Parkinson's Disease affects more than a million Americans a year and is distributed equally geographically, in both men and women, and between socio-economic classes (PD Web, 1998). Although the probability of developing the disease is somewhat equal in all populations, recent studies have shown that African-Americans and Asians are less likely to exhibit Parkinson's symptoms than those of European descent (PD Web, 1998). It was first formally identified by British physician James Parkinson in 1817 as "The Shaking Palsy", however, it is thought that the disease has been around for thousands of years. Described as early as 5000 B.C. in the Indian Ayurvedic medicinal tradition and in the Nei Jing, the first Chinese medical text 2500 years ago, Parkinson's disease has been a constant challenge to public health around the world (NHGRI, 1998).
With increasing concern over the state of the nation's health care, it is important to realize the impact of Parkinson's Disease. The National Parkinson's Foundation estimates that each PD patient pays $2500 a year on medicines alone. When accounting for Social Security and nursing home payments, Parkinson's Disease costs over $5.6 billion annually to the nation (PD Web, 1998). Despite the high occurrence of Parkinson's, it is still not always recognized as a significant medical problem. The symptoms are often ignored in the elderly because they are thought to be part of the natural process of aging (PD Web, 1998). Symptoms include tremors in hands, arms, legs, jaw, and face; slowness of movement, or bradykinesia, and difficulties in balance and coordination. As the chronic disease progresses, PD patients may have difficulty with simple tasks, such as walking and talking (PD Web, 1998). Much of the oversight of PD in medical research, and of other neurodegnerative diseases associated with elderly populations, like Alzheimers, could be a reflection of a dismissive attitude towards the aging process in the medical community and American culture.
The primary symptoms of Parkinson's Disease stem from the deterioration of the part of the brain that controls motor functioning (NHGRI, 1998). This region is the substantia nigra which is found deep within the brain stem and contains neuronomelanin, pigment cells, which synapse to cells of the striatum. The striatum is responsible for balance, control of movements, and walking (PD Web, 1998) (Cosgrove, 1998). Dopamine, produced in the substantia nigra, passes messages between the striatum and the substantia nigra. When the cells of the substantia nigra deteriorate, as in the case of Parkinson's, there is a corresponding decrease in the amount of dopamine produced between these cells. The decreased levels of dopamine cause the neurons of the striatum to fire uncontrollably, preventing the patient to be able to direct motor function.
To compensate for the loss of dopamine and the destroyed cells of the substantia nigra, the brain may boost the level of activity in the pigment cells, or increase the sensitivity of the cells of the striatum (PD Web, 1998). In the normal process of aging these mechanisms can compensate for neuronal degeneration in the substantia nigra. However, in the Parkinson's example, the post-synaptic compensatory mechanism can only account for 75% of the loss of dopamine. Thus, the levels of dopamine are so minimal that the heightened post-synaptic activity cannot counteract the imbalance in neurotransmission.
There are three kinds of receptors for dopamine. D1, the first kind of dopamine receptor, is found on a subset of cells on the striatum. Another kind, D2, is found on elongated cells that have their cell bodies in the cortex. The third variety is found on the processes of the cells of the substantia nigra. Drug therapies used in treating Parkinson's Disease target these areas in attempt to alleivate Parkinson's symptoms (PD Web, 1998). PET Scans can monitor dopamine receptor activity to determine if the decrease in dopamine levels comes before or after neuronal degeneration of the substantia nigra (NINDS, 1998).
When the level of dopamine decreases, another neurotransmitter, acetylcholine, is also adversely affected. The motor function of the striatum is also dependent on the equilibrium reached between dopamine and acetylcholine. This disrupted balance of neurotransmitters contributes to disease progression. Other neurotransmitter deficiencies, norepinephrine, normally found in the locus ceruleous and lateral tegmental areas of the brain, serotonin, and gamma amino butyric (GABA), may contribute to secondary symptoms (PD Web, 1998).
The initial causes of Parkinson's Disease are still speculative, though they are likely to involve a combination of genetics and the environment. One theory hypothesizes that neuronal deterioration in the substantia nigra is due to the accumulation of free radicals. These free radicals react with surrounding cells through oxidation, causing neuronal degeneration (PD Web, 1998). The presence of increased levels of iron in the brain substantiates this theory, as it is involved in the chelation and isolation of free radicals in the brain. Possible therapeutic approaches include anti-oxidants which can pass the blood-brain barrier. The implantation of dopamine-producing cells is also being explored.
Another theory contends that the buildup of toxins, possibly from pesticides or in the food supply, causes the deterioration of dopaminergic neurons. This theory is supported by the fact that toxins such as MPTP and neuroleptic drugs cause Parkinson-like symptoms (PD Web, 1998). Studies have shown that some PD patients also have close relative who suffered from the disease, thus, theorizing a genetic disposition in some PD patients. Researchers speculate that PD may impair mitochondrial DNA, as studies of MPTP interfere with the functioning of neuronal mitochondria (PD Web, 1998).
Gitlin et al. at Washington University School of Medicine recently uncovered a possible gene associated with Parkinson's Disease. They identified a rare disease, aceruloplasminemia, which produces Parkinson-like symptoms. The disease is thought to be caused by a mutation in the ceruloplasmin gene, which disrupts normal iron transport. When there is a mutant form of this gene, there is an inability to make ceruloplasmin, a protein that sequesters iron from cells. In the mutant phenotype, the iron accumulates in the basal ganglia, causing neurological deterioration and dysfunction (PD Web, 1998).
A hallmark characteristic in the clinical diagnosis of Parkinson's Disease is the presence of damaged neurons cells contain Lewy bodies, pink stained spheres, that are thought to include aggregated proteins (PD Web, 1998). However, these microscopic structures can only be seen during an autopsy; hence, there is no standard laboratory or blood test able to diagnose the early stages of Parkinsons (NHGRI, 1998). Before the introduction of levodopa, L-dopa, which replaces the lost dopamine in the brain, surgery was often used to alleviate Parkinson's symptoms. Procedures such as cryothalamotomy eliminate the area of the brain that produces tremors. Also, pallidotomy was recently re-introduced in 1985 as a possible treatment for severe symptoms. In this procedure the Globus Pallidus is lesioned which disrupts the pathway between it and the striatum (PD Web, 1998) (Cosgrove, 1998).
One of the biggest breakthroughs in the treatment of Parkinson's Disease has been the introduction of L-dopa, a natural pre-cursor to dopamine in the brain. L-dopa crosses the blood-brain barrier and is converted into dopamine via the amino acid decarboxylase inhibitor enzyme (AADC) (Awakenings, 1998). However, due to the large deficiencies of dopamine in PD, large doses of L-dopa are required, and often causes undesirable side effects (PD Web, 1998). Another drawback of L-dopa treatment is that overtime the effectiveness wears off and sometimes may aggravate involuntary movements. Another drug therapy recently developed, Seligiline, is an inhibitor of the enzyme monoamine oxidase B, which breaks down dopamine. Seligiline allows normal amounts of dopamine to be stored in the brain and delays the presentation of Parkinson's symptoms (PD Web, 1998).
Parkinson's Disease is a complex neurodegenerative disorder which prompts more questions than it answers. Past research in the accumulation of free-radicals and toxins, dopamine receptors, induction of dopamine production, and blocking the breakdown of dopamine, have layed the foundation for future studies on Parkinson's Disease. Future studies should further explore the interactions between genetics and the environment in Parkinson's patients.
Awakenings. 1998. Parkinson's Disease, Treatment Options.
Cosgrove, G.R. 1998. Neurosurgery Web Page. Practical Information Regarding Stereotactic Pallidotomy for Parkinson's Disease.
Delcomyn, F. 1998. Foundations of Neurobiology. New York: W.H. Freeman and Company.
Grobstein, P. 1998. Neurobiology and Behavior Lectures, Bryn Mawr College.
National Human Genome Research Institute. 1998. Parkinson's Disease- Research News.
National Institute of Neurological Disorders and Stroke. NINDS Hope Through Research.
PD Web: Parkinson's Disease Website. 1998.
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