In most cases, there is no way to predict or prevent
sporadic Parkinson Disease. However, researchers are looking for a biomarker a
biochemical abnormality that all patients with Parkinson Disease might share that could
be picked up by screening techniques or by a simple chemical test given to
people who do not have any parkinsonian symptoms. This could help doctors
identify people at risk of the disease. It also might allow them to find
treatments that will stop the disease process in the early stages.
Positron emission tomography (PET) scanning may lead to
important advances in our knowledge about Parkinson Disease. PET scans of the brain produce
pictures of chemical changes as they occur. Using PET, research scientists
can study the brain's dopamine receptors (the sites on nerve cells that bind
with dopamine) to determine if the loss of dopamine activity follows or
precedes degeneration of the neurons that make this chemical. This
information could help scientists better understand the disease process and
may potentially lead to improved treatments.
In rare cases, where people have a clearly inherited
form of Parkinson Disease, researchers can test for known gene mutations as a way of
determining an individual's risk of the disease. However, this genetic
testing can have far-reaching implications and people should carefully
consider whether they want to know the results of such tests. Genetic
testing is currently available only as a part of research studies.
In recent years, Parkinson's research has advanced to
the point that halting the progression of Parkinson Disease, restoring lost function, and
even preventing the disease are all considered realistic goals. While the
ultimate goal of preventing Parkinson Disease may take years to achieve, researchers are
making great progress in understanding and treating Parkinson Disease.
One of the most exciting areas of
Parkinson 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
Disease occurs,
develop animal models that accurately mimic the neuronal death in human
Parkinson 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 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 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 Disease.
Researchers funded by NINDS are gathering information
and DNA samples from hundreds of families with Parkinson Disease and are conducting
large-scale gene expression studies to identify genes that are abnormally
active or inactive in Parkinson Disease. They also are comparing gene activity in
Parkinson 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
Disease, while
other variations are associated with a lowered risk of the disorder. They
also have found that Parkinson 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 Disease.
In addition to identifying new genes for
Parkinson Disease,
researchers are trying to learn how known Parkinson 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 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 Disease. Other studies have suggested that prenatal exposure to
certain toxins can increase susceptibility to Parkinson 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 Disease.
Another major area of Parkinson 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 Disease.
Other studies focus on how Lewy bodies form and what
role they play in Parkinson 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
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 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 Disease. Inflammation is common to a variety of neurodegenerative
diseases, including Parkinson 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 Disease have higher levels of an inflammatory enzyme called COX-2 than those of
people without Parkinson Disease. Inhibiting COX-2 doubled the number of neurons that
survived in a mouse model for Parkinson 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 Disease.
Biomarkers for Parkinson 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 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 Disease and to determine how these changes
relate to disease symptoms. Other potential biomarkers for Parkinson
Disease include
alterations in gene expression.
Researchers also are conducting many studies of new
or improved therapies for Parkinson Disease. While deep brain stimulation (DBS) is now
FDA-approved and has been used in thousands of people with Parkinson 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 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 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 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 Disease.
A variety of new drug treatments are in clinical trials
for Parkinson 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 Disease patients. Other studies are testing whether a drug called
istradefylline can improve motor function in Parkinson 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 Disease patients. Other topics of research include controlled-release formulas
of Parkinson 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 Disease. One study, called
NET-Parkinson 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
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 Disease.
Nerve growth factors, or neurotrophic factors, which
support survival, growth, and development of brain cells, are another type
of potential therapy for Parkinson 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 Disease. This drug has been tested
in several clinical trials for people with Parkinson 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 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 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 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
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 Disease, such as depression and
swallowing disorders. One clinical trial is investigating whether a drug
called quetiapine can reduce psychosis or agitation in Parkinson 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 Disease, and whether levetiracetam, a drug approved to treat epilepsy,
can reduce dyskinesias in Parkinson's patients without interfering with
other Parkinson Disease drugs.
Another approach to treating Parkinson
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 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 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 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 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 Disease. A
study of gene therapy in non-human primate models of Parkinson 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 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 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 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 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.
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