Why do Parkinson’s disease patients fall so often?

Parkinson’s disease leads to rigidity, impaired balance and slowness of movement or freezing. This means that even when a Parkinson’s patient foresees a potential hazard, he/she cannot accommodate with rapid countermovements. The postural instability also means that a person cannot stay firmly planted when stationary or even when walking slowly and is therefore prone to falls and associated injuries. As the condition progresses, the frequency and often severity of falls increases proportionally. With time, a person loses his/her confidence and actually becomes more prone to falling by ’second guessing’ their movements and countermovements when standing and walking. Orthostatic hypotension (postural low blood pressure) is also frequently seen in Parkinson’s disease and may also be cause of frequent falls although this association has not been conclusively proven. Visual problems also need to be taken into account as a possible cause of falls in Parkinson’s disease.

Effects of Frequent Falls

Falls are the second most common cause for hospitalization in Parkinson’s patients. Frequent falls may lead to repeated fractures and other soft tissue injury. Fractures are also more likely as osteoporosis is more common in older patients meaning that the bones are weaker. Fractures and related injuries lead to longer periods of immobilization which in itself has its own consequences such as depression, constipation, weakness, loss of confidence and insomnia. More severe falls can even lead to traumatic brain injury causing concussions, seizures and depending on the complications even contribute to death.

Tips for Preventing Frequent Falls

There is no single solution to preventing falls in Parkinson’s disease. In fact, it is not a matter of preventing falls entirely as this is common in life and particularly with old age, apart from the Parkinson’s disease component. Therefore the focus should be on preventing frequent falls and minimizing the extent of the injury. This involves a number of factors that both Parkinson’s disease patients and caregivers need to bear in mind :

• Take medication as prescribed to reduce the severity of motor symptoms.
• Consider safety tips advised for Parkinson’s patients and appropriate changes in the home environment that will limit falls and the extent of injuries.
• Some studies have shown that exercise and physical therapy may reduce the frequency of falls as it improves postural stability and balance.
• Always seek medical attention even after a minor fall to identify the full extent of injuries and have it treated immediately to limit the complications.
• Wear appropriate footwear that may be helpful in moving without restriction and enhancing postural stability. Heels should be avoided as far as possible.
• Never have both hands occupied when walking to ensure that one hand can grab onto surrounding objects and break the force of the fall.
• Do not get distracted while walking as even talking can be a contributing factor to falls since multitasking may be difficult for the Parkinson’s brain.

Age

Most cases of Parkinson’s disease are seen in the elderly. In the United States about 1 out of ever 100 people over the age of 60 years has Parkinson’s disease. This incidence varies across the globe and even among certain communities as discussed below. The number of people living with Parkinson’s disease has increased over the years but this may not be necessarily due to a rise in the percentage of people developing PD. Instead this has to do with a longer life expectancy. Modern medicine, better living conditions and accessibility to health care services means that the “older live longer”. Naturally the number of people living with Parkinson’s disease has increased accordingly. This is further reflected in the difference of prevalence where there is now about 1 million more people living with Parkinson’s disease in the United States compared to 2005 when there was only about 500,000 Americans with PD.

Gender

Parkinson’s disease affects both men and women. It is, however, more common in men and in some countries like in the  United States this may be as much as 1.5 times. This could correlate with certain risk factors like exposure to pesticides and industrial pollutants which may be associated with more male-dominated jobs. However, with more women entering the workplace and having a similar exposure, not to mention the non-occupational exposure, it seems that men are at greater risk for unknown reasons.

Nationality and Ethnicity

The incidence of Parkinson’s disease varies across the globe. However, this distribution may not be as simple as a geographical or ethnic factor. It is known that the Parkinson’s disease is more prevalent in North America and Europe than in Asia and West Africa. However, certain findings like that of the Parsi community in India indicates that this may not just be a geographical difference. The Parsi community in Mumbai has the world’s highest incidences of Parkinson’s disease where it affects about 328 out of every 100,000 people despite living in a country, India, with one of the world’s lowest incidence of PD (70 out of 100,000).

Family History and Genetic

Despite the focus on a family history and genetics, it is believed this accounts for less than 5% of cases. More genes are being identified in familial PD, like the recent VPS35 genetic mutation, but its role is sometimes overstated and hyped in the media. There is no evidence of any genetic mutation or strong family history in the majority of Parkinson’s disease patient although family history is an accepted risk factor. This is further supported by the fact that the incidence in monozygotic and dizygotic twins is about the same. Had genetics been a major factor, the incidence would have been higher in the monozygotic twins.

The Parkinson’s Patient

Based on these factors, once could surmise that the person who is at greatest risk would be :

• Over the age of 60
• Male
• Living in North America
• From a family with a strong history of PD

However, with Parkinson’s disease the incidence and risk factors are not as conclusive as one would think. It is safe to say that in the backdrop of the unidentified causes in the majority of PD cases, the epidemiology has not provided definitive risk factors apart from age.

Depression

Depression in Parkinson’s disease is common and is largely due to the impact of being diagnosed with the disease, the prognosis and living with PD. People who were otherwise independent may find that the disease can ‘rob’ them of their normal level of functioning and force them to become more dependent on others. Parkinson’s disease not only affects the life of the patient but impacts on interpersonal relationships and the lives of loved one’s and the impact of this can also lead to depression. Read more on depression and Parkinson’s disease.

Difficulty Swallowing

The progressive muscle loss in Parkinson’s disease, both of the muscles under voluntary and involuntary control, affects various functions. Swallowing and chewing are some of these activities that are affected to varying degrees in Parkinson’s disease. The danger with this complication lies in the risk of choking, particularly on larger particles of food that have not been chewed properly. In addition, difficulty and chewing may discourage food intake and cause secondary complications related to nutrition. Read more on difficulty swallowing in Parkinson’s disease.

Sleep Problems

Problems with sleep are a common complaint of PD patients. It may be directly related to the low dopamine levels, a side effect of PD medication or arise secondary to depression and dementia. The sleeping problems are not only related to difficulty falling asleep or maintaining sleep (insomnia) but also with excessive daytime sleepiness. It may also be related to other problems at night like the need to urinate frequently which may disturb sleep and nightmares. Read more on sleeping problems in Parkinson’s disease.

Urinary Problems

Urinary incontinence or retention are not uncommon in Parkinson’s disease. The bladder is a muscular hollow sac and loss of voluntary and involuntary muscle control in PD can affect urinary function. This may also be a consequence of certain medication, prostate problems in men or immobility which affects the ability to reach a toilet. Read more on urinary disturbances in Parkinson’s disease.

Sexual Dysfunction

A decrease in sex drive (libido) may be due to a combination of physical and psychological factors in Parkinson’s disease. It is more commonly seen in men with PD. This can happen in many other chronic conditions and can also be a consequence of depression in PD and the use of certain PD medication. However, another extreme is hypersexuality which may be seen with the use of certain PD drugs. This is discussed further under compulsive behavior in Parkinson’s disease.

Low Dopamine Levels in Parkinson’s Disease

As explained under Parkinson’s disease brain chemistry,  dopamine is a brain hormone (neurotransmitter) that is deficient in PD patients. This is accompanied by a loss of dopaminergic neurons. When more than 60% of these neurons in the substantia nigra and corpus striatum of the brain are lost then the motor signs of Parkinson’s disease becomes evident. L-dopa may therefore help to counteract these symptoms by restoring dopamine levels. When dopaminergic neurons are stimulated, it is released at the nerve terminal into the gap junction known as the synapse. This dopamine is recycled by dopamine transporters (DaT) which pumps it back into the nerve cells and stored for use at a later stage.

Detection of DaT Activity

A substance developed by GE Healthcare known as DaTscan can help to detect these dopamine transporters. If the transporters are working then it indicates the presence of healthy dopaminergic neurons. Until now there was no significant structural change in the brain that were detectable by conventional imaging techniques. Therefore the loss of these dopaminergic neurons could not be isolated in the living patient although microscopic evaluation of brain tissue post mortem noted pallor of the substantia nigra and the loss of these neurons. With the use of DaTscan, dopaminergic neurons are highlight on a SPECT scan. This is type of nuclear imaging study that stands for single-photon emission computerized tomography (abbreviation~ SPECT). DaTscan is a contrast agent that is visible on a SPECT scan.

DaTscan Results

With DaTscan, the brain function can be evaluated rather than just the structural changes associated with Parkinson’s disease.  Healthy dopaminergic neurons are illuminated on a SPECT scan with the use of the DaTscan contrast agent. Therefore the more illuminated areas, the greater the number of healthy neurons. Conversely, dark areas indicate low dopamine activity.

This test holds much promise for accurately identifying patients with Parkinson’s disease or other parkinsonism syndromes. It removes uncertainty associated with undiagnosed or even misdiagnosed cases. While it may not be necessary for every PD patient to confirm the diagnosis, it is hoped that this scan will be a reliable technique to monitor progression of the disease and therefore any treatment that can slow its progression. Currently (August 2011) clinical trials are underway by some 14 medical centers in the United States to evaluate DaTscan as a means of monitory disease progression. This is part of the biomarkers study by the Michael J. Fox Foundation known as the Parkinson’s Progression Markers Initiative.

Nicotine Effect on Dopamine Release

Nicotine, whether on its own or with other monoamine oxidase inhibitors and yet undiscovered chemicals in cigarette smoke, stimulates the dopaminergic neurons in the brain. These dopamine-producing nerve cells are progressively destroyed in Parkinson’s disease and dopamine is supplemented with the aid of medication like L-dopa. However, the drawback with L-dopa is the side effects and attempting to reduce the dose only worsens the symptoms.

Although previous studies did indicate that the damage to the substantia nigra, the area of the brain most affected in Parkinson’s disease, was limited with nicotine and exacerbated by pesticides and toxins, the exact mechanism and receptor sites for this neuroprotective effect of nicotine were not conclusively verified. It was believed to be those same receptors, alpha-7 nicotine receptors, as was verified by the recent study. These previous studies also put forward the idea that other non-receptor mediated mechanisms may offer protection by suppressing the effect of toxins and altering the activity of the enzyme monoamine oxidase.

Nicotine Receptors on Dopamine Nerves

In the recent study conducted in France, it was found that nicotine spares the gradual loss of these neurons by acting on alpha-7 nicotine receptors. Mice that were genetically engineered without these receptors were shown to be more likely to lose dopaminergic neurons than normal mice with these receptors. These findings were recently published in the FASEB journal (August 2011) and go a long way in opening up possibilities of new drugs that target the alpha-7 nicotine receptors. New generation drugs may be able to prevent Parkinson’s disease in high risk individuals or slow the progression of the disease.

Smoking Benefit in Parkinson’s Disease

The findings of the recent study are promising and offers new hope for Parkinson’s disease like the recent VPS35 genetic mutation discovery which sheds new light on familial Parkinson’s disease. However, this should not encourage every PD patient to take up cigarette smoking. The host of carcinogens (cancer-causing chemicals) in cigarette smoke may be a greater risk to one’s health and lifespan, along with the known cardiovascular implications of cigarette smoking. Nevertheless, the finding does open up some exciting avenues for future development of drugs that can take advantage of the neuroprotective effect of nicotine by now identifying the specific receptors responsible for this benefit.

These diagnostic tests should be conducted routinely on patients who are possibly at risk, like those with a familial history. Screening, however, is not as simple as with other conditions as familial Parkinson’s disease accounts for only a small number of cases. Other risk factors like age, gender and environmental factors are too arbitrary to define known risk groups who should undergo routine screening. Most cases of PD are due to unknown cause without clearly identified risk factors.

What is the test for Parkinson’s disease?

There is no definitive test for Parkinson’s disease. Laboratory biomarkers that would normally be identified when testing the blood, other body fluids or tissue samples as is the case with scores of other medical conditions is not available. Instead it is identified by a clinical diagnosis which means that it based on the medical history and findings suggestive of Parkinson’s disease upon conducting a neurological examination.

Imaging techniques like an MRI and CT do not show any clearly identifiable features that is conclusively indicative of Parkinson’s disease. It is known that post mortem examination of the brain of a PD patient shows paleness of the substantia nigra. This is a part of the brain rich in dopamine-producing neurons and the paleness may be visible with the naked eye. Microscopically there may be a noticeable loss of catecholaminergic neurons and Lewy bodies may be found in the remaining neurons.

Genetic Testing for Parkinson’s Disease

Although the most common forms of Parkinson’s disease are not related to inherited genetic abnormalities, it may still be useful for families with a history of PD. Five genetic mutations have been identified in familial Parkinson’s disease and more recently, a new genetic mutation VPS35, has also been discovered. This holds hope for identifying high risk family members and possibly undertaking preventative measures before the onset of the disease. Some genetic abnormalities may not be inherited but rather acquired in life with advancing age or due to environmental factors. Early identification of this genetic damage my also help to identify a person who is more at risk of developing Parkinson’s disease and therefore the necessary steps may be taken at the outset.

The lack of clearly identifiable biomarkers should not discourage those who are apprehensive about developing Parkinson’s disease. Understanding the risk factors, reducing it and identifying the early signs and symptoms and seeking medical attention are all measures that one can undertake to prevent or slow the progression of Parkinson’s disease.

An Overview of Stem Cell Therapy for Parkinson’s Disease

Stem cells are immature cells which differentiate into different cells in the body. It is most abundant in fetal life but small amounts of partially differentiated stem cells are available in various tissues even in adulthood. Some tissues have large amounts of stem cells, like the bone marrow with its hematopoietic stems cells, but these cells are partially differentiated already and therefore only capable of forming the necessary blood cells.

A recent procedure has been able to ‘wipe’ clean these partially differentiated stems cells to once again form ‘blank’ stem cells that can then be stimulated to differentiate into a cell types of choice. These cells are known as induced pluripotent stem cells (iPSC’s) and made waves in the medical science community in 2010. It holds much promise for a number of conditions, not only Parkinson’s disease.

Parkinson’s disease arises due to a progressive decrease in the number of dopamine-producing neurons (dopaminergic neurons) in the substantia nigra of the brain. The lower than normal levels of dopamine, a neurotransmitter, is responsible for the features of Parkinson’s disease. In a nutshell, stem cell therapy holds the hope that by differentiating ‘blank cells’ into dopamine-producing neurons, at least partially, and injecting it into the substantia nigra, more dopamine-producing neurons will be available. Read more on Would Stem Cell Therapy Be A Parkinson’s Cure?

Stem Cell Clinics for Parkinson’s Disease

One of the challenges with regards to induced pluripotent stem cells is controlling the ‘reprogramming’ of the cell to form the dopaminergic neurons and integrating it into the brain tissue. In experiments on lab rats it was seen that integrating these dopaminergic neurons could be achieved on the rat. The net result could be an improvement in the clinical symptoms of Parkinson’s disease. However, the efficacy on human subjects has to be ascertained by properly structured and controlled clinical trials.

Stem cell therapy is available at a number of clinics but the long term effects and potential complications have yet to be ascertained. Although many of clinics market these techniques quite aggressively, particularly on the internet, none can truly lay claim to ‘curing’ Parkinson’s disease. There are also the concerns that undifferentiated stem cells contained in the ‘mix’ may also be delivered into the brain tissue. These cells may have the potential to differentiate abnormally and grow rapidly and become tumors. The other factor to consider is that the exact pathogenic mechanism of Parkinson’s disease is still not clearly known. Therefore the very mechanism that can affect the naturally-occurring dopaminergic neurons may also affect the iPS dopaminergic neurons. Considering the cost factor of stem cell therapy, this can be an expensive procedure that may only offer short term results, if any.

This is not to say that the therapy offered by these clinics are not beneficial to some patients to some degree but it should not offer false hope. Most dedicated Parkinson disease organizations are critical of these clinics and the therapy on offer not because of the therapy itself, but rather in the manner that it is marketed and the sometimes blatant but often subtle promise of a cure.

Global Study

The study which appeared in the American Journal of Human Genetics (July 2011 issue) involved a global collaboration with researchers from the United States, United Kingdom, Canada, Europe and Asia. The research was led by Mayo Clinic neuroscientists and funded by several organizations, including in part by the Michael J. Fox Foundation.

The biochemical processes in Parkinson’s disease, particularly at the cellular level, is complex and not completely understood. The study has indicated that the VPS35 gene mutation disrupts the nerve cell’s (neurons) ability to recycle proteins facilitated by special protein complexes known as retromers. A faulty retromer therefore cannot play the integral role it usually does in this protein recycling process.

Exome Sequencing

A new genetic sequencing technique was used to find the VPS35 mutation in first cousins of the large Swiss family with a strong history of Parkinson’s disease. By sequencing just the exome, the portion of the genome responsible for manufacturing proteins, the genetic mutation was discovered without the more costly and time consuming process of analyzing the entire genome. Exons constitute less than 2% of the human genome and exome sequencing allows scientist to identify genetic variations that causes changes in specific protein sequences.

This latest discovery adds to the five other genetic mutations already found to be associated with Parkinson’s disease. However, the VPS35 mutation discovery is not applicable to every case of PD and is more likely associated with late-onset Parkinson’s disease. Furthermore the mutation may not only be significant for Parkinson’s disease, as reduced gene expression was also seen with other neurodegenerative diseases like Alzheimer’s disease.

Clinical Significance of the VPS35 Discovery

The clinical significance of this discovery cannot as yet be fully appreciated but may go a long way in contributing to the development of specific drugs that can target the subsequent biochemical disruption associated with the VPS35 mutation. However, there is still a significant amount of research that has still has to be done surrounding this discovery and as one of the co-authors of the study, Own Ross (Ph.D.) stated, “… it appears to be a rare cause of Parkinson’s disease …”.  Nevertheless, every discovery in the study of Parkinson’s disease holds new hope for all PD patients and contributes to a greater understanding of the disease as a whole.

As another co-author of the study, Zbigniew Wszolek (M.D.) , so accurately pointed out, “This finding provides an exciting new direction for Parkinson’ s disease research. Every new gene we discover for Parkinson’s disease opens up new ways to understand this complex disease, as well as potential ways of clinically managing it.”

Sources

1. Mayo Researchers: Genetic Mutation Linked to Parkinson’s Disease. Mayo Clinic
2. Parkinson’s Disease: Mutation In VPS35 Gene Linked To Late-Onset. Medical News Today

What are Pluripotent Stem Cells?

Stem cells are those unspecialized cells that have the potential to develop into different types of cells in our body during early life. There are also some partially differentiated stem cells in different tissues in adults which can replenish worn out cells. The most significant quantity of these cells lie within the hemopoietic tissue where new blood cells are constantly produced. In other tissues, cell replacement is via cell division although small amounts of stem cells will allow for replacement of tissue.

Types of Stem Cells

Embryonic stem cells – all cell types of the body are derived from these cells. These stem cells are also capable of dividing and replicating over a long period of time without differentiating into other cell types. Human embryonic stem cells are derived from human embryos and grown in the laboratory. Present research is aiming at stimulating these stem cells to undergo differentiation into specific cell types which can be used in the treatment of various diseases, including Parkinson’s disease, by transplanting these differentiated cells into specific diseased regions of the body.

Non-embryonic stem cells (adult or somatic stem cells) – these are undifferentiated or partially differentiated cells present amongst differentiated cells in a tissue or organ. These stem cells undergo differentiation into cells similar to the neighboring ones only and are mainly involved with tissue repair.

Induced pluripotent stem cells (iPSCs) – specialized adult cells may be reprogrammed genetically (through introduction of embryonic genes) to behave like embryonic stem cells. These are known as induced pluripotent stem cells, which have the potential of differentiating into and generating specific cells and tissues.

Induced Pluripotent Stem Cell Therapy in Parkinson’s Disease

An insufficient number of of dopamine-producing neurons (nerve cells) due to cell degeneration causes the symptoms of Parkinson’s disease. Replacing these cells with other dopaminergic neurons is the basis of iPSC therapy in PD.  Differentiation of the iPSCs into specific cells and generation of new cells may cause improvement in PD.

IPSCs produce a renewable source of replacement cells which may be effective in treating various disorders, including PD. By using the patient’s own adult stem cells to produce these iPSCs, chances of rejection by the immune system are greatly reduced. Cells generated from human iPSCs may be used to test the efficacy and safety of new drugs. Development of the disease process may be studied and better understood, thus helping in finding new ways of controlling and preventing the disease.

Challenges of iPSC Therapy

Scientists face the challenge of controlling the development of iPSCs into different cells in the body. Ethical issues also need to  be addressed although iPSC therapy is less contentious since embryonic stem cells from discarded fertilized embryos are not used.

Before iPSCs can be used successfully in therapy for Parkinson’s disease or any other disorder, certain points have to be kept in mind, which are very essential if transplantation and grafting are to be effective during treatment. The iPSCs should :

• Survive in the recipient after transplant.
• Integrate into the surrounding tissue after transplant.
• Function properly for the duration of the patient’s life.
• Cause no harm to the recipient.
• Viruses used to introduce the reprogramming factors into adult cells in animals may have other health consequences and the safety in humans needs to be considered.

Related Articles

1. Would Stem Cell Therapy Be a Parkinson’s Cure?

]]> http://pdring.com/induced-pluripotent-stem-cell-therapy-in-parkinsons-disease.htm/feed 2 http://pdring.com/gene-therapy-in-parkinsons-disease.htm http://pdring.com/gene-therapy-in-parkinsons-disease.htm#comments Sun, 31 Oct 2010 23:07:57 +0000 Dr. Chris http://pdring.com/?p=286 Significant research and several clinical trials have been done regarding the efficacy of gene therapy in Parkinson’s disease (PD). While many claims have been made involving numerous wonder cures for PD, gene therapy may hold the exciting possibility of not only delaying disease progression but also halting it completely.

Parkinson’s disease is progressive a neurodegenerative disorder where there is steady loss of brain cells of the substantia nigra involved in the production of the chemical neurotransmitter dopamine. Refer to Parkinson’s Disease Brain Chemistry for more information.

Medication with levodopa and other related drugs are the mainstay of treatment which can only offer temporary relief but no lasting cure. Research focused on developing other methods, such as gene therapy, which can help to treat or modify the disease process more effectively is continuously being done.

What is gene therapy?

Simply, gene therapy involves the introduction of healthy genes into a person with defective genes which may be the cause of a certain medical problems, such as Parkinson’s disease. The healthy genes are expected to work on the target cells and cause changes in them that will trigger them to resume producing dopamine and thus reduce symptoms or altogether halt the progress of PD. For this new therapy to be acceptable, the benefits should be long-term and without other complications or side effects.

Virus Carriers for Gene Therapy

During gene therapy, genetic material is transferred to the recipient using a vector virus which is considered not to be harmful to humans. Either recombinant adeno-associated virus type 2 (rAAV2) or lentivirus vectors have been used
in clinical trials in an attempt to trigger :

• Increased dopamine levels via increased neurotransmitter production.
• Modulation of the neuronal phenotype.
• Neuroprotection.

Increased dopamine production may be achieved by means of the first two methods, by direct delivery of genes involved in neurotransmitter production (amino acid decarboxylase, tyroxine hydroxylate and GTP (guanosine triphosphate) cyclohydrolase 1).

To bypass the degenerating nigrostriatal pathway, rAAV2 is used to transfer glutamic acid decarboxylase (GAD) to the subthalamic nucleus (STN). GAD acts as a catalyst in the production of a neurotransmitter called GABA, which acts as a direct inhibitor on the overactive cells in the STN.

Protection of the degenerating nigrostriatum (neuroprotection) is hoped to be achieved by striatal delivery of rAAV2 containing the neuroprotective gene neurturin.

Stem Cells and Gene Therapy for Parkinson’s Disease

Research continues so as to find newer and more effective means of delivering genes and sustaining their effects. Using stem cells as a means of introducing genes is being studied. It is claimed that hematopoietic stem cells from blood and bone marrow can be genetically transformed outside the body and then re-introduced into the patient so as to eliminate the necessity of repeated introduction of gene into the patient but results have not been too promising. Embryonic stem cells (because of their versatility) may be a better alternative to hematopoietic stem cells but ethical issues may have to be looked into.

Although studies done so far seem promising regarding gene therapy as a means of treating PD, longer follow-up still needs to be done to determine if improvements can be sustained over a prolonged period. It is to be hoped that gene therapy will be more effective and less invasive than the current medical or surgical treatments available, with less side effects.