John Paul Barringer Kenyon College Intro to Neuroscience

An Overview of our Understanding of the Neurodegenerative Disorder and Current Research on the Topic.

Professor Williams; Professor Lutton; Professor McFarlane

An Overview of our Understanding of the Neurodegenerative Disorder and Current Research on the Topic.

James Parkinson was the first westerner to describe what is now called Parkinsonism, in his 1817 Essay on the Shaking Palsy. The most common form of Parkinsonism, and the subject of this composition, is Primary Parkinsonism or Paralysis Agitans, which is more widely known as Parkinson's Disease (PD).

Parkinson's disease is caused by the loss, or neurodegeneration, of a majority of the dopaminergic cells found in the substantia nigra of the midbrain (mesencephalon). These cells produce dopamine (or Hydroxytyramine), an important neurotransmitter which, among other things, inhibits neuronal impulse propagation. Dopamine, which is a metabolyte of the amino acid tyrosine, is a key player not only in motor movement, but also in the recently discovered reward system, by which behaviors are reinforced. Dopamine is also fundamental in understanding cocaine and heroine addictions, (the 'high' is a result of synaptic dopamine increase), and schizophrenia (caused by an excess of dopamine in the brain) dopamine is the precursor to epinephrine and norepinephrine, two important hormones involved in cardiac regulation, among other things. In the case of Parkinson's Disease, the dopamine production projecting through the nigrostriatal pathway is most disrupted, resulting in a dopamine deficiency, especially in the Corpus Striatum and Basal Ganglia of the brain. This in turn results in uninhibited random firing of the motor control neurons, leading to the characteristic tremor seen in those afflicted with Parkinson's Disease.

There are four primary symptoms, the first of which is the resting tremor, where limbs tend to exhibit a slight to moderate amount of uncontrollable movement when at rest. This is usually more apparent on one side of the body, opposite the most affected side of the brain. The second major symptom is rigidity of the limbs, face, and trunk, and the third is bradykinesia, or slow movement. The last of the primary symptoms is postural instability, or impaired balance. In addition to these, one or more of the following symptoms is usually also present: Micrographia (small handwriting), lack of arm swing on the more affected side, Hypomimia (decreased facial expression), Dysarthia (Lowered vocal volume), depression or anxiety, 'Freezing'-feeling 'stuck in place'-when taking a step, minor foot drag on most affected side, dandruff, oily skin, and less frequent blinking or swallowing.

Parkinson's Disease is not a minor problem by any stretch of the imagination. It is second only to Alzheimer's disease in numbers affected, with an estimated number of up to 1.5 million Americans suffering from the disorder at any given time. Over one percent of all americans over the age of 60 are affected, with only 15% of all cases developing before the age of fifty. Some of the better know Parkinson's victims include Michael J. Fox, Mohammed Ali, Janet Reno, and Pope John Paul II.

Possible Causes for Dopaminergic Neurodegeneration

Many possible causes have been suggested for the loss of dopaminergic neurons in Parkinson's Disease, and more generally, in Parkinsonism. Environmental factors have been proposed including chemical exposure, drug abuse, oxidative stress, and excess mineral presence in the blood (Iron and Manganese). Pathogens are also investigated from time to time, but more progress has been made in genetics: certain genetic defects have now been proven to cause faulty proteins which may lead to Parkinsonism. Mitochondrial DNA has also received a lot of recent attention, due to discoveries in the mitochondrial aging process and the correlation between mono amine oxidase (MAO) and mitochondrial electron flow.

Many environmental factors have been implicated in the development of Parkinson's Disease. The most distressing data is that which suggests that many of the pesticides, herbicides, and fungicides which are used today contribute to the disease. Some studies showed that pesticide use within the home increased a person's risk of getting Parkinson's Disease by 70%. Other studies using rats showed a marked decrease in motor ability (40%) following exposure to common pesticides and/or fungicides, especially when the exposure was repeated. The damage was shown to be Irreversible, suggesting cell damage. (See web sources: current research)

Oxidative stress is another problem which has been identified, particularly in regards to the Synuclein protein, which, when nitrogenated by free radicals has a tendency to aggregate into Lewy Bodies and cause neuronal apoptosis. Lewy Bodies can be found in the brain of almost all Parkinson's victims post mortem. They are largely comprised of synuclein, and it has been suggested that one reason that they accumulate is that the modified protein (synuclein) is resistant, if not detrimental, to the proteases normally found in the brain. Alternately, it has been suggested that the Lewy bodies arise as a result of defective proteases, not resistant synucleins. (See web sources: current research)

Drug abuse has long been known to relate to parkinsonism. The first case of drug induced parkinsonism was from a contaminated form of heroine containing MPTP, a neurotoxin. MPTP selectively kills off the Dopaminergic cells in the brain, causing almost immediate and irreversible parkinsonism. Cocaine and heroin both relate to the dopamine pathway and the reward system in the brain, and can cause permanent damage to the dopaminergic cells in the substantia nigra as well.

A final environmental cause for cell loss is an excess of certain elements: Manganese has been associated with Dopaminergic neuronal damage for quite some time, and a more recent study performed at NIH demonstrated that excess iron can aggregate in much the same way that synuclein does in Lewy bodies, also resulting in neuronal damage. (See web sources: current research)

Pathogens have also been suggested as a cause for Parkinson's disease. This possibility was brought to the attention of the scientific community originally as a result of a worldwide outbreak of Encephalitis lethargica ("sleeping sickness") which resulted in the widespread development of postencephalitic parkinsonism in many survivors. Although this can cause Parkinsonism, Encephalitis does not account for a large proportion of the cases, and so that research was generally halted. Of more interest to us today is the discovery of Prions - self replicating deformed proteins which somehow cause neuronal deterioration through unknown (as of yet) means. Sometimes these proteins aggregate in much the same way as nitrogenated Synucleins. It would be interesting to see if there is some link between prions and nitrogenated synucleins: Might the modified Synucleins have the ability to alter other Synucleins around them?

Genetically induced forms of Parkinson's Disease have been discovered, with errors on the fourth and sixth chromosomes, but they do not represent the majority of Parkinson's cases, so their value stems more from increasing our understanding of the pathways and interactions at play in the brain. The more significant of the two genetic defects, the one found on the fourth chromosome, is on the gene coding for Synuclein . It consists of only two point mutations, (Ala to Thr at position 53; Ala to Pro at position 30) but these mutations seem to have much the same effect as oxidation of the synuclein proteins, in that it causes them to be resistant to proteases which would normally prevent aggregation. In addition to this, the mutations seem to have made them more hydrophobic, which increases the natural affinity for aggregation, further enhancing the protein's ability to form into Lewy Bodies. (See Journal Articles: 1)

Finally, It has been shown that mitochondrial aging and death within Dopaminergic Neurons would cause cell death. This has received a lot of coverage recently with findings suggesting the buildup of deleterious Mitochondrial DNA with age in specific cell types (Neurons being one of the main groups). This would cause them to age faster and thereby explain the rapid loss of dopaminergic cells. It has also been demonstrated that hyperactivity in MAOs (monoamine oxidases) can lead to mitochondrial damage through peroxide buildup. This damage can be reversed by the natural process of mitochondrial electron flow. (See Journal Articles: 7, 11, 16)

- - On a side note - - It is interesting to note the similarities between the senile plaques found in Alzheimer's disease and Lewy bodies found in Parkinson's. They are both areas of aggregated protein in which the cytoskeleton of the original cells has been removed, killing the neurons and other original inhabitants. The primary difference is the location of the aggregates, and their composition, with Lewy bodies containing modified Synuclein, while the senile plaques are mostly -amyloid (A). Many researchers believe that they may share a common cause, some sort of deformed pathway, etc. with slight variations leading to the slight structural differences. The only idea which accounts for this as of yet is the concept that the proteins (Synucleins and -amyloid) are unchanged, and that the true cause of the problem is a faulty protease gene. Unfortunately, there has been little lab evidence to support this idea. (See Journal Articles: 2)

Parkinson's treatment has progressed quite a bit since it was discovered in 1817. The most important step forward in treatment was, unarguably, the isolation of Levodopa in the 1960's. Levodopa is the precursor to Dopamine, and as such, possesses a few advantages over dopamine. The largest advantage of L-Dopa is that it can pass through the blood-brain barrier, which dopamine cannot do. It can also be regulated by the body slightly more effectively than a straight dopamine injection, as it still must be converted into dopamine to be active. L-Dopa by itself works, but it is broken down outside of the brain as well as inside, so it requires large doses when administered on its own. This can be risky, as excessive amounts of dopamine can trigger episodes of schizophrenia. Also, patients tend to develop a tolerance over time, necessitating other treatments to avoid a psychotic episode. (See Web Sources: Drugs)

Carbidopa is now used to combat issues with Levodopa use. By preventing the metabolysis of L-Dopa until it has crossed the blood-brain barrier, Carbidopa not only increases Levodopa effectiveness, but it allows smaller doses to be used, which lowers the chance of side effects. But even with the lower doses associated with Carbidopa use, side effects are possible. They include Dyskinesia, or involuntary muscle movement such as twitching; this tends to happen in response to long term exposure to high dosages of L-Dopa.

Another drug commonly used in the treatment of Parkinson's disease is Tolcapone. Tolcapone inhibits the extracortical breakdown of L-Dopa, and thereby increases it's effectiveness (much like Carbidopa).

Yet another group of drugs includes Bromocriptine, Pergolide, Pramipexole, and Ropinirole: they are all substances that mimic dopamine in the brain, and are commonly used on their own or with L-Dopa to magnify the effects.

Selegiline, or Deprenyl is another drug which prolongs L-Dopa response by inhibiting Monoamine Oxidase B (MAO-B) so as to keep it from recycling the intra-synaptic dopamine. It can delay the need for L-Dopa therapy for up to nine months beyond normal expectations. Selegiline is best used with L-Dopa, Tolcapone, and Carbidopa.

Before L-Dopa was isolated, the only treatments open to Parkinson's victims were Anticholinergics. These medicines block acetylcholine, a neurotransmitter which is normally kept in check by dopamine levels. Anticholinergics tend to be more effective on drug-induced Parkinsonism, but they generally have a lower rate of success than L-Dopa and some of the newer treatments.

Finally, Amantadine is an antiviral drug that helps with Parkinson's somehow. It reduces the symptoms noticeably, but it is recommended for use with L-Dopa and an Anticholinergic drug, as it is not nearly good enough to be used on it's own, except in incredibly minor cases.

Many new surgical treatments have been developed for Parkinson's disease, mostly with the aim of suppressing debilitating tremors. Subthalamic Nucleic Lesions were a common surgical procedure in Parkinson's treatment, but today, with all of the different drugs that can be administered to alleviate Parkinson's, doctors are more and more reluctant to resort to surgery. A few promising treatments are within reach for the near future, and our pharmaceutical progress has made that wait much more bearable for Parkinson's patients. (See Journal Articles: 14)

One very promising treatment is a Pallidotomy. In this procedure, cryosurgery or ultrasound techniques are used to destroy part of the pallidus. This balances out the remaining dopamine production with that of other neurotransmitters (norepinephrine and acetylcholine in particular), and helps to stop the transmission of erroneous impulses which cause the tremors typically associated with Parkinson's disease.

A less invasive and reversible variant on this surgery is the "Deep Brain Stimulation" program, in which a pacemaker-like device is attached through a micro probe, to a region in the Pallidus of the brain (or the thalamus), and it sends out electrical shocks, temporarily debilitating the surrounding neurons. This is all done with the specific intent of removing, or at least helping, the tremor which is the hallmark of Parkinson's disease. The only real problem so far is that only the Thalamic stimulation was approved by the FDA, and the Pallidus surgery, while it is still done, is much more regulated even though it is more effective at treating the tremors which the surgery set out to treat.

Much press has been given in the past ten years to stem cells and fetal transplant surgery. It has been the hope of many researchers that embryonic stem cell transplants would allow the regrowth of old neurons . The trial transplantations of fetal neurons had mixed results; although the transplants were generally successful; The fetal stem cell issue has become quagmired in the stigma of the abortion debates, with the interests of life on both sides of the argument. (See Journal Articles: 5,6)

One of the most exciting recent developments in regards to Parkinson's Disease treatment is the discovery that bone marrow cells can become nearly whatever you transplant them to (much like stem cells). This has widespread implications, especially in regard to Parkinson's treatment, because it allows physicians and patients to escape the abortion debate and just give or get treatment. Another great advantage of using bone marrow is that there is no acclimatization period, and there is no danger that the body will reject the transplant, as it is native tissue. Also, there is no lack for donors. (See web sources: surgical treatments/future treatments)

One specific case of Parkinson's disease was documented by Pinel: "the Lizard", or the story of Roberto Garcia d'orta. Roberto developed Parkinson's disease and was almost entirely incapacitated by it until his doctor prescribed L-Dopa. He regained his normal functioning for a period of time, but after three years, L-Dopa ceased to be enough to keep him functioning normally. Having heard of an experimental surgical procedure in which the adrenal medulla was transplanted into the substantia nigra, he switched doctors until he found one who would perform the procedure on him. Ultimately, he died of a stroke, of complications arising from surgery. (See Pinel, 81, 148-149, 431)

There is quite a bit of research attempting to further our understanding of the process of neurodegeneration in Parkinson's Disease and Alzheimers Disease. It seems that on some level the two are related, and in this regard, the idea that prions are involved would make a lot of sense; on the other hand, it seems more likely to be some sort of environmental factor, which is why quite a bit of the current research is trying to correlate environmental aspects of living with Parkinson's disease. It is almost ironic that a lot of the substances that we, as humans, use to control the environment are detrimental to the health of our neurons, which in turn, enable us to interact with and control the environment around us.

Another area of Parkinson's research is focused on learning more about the consequences of Parkinson's disease, and possible solutions. Olfaction has had a good bit of press coverage recently, because a study reported that a deeper sniff on the part of Parkinson's patients would allow them to smell more accurately. Another study has found evidence that Parkinson's disease lowers the number of norepinephrine receptors on the heart, proving that Parkinson's disease is not simply a mental degenerative disorder, but has consequences and repercussions throughout the body.

As a result of our ever increasing knowledge of Parkinson's Disease, we are always striving to control and understand it, and in doing so, attempt to create new treatments to help take advantage of our better understanding. Deep brain stimulation is a very promising alternative to having full surgery, in part because it keeps the option of further treatments open, as it is a reversible procedure. Another active area of development, despite the moral dilemma, is neuronal implants. Not only do fetal cells show promise: bone marrow differentiation and transplantation is a really good future technology, and could solve all problems in regards to moral dilemmas, and fetal transplants.

Finally, one area of research that hasn't been addressed yet: Gene therapy has been a good technology in theory, but it has had too many complications to do effectively in actuality. A major leap was made in regard to the formerly impenetrable blood brain barrier. The blood brain barrier is breached by attaching molecules to it by an antibody. Now all that is needed is a good insert to produce a protein - GDNF? GDNF is short for "Glial cell line-Derived Neurotrophic Factor", and is a "Promising protein for Parkinson's" because it induces Dopaminergic cell growth and survival without influencing other neurons. (See Journal Articles: 9)

At the same time as all this other research, correlational studies are taking place, examining where we fit into the world around us, and how those interactions relate to Parkinson's disease. Some of the results from these studies have been quite surprising. For example, caffeine and smoking reduce your risk of Parkinson's Disease. Iron and manganese are toxic in large quantities, and cause neurodegeneration. (See Web Sources: current research)

Parkinson's disease affects a large number of Americans. Luckily, it no longer has to be debilitating, and people are able to live a reasonably comfortable life. Many steps have been taken recently to understand all causes of parkinsonism, and as we increase our understanding of how Parkinson's disease works, our ability to create new treatments also increases. There are quite a few promising treatments in development, and it may not be long until Parkinson's disease is permanently cured. Hopefully, at this rate, it will be within the next decade or so.

• Reichert, Heinrich, Ph.D. Introduction to neurobiology

©1992, George Thieme Verlag, New York (P.143, 220)

• Pinel, John P.J. Biopsychology: 4^th edition

©2000, Allyn&Bacon, New York (P. 75, 81, 148-149, 156, 431, 485)

• Ultra-Preliminary research done at http://www.brittannica.com

<<Remaining sources are all printed in research packs. Journal pack also includes research CD with more unprinted articles which were not directly used>>

Most of the information represented in this paper was acquired on the web (from reputable sources), and is presumed to be public. -JP