An incurable neurodegenerative disorder affecting the parts of the brain that direct voluntary movement. Researchers believe most Parkinson’s disease is caused by a combination of genetic and environmental factors. Some people with Parkinson’s have a clear family history of the disease; in those cases gene mutations likely are a stronger influence than in people without such a family history. There do not appear to be any forms of Parkinson’s that are exclusively genetic, unlike in other neurodegenerative diseases such as huntington’s disease, the disease will develop in a person who has the gene mutation.
Most people with Parkinson’s have what doctors call idiopathic Parkinson’s disease, to indicate that the reason for its development is unknown. Though Parkinson’s disease has been diagnosed in only about 0.3 percent of the U.S. population, reports of its presence in the elderly is much higher. one report found that 50 percent of community-dwelling people over age 85 met criteria for parkinsonism; another study found parkinson-ism in 10 percent of general medicine clinic patients order than age 60. Parkinson’s disease that develops in a person before age 50 is considered early-onset Parkinson’s. Somewhat more men than women have Parkinson’s disease. Although Parkinson’s is incurable and progressive, it is seldom fatal and does not shorten life expectancy for most people who have it. it is possible to live with Parkinson’s disease for several decades. The disease’s progression and symptoms are unpredictable and inconsistent, however, and those who have it respond differently to treatment.
Pathological Features and Symptoms
An excessive loss of dopaminergic neurons (dopamine-producing neurons) in the substantia nigra region of the brainstem in the brain is the hallmark pathological condition of Parkinson’s disease. The substantia nigra is closely connected to structures of the basal ganglia, which regulate voluntary movement in the body. dopamine is the brain neurotransmitter essential to this regulation. When the number of dopaminergic neurons declines to about 20 percent of normal, the level of dopamine they produce is no longer adequate. This mechanism establishes a situation of dopamine depletion. The results are manifested by various motor symptoms, the most characteristic of which are
• Resting tremor
• BRADYKINESIA
• POSTURAL INSTABILITY
• RIGIDITY
These four primary or cardinal symptoms are asymmetrical (predominantly affect one side of the body) until the disease is fairly advanced. The presence of one or two of these symptoms is somewhat inconclusive, with the triad of tremor, bradykine-sia, and rigidity being most indicative of Parkinson’s disease. The presence within the first three years of symptoms of postural instability strongly argues against Parkinson’s. The presence of abnormalities on exam that suggest other motor system abnormalities, other than signs that are typical of the extrapyramidal tract, or early dysfunction of the autonomic nervous system, are also suggestive of a diagnosis other than Parkinson’s disease; three or four of them is considered conclusive of the diagnosis. There is no specific diagnostic test or bio-marker that identifies Parkinson’s. As a result mis-diagnosis, particularly in early stage disease, is common; as many as 25 percent of people receive an incorrect diagnosis. other symptoms that may accompany the cardinal symptoms include
• DEPRESSION
• Soft voice and difficulty in speaking
• GAIT DISTURBANCES
• akinesia (lack of movement) typically in a single body part such as a finger
The other conclusive pathological feature of Parkinson’s disease is the presence of Lewy bodies, protein-based inclusions that develop within the neurons in the substantia nigra. These distinctive structures are made mostly of a protein called alpha-synuclein and are detectable only at autopsy after death. Lewy bodies are always present in Parkinson’s disease, but there are a handful of other diseases that also are characterized by the presence of Lewy bodies. Some, but not all, people who have Parkinson’s have mutations of the alpha-synuclein gene, which controls how the body handles alpha-synuclein. Researchers do not fully understand what causes Lewy bodies to form or how they affect neuron function; the deposits appear to “clog” the cell and interfere with its metabolic activities.
Causes
The causes of Parkinson’s disease remain unknown. Most researchers believe a complex interplay of various genetic and environmental factors sets in motion the events that result in the disease’s development. Some scientists believe this interplay accelerates apoptosis (natural cell death); others believe damage to neurons, such as through exposure to neurotoxins or mitochondrial dysfunction, causes them to die. Although there are families in whom Parkinson’s disease is prevalent and those in whom it develops have specific gene mutations, there is no evidence to date that specific gene mutations unequivocally cause Parkinson’s disease or that there is a solely genetic cause of Parkinson’s disease. Some chemicals are known to cause Parkinson’s disease irrespective of genetic factors. These include the illicit narcotic contaminant MPTP. However, researchers do not know the mechanisms through which these chemicals act on the brain or why they selectively affect dopaminergic neurons. Most of the time doctors do not know what causes the development of Parkinson’s disease.
Risk Factors
Although most Parkinson’s disease is idiopathic, there are four key risk factors that make it more likely a person will develop the disease. The more of these factors that are present, the higher the risk. They are
• Age
• cumulative exposure to environmental toxins
• Genetic mutations
• Alzheimer’s disease
The leading risk factor for Parkinson’s disease is age. Eighty-five percent of people with Parkinson’s disease are older than age 60; the percentage of people who have Parkinson’s disease increases with each decade of life after age 60. Some scientists speculate that in every person who lives long enough Parkinson’s disease will in fact develop, as apoptosis (regular, programmed cell death) among dopaminergic neurons would eventually drop the neurons’ level below that capable of meeting the brain’s dopamine needs. Genetic risk factors include mutations of the alpha-synuclein gene and the parkin gene, as well as numerous mutations in certain areas on more than a half-dozen chromosomes. Environmental risk factors include cumulative exposure to chemical toxins such as pesticides and herbicides and to industrial pollutants such as mercury and polychlorinated biphenyls (PCBs). Medications such as the potent antipsychotic haloperidol also cause damage to the brain that manifests in the form of Parkinson’s disease.
Diagnosis
The diagnosis of Parkinson’s is clinical, based on an assessment of symptoms; there are no conclusive biomarkers or tests for the disease. About 25 percent of people are misdiagnosed, particularly in the early stages, when symptoms can suggest a number of neurodegenerative conditions similar to Parkinson’s that also lack definitive tests. The most conclusive diagnostic evidence includes
• The presence of three or all four of the cardinal
SYMPTOMS
• Asymmetrical (predominantly one-sided) symptoms
• Positive response to a trial of Levodopa therapy
Functional imaging studies such as computed tomography (CT) scan or magnetic resonance imaging (MRI) are most useful for ruling out other causes such as stroke or lesions in the basal ganglia or brainstem. If symptoms are markedly relieved by levodopa, the diagnosis is almost certainly Parkinson’s. One exception is the Parkinson’s-like complex of disorders known collectively as multiple system atrophy (MSA), which is characterized by a similar loss of dopaminergic neurons and dopamine depletion. About a third of people with MsA also respond favorably to initial levodopa therapy.
Treatment
The dopamine precursor levodopa remains the cornerstone of treatment for advanced Parkinson’s disease. Although the dopamine molecule is too large to cross the blood-brain barrier, the lev-odopa molecule is small enough for such passage. once levodopa is in the brain it must enter a surviving substantia nigra neuron where dopa decarboxylase metabolizes it to dopamine and it is stored as a neurotransmitter. The substantia nigra neuron eventually releases the stored dopamine into the synapse where its effect is temporary, as once in the synapse it is in turn metabolized into another element. Early in Parkinson’s a levodopa dose might provide benefit for many hours, as there are many surviving substantia nigra neurons and, hence, both lots of storage capacity for dopamine and little significant dopaminergic deficit; late in the disease, the symptomatic effects of a levodopa dose can last less than an hour. The loss of dopamine storage capacity and increasing dopamine deficit in the brain is complicated by poorer digestive system absorption of levodopa making it necessary to take dosages that are significantly higher than the amount of the drug that will reach the brain.
Peripheral levodopa metabolism causes a number of unpleasant side effects including nausea, lightheadedness, and palpitations. For this reason most people take levodopa in combination with carbidopa (Sinemet) or benserazide (Madopar). These drugs are dopa decarboxylase inhibitors that slow peripheral metabolism of levodopa to allow more of it to reach the brain. The occurrence of the above side effects with initiation of sinemet therapy usually resolves with the addition of more carbidopa (Lodosyn). For this reason, Sinemet 10/100 tablets are usually a poor choice for initiation of therapy and should be reserved for people with advanced disease who are taking more than 800 mg of levodopa per day. Though motor complications commonly occur after a few years on lev-odopa, and the underlying disease progresses, levodopa remains an effective treatment for motor symptoms throughout the course of the disease, supplying significant relief from symptoms for decades in many people. Most people with advanced Parkinson’s remain on it until intolerable side effects develop.
Other anti-Parkinson’s medications have a role as monotherapy in early or moderate disease and may supplement levodopa in advanced disease. They include
• Amantadine, which has a mild dopamine agonist effect and reduces levodopa-induced dyski-nesias
• Anticholinergics, which inhibit acetylcholine to control tremors
• coMT inhibitors, which increase the duration and effectiveness of levodopa
• Dopamine agonists, which activate dopamine receptors in the brain to simulate dopamine
• Muscle relaxants, which act on the muscles to relieve rigidity
Course of Disease and Prognosis
Although the progression of Parkinson’s disease is inevitable, the rate of degeneration and the kinds and severity of symptoms vary widely among individuals. some people have virtually no symptoms and go for many years on dopamine agonists or very low dose with levodopa therapy and others are significantly debilitated within a few years despite trying multiple medications and attempting to maximize levodopa. Most people have a course between the extremes, with periods when symptoms are repressed and other periods when they are not. There is no way to predict how a person will respond to treatment, whether Parkinson’s will become debilitating, or which symptoms will be prominent.
Most people who have Parkinson’s disease when they die do not die of the disease. Parkinson’s disease is seldom a cause of death, although it can establish the circumstances that allow life-threatening infections such as pneumonia to develop. Other diseases that coexist with Parkinson’s, such as diabetes or heart disease, are likely to have a far greater effect on quality of life and longevity than is Parkinson’s disease.
Outlook for a Cure
Hundreds of research studies are under way in the quest for a cure for Parkinson’s. Some of the most promising results are those from the field of genetics, as scientists continue to decode the human genome and gain further insights into the effects of genes on health. other research explores new drugs that can specifically and precisely target certain cells and functions in the brain. still other studies are looking at ways to protect neurons, which the body does not replace when they die, from oxidative stress and other factors known to cause cell damage and death.
