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Parkinson's Disease Research Agenda

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DEPARTMENT OF HEALTH AND HUMAN SERVICES
NATIONAL INSTITUTES OF HEALTH

Parkinson's Disease Research Agenda

Ruth L. Kirschstein, M.D.
Acting Director, NIH

March 2000

Contents:

CONGRESSIONAL REPORT LANGUAGE

This report has been prepared by the National Institutes of Health (NIH) of the Department of Health and Human Services in response to the following requests from Congress.

In its report on the Fiscal Year 2000 budget for the Department of Health and Human Services, the Conference Committee stated:

"NIH is expected to consult closely with the research community, clinicians, patient advocates, and the Congress regarding Parkinson's research and fulfillment of the goals of the Morris K. Udall Parkinson's Research Act. NIH is requested to develop a report to Congress by March 1, 2000 outlining a research agenda for Parkinson's focused research for the next five years, along with professional judgment funding projections. The NIH Director should be prepared to discuss Parkinson's focused research planning and implementation for fiscal year 2000 and fiscal year 2001." (Conference Report No. 106-479, page 607.)

The following report has been prepared by the National Institutes of Health of the Department of Health and Human Services in response to this request.

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EXECUTIVE SUMMARY

A new optimism that Parkinson's disease can be defeated is energizing the research community and patient advocates. Halting the progression of Parkinson's disease, restoring lost function, and even preventing the disease are all realistic goals. This hope is fueled by the accelerating pace of discovery in neuroscience research generally, by advances in understanding what causes Parkinson's disease, and by a wide range of new treatments on the horizon including stem cell transplants, precision surgical repair, chronic brain stimulation, and natural growth factors to name a few. Optimism is tempered by the recognition that we cannot yet cure any major neurodegenerative disorder, and defeating Parkinson's disease requires crossing a major frontier of medicine.

The National Institutes of Health (NIH) conducts a vigorous and expanding program of research focused on Parkinson's disease. At a landmark meeting in November 1999, the directors and staff of the major components of NIH conducting Parkinson's disease research, working together with patient advocates, initiated a planning process to ensure that extraordinary opportunities to move toward a cure are adequately supported and that critical obstacles to progress are addressed. On January 4-6, 2000 a Workshop including intramural, extramural and industry scientists, representatives from several Parkinson's advocacy groups, and ethicists discussed an agenda for Parkinson's disease research, which formed the basis for this document.

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UNDERSTANDING PARKINSON'S DISEASE

Parkinson's disease is a devastating and complex disease that progressively affects the control of movement and also produces a wide range of other problems for patients. The symptoms reflect the gradual loss of nerve cells in particular areas of the brain. Among these, cells that produce the neurotransmitter dopamine die in a small brain area called the substantia nigra. What triggers the death of these nerve cells is unknown.

Using genetics to understand Parkinson's disease: Although most people do not inherit Parkinson's disease, studying the genes responsible for the inherited cases is advancing our understanding of both common and familial Parkinson's disease. Identifying genes that can cause Parkinson's disease is crucial for understanding the disease process, revealing drug targets, improving early diagnosis, and developing animal models that accurately mimic the slow nerve cell death in human Parkinson's disease. Beyond single genes, we must unravel the complex interactions between genetic predisposition and environmental influences that cause most cases of Parkinson's disease.

Epidemiology to determine environmental risk factors for Parkinson's disease: Epidemiological investigations can provide essential clues to what causes Parkinson's disease, to risk factors that predispose people to this disease, and to preclinical characteristics of this disorder. In the short term, case control studies that compare people with and without Parkinson's disease can provide valuable information about environmental risk factors and the interaction of genetic and non-genetic factors. In the long run, a prospective study, which follows people who do not yet have the disease, would help identify the causes of Parkinson's disease and provide other needed epidemiological information. It would be highly efficient in such a study to include other disorders.

Life and death of neurons involved in Parkinson's disease: Parkinson's disease kills only certain types of brain cells. Understanding the normal biology of neurons susceptible to Parkinson's disease is crucial for understanding this selectivity and for developing new therapies that rescue or even replace those cells. Studying how inherited defects in genes for proteins, such as synuclein and parkin, can cause Parkinson's disease is important to understanding the disease. Other important areas for research include the role of mitochondrial impairment, protein aggregation, excitotoxicity, the immune system, and apoptosis pathways in Parkinson's disease.

Neural circuits and systems in Parkinson's disease: While there has been considerable progress in understanding how the normal brain controls movement, there is a great deal we do not yet understand about the brain's movement control systems. Moreover, we do not understand how Parkinson's disease disrupts these systems to produce the major symptoms and other problems associated with this disease. A variety of studies using anatomical, electrophysiological, neurochemical, and imaging methods are needed.

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DEVELOPING NEW TREATMENTS FOR PARKINSON'S DISEASE

Developing therapies to prevent Parkinson's disease, to suppress symptoms, to halt disease progression, and to repair damage are all fundamental goals. Available drugs suppress symptoms early in Parkinson's disease, but progressively fail as more nerve cells die. The emergence of drug-induced dyskinesias and motor fluctuations often limits drug benefits. A wide range of therapeutic approaches are now at various stages of development, including precision surgical ablation, chronic electrical stimulation, cell implantation, and several types of drugs. To achieve therapeutic goals, many separate studies are required, from the first steps in translating basic research advances, animal testing, preliminary safety studies in human patients, and finally large trials to evaluate the effectiveness of a therapy.

Pharmacological approaches: A series of small Phase II clinical trials could help to rapidly identify promising candidate drugs for large-scale clinical trials. Major large randomized controlled clinical trials aimed at preventing the progression of Parkinson's disease can evaluate the efficacy of promising experimental drugs. NIH could also foster studies to evaluate which known treatments for non-motor symptoms are best for people with Parkinson's disease. Delaying or preventing Parkinson's disease is an important goal, but the lack of information about susceptible subpopulations requires very large numbers of people to assess prevention therapies. Prevention trials focusing on people at high risk, such as large families with genetic markers for Parkinson's disease, are likely to be more efficient.

Deep brain stimulation and other surgical approaches: Neurosurgical approaches are becoming increasingly important in the treatment of Parkinson's disease, including precision ablation therapies, deep brain stimulation, and cell transplantation. An emerging field is the direct micro-delivery of neuroactive substances to the brain. A wide range of studies are needed to understand how these interventions affect the brain, to improve the technologies involved, and to evaluate the results of the various approaches in patients.

Cell implantation: Restoration of function is critical for people who have Parkinson's disease, and cell implantation is one promising approach to brain repair. Early results from embryonic tissue transplantation trials present a proof of principle that this strategy is worth pursuing, but also show that, at the present stage of development, these approaches produce insufficient benefit and unexpected complications which preclude their widespread use. Transplantation strategies based on stem cells present enormous potential, but we must better understand the fundamental biology of stem cells before they can safely and effectively be used for therapy of Parkinson's disease.

Gene therapy: In the long run gene therapy offers potential for Parkinson's disease and many other brain disorders. Although holding promise, the development of efficient and safe means to deliver genes to brain cells is needed before gene therapy can be used.

Rehabilitation: Rehabilitation may help to improve the quality of life for individuals with Parkinson's disease, by focusing on problems such as gait and voice disorders, tremors and rigidity, and cognitive decline and depression. As researchers better understand the mechanisms controlling neural plasticity and how to reorganize central nervous system function, new approaches may be developed to enhance motor learning and sensory stimulation.

Outcomes research and evidence based medicine in Parkinson's disease: NIH can work with other appropriate government agencies and private sector organizations to use "evidence based" methods to develop recommendations for treating Parkinson's disease. Given the increased incidence of Parkinson's disease with aging, another goal is to determine the resources needed to treat this disease, which is essential for planning to care for the aging US population.

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CREATING NEW RESEARCH CAPABILITIES

Several resources and tools could be provided to promote research on Parkinson's disease.

Array technologies: Gene array technologies allow simultaneous monitoring of the activity of thousands of genes. Methods are also becoming available to track the protein components of a cell. Researchers studying Parkinson's disease should apply these methods to understand, at the molecular level, the causes and progression of disease and the responses of neurons to treatment.

Models of Parkinson's disease: Non-human models of Parkinson's disease are essential for understanding the causes and progression of nerve cell death and for efficiently developing new therapies. Present models do not adequately mimic the cause or clinical course of human Parkinson's disease, the gradual cell loss, or the destruction of non-dopamine cells. A range of models from in vitro molecular and cellular models through simple organisms like fruitflies and nematode worms, to transgenic mice and primates is needed.

Biomarkers: Better biomarkers, that is, reliable indicators of risk, disease state, and disease severity, would accelerate research on the causes and progression of Parkinson's disease and the development and testing of therapies. To be most useful, biomarkers must not only be specific and sensitive, but also sufficiently risk-free and simple that they may be used routinely.

Neuroimaging: At present the most developed biomarkers for Parkinson's disease rely upon neuroimaging. Beyond biomarkers, there is a wide spectrum of imaging methods that may yield insights into the causes and treatment of this disease.

High throughput drug screening for Parkinson's disease: Recent spectacular advances in robotic and synthetic chemistry, combined with increased understanding of molecular targets of drug therapy, make it possible to rapidly screen large numbers of potential drugs. NIH should encourage the development of molecular and, especially, cellular assays for screening drugs for Parkinson's disease and explore ways to make the technology for high throughput screening more widely available.

Brain banks and other repositories: The systematic collection, maintenance, and distribution of biological and clinical materials would contribute substantially to advancing basic and clinical research on Parkinson's disease.

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ENHANCING THE RESEARCH PROCESS

Ethics: NIH is committed to being a leader not only in basic and clinical research on Parkinson's disease, but also in the ethical dimensions of the research it funds. Ethical issues arise both from research and, more broadly, from care of patients with this disease.

Innovative funding mechanisms: Advancing research against Parkinson's disease will require innovative funding mechanisms such as providing seed money to draw new investigators into the field, supplements to rapidly enhance the research of current investigators, and accelerated review for some types of proposals.

Public-private partnerships: Private organizations play a critical role in Parkinson's disease research that complements the NIH mission. NIH is committed to coordinating efforts in partnership with private organizations. Private organizations play particularly important roles in recruiting patients for genetic, epidemiological, and clinical studies; in funding, especially for pilot projects and new investigators; in interactions with industry; in disseminating reliable information; and in planning the research agenda.

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CONCLUSION

This document highlights the exceptional opportunities for making progress on the causes and treatment of Parkinson's disease. The professional judgment estimate for these research opportunities would call for approximately $70 million of new spending for the first year. The agenda would include additional increases in subsequent years rising to $287 million in the fifth year, as detailed in the appendix to this document. It must be noted that this estimate is based on our assessment of scientific opportunities over the next five years. We have not taken into account economic constraints and the need to address other competing public priorities and responsibilities of NIH or the rest of the Federal government.

The task of finding a cure for Parkinson's disease is all the more difficult because we cannot yet cure any major neurodegenerative disorder. Many of the critical research needs highlighted by the Workshop, if solved for Parkinson's disease, would immediately apply to other disorders. For others there is substantial, though not complete, overlap. While this document is properly focused on Parkinson's disease research, the relevance of this research agenda for other diseases should be noted. Parkinson's disease research can lead the way in the fight against all forms of neurodegeneration. The converse is also true. Research on other types of neurodegeneration may provide vital clues to curing Parkinson's disease.

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INTRODUCTION

A new optimism that Parkinson's disease can be defeated is energizing the research community and patient advocates. Halting the progression of Parkinson's disease, restoring lost function and even preventing the disease all now seem realistic goals. Several factors fuel this hope. The pace of discovery in basic neuroscience is accelerating and there is growing understanding of the cellular mechanisms that damage cells and trigger cell death. New genetic findings in Parkinson's disease present a foothold to harness the power of molecular biology to combat this disorder. And, an extraordinary range of new therapies is on the horizon — stem cell transplants, precision surgical repair, new approaches to drug development, natural growth factors, and chronic brain stimulation through implanted devices — to name just a few. Optimism is tempered by the realization that we have not yet cured any neurodegenerative disorder, and defeating Parkinson's disease will require new discoveries that cannot now be predicted with certainty. To optimize our chances for success we propose to explore all relevant opportunities at all levels ranging from fundamental neuroscience through clinical trials. The hope and the difficulty together make this a particularly important time to plan an agenda for Parkinson's disease research.

What is Parkinson's disease?

Parkinson's disease is a devastating and complex disease that progressively affects the control of movement. The cardinal symptoms include tremor at rest, bodily rigidity, marked slowness of movement, postural changes, gait disturbances, and difficulty initiating voluntary movement. However, physicians and patients have long recognized that this disease, or treatment complications, can cause a wide spectrum of other symptoms, including dementia, abnormal speech, sleep disturbances, swallowing problems, sexual dysfunction, and depression. These other symptoms are often extremely important to patients and present a challenge for future research.

Parkinson's disease is a neurodegenerative disorder, that is, it arises from the gradual death of nerve cells. In particular, nerve cells in a small area of the lower brain called the substantia nigra are most noticeably affected. These cells normally connect to the striatum in the brain's basal ganglia, which lie under the cerebral cortex, and release the neurotransmitter, dopamine. These connections are part of the brain circuitry that controls voluntary movement. While the loss of dopamine in the striatum is clearly a major factor that underlies the symptoms of Parkinson's disease, there is increasing recognition that this disease has other effects on the brain. These include loss of dopamine in other brain areas and degeneration of nerve cells that rely upon other neurotransmitters.

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What causes Parkinson's disease?

We do not know what triggers the death of nerve cells in most people with Parkinson's disease. Different initial causes may be at work in different patients with the symptoms of Parkinson's disease, though present indications suggest a final common path to cell death. We know that some people inherit the disease while others acquire disease from other causes. Physicians have also long recognized that several types of insults can produce syndromes similar to Parkinson's disease including, for example, trauma, tumors, metabolic disturbances, and toxins. These similar symptom complexes are collectively referred to as "Parkinsonism". There are also several "Parkinson's-Plus" syndromes that overlap considerably with Parkinson's in symptoms and neurodegeneration pattern, but are each also marked by other characteristic features. The diagnostic distinctions are not merely an academic exercise. Comparing the different patterns of symptoms and pathology provides essential clues to fighting all of these disorders. Furthermore, as new treatments become available that target different steps in the disease process, similar syndromes are likely to respond differently. Therefore, the scope of this Parkinson's disease research agenda must include not only common Parkinson's disease, but also other forms of Parkinsonism and Parkinson's-Plus syndromes.

Are treatments available for Parkinson's disease?

The drug levodopa, which brain cells convert to dopamine, is the mainstay of pharmacological treatment for Parkinson's. While levodopa helps boost the brain's dwindling supply of dopamine, this treatment fails to slow or stop the death of the dopamine producing cells. As more and more dopamine producing cells degenerate, higher and higher doses of levodopa are required. This typically leads to side effects including drug-induced involuntary movements (dyskinesias) and motor fluctuations, which prevent adequate treatment. Drugs that target other neurotransmitters, such as glutamate, may also play an important role in treatment but none of the available drugs halts the underlying neurodegeneration. Researchers are now investigating a wide range of conventional and non-conventional pharmacological and surgical treatments for the disease.

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What research is now underway?

The National Institutes of Health conducts a vigorous and expanding program of research focused on Parkinson's disease. Several components of NIH support research relevant to this disease from the different perspectives of their missions. The National Institutes of Neurological Disorders and Stroke (NINDS) is the lead NIH institute for Parkinson's disease research with a broad portfolio of research on the causes and treatment. Research supported by the National Institute on Aging (NIA) supports research on many relevant basic science issues and particularly on how aging affects the vulnerability of the brain to Parkinson's disease. NIA also leads NIH efforts against Alzheimer's disease, and there is increasing recognition of the interrelationships between many aspects of Alzheimer's and Parkinson's disease research. The National Institute of Environmental Health Sciences has recently launched an initiative on possible environmental causes and risk factors for Parkinson's disease. The National Institute of Mental Health funds research on dementia, depression and other mental health problems associated with Parkinson's disease, and along with the National Institute on Drug Abuse, the National Institute of Diabetes, Digestive and Kidney Diseases and NINDS, supports a strong program of research on dopamine nerve cell biology. The National Institute on Deafness and Other Communication Disorders supports research concerning the effects of Parkinson's disease on communication and sensory function, and also supports basic research on dopamine neuronal biology. The National Human Genome Research Institute continues to play a major role in studying the genetics of Parkinson's disease. The National Center for Research Resources develops and provides critical research resources through support of biomedical technology, clinical research, comparative medicine, and other research infrastructure, which underpin Parkinson's disease research. The National Institute of Nursing Research supports research aimed at improving the care of patients with debilitating disorders such as Parkinson's disease. The National Center for Complementary and Alternative Medicine supports research on complementary treatments for neurodegenerative disorders. To enhance the coordination of these various efforts in 1999, NIH re-formed the Parkinson's Disease Coordinating Committee with expanded membership led by NINDS.

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The planning process:

The initiative, ingenuity, and insight of independent scientists throughout the country and the world have produced the dazzling progress of medical science in the modern era. NIH is committed to supporting that productive marketplace of ideas. Investigator initiated research with peer review will remain the major part of the NIH effort against Parkinson's disease. However, although all components of NIH engage in broad strategic planning, there is a need for planning specific to Parkinson's disease to ensure that extraordinary opportunities to move toward a cure are adequately supported and that critical obstacles to progress are addressed.

Following the fiscal year 2000 Congressional directive for a Parkinson's disease research agenda, NIH organized a joint meeting of the NIH Parkinson's Disease Coordinating Committee and several private organizations on November 3, 1999, to begin the process of formulating a research plan. At this landmark meeting representatives from Parkinson's disease advocacy groups joined with the directors and staff of the major NIH components conducting Parkinson's research to initiate a planning process. Subsequently, a steering committee including patient advocates, extramural basic and clinical scientists, and NIH staff organized a Task Force Workshop to develop a research agenda. That workshop was held on January 4-6, 2000 in Bethesda, Maryland. The workshop included 25 intramural, extramural and pharmaceutical industry scientists, representatives from 6 Parkinson's advocacy groups, ethicists, and program directors from NIH. Participants in the planning workshop were urged to take a forward-looking approach. Rather than only focusing on what research is now being conducted, participants highlighted opportunities, critical needs and gaps in knowledge, and suggested specific actions that NIH might undertake to advance the fight against Parkinson's disease. It is important to note the extraordinary efforts made by these leading scientists and lay persons to mobilize on short notice and to work together for two days to identify research needs, opportunities, and to develop a focused, yet comprehensive research agenda for the next five years.

Congress charged NIH with developing a research agenda focused on the etiology, pathogenesis, and treatment of Parkinson's disease. The areas of research identified by the participants at the planning Workshop represent one assessment of what research would be most critical for progress against Parkinson's disease. However, medical science moves quickly and in unexpected directions. The evident relevance of research to Parkinson's disease changes rapidly with progress in understanding this disorder and with advances in other areas of neuroscience. Several areas of research that were major topics of discussion at these planning meetings would have received little, if any, discussion a decade earlier. These include, for example, fundamental investigations of cell death mechanisms, neurotrophic factors for dopamine cells, and stem cells; technologies such as gene arrays, genetic engineering, and high throughput screening; and specific mechanisms of neurodegeneration in diseases such as Alzheimer's, Huntington's, supranuclear palsy, and multiple system atrophy. Thus, it is important to note that this research agenda is a snapshot of what must be a continuous process. Scientists, the advocacy community, and NIH staff must continue to work together to refine priorities, measure progress and exploit new opportunities as the scientific landscape changes. This planning document can serve as a management tool against which to assess progress and to redirect resources as needed.

The professional judgment estimate:

This professional judgment estimate highlights the exceptional opportunities for making progress on the causes and treatment of Parkinson's disease. The professional judgment estimate for these research opportunities would call for approximately $70 million of new spending for the first year. The agenda would include additional increases in subsequent years rising to $287 million in the fifth year, as detailed in the appendix to this document. The cost estimates are professional judgments based on our assessment of scientific opportunities without regard to economic constraints or other competing priorities of the Federal government. Since NIH supports ongoing research in all areas discussed at the planning workshop, it is important to emphasize that the estimates reflect increases beyond current levels. Sufficient, skilled staff is available to carry out each initiative, but there is a critical need to attract scientists from other fields to these problems. Training initiatives to support future needs are critical to long-term success. Because many of the research opportunities would require intensive engagement of NIH Program Directors and other staff, the professional judgment estimate reflects a need for increased research management and support.

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PARKINSON'S DISEASE RESEARCH AGENDA

Progress in Parkinson’s disease will require synchronous and coordinated efforts that span the basic sciences and continue through therapeutic approaches. Efforts in clinical research can be increased as new drugs and other therapies flow from discoveries in the scientific laboratory. Accelerating the process would require extensive investment in new technologies for laboratory scientists, additional efforts for rapid application of scientific discoveries to patient care, and increased participation of Parkinson’s disease patients in clinical research and in genetic and epidemiological efforts.

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UNDERSTANDING PARKINSON’S DISEASE

Using Genetics to Understand Parkinson’s Disease

Molecular genetics is revolutionizing our understanding of human disease, even those diseases that are not inherited. Although mutations in the synuclein gene directly cause Parkinson’s disease in very few people, the discovery of those mutations led to new understanding of the critical role of synuclein in common Parkinson’s disease. Mutations and variability in the tau gene have been shown to underlie frontal-temporal dementia with parkinsonism and progressive supranuclear palsy, and mutations of the parkin gene have been shown to underlie juvenile parkinsonism, each also providing important clues to what causes neurons to die in common Parkinson’s disease. These known genes account for only a small proportion of inherited cases of Parkinson’s disease. Furthermore, interactions between complex genetic predisposition and environmental influences cause most cases of Parkinsonism. Clearly, major priorities must be to discover other gene defects that can cause or increase risk for Parkinson’s disease, to develop a more complete understanding of the role of these genes in parkinsonisms, and to use these genetic findings to make useful cellular and animal models of disease that would enable researchers to study the disease process and test new treatments.

Identifying other genetic loci is crucial for several reasons:

  • They will provide crucial biochemical information about the pathologic biochemical pathways, which will be drug targets.
  • They will aid in diagnosis.
  • They will aid in identifying those at high risk for disease, both for studies aimed at identifying early symptoms and signs and for ensuring treatments can be started early in, or even before, the disease is manifest.
  • They will aid in the development of cellular and transgenic models of disease that accurately mimic the slow nerve cell death in human Parkinson’s disease.

Conceptually, the identification of single genes involves little new technology. The problems of understanding complex genetic influences on Parkinson’s disease, however, are formidable in both logistics and cost. Finding ways to confront such complex influences is crucial for Parkinson’s and many other diseases.

a. Identification of the other genes involved in autosomal dominant disease.

There are two autosomal dominant genes which, when defective, can cause Parkinson’s disease, one on chromosome 2p and one on chromosome 4p. Work aimed at identifying these genes is already funded using conventional strategies, although identifying and collecting other families with autosomal dominant disease would be aided by recruitment through the Parkinson’s Centers, the Parkinson Study Group and other clinicians. Families with monogenic disease are exceedingly rare and genealogical expansion of pedigrees is required to make them of sufficient size to map the underlying disease gene. In addition, families with different mutations within the same gene are required. This would aid the understanding of gene function and the relationship of genotype to phenotype.

b. Identification of ‘risk factor genes’.

This is more difficult than the simple Mendelian traits. Three methods are applicable:

  • Affected pedigree member (APM)/sibpair studies.

APM/sibpair studies have been used to localize common (rather than rare) risk factor loci of minor effect in a number of complex traits. They offer a robust method of analysis, but require the collection of very large numbers of affected sibpairs. However, more than 500,000 Americans are presently affected by Parkinson’s disease. Since genetic susceptibility may explain 10 percent, participants can be recruited from a pool of 25,000 APM/sibpairs. The inherent diagnostic uncertainty in clinical ascertainment is not an issue in an APM/sibpair method because family members who do not share alleles at genetic loci do not contribute to the positive peaks identified in a genome screen. The shortfall in diagnostic accuracy may be overcome by genotyping additional APM/sibpairs. Genomic approaches to identify genes and pathways in normal development and neurodegenerative disease are presently being revolutionized by cDNA array approaches and cluster analysis. Clearly, APM/sibpair data allowing a dissection of complex traits at a population level would be a timely complement. Furthermore, once loci are identified, such genomic targets would facilitate gene mapping prioritizing candidates for gene sequencing. The human genome initiative will also greatly accelerate the process. Two sibpair studies are currently underway: one from Duke and one from Harvard: however, to aid in this effort it would be extremely helpful if immortal samples from these studies could be banked and made widely available to geneticists; and also if more samples could be collected and banked, again using the PD Centers and other interested clinicians.

  • Genetic analysis of isolated populations.

Genetic analysis of isolated populations derived from relatively few founders offers a powerful route to the identification of risk factor loci. In these populations the genetic diversity is less and the disease will have a simpler etiology. This type of work is impossible in most US populations and best done in collaboration with investigators from more homogenous populations.

  • Association studies of candidate genes.

This type of work requires large numbers of case and control subjects. While this work is technically easy, it has produced many false leads. However, as studies of affected pair members and isolated populations generate leads, and as we learn more about the biology of the disease and as more single nucleotide polymorphisms are identified for DNA chip analysis, this approach will become more powerful. To be effective, we need to collect large numbers of cases and either spouse, or unaffected sib controls. Funding for this should be included in clinical protocols, and virtually all Parkinson’s clinical trials should be structured with advice from geneticists. It is worth noting that it is likely that genetics influences not only one’s risk of developing disease but also one’s response to treatment, and for this reason alone, it is worth collecting samples so that, retrospective analysis of clinical trials can be undertaken to determine whether there were subgroups of patients who responded in ways corresponding with certain genetic factors. A central lab, processing and storing blood samples for analysis, would be most appropriate.

For all of these issues, the establishment of a web-based patient registry must remain a high and urgent priority. A cooperative effort by NIH working closely with several Parkinson’s disease groups is already well underway to accomplish this.

Already, families with the inherited form of Parkinson’s disease offer a route to developing a clearer understanding of the precise natural history of the disease from preclinical to postmortem, and as we develop clearer understanding of other genetic and environmental risk factors, the pool of individuals whom we can predict will develop the disease will increase. These individuals offer a focused way to develop a better understanding of disease mechanisms and progression. Clearly, there are ethical issues, although it is most investigators’ experience that such individuals wish to be studied, both for altruistic reasons and because they want to help others in their families.

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Epidemiology to Determine Environmental Risk Factors for Parkinson’s Disease

Epidemiological investigations can provide essential clues to what causes Parkinson’s disease, to risk factors that may predispose people to this disease, and to preclinical characteristics of the disorder. Such investigations also provide essential information for evaluating public health impact. Trends showing changes in age of onset or large disparities in geographical distribution should evoke special concern, but we presently have little data on these issues. A thorough investigation of ethnic and gender differences is also badly needed. Some studies, using information from death certificates, have reported that Parkinson’s disease mortality is significantly higher for men and Whites than for women and Blacks, while door-to-door studies suggest that the reported ethnic and gender differences reflect not only under-recognition of Parkinson’s disease in minority populations during life, but also under-reporting as a cause of death. In order to address these concerns, a combination of short-term case control studies and long-term prospective studies would be needed.

a. Short-term case control studies:

Case control studies, which compare people with and without Parkinson’s disease, can provide valuable information about environmental risk factors as well as the interaction of genetic and non-genetic (e.g., environmental) factors. Such studies would take advantage of currently available cohorts and other potentially informative populations, such as families or people exposed to potential toxins. Development of improved methods for the direct assessment of current exposure to toxicants and validation of exposure assessment methods can take advantage of new technology. In addition, novel biostatistical approaches for testing hypotheses involving complex exposure and gene-exposure combinations, incorporating exposure dose, duration and intensity, and for maximizing information using relatively small sample sizes are needed. These in turn could possibly lead to finding the cause or causes, and provide important topics for laboratory investigations of disease mechanisms as well as potential therapeutic interventions. This area of investigation has been relatively neglected because of the labor-intensive nature of such studies. There are current NIH initiatives to address many of these issues, especially those related to possible environmental causes. In Fall 1999, NIH issued two RFA’s, one on the role of the environment in Parkinson’s disease and another on training needs to address this issue.

b. Long term prospective studies:

A prospective cohort study, which follows people who do not yet have disease, would help to identify the causes of Parkinson’s disease and to provide other badly needed epidemiological information. In spite of retrospective, clinic-based and case-control studies we still have only clues regarding the etiologic determinants, risk factors and preclinical characteristics of Parkinson's disease. This can only be answered definitively with a prospective cohort investigation. This is particularly critical in view of recent evidence in twins that there are nongenetic factors in most cases. For this reason, the time has come to consider a prospective and potentially definitive study looking for the cause of Parkinson's disease. Such a study would be particularly timely with the advent of biomarkers such as beta-CIT, and the rapid technologic advances in microarray gene chip technology and other techniques allowing identification of multiple proteins or other potential biomarkers. Given the expense of long-term prospective studies and the likelihood that healthy persons will develop Parkinson’s disease, it would be highly efficient in such a study to include other neurodegenerative disorders.

An effort of this magnitude and scope cannot be achieved without the creative leadership and long-term commitment of NIH. The major participation of NIH would be important during the planning phase and coordination of other Federal resources, which could contribute to this effort. Initial efforts should incorporate recent scientific advances in order to refine priorities for assembling a representative cohort reflecting the US population demographically and socioeconomically. It would be important to identify cooperating groups, to establish a research team and oversight committees, and to develop, pilot test (when needed ) and implement methods for ascertaining, serially evaluating, and retaining individuals in the cohort. Early consideration would also need to be directed toward design of a data management system, including tissue repositories.

NINDS, NIA, and NIMH have studies underway of design considerations for a long-term prospective study of cognitive and emotional health. The results of those ongoing assessments will help determine whether a prospective study of Parkinson’s disease is best undertaken as part of a broader effort or as a separate enterprise.

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Life and Death of Neurons Involved in Parkinson’s Disease

a. Cell biology of neurons in Parkinson’s disease

Although the nerve cells that die in Parkinson’s disease and other neurodegenerative diseases may follow a "final common pathway" to death, each disease inexplicably affects specific groups of cell types. We do not understand why Parkinson’s disease selectively affects certain groups of brain cells, such as dopamine neurons in the substantia nigra. Understanding the normal biology of neurons susceptible to Parkinson’s disease is crucial for understanding their selective loss, and for developing new therapies that rescue or even replace those cells. The application of new cellular and molecular research approaches have dramatically advanced our understanding of other nerve cell types, such as motor neurons of the spinal cord, but these approaches have not yet been applied to cells critically affected in Parkinson’s disease. The cellular and molecular characteristics, which need to be studied, include:

  • Determination of the specific genes expressed by neurons that die in Parkinson’s disease, such as the dopamine cells of the substantia nigra. Finding genes unique to these cells is critical for the design of potential gene therapies. Included would be the identification of proteins that undergo selective post-translational modification in these cells.
  • Determination of the developmental steps that control the differentiation of PD-susceptible neurons, including the logic of the assembly of the neuronal phenotype. This information could help determine the optimal methods for directing the differentiation of stem cells into cells useful for cell transplantation therapies.
  • The plasticity of dopamine neurons in response to injury. Little is known about how surviving neurons adjust to compensate for loss of other neurons early in the course of Parkinson’s disease or during treatment. Such adaptations might slow the onset of symptoms or complicate the anticipated effects of some therapies.
  • Study of cell death pathways in neurons affected by Parkinson’s disease. While cell death pathways in nerve cells follow common themes, there are variations in different neuron types that may present critical steps for therapies designed to halt cell death processes.
  • The role of neurotrophins in all of the above processes will be critical to their potential use in neuroprotection therapies.

Knowledge of the unique genetic, molecular, and cellular make-up of dopamine neurons would benefit Parkinson’s disease research on many fronts. In addition to discovery of new or improved therapeutic approaches such as gene therapy, neuroprotectants, stem cell replacement, and pharmacological approaches, it also could lead to production of better cellular and animal models of dopamine neurodegeneration, and provide insight into neurodegenerative processes in general.

b. Functional studies of proteins implicated in Parkinson’s disease

1. Opportunities arising from the discovery of Synuclein.

In 1995, a NIH Parkinson’s disease workshop highlighted the opportunity for genetic studies in this disease. A collaboration of scientists from NINDS, NHGRI, and the extramural program rapidly formed. They discovered the first genetic defect that can cause Parkinson’s disease, an inherited defect that produces mutations in the protein alpha-synuclein. Since then, a remarkable paradigm shift in Parkinson's disease research has resulted from evidence that directly implicates synucleins in not only familial Parkinson’s, but also in the common sporadic form of the disease, and in other disorders such as multiple system atrophy and Hallovorden-Spatz disease. Thus, disorders with prominent synuclein pathologies now are known as synucleinopathies. New insights into the role of synucleins in the pathobiology of Parkinson’s disease would accelerate discovery of more effective therapies and provide fresh research opportunities to advance our understanding of Parkinson’s disease.

Alpha-synuclein occurs in Lewy bodies, abnormal aggregates that are a pathological hallmark found in the brains of persons with Parkinson’s diseases. This protein is also associated with amyloid plaques that are pathological clumps of proteins in the brains of people with Alzheimer’s. In addition to Parkinson’s disease, related synucleinopathies, and Alzheimer’s disease, emerging data implicate protein aggregates in many other sporadic and hereditary neurodegenerative disorders such as Huntington’s disease, Creutzfeld-Jakob disease and spinocerebellar ataxias. Thus, a growing body of data provides a mechanistic link between abnormal filamentous aggregates and the degeneration of affected brain regions in neurodegenerative disorders.

For the reasons summarized here, it is timely to launch a basic and clinical research program to accomplish the following goals:

  • Elucidate the normal functions and metabolism of synucleins in neurons and glia of the developing and mature nervous system. This would include the normal cellular interactions of synucleins with other proteins and organelles, and the biological significance of these interactions.
  • Determine how the A53T and A30P alpha-synuclein gene mutations in FPD disrupt the normal functions of alpha synuclein and the implications of this for disease.
  • Develop informative in vivo (e.g., transgenic mice and flies) and in vitro (e.g., transfected cultured cells or recombinant proteins) model systems for mechanistic studies of the normal and abnormal biology of synucleins.
  • Use these model systems to study the mechanisms of synuclein aggregation and fibrillogenesis in the onset/progression of Parkinson’s disease and other neurodegenerative synucleinopathies, and to discover and screen novel therapeutics.
  • Investigate the existence and roles of other genetic and epigenetic factors in the onset and progression of neurodegenerative synucleinopathies, including factors that commonly predispose many patients to develop both Parkinson’s disease and Alzheimer’s disease.

2. Additional proteins of interest include parkin and ubiquitin hydroxylase

Since the discovery of the synuclein mutations, genetic mutations in other proteins have been found in familial Parkinson’s disease, and more are likely to follow. It is important to understand how these mutations cause disease and the possible role of these proteins in common Parkinson’s disease. The parkin protein, for example, has been implicated in early onset forms of Parkinson’s disease. Like the alpha-synuclein protein, the function of parkin is unknown. However, its biochemical structure would suggest that it may function in the ubiquitin pathway, which regulates how cells dispose of unwanted proteins or cellular waste. If cells cannot degrade and dispose of proteins properly, it may lead to abnormal build up of aggregates in cells and/or eventual neurodegeneration. Moreover, a polymorphism in a ubiquitin hydroxylase (UHC) gene, another component of this degradation pathway, has been discovered in a few individuals with Parkinson’s disease. Abnormal aggregation of proteins occurs in common Parkinson’s disease and in several other neurodegenerative diseases.

Goals for this research should include:

  • Familial genetic studies on the parkin/UHC-L1 mutations in PD families.
  • Studies on the function of parkin, including its potential role in the ubiquitination pathway.
  • Development of animal models, such as knockouts in mice, flies, or worms, to study the roles of parkin and UHC-L1.
  • Studies of the role of parkin as a potential transcriptional activator and identification of those genes controlled by parkin.

When other Parkinson’s related genes are discovered, similar approaches to discovering their normal function and role in disease would be a high priority.

c. Mitochondrial impairment in Parkinson’s disease

Postmortem studies and animal models strongly implicate mitochondrial impairment in the pathogenesis of Parkinson’s disease. MPTP, an inhibitor of the mitochondrial electron transfer chain, induces Parkinsonism in experimental animals and in humans after inadvertent ingestion. Chronic exposure to rotenone, a common pesticide and potent inhibitor of the electron transfer chain, also produces selective nigrostriatal degeneration and cytoplasmic inclusions reminiscent of Lewy bodies. Mitochondrial dysfunction has numerous consequences, including energetic failure, generation of reactive oxygen species, disregulation of calcium homeostasis and induction of apoptosis, each of which may be important in Parkinson’s disease. Secondary consequences of mitochondrial dysfunction may include oxidative damage to cellular components and abnormal protein aggregation. Thus, there is a compelling need to elucidate the role of mitochondrial defects in Parkinson’s disease, to define the mechanisms by which mitochondrial impairment kills neurons, and to identify therapeutic strategies to prevent the cell death that accompanies mitochondrial dysfunction.

Among the issues that need further study are:

  • The roles of mitochondrial defects and oxidative damage in familial as well as idiopathic Parkinson's disease.
  • The extent to which mitochondrial impairment is found in "peripheral" tissues and determination of whether it might serve as a presymptomatic biomarker.
  • Establishment of cell lines that approximate the intact brain in terms of their requirements for mitochondrial respiration rather than glycolysis.
  • Establishment of stable cytoplasmic hybrid (cybrid) cell lines, using true neuronal cells as the parental line, that are widely available as shared reagents.
  • The mechanisms by which mitochondrial defects produce abnormal aggregation of proteins (e.g., oxidative modifications, impairment of proteosome function).
  • The interactions between excitotoxicity and mitochondrial impairment.
  • The role of mitochondria and the mitochondrial permeability transition pore in apoptosis of dopaminergic neurons and other neurons affected by Parkinson’s disease.

NINDS has prepared an RFA focusing on the role of mitochondria in neurodegenerative disease that was published in March 2000.

d. Understanding and preventing cell death in Parkinson’s disease

There is a great need to understand the mechanism(s) by which nerve cells die in response to the degenerative process of Parkinson’s disease. Identification of the predominant cell death pathways and the possible unique contributors to cell death in these neurons would provide opportunities for novel therapeutic targets. Many of these opportunities stem from the dramatic advances in the basic understanding of common mechanisms of cell death that contribute to many neurological disorders, including apoptotic, excitotoxic and mitochondrial mediated death mechanisms. These advances in the knowledge about cell death coupled with identification of genes linked to familial Parkinson’s disease provide an opportunity to characterize the basic mechanisms of cell death and survival in idiopathic and familial Parkinson’s disease. Capitalizing on these advances should include support for understanding the basic processes that promote cell survival and regeneration, the mitochondrial aspects of cell death, and protein turnover and degradation. Other relevant aspects include:

  • Studying apoptotic (caspase dependent and independent) pathways, including whether there are components of this pathway that are unique to neurons that die in Parkinson’s disease.
  • Examining the role of excitotoxicity in cell death during Parkinson’s disease. Chronic low-grade excitotoxic injury to dopamine neurons is a major hypothesis for the pathogenesis of Parkinson’s disease.
  • Understanding the emerging role of poly (ADP-ribose) polymerase (PARP) and poly (ADP-ribose) glycohydrolase and the molecular substrates of ADP-ribosylation in the death of dopamine neurons.
  • Elucidating the role of immune activation in neuron cell death during Parkinson’s disease and the role of immunophilins in normal neuronal physiology and in promoting cell survival and regeneration.
  • Developing vertebrate and invertebrate animal models of familial Parkinson’s disease (mutations in Parkin and a -synuclein and other linked genes as they are identified) which exhibit progressive loss of neurons and the presence of cytoplasmic eosinophilic inclusions (Lewy bodies), which can be used to explore the above molecular mechanisms of cell death and to test potential therapeutics, genetic modifiers, as well as the role of exogenous toxins and other perturbations on disease pathogenesis.
  • Understanding the role of ubiquitin and the proteosome degradation pathway and other mechanisms of protein turnover and degradation and its relationship to the above processes and the relationship of familial Parkinson’s disease-linked genes in the molecular mechanisms of cell death.

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Neural Circuits in Parkinson’s Disease

Understanding the pathophysiologic basis of the cardinal motor disturbances of Parkinson’s (tremor, rigidity, akinesia/bradykinesia, impaired gait and balance), as well as the changes that affect autonomic function, cognition and sleep, remains one of the major challenges of the field. This understanding is vital for the development of new therapeutic approaches.

While there has been considerable progress in our understanding of the circuitry and physiology of the basal ganglia and other components of the motor system, basic questions remain about the normal function of these brain systems. Moreover, there is major uncertainty regarding the nature of the disturbances in these systems that follow from the degeneration of neurons in Parkinson’s disease. Circuit models of Parkinson’s and other movement disorders have contributed to our understanding of these disorders and to the development of novel surgical approaches. These models, however, are highly simplistic and cannot satisfactorily explain the signs and symptoms of Parkinson’s disease and related disorders. Thus, there is an urgent need for further studies in the pathophysiology of Parkinson’s disease in animal models (rodent and primate) using a combination of modern molecular and cellular approaches and anatomical, electrophysiologic, neurochemical, and imaging techniques. Included would be studies of the circuitry and transmitter interactions involving the basal ganglia. There is also a need to obtain complementary data in human subjects with these disorders in the course of neurosurgical procedures and to study the mechanism of action of current neurosurgical approaches such as pallidotomy and deep brain stimulation.

While the loss of dopamine input in the striatum has been a principal focus of research on pathophyiology of Parkinson’s disease, several other aspects of neurodegeneration in this disease raise important questions about how brain circuits are affected. One poorly understood area concerns the consequences of dopamine loss outside the striatum. For example, we know little about how the role of the substantia nigra in the regulation of eye movements is affected by disease. Disruption of this circuit might be an early event in Parkinson’s disease. The mechanisms underlying the severe complications of dopaminergic agonist therapy (dyskinesias) may also involve dysfunction in extrastriatal regions. Similarly, although drugs targeting other neurotransmitter systems, such as glutamate, are used in the treatment of Parkinson’s disease, and the death of non-dopamine cells has been demonstrated, the consequences of this degeneration are not at all understood. Finally, the loss of dopamine leads to chronic alterations in other neurotransmitter systems within and outside basal ganglia. Subsequent changes in surviving nerve cells, synapses, and circuits are likely to occur throughout the course of disease. These are likely to include molecular modification of receptors and signal transduction mechanisms that may contribute to the symptoms and provide new therapeutic targets. Plasticity may play a positive role in adjusting to disease and drug treatment, but might conceivably also contribute to problems such as dyskinesias. While plasticity research is one of the most active areas of neuroscience, very little is known about how such changes come into play during the course and treatment of Parkinson’s disease.

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DEVELOPING NEW TREATMENTS FOR PARKINSON’S DISEASE

Developing therapies to prevent Parkinson’s disease, to treat symptoms, to halt progression and to repair damage are all fundamental goals. A wide range of therapeutic approaches are now at various stages of development, including precision surgical ablation, electric stimulation, cell implantation, and several drugs. Some drugs target neurotransmitter systems, including not only dopamine but also others such as glutamate. Other drugs are designed to interfere with steps in the neurodegenerative processes, such as free radical damage, excitotoxicity, or apoptosis, while others are molecules that sustain nerve cells. To achieve all of these therapeutic goals, many separate studies are required, from the first steps in translating basic research advances, animal testing, preliminary safety studies in human patients, and finally large trials to evaluate the effectiveness of a therapy. Better biomarkers, that is, reliable indicators of risk, disease state, and progression, are essential to accomplish all of these goals. Markers for early detection of persons at risk or in early stages of disease will be particularly critical, as methods to slow neurodegeneration become available.

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Pharmacological Approaches

Developing new pharmacological approaches for treating Parkinson’s disease must remain a priority. Current drug therapies lose efficacy, induce side effects, have little effectiveness against non-motor symptoms and do not address the underlying disease process. Surgical approaches may offer symptomatic relief but will remain costly and may be appropriate for selected patients. As indicated, basic research is needed to identify new drug targets based on better understanding of the disease. This must be followed by efficient efforts to bring these drug candidates to the clinic.

a. Phase II Clinical Trials

  1. In order to rapidly identify promising candidate drugs for definitive assessment of efficacy, a series of relatively small Phase II trials should be supported to establish the safety, tolerability, and dosage of new drugs. These studies could be accomplished with less than 100 subjects per trial. Increased investment is needed so that trials can proceed not merely in series but concurrently.
  2. Acceleration of the Conduct of Safety/Tolerability/Dose-Finding (Phase II) Studies of Promising Therapeutic Interventions.

There are promising therapeutic interventions for Parkinson’s disease which have not undergone the requisite studies for safety, tolerability and dose-response effects. These studies usually require less than 100 total research subjects to examine safety, tolerability and dose finding. The data emerging from such studies would be used to further assess the rationale and feasibility of carrying out more definitive Phase III trials. Each of these Phase II trials can be conducted over a 3-year period, including, the planning, initiation, implementation, data collection and management, analysis and reporting.

It is important to note that the NIH Intramural Program and Clinical Center present unique advantages for many aspects of clinical research on Parkinson's disease, including the ability to quickly initiate and conduct small scale clinical trials of drugs or other treatments.

b. Major large randomized controlled clinical trials

A careful review of existing and developing pharmaceutical agents is necessary to evaluate their potential relevance for the delay of the onset of Parkinson disease or the slowing of its progression. A limited number of major, large, randomized controlled clinical trials aimed at preventing the progression of Parkinson’s disease can be mounted to definitively evaluate the efficacy of promising experimental drugs. Each of these trials would require from about 600 to perhaps 2000 patients, depending on the size of the expected effect, and patients would be followed for three to five years. Two large randomized controlled trials, examining 2-4 interventions in a factorial design could detect relatively small but clinically important effects. Initiating these trials now would provide valuable information for testing new and more effective drugs as they become available. Experimental interventions such as anti-oxidants, anti-inflammatory agents, glutamate antagonists, inhibitors of the dopamine transporter, and neuroimmunophilins would be examples of potential drugs to test. There is also an opportunity to partner with industry in this process of therapeutic development.

c. Complications and non-motor symptoms

People with Parkinson’s disease must confront a wide range of symptoms beyond the disruptions of movement control that are the cardinal features of this disease. Some of these symptoms are caused by the disease, others are side effects of the drugs, like levodopa, used to treat it.

Complications of treatment, particularly dyskinesias, are very common, and frequently become disabling and dose-limiting, often at a time when patients are more in need of additional medication than ever. Indeed, they represent one of the great barriers to successful treatment that we currently face, and solving this and related problems would have an enormous and immediate impact on our ability to treat the disease. Another serious dose-limiting complication of dopamine precursor and agonist therapy is the development of psychosis/hallucinations. We now have an excellent animal model for dopa-dyskinesias, so a research investment in this area could pay rewarding therapeutic dividends.

We must pay attention to drug interactions in all pharmacological treatments of Parkinson’s disease. It is worth noting that chronic administration of methamphetamine, a commonly abused drug, can have profound effects on dopamine actions in the brain. This illustrates general principles regarding effects of other drugs on circuits that influence motor control and the complications such unanticipated actions may have for therapy.

Non-motor symptoms of Parkinson’s disease may include cognitive and emotional difficulties, including dementia and clinical depression, serious sleep disturbances, visual hallucinations, sexual dysfunction, bowel and bladder problems, speech difficulties, swallowing problems and many other changes that seriously affect the quality of life. Understanding of the causes of these difficulties and ways to avoid them is poor and there is insufficient research directed at these problems. For the short-term NIH could foster studies to evaluate which known symptomatic treatments are best for people with Parkinson’s disease. Moreover, because Parkinson’s disease is a heterogeneous disease, these studies can seek to identify which subpopulations respond well to which treatments. For the long term, studies to understand how Parkinson’s disease and its treatment causes these symptoms may help treat the problems themselves and lead to a better understanding of the pathophysiology of Parkinson’s disease in general.

Research is needed with the overall goals to manage symptoms effectively, to prevent secondary effects of the condition when possible, to maximize the health potential, and to improve the health-related quality of life for patients, caregivers, and families. These issues might be addressed in part with smaller trials using physiological and behavioral therapies that may already exist but have not been evaluated in this population.

d. Prevention Trials

Delaying or preventing the onset of Parkinson disease is the ultimate goal. Unfortunately, the lack of information about susceptible subpopulations requires very large numbers of people to be exposed to the treatment to prevent even a single case. Several large trials are ongoing, but the extent of neurological follow up and diagnosis is limited. Secondary prevention trials could be done in large families with identified genetic markers for Parkinson’s disease. The key to mounting effective prevention trials is identifying a valid and reliable biomarker that confidently reflects the preclinical trait of Parkinson’s disease.

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Deep Brain Stimulation and Other Surgical Approaches

Neurosurgical interventions are becoming increasingly important in the treatment of Parkinson’s disease. The factors contributing to this are the shortcomings of current pharmacotherapy, the increased understanding of the neuroanatomical and pathophysiological substrates of parkinsonism and the important advances in brain imaging, neurosurgical techniques and brain-implantable devices. Current surgical approaches include precision ablation therapies, deep brain stimulation, and cell transplantation. An emerging field is the direct micro-delivery of neuroactive substances through microinjection/infusion techniques to selectively modulate the activity of dysfunctional brain circuits or provide agents with neurotrophic properties to selected brain targets. Delivery of potentially therapeutic compounds to the brain is a critical consideration for all pharmacological approaches.

In some patients, chronic electrical stimulation through electrodes implanted deep in the brain can relieve some of the major symptoms of Parkinson's disease. Based on results from about 30 patients, the FDA recently approved deep brain stimulation (DBS) within the thalamus for relief of tremor of Parkinson's disease and also for non-Parkinsonian "essential tremor." Now evidence, mostly from Europe, suggests that DBS can relieve other, more debilitating symptoms of Parkinson's disease such as bradykinesia and rigidity. Not only does the benefit appear to be long lasting, but also there is tantalizing evidence that chronic stimulation may slow progression of the disease. DBS may alter the response of cells to intrinsic signaling molecules and, perhaps, to drugs. Side effects of chronic stimulation seem to be less problematic than drugs, and stimulation therapy is less destructive than surgical ablation therapies, and thus potentially reversible if more complete treatments become available.

In March 1999, NINDS convened a Workshop on Deep Brain Stimulation for Parkinson's disease to evaluate the current information and identify the need for future research. Following this workshop, NINDS issued a Request for Applications calling for a broad program of studies necessary for progress in applying this new therapeutic approach to Parkinson's disease. These range from investigation of the mechanism of brain stimulation effects, which is poorly understood, through technology development, and evaluation of long-term effects in clinical trials. The response to the RFA from the scientific community has been very positive.

In addition to ongoing efforts to increase research on deep brain stimulation, research priorities include an assessment of the relative attributes of different neurosurgical interventions in current use including DBS, ablation (thalamotomy, pallidotomy, subthalamic nucleus lesions) and cell implantation. Both DBS and microdelivery require advances in device design. For microdelivery identification of candidate compounds and proof of principle of therapeutic benefit and safety of direct intra-parenchymal brain delivery are immediate goals.

There is the possibility to partner with industry, particularly device manufacturers, to contribute to this investment and to share in technological advances. Also required is an assessment of current capacity and manpower/education/training considerations for the anticipated increase in number of neurosurgical interventions for Parkinson’s disease.

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