Parkinson's Disease (cont.)
What Research is Being Done on Parkinson's Disease?
In recent years, Parkinson's research has advanced to the point that halting
the progression of Parkinson's disease, 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 disease 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 Parkinson's disease occurs, develop animal models that accurately
mimic the neuronal death in human Parkinson's disease, identify new drug targets, and improve
diagnosis.
As discussed in the "What Genes are Linked to Parkinson's Disease?" section,
several genes have been definitively linked to Parkinson's disease 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 Parkinson's disease 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 disease.
Researchers funded by NINDS are gathering information and DNA samples from
hundreds of families with Parkinson's disease and are conducting large-scale gene expression
studies to identify genes that are abnormally active or inactive in Parkinson's
disease. They
also are comparing gene activity in Parkinson's disease with gene activity in similar diseases
such as progressive supranuclear palsy.
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 Parkinson's disease, while other variations are associated
with a lowered risk of the disorder. They also have found that Parkinson's
disease patients have
more mitochondrial DNA (mtDNA) variations than patients with other movement
disorders or Alzheimer's disease. Researchers are working to define how these
mtDNA variations may lead to Parkinson's disease.
In addition to identifying new genes for Parkinson's disease, researchers are trying to learn
how known Parkinson's disease genes function and how the gene mutations cause disease. For
example, a 2005 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.
Scientists continue to study environmental toxins such as pesticides and
herbicides that can cause Parkinson's disease 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 Parkinson's disease 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 disease.
Another major area of Parkinson's disease 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 disease.
Other studies focus on how Lewy bodies form and what role they play in
Parkinson's disease.
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 Parkinson's disease 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 Parkinson's disease 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 Parkinson's disease. 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 disease have higher levels of an inflammatory
enzyme called COX-2 than those of people without Parkinson's disease. Inhibiting COX-2 doubled the number of
neurons that survived in a mouse model for 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. 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 Parkinson's disease – 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 Parkinson's disease 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 disease and to determine how these changes relate to disease symptoms. Other
potential biomarkers for Parkinson's disease include alterations in gene expression.
Researchers also are conducting many studies of new or improved therapies for
Parkinson's disease. While deep brain stimulation (DBS) is now FDA-approved and has been used in
thousands of people with Parkinson's disease, 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 Parkinson's disease. 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.
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 Parkinson's disease patients 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 Parkinson's
disease.
A variety of new drug treatments are in clinical trials for
Parkinson's disease. 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 Parkinson's disease patients. Other
studies are testing whether a drug called istradefylline can improve motor
function in Parkinson's disease, 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 Parkinson's disease patients. Other topics of research
include controlled-release formulas of Parkinson's disease 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 Parkinson's disease. One study, called NET-Parkinson's
disease (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-Parkinson's disease 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 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 Parkinson's disease. This drug has been tested in several clinical trials for people
with Parkinson's disease, 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 Parkinson's disease 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
Parkinson's disease,
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 Parkinson's disease. The study also suggested that dietary restriction affected dopamine
activity in the brain. Another study showed that dietary restriction before the
onset of Parkinson's disease 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 Parkinson's disease, such as depression and swallowing disorders. One
clinical trial is investigating whether a drug called quetiapine can reduce
psychosis or agitation in Parkinson's disease 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 Parkinson's disease, and whether levetiracetam, a drug
approved to treat epilepsy, can reduce dyskinesias in Parkinson's patients
without interfering with other Parkinson's disease drugs.
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 Parkinson's disease. 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 Parkinson's disease. 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.
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 Parkinson's
disease. 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 disease. 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.
Gene therapy is yet another approach to treating Parkinson's disease. A study of gene therapy
in non-human primate models of Parkinson's disease 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 Parkinson's disease. 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.
Another potential approach to treating Parkinson's disease 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
Parkinson's disease.
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 Parkinson's disease 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.
Next: What is the Role of the NINDS? »
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