Parkinson’s Disease (PD), "the shaking palsy" first described by James Parkinson in 1817, is a progressive neurodegenerative disorder which affects in upwards of 1.5 million Americans. The disease begins to occur around age 40 and has incidence with patient age. One survey found that PD may affect 1% of the population over 60. Incidence seems to be more prominent in men, and tends to progress to incapacity and death over one or two decades.

Clinical diagnosis of PD is currently solely dependent on the presentation of the symptoms by the patient which reflect a deficiency of striatal dopamine caused by the destruction of the cells in the substantia nigra. Imaging and other laboratory techniques can be used to rule out other disorders, but are not necessary for the actual diagnosis of PD. The first sign of PA is usually bradykinesia. Movements are usually quite slow. Routine activities may require deliberate planning and thought for execution. Difficulty initiating movements or akinesia, may also be present. Rigidity in the flexors is also present. This is due to an exaggerated response to normal proprioceptive return from the somatic musculature. A resting tremor of 3-6 Hz is also a prominent feature of PD. This may cause difficulties in handwriting as a symptom. Impaired postural reflexes is also a presenting feature in PD. Patients can easily lose their balance when pushed slightly, and may need to be caught to keep from falling. These signs can be tested by observing the patients walking, getting out of deep chairs, and performing rapid repetitive movements. Increased disturbances in cognitive abilities can also show evidence of PD. Even with all these signs of PD, it may be present and undiagnosed for years.

Autonomic nervous system disturbances often times accompany the other symptoms of PD. Patients may present with difficulties in salivation, micturition, and gastrointestinal function, as well as defective control over the cardiovascular system and temperature regulation. Gastrointestinal dysfunction is probably the most common autonomic problem in PD. Sialorrhea, excessive production of saliva, is a common late symptom seen in Parkinson’s. This is probably due to the lack of autonomic swallowing and is therefore regarded as being due to hypokinesia (Korczyn, 464). In more advanced cases, difficulties in swallowing may need to be alleviated by administration of drugs which liquefy the saliva. Constipation is also a common clinical autonomic symptom. This is often made worse by the use of the anti-Parkinsonian drugs. Weight loss to varying degrees can also accompany the disease. Cardiovascular problems can be seen in PA patients, but these are to a lesser extent than the gastrointestinal problems. Cardiac arrhythmia’s were found in a number of patients, but the most incapacitating cardiovascular symptom is orthostatic hypotension. Interestingly, the hypotension in PD is more common following meals. This hypotension can also be caused by Parkinson drug treatment including Levodopa (Korczyn, 465). These symptoms can be seen in most PD patients, and the pattern by which they appear seems to be quite different from those seen in a normal progressive autonomic failure.

The cause of PD is still unknown at this time, although a number of theories are presently being considered. What is known, however, is the primary change in the Parkinson patient is a loss of dopamine containing cells in the pars compacta of the substantia nigra. A corresponding loss of dopamine throughout the entire forebrain is also seen. Aging itself seems to be the key factor in PD. One study pointed out that there is evidence that shows a gradual decline in dopamine concentrations throughout life, 5 to 8% per decade (Langston, 13). The reason for this is not known, although some speculate that the process is controlled genetically.

Others believe that the cause of PD may be caused by injury of some sort to the nigrostriatal dopaminergic system. The two most probable causes for this injury are oxygen free radicals and the accumulation of neuromelanin. For each mole of dopamine that is oxidized upon use, a mole of hydrogen peroxide is generated. This excess hydrogen peroxide could be damaging to neurons if the enzymes controlling these agents, superoxide dimutase and glutathione peroxidase, fail to keep levels at a minimum. Neuromelanin is thought to be made up of dopamine polymers and lipofuscin, and seems to accumulate as a normal phenomenon. Neuromelanin is thought to make neurons vulnerable to the agent that causes PD because there is "an almost direct relationship between the distribution of neuromelanin-bearing cells in the substantia nigra, and the pattern of cell loss in Parkinson’s disease" (Langston 14).

Another theory behind the cause of PD is that the damage to the dopamine system is accelerated by some environmental factor. This theory was based on the fact that it appears that the rate of dopaminergic cells lost is considerably higher in Parkinson patients than could be accounted for in the age-related loss. The symptoms are not seen until nearly 80% of the cells of substantia nigra are lost. Even after partial loss of cells, the remaining dopamine utilizing cells try to compensate for the loss of the rest of the cells. This may lead to increased oxidative stress which could cause more cell loss, thereby still increasing the rate at which the disease progresses.

A selective neurotoxin was later found that induced Parkinsonism and supported the theory of an environmental factor. The toxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a protoxin which upon conversion to a metabolite, selectively destroys dopamine containing cells of the substantia nigra. MPTP is a substrate for monoamine oxidase B (MAO B). The end product of MAO B is 1-methyl-4-phenyl-pyridinium (MPP+). MPP+ is actively accumulated by dopaminergic neurons, and this uptake may be elevated in the presence of neuromelanin. The specific action by which the neurons are killed by MPP+ is by inhibition of mitochondrial energy metabolism. MAP+ can be actively accumulated by the mitochondria up to 50-100 times the external concentrations. The interference in the mitochondria is somewhere between NADH dehydrogenase and coenzyme Q. Consequences of this action are depletion of cellular ATP, decreased amounts of reduced glutathione, altered cellular calcium levels, and ultimate cell death (Jenner, 23). MPTP is converted to MPP+ in a two-stage reaction which produces increased levels of toxic oxygen free radicals which can destroy the cells of the substantia nigra.

Another theory behind PD, speculates that some endogenous agent might be acting to increase the free radical formation. The agent under investigation is iron since it is known that iron can stimulate oxygen free radical formation. Upon study of the Parkinsonian brain, a substantial increase in total iron content was found in the substantia nigra. The increase was not seen in any other brain structure, while there was a reduction in iron content within adjacent structures. The increased iron levels could be enhancing oxygen radical formation and increasing dopamine cell death.

Furthermore, some believe that the possible environmental factor may alter the dopamine cells ability to express its genetic code. The defect would not be likely to be in DNA due to the specificity of the cell death. The alteration could also be a selective change in the cell’s ability to produce messenger RNA. Still to this day, the ultimate cause of PA is not known.

Currently, there is no single best treatment for PD. Patients with PD must be treated individually according to the symptomology seen upon examination. Problems with speech and balance are not as well treated as the tremor symptoms. Physical therapy for gait, muscle relaxation, and general well being is often helpful and encouraged. Drug treatment for the disease is quite variable, and in general, only one drug is tried at a time in moderate doses. Levodopa is probably the most commonly used drug in the treatment of PD. It is the most effective treatment for treating bradykinesia and rigidity. Levodopa works by increasing blood levels of dopamine. The correct dosage is the lowest dose that provides a satisfactory response, because side effects may accompany treatment. Nausea, increased dementia’s, and sleep disturbances may be seen with its first use.

Other dopaminergic agents can be used also in the treatment or PD. These supply dopamine to the still existing dopaminergic receptors, although these too deteriorate with the progression of PC, making them less effective as the disease progresses. Amantadine HCl is one such agent which is thought to cause the release of the dopamine from intact dopaminergic cells in the substantia nigra and elsewhere. Hallucinations and confusion may accompany the use of this drug.

Central-acting anticholinergic drugs are also widely used, especially in the treatment designed to relieve the tremor associated with PD. These include procyclidine, trihexyphenidyl HCl, benztropine mesylate, and biperiden. Potential side effects with these drugs include effects on the pupils, bladder disturbances, and severe constipation.

Finally, a new drug known as Seligiline HCl is currently being used. This drug is an irreversible inhibitor of MAO and is thought to increase levodopa dopaminergic activity. This is a relatively expensive drug and has been thought to delay the progression of PD. It is often considered and used in younger patients with newly diagnosed PD, in the hopes that the disease may be delayed.

Parkinson’s Disease is still being avidly researched today. Hopefully, the disease will soon be able to be diagnosed early enough that its progression can be stopped and be cured. With current research and development, this day may soon come.

WORKS CITED:

Jenner, P. Clues to the mechanism underlying dopamine cell death -in Parkinson’s disease. Journal of Neurology’ Neurosurqerv, and Psychiatry (1989): 22-28.

Korczyr., A. D. Autonomic Nervous System Disturbances in Parkinson’s Disease. Advances in Neurology, 53 (1990): 463-68.

Kingston, J. W. Current theories on the cause of Parkinson’s disease. Journal of Neurology, Neurosurgery, and Psvchiatry, (l989): 13-17.

Langston, J. W. and W. C. Koller. The next frontier: Presymptomatic detection. Geriatrics, Aug. 1991: 5-7.

Paulson, G. W. Management of the patient with newly -diagnosed Parkinson’s disease. Geriatrics, Feb. 1993: 30-40.