Parkinson's Disease Research Paper
Parkinson’s is a chronic, severe and debilitating brain disorder which cannot yet be cured: so what are the current available treatments to help relieve the disorder’s symptoms?
The Problem
Parkinson’s disease (PD) is a progressive, degenerative neurological disorder which is caused by nerve cell death in the midbrain called the substantia nigra which is responsible for producing neurotransmitters dopamine. The disease is named after the English doctor James Parkinson, who published the first detailed description in An Essay on the Shaking Palsy in 1817 after his observation of 6 cases [1-2]. An estimated 7 to 10 million people worldwide are living with PD. Even though a similar cell death is associated with ageing, for someone with the Parkinson’s …show more content…
gene, this process is much faster. There are yet no known cures for PD. Parkinson’s typically develops after the age of 65, about 15% of people with the condition develop "young-onset" Parkinson 's disease before reaching age 50. [5]
As the disorder progresses, the symptoms are stronger and disabling making normal everyday activities much harder to perform, for example, brushing your teeth is so much slower than usual. [2]
The 4 primary symptoms of this disease are tremor (this is the involuntary movement of limbs, head or whole body), Rigidity (stiffness or inflexibility of the limbs or joints). Bradykinesia or akinesia (slowness of movement or absence of movement) and Postural Instability (impaired balance and coronation) lokkomg at fig.1 you can see where this symptoms affects a Parkinson’s sufferer. [3]
Symptoms are caused by the breakdown of certain dopamine-containing nerve cells in the brain. The brain is always using dopamine to control nerve signals, which in turn control the body’s movements. Dopamine, like other neurotransmitters, is constantly produced and used up (destroyed). In Parkinson 's, the production of dopamine is impaired whilst its use and destruction remains. This causes a dopamine deficit, whereby the body’s movement control is impaired. [4] Possible solution 1
Stem cell therapy
Stem cells are unspecialised cells that can develop into many different types of cells. All cells in the body are derived from stem cells as seen on fig.3. There are two main types of stem cells: embryonic and adult stem cells. Stem cells can be use to replace the lost or faulty nerve cells that produce dopamine in Parkinson’s sufferers. [6]
Embryonic stem cells are obtained from early embryos. To do this in a laboratory, IVF (In-vitro fertilisation) is carried out. Once the human egg has been fertilised, it will develop into a blastocyst which consists of cells called the inner cell mass. These cells are then transferred to a culture medium where they are cultured into embryonic stem (ES) cells. ES cells are pluripotent- they can differentiate into almost any type of cell in the human body. [6-7]
Adult/ somatic stem cells are found in body tissues of an adult e.g. can be found in bone marrow. They can be extracted and obtained by an operation. The donor is anaesthetised and a needle is inserted into the centre of the bone, usually from the hip, and a small amount of bone marrow is removed. This operation can cause a lot of discomfort to the person. However, adult stem cells are multipotent and can only differentiate and produce a limited number of cell types. [6-7]
Overview
I will be outlining 2 studies which build on from one another adjusting the stem cells to avoid tumour growth. I will outline the changes made by the different researchers and why they were made.
Professor Arenas a lead researcher in a 2008 study were able to use human stem cells to create dopamine neurons which were implanted in animal models with Parkinson’s like lesions. The animals were able to survive, and in the mice and rats the movement problems normally seen were reversed. Dr Lorenz Studer criticised Arena’s study as the first transplanted of the human stem cells transplanted into the animal models caused tumour growth. The stem cells used for the transplantation in to the animal model were modified so as to avoid tumour growth.
Dr Leveque lead researcher of a study carried out in 2011 reviewed Arena’s study and the modification implemented by Dr Lorenz. He modified the stem cells such that the stem cells were appropriate to be transplanted into the brain of a human suffering from Parkinson’s disease.
Research studies
The approach using stem cells for treating Parkinson’s disease is growing them into new brain cells and transplanting it in to the sufferer this cells are also ideal cells for developing and testing new drugs for this disorder. In 2008 professor Arenas and his team grew dopaminergic neurons from embryonic stem (can be induced to grow a wide variety of different cell types) produced stem cells which were transplanted into animal models of Parkinson’s disease. Two of the animal models in which this stem cells were transplanted to developed tumours induced by the cells and died. Professional arena’s team went on to use neural stem cells which were programmed to develop into nerve cells. These cells were then transplanted into 6 laboratory animals with a damaged substantial nigra region of the brain and the results were promising. [8] These animals were 2 monkeys, 2 rats and 2 mice. Professor Arenas said “the transplanted cells reversed almost completely the behavioural abnormalities, and neurons differentiated, survived and the treatment re-innervated the relevant part of the brain better."
Method used by Professor Arena’s study
The team gave animals six injections of more than a million cells each, to parts of the brain affected by Parkinson 's. The neurons survived, formed new connections and restored lost movement in mouse, rat and monkey models of the disease, with no sign of tumour development.
In vivo survival and function is demonstrated in Parkinson’s disease models using three host species. Long-term engraftment in 6-hydroxy-dopamine-lesioned mice and rats demonstrates robust survival of midbrain DA neurons derived from human embryonic stem cells, complete restoration of amphetamine-induced rotation behaviour and improvements in tests of forelimb use and akinesia. Scalability is demonstrated by transplantation into parkinsonian monkeys. Excellent DA neuron survival, function and lack of neural overgrowth (a potential overproduction of new brain cells) in the three animal models indicate promise for the development of cell-based therapies in Parkinson’s disease. [9-11]
Results from the study showing improvement in scans after the dopamine embryonic stem cells transplantation
Fig. 4(a). Immunochistochemical analysis of short-term (6 weeks) in vivo survival Studies in adult intact (unlesioned) mouse striatum
fig.4(b) shows a comparison of the mouse lesion which developed tumours. The picture shows a negative dopaminergic neurons. Forkhead box protein A2 (FOXA2) expressing cells (red) were only found in the graft but not in the surrounding host striatum demonstrating graft origin and midbrain identity of the cells. Nearly all expressed tyrosine hydroxlylase neurons (green) co-expressed FOXA2 (red). However, a considerable proportion of FOXA2+ cells did not co-express tyrosine hydroxlylase suggesting that these cells have not yet acquired a mature dopamine phenotype or represent another expressed FOXA2 neuronal population negative for dopamine neuron markers. http://www.nature.com/nature/journal/v480/n7378/extref/nature10648-s1.pdf
The rosette pattern consists of a halo or spoke-wheel arrangement of cells surrounding a central core or hub which may be empty or contain fibers, cytoplasmic processes, or a blood vessel.
Fig.5 (e-h). Analysis of rosette-derived grafts: Neural overgrowth with compression of host brain tissue. The majority of cells were positive for both Neural Cell Adhesion Molecule (NCAM) is a homophilic binding glycoprotein expressed on the surface of neurons (red) and doublecortin (DCX (green)) suggesting neuronal fate indicating dopamine nerone phenotype present. Neuronal fate is the process in which developmental fate of a cell becomes restricted such that it will develop into a neuron.
Within the graft core they observed multiple DCX+ doublecortin clusters which bind microtubules further indicting the development of dopamine neurones. (h) Only very few expressed tyrosine hydroxlylase cells (green) and fibers were observed at graft periphery and nearly all rosette-derived expressed TH cells in vivo were negative for FOXA2 (blue). This indicates positive dopamine phenotype development thus the improvement of the symptoms of the monkeys. http://www.nature.com/nature/journal/v480/n7378/extref/nature10648-s1.pdf
Fig.5: According to the study, the results from a mouse and rat demonstrate excellent graft survival and behavioural outcome. However, the number of DA neurons required in a mouse or rat brain represents only a fraction of the cells needed in a human.
The researcher investigated whether their approach could treat two monkeys with Parkinson’s like symptoms. Cells were injected at three locations on each side of the brain and the animals were immune suppressed with cyclosporine-A. One month after the transplantation the dopamine neurons successfully grafted into the brains of the monkey improving the Parkinson like symptoms.
Fig.6. DA neurons were grafted into the striatum of adult monkeys.
(a) Graft cytoarchitecture (the arrangement of neuronal soma in the brain) is illustrated by immunohistochemistry(detecting antigens in cells of the brain section by exploiting the principle of antibodies binding specifically to antigens in that section of the brain) for the human specific marker.
(b) Analysis of green fluorescent protein (GFP) expression in graft cores further confirmed human identity of the cells. (c) Higher resolution image of the expression of GFP graft using DAB detection (a multimer-technology based detection system intended for the specific and sensitive detection of mouse and rabbit primary antibodies) showing numerous presences of GFP cells at graft periphery exhibiting neuroblast morphology.
Previous researchers had already generated the right type of nerve cells from human stem cells to produce the chemical dopamine that is depleted in Parkinson 's, but there were problems when the cells were transplanted into models of Parkinson 's animals. The cells continued to grow and some transformed into tumours.
Dr Lorenz lead a study to address this problem, he stated “in this 2009 study, the researchers used a different procedure to differentiate the stem cells into nerve cells. This time they remained as correctly working nerve cells, did not form tumours, and overcame some of the symptoms of Parkinson 's in the monkeys. Stem cell therapy may still be some way off. However, this study has shown for the first time that it is possible to transplant nerve cells that work from human stem cells." [8]
A successful transplantation of adult stem cell research which reversed the effects of Parkinson’s disease in Human trial was reported by Dr. Michel Levesque. This was the first ever successful stem cell transplantation human trial which reverses the effects of Parkinson’s disease and demonstrated the long term safety and therapeutic effects.
They reported the long-term clinical results following the autologous transplantation of differentiated neural stem cell-derived neurons unilaterally into a patient with Parkinson’s disease. His medical therapy with dopamaninerative agents showed a small improvement on his symptoms of rigidity and tremor. These were the drugs he was taking before the transplantation. [12]
Levesque’s team were able to isolate the patient-derived neural stem cells – adult stem cells (harvested from the prefrontal cortical sub cortical region), multiply them in vitro and ultimately differentiate them to produce mature neurons before they were reintroduced into the brain. Unlike the animal trial above, in this trial, they injected the adult stem cells without the need for immunosuppressant (immunosuppressant decrease the function of the immune system to prevent and/or treat stem cell rejection.) [12] Fig 8 shows the improvement of the Transplantation of Differentiated Human Adult Neural Stem Cells.
Results from Dr Lévesque’s Study
Fig. (8). 18-Fluoro-DOPA and Positron Emission Tomography Studies.
Functional brain imaging with positron emission tomography (PET) and the radiotracer 18-fluorodopa (FDOPA) is capable to quantify the deficiency of dopamine synthesis and storage within pre-synaptic striatal nerve terminals.
FDOPA-PET imaging permits the follow-up of disease progression, the assessment of medical and surgical PD therapy strategies with possible neuroprotective properties.
(a) Pre transplant uptake study showing decrease nerve terminal density in the striatum, worse on left (right on picture), consistent with Parkinson’s disease.
(b) Post transplantation study with increase activity of marker at the site of micro-injections in left putamen.
Fig.7 this graphs illustrates the number of years the effect of the stem cells transplantation in the Lévesque’s research on the one sufferer who took part.
For the five years after the procedure, the patient’s motor scales improved by 80% for at least 36 months. Stem cells enhancement was dramatically noticeable. [12-13]
The baseline shoed the starting point of the experiment. As the sufferer was already taking medication before the transplantation, there was some improvement and so this is why the baseline is not from the black point of the graph. The blue line shows a placebo outcome however, there was no patent in which to give a placebo to and this was given as the expected placebo out come so that the results of this study could be
compared.
On the trials using stem cells, most participants showed drastic improvement within the first week of transplantation. The hope in the future for using stem cell therapy for treating PD is that biologist will be able to grow new dopamine-producing nerve cells.
Evaluation of results
The result from Lévesque’s study supports those from Dr Arena’s study. The build up and modifications of the stem cells that enabled the prevention of the formation of tumours makes the results more reliable. Both results provide evidence of the effectiveness of using stem cells to treat Parkinson’s disease. However, the sample size of Dr Lévesque’s study was not high to draw a valid conclusion about the results as only one Parkinson’s sufferer had the stem cells transplanted to their brain. Even though the sufferer showed drastic improvement, more trials will have to be carried out using humans so as to further support the findings. However, comparing Lévesque’s results (the actual stem cells transplantation) that he expected placebo outcome shoes a significant improvement when using stem cells.
All the studies were double blind studies. This means that neither the patience nor the doctor knows was receiving placebo or the medication. The means that the results were not skewed by doctors or even the patience who wanted the treatment to work in the way they wanted. For example, at every visit the treating investigator inquired about adverse events. The primary rater, who was also blinded to the treatment assignment and was kept unaware of information obtained during the course of the study. This ensured that event the investigator should not change the doses of the control patience or do something to favour their research. This makes the results more reliable.
Just as with the study above, other experiments have used stem cells to increase dopamine producing brain cells. Dr Lorenz Studer (2009) has experiments in which dopamine neurons were created from mouse stem cells. This study however has not been successfully reproduced in humans. This result has risen which have also raised safety concerns that dopamine neurons developed from human cells might trigger growth of tumours. [9]
Implications
Social and ethical issues
Most Parkinson’s sufferer’s symptoms drastically decrease their quality of life. Some are unable to work and provide for their families and can barely do normal daily activities which we consider easy e.g. brushing your teeth. This causes some burden to the family and friends especially their love once. In the book ‘Always Looking Up’ written by Michael J. Fox where he writes about the hard-won perspective that helped him sees challenges as opportunities. Instead of building walls around himself, he developed a personal policy of engagement and discovery: an emotional, psychological, intellectual, and spiritual outlook that has served him throughout his struggle with Parkinson 's disease. [14]
Michael J Fox a Parkinson’s suffer stated in his book ‘the last ten years, which is really the stuff of this book, began with such a loss: my retirement from Spin City. I found myself struggling with a strange new dynamic: the shifting of public and private personas. I had been Mike the actor, then Mike the actor with PD. Now was I just Mike with PD Parkinson 's had consumed my career and, in a sense, had become my career. But where did all of this leave me? I had to build a new life when I was already pretty happy with the old one...’ Always looking up [13]
The use of stem cells can dramatically reduce Parkinsonism symptoms. Great levels of success and potential have been shown from research using adult stem cells Transplantation can improve in the quality of life for many sufferers e.g. by partially replacing the damage dopamine levels in the brain for quite a long period of time. [15]
However the use of stem cells is a continuous debate in the society. Obtaining stem cells from embryos by IVF raises ethical issues - the embryo must be destroyed at around 5-7 days after fertilisation (the blastocyst stage) by harvesting the cells from the part of the embryo called the inner cell mass and could have been a potential human life. The question is whether it is right to do this. Many people believe that life begins at conception, and it is immoral and wrong to destroy and embryo, even to reduce suffering in existing human life. Scientists are ‘playing god’ and ‘messing with human life’. [2, 16]
Society has to consider all the arguments for and against stem cell research before allowing it to go ahead. To help society make these decisions, regulatory authorities have been established, such as the Human Fertilisation and Embryology Authority (HFEA).
The work of regulatory authorities includes, looking at proposals of research – this ensures that research involving embryos is carried out for a good reason, and is not repeated elsewhere. [17]
Economical
According to the Parkinson’s Action Network, drugs commonly used e.g. Levadopa to treat Parkinson’s disease cost between $1,000 and $6,000 per year per patient. Annual medical care, including doctors’ visits, physical therapies and treatment for co-occurring illnesses (such as depression) is estimated at $2,000 to $7,000 for people in early stages of the disease this amount increases for advance patients. This amount increases drastically using surgical treatments which can go up to $25,000 or more. . [, 5, 18]
The annual cost in nursing-home care for Parkinson 's disease alone in the UK is estimated to be about £600-800 million. [5] Estimates of the overall cost of Parkinson’s disease range widely. The National Institute of Neurological Disorders and Stroke (NINDS) puts the figure in excess of $5.6 billion, including both direct medical expenses and indirect costs such as lost income, disability payments and medical costs. This amount does not include research cost. [19] Many experts estimate a much higher annual cost for Parkinson’s.
Benefits and risk
The stem cell transplantation in the animal model of Parkinson’s disease proves that it is capable of relieving symptoms and restoring damaged brain function. Even with the current human trials, adult stem cells show a beneficial result for a long period of time. People do get better when this stem cell transplantations happen thus can have a chance to lead rewarding and more meaningful lives around their families. So stem cells can enhance the quality of live which is always hoped for by the sufferers. [6-13, 20)
The risks associated with research participants undergoing stem cell transplantation include tumour formation, inappropriate stem cell migration, immune rejection of transplanted stem cells, haemorrhage during neurosurgery and postoperative infection. Although some of these risks are general to neurosurgical transplantation and may not be reduced for participants, the potential risk of tumour formation and inappropriate stem cell migration must be minimized before the transplantation takes place. [9, 21) every surgical procedure carries a certain amount of risk. Transplantation of these stem cells could create a different problem in the brain as the stem cells could mutate and cause a negative effect.
Alternative solutions
Drug treatment (solution 2)
There are quiets a few drugs available for sufferers of Parkinson’s disease and this drugs are prescribed to them according to the level or stage in which are in. drug treatment available are targeting the symptoms of this disease. For example, dopamine agonists; it mimics the role of dopamine in the brian which can be taken alongside Levedopa. Mao-B inhibitors slow down an enzyme in the brain responsible for the breakdown of dopamine. [2, 22]
Levodopa is the most sophisticated drug treatment for Parkinson’s disease. Studies demonstrated the use of levodopa in 2011 found that those with the early onset of Parkinson’s who had long exposure to levodopa did not lose dopamine neurons when compared with the control group. [25] As people cannot easily take dopamine pills because it does not easily pass from the bloods to the brain, levodopa is a form that can be transported in to the brain. Nerve cells can use levadopa to make dopamine and replenish the brain 's dwindling supply. However people taking this drugs for a long time, over the year they develop motor fluctuations (time when the medication works and times when they do not work) and dyskinesias (involuntary movement). [23]
Patients turn to combine other drugs alongside L-dopa which allows more L-dopa to get to the brain and thus increases the supply of dopamine in the brain. It decreases side effects caused by increased dopamine levels outside the brain (e.g. dyskinesias) by reducing the supply of "free" dopamine outside the brain. Some of these drugs include COMT inhibitors Amantadine and carbidopa. [22]
Deep Brian Stimulation (solution 3)
Many Parkinson’s patients who do not response to drug treatments can potentially be treated by deep brain stimulation. This treatment involves implanting a battery operated devise called a neurostimulator similar to a pacemaker to deliver electrical impulses that stimulate areas of the brain that control movement. The impulses are thought to block abnormal signals that cause many of the symptoms of Parkinson’s, like tremors, slowness, stiffness, and difficulty with speech. [3, 24]
Fig.10 shows the position in which the neurostimulatore and the electrodes are placed in the brain and the body.
Most patients still need to take medication after undergoing deep brain stimulation; many patients experience a great reduction of their Parkinson’s symptoms and are able to greatly reduce their medications. However a review suggests that amount of reduction varies from patient to patient. This may cause some patience to reduce their medication which could leads to a significant improvement in side effects such as dyskinesias (involuntary movements caused by long-term use of levodopa). [25]
Evaluation of Sources
The sources of the study come from the Nature Journal and the Open Cell Journal so have been peer reviewed (14, http://www.benthamscience.com/open/toscj/articles/V001/20TOSCJ.pdf , [10] http://www.nature.com/nature/journal/v480/n7378/full/nature10648.html#/supplementary-information . These sources are reliable as it also agrees with many other sources.
The article is based on peer-reviewed results that have gone through all the stages ensuring they are valid and addresses the complication with research progression.
"This evidence had been presented previously, but we now have the peer-reviewed scientific evidence for the effectiveness of adult stem cells in alleviating Parkinson’s symptoms," he said. "While the data show that the technique needs refinement, this patient went for several years with little to no symptoms of his disease, even with only half of the brain treated with his own adult stem cells." Dr David Prentice.
[http://www.ninds.nih.gov/disorders/parkinsons_disease/detail_parkinsons_disease.htm]
I found this source very reliable and useful in providing in-depth information, support and education related to Parkinson’s disease. This website contains a lot of review articles and researches of the disease. The NINDS provide cost-effective management in operating multiple Parkinson’s trials.
Levesque is a principal investigator for NeuroGeneration, a biotechnology company, and is affiliated with the UCLA School of Medicine and the Brain Research Institute. This put his reputation at the top of the chards as he can be seen as trustable. This institution dedicates to clinical research of Parkinson disease and other brain disorders known worldwide. Its high credibility is as such that both studies can be taken as extremely reliable along with their sources in terms of where they come from.
The 2 studies above were funded by different organisation which are having high credibility and good reputations an so it cannot be said that the lead doctors in the studies were attempting to find positive data which could put them in books for being the first to find the cure for Parkinson’s. Professor Arena and Dr. Michel Levesque who was head of their trials, seems to have had no hidden agenda, and there is no evidence suggest that they have a vested interest in finding a cure for Parkinson’s disease due to professional history.
Bibliography
1. James Parkinson, 2009, ‘An Essay on the Shaking Palsy’, available at: http://www.manybooks.net/support/p/parkinsonj/parkinsonj2377723777-8iliad.pdf (accessed 17/02/2012)
2. http://www.ninds.nih.gov/disorders/parkinsons_disease/detail_parkinsons_disease.htm
3. Basic Information About Parkinson 's Disease at http://en.wikipedia.org/wiki/Parkinson%27s_disease
4. Why symptoms occur - www.parkinson.org
5. Statistics - http://www.pdf.org/en/parkinson_statistics
6. Stem cells therapy - http://www.ninds.nih.gov/research/stem_cell
7. http://stemcells.nih.gov/info/basics/basics3.asp
8. European Science Foundation (2008, January 18). Stem Cell Research Aims To Tackle Parkinson 's Disease. ScienceDaily. Retrieved February 26, 2012, from http://www.sciencedaily.com /releases/2008/01/080118101925.htm
Parkinson 's stem cell research shows promise. http://www.nhs.uk/news/2011/11November/Pages/can-stem-cells-replace-parkinsons-brain-cells.aspx http://www.guardian.co.uk/science/2011/nov/06/stem-cells-brain-parkinsons-disease 9. The nature journal. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Published online 06 November 2011. http://www.nature.com/nature/journal/v480/n7378/full/nature10648.html#/supplementary-information
10. Lorenz Studer, MD. www.mskcc.org/research/lab/lorenz-studer
11. http://www.placidway.com/subtreatmentdetail/treatment,31,subtreatment,244.html/Parkinsons-Disease-Stem-Cell-Treatment-Treatment-Abroad
12. The Open Stem Cell Journal, Volume 1, 2009 http://www.benthamscience.com/open/toscj/articles/V001/20TOSCJ.pdf
Michel F. Lévesque, Toomas Neuman and Michael Rezak Pp 20-29 - Therapeutic Microinjection of Autologous Adult Human Neural Stem Cells and Differentiated Neurons for Parkinson 's Disease: Five-Year Post-Operative Outcome.
13. A Book, Always Looking Up: The Adventures of an Incurable Optimist by Micheal J fox. 2009
14. Oonagh Corrigan, Kathleen Liddell, John McMillan, Alison Stewart, Susan Wallace, March 2006. Cambridge Genetic Knowledge Park, 2nd Edition - “Ethical legal and social issues in stem cell research and therapy” Page 2 – 9.
15. The debate about stem cell - http://www.stemcellpioneers.com/showthread.php?t=3065
16. regulatory authorities about the usage of stem cells - http://www.hfea.gov.uk/119.html
Economical implications
17. http://www.parkinsoninfo.org/more_info.asp
18. http://www.ninds.nih.gov/disorders/parkinsons_disease/detail_parkinsons_disease.htm
Benefits and risk
19. http://www.tissustemcell.com/index.php/treatments/parkinsons_disease
20. http://jme.bmj.com/content/33/3/169.abstract
21. Levodopa and Carbidopa benefits - http://www.webmd.com/parkinsons-disease/levodopa-medications-for-parkinsons-disease (accessed 16/02/2012)
22. L-dopa most sophisticated drug treatment for PD - http://www.medicalnewstoday.com/info/parkinsons-disease (accessed 15/02/2012)
23. DEVELOPING NEW TREATMENTS FOR PARKINSON’S DISEASE, Deep Brian Stimulation http://www.ninds.nih.gov/about_ninds/plans/nihparkinsons_agenda.htm#Deep%20brain (accessed 15/02/2012)
24. Morten L Kringebach, Alex l Green, Erlick A C Pereira, Sarah L F Owen and Tipu Z Aziz, 2009. Deep Brian Stimulation. Biology Science Review. Volume 56 Number3, August 2009, pages 144 – 148.
25. http://www.pdf.org/en/science_news/release/pr_1321637533 (accessed 17/02/2012)
The Problem
Parkinson’s disease (PD) is a progressive, degenerative neurological disorder which is caused by nerve cell death in the midbrain called the substantia nigra which is responsible for producing neurotransmitters dopamine. The disease is named after the English doctor James Parkinson, who published the first detailed description in An Essay on the Shaking Palsy in 1817 after his observation of 6 cases [1-2]. An estimated 7 to 10 million people worldwide are living with PD. Even though a similar cell death is associated with ageing, for someone with the Parkinson’s …show more content…
gene, this process is much faster. There are yet no known cures for PD. Parkinson’s typically develops after the age of 65, about 15% of people with the condition develop "young-onset" Parkinson 's disease before reaching age 50. [5]
As the disorder progresses, the symptoms are stronger and disabling making normal everyday activities much harder to perform, for example, brushing your teeth is so much slower than usual. [2]
The 4 primary symptoms of this disease are tremor (this is the involuntary movement of limbs, head or whole body), Rigidity (stiffness or inflexibility of the limbs or joints). Bradykinesia or akinesia (slowness of movement or absence of movement) and Postural Instability (impaired balance and coronation) lokkomg at fig.1 you can see where this symptoms affects a Parkinson’s sufferer. [3]
Symptoms are caused by the breakdown of certain dopamine-containing nerve cells in the brain. The brain is always using dopamine to control nerve signals, which in turn control the body’s movements. Dopamine, like other neurotransmitters, is constantly produced and used up (destroyed). In Parkinson 's, the production of dopamine is impaired whilst its use and destruction remains. This causes a dopamine deficit, whereby the body’s movement control is impaired. [4] Possible solution 1
Stem cell therapy
Stem cells are unspecialised cells that can develop into many different types of cells. All cells in the body are derived from stem cells as seen on fig.3. There are two main types of stem cells: embryonic and adult stem cells. Stem cells can be use to replace the lost or faulty nerve cells that produce dopamine in Parkinson’s sufferers. [6]
Embryonic stem cells are obtained from early embryos. To do this in a laboratory, IVF (In-vitro fertilisation) is carried out. Once the human egg has been fertilised, it will develop into a blastocyst which consists of cells called the inner cell mass. These cells are then transferred to a culture medium where they are cultured into embryonic stem (ES) cells. ES cells are pluripotent- they can differentiate into almost any type of cell in the human body. [6-7]
Adult/ somatic stem cells are found in body tissues of an adult e.g. can be found in bone marrow. They can be extracted and obtained by an operation. The donor is anaesthetised and a needle is inserted into the centre of the bone, usually from the hip, and a small amount of bone marrow is removed. This operation can cause a lot of discomfort to the person. However, adult stem cells are multipotent and can only differentiate and produce a limited number of cell types. [6-7]
Overview
I will be outlining 2 studies which build on from one another adjusting the stem cells to avoid tumour growth. I will outline the changes made by the different researchers and why they were made.
Professor Arenas a lead researcher in a 2008 study were able to use human stem cells to create dopamine neurons which were implanted in animal models with Parkinson’s like lesions. The animals were able to survive, and in the mice and rats the movement problems normally seen were reversed. Dr Lorenz Studer criticised Arena’s study as the first transplanted of the human stem cells transplanted into the animal models caused tumour growth. The stem cells used for the transplantation in to the animal model were modified so as to avoid tumour growth.
Dr Leveque lead researcher of a study carried out in 2011 reviewed Arena’s study and the modification implemented by Dr Lorenz. He modified the stem cells such that the stem cells were appropriate to be transplanted into the brain of a human suffering from Parkinson’s disease.
Research studies
The approach using stem cells for treating Parkinson’s disease is growing them into new brain cells and transplanting it in to the sufferer this cells are also ideal cells for developing and testing new drugs for this disorder. In 2008 professor Arenas and his team grew dopaminergic neurons from embryonic stem (can be induced to grow a wide variety of different cell types) produced stem cells which were transplanted into animal models of Parkinson’s disease. Two of the animal models in which this stem cells were transplanted to developed tumours induced by the cells and died. Professional arena’s team went on to use neural stem cells which were programmed to develop into nerve cells. These cells were then transplanted into 6 laboratory animals with a damaged substantial nigra region of the brain and the results were promising. [8] These animals were 2 monkeys, 2 rats and 2 mice. Professor Arenas said “the transplanted cells reversed almost completely the behavioural abnormalities, and neurons differentiated, survived and the treatment re-innervated the relevant part of the brain better."
Method used by Professor Arena’s study
The team gave animals six injections of more than a million cells each, to parts of the brain affected by Parkinson 's. The neurons survived, formed new connections and restored lost movement in mouse, rat and monkey models of the disease, with no sign of tumour development.
In vivo survival and function is demonstrated in Parkinson’s disease models using three host species. Long-term engraftment in 6-hydroxy-dopamine-lesioned mice and rats demonstrates robust survival of midbrain DA neurons derived from human embryonic stem cells, complete restoration of amphetamine-induced rotation behaviour and improvements in tests of forelimb use and akinesia. Scalability is demonstrated by transplantation into parkinsonian monkeys. Excellent DA neuron survival, function and lack of neural overgrowth (a potential overproduction of new brain cells) in the three animal models indicate promise for the development of cell-based therapies in Parkinson’s disease. [9-11]
Results from the study showing improvement in scans after the dopamine embryonic stem cells transplantation
Fig. 4(a). Immunochistochemical analysis of short-term (6 weeks) in vivo survival Studies in adult intact (unlesioned) mouse striatum
fig.4(b) shows a comparison of the mouse lesion which developed tumours. The picture shows a negative dopaminergic neurons. Forkhead box protein A2 (FOXA2) expressing cells (red) were only found in the graft but not in the surrounding host striatum demonstrating graft origin and midbrain identity of the cells. Nearly all expressed tyrosine hydroxlylase neurons (green) co-expressed FOXA2 (red). However, a considerable proportion of FOXA2+ cells did not co-express tyrosine hydroxlylase suggesting that these cells have not yet acquired a mature dopamine phenotype or represent another expressed FOXA2 neuronal population negative for dopamine neuron markers. http://www.nature.com/nature/journal/v480/n7378/extref/nature10648-s1.pdf
The rosette pattern consists of a halo or spoke-wheel arrangement of cells surrounding a central core or hub which may be empty or contain fibers, cytoplasmic processes, or a blood vessel.
Fig.5 (e-h). Analysis of rosette-derived grafts: Neural overgrowth with compression of host brain tissue. The majority of cells were positive for both Neural Cell Adhesion Molecule (NCAM) is a homophilic binding glycoprotein expressed on the surface of neurons (red) and doublecortin (DCX (green)) suggesting neuronal fate indicating dopamine nerone phenotype present. Neuronal fate is the process in which developmental fate of a cell becomes restricted such that it will develop into a neuron.
Within the graft core they observed multiple DCX+ doublecortin clusters which bind microtubules further indicting the development of dopamine neurones. (h) Only very few expressed tyrosine hydroxlylase cells (green) and fibers were observed at graft periphery and nearly all rosette-derived expressed TH cells in vivo were negative for FOXA2 (blue). This indicates positive dopamine phenotype development thus the improvement of the symptoms of the monkeys. http://www.nature.com/nature/journal/v480/n7378/extref/nature10648-s1.pdf
Fig.5: According to the study, the results from a mouse and rat demonstrate excellent graft survival and behavioural outcome. However, the number of DA neurons required in a mouse or rat brain represents only a fraction of the cells needed in a human.
The researcher investigated whether their approach could treat two monkeys with Parkinson’s like symptoms. Cells were injected at three locations on each side of the brain and the animals were immune suppressed with cyclosporine-A. One month after the transplantation the dopamine neurons successfully grafted into the brains of the monkey improving the Parkinson like symptoms.
Fig.6. DA neurons were grafted into the striatum of adult monkeys.
(a) Graft cytoarchitecture (the arrangement of neuronal soma in the brain) is illustrated by immunohistochemistry(detecting antigens in cells of the brain section by exploiting the principle of antibodies binding specifically to antigens in that section of the brain) for the human specific marker.
(b) Analysis of green fluorescent protein (GFP) expression in graft cores further confirmed human identity of the cells. (c) Higher resolution image of the expression of GFP graft using DAB detection (a multimer-technology based detection system intended for the specific and sensitive detection of mouse and rabbit primary antibodies) showing numerous presences of GFP cells at graft periphery exhibiting neuroblast morphology.
Previous researchers had already generated the right type of nerve cells from human stem cells to produce the chemical dopamine that is depleted in Parkinson 's, but there were problems when the cells were transplanted into models of Parkinson 's animals. The cells continued to grow and some transformed into tumours.
Dr Lorenz lead a study to address this problem, he stated “in this 2009 study, the researchers used a different procedure to differentiate the stem cells into nerve cells. This time they remained as correctly working nerve cells, did not form tumours, and overcame some of the symptoms of Parkinson 's in the monkeys. Stem cell therapy may still be some way off. However, this study has shown for the first time that it is possible to transplant nerve cells that work from human stem cells." [8]
A successful transplantation of adult stem cell research which reversed the effects of Parkinson’s disease in Human trial was reported by Dr. Michel Levesque. This was the first ever successful stem cell transplantation human trial which reverses the effects of Parkinson’s disease and demonstrated the long term safety and therapeutic effects.
They reported the long-term clinical results following the autologous transplantation of differentiated neural stem cell-derived neurons unilaterally into a patient with Parkinson’s disease. His medical therapy with dopamaninerative agents showed a small improvement on his symptoms of rigidity and tremor. These were the drugs he was taking before the transplantation. [12]
Levesque’s team were able to isolate the patient-derived neural stem cells – adult stem cells (harvested from the prefrontal cortical sub cortical region), multiply them in vitro and ultimately differentiate them to produce mature neurons before they were reintroduced into the brain. Unlike the animal trial above, in this trial, they injected the adult stem cells without the need for immunosuppressant (immunosuppressant decrease the function of the immune system to prevent and/or treat stem cell rejection.) [12] Fig 8 shows the improvement of the Transplantation of Differentiated Human Adult Neural Stem Cells.
Results from Dr Lévesque’s Study
Fig. (8). 18-Fluoro-DOPA and Positron Emission Tomography Studies.
Functional brain imaging with positron emission tomography (PET) and the radiotracer 18-fluorodopa (FDOPA) is capable to quantify the deficiency of dopamine synthesis and storage within pre-synaptic striatal nerve terminals.
FDOPA-PET imaging permits the follow-up of disease progression, the assessment of medical and surgical PD therapy strategies with possible neuroprotective properties.
(a) Pre transplant uptake study showing decrease nerve terminal density in the striatum, worse on left (right on picture), consistent with Parkinson’s disease.
(b) Post transplantation study with increase activity of marker at the site of micro-injections in left putamen.
Fig.7 this graphs illustrates the number of years the effect of the stem cells transplantation in the Lévesque’s research on the one sufferer who took part.
For the five years after the procedure, the patient’s motor scales improved by 80% for at least 36 months. Stem cells enhancement was dramatically noticeable. [12-13]
The baseline shoed the starting point of the experiment. As the sufferer was already taking medication before the transplantation, there was some improvement and so this is why the baseline is not from the black point of the graph. The blue line shows a placebo outcome however, there was no patent in which to give a placebo to and this was given as the expected placebo out come so that the results of this study could be
compared.
On the trials using stem cells, most participants showed drastic improvement within the first week of transplantation. The hope in the future for using stem cell therapy for treating PD is that biologist will be able to grow new dopamine-producing nerve cells.
Evaluation of results
The result from Lévesque’s study supports those from Dr Arena’s study. The build up and modifications of the stem cells that enabled the prevention of the formation of tumours makes the results more reliable. Both results provide evidence of the effectiveness of using stem cells to treat Parkinson’s disease. However, the sample size of Dr Lévesque’s study was not high to draw a valid conclusion about the results as only one Parkinson’s sufferer had the stem cells transplanted to their brain. Even though the sufferer showed drastic improvement, more trials will have to be carried out using humans so as to further support the findings. However, comparing Lévesque’s results (the actual stem cells transplantation) that he expected placebo outcome shoes a significant improvement when using stem cells.
All the studies were double blind studies. This means that neither the patience nor the doctor knows was receiving placebo or the medication. The means that the results were not skewed by doctors or even the patience who wanted the treatment to work in the way they wanted. For example, at every visit the treating investigator inquired about adverse events. The primary rater, who was also blinded to the treatment assignment and was kept unaware of information obtained during the course of the study. This ensured that event the investigator should not change the doses of the control patience or do something to favour their research. This makes the results more reliable.
Just as with the study above, other experiments have used stem cells to increase dopamine producing brain cells. Dr Lorenz Studer (2009) has experiments in which dopamine neurons were created from mouse stem cells. This study however has not been successfully reproduced in humans. This result has risen which have also raised safety concerns that dopamine neurons developed from human cells might trigger growth of tumours. [9]
Implications
Social and ethical issues
Most Parkinson’s sufferer’s symptoms drastically decrease their quality of life. Some are unable to work and provide for their families and can barely do normal daily activities which we consider easy e.g. brushing your teeth. This causes some burden to the family and friends especially their love once. In the book ‘Always Looking Up’ written by Michael J. Fox where he writes about the hard-won perspective that helped him sees challenges as opportunities. Instead of building walls around himself, he developed a personal policy of engagement and discovery: an emotional, psychological, intellectual, and spiritual outlook that has served him throughout his struggle with Parkinson 's disease. [14]
Michael J Fox a Parkinson’s suffer stated in his book ‘the last ten years, which is really the stuff of this book, began with such a loss: my retirement from Spin City. I found myself struggling with a strange new dynamic: the shifting of public and private personas. I had been Mike the actor, then Mike the actor with PD. Now was I just Mike with PD Parkinson 's had consumed my career and, in a sense, had become my career. But where did all of this leave me? I had to build a new life when I was already pretty happy with the old one...’ Always looking up [13]
The use of stem cells can dramatically reduce Parkinsonism symptoms. Great levels of success and potential have been shown from research using adult stem cells Transplantation can improve in the quality of life for many sufferers e.g. by partially replacing the damage dopamine levels in the brain for quite a long period of time. [15]
However the use of stem cells is a continuous debate in the society. Obtaining stem cells from embryos by IVF raises ethical issues - the embryo must be destroyed at around 5-7 days after fertilisation (the blastocyst stage) by harvesting the cells from the part of the embryo called the inner cell mass and could have been a potential human life. The question is whether it is right to do this. Many people believe that life begins at conception, and it is immoral and wrong to destroy and embryo, even to reduce suffering in existing human life. Scientists are ‘playing god’ and ‘messing with human life’. [2, 16]
Society has to consider all the arguments for and against stem cell research before allowing it to go ahead. To help society make these decisions, regulatory authorities have been established, such as the Human Fertilisation and Embryology Authority (HFEA).
The work of regulatory authorities includes, looking at proposals of research – this ensures that research involving embryos is carried out for a good reason, and is not repeated elsewhere. [17]
Economical
According to the Parkinson’s Action Network, drugs commonly used e.g. Levadopa to treat Parkinson’s disease cost between $1,000 and $6,000 per year per patient. Annual medical care, including doctors’ visits, physical therapies and treatment for co-occurring illnesses (such as depression) is estimated at $2,000 to $7,000 for people in early stages of the disease this amount increases for advance patients. This amount increases drastically using surgical treatments which can go up to $25,000 or more. . [, 5, 18]
The annual cost in nursing-home care for Parkinson 's disease alone in the UK is estimated to be about £600-800 million. [5] Estimates of the overall cost of Parkinson’s disease range widely. The National Institute of Neurological Disorders and Stroke (NINDS) puts the figure in excess of $5.6 billion, including both direct medical expenses and indirect costs such as lost income, disability payments and medical costs. This amount does not include research cost. [19] Many experts estimate a much higher annual cost for Parkinson’s.
Benefits and risk
The stem cell transplantation in the animal model of Parkinson’s disease proves that it is capable of relieving symptoms and restoring damaged brain function. Even with the current human trials, adult stem cells show a beneficial result for a long period of time. People do get better when this stem cell transplantations happen thus can have a chance to lead rewarding and more meaningful lives around their families. So stem cells can enhance the quality of live which is always hoped for by the sufferers. [6-13, 20)
The risks associated with research participants undergoing stem cell transplantation include tumour formation, inappropriate stem cell migration, immune rejection of transplanted stem cells, haemorrhage during neurosurgery and postoperative infection. Although some of these risks are general to neurosurgical transplantation and may not be reduced for participants, the potential risk of tumour formation and inappropriate stem cell migration must be minimized before the transplantation takes place. [9, 21) every surgical procedure carries a certain amount of risk. Transplantation of these stem cells could create a different problem in the brain as the stem cells could mutate and cause a negative effect.
Alternative solutions
Drug treatment (solution 2)
There are quiets a few drugs available for sufferers of Parkinson’s disease and this drugs are prescribed to them according to the level or stage in which are in. drug treatment available are targeting the symptoms of this disease. For example, dopamine agonists; it mimics the role of dopamine in the brian which can be taken alongside Levedopa. Mao-B inhibitors slow down an enzyme in the brain responsible for the breakdown of dopamine. [2, 22]
Levodopa is the most sophisticated drug treatment for Parkinson’s disease. Studies demonstrated the use of levodopa in 2011 found that those with the early onset of Parkinson’s who had long exposure to levodopa did not lose dopamine neurons when compared with the control group. [25] As people cannot easily take dopamine pills because it does not easily pass from the bloods to the brain, levodopa is a form that can be transported in to the brain. Nerve cells can use levadopa to make dopamine and replenish the brain 's dwindling supply. However people taking this drugs for a long time, over the year they develop motor fluctuations (time when the medication works and times when they do not work) and dyskinesias (involuntary movement). [23]
Patients turn to combine other drugs alongside L-dopa which allows more L-dopa to get to the brain and thus increases the supply of dopamine in the brain. It decreases side effects caused by increased dopamine levels outside the brain (e.g. dyskinesias) by reducing the supply of "free" dopamine outside the brain. Some of these drugs include COMT inhibitors Amantadine and carbidopa. [22]
Deep Brian Stimulation (solution 3)
Many Parkinson’s patients who do not response to drug treatments can potentially be treated by deep brain stimulation. This treatment involves implanting a battery operated devise called a neurostimulator similar to a pacemaker to deliver electrical impulses that stimulate areas of the brain that control movement. The impulses are thought to block abnormal signals that cause many of the symptoms of Parkinson’s, like tremors, slowness, stiffness, and difficulty with speech. [3, 24]
Fig.10 shows the position in which the neurostimulatore and the electrodes are placed in the brain and the body.
Most patients still need to take medication after undergoing deep brain stimulation; many patients experience a great reduction of their Parkinson’s symptoms and are able to greatly reduce their medications. However a review suggests that amount of reduction varies from patient to patient. This may cause some patience to reduce their medication which could leads to a significant improvement in side effects such as dyskinesias (involuntary movements caused by long-term use of levodopa). [25]
Evaluation of Sources
The sources of the study come from the Nature Journal and the Open Cell Journal so have been peer reviewed (14, http://www.benthamscience.com/open/toscj/articles/V001/20TOSCJ.pdf , [10] http://www.nature.com/nature/journal/v480/n7378/full/nature10648.html#/supplementary-information . These sources are reliable as it also agrees with many other sources.
The article is based on peer-reviewed results that have gone through all the stages ensuring they are valid and addresses the complication with research progression.
"This evidence had been presented previously, but we now have the peer-reviewed scientific evidence for the effectiveness of adult stem cells in alleviating Parkinson’s symptoms," he said. "While the data show that the technique needs refinement, this patient went for several years with little to no symptoms of his disease, even with only half of the brain treated with his own adult stem cells." Dr David Prentice.
[http://www.ninds.nih.gov/disorders/parkinsons_disease/detail_parkinsons_disease.htm]
I found this source very reliable and useful in providing in-depth information, support and education related to Parkinson’s disease. This website contains a lot of review articles and researches of the disease. The NINDS provide cost-effective management in operating multiple Parkinson’s trials.
Levesque is a principal investigator for NeuroGeneration, a biotechnology company, and is affiliated with the UCLA School of Medicine and the Brain Research Institute. This put his reputation at the top of the chards as he can be seen as trustable. This institution dedicates to clinical research of Parkinson disease and other brain disorders known worldwide. Its high credibility is as such that both studies can be taken as extremely reliable along with their sources in terms of where they come from.
The 2 studies above were funded by different organisation which are having high credibility and good reputations an so it cannot be said that the lead doctors in the studies were attempting to find positive data which could put them in books for being the first to find the cure for Parkinson’s. Professor Arena and Dr. Michel Levesque who was head of their trials, seems to have had no hidden agenda, and there is no evidence suggest that they have a vested interest in finding a cure for Parkinson’s disease due to professional history.
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Economical implications
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