with PD patients have the most disrupted sleep.

Dr. DeLong commented that neurology has overlooked the importance of sleep and has neglected sleep research for too long. Centers should be developed to study sleep, because such centers bring investigators from different disciplines and different institutions.

The balance of the workshop included discussion of how the NIH could support funding research the issues, and how new therapies could be developed.

A. NIH funding

Participants discussed about basis for funding research in the ideas from the working group presentations. Some participants favored supporting facilities that could be named "Centers for Sleep Neurology". However, other participants were unsure about supporting such centers. They argued that the information base and number of researchers are not yet there to support establishing sleep centers. Instead, RO-1 grant applications should drive the research funding.

Some participants suggested that high-risk, high-reward, exploratory pilot grants (perhaps $100,000 for 1 year) be instituted. The reason is that RO-1 grant applications require extensive preliminary data to be competitive for consideration by study sections. Some participants also noted that it is important to think of smaller-start-up grant applications, such as RO-3 grant applications, as different from RO-1 grant applications. Participants noted that study sections give RO-3 proposals lower priority than RO-1 grant applications. Perhaps separate study sections should review RO-3 grant applications, so as to them more consideration and to avoid their being judged in the same way as RO-1 grant applications. In any event, participants repeatedly raised concerns about the need for funding smaller pilot or start-up applications and the problem of competing with RO-1 grant applications.

Participants agreed with Dr. DeLong in favor of broad opportunity for funding--from centers to RO-1 grant applications to startup grant applications. Interdisciplinary work should be encouraged. For example, defining animal models should involve veterinarians. The observation of narcolepsy in dogs arose when a veterinarian brought a narcoleptic dog to the attention of researchers. Dr. DeLong added that decisions on funding mechanisms should be left to NIH staff and the study sections to sort out.

Dr. McCutchen noted that the group could recommend that caps on research proposals be lifted and that the quality of the proposal determine the amount that is allocated. Dr. McCutchen also discussed simplifying and extending eligibility for applying for career development awards ("Ks"). She offered that the group could support the trend to streamlining requirements for obtaining career-development support and for giving such support even to investigators who have had extensive fellowship experience. Participants did not formally recommend any of these suggestions, but did not raise any objections, either.

B. New therapies

Participants encouraged cooperation with pharmaceutical companies. An request for applications/small business innovation research program (RFA/SBIR) could accomplish this. However, the SBIR program excludes large companies. Dr. McCutchen explained that small companies can get a start with an SBIR grant to do feasibility and pilot studies. With these studies accomplished, the smaller company can interest a larger company with its more extensive resources.

Participants discussed why pharmaceutical companies are not interested in developing therapies for RLS. One participant noted that the companies don't believe that RLS is a occurs frequently, and hence is not subject a real market. Another participant commented that pharmaceutical companies are convinced that there are a large number of RLS patients, but many cases of RLS are undiagnosed. Therefore, pharmaceutical companies would have to spend a huge sum to educate physicians.

A participant from a pharmaceutical company explained that in his company's view, the biggest single obstacle to allocating resources for RLS drug development is the perception that disease burden is insufficient to justify investment. The lack of animal model or the lack of sufficient epidemiologic data is not a large obstacle. RLS is sufficiently prevalent and incident. The single most helpful factor to interest drug companies is to address the issue of disease burden, which was not discussed during the workshop. Disease burden translates into market.