Stem Cell Therapy for Parkinson's Disease
Parkinson’s disease (PD) is a disorder of the central nervous system in which the dopamine-producing cells in the substantia nigra region of the brain degenerate. Since dopamine is responsible for transmitting the electrical signals that are required for normal physical motion, a lack of the cells which produce this chemical results in the abnormal movement associated with this disease. PD is both chronic and progressive, meaning that, once diagnosed, it lasts throughout one’s lifetime and worsens over time.
According to the National Institute of Neurological Disorders and Stroke (NINDS), a division of the National Institutes of Health (NIH), Parkinson’s disease (PD) is defined as follows:
“Parkinson's disease (PD) belongs to a group of conditions called motor system disorders, which are the result of the loss of dopamine-producing brain cells. The four primary symptoms of PD are tremor, or trembling in the hands, arms, legs, jaw, and face; rigidity, or stiffness of the limbs and trunk; bradykinesia, or slowness of movement; and postural instability, or impaired balance and coordination. As these symptoms become more pronounced, patients may have difficulty walking, talking, or completing other simple tasks. PD usually affects people over the age of 50. Early symptoms of PD are subtle and occur gradually. In some people the disease progresses more quickly than in others. As the disease progresses, the shaking, or tremor, which affects the majority of PD patients may begin to interfere with daily activities. Other symptoms may include depression and other emotional changes; difficulty in swallowing, chewing, and speaking; urinary problems or constipation; skin problems; and sleep disruptions. There are currently no blood or laboratory tests that have been proven to help in diagnosing sporadic PD. Therefore the diagnosis is based on medical history and a neurological examination. The disease can be difficult to diagnose accurately. Doctors may sometimes request brain scans or laboratory tests in order to rule out other diseases.” (From www.ninds.nih.gov).
In the United States alone, at least 500,000 people are known to be afflicted with PD, although the actual number of individuals who suffer from this disease is believed to be higher. Approximately 50,000 new cases of PD are diagnosed in the U.S. each year, but an accurate number is difficult to obtain since many people in the early stages of the disease mistake their symptoms for those of normal ageing and do not seek the evaluation of a physician. In general, diagnosis of PD is difficult since other conditions may produce similar symptoms, and no definitive diagnostic test exists. It is not uncommon for people with PD to be misdiagnosed as having other disorders, and similarly, people who do not have PD but who exhibit PD-like symptoms may be incorrectly diagnosed with PD.
Data on the global prevalence of PD is scarce, due to these very same reasons which are also compounded by a lack of adequate awareness of PD in many developing countries. In 1990 it was estimated that 4 million people worldwide had been officially diagnosed with PD, although this, also, is considered to be a conservative estimate. In Europe, the prevalence of PD is estimated at 1.6 per 100 people over the age of 65. In the United States, PD is second only to Alzheimer’s disease as the most common neurodegenerative disorder. (From www.ninds.nih.gov).
Due to ageing populations worldwide, the impact of PD on public health issues and on societies in general is expected to increase. The World Health Organization (WHO) and other agencies are therefore placing a renewed emphasis on epidemiological studies in an effort to assess the full extent of PD, and the costs associated with it. As stated on the website of the NIH:
“Society pays an enormous price for PD. The total cost to the nation (the U.S.) is estimated to exceed $6 billion annually. The financial and public health impact of this disease is expected to increase as the population ages.” (From www.ninds.nih.gov).
Also from the same website, NIH researchers add,
“At present, there is no cure for PD.”
A degenerative disorder of the central nervous system, Parkinson’s disease was first described in 1817 by the British physician James Parkinson, who wrote about a “shaking palsy”, which would later bear his name, in a paper that he published that same year. Like many other neurological illnesses, PD is chronic, progressive, and, as stated above by the NIH, considered to be incurable by conventional medical techniques. Traditionally, the standard treatment for PD has consisted primarily of drug therapy, which is occasionally augmented with neurosurgery.
PD is grouped within a classification of conditions known as movement disorders. “Parkinsonism” is the general term for a group of disorders with similar characteristics, of which PD is the most common. PD is also known as “primary parkinsonism” or “idiopathic Parkinson’s disease”, the latter of which indicates by the term “idiopathic” that the cause is unknown. There are four main symptoms of PD, which include:
1. tremor, which may consist of trembling in the hands, arms, legs, jaw, or head,
2. rigidity, which is a stiffness of the limbs and trunk,
3. bradykinesia, which is a slowness of movement, and
4. postural instability, or impaired balance.
It should be noted, however, that not everyone with one or more of these symptoms has PD. For those who do have PD, however, such symptoms usually begin gradually and worsen over time, eventually leading to difficulty with basic motor skills such as walking and speaking.
Although most forms of parkinsonism are idiopathic, some cases have been found in which the cause is known or suspected to be related to other disorders, such as changes in the brain's blood vessels.
Some well-known individuals with PD have included the heavy weight boxer Muhammed Ali (Cassius Marcellus Clay), the actor Michael J. Fox, former U.S. Attorney General Janet Reno, Pope John Paul II, and the former U.S. Congressman Morris K. Udall, after whom the Morris K. Udall Parkinson’s Disease Research Centers of Excellence were established throughout the United States. (Please see section, below, describing these Centers).
Additionally, the Mohammed Ali Parkinson Center at the Barrow Neurological Institute in Phoenix, Arizona, has developed a national registry of people with PD in order to facilitate the development of new therapies and to allow researchers to quickly identify and notify people about research studies for which they are eligible. Anyone diagnosed with PD is eligible to take part in this registry. More information is available at their website, www.maprc.com.
Some states, including California and Nebraska, have also established their own independent registries of people with PD.
Approximately two-thirds of all PD cases are considered to be “sporadic”, meaning that the disease does not appear to be inherited. The remaining one-third of all cases do appear to be hereditary and are traceable to specific genetic mutations. A small subset of cases within the hereditary group appear to follow a pattern of autosomal dominant inheritance, although most of the hereditary cases do not exhibit a recognizable inheritance pattern. In order to understand the heritability of this disease more clearly, researchers continue to study familial aggregation in first- and second-degree relatives, and the data from more than 10 studies have suggested an increased risk of PD in the first-degree relatives of affected persons with PD that is as much as 14 times higher than the frequency of the disease that is found in the general population.
Most researchers agree that PD seems to be the result of a combination of factors, such as genetic predisposition and environmental exposure to various agents that may trigger the disease.
Regardless of the specific causes, however, PD is characterized by a destruction of the dopamine-producing cells of the brain. Located in the substantia nigra, these cells are responsible for producing the key chemical that is involved in the transmission of electrical signals across the neurons that run between the substantia nigra and the corpus striatum, the normal result of which is smooth, purposeful movement in healthy individuals. Without dopamine, however, the electrical firing patterns of the neurons become abnormal, and so does the resulting physical motion. By the time symptoms appear throughout the body, most PD patients have already lost between 60 to 80% of the dopamine-producing cells in the substantia nigra. It has also been found that people with PD exhibit a loss of the nerve endings that produce epinephrine, which is another neurotransmitter, similar in its structure and function to dopamine, and which is the main chemical messenger of the sympathetic nervous system - which is responsible for the regulation and control of the body’s automatic functions, such as blood pressure and pulse. People suffering with PD often exhibit other abnormalities of a non-motor nature, such as in their blood pressure regulation, which would be at least partially explained by this loss of norepinephrine.
It has been found that people with PD have brain cells which contain “Lewy bodies”, which are unusual deposits or clumps of the protein alpha-synuclein and which are often combined with other proteins. Some studies seem to indicate that the alpha-synuclein clumps alter gene expression, although the full significance of the presence of these proteins, and the precise mechanisms by which such Lewy bodies form, are not yet known.
Several genetic mutations associated with PD have been identified, and it is believed that many other genes, still unidentified, are related to the disease. Researchers hope that by studying the genes which are known to be associated with the heritable forms of PD, they may also discover how other genes are altered in the sporadic, or non-inherited, cases of PD. It has been estimated that PD appears in approximately 15 to 25% of the relatives of people with PD.
Age is known to be a “risk factor” for PD, as the average onset of the disease is 60 years, and the frequency with which the disease appears increases with age. Only between 5 and 10% of all people with PD have the “early onset” type of the disease that develops prior to the age of 50. The “juvenile parkinsonism” that occurs in some people prior to the age of 20 is extremely rare, is most commonly found in Japan and has been associated with a mutation in the parkin gene.
PD appears approximately one-and-a-half times more frequently in men than in women, and there is an overall higher incidence of the disease in developed countries than in developing countries. The disease seems to be found most often among people who live in rural areas, and who are in certain professions which experience a high exposure to pesticides and to other toxins. However, conclusive data which might explain any of these risks do not yet exist.
Although the importance of genetics in PD is increasingly recognized, most researchers believe that environmental exposure to specific toxins increases a person's risk of developing the disease. Even in familial cases, an inherited gene or group of genes in and of itself is not sufficient to manifest PD, and it is believed that exposure to toxins or to other environmental factors plays a key role in influencing both the manifestation and the progression of the disease. Several toxins have already been identified as triggering “parkinsonian” symptoms, such as, for example, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, also known as MPTP, which is chemically related to the opioid analgesic drugs and which is known to be present in certain types of synthetic heroin.
Further evidence has also been compiled implicating the importance of environmental factors in causing the development of PD. Namely, it has been found that the PD phenotype may result from toxicity to dopaminergic neurons caused either by the misfolding and aggregation of proteins, which results in an inhibition of the ubiquitin-proteasome system and which in turn causes severe cell dysfunction, or by the oxidative stress that results from mitochondrial dysfunction and which in turn causes an increase in the number and extent of protein misfolding. The ubiquitin-proteasome system is often referred to as a “protein disposal system”, which exists in each cell of the body. When this system fails, for whatever reason, cell death results. As research progresses, it is becoming increasingly clear that the causative factors of PD are numerous and interrelated.
In fact the mitochondria are recognized as playing an important role in the development of PD, and much research is focused on the role of these energy-producing components of the cell. Mitochondria are major sources of free radicals, which are known to damage cell membranes, proteins, DNA, and other parts of the cell in a process that is commonly known as “oxidative stress.” Such cellular stress and damage has been extensively found in the DNA, proteins, and fats of the brains of PD patients. Paradoxically, there are certain types of variations in the DNA of mitochondria which have been found to increase the risk of PD, while other variations are correlated with a lower risk of PD. People with PD have been known to have more variations in their mitochondrial DNA (mtDNA) than do people with other neurological disorders. The precise mechanisms by which mtDNA variations may lead to the development of PD are not yet known.
Viruses in particular are suspected of playing a major role in triggering PD, and several specific cases of this have been documented. After the influenza epidemic of 1918, it was reported that people who developed encephalopathy were later also found to have developed parkinsonian symptoms. Parkinsonian symptoms, along with inflammation of the substantia nigra, were similarly observed in a group of Taiwanese women after they contracted the herpes virus, although the parkinsonian symptoms later disappeared along with the inflammation.
Inflammation itself is increasingly becoming an area of intense medical research, as it seems to be an important factor in a number of diseases, including PD. Researchers are therefore investigating the precise mechanisms by which inflammation and the destruction of dopamine-producing cells are related.
Molecular genetic studies have identified at least 3 genes that are associated with PD, and researchers continue to investigate the specific mutations involved in such genes, as well as the localization of other chromosomal regions that may be associated with PD. The 3 main genes identified thus far are alpha-synuclein (SNCA), parkin, and synphilin-1 (SNCAIP). The alpha-synuclein gene was first discovered in the 1990s when researchers at NIH and other institutions studied the genetic profiles of a large Italian family and three Greek families with familial PD. In these families PD was discovered to be related to a mutation in this gene, and later a second alpha-synuclein mutation was discovered in a German family with PD. Alpha-synuclein continues to be a primary focus of PD research, and it was from the study of this gene that Lewy bodies (clumps of the alpha-synuclein protein) were found in people with the sporadic form of PD, thus revealing a potential link between hereditary and sporadic forms of PD. In 2003 it was further discovered in one large family that the heritable form of PD was caused by a triplication of the normal alpha-synuclein gene on one copy of chromosome 4, which caused an overproduction of alpha-synuclein. This was the first evidence that PD may be caused not merely by an abnormal form of protein but also by the excessive presence of a protein.
Other genes that have been found to be associated with PD include DJ-1, PINK1, and LRRK2. It has been determined that parkin, DJ-1, and PINK-1 are together responsible for causing the rare, early-onset forms of PD, since the parkin gene is translated into a protein that normally facilitates the breakdown and recycling of proteins within cells, while DJ-1 is known to help regulate gene activity and protect cells from oxidative stress. Similarly, PINK1 is known to code for a protein that is active within mitochondria, so an increase in cellular stress is believed to result from mutations in this gene. Researchers have further determined that LRRK2, which is translated into a protein called dardarin, is responsible for the late-onset form of PD. LRRK2 was originally identified in several English and Basque families and has since been found in other families with PD as well as in a small percentage of people with sporadic PD.
Several studies that were conducted between 1996 and 2003 have indicated a possible association between PD and type 1 Gaucher disease. According to the National Institute of Neurological Disorders and Stroke (NINDS), a division of the National Institutes of Health (NIH),
“Gaucher disease is an inherited metabolic disorder in which harmful quantities of a fatty substance called glucocerebroside accumulate in the spleen, liver, lungs, bone marrow, and sometimes in the brain. There are three types of Gaucher disease.” (From www.ninds.nih.gov).
Some people with type 1 Gaucher disease have been known to develop a particularly refractory and atypical parkinsonism which begins in the 4th to 6th decades of life, which progresses steadily and which does not respond to anti-parkinson therapy. According to NINDS,
“Gaucher disease is the most common recessively-inherited disorder of glycolipid storage; it is due to deficiency of the lysosomal enzyme, glucocerebrosidase, and involves multiple organs, primarily the spleen, liver, bones, and bone marrow. Type 1 Gaucher disease - the milder type of the disease - occurs in all ethnic groups, but is particularly prevalent among Ashkenazi Jews, with a carrier rate of 1 in 17 for the disease-associated variant of the glucocerebrosidase gene (GBA). These observations suggest that homozygotes and heterozygotes for Gaucher disease mutations may have an increased risk for developing Parkinson's disease, which could reflect a significant health risk for certain ethnic populations, particularly Ashkenazi Jews.” (From www.ninds.nih.gov).
Additionally, the SNCA gene has been tested for the A53T mutation as an autosomal trait and has been found to have a frequency of approximately 1 in 186, or 0.5% (Scott et al., 1999). In the SNCAIP gene the R621C mutation has been found with a frequency of approximately 1 in 164, or 0.6% (Marx et al., 2003). Although such genetic variants do not constitute the majority of PD cases, and are known to occur very infrequently in people with sporadic or familial disease, they are nevertheless pieces of the puzzle and therefore constitute areas of ongoing research. (From www.cdc.gov).
A number of other genes and chromosomes have been identified as potentially playing a role in PD, but the precise nature of such links is not yet understood.
Accurate diagnosis of PD has always been difficult, since decisive diagnostic tools for this disease do not exist. Even for sporadic PD, there are currently no blood or laboratory tests that offer a definitive diagnosis. Physicians must therefore base their assessment of any patient suspected of having PD on medical history and neurological examination. As previously described, it is not uncommon for the early symptoms of PD to be dismissed as normal signs of ageing. Brain scans and other laboratory tests may be effective in ruling out the presence of other diseases, but they are not effective in determining the presence of PD, since the CT and MRI brain scans of people with PD usually appear to be normal. It has been estimated that approximately 15% of everyone diagnosed with PD may in fact be suffering from something other than PD. Despite the difficulty of diagnosing PD, the early identification of the disease is essential for proper treatment of the patient.
A newly developed diagnostic test for PD is currently being tested, however, and may offer a reliable tool with which to identify PD in the future. Researchers at the Howard Florey Institute in Melbourne, Australia have designed a device which not only is capable of testing for PD but which may also allow the scientists to conduct a large-scale study of the genetic basis of PD. If successful, this will be the first diagnostic test that is specific to PD. Although DNA sequencing is available for the 6 genes that are already known to be associated with PD, the cost of such DNA sequencing is around $4,000 and is not covered by Medicare. This newly developed diagnostic test, invented by Dr. Justin Rubio, contains a “gene-sequencing chip” that screens for 17 genes, which includes eleven genes beyond those 6 that have already been identified. The total cost for such a test is approximately $500. The test is convenient to perform, involving only the collection of a small sample of blood or saliva. In addition to identifying genes related to PD, the chip is also designed to identify genetic changes that may predispose a person to PD. This gene-sequencing chip will allow for the routine, inexpensive testing of people suspected of having Parkinson’s disease. In Australia alone, approximately 100,000 people have been diagnosed with PD but very few of these people have actually been tested for the precise genes involved in the disease. A similar situation exists in all other countries, where only a very small percentage of the people who have been formally diagnosed with PD have actually been tested for the genes that are involved. In Australia, researchers are planning a nationwide, large-scale testing of people with this device, from which a cumulative database is to be constructed, which in turn should provide a better understanding of some of the other genes that are involved in PD. Known as the “Gene Discovery” project, the applications of such large-scale testing may eventually be extended to other diseases.
PD symptoms typically begin to appear on one side of the body, eventually affecting both sides as the disease progresses. However, even when both sides of the body are involved, the symptoms are often more pronounced on one side than on the other.
The primary symptoms may include:
rigidity (resistance to movement),
bradykinesia (slowing of movement), and
postural instability (impaired balance).
Additional, secondary symptoms may include:
difficulty with swallowing and chewing,
urinary problems or constipation,
dementia or other cognitive problems,
orthostatic hypotension (a sudden drop in blood pressure when standing up from a lying-down position),
muscle cramps and dystonia (sustained muscle contractions, caused by fluctuations in dopamine levels),
muscle and joint pain,
fatigue and loss of energy, and
Many symptoms are often the result of an improperly functioning autonomic nervous system, and are typically treated with medication.
Some people with PD experience a rare type of symptom, known as “central pain”, which consists of stabbing, burning sensations throughout the body. Such perceptions are known to originate not in the parts of the body where the sensations are perceived, but rather in the brain, and are often treated with dopaminergic drugs, opiates, or antidepressants.
Treatment of PD has typically consisted primarily of medications that mimic dopamine, although brain surgery is occasionally used for particular types of the disease, and most often only in the latter stages.
While such methods of treatment may alleviate some of the symptoms of PD, they do not alter the progression of the disease itself, and none of these therapies are considered to be “cures”.
PD does not shorten life expectancy, but resulting complications, such as choking, pneumonia, and falls, may be life-threatening. The types of medication that are prescribed to PD patients are therefore most often determined according to the extent of the progression of the disease in each individual. In some people, PD may take 20 years or more for symptoms to develop, while in other people the course of the disease may advance more rapidly. The “Hoehn and Yahr” scale is often employed as a means of measuring the progression of PD symptoms, and according to this scale doctors may prescribe the corresponding regimen of medication that is appropriate to the specific individual who is to be treated. Such medications may include any of the following:
Levodopa, (also called L-dopa, abbreviated from L-3,4-dihydroxyphenylalanine). Nerve cells are able to use levodopa to make dopamine and thereby replenish the brain's supply. Since levodopa does not pass through the blood-brain barrier, however, it must be taken with carbidopa in order to be utilized by the brain. Levodopa is prescribed for reducing tremors, bradykinesia and rigidity during the early stages of the disease, although it does not typically alleviate problems with balance, depression or other non-motor symptoms that are associated with PD. Although it may reduce some of the symptoms of PD, it does not replace lost nerve cells and it does not stop the progression of the disease. The effectiveness of levodopa typically diminishes over time with increased use, and the medication may ultimately have to be discontinued. The most common side effects of levodopa include nausea, vomiting, low blood pressure, and restlessness. Long-term use may also cause psychosis, hallucinations and dyskinesias, which are involuntary movements such as twitching and writhing. One of the most important, and difficult, aspects of drug therapy for any PD patient is for the appropriate amount of levodopa to be determined. It is a delicate balance for the physician and the patient to arrive at the proper amount of this, and any, drug, such that the benefits outweigh the side effects. If the resulting dyskinesias that is caused by the levodopa is considered to be severe, neurosurgery may be recommended.
Dopamine agonists may also be prescribed, which include bromocriptine, apomorphine, pramipexole, and ropinirole. These drugs mimic the role of dopamine in the brain, and many of the potential side effects are similar to those linked to levodopa. Additionally, bromocriptine may also potentially cause the development of fibrosis (a buildup of fibrous tissue) in the heart valves or chest cavity, so patients on bromocriptine should be monitored closely for such complications.
MAO-B inhibitors inhibit the enzyme monoamine oxidase B, or MAO-B, which
breaks down dopamine in the brain, and therefore may alleviate some of the symptoms of PD by causing dopamine to accumulate in the remaining nerve cells. MAO-B inhibitors include rasagiline and selegiline (deprenyl), the latter of which is the most common and which should not be taken with certain other types of medication. As with any other drug, side effects should be discussed with one’s physician.
Another class of drugs are the COMT (catechol-O-methyltransferase) inhibitors. COMT is an enzyme that helps to break down dopamine. In the U.S. there are currently two COMT inhibitors which are approved for use in the treatment of PD, namely, entacapone and tolcapone, both of which have been shown to prolong the effects of levodopa by preventing the breakdown of dopamine. Because the potential side effects of tolcapone include a rare but severe liver disease, patients on this particular medication are regularly monitored for liver function.
Antivirals that are typically prescribed in the treatment of PD include amantadine, which is often used in the early stages of the disease.
Anticholinergics include trihexyphenidyl, benztropine, and ethopropazine, all of which decrease the activity of the neurotransmitter acetylcholine and help to reduce tremors and muscle rigidity in PD patients. However, no more than approximately half of all people who suffer from PD and who receive anticholinergics exhibit an improvement, and in those who do improve it is often only a slight improvement, measurable as 30 % or less. The typical side effects may include dry mouth, constipation, urinary retention, hallucinations, memory loss, blurred vision, and confusion.
Since hallucinations, delusions, and other manifestations of psychotic behavior are not uncommon among PD patients, it should be noted that these symptoms are often caused by the other drugs that are regularly prescribed for PD. When a patient develops such behavior, an attempt should be made to reduce the other PD medications. If this is not effective, “atypical antipsychotic” drugs may be prescribed, which include quetiapine and clozapine, the latter of which may also help to control dyskinesias, although it may also cause a serious blood disorder known as “agranulocytosis”, and people who are on clozapine must have their blood monitored frequently.
In March of 2007, the FDA decided to remove the common PD medication pergolide from the market when it was found to be associated with an increased risk of heart disease. In response to this recall, the director of the National Parkinson’s Foundation (NPF), Michael S. Orkun, M.D., formally issued the following statement:
“Dear Parkinson disease patients and families,
We have been watching closely the evolving situation with Permax (pergolide) and its association with valvular heart disease. This week there was a voluntary recall on this medication. We know many of you with Parkinson disease and movement disorders are currently on pergolide. It is important not to panic. There are two drugs (pramipexole and ropinerole) which are safer and have similar mechanisms of action. Please contact your doctor's office as soon as you can to initiate a switch over to these presumably safer drugs.” (From www.parkinsons.org).
Prior to the use of levopoda as a drug, neurosurgery was a common practice in treating PD. With the discovery of levodopa’s properties, surgical techniques fell out of favor with many physicians as a therapy for PD. Recent technological advances, however, have once again brought neurosurgery back to the forefront of conventional medical PD treatment, primarily for patients who do not respond to drug therapy.
Although pallidotomy and thalamotomy were among some of the earliest types of surgical methods used on PD patients, these procedures are considered greatly refined today when compared to their earlier forms. Both of these procedures are employed to remove specific parts of the brain that are most seriously affected by PD: in pallidotomy, the globus pallidus is removed, while in thalamotomy the thalamus is removed. Pallidotomies are used primarily to improve symptoms of tremor, rigidity and bradykinesia by destroying the connections between the globus pallidus and the striatum or thalamus. Thalamotomies are used to reduce tremor.
Such surgical procedures, however, are irreversible since they permanently destroy brain tissue. Consequently, they are being replaced by deep brain stimulation (DBS), in which an electrode that is surgically implanted into the brain is connected by a wire under the skin to a pulse generator implanted in the chest. The electrical signal that is sent to the brain by this pulse generator has been found to alleviate some of the symptoms of PD. DBS is used primarily to stimulate the globus pallidus, the thalamus, or the subthalamic nucleus, which is the most common target in PD patients.
DBS usually reduces the need for levodopa and related drugs, which in turn decreases the dyskinesias that often results from drug therapy. However, DBS is not helpful in reducing problems associated with posture and balance, speech, or dementia.
Although DBS does not stop the progression of PD, and the long terms effects of such deep brain electrical stimulation are still unknown, DBS has been approved by the Food and Drug Administration (FDA). Stroke and brain hemorrhage are among the potential complications of DBS, and the stimulator itself may cause dyskinesias or problems with balance and speech. DBS is not generally considered to be a treatment that is applicable to all PD patients, but only to those with advanced PD who have developed dyskinesias, and who have previously exhibited some responsiveness to levodopa. DBS is not used to treat PD patients who have exhibited a poor response to levodopa, nor is it used to treat those PD patients with dementia or hallucinations.
Clinical studies with DBS are ongoing, as is further research to improve the technology employed in DBS.
Researchers continue to look for ways to detect biomarkers which may help identify people who are at risk of developing PD, and research is also ongoing in developing treatments that will halt the progression of the disease in its early stages. So far, however, both goals remain elusive.
Positron emission tomography (PET), which produces pictures of chemical changes as they occur in the brain, is useful in studying the brain's dopamine receptors as they change over time in PD patients, and as neurons progressively degenerate.
Genetic testing, which may help identify those people who have the inherited form of PD, is currently available only in research studies, since the ethicality of routine genetic testing, for any disease, is a topic of increasing debate. Within the boundaries of specifically controlled research studies, however, scientists are hopeful that they will be able to discover additional genes that are associated with PD, and that the discovery of such genes will also lead to an understanding of what it is that happens to the genes of people who develop the nonheritable forms of PD.
In general, however, since the precise causes of PD are not fully known, neither are any methods by which the disease may be prevented.
Future research directions:
The two main areas of emphasis in standard medical PD research are genetics and drug therapy.
Although the inherited form of PD is relatively rare, researchers are hoping that they may learn more about the nonheritable forms of PD by studying the genes that are associated with the inherited cases. Similarly, in an ongoing effort to develop new drugs for the treatment of PD, scientists are developing animal models in which neuronal death is mimicked, and on which new drug therapies are tested.
One common objective of researchers is to acquire as much genetic information on as many PD patients as possible, thereby establishing large-scale data bases which may be analyzed and which may hopefully shed some light on the common denominators shared by all people who suffer from PD. While several chromosomal regions have already been identified in some families with PD, researchers hope to be able to identify new genes that are linked to PD, and to learn how mutations in normal genes may contribute to the disease. Scientists hope that DNA samples from hundreds of families with PD will help identify precisely which genes are active and which genes are inactive in PD.
Researchers also continue to study the role of environmental toxins in PD, since pesticides and herbicides have been found to cause PD-like symptoms in animal models. Rodents exposed to the pesticide rotenone, for example, have been found to exhibit cellular and behavioral abnormalities similar to those seen in humans with PD. A program sponsored by the National Institutes of Health (NIH), entitled the “Collaborative Centers for Parkinson’s Disease Environmental Research” (CCPDER) was organized to study the extent to which occupational exposure to various toxins may contribute to PD.
Excititoxicity and inflammation are also areas of active interest in PD research. In excitotoxicity - which is the damage, and even the death, of nerve cells as a result of overstimulation - the brain becomes oversensitized to the neurotransmitter glutamate, which increases activity in the brain. Related studies have shown that inflammation is common not only among PD patients but also among people suffering from a variety of other neurodegenerative disorders, such as Alzheimer's disease, HIV-1-associated dementia, and amyotrophic lateral sclerosis. Researchers have found that molecules which promote inflammation also increase cell death after treatment with the toxin MPTP, and the ability to inhibit this inflammation has proven effective in preventing some types of neuronal degeneration. It has also been found that dopamine neurons in the brains of patients with PD have higher levels of an inflammatory enzyme called COX-2 than do those of people without PD, and the inhibition of COX-2 in mouse models was found to double the number of neurons that survived. Since discovering that MPTP causes PD-like symptoms in humans, researchers have used MPTP for inducing and studying PD-like symptoms in laboratory animals.
Transcranial electrical polarization (TEP) and transcranial magnetic stimulation (TMS) are also being studied for their potential in reducing the symptoms of PD. In TEP, electrodes placed on the scalp are used to generate an electrical current that modifies signals in the brain’s cortex, and in TMS an insulated coil of wire on the scalp is used to generate a transient electrical current which in turn produces a magnetic field. Both methods of treatment indicate some promise in partially alleviating some of the symptoms of PD, although neither method is able to change or delay the course of progression of the disease.
The development of new drugs is an ongoing area of focus, and several newly developed medications are currently in clinical trials for PD. Included among these is the new drug known as “GM1 ganglioside”, which is being studied for its ability to increase dopamine levels in the brain. Another drug, known as “istradefylline”, is being tested for its ability to improve motor function in PD, and a drug known as “ACP-103” is being tested for its ability to block receptors of the neurotransmitter serotonin. Of particular interest not only to researchers but also to doctors and patients are any types of drug which may possibly replace levodopa or be used in combination with levodopa such that the complications associated with levodopa may be alleviated.
Various chemical agents are also being tested for their neuroprotective ability. In a study known as the “Neuroexploratory Trials in Parkinson's Disease” (NET-PD), researchers evaluated minocycline, creatine, coenzyme Q10, vitamin B12, and GPI-1485 for the potential ability of these chemicals to mitigate the symptoms of PD. Additionally, scientists are also studying various nerve growth factors, or neurotrophic factors, such as the “glial cell line-derived neurotrophic factor” (GDNF), which has been found to protect dopamine neurons and to promote their survival in animal models of PD. However, a phase II clinical trial with GDNF was halted in 2004 due to indications that it might be harmful. Researchers are therefore also studying other neurotrophins which may prove to be useful for treating PD, such as neurotrophin-4 (NT-4), brain-derived neurotrophic factor (BDNF), and fibroblast growth factor 2 (FGF-2). Additionally, quetiapine is being studied for its ability to reduce psychosis and anxiety in PD patients with dementia.
Another approach to treating PD is by the implantation of cells in the brains of PD patients. Such cells are not stem cells, and they are being studied primarily for their potential ability to enhance the production of dopamine via the replacement, rather than the regeneration, of dopamine-producing cells in the brain. Human retinal epithelial cells, for example, when attached to microscopic gelatin beads and implanted into the brains of people with advanced PD, have been shown to produce dopamine, thereby enhancing levels of dopamine in the brain without actually regenerating the brain’s own neurons.
However, the actual use of stem cells to regenerate damaged neural tissue is an area of intense interest and research, and experimental studies have been conducted with varying degrees of success, depending on the particular types of stem cells that were employed. In the 1990s, stem cells from fetal tissue were directly implanted in people with PD in an attempt to regenerate their dopamine-producing neurons, and although many of the implanted cells were indeed found to produce dopamine in the brains of the patients, the patients themselves did not exhibit gross improvement. Some of the patients even developed a disabling dyskinesias that could not be relieved by the usual reduction in antiparkinsonian medications. Indeed, fetal and embryonic stem cells have been shown to carry a number of substantial medical risks to the patient, whereas such risks do not exist in the use of adult stem cells. (Please see the section below, on Stem Cells).
Geneticists are studying several possible vectors in the treatment of PD, which include the adeno-associated virus type 2 (AAV2) for the delivery of the gene for neurturin, which is a nerve growth factor, and AAV for the delivery of a gene for human aromatic L-amino acid decarboxylase, an enzyme that helps convert levodopa to dopamine in the brain. It is believed that increasing the amount of glutamic acid decarboxylase, which helps produce GABA, an inhibitory neurotransmitter, might reduce the overactivity of neurons in the brain that results from a lack of dopamine.
Vaccines are also being tested, which may potentially protect dopamine-producing neurons by modifying the immune system. Copolymer-1, for example, has been found to increase the number of immune T cells that secrete anti-inflammatory cytokines and growth factors in a mouse model of PD, and is therefore being studied for possible use in a vaccine. Similarly, when alpha-synuclein was administered to mice, the mice were found to develop antibodies which reduced the accumulation of abnormal alpha-synuclein. While such vaccines have only been tested on laboratory animals, researchers hope that the studies may prove successful enough to be tested on humans someday.
In 1998, the World Health Organization (WHO), the European Parkinson’s Disease Association (EPDA) and the U.S.-based National Parkinson Foundation (NPF) jointly launched the “Global Parkinson’s Disease Survey” (GPDS), the first international study of its kind on people suffering with PD. The goal of the study was to investigate factors influencing the quality of life for people with PD, and more than 2,000 patients were randomly chosen and evaluated from 6 countries in 3 continents, namely, Italy, Spain, Japan, Canada, the UK, and the United States. Quality-of-life issues are expected to become increasingly important for PD patients throughout the future, with widespread financial and economic implications for each country.
The Morris K. Udall Centers:
The U.S. National Institute of Neurological Disorders and Stroke (NINDS), a division of the National Institutes of Health (NIH), supports a wide range of basic laboratory studies and clinical trials in PD at its Bethesda, Maryland , location and at grantee institutions around the world. In this capacity, the NINDS supports eleven Morris K. Udall Parkinson’s Disease Research Centers of Excellence throughout the United States. According to their website,
“The Centers’ multidisciplinary research environment allows scientists to take advantage of new discoveries in the basic and technological sciences that could lead to clinical advances. Most of the Centers also provide state-of-the-art training for young scientists preparing for research careers investigating PD and related neurological disorders. Among other topics, the Centers carry out studies of genes, of proteins involved in cell death and degeneration, and of the brain chemicals involved in Parkinson’s disease. They also study the brain using PET brain scans and test potential Parkinson’s disease treatments in animals. The NINDS hopes that research at these Centers of Excellence will lead to clinical trials of new therapies in humans with Parkinson’s disease.” (From www.ninds.nih.gov).
These Centers of Excellence for Parkinson’s Disease Research were established in honor of former Congressman Morris K. Udall, who died in 1998 after a long battle with PD. Mr. Udall was elected to the U.S. House of Representatives in 1961 in a special election to replace his brother, Steward Udall, who had left the position to become President John F. Kennedy’s Secretary of the Interior. Although Representative Morris K. Udall was diagnosed with PD in 1979, he continued to serve as an active member of Congress until May of 1991.
On November 13th, 1997, U.S. President Clinton signed into law The Morris K. Udall Parkinson’s Disease Research Act. Prior to the passage of this Act, the NINDS had already recognized the need to establish Centers of Excellence in PD research, and as a result of this Act NINDS released an initial Request for Applications (RFA) to solicit these centers. Of the applications that were received in response to this RFA, NINDS selected 3 centers for funding. Following the passage of the Udall Act, NINDS issued a second RFA for PD Centers of Excellence and funded 8 additional grants. All of the Udall Centers focus on scientific research designed to improve the diagnosis and treatment of patients with PD and related neurodegenerative disorders, and on research to gain a better understanding of the fundamental causes of the disease. (From www.ninds.nih.gov).
Some areas of research in which the Morris K. Udall Centers of Excellence are involved include:
-Neuronal and mitochondrial genetic studies to elucidate key proteins involved in neurodegeneration and to determine genetic differences between familial and sporadic PD,
-Studies of the structure and function of proteins involved in cell death and degeneration,
-Studies of the anatomical structures and brain chemicals involved in PD,
-Studies to improve animal models of PD,
-Imaging studies involving PET scans,
-Studies of PD risk factors in people of different gender and ethnicity,
-Animal studies testing possible PD treatments such as neuroprotective therapies, implantation of genetically engineered cells, DBS, and levodopa drug therapy.
Although stem cell research per se is not listed as an area of study identified by these Centers, stem cell research for PD is nevertheless a field of intense focus in laboratories and clinics around the world.
Among other accomplishments, the Udall Centers are responsible for having achieved the following milestones in PD research:
-The discovery of the UCH-L1, PACRG, and GSTO-1 genes,
-The development of the rotenone rat model for PD,
-The discovery that PD mitochondrial gene expression is sufficient to spontaneously cause development of Lewy bodies in cells,
-The first U.S. clinical trial of chronic GDNF administration in patients with advanced PD.
The Udall Centers offer a multidisciplinary setting in which specialized methods of research may be utilized. Additionally, NINDS collaborates with the National Institute of Environmental Health Sciences to provide funding for the Udall Centers.
Perhaps the most unique and significant function of the Udall program is the coordination of all data and information from its various Centers, which none of the privately established PD organizations are able to oversee. In fact, NINDS has funded a Parkinson’s Disease Data Organizing Center (PD-DOC) which collects information not only from all of the Udall Centers, but also from all PD centers in general, thus allowing for standardized data, resources and reagents to be shared widely throughout the global PD community.
Udall Centers across the United States include the following locations:
-Brigham and Women’s Hospital, Boston, MA
-Columbia University, New York, NY
-Duke University, Durham, NC
-Harvard University Medical School and McLean Hospital, Belmont, MA
-Johns Hopkins University School of Medicine, Baltimore, MD
-Massachusetts General Hospital and the Massachusetts Institute of Technology,
-The Mayo Clinic, Jacksonville, FL
-Northwestern University, Chicago, IL
-University of California at Los Angeles, Los Angeles, CA
-University of Kentucky, Lexington, KY
-University of Pittsburgh, Pittsburgh, PA
-University of Virginia, Charlottesville, VA
The headquarters for the coordination of data and resources for all the Centers is:
-Parkinson’s Disease Organizing Center, University of Rochester, Rochester, NY
Since it is the dopamine-producing cells of the brain which degenerate in PD, an appropriate treatment for PD would be one which is capable of regenerating these dopamine-producing cells. In fact, this would constitute the only truly effective treatment of PD.
Adult stem cell therapy does exactly that.
Although adult stem cell therapy as a treatment for PD is not specifically targeted per se as an isolated area of research at many of the finest research laboratories, nevertheless, there have been numerous studies conducted by some of the finest researchers throughout the world, from which very promising results have been obtained. Indeed, the transplantation of adult stem cells directly into the brains of PD patients has already been performed and has already shown marked success.
One such PD patient, who received his own adult stem cells, testified before the U.S. Senate Committee on Science, Technology, and Space on July 14th of 2004, regarding his own progress as a result of this treatment. The headlines from this very newsworthy event read, “Beneficiary of Adult Stem Cell Treatment for Parkinson’s Disease: Safaris and Swimming with Sharks.” The Committee was chaired by Senator Brownback, and the patient who received this novel treatment was Dr. Dennis Turner who had suffered with PD for 14 years. His poor responsiveness to conventional medications made him an ideal candidate for the experimental treatment, which was performed by Dr. Levesque. The procedure itself involved removing a very small tissue sample from Dennis Turner’s brain, from which adult neural stem cells were extracted and cultured into matured dopamine-producing neurons which were then injected back into the left side of his brain, which controls the right side of the body, which was the side that was most severely affected in his particular case. The procedure was performed in 1999. A portion of Dr. Dennis Turner’s testimony before the U.S. Senate Committee is included herein:
“Dr. Levesque did not tell me that this treatment would permanently cure my condition. Science has yet to learn what causes Parkinson’s disease, much less how to remove it. However, since this cell-replacement approach had never been tried in a human patient we hoped for the best. And since my only other realistic alternative was to continue growing worse until I eventually died, I decided to have the surgical procedures in 1999, one to remove the tissue and another to inject the cells. I was awake for both procedures under local anesthesia.”
“Soon after having the cells injected my Parkinson’s symptoms began to improve. My trembling grew less and less, until to all appearances it was gone, only slightly reappearing if I became upset. Dr. Levesque had me tested by a neurologist, who said he wouldn’t have known I had Parkinson’s if he had met me on the street. I was once again able to use my right hand and arm normally, enjoying activities that I had given up hope of ever doing.”
“Since being diagnosed with Parkinson’s disease my condition had slowly, but continuously worsened. I can’t say with certainty what my condition would have become if Dr. Levesque had not used my own adult stem cells to treat me. But I have no doubt that because of this treatment I’ve enjoyed five years of quality life that I feared had passed me by.”
“Because of my improvements through Dr. Levesque’s treatment I’ve been able to indulge in my passion for big game photography these past five years. While on safari in 2001 I scrambled up a tree to avoid being run over by a Rhino. I swam in the South Atlantic with Great White Sharks. Two weeks ago I returned from Africa after photographing cheetahs and leopards in the wild. Here are a few examples of the pictures I took. They represent memories and experiences I feel I have Dr. Levesque to thank for. I came here to offer him my sincere gratitude, and to offer others with Parkinson’s concrete reason for hope.”
“This summarizes my history with Parkinson’s and the positive effects I experienced through a treatment that used my own adult stem cells. I’m very happy with its results and would dearly love to have a second treatment.”
The entire U.S. Senate Committee testimony and background may be read at: http://commerce.senate.gov/hearings/testimony.cfm?id=1268&wit_id=3676.
In another study, rather than receiving stem cells, five PD patients simply received an injection of a normal protein known as glial cell line-derived neurotrophic factor, which stimulates their own adult stem cells in their brains. Within a year, all five patients were found to exhibit a 61% increase in their physical coordination and a lessening in the severity of their PD symptoms.
Stem cells that are derived from adult bone marrow have been found to be particularly effective in regenerating the dopamine-producing nerve cells of the brain. One method of treatment involves transplanting these stem cells into the specific target sites of the brain that need dopamine. Indeed, it is precisely because of the fact that PD is caused by the degeneration of a very specific type of cell that this disease is actually one of the best candidates for stem cell therapy, as patients with PD may be among the most responsive of all patients to treatment with stem cells.
Prior to success with humans, numerous other studies were conducted on laboratory animals in the treatment of PD-like symptoms by adult stem cells. At Kyoto University in Japan, researchers were able to demonstrate that adult monkey stem cells generated dopamine-producing neurons which were then transplanted into the brains of monkeys suffering from PD. The results of such transplantation yielded a reversal of the symptoms. Mouse stem cells were also shown to differentiate into neurons under certain specific conditions. Similarly, researchers at the National Institutes of Health (NIH) have demonstrated that rat stem cells which are grown in culture and transplanted into rats with PD will differentiate into healthy, mature brain cells, resulting in neurological recovery for the rats.
Adult stem cell therapy has shown great promise at regenerating the central nervous system in general. In PD in particular, the neurons that die are responsible for connecting a structure in the brain called the substantia nigra to another structure called the striatum, which is composed of the caudate nucleus and the putamen. Such “nigro-striatal” neuronal connections allow for the release of the chemical transmitter dopamine onto their target neurons in the striatum, which controls body movement. As previously described, it is the degeneration of these dopamine-producing neurons which results in PD. Logically, therefore, it is the regeneration of these same dopamine-producing neurons which restores normal body movement and reverses the symptoms of PD. Adult stem cells have been shown to be effective at this regeneration, with the neuronal connections reestablished well into the striatum.
It is neither necessary nor advisable to use embryonic stem cells in such a therapy, since adult stem cells carry the required pluripotency to differentiate into neurological tissue, yet adult stem cells lack the risk of forming teratomas (tumors) which have always been the identifying feature of embryonic stem cells. Ethics and politics aside, purely from a scientific perspective, the characteristics and behavior of adult stem cells are highly preferable to those of embryonic stem cells.
Even within the brain itself, the white matter is known to contain multipotent progenitor cells that are able to differentiate into all the major cell types of the brain, including neurons. Scientists are therefore hoping to discover additional ways in which to stimulate the brain’s own stem cells for localized repair and regeneration. Specific stem cells have been discovered in two locations within the adult primate brain, namely, in the subventricular zone and in the dentate gyrus of the hippocampus. In the 1990s, researchers discovered that stem cells from these two areas of the brain are naturally mobilized and stimulated automatically to migrate toward a site of injury, whenever the brain incurs damage.
Researchers at the University of Minnesota have offered still further evidence that stem cells derived from adult bone marrow may be induced to differentiate into cells of the midbrain. Such a discovery, which was published in the Proceedings of the National Academy of Sciences, offers great promise for the treatment of a wide variety of central nervous system diseases, including PD. Such findings provide further demonstration of the multipotency of adult progenitor cells.
Researchers in the Faculty of Medicine at the Universite Laval, in Quebec, Canada, reported in the Journal of Cellular Physiology that they succeeded in producing neurons in vitro from stem cells that were extracted from adult human skin. Such findings represent the first time that stem cells derived from human skin have differentiated into nerve cells. The scientists extracted neuron precursor cells from skin obtained by plastic surgery procedures, which was then cultivated in vitro. Professor Francois Berthod, who led the research, described the achievement as an important breakthrough in the treatment of neurodegenerative illnesses such as PD. After the stem cells began differentiating into neurons, they also began producing biomarkers and molecules associated with the transmission of nerve impulse between neurons, representing the initial stages of synapse formation. As Dr. Berthod explains, “We could take a patient’s skin cells and use them to produce perfectly compatible neurons, thus eliminating the risk of rejection. We could then transplant these nerve cells in the diseased areas of the brain. This type of procedure seems particularly interesting for diseases such as Parkinson’s.”
Meanwhile, the risk of teratoma (tumor) formation that results from embryonic stem cells remains a serious concern, and the mounting evidence of the formation of such tumors continues to be reported in leading medical journals. Such a risk of tumor formation does not exist with adult stem cells. These distinctly different, defining characteristics inherent in the various types of stem cells have been commonly known since the very early days of stem cell research, when, if a particular type of stem cell was able to form a tumor it was identified as an embryonic stem cell, and if it was unable to form a tumor it was identified as some other, non-embryonic type of stem cell.
At the University of Rochester Medical Center in New York, researchers discovered newly forming tumors in the brains of rats after having injected human embryonic stem cells into the rats. Instead of developing into dopamine-releasing neurons, for the potential treatment of PD, the stem cells instead began dividing into tumors. The experiment, which was led by Dr. Steven Goldman, was halted and the animals were euthanized.
Similarly, a noted stem cell researcher from the Massachusetts Institute of Technology, Professor James Sherley, who is also a Fellow of the Royal Society, spoke to legislators in Australia about the risks of embryonic stem cells, urging the legislators not to support legislation that would promote embryonic stem cell research. Dr. Sherley spoke at length about the ability of embryonic stem cells to form teratomas (tumors) when injected into human tissue, pointing out that the tumor-forming property of embryonic stem cells has always been an inherent, identifying feature of embryonic stem cells, characteristically separating embryonic stem cells from other types of stem cells. University of Melbourne Emeritus Professor of Medicine, Thomas Martin, joined Dr. Sherley in pointing out the risks of embryonic stem cells, and in bringing to the attention of the legislators the fact that previous reviews conducted by the Lockhart panel in Australia had failed to take into consideration this predominant trait of embryonic stem cells to form teratomas.
In a recent study with adult stem cells it was found that approximately 20% of the stem cells harvested from the brains of PD patients automatically matured into dopamine-secreting neurons. Within 3 months after these cells were injected back into patients’ brains, the patients were found to exhibit a 55.6% increase in their dopamine production which resulted in a 37% improvement in their motor skills. One year after the procedure, the patients’ overall Unified Parkinson’s Disease Rating Scale had improved by 83% without the use of any PD medication.
Many organizations which have been portrayed by the media as advocating only embryonic stem cell research, at the exclusion of all other types of research, have in fact given generously to the financial support of non-embryonic stem cell research.
One such example is the Michael J. Fox Foundation for Parkinson’s Research (MJFF), which, between the years 2000 and 2006, generously provided over $90 million in the funding of PD research, not all of which has been limited exclusively to embryonic stem cells. A case in point is Dr. David Yurek of the University of Kentucky, who was awarded $66,000 from the MJFF under the Foundation’s “Rapid Response Innovation Awards” program. Dr. Yurek, a professor in the Division of Neurosurgery at the UK College of Medicine, directs a laboratory that is focused on the development of new techniques for regenerating the dopamine-producing cells of the brain, specifically for the therapeutic treatment of late-stage PD. In this particular instance, Dr. Yurek and his colleagues received this award from the MJFF for their development of a new type of treatment which they have named “Nanoparticle Gene Therapy for Parkinson’s Disease”. This novel therapy, which extends the principles of nanotechnology to bioengineering, utilizes DNA plasmids which are condensed and compacted into nanoparticles and then delivered to the brains of PD patients. It is hoped that this method may be able to repair the faulty genes that occur in PD, since the condensed DNA nanoparticles encode for a neurotrophic factor which has been shown in animal models to stimulate dopamine-producing neurons. The faulty genes that are associated with PD may then be repaired via the process of transduction, by which the healthy gene is expressed in a cell such that the DNA is delivered into the cell, and proteins corresponding to the DNA are then synthesized and incorporated into the cell. As Dr. Yurek explains, “We plan to use this technology to transduce brain cells so that they express proteins beneficial to the cell’s survival.” So far this experimental therapy has shown promise with animal models.
Scientific research in any field is at its best and most successful not when specialists from any one particular discipline are narrowly focused on the discovery of only one type of solution to a particular problem, but rather when multidisciplinary collaboration and cooperation allow for the open-minded discovery of as many diverse solutions to the problem as possible. The recognition of the potential application of nanotechnology to the medical treatment of a disease is one such positive step in this direction, as is the growing recognition of the increasing success of adult stem cells in the treatment of a wide variety of disorders.
Adult stem cells offer a safe and potentially successful method of treatment for a disease which previously has been considered irreversible.
A free copy of the most recent publication by NIH on stem cells, entitled “Regenerative Medicine 2006”, is available at the following website:
More information on Parkinson’s disease is available from the following organizations:
American Parkinson Disease Association - www.apdaparkinson.org
National Parkinson Foundation - www.parkinson.org
Parkinson Alliance - www.parkinsonalliance.org
Michael J. Fox Foundation for Parkinson's Research - www.michaeljfox.org
The Muhammad Ali Parkinson Center: - www.maprc.com
Parkinson's Action Network (PAN) - www.parkinsonsaction.org
Parkinson's Disease Foundation (PDF) - www.pdf.org
Parkinson's Institute - www.thepi.org
Parkinson's Resource Organization - www.parkinsonsresource.org
WE MOVE (Worldwide Education & Awareness for Movement Disorders) - www.wemove.org
Bachmann-Strauss Dystonia & Parkinson Foundation - www.dystonia-parkinsons.org
The World Health Organization: - www.who.int
The Centers for Disease Control and Prevention: - www.cdc.gov