Parkinsons Disease

PD normally affects people over the age of 50. It becomes more common with increasing age. ‘About 5 in 1,000 people in their 60s and about 40 in 1,000 people in their 80s have PD'1. It affects both men and women but is a little more common in men. PD is not usually inherited, and can affect anyone. However, genetic factors may be important in the small number of people who develop the disease before the age of 50. PD therefore affects a lot of people in the UK and I have chosen this topic so I have a greater understanding of what they go through and how we can help those affected. Background: Biology of Parkinson's disease? Parkinson's disease is a chronic disorder of part of the brain called the substantia nigra. It mainly affects the way the brain co-ordinates the movements of the muscles in various parts of the body. This area of the brain sends messages down nerves in the spinal cord to help control the muscles of the body. Messages are passed between brain cells, nerves and muscles by chemicals called neurotransmitters. Dopamine is the main neurotransmitter that is made by the brain cells in the substantia nigra1.Muscular System: Muscle Metabolism In PD, cells in the substantia nigra are damaged and die. The cause is unknown. Over time, more and more cells become damaged and die. The more cells that are damaged the less dopamine is produced. The reduction of cells and the low level of dopamine in the cells in this part of the brain causes nerve messages to the muscles to become slowed and abnormal1. In the long term PD will ultimately lead to death. Causes We are still unsure of the causes of PD but here are the most likely and most talked about suggestions: 1. The hereditary form of PD occurs in fifteen per cent of cases2. The genes affected help clear nerve cells of excess proteins. Scientists are not sure but it is thought that when the ‘production process for protein manufacture breaks down, little clumps of ill-formed proteins begin to accumulate in cell' 17, causing cell death. Tests carried out on rats using rotenone imply that pesticides and toxins may lead to PD. The rats experienced shaking and a loss of muscle control as well as developing Lewy bodies (spherical lumps found in dying brain cells), which are commonly associated with Parkinson's disease. However, researchers are yet to find evidence for any definitive link to a particular toxin or drug in humans. 2. There seems to be a link between variants of the mitochondrial genes and PD. The Parkinson's Disease Research Agenda states that â€Å"mitochondrial dysfunction has numerous consequences, including energetic failure, generation of reactive oxygen species, disregulation of calcium homeostasis and induction of apoptosis, each of which may be important in Parkinson's disease†3. 3. High concentrations of free-radicals in the body and a lack of antioxidants. Free radicals damage cells and if too many dopamine-producing cells were damaged then this could lead to PD. Antioxidants prevent the production of free radicals and repair damage done by them. Symptoms and effects There is no easy test to diagnose PD, so it is diagnosed by ruling out other diseases and looking for the classic symptoms: * Slowness of movement (bradykinesia)1. It will become more of an effort to walk or get out bed. People may just think they are getting old and it is not till other symptoms develop that you may think about PD. * Stiffness of muscles (rigidity) and muscles may feel tenser. Also, your arms do not tend to swing as much when you walk. * Shaking (tremor) is common, but does not always occur. It normally affects the fingers, thumbs, hands, and arms, but can affect other parts of the body. It is most noticeable when you are resting and may become worse when you are anxious or emotional. It's generally less obvious when you use your hand to do something such as picking up an object or writing. Symptoms will tend to get worse and worse and as the disease develops. Some other symptoms may develop due to problems with the way affected brain cells and nerves control the muscles. These include: * Fewer facial expressions such as smiling or frowning. Less blinking. * Difficulty with fine movements such as tying shoe laces or buttoning shirts. * Difficulty with writing (handwriting tends to become smaller), balance and posture and swallowing. * Speech may become slow and monotonous. * Tiredness aches and pains. As PD gets really bad, symptoms such as the following might develop, dependant on the individual: * Constipation- †PD prevents the proper transmission of the neurological messages that tell the rectal sphincter muscles to open†7 * Hallucinations (seeing, hearing or smelling things that are not real) * Sweating- PD can affect the autonomic nervous system8 that controls the autonomic functions (functions done automatically by the brain and body without conscious thought) such as sweating, breathing etc. * Difficulties with sleeping * Weight loss- there is a generally decreased appetite associated with PD. This may largely be due to swallowing difficulties and other gastrointestinal disturbances8 * Pain * Depression & Anxiety- anxiety disorders occur in up to 40% of patients with Parkinson's disease (PD)9. The article states †Current evidence suggests that anxiety may not be a psychological reaction to the illness but rather may be linked to specific neurobiological processes accompanying PD.† * Problems with controlling impulses (for example compulsive eating, shopping or gambling) Most people will only suffer form a few of these symptoms and which ones will get worse and the speed at which they get worse varies hugely from person to person. Some rare brain diseases can have very similar symptoms in which case a specialist brain scan can often be used to distinguish between them. The Treatments At the moment there is no cure for PD and most treatments simply have the job of relieving symptoms. 1. Drugs Intro: there are two main types of drug used in PD treatment. Firstly, drugs that target the neurotransmitter systems (e.g. dopamine) or secondly drugs that are designed to interfere with steps in the neurodegenerative processes (they may aim to sustain nerve cells or tackle the issue of free radicals). Drugs are cheap and effective, especially in relieving symptoms but show little potential as a full cure to the disease. Most also need to be taken daily for the remainder of a patients lifetime. Many drugs may have minor side affects. Some side affects have social impacts such as mood swings or may not allow the user to fly or travel to certain places. Dopaminergic Agents- use to activate the production or use of Dopamine. Levodopa- is an amino acid that is converted in the brain into dopamine. According to the WE MOVE website10 ‘Levodopa was introduced as a PD therapy in the 1960s, and remains the most effective therapy for motor symptoms' although there are many drugs that do a similar job such as Rasagiline. It reduces the effect of and helps control the symptoms of PD. Like most amino acids levodopa is absorbed into the blood stream through the wall of the intestines. Amino acids require a ‘transporter' to transfer them across the membrane of the intestines and into the blood stream. These transporters can only work at a certain rate and so diet is important. To much dietary protein can slow the transport of levodopa into the blood stream meaning the dose may be ineffective. Alternatively to avoid the competition with other amino acids, doses should be taken between meals. Levodopa has to cross from the blood stream into the brain using the same transport system again, making diet and timing doubly important. MAO-B Inhibitors- slow the breakdown of dopamine in the brain and aim to prevent or slow the death of neurons. ‘MAO is responsible for the mitochondrial metabolism of monoamine neurotransmitters, including dopamine and serotonin.'11 Ethical implications Some of the many ethical issues revolve around the decision to move from testing on artificial tissue (often grown from stem cells, which may in the future replace animal testing altogether. Stem cells, however create there own ethical issues) to animals, and further on the line, of animal testing to trails on human patients. The graph below shows the stages involved in developing a new drug and is taken from the MSD website (21/3/10): (http://www.msd.com.hk/health_info/drug_education/e_ddp_introduction.html) Animal testing is very closely regulated in the UK however many, often false, accusations of animal abuse have lead to darkened perceptions of animal testing in the public eye. Animal abuse is definitely a reality but ‘improved transparency, accountability and regulations'12 should reduce it happening and make sure those responsible are prosecuted. Unlike humans, animals are unable to consent to testing. It is forced upon them and often involves a certain amount of pain, stress, suffering and discomfort. Researchers will try to reduce this, possibly using anaesthetics although this can often interfere with the drug being tested so the animal may have to suffer the full amount of pain. Unfortunately, in PD, a number of animals are tested on normally starting with mice or rats before moving on to monkeys and finally human trails. Some people believe that animals like monkeys and most primates shouldn't be experimented upon as they aren't in the same plentiful supply that rats and mice are in, nor are they considered pests. However, for potentially dangerous drugs it is essential animals with a similar genetic make up (primates) are tested on to greatly reduce the risks in human clinical trails. Economics of drugs in PD As shown in figure 1.2 drug development requires a huge amount of research and testing and can take more than 10 years before a useable drug is created. This obviously requires a huge amount of investment and general drug development costs vary between 500 and 2,000 million dollars. R;D is often done by independent companies or government organizations. Most companies or organizations will link with universities to share information and facilities and hopefully quicken to process of discovering a new drug. ‘After approval, pharmaceutical companies have a short period of exclusivity before patents expire and other companies can market the same drugs as generics. This time is used to recoup the massive investment required to develop and launch a new drug. However, the companies must also continue to test their drugs and monitor the feedback from healthcare professionals in order to identify undiscovered side effects, risk factors and interactions.'13 Drug companies are some of the most profitable industries in the world and although a large amount of money is needed in research and development (R;D) only 1 in 5 dollars made is then invested in further research. Many companies spent nearly twice as much money on advertising and marketing than R;D and demand is so much higher than it needs to be that companies can afford to boost prices to maximise profit. Luckily with PD this becomes less of a problem as people are unlikely take and therefore buy drugs that are meant for PD when they don't actually need it. This is because the symptoms tend to be quite clear and drugs like levodopa are not readily available unless prescribed. Benefits to humans Drugs can have a massive impact on people suffering from PD and they aim to do a number of things: 1) Improve standards of living- by reducing the affects of PD and slowing the process of neurodegeneration it should allow the person suffering to do basic things (such as tying shoelaces, writing etc) more easily and for longer before they require full time medical care. This allows them to be more independent. 2) The use of drugs such as levodopa, in the long term, will reduce the affects of symptoms such as tiredness, aches and pains. Painkillers like amantadine will also be used for more short term relieve along side drugs like levodopa. This will simply make life less painful for a PD patient. 3) Drugs are the most well know and reliable of PD treatments. This reduces the risks of any unknowns or mistakes and far fewer mistakes will be made than in using other treatments. Risks to humans 1) Unfortunately Nausea and vomiting are common side effects of using levodopa that are due to the building up of dopamine in the bloodstream. The most serious and severe effect of this treatment is dyskinesias. ‘Dyskinesias are uncontrolled movements, including writhing, twitching, and shaking. Dyskinesias result from the combination of long-term levodopa use and continued neurodegeneration. They typically begin to develop in milder forms after 3 to 5 years of treatment, but are more severe after 5 to 10 years of treatment.'10 2) There is always risk of allergies when using drugs and for some unfortunate people drugs may do more damage than good. 3) Side affects of drugs vary from person to person and it is impossible to know beforehand how a certain drug will affect an individual. For some, side affects may be far worse than for others. 4) Dosages need to be got right and it is a common problem that people take to little and don't get the full benefit of the drug or take to much and suffer more/worse side affects. A massive overdose will likely lead to death. Alternative Cures? 2. Gene therapy- is still in early research stages and it is likely to be a while before this technique is actually used on humans. Like stem cells it has exciting potential to provide a future cure and avoid the ethical issues associated with stem cells. How it works? Gene therapy aims to introduce new and functioning genetic material into cells that have abnormal genes that are causing proteins (in the case of PD, dopamine) not to be created or created faulty. The genetic material can normally be inserted into the cells using viruses. ‘Some types of virus, such as retroviruses, integrate their genetic material (including the new gene) into a chromosome in the human cell. Other viruses, such as adenoviruses, introduce their DNA into the nucleus of the cell, but the DNA is not integrated into a chromosome.'13There is still much development needed as scientists are still unable to target specific cells and there is the potential threat of virus mutation which may cause even further problems. There is also major worry about the potential for gene therapy to be used to improve basic human traits such as height, intelligence etc. People could simply choice characteristics and this in many people's eyes could be used for the wrong reason. For example, this may be used to give some athletes a major advantage over others or possibly creating super humans. 3. Stem Cells I think stem cells have shown exciting potential and will hopefully provide a full time future cure for the disease. How they work? Stem cells are unspecialised cells that have the ability to develop into highly specialised cells like nerve cells. They can also self-renew, which means they are capable of replenishing themselves for long periods of time by dividing4. For Parkinson's disease it is hoped that large numbers of the brain cells that produce dopamine can be produced and inserted, through transplantation, into a patient's brain. Therefore, nerve messages to all parts of the body will be normal again. However, stem cells not been successfully used to cure PD yet and there are many problems facing researchers. Therefore stem cells are relatively useless for PD at the moment but may be able to provide an easy and affective cure in the future. Problems with the types of Stem cells There are three main types of stem cells: 1. Adult stem cells can come from Skin, Bone marrow, Brain, Blood vessels, Liver and Skeletal muscle. However, adult stem cells are found in such small quantities it is difficult to identify and isolate them in viable numbers. Because adult stem cells aren't as ‘young' as embryonic stem cells, they contain more DNA abnormalities acquired with age4. These can be caused by the environment, toxins or errors in DNA replication. Adult stem cells have limited potential because unlike embryonic stem cells they can not differentiate into any specialised cell in the body. 2. Cord blood cells are normally found in the umbilical cord and placenta after the cord is cut. One problem is the lack of cells obtained and these may not be enough relative to a patient's size. Cord blood cells generally take longer to grow, therefore completion of therapy will take longer. It obviously requires a pregnant woman to donate the cells. 3. Embryonic stem cells are found in human embryos and have a seemingly unlimited potential to develop into any cell in the human body. However they are surrounded by a number of ethical issues. Many people and especially religious group condemn the use of embryonic stem cells as they believe it is destroying a life. They believe it is immoral to save a life at the expense of another. However new developments in stem cells research means that Totipotent* stem cells can now be collected without the loss of embryo life: Somatic cell nuclear transfer (SCNT) – nucleus is removed from a somatic cell and is then implanted into a donor egg that has had its nucleus removed6. It divides just as normal before forming an embryo. Cells from the inner cell mass are extracted and cultured to provide embryonic stem cells but the technique destroys the embryo. Although the embryo is destroyed it is a created clone and so may not be considered the loss of new, individual life. Altered nuclear transfer (ANT), however, prevents an embryo from actually being created. The nucleus of the somatic cell is altered, or genetically reprogrammed, before being transferred into the egg. The alteration consequence is that the somatic cell DNA still produces stem cells but does not generate an embryo. Blastomere Extraction is performed on a two-day old embryo, following the division of the fertilized egg into eight blastomeres (cells). One blastomere is removed and can be triggered to divide and the resulting stem cells could still be used for research and disease treatment. The embryo, ‘now with only seven blastomeres can still be implanted into the mother and assuming no defect has been found these embryos will still grow into healthy babies'4. 1. Name of article: Parkinson's Disease Url: http://www.patient.co.uk/health/Parkinson's-Disease.htm Date accessed: 15/2/10 Evaluation: The article is certified as a reliable source of health and social care information. It certificate states- ‘The authors and editors of this article are employed to create accurate and up to date content reflecting reliable research evidence, guidance and best clinical practice. They are free from any commercial conflicts of interest.' The article states that Parkinson's disease affects the part of the brain know as the substantia nigra. WE MOVE (Worldwide Education and Awareness for Movement Disorders- http://www.wemove.org/par/par_subn.html) states: ‘In PD, cells of the SN (substantia nigra) degenerate, and therefore can no longer produce adequate dopamine.' This information is further backed up on the Parkinson's Disease Research Agenda that states ‘cells that produce the neurotransmitter dopamine die in a small brain area called the substantia nigra.' As the information provided is backed by what I consider to be reliable resources I think that the i nformation on the website is also therefore reliable, but should be checked with other sources before being used. 2. Name of article: Possible Causes of Parkinson's Disease (PD) Url: http://www.healthtree.com/articles/parkinsons-disease/causes.php Date accessed: 20/2/10 3. Name: Parkinson's Disease Research Agenda URL: http://www.ninds.nih.gov/about_ninds/plans/nihparkinsons_agenda.htm#Parkinson Date accessed: 20/2/10 Evaluation: Parkinson's disease Research Agenda is written by the National Institute of Neurological Disorders and Stroke (NINDS). It primary aim is to †reduce the burden of neurological disease – a burden borne by every age group, by every segment of society, by people all over the world.† It is funded by the government so should provide no bias and the site aims to educate people about various neurological disorders including Parkinson's disease. It states â€Å"mitochondrial dysfunction has numerous consequences†¦ each of which may be important in Parkinson's disease.† This is also backed by an article: http://www.nature.com/nrneurol/journal/v6/n2/full/nrneurol.2009.221.html that states † dysfunctional energy metabolism might be a central element of the pathological process underlying the development of PD.† The site was last updated on the 25th of July 2008. As the site is run and updated by the government with no other purpose but to inform I think it can be used a very reliable source of information.