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Parkinson's Disease Research Agenda


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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Cell Implantation

Restoration of function is critical for people who have Parkinson’s disease. Cell implantation is one promising approach to brain repair, and early results from trials of embryonic tissue transplantation present a proof-in-principle that this therapeutic strategy is worth pursuing. Moreover, some patients have shown long-term benefit, but those surgeries were not part of double-blind studies. Two NIH-funded, placebo-controlled, surgical trials on fetal tissue transplants in patients with advanced Parkinson’s disease are now underway. One of these has completed its double-blind phase, and results will be submitted for publication soon, while the other should be completed in a year. Because these studies tested different variables, we need to wait for the results of the second to determine what new questions arise and need to be answered before deciding on any major new studies in humans. In the near future, studies should be carried out in nonhuman primates to answer questions such as whether immunosuppressive therapy is needed, what is the best technique for tissue preparation (solid noodle vs. dispersed cells), best target for controlling symptoms such as the freezing phenomenon, and the optimal cell dose and what factors affect cell survival. The one completed study suggests there is insufficient benefit, unexpected complications of uncontrolled dyskinesias and dystonia, and that further study is necessary before making this treatment modality available to the public at large. A vigorous investigation of the key variables in primate studies is important, particularly so because this therapy is one holding long-term promise for people with advanced disease.

Transplantation strategies based on stem cells present enormous potential for repairing the damage caused by Parkinson’s disease and other brain disorders. In recent years fundamental studies of neuroscience have revolutionized understanding of neural stem cells and what they might be coaxed to do. Animal studies demonstrate that transplanted stem cells can not only survive, but also integrate into existing brain circuitry and reverse behavioral deficits in animal models, such as the 6-hydroxydopamine rat model of Parkinson’s disease. Startling results have also demonstrated that progenitor cells with the potential to differentiate into neurons are still present even in the brains of 60 year old people and that adult stem cells can respond to a variety of external and internal influences, such as brain damage, circulating hormones, and behavioral experience. Given that potentially unlimited production of GABAergic and glutamatergic neurons from stem cells has been achieved in the laboratory, in the near future it should be possible to differentiate stem cells into adequate supplies of dopamine neurons for implantation. Stem cells may also be preferable to other tissues, especially if they can be derived from the patient’s own body, avoiding potential immunological problems.

While stem cell research is currently one of the most exciting areas in neurobiology, there is a great deal we must learn about the fundamental biology of stem cells before the stem cell implantation therapies can safely and effectively be developed for Parkinson’s disease. The best sources for cells could be explored, including whether cells derived from adult brain or even non-neural tissues are most useful. Studies of the natural signals that control stem cell proliferation are essential to develop methods to produce the large numbers of cells of the specialized types that are required for implantation. In addition to the development of effective methods for delivery of cells into the brain, we need to understand how to promote survival and integration of cells implanted within the adult brain. Once implanted, prevention of uncontrolled proliferation or other potentially harmful effects must also be a key consideration. Genetic engineering may be able to provide control "switches" for implanted cells. Because of the many uncertainties, stem cell transplantation studies should be carried out in animal models prior to humans. Primate studies are particularly important, and primate facilities must be available for investigators to carry out these investigations. It is through these studies that transplantation can become a therapeutic reality.

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Gene Therapy

In the long run gene therapy offers tremendous potential for Parkinson’s disease and many other disorders. Although holding promise, gene therapy for Parkinson’s disease requires systematic evaluation of various parameters before its utility as a clinical tool can become established. Multiple vector systems derived from viruses have been developed each with potential advantages and disadvantages for application to Parkinson’s disease. Considerations that may affect further development are intrinsic capacity for gene delivery and expression, immunogenicity, cytotoxicity, efficiency of transduction among others. Successful application of gene therapy will require the ability to selectively target gene expression to elements of the neural circuitry affected in Parkinson’s disease. Moreover, regulated gene expression will be needed to achieve specific levels of gene product synthesis. Progress in these areas will depend heavily on basic studies of gene expression in dopamine neurons. The ability to modulate gene expression from vectors may attenuate potential toxicity associated with supraphysiologic amounts of the engineered gene products. Unresolved issues in Parkinson’s disease gene therapy include:

  • identification of which genes to use for gene therapy approaches;
  • toxicological analyses of novel vector approaches;
  • comparative evaluation of different vector systems in multiple species and in Parkinson’s disease models;
  • development of safe marker genes that can be delivered and facilitate serial neuroimaging; molecular genetic switches capable of regulating gene expression in the Central Nervous System (CNS);
  • development of new genomic level DNA repair approaches such as chimeroplasty and relevant ethical studies;
  • development of technologies or methods to distribute or disperse vectors in the CNS.

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Rehabilitation

Rehabilitation may not only be efficacious but may help to improve the quality of life for individuals with Parkinson's Disease who have such selected problems 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. Use of biofeedback, functional electrical stimulation, adaptive and augmentative devices, and different schedules of rehabilitation including chronic maintenance schedules need to be explored, in concert with new pharmacological and implant technologies, to address some of these difficult problems.

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Outcomes Research And Evidence Based Medicine In Parkinson's Disease

Although there is an urgent need to develop dramatically improved treatment options, there is also a proper place for research aimed at measuring the success of existing treatments. In addition, an awareness of public health costs associated with Parkinson’s disease is important for planning long term health expenditures likely to be incurred by the demographically aging U.S. population. 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 and to help evaluate the public health impact of Parkinsonism. Possible activities in the next five years include:

  1. Developing a set of treatment guidelines with level of evidence classifications for all aspects of Parkinson's disease. This should form the basis for physician and patient education programs, including the use of Internet technology to promote education and encourage participation in research.
  2. Developing partnerships with existing organizations involved in or supporting outcomes research such as the Cochrane Collaboration, the Movement Disorders Society, the American Neurologic Association, the American Academy of Neurology, third party payers including managed care groups, and relevant government agencies.
  3. Initiating specific clinical research projects to compare therapies.

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CREATING NEW RESEARCH CAPABILITIES

High Throughput Drug Screening

Recent spectacular advances in robotics and synthetic chemistry, combined with increased understanding of molecular targets for drug therapy, make it possible to rapidly screen large numbers of potential drugs. Large pharmaceutical companies routinely screen their own proprietary libraries of hundreds of thousands of compounds against disease-associated targets. The discovery of synuclein and other Parkinson’s related genes and increasing understanding of the molecular events that underlie this disease present the opportunity to develop assays suitable for high throughput screening of potential Parkinson’s therapeutic drugs. Drug-like molecules revealed by such screening are also extremely valuable research tools, since they allow one to influence the behavior of a chosen protein in a complex cellular or animal model of Parkinson’s disease. However, for economic reasons, it is unlikely that Industry would undertake such efforts. For these reasons, NIH is exploring an initiative to establish academic centers for high throughput screening for Parkinson’s disease. Such centers would necessarily include not only equipment but also personnel including chemists and experts in adapting knowledge about disease targets to assays suitable for screening. NINDS has been exploring the potential of this technology for neurodegenerative diseases and is organizing a workshop, including academics and industry, for Spring, 2000. Efforts to develop suitable assays are also underway in at least one Udall Center.

In addition to molecular assays, which are often favored by industry, high throughput screening (HTS) to identify new drugs for Parkinson’s disease requires the development of cellular models of disease-causing events. These models may be based on any of the suspected disease mechanisms, such as the dysfunction of mutant proteins linked to Parkinson’s disease or apoptosis of dopaminergic neurons. The models can be modified for use as assays in high throughput drug screens: drugs that block these cellular processes are immediate candidates for Parkinson’s disease treatments. These cellular disease models would be designed by individual investigators. Adapting the models as assays for HTS and testing the drugs would be carried out in collaboration with centralized HTS facilities. An initiative to be published this year will encourage investigators to identify and refine potential HTS assays and to evolve strategies for evaluating candidate drugs that emerge from the screen. In addition, national centers will be established in the US to refine the assays and to perform the screening with large panels of different molecules to select those that could be effective in interventions and to discover new scientific leads.

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Array Technologies

Monitoring which genes are active is an important key to understanding how cells react to Parkinson’s disease and to therapy. Gene array technologies allow simultaneous measurement of the activity of thousands of genes—soon all genes—in a tissue. Complementary methods are rapidly advancing the ability to monitor proteins, including turnover and post-translational changes that are critical for cell function. Researchers investigating Parkinson’s disease could apply these technologies to understand at the molecular level the causes and progression of this disease and the responses of neurons to drugs, brain stimulation, and other potential treatments. Because array technology is critical for progress against many diseases, several components of NIH are actively exploring the best approaches for providing access and for promoting the development of array technology, including arrays specific for primates and other species. As progress evolves it is essential to ensure, by whatever mechanisms are appropriate, that this rapidly developing arena of technology is applied to Parkinson’s disease.

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Models of Parkinson’s Disease

Non-human models of Parkinson’s disease are essential for understanding the causes and progression of neurodegeneration and for efficiently developing new therapies. The standard animal models now used are the 6-hydroxydopamine treated rodent and the MPTP treated primate. Both are based on toxic destruction of dopaminergic brain cells (and some other types), and usually employ young, otherwise healthy animals. Because these models reproduce some key features of Parkinson’s disease, they are useful to test emerging new therapies. To this end better behavioral assessment of these models, particularly rodents, is needed. While these models will continue to have an important role in the study of Parkinson’s disease, they are far from adequate. They do not mimic the cause of human Parkinson’s disease, the progressive neurodegeneration, or the destruction of non-dopamine cells. A spectrum of new models is necessary to study all aspects of the disease.

Molecular assays based on the new molecular understanding of synuclein, parkin and other proteins involved in the pathogenic process are now being developed. There also is a critical need for the development of cellular models of two types: primary neurons and transformed cells. These models should have the following characteristics: (a) they must be homogenous; (b) they must exhibit as much similarity to the dopamine neurons of the substantia nigra pars compacta as possible, (c) they must be readily transfectable, and (d) they must be freely available within the scientific community. These cultures are necessary for relevant studies of many types, including studies of the impact of manipulation of the intracellular environment (including genetic manipulations), and exposure to toxins and/or neuroprotective agents.

Simple organisms like fruitflies, nematode worms, and even yeast could also be harnessed in efforts to better understand Parkinson’s disease. Increasing recognition of the similarities among the genes of humans and simple organisms is spearheading dramatic progress in understanding the mechanisms of cell death in human disease.

Transgenic mice present the best hope for producing animal models that faithfully represent the pathogenesis and progressive neurodegeneration of Parkinson’s. Such mouse models already have had a dramatic impact on research in Alzheimer’s disease, ALS, and inherited ataxias among many other neurological disorders, but have not yet become available for Parkinson’s disease. In addition to developing mouse models, insuring wide access will become increasingly important. Another possibility to explore is the use of cloning technologies to produce better and more reliable, e.g., less variable, mouse models.

Non-human primate models of Parkinson’s disease are also essential for progress in understanding the normal role of the basal ganglia, in understanding the pathophysiology of disease and in developing and testing new therapies, such as cell transplantation. The non-human primate brain bears a stronger similarity to the human brain than do brains of other species. It is increasingly apparent that many of the neurochemical changes associated with nigrostriatal dopaminergic depletion that are seen in humans and monkeys cannot be demonstrated in rodents. Additionally, because the non-human primate motor repertoire closely resembles that of humans, it is easy to recognize signs of Parkinsonism in MPTP-treated monkeys, and to interpret the clinical significance of effective clinical interventions in this model. The MPTP-treated non-human primate is currently the most accurate model of Parkinson’s disease in terms of neurochemical anatomy and response to symptomatic and restorative treatment.

Unfortunately, relatively few investigators have the resources to use primates and many research institutions lack primate facilities. In addition to primate housing and routine care, specialized resources are essential for many types of studies, including neuroimaging capabilities and expertise in neurosurgery, Parkinson’s models, and clinical evaluation of primates. NIH could explore the most effective means for providing these resources, whether via existing primate centers or other mechanisms.

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Biomarkers

Biomarkers are biological characteristics used to indicate or measure disease risk, presence of disease, and disease progression. Development of reliable biomarkers for Parkinson’s disease would dramatically accelerate research on the etiology, pathophysiology, disease progression and therapeutics of Parkinson’s disease. To be most useful, biomarkers must not only be specific and sensitive, but also sufficiently risk-free and simple that they may be used in routine medical examinations.

At present, the most mature biomarkers for Parkinson’s disease are both based on imaging using radioactive nucleides. PET/F-Dopa measures dopamine function and SPECT/B-CIT tags the dopamine transporter. Both reflect Parkinson’s disease trait (does one have the disease?) and state (at what stage is the disease?). During the next five years, imaging biomarkers will play a critical role in monitoring Parkinson’s disease ‘state’ in longitudinal studies of disease progression. As we are poised on the brink of studies to assess new protective and restorative therapies for Parkinson’s disease, neuroimaging offers the potential to provide an objective endpoint for these therapeutic trials. While these technologies are inappropriate for widespread population screening, following persons with increased risk for developing Parkinson’s disease, such as unaffected family members, also may provide valuable information about pre-symptomatic Parkinson’s disease and its progression. For these reasons, it is now essential to develop additional resources and design studies to expand the use of imaging biomarkers.

Beyond insuring optimal use of existing imaging biomarkers, it is critical to foster the development of new markers. Given the likely multiple etiologies of Parkinson’s disease and the clear heterogeneity in expression of the clinical manifestations and progression of Parkinson’s disease, several biomarkers will be necessary to fully understand the disorder. During the next five years several studies should be funded to develop and validate new biomarkers for Parkinson’s disease. These markers are likely to arise from both new and conventional technologies. Areas likely to contribute would include:

Genetic markers from large families, association studies. Novel proteins identified from tissue, CSF, serum of Parkinson’s disease subjects and/or families from high throughput screening technologies. Markers derived from known etiologic proteins in at risk populations (i.e., synuclein-related markers).

Markers derived from known or potential mechanisms of cell degeneration (markers for mitochondrial dysfunction, apoptosis).

Novel imaging markers including new radioligands and use of MRI spectroscopy and functional MRI and magnetoencephalography.

Early clinical markers - biomarkers of abnormal motor physiology, cognitive dysfunction, sleep disturbance (REM sleep disorder), loss of olfaction.

Pharmacogenomic markers for response to Parkinson’s disease medications. Markers specifically to identify non-motor manifestation of Parkinson’s disease - cognitive dysfunction, autonomic dysfunction, speech disturbance.

The efficient testing of potential biomarkers, perhaps simultaneously, and the optimal use of current or expanding repositories of tissue or genetic materials from Parkinson’s disease subjects for this purpose should be encouraged.

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Neuroimaging

Neuroimaging provides noninvasive measurements of brain structure and function. There are multiple important roles for neuroimaging in Parkinson’s disease research that cut across a variety of research areas including development of biomarkers, investigations of pathogenesis, studies of pathophysiology and applications to treatment trials. There is a wide spectrum of types of measurements that may reveal important insights into the other aspects of Parkinson’s disease not directly related to biomarkers and treatment trials. These include measurements of various transmitter/receptor systems with PET or SPECT for direct measures of radioligand binding, effects of selective drugs on blood flow or metabolism (pharmacologic activation); measures of endogenous dopamine; physiological activation with specific motor, cognitive or mood paradigms; stereological measures, MR spectroscopy, and effects of selective electrical or magnetic stimulation. A variety of imaging modalities may be appropriate for such studies including PET, SPECT, MRI, functional MR, MR spectroscopy, magnetoencephalography or optical imaging. Further, there is great potential to integrate these studies with other investigations either at the systems or molecular level.

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Brain Banks And Other Repositories

The systematic collection, maintenance, and distribution of biological and clinical materials are essential resources in advancing basic and clinical research for Parkinson’s disease. More than ever access to well preserved and clinically well characterized post-mortem specimens from patients with Parkinson’s disease is critical for progress. Indeed, post-mortem studies provide the acid test of relevance of new hypothesis to the human disease. It will be important to examine new markers that emerge as a result of genetic studies and cell biological studies of mechanisms of cell death in post-mortem tissue. Furthermore, definitive diagnosis of Parkinson’s disease and of other forms of Parkinsonism can presently only be provided by post-mortem studies. This diagnosis is essential to validate data from epidemiological studies and emerging biomarkers.

Unfortunately, brain collection at the moment is rare for Parkinson’s disease, available brains are not always widely available to researchers and are not always collected or handled in a way that permits those studies important for Parkinson’s disease. In addition to brain banks, there are other unmet needs for repositories of biological specimens and correlative databases relevant to Parkinson’s disease. Several repositories have already been established in North America and world wide, but there is a lack of standardization in collecting procedures, awareness and use by researchers, and financial support for the collection, preparation and maintenance of these materials.

NIH can play a key role in facilitating and catalyzing the maintenance, growth and expansion of these vital resources. NIH should consult with directors of existing brain banks and other repositories for Parkinson’s disease in order to determine the most effective approaches for establishing, maintaining, and providing access to these resources, including the establishment of necessary standards for the collection of brains and other specimens.

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ENHANCING THE RESEARCH PROCESS

Ethical Issues in Research Involving Persons with Parkinson's Disease

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 relating to Parkinson’s disease arise both from research and, more broadly, from care of patients with this disease.

Elements of clinical study design that may raise ethical or policy questions include: the decision to move from animal models to trials in human patients; surgical trial design; selection of control groups, including use of placebo controls; equitable selection of subjects; complex assessments of risks and benefits; consent procedures for complex decisions by patients with and without intact decision making capacity and their proxies; and reducing constraints on the voluntariness of subject participation.

Several interventions under study for the treatment of Parkinson’s disease raise special ethical and policy questions. These include, for example, the implantation of neural stimulators and other devices, fetal tissue and stem cell implants, xenografts, and gene therapy. Other policy issues that may arise in the study of interventions for the diagnosis, prevention, and treatment of Parkinson’s disease include: the relative cost-effectiveness of alternative interventions; off-label use of interventions; incentives driving diffusion of technology and drug availability; patent rights and responsibilities; the relationships among industry, academic centers, NIH and patients; principles and procedures used by payers to make coverage decisions; relationships between NIH and HMOs; storage of DNA, tissue specimens, and health records with identifiers for research purposes; and the use of presymptomatic screening before interventions become available to slow the disease. Finally, as with many progressive diseases, care of patients with Parkinson’s disease also raises issues relating to quality of life, advance directives, and end of life decisions.

NIH should support studies of the ethical, policy, and social challenges raised by interventions to diagnose, prevent, and treat Parkinson’s disease and the methodologies used to study these interventions. Such studies may be an integral part of ongoing clinical efforts, a component of Parkinson’s center activities, or independent investigations of particular issues. Preclinical and clinical studies concerning Parkinson’s disease supported by NIH should identify, address, and where appropriate, study central ethical and policy challenges raised by the intervention or study design. Patients and their representative should participate in evaluation of the ethical and policy issues.

Innovative Funding Mechanisms

The preceding sections recommend specific research topics that could be addressed in Parkinson’s disease research. Mounting the most effective campaign would require new approaches to supporting the research enterprise as well.

a. Seed money

Many of the opportunities for innovative projects to understand and treat Parkinson’s would involve applying new technologies to old questions, asking entirely new questions, or addressing the problem from the perspective of related but previously underutilized scientific disciplines. Starting down a new pathway of research would require that we take funding risks on projects with much less certain outcomes than we traditionally expect. We therefore would plan to expand the use of Exploratory Grants for Innovative Research (R21) or Small Grants (R03), through Program Announcements or Requests for Applications that explicitly decrease emphasis on preliminary data as a criterion for peer review. Budgets for these pilot grants would depend on the nature of the science in each solicitation. A sufficient number of these exploratory grants would have to be funded in the next few years to generate a reasonably large pool of follow-on grants in subsequent years.

b. Research Supplements

An effective way to make rapid progress in areas of immediate scientific opportunity is to provide supplements to existing projects. The appropriate supporting environment is already in place, and start-up time for this new direction is minimized. Supplements to existing Morris K. Udall Parkinson’s Disease Research Centers of Excellence or Alzheimer’s Disease Centers would be an efficient vehicle for such supplementation, either for current Center participants or other investigators who would become affiliates for this purpose. Supplements to other grants not currently focused on Parkinson’s disease should also be considered, in collaboration with other NIH Institutes and funding organizations, to add a new Parkinson’s component. The latter might be especially effective in attracting scientists with new approaches to working on Parkinson’s disease.

c. Accelerated Review

Once an investigator has an idea for a project, it is crucial that funding be provided as quickly as possible. With innovative approaches to referral and review of the applications, time from receipt to award could be reduced to no more than six months for standard grants. For pilot studies, an abbreviated application and delegated authority to staff to make awards without formal Council review could reduce the time line even further. Success of such a process would depend upon the willingness of scientists to respond quickly to requests for reviews in their areas of expertise.

d. Targeted research

Though investigator-initiated research would remain the primary NIH funding model, this planning process has identified opportunities for targeted research to fill key gaps in the overall research landscape. Taking such a comprehensive perspective would require enhancing NIH’s professional staff and improved use of devices such as RFA’s, Program Announcements, contracts and cooperative agreements.

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Public-Private Partnerships

Private organizations and NIH play critical roles in Parkinson’s disease research that are complementary to the NIH mission. NIH is committed to fostering a public-private partnership to coordinate efforts to defeat this disease. The Parkinson’s Research Planning Agenda Workshop highlighted several areas in which NIH and advocacy groups can work together.

  • Private organizations because of their extensive contacts and their trusted position in the Parkinson’s community play essential roles in the recruitment of patients and families to participate in genetic studies, clinical trials and outcomes studies. NIH is already working closely with several groups to establish a Web-based Parkinson’s disease registry.
  • In the funding arena, private organizations can target funds quickly, provide needed seed money for investigators to accumulate preliminary data for NIH grant applications, and can, through persuasion as well as funds, bring talented new investigators to the challenges of Parkinson’s disease research.
  • Private groups can also interact with Industry in a manner that might be inappropriate for government.
  • Advocacy groups are already the most important source of information for patients. In the rapidly changing arena of Parkinson’s clinical research, NIH and these organizations must work together to disseminate reliable knowledge to patients, scientists and physicians. Parkinson’s groups must help guide NIH in confronting the many ethical issues arising from advances in research.
  • NIH must also work together with private groups to resolve questions regarding the best ways to track NIH spending on Parkinson’s disease research, including monitoring efforts to implement the research agenda as a management tool.
  • Finally, representatives from several Parkinson’s advocacy groups were actively engaged in the planning process leading to this report. NIH found their involvement exceedingly useful and constructive. NIH is committed to working collaboratively with the Parkinson’s community to refine and update the Parkinson’s Disease Research Agenda, to implement the agenda to the extent funding permits and to monitor its progress.

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CONCLUSIONS

This report tracks the recommendations of the January 4-6, 2000 planning conference. It covers seven broad topics. The first topic is research to improve our understanding of Parkinson’s disease. This encompasses research into the genetic and environmental risk factors relevant to the etiology and pathogenesis of the disease; the cell biology involved in the life and death of nerve cells relevant to Parkinson’s disease; and the nature and changes in neural circuits involved in Parkinson’s disease. The second broad topic focuses on research directly aimed at developing improved therapies, both pharmacological and surgical, to treat Parkinson’s disease. The third topic, briefly addressed, is outcomes-based research to provide evidence upon which clinicians can more scientifically select among existing treatment options for particular patients. The fourth topic is increasing the productivity of NIH’s research investment through selective use of centralized resources and other means. The report identifies several ways in which progress could be advanced by NIH taking a leadership role to facilitate use of array technologies, animal models, data collection and sharing, the development and use of biomarkers, and support for high throughput drug screening methods. Fifth, the report discusses the need for research assessing the ethical issues underlying clinical trials and other ethical, policy and social issues presented by the search to cure Parkinson’s disease. Sixth, the report discusses the need for innovative funding mechanisms if the pace of progress is to be accelerated. Finally, the report provides professional judgment estimates regarding what it would cost to implement this agenda over the next five years without regard to economic constraints or other competing priorities of the Federal government.

The difficulty of finding a cure for Parkinson’s disease is all the more evident because we cannot yet cure any major neurodegenerative disease. Thus, Parkinson’s disease could lead the way to helping people with many devastating disorders that damage and ultimately destroy cells in the nervous system. Indeed, several of the critical problems highlighted in this Agenda, if solved for Parkinson’s, would immediately apply to other disorders. Designing vectors for gene therapy in the nervous system and finding ways to deliver drugs to the brain are problems for most brain diseases. Dopamine biology is critical not only for Parkinson’s, but also for dystonia, Tourettes, drug addiction, and schizophrenia to name just a few. Many mechanisms of cell death implicated in Parkinson’s disease are also culprits in other brain disorders. The same prospective epidemiological studies are likely to yield much needed information for many diseases of the brain. The development of technologies such as gene arrays, brain imaging, and high throughput drug screening have obvious synergies with other disorders, and perhaps less obviously, so do cell transplantation and deep brain stimulation. Innovative mechanisms for research support and for attracting talented scientists may also be widely applicable if successful for Parkinson’s disease. Likewise the ethical concerns that confront Parkinson’s disease are issues for many diseases of the brain. While this document is properly focused on Parkinson’s disease research, the relevance of this research agenda for many disorders of the brain 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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APPENDIX


 

PROFESSIONAL JUDGMENT ESTIMATES


Parkinson's Disease (PD) Research Agenda Budget Estimates


 

Dollar Increases Over Baseline Budget (Thousands of Dollars)


 

(* Agenda began mid-year in FY 2000)

I.     Research

A.  Understanding PD
Category FY2001* Year 1 FY2002 Year 2 FY2003 Year 3 FY2004 Year 4 FY2005 Year 5 Subtotal 5 Years
Genetics 5,000 10,200 10,600 11,000 11,400 48,200
Epidemiology 5,000 15,200 25,800 26,800 27,800 100,600
Life&Death of Neurons in PD 10,000 26,400 33,500 41,600 43,400 154,900
Circuits 2,000 4,100 6,300 8,800 9,200 30,400
Understanding PD-Subtotal 22,000 55,900 76,200 88,200 91,800 334,100

B.  Treating PD
Category FY2001* Year 1 FY2002 Year 2 FY2003 Year 3 FY2004 Year 4 FY2005 Year 5 Subtotal 5 Years
Pharmacological Approaches            
   Phase I/Pilot Studies 4,000 4,100 4,200 4,400 4,600 21,300
   Large Clinical Trials 8,000 12,300 16,700 17,200 17,800 72,000
   Complications and Non-motor Symptoms 2,000 2,100 2,200 2,300 2,400 11,000
   Prevention Trials 1,000 1,000 1,000 1,000 1,000 5,000
Pharmacological Approaches-Subtotal 15,000 19,500 24,100 24,900 25,800 109,300
Other Approaches            
Deep Brain Stimulation and Other Surgical Approaches 10,000 15,400 21,000 21,800 22,600 90,800
Cell Implantation 2,000 4,100 6,300 12,600 13,700 38,700
Gene Therapy 2,000 3,100 5,200 7,400 9,300 27,000
Rehabilitation 1,000 1,000 1,000 1,000 1,100 5,100
Outcomes Research 1,000 2,000 2,000 2,000 3,000 10,000
Other Approaches-Subtotal 16,000 25,600 35,500 44,800 49,700 171,600
Treating PD-Subtotal 31,000 45,100 59,600 69,700 75,500 280,900

C.  Creating New Research Capabilities
Category FY2001* Year 1 FY2002 Year 2 FY2003 Year 3 FY2004 Year 4 FY2005 Year 5 Subtotal 5 Years
Creating New Research Capabilities 15,000 35,500 51,800 78,600 106,500 287,400

D.  Enhancing the Research Process
Category FY2001* Year 1 FY2002 Year 2 FY2003 Year 3 FY2004 Year 4 FY2005 Year 5 Subtotal 5 Years
Enhancing the Research Process - Ethics 1,000 2,000 3,000 3,000 3,000 12,000


 
Category FY2001* Year 1 FY2002 Year 2 FY2003 Year 3 FY2004 Year 4 FY2005 Year 5 Subtotal 5 Years
Research-Subtotal 69,000 138,500 190,600 239,500 276,800 914,400


II.     Program Management and Direction

Category FY2001* Year 1 FY2002 Year 2 FY2003 Year 3 FY2004 Year 4 FY2005 Year 5 Subtotal 5 Years
Program Management and Direction 2,400 5,000 6,800 8,600 9,900 32,700


 
Category FY2001* Year 1 FY2002 Year 2 FY2003 Year 3 FY2004 Year 4 FY2005 Year 5 Subtotal 5 Years
Grand Total 71,400 143,500 197,400 248,100 286,700 947,100

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LIST OF PARTICIPANTS

Kenneth A. Aidekman
Chairman of the Board
Parkinson’s Unity Walk

Robert E. Burke, M.D.
Department of Neurology
Columbia University

Marc G. Caron, Ph.D.
Department of Cell Biology
Duke University Medical Center/HHMI

Marie-Francoise Chesselet, M.D., Ph.D.
Department of Neurology
UCLA

Perry D. Cohen, Ph.D.
Parkinson’s Disease Foundation

Ted M. Dawson, M.D., Ph.D.
Department of Neurology
Johns Hopkins University
School of Medicine

Mahlon R. DeLong, M.D.
Chairman
Department of Neurology
Emory University

Robin Elliott
Executive Director
Parkinson’s Disease Foundation

Stanley Fahn, M.D.
Department of Neurology
College of Physicians

Howard J. Federoff, M.D., Ph.D.
Center for Aging and Developmental Biology
University of Rochester

Joel Gerstel
Executive Director
American Parkinson Disease Association, Inc.

J. Timothy Greenamyre, M.D. Ph.D.
Department of Neurology
Emory University

John A. Hardy, Ph.D.
Research Division
Mayo Clinic Jacksonville

Lawrence Hoffheimer, J.D.
Washington Counsel
National Parkinson Foundation

Thomas M. Jessell, Ph.D.
Department of Biochemistry &
Molecular Biophysics
Columbia University

Karl Kieburtz, M.D., MPH
Department of Neurology
University of Rochester Medical Center

William C. Koller
Department of Neurology
University of Miami

James W. Langston, M.D.
President
The Parkinson’s Institute

Peter T. Lansbury, Jr., Ph.D.
Department of Neurology
Harvard Medical School and
Brigham & Women’s Hospital

Andres M. Lozano, M.D., Ph.D.
Department of Surgery
University of Toronto
Toronto Western Hospital

Ken Marek, M.D.
Director, Movement Disorders Clinic
Yale University School of Medicine

Jeffrey C. Martin
Partner – Shea & Gardner
Senior VP – Saks Incorporated

Perry Molinoff, M.D.
Vice President
Neuroscience/GU Drug Discovery
Bristol-Meyers Squibb

Joel S. Perlmutter, M.D.
Department of Neurology
Washington University School of Medicine

Donald Price, M.D.
Department of Pathology
Johns Hopkins University

Arnon Rosenthal, Ph.D.
Department of Molecular Biology
Genentech, Inc.

Joan I. Samuelson, J.D.
President
Parkinson’s Action Network

Ira Shoulson, M.D.
Department of Neurology
University of Rochester

Nathan Slewett
Chairman of the Board
National Parkinson Foundation.

Caroline M. Tanner, M.D., Ph.D.
Director, Clinical Research
The Parkinson’s Institute

John Q. Trojanowski, M.D., Ph.D.
Department of Pathology and Laboratory Medicine
University of Pennsylvania

Marty Tuchman
National Parkinson Foundation

Dorothy E. Vawter, Ph.D.
Minnesota Center for Health Care Ethics

Michael J. Zigmond, Ph.D.
Department of Neurology
University of Pittsburgh

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NIH Staff

Beth Ansel, Ph.D.
Program Director, Voice & Speech
National Institute on Deafness and Other Communication Disorders
National Institutes of Health

Marian Emr
Director, Office of Communications and Public Liaison
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Judith A. Finkelstein, Ph.D.
Health Scientist Administrator
Neuroscience/Neuropsychology of Aging
National Institute on Aging
National Institutes of Health

Gerald Fischbach, M.D.
Director
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Kenneth H. Fischbeck, M.D.
Chief, Neurogenetics Branch
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Mark Hallett, M.D.
Clinical Director
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Jill Heemskerk, Ph.D.
Program Director
Neurodegeneration Cluster
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Bill Heetderks, M.D., Ph.D.
Program Director
Repair and Plasticity Cluster
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Annette G. Kirshner, Ph.D.
Health Science Administrator
Division of Extramural Research and Training
National Institutes of Environmental Health Sciences
National Institutes of Health

Story Landis, Ph.D.
Scientific Director
National Institute of Neurological Disorders and Stroke
National Institutes of Health

John R. Marler, M.D.
Associate Director for Clinical Trials
Neurodegeneration Cluster
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Ron D. McKay, Ph.D.
Chief, Laboratory of Molecular Biology
National Institute of Neurological Disorders and Stroke
National Institutes of Health, LMB

Mary L. Miers, M.A.
Chief, Science Policy and Analysis Branch
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Diane D. Murphy, Ph.D.
Program Director
Neurodegeneration Cluster
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Eugene Oliver, Ph.D.
Program Director
Neurodegeneration Cluster
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Curt Pospisil
Public Health Analyst
Neurodegeneration Cluster
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Jon Retzlaff
Senior Legislative Advisor
Science and Policy Analysis Branch
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Carol Rowan
Chief, Public Inquiries
Office of Communications and Public Liaison
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Paul A. Scott, Ph.D.
Science Advisor
Science Policy and Analysis Branch
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Paul A. Sheehy, Ph.D.
Scientific Review Administrator
Division of Extramural Activities
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Mary Tomanek
Special Assistant to the Director
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Allison Wichman, M.D.
Deputy Director
Office of Human Subjects Research
National Institutes of Health

Brad Wise, Ph.D.
Program Director
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
National Institutes of Health

Robert A. Zalutsky, Ph.D.
Senior Science Advisor
Science and Policy Branch
National Institute of Neurological Disorders and Stroke
National Institutes of Health

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Reviewed July 1, 2001

Last updated June 26, 2012