What is Parkinson's disease?

Causes and Symptoms

In 1817, James Parkinson, a British physician, wrote a description of six patients
suffering from a slowly progressing disease characterized by “involuntary
tremulous motion, with lessened muscular power in parts not in action even when
supported, with a propensity to bend their trunks forward from a walking to a
running pace.” Throughout the modern world, this disease—which Parkinson named
shaking palsy—is called Parkinson’s disease.

Parkinson’s disease, also called paralysis agitans, is now defined as a medical
condition characterized by a combination of symptoms including involuntary shaking
(tremor) of the limbs at rest, stiffness of the muscles
(rigidity), slowed or reduced ability to move the limbs and facial muscles
(bradykinesia), and general muscular weakness. Onset usually occurs after the age
of fifty.

The clinical scale most often used to describe the extent of severity of
Parkinson’s disease is that of Melvin Yahr and Margaret Hoehn, which is divided
into five stages. In stage 1, mild tremor or rigidity is seen on one side of the
body. In stage 2, tremor, rigidity, and bradykinesia occur on both sides of the
body, without any loss of balance. In stage 3, added to the symptoms of stage 2
are balance difficulty, loss of posture control, and hunching over. With stage 4,
the extent of the functional disability increases, but some independent function
is still possible. Such severe symptoms occur in stage 5 that patients require a
wheelchair or are bedridden without assistance.

The body site of Parkinson’s disease is clear, but most cases are idiopathic,
meaning that although their site of action is known, the basic cause is not and
their occurrence is spontaneous. Parkinson's disease is estimated to have a 30 to
40 percent rate of heritability. Mutations in the parkin (PARK2)
gene on chromosome 6 are found in approximately 8.6 percent of patients with
early-onset Parkinson's disease; researchers have identified more than two hundred
PARK2 gene mutations involved in the development of
Parkinson's disease. Multiple genes may be involved in idiopathic late-onset
Parkinson's disease; the tau gene is being investigated as a possible cause of
idiopathic Parkinson's disease.

Although a genetic susceptibility may be responsible for some cases of
Parkinson's, many researchers increasingly believe that the root of Parkinson’s
disease is related to environmental factors. While a handful of gene mutations
have been identified for early-onset Parkinson’s, which strikes before the age of
forty, these cases account for fewer than one out of every ten patients. Some
scientists believe that the genes involved in Parkinson's may be “activated” by
exposure to an environmental agent, such as solvents, pesticides, or viruses, and
that such agents may prompt the onset of the disease even in those individuals who
carry none of the suspected genes. Recent findings seem to support such expert
hypotheses. For example, common clusters of individuals with the disease have been
discovered, most notably three people who worked in Canada during the 1980s with
Michael J. Fox, the television and film actor who announced in 1998 that he was
suffering from Parkinson’s disease. Medical detectives are examining whether any
shared environmental exposure among this group of four can be found. Moreover,
Japanese scientists showed that a virulent strain of influenza A accumulates in
the same area of the brain attacked in Parkinson’s disease. Other studies have
shown that health care workers and teachers, individuals in fields exposed at a
greater rate to influenza strains, show a twofold increased risk of
developing the disease. Finally, epidemiological studies show that people living
in rural areas and farmers are much more likely to develop the disease than their
urban counterparts, a fact that could point to pesticide exposure or the use of
well water.

The symptoms of Parkinson’s disease begin slowly, most often presenting as stage 1
tremor. After this, the progression to stage 3 usually takes five to ten years.
This progression appears to be caused by the deterioration of several of the four
brain structures called basal ganglia (the corpus striatum, thalamus, substantia
nigra, and globus pallidus), which is related to depletion of the neurotransmitter
dopamine. Dopamine depletion is most extreme in the normally dark-pigmented
substantia nigra, which is often colorless in the autopsied brains of parkinsonism
patients.

The side effects of some drugs can produce symptoms of Parkinson’s disease that
are difficult to distinguish from non-drug-induce Parkinsonism, and they have
provided clues about the disease. Many of these drugs affect dopamine levels in
the brain and include antipsychotic medications, metoclopramide, reserpine,
tetrabenazine, some calcium channel blockers, and stimulants such as amphetamines
and cocaine. Drug-based symptoms do not appear to be causes of permanent
Parkinson’s disease because the symptoms diminish and slowly disappear after
discontinuation of the causative drugs. Many have been linked, however, to
decreased dopamine levels. Similarly, many stroke-related symptoms appear to be
caused by drug therapy that diminished brain dopamine content. The effects of
tumors have also offered helpful data because their location
can better identify the brain areas associated with the disease. For example,
information of this sort first linked the substantia nigra and corpus striatum to
Parkinson’s disease. In addition, viral encephalitis is still suspected by many of
being an important causative factor. Belief in its involvement arose, however,
from a 1918–1925 epidemic that damaged the basal ganglia, and contemporary
Parkinson’s disease as a result of encephalitis is very rare. Finally, discovery
of the MPTP connection, a neurotoxin precursor to MPP+, has yielded a useful model
for Parkinson’s disease related to psychoactive drugs that cause it.

Tremor is the most conspicuous symptom. Despite the fact that it is usually the
least disabling aspect of the disease, tremor is often embarrassing to the
affected person and it is usually the phenomenon that brings patients to a
physician for initial diagnosis. In stage 1 of Parkinson’s disease, tremor appears
only when afflicted people are very fatigued. Later in the course of the disease,
it becomes increasingly widespread and continual. It is interesting to note that
tremor ceases when a parkinsonism patient is asleep.

Although Parkinson’s disease does not alter the mental abilities of afflicted
persons, it eventually impairs their ability to carry out tasks that require
rapid, repetitive movement and manual dexterity. For example, Parkinson’s disease
very often causes handwriting to deteriorate to an illegible scrawl, makes it
impossible to fasten a shirt’s collar buttons or a brassiere, and turns shaving or
brushing the teeth into a difficult chore.

Bradykinesia is the most incapacitating aspect of Parkinson’s disease because it
impairs communication by characteristic gestures; results in an awkward gait, with
failure to swing the arms normally when walking; and produces an immobile facial
expression common to later stages. Other symptoms include drooling, caused by
problems with swallowing, and the development of a slow, muffled speech. Both are
caused by diminished mobility of the muscles of the mouth, jaws, and throat.

The nature of Parkinson’s disease is best understood after considering nerve
impulse transmission between the cells of nervous tissue (neurons) and the
arrangement and interactive function of the brain and nerves.

Nerve impulse transport between neurons is an electrochemical process that
generates the weak electric current that makes up the impulse. The impulse leaves
each neuron via an outgoing extension, called an axon, passes across a tiny
synaptic gap that separates the axon from the next neuron in line, and then enters
an incoming extension (dendrite) of that cell. This process is repeated many times
in order to transmit a nervous impulse to its site of action. The cell bodies of
neurons constitute the impulse-causing gray matter, and axons and dendrites (white
matter) may be viewed as their connecting wires (nerve fibers). Nerve impulse
passage across the synaptic gaps between neurons is mediated by chemical
messengers called neurotransmitters, such as dopamine.

The brain and nerves—the central nervous system—are a complex arrangement of
neurons designed to enable an organism to respond in a coordinated way to external
stimuli. The brain may be viewed as the central computer in the system. Its most
sophisticated structure is the cerebrum, which controls the higher mental
functions. Underneath the cerebrum are the cerebellum and the brain stem, which
connects both the cerebrum and the cerebellum to the spinal cord.
This cord, a meter-long trunk of nerve fibers, carries nerve impulses between the
brain and the peripheral nerves that control muscles and other body tissues. Most
important to Parkinson’s disease are the motor nerves, which control body motions.
This control involves a portion of the cerebrum that deals with skilled motor
patterns; the cerebellum, which controls posture and balance; and the basal
ganglia, which are processing centers for movement information.

Particularly important to Parkinson’s disease are the substantia nigra and the corpus striatum. Discovery of a functional interface between dopamine and Parkinson’s disease began when it was found that this neurotransmitter was associated with the substantia nigra and connected the substantia nigra and the corpus striatum. Next, it was discovered that temporary Parkinson’s disease mediated by reserpine was associated with dopamine depletion and that the brains of patients contained very little dopamine in the substantia nigra. Soon, it was confirmed that dopamine controlled movement in an inhibitory fashion that arose in the substantia nigra and occurred in the corpus striatum. From these observations, it has been inferred that bradykinesia results from the damage of the dopamine-containing nerve tissue that connects the substantia nigra to the corpus striatum. It is also suggested that decreased function of these fibers—and lack of their inhibitory action because of dopamine—allows excess, undesired nerve impulses to cause both the tremor and the rigidity seen in Parkinson’s
disease.

Treatment and Therapy

Parkinson's disease can be difficult to diagnose, particularly in the early
stages. Parkinson’s disease is most often identified by physical evidence (such as
tremor and bradykinesia), coupled with a careful study of the medical history of
the patient being evaluated. In all but a few cases, no diagnostic information can
be obtained via the three powerful tools useful in many other neurologic exams:
The complex X-ray method, computed tomography (CT) scanning, is
informative only when stroke or tumor is involved; magnetic resonance imaging
(MRI) gives no more information than do CT scans; and electroencephalograms (EEGs)
do not show abnormal electrical discharge such as that observed in brains of
patients with epilepsy. In practice, however, many physicians carry out CT scans,
MRI, and EEGs and count their negative results into a diagnostic positive for
Parkinson’s disease.

Once Parkinson’s disease is diagnosed, three main methods exist for managing it:
medications, physical therapy, and surgery. All these methods—alone or in
combination—are intended for symptom reversal because there is no cure for the
disease. Medications are the first-line treatment mode in most cases. Many
different medications are used, such as levodopa (L-Dopa), dopamine agonists,
monoamine oxidase type B inhibitors, and anticholinergic drugs.

The anticholinergics were the first drugs used for Parkinson’s disease, and they
are still often prescribed for younger patients with severe tremors, but they are
now associated with limited efficacy and neuropsychiatric side effects. The first
anticholinergic drug used, in the 1890s, was scopolamine, initially isolated from
Datura stramonium (jimsonweed). Other anticholinergics include
atropine and the antihistamine diphenhydramine (Benadryl). These drugs operate by
interfering with the action of acetylcholine, a neurotransmitter
involved in nerve impulse transport. High doses of anticholinergic drugs produce
many side effects, including confusion, slurred speech, blurred vision, and
constipation because of the wide influence of cholinergic nerves on body
operation.

Levodopa, the amino acid that is made into dopamine by the body, is a first-line
choice in the treatment of Parkinson's. Levodopa is a metabolic precursor of
dopamine and can improve motor impairment. Dopamine itself is not used because a
blood-brain barrier prevents brain dopamine uptake from the blood. The blood-brain
barrier does not stop levodopa uptake, and its administration reverses symptoms
dramatically. Therefore, it has become the mainstay of modern chemotherapy for the
disease.

A difficulty associated with use of levodopa is that the biochemical mechanism
that converts it to brain dopamine also occurs outside the brain. When this
happens in patients given high doses of levodopa, body (nonbrain) dopamine levels
rise. This dopamine and the chemicals into which it transforms outside the brain
cause such side effects as nausea, fainting, flushing, confusion, and the
involuntary muscular movements called dyskinesia. The dose should be kept low
to maintain function and reduce motor complications. To minimize these
unwanted—and sometimes irreversible—side effects, modern levodopa therapy
sometimes combines the drug with its chemical cousin, carbidopa. Carbidopa
prevents the conversion of levodopa to dopamine. Because it cannot cross the
blood-brain barrier, carbidopa has no effect on the brain’s conversion of levodopa
to dopamine.

Another first-line medication for treating Parkinson’s disease is dopamine
agonists. These chemicals mimic dopamine action, reacting with the brain’s
receptors that produce dopamine effects in the corpus striatum and other sites.
Monoamine oxidase type B (MAO-B) inhibitors may be used for patients with early
disease. MAO-B inhibitors such as selegiline can delay the onset of motor
complications compared to levodopa but may be less effective in the treatment of
functional impairment.

Furthermore, it is not uncommon for those afflicted with Parkinson’s disease to
suffer from depression as they lose control of their motor functions.
This is probably the case because, as noted by James Parkinson, “the senses and
intellect are unimpaired” in such patients. However, traditional antidepressants
may not reduce depression in patients with Parkinson's disease, and several
antidepressant medications can have negative interactions with the medical
treatment of Parkinson's. Pramipexole, a dopamine agonist, is associated with
improvement in depressive symptoms in patients with Parkinson's disease.
Venlafaxine, an antidepressant and serotonin-norepinephrine reuptake inhibitor,
may also be used in the treatment of depression in patients with Parkinson's.

Surgical treatment of Parkinson’s disease was once attempted quite often, but it
became relatively rare by the 1970s, after modern medications were developed.
Since then, its utilization occurs when CT scanning or MRI indicates the presence
of a tumor or brain damage caused by a severe trauma. An implant that provides
deep brain
stimulation has been used to suppress tremors and improve
quality of life. Thalamotomy, the destruction of the thalamus—the brain region
that controls some involuntary movements, was also once more commonly used in the
surgical treatment of Parkinson's, but it is a highly invasive procedure and it is
only rarely used for the treatment of severe drug-resistant tremors. More
recently, thalamic stimulation appears to be as effective as thalamotomy with
fewer adverse effects.

Two final topics worth mentioning are cognitive-behavioral therapy and physical
therapy. Part of their purpose is to address the depression that often accompanies
severe Parkinson’s disease. Cognitive-behavioral therapy for Parkinson's diseases
often includes exercise, behavioral activation, thought monitoring and
restructuring, relaxation training, worry control, and sleep hygiene.
Cognitive-behavioral therapy provides emotional support to patients with
Parkinson's and has been found to improve global symptom severity. Physical
therapy can help patients to overcome some motor effects of the disease, not only
improving the lifestyle possible for them but also elevating morale and curing
depression. Endurance exercises and progressive resistance exercises have been
found to improve physical performance in patients with Parkinson's disease.

Perspective and Prospects

Treatment of Parkinson’s disease has evolved tremendously, particularly since the
late 1960s, when wide use of levodopa began. At that time, most physicians were
astounded to observe that its use converted many stage-5 patients, who were
bedridden or wheelchair-bound, to much more functional, mobile states. A temporary
setback occurred when severe levodopa side effects were observed at high
doses.

The discovery of carbidopa and related inhibitors of nonbrain dopamine
decarboxylase ended this problem and produced a new generation of chemotherapy.
Patients could take levodopa at lower concentrations, which minimized its side
effects, because diminished nonbrain levodopa conversion to dopamine left more
levodopa available to enter the brain. In addition, carbidopa was the forerunner
of a group of dopamine agonists that became candidates for independent use or use
in mixed therapy.

Researchers at the turn of the twenty-first century closely examined the genetic
links in familial forms of Parkinson’s disease. One gene, α-synuclein, is a
presynaptic neuronal protein that is believed to play a significant role in
neuronal plasticity. α-synuclein was previously associated with Alzheimer’s
disease as the nonamyloid component of Alzheimer’s amyloid plaques (NAC peptide),
and it is a component of the Lewy inclusion bodies found in the
Parkinson’s-associated Lewy body dementia. Mutations in another gene, Parkin
(PARK2), were found to underlie the development of
juvenile-onset Parkinson’s disease. Parkin is believed to play a role in cellular
protein degradation by interacting with ubiquitin, a protein that targets other
proteins for degradation. It is hoped that the identification of these genes will
lead to a better understanding of the pathogenic mechanisms underlying nonfamilial
(sporadic) Parkinson’s disease.

Discovery that cognitive-behavioral therapy and exercise can ease the depression
observed in many afflicted people and help to control the disease’s progression
has also been of great value. Perhaps even more exciting have been reports that
the injection of human fetal cells into the brains of those afflicted with
Parkinson’s disease may be able to reverse the disease. It is too soon, however,
to judge the results of this procedure.

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