By National Institute of Neurological Disorders & Stroke
In recent years, Parkinson's research has advanced to the point that halting the progression of Parkinson's disease (PD), restoring lost function, and even preventing the disease are all considered realistic goals. While the ultimate goal of preventing Parkinson's disease may take years to achieve, researchers are making great progress in understanding and treating Parkinson's disease.
One of the most exciting areas of Parkinson's research is genetics. Studying the genes responsible for inherited cases can help researchers understand both inherited and sporadic cases of the disease. Identifying gene defects can also help researchers understand how PD occurs, develop animal models that accurately mimic the neuronal death in human PD, identify new drug targets, and improve diagnosis.
Several genes have been definitively linked to PD in some people. Researchers also have identified a number of other genes that may play a role and are working to confirm these findings. In addition, several chromosomal regions have been linked to PD in some families. Researchers hope to identify the genes located in these chromosomal regions and to determine which of them may play roles in Parkinson's.
Researchers funded by the National Institute of Neurological Disorders and Stroke (NINDS) are gathering information and DNA samples from hundreds of families with PD and are conducting large-scale gene expression studies to identify genes that are abnormally active or inactive in PD. They also are comparing gene activity in PD with gene activity in similar diseases such as progressive supranuclear palsy.
Researchers Attempt to Determine Cause of Parkinson's Disease
Some scientists have found evidence that specific variations in the DNA of mitochondria – structures in cells that provide the energy for cellular activity — can increase the risk of getting PD, while other variations are associated with a lowered risk of the disorder. They also have found that people with Parkinson's disease have more mitochondrial DNA (mtDNA) variations than patients with other movement disorders or Alzheimer's disease. Researchers are working to define how these DNA variations may lead to Parkinson's disease.
In addition to identifying new genes for PD, researchers are trying to learn how known PD genes function and how the gene mutations cause disease. For example, a study found that the normal alpha-synuclein protein may help other proteins that are important for nerve transmission to fold correctly. Other studies have suggested that the normal parkin protein protects neurons from a variety of threats, including alpha-synuclein toxicity and excitotoxicity.
Environmental Impact on Parkinson's
Scientists continue to study environmental toxins such as pesticides and herbicides that can cause PD symptoms in animals. They have found that exposing rodents to the pesticide rotenone and several other agricultural chemicals can cause cellular and behavioral changes that mimic those seen in Parkinson's disease.
Other studies have suggested that prenatal exposure to certain toxins can increase susceptibility to PD in adulthood. An NIH-sponsored program called the Collaborative Centers for Parkinson's Disease Environmental Research (CCPDER) focuses on how occupational exposure to toxins and use of caffeine and other substances may affect the risk of Parkinson's.
Protein Disposal System
Another major area of PD research involves the cell's protein disposal system, called the ubiquitin-proteasome system. If this disposal system fails to work correctly, toxins and other substances may build up to harmful levels, leading to cell death. The ubiquitin-proteasome system requires interactions between several proteins, including parkin and UCH-L1. Therefore, disruption of the ubiquitin-proteasome system may partially explain how mutations in these genes cause Parkinson's.
Main Areas of Parkinson's Disease Research in Geriatric Health
Other Parkinson's disease studies focus on how Lewy bodies form and what role they play in PD. Some studies suggest that Lewy bodies are a byproduct of degenerative processes within neurons, while others indicate that Lewy bodies are a protective mechanism by which neurons lock away abnormal molecules that might otherwise be harmful. Additional studies have found that alpha-synuclein clumps alter gene expression and bind to vesicles within the cell in ways that could be harmful.
Another common topic of PD research is excitotoxicity – overstimulation of nerve cells that leads to cell damage or death. In excitotoxicity, the brain becomes oversensitized to the neurotransmitter glutamate, which increases activity in the brain. The dopamine deficiency in PD causes overactivity of neurons in the subthalamic nucleus, which may lead to excitotoxic damage there and in other parts of the brain. Researchers also have found that dysfunction of the cells' mitochondria can make dopamine-producing neurons vulnerable to glutamate.
Other researchers are focusing on how inflammation may affect PD. Inflammation is common to a variety of neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, HIV-1-associated dementia, and amyotrophic lateral sclerosis. Several studies have shown that inflammation-promoting molecules increase cell death after treatment with the toxin MPTP. Inhibiting the inflammation with drugs or by genetic engineering prevented some of the neuronal degeneration in these studies.
Other research has shown that dopamine neurons in brains from patients with Parkinson's have higher levels of an inflammatory enzyme called COX-2 than those of people without PD. Inhibiting COX-2 doubled the number of neurons that survived in a mouse model for PD.
Clinical Studies on Causes and Treatments of Parkinson's Disease
Since the discovery that MPTP causes parkinsonian symptoms in humans, scientists have found that by injecting MPTP and certain other toxins into laboratory animals, they can reproduce the brain lesions that cause these symptoms. This allows them to study the mechanisms of the disease and helps in the development of new treatments for Parkinson's disease.
They also have developed animal models with alterations of the alpha-synuclein and parkin genes. Other researchers have used genetic engineering to develop mice with disrupted mitochondrial function in dopamine neurons. These animals have many of the characteristics associated with Parkinson's disease.
Biomarkers for PD – measurable characteristics that can reveal whether the disease is developing or progressing – are another focus of research. Such biomarkers could help doctors detect the disease before symptoms appear and improve diagnosis of the disease. They also would show if medications and other types of therapy have a positive or negative effect on the course of the disease. Some of the most promising biomarkers for PD are brain imaging techniques.
For example, some researchers are using positron emission tomography (PET) brain scans to try to identify metabolic changes in the brains of people with Parkinson's and to determine how these changes relate to disease symptoms. Other potential biomarkers for PD include alterations in gene expression.
Research on Treatments for Parkinson's
Researchers also are conducting many studies of new or improved therapies for Parkinson's. While deep brain stimulation (DBS) is now FDA-approved and has been used in thousands of people with PD, researchers continue to try to improve the technology and surgical techniques in this therapy. For example, some studies are comparing DBS to the best medical therapy and trying to determine which part of the brain is the best location for stimulation. Another clinical trial is studying how DBS affects depression and quality of life.
Other clinical studies are testing whether transcranial electrical polarization (TEP) or transcranial magnetic stimulation (TMS) can reduce the symptoms of PD. In TEP, electrodes placed on the scalp are used to generate an electrical current that modifies signals in the brain's cortex. In TMS, an insulated coil of wire on the scalp is used to generate a brief electrical current.
Medications and the Progression of Parkinson's Disease
One of the enduring questions in Parkinson's disease research has been how treatment with levodopa and other dopaminergic drugs affects progression of the disease. Researchers are continuing to try to clarify these effects.
One study has suggested that people with Parkinson's with a low-activity variant of the gene for COMT (which breaks down dopamine) perform worse than others on tests of cognition, and that dopaminergic drugs may worsen cognition in these people, perhaps because the reduced COMT activity causes dopamine to build up to harmful levels in some parts of the brain. In the future, it may become possible to test for such individual gene differences in order to improve treatment of PD.
A variety of new drug treatments are in clinical trials for Parkinson's. These include a drug called GM1 ganglioside that increases dopamine levels in the brain. Researchers are testing whether this drug can reduce symptoms, delay disease progression, or partially restore damaged brain cells in PD patients.
Other studies are testing whether a drug called istradefylline can improve motor function in PD, and whether a drug called ACP-103 that blocks receptors for the neurotransmitter serotonin will lessen the severity of parkinsonian symptoms and levodopa-associated complications in PD patients. Other topics of research include controlled-release formulas of PD drugs and implantable pumps that give a continuous supply of levodopa.
Some researchers are testing potential neuroprotective drugs to see if they can slow the progression of PD. One study, called NET-PD (Neuroexploratory Trials in Parkinson's Disease), is evaluating minocycline, creatine, coenzyme Q10, and GPI-1485 to determine if any of these agents should be considered for further testing. The NET-PD study may evaluate other possible neuroprotective agents in the future.
Drugs found to be successful in the pilot phases may move to large phase III trials involving hundreds of patients. A separate group of researchers is investigating the effects of either 1200 or 2400 milligrams of coenzyme Q10 in 600 patients. Several MAO-B inhibitors, including selegiline, lazabemide, and rasagiline, also are in clinical trials to determine if they have neuroprotective effects in people with Parkinson's.
Research on Nerves and Brain Cells Regarding Parkinson's Disease
Nerve growth factors, or neurotrophic factors, which support survival, growth, and development of brain cells, are another type of potential therapy for Parkinson's disease. One such drug, glial cell line-derived neurotrophic factor (GDNF), has been shown to protect dopamine neurons and to promote their survival in animal models of PD.
This drug has been tested in several clinical trials for people with PD, and the drug appeared to cause regrowth of dopamine nerve fibers in one person who received the drug. However, a phase II clinical study of GDNF was halted in 2004 because the treatment did not show any clinical benefit after 6 months, and some data suggested that it might even be harmful. Other neurotrophins that may be useful for treating PD include neurotrophin-4 (NT-4), brain-derived neurotrophic factor (BDNF), and fibroblast growth factor 2 (FGF-2).
While there is currently no proof that any dietary supplements can slow PD, several clinical studies are testing whether supplementation with vitamin B12 and other substances may be helpful. A 2005 study found that dietary restriction — reducing the number of calories normally consumed – helped to increase abnormally low levels of the neurotransmitter glutamate in a mouse model for early PD. The study also suggested that dietary restriction affected dopamine activity in the brain. Another study showed that dietary restriction before the onset of PD in a mouse model helped to protect dopamine-producing neurons.
Other studies are looking at treatments that might improve some of the secondary symptoms of PD, such as depression and swallowing disorders. One clinical trial is investigating whether a drug called quetiapine can reduce psychosis or agitation in PD patients with dementia and in dementia patients with parkinsonian symptoms. Some studies also are examining whether transcranial magnetic stimulation or a food supplement called s-adenosyl-methionine (SAM-e) can alleviate depression in people with PD, and whether levetiracetam, a drug approved to treat epilepsy, can reduce dyskinesias in Parkinson's patients without interfering with other PD drugs.
Higher Dopamine Levels Linked to Treating Parkinson's Disease
Another approach to treating Parkinson's disease is to implant cells to replace those lost in the disease. Researchers are conducting clinical trials of a cell therapy in which human retinal epithelial cells attached to microscopic gelatin beads are implanted into the brains of people with advanced PD. The retinal epithelial cells produce levodopa. The investigators hope that this therapy will enhance brain levels of dopamine.
Starting in the 1990s, researchers conducted a controlled clinical trial of fetal tissue implants in people with PD. They attempted to replace lost dopamine-producing neurons with healthy ones from fetal tissue in order to improve movement and the response to medications. While many of the implanted cells survived in the brain and produced dopamine, this therapy was associated with only modest functional improvements, mostly in patients under the age of 60. Unfortunately, some of the people who received the transplants developed disabling dyskinesias that could not be relieved by reducing antiparkinsonian medications.
Stem Cells in Parkinson's Research
Another type of cell therapy involves stem cells. Stem cells derived from embryos can develop into any kind of cell in the body, while others, called progenitor cells, are more restricted. One study transplanted neural progenitor cells derived from human embryonic stem cells into a rat model of PD. The cells appeared to trigger improvement on several behavioral tests, although relatively few of the transplanted cells became dopamine-producing neurons. Other researchers are developing methods to improve the number of dopamine-producing cells that can be grown from embryonic stem cells in culture.
Researchers also are exploring whether stem cells from adult brains might be useful in treating Parkinson's. They have shown that the brain's white matter contains multipotent progenitor cells that can multiply and form all the major cell types of the brain, including neurons.
Scientists Test Gene Therapy to Treat Parkinson's Disease
Gene therapy is yet another approach to treating Parkinson's disease. A study of gene therapy in non-human primate models of PD is testing different genes and gene-delivery techniques in an effort to refine this kind of treatment. An early-phase clinical study is also testing whether using the adeno-associated virus type 2 (AAV2) to deliver the gene for a nerve growth factor called neurturin is safe for use in people with PD.
Another study is testing the safety of gene therapy using AAV to deliver a gene for human aromatic L-amino acid decarboxylase, an enzyme that helps convert levodopa to dopamine in the brain. Other investigators are testing whether gene therapy to increase the amount of glutamic acid decarboxylase, which helps produce an inhibitory neurotransmitter called GABA, might reduce the overactivity of neurons in the brain that results from lack of dopamine.
A Vaccine for Parkinson's?
Another potential approach to treating Parkinson's is to use a vaccine to modify the immune system in a way that can protect dopamine-producing neurons. One vaccine study in mice used a drug called copolymer-1 that increases the number of immune T cells that secrete anti-inflammatory cytokines and growth factors. The researchers injected copolymer-1-treated immune cells into a mouse model for PD.
The vaccine modified the behavior of supporting (glial) cells in the brain so that their responses were beneficial rather than harmful. It also reduced the amount of neurodegeneration in the mice, reduced inflammation, and increased production of nerve growth factors. Another study delivered a vaccine containing alpha-synuclein in a mouse model of PD and showed that the mice developed antibodies that reduced the accumulation of abnormal alpha-synuclein.
While these studies are preliminary, investigators hope that similar approaches might one day be tested in humans.
The National Institute of Neurological Disorders and Stroke (NINDS) conducts and supports research on brain and nervous system disorders.