Wednesday 1 October 2014
 
 

Parkinson's Disease

Today, Parkinson's disease is recognized as the most common neurodegenerative disorder...

by Michael Sugarman

Parkinson's disease was first described in 1817 by James Parkinson, a British physician, in his Essay on the Shaking Palsy . Today, Parkinson's disease is recognized as the most common neurodegenerative disorder (condition in which neurological tissue- in this case the brain - breaks down and dies) after Alzheimer's disease. Estimates of those afflicted with Parkinson's in the United States vary from 500,000 up to 1.5 million people . The disease is far more common in the elderly population, with roughly 3% of all people over 65 afflicted with Parkinson's . A rare hereditary form of the disease exists, accounting for 5-10% of all cases, while the remaining majority of cases occur sporadically (meaning that its exact cause is unknown). Sporadic cases may eventually be shown to be attributable to unidentified genetic or environmental factors or a combination of genetic predispositions and certain environmental conditions.

Clinical Symptoms of Parkinson's disease. The most prominent deficiencies that Parkinson's disease patients have are motor ( i.e. movement) in nature and can be divided into 3 broad categories: [1] rhythmic tremors in the extremities (arms and legs) of the body, [2] muscular rigidity (stiffness) and [3] bradykinesia, which means difficulty in performing voluntary movements. Rhythmic tremors in the extremities, usually first noticed in only one hand, occur while the patient is inactive ( e.g. sitting, lying down or standing motionless). Some of these tremors resemble the motion of rolling a pill between the thumb and forefinger. The rigidity results in jerky movements in the extremities and can eventually lead to a stooped-forward posture, in which the arms do not swing normally and are bent upwards. As a result of this posture imbalance, the patient may frequently fall. As the disease progresses, patients experience difficulty in initiating movements (bradykinesia). For example, the seemingly simple task of rising out of a chair to a standing position is nearly impossible for someone in the later stages of Parkinson's.

During the early phases of the disease, motor symptoms may be relatively subtle but gradually become worse as the disease progresses. The clinical course can last from 10-20 years from the time when symptoms become noticeable. Typically, in the sporadic forms of Parkinson's disease, symptoms begin to manifest around 60 years of age. The typical age of onset for hereditary forms of Parkinson's is generally much earlier than in sporadic cases and ranges from 30-60 years of age. It is interesting to note that in a very rare hereditary form of the disease, termed juvenile parkinsonism , the age of onset is generally in the patient's 30's.

In addition to the primary motor deficiencies, there may be other secondary nonmotor symptoms associated with the disease. One of the most common of these (especially towards the later stages) is dementia , which is defined as a loss of intellectual abilities that is sufficient to interfere with social or occupational functioning. Dementia occurs in a sub-population of Parkinson's patients. Studies estimate that as many as 20-40% of all patients have dementia, although the precise number is somewhat controversial. Some patients experience additional mental disturbances, including depression, lack of motivation and speaking difficulties.

Neurobiology and anatomy of the brain region(s) affected in Parkinson's disease. To fully understand Parkinson's disease, it is important to comprehend the basic neurobiology and circuitry of the primary brain area affected by the disease: the basal ganglia . The basal ganglia are a group of nuclei (a large aggregate of brain cells or neurons) lying deep within the basal (the underside) forebrain (towards the front of the head) that are crucial in organizing motor behavior. The major components of the basal ganglia are the caudate nucleus and putamen (collectively comprising the striatum), globus pallidus, subthalamic nucleus and substantia nigra. Neurons within the substantia nigra (so named because cells in this region contain a black substance, the pigment neuromelanin) send axonal projections (analogous to wires carrying an electrical signal) to another area of the brain called the caudate/putamen. These neurons are involved in initiating, coordinating and controlling movement via a complex pathway through the basal ganglia, thalamus (the sensory center of the brain) and then out to a region at the top of the brain called the motor cortex (see Figure below).

Destruction of cells within the substantia nigra of the brain results in Parkinson's. Parkinson's disease is characterized by the degeneration of dopamine-producing neurons within the substantia nigra. Dopamine is one of several catecholaminergic neurotransmitters that is synthesized via conversion of the amino acid precursor tyrosine through several enzymatic reactions (see Figure below).

Neurons in the substantia nigra are responsible for producing nearly 80% of the dopamine in the central nervous system. The destruction of these dopaminergic neurons has profound clinical implications as it eventually leads to an overall decrease of activity in the premotor cortex. It is critical to note that the dopaminergic neurons in the substantia nigra die as a normal physiological consequence of aging. Thus it appears to be mainly a quantitative difference that determines whether clinical symptoms of Parkinson's disease will develop. For example, there is an average loss of 37% of these neurons in most individuals by the age of 60. Parkinson's disease symptoms however do not result until about 70-80% of these dopamine-producing cells are destroyed (Bernheimer et al., 1973. J. Neurol. Sci.). Since the brain areas that predominantly degenerate in Parkinson's disease are involved in coordinating motor behavior, the clinical symptoms manifested during the course of the disease are, not surprisingly, motor related.

What are Lewy Bodies?

Lewy Bodies represent the classic feature found within the Parkinson's brain that are not present in a healthy brain. Lewy bodies are spherical cytoplasmic (found inside the cell) inclusions that were first described in 1913 by, and hence named for, Lewy. These inclusion bodies are predominantly found within some of the surviving neurons of the substantia nigra. Lewy bodies have been found in other brain regions, including the pars compacta, locus ceruleus, nucleus basalis, hypothalamus, cerebral cortex, and cranial nerve motor nuclei. They are generally considered to represent the hallmark feature of this disorder and are used as a post-mortem diagnostic criterion for Parkinson's disease. However, Lewy bodies can be found in cortical and subcortical neurons of patients with dementia. It remains to be determined whether Lewy bodies represent a cause or consequence of the break down and death of neurons in the brain.

What causes Parkinson's disease in sporadic cases?

The exact cause(s) of sporadic cases is still largely a mystery, although several environmental factors have been implicated, including heavy metals (such as manganese), carbon monoxide (CO) as well as certain pesticides and herbicides. However, none of these environmental agents have been conclusively linked to Parkinson's disease. One of the most infamous environmental factors that causes Parkinson's disease-like symptoms (parkinsonism) is a chemical: N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine ( a.k.a. MPTP). In the 1980s, several heroin addicts unknowingly used a batch of the drug that was contaminated with this chemical, MPTP. They subsequently developed parkinsonism after taking the drug. MPTP (actually its by-product MPP+) mimics what happens in Parkinson's disease by selectively destroying the dopamine-producing cells in the substantia nigra, thus paralleling the neuronal cell death and clinical symptoms observed in Parkinson's disease (Langston JW et al, Science 1983). This finding has led to the use of MPTP injections into animal brains to model Parkinson's disease. These intriguing, albeit accidental findings raise the notion that an MPTP-like chemical compound commonly found in the environment may act in a comparable fashion to cause Parkinson's disease. Yet, to date, despite other potential candidates, no other compounds have been definitively established.
REFERENCES

Parkinson, J., An Essay on the Shaking Palsy. Sherwwod, Neely and Jones, London . 1817

Wikipedia: The free online enyclopedia. http://en.wikipedia.org/wiki/Parkinson's_disease

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