Read about patient concerns, family dilemmas, and the clinical dynamics of a weekly movement disorder clinic. Observe ways a movement disorder neurologist manages patient symptoms with medications, surgical referrals, physical therapy, and caregiver options. Find out more in my Weekly Journal.
A Vaccine for PARKINSON’S DISEASE
According to Wiki-pedia, a vaccine is “a substance used to stimulate production of antibodies and provide immunity against one or several diseases, prepared from the causative agent of a disease, its products or a synthetic substitute, treated to act as an antigen without inducing the disease.” There is no cure for PARKINSON’S DISEASE, and treatments, while helpful to some degree, do not stop the progression of the disease. But Parkinson’s is not like Mumps, Measles, Pertussis, or Rubella, diseases that vaccines have nearly eliminated. But there is hope on the horizon. An Austrian pharmaceutical research company, AFFiRiS AG has just announced that the first trial of a new medication has proven safe and tolerable in a group of 24 test subjects.
PD01A is a new therapeutic drug designed to generate antibodies specific to alpha-synuclein, thought to be a causative agent in PARKINSON’S DISEASE. In this study, two groups of subjects received two different doses once a month for four months. 8 subjects received “best medical care” but no vaccinations and served as control subjects and all the subjects were followed for the course of one year. At the end of the year, they were all evaluated and clinical specimens were obtained. Half of the subjects that received PD01A developed alpha synuclein specific antibodies in both their serum and their cerebrospinal fluid. These subjects also demonstrated a trend toward stabilization of their functional capacities. The company regards these results as very encouraging and plans to begin further clinical trials beginning this September.
PD01A represents a novel approach to the treatment of PARKINSON’S DISEASE. The role of alpha-synuclein is still not clearly understood and researchers do not agree whether its removal would be clinically beneficial or not. The disease pathology of PARKINSON’S DISEASE is still being studied and is by no means clearly established. Alpha synuclein is definitely involved in some genetically inherited forms of the disease and also is found in the post mortem brain tissues of subjects with Lewy body disease. In animal models, added alpha synuclein does cause clinical symptoms and progression similar to those seen in humans.
Much of the neurodegeneration in PARKINSON’S DISEASE occurs well before the symptoms become manifest. By some estimates, as much as 75% of dopamine producing neurons are affected before a subject shows any symptoms. If a vaccination is to be effective in disease modification, intervention would have to come sooner rather than later. A vaccine may not be effective if the disease is already extensive and the neurodegeneration is irreversible. Biomarkers for PARKINSON’S DISEASE might provide that early warning system, but that also raises ethical issues and much more research is needed Also, the relationship of alpha-synuclein to the later dysfunction of mitochondria and oxidative stress is still under investigation.
The results of this first small trial of PD01A are exciting and encouraging. The next study will address the immunological and clinical effects of a booster vaccination and will be done in Vienna. Development of this vaccine will be slow and cautious. A warning from a similar situation must also be heeded: the development of a vaccine to remove the tau protein from Alzheimer’s brains resulted in development of serious, life threatening side effects and had to be discontinued.
Article by Marcia McCall
Clinical Trials Begin for Novel Administration of Levodopa in Advanced PD
The Israeli pharmaceutical company, NeuroDerm Ltd., has begun clinical trials in human subjects with advanced stages of PARKINSON’S DISEASE who are unable to tolerate oral types of levodopa/carbidopa medications. They expect to have completed the first stage by the end of this year and will make their data public.
As PARKINSON’S DISEASE progresses and patients age, they become less able to tolerate the motor and non-motor fluctuations caused by absorption problems with orally administered levodopa/carbidopa. In advanced stages, oral levodopa no longer seems to be effective, and patients must decide between considering deep brain stimulation or the surgical insertion of an intra-duodenal levodopa/carbidopa pump. Both surgeries are invasive and subject to serious complications and for some people, neither feasible nor desirable.
NeuroDerm has developed a proprietary formulation of liquid levodopa/carbidopa, which they are able to deliver in a continuous dose subcutaneously with a patch and a pump worn on the belt. Delivering a continuous dose of levodopa/carbidopa will eliminate the uneven responses that come from scheduled doses not uniformly absorbed through the digestive tract. Using a pump to deliver a continuous, uniform dose directly under the skin both day and night should improve the effectiveness of levodopa/carbidopa and reduce motor complications and make life easier for people with PARKINSON’S DISEASE.
The present trial is designed to evaluate the response of people with advanced stages of PARKINSON’S DISEASE to various dosage strengths of NeuroDerm’s liquid formula levodopa/carbidopa. Safety and tolerability have already been established, this study will measure drug concentrations in blood levels and motor responses to the doses.
The company has also prepared a low-dose form of liquid levodopa/carbidopa for people with moderate stages of PARKINSON’S DISEASE. A Phase II double blind, randomized, placebo-controlled trial has just finished enrolling all the subjects and completed their treatment. The data is presently being analyzed and the results will soon be made available.
NeuroDerm is a company focused on developing and providing enhanced treatments for major neurodegenerative diseases that will overcome problems encountered with traditional therapies. All of their products are designed to be delivered in a continuous, steady dose delivered subcutaneously by a small pump worn on a belt. They have developed three types of liquid levodopa/carbidopa for patients with moderate to advanced stages of PARKINSON’S and another for an even more severe stage. They are currently developing a formula for liquid apomorphine for patients with severe stages of PARKINSON’S who do not respond to levodopa.
Information provided by NeuroDerm LLC, Rohovot, Israel
Reviewed by Marcia McCall
Klotho, The Genetic Spinner of Aging Destiny
Indeed, we are all destined to age, but some age better than others. Some age faster and some slower. A gene called Klotho appears to be the cause. Klotho seems a rather strange name for a gene, but it comes from the name of one of the triad of Greek Goddesses known as the Fates, those independent controllers of destiny, to whom even the gods must submit. The genetic Klotho was accidentally discovered as the missing gene that caused premature aging in a group of transgenic mutated laboratory mice. Many studies implicated of the lack of Klotho in disease processes, including kidney disease. Newer studies have shown the protective qualities the presence of Klotho provides on reducing oxidative stress, improving blood pressure and preserving the retina in the eye. Klotho can slow aging and prevent loss of mental abilities. Now the newest study shows additional Klotho promotes neuroprotection in the brain.
A team of researchers for Boston University has recently published their study findings in the Journal of Biological Chemistry showing the neuroprotective effect of Klotho against Alzheimer’s disease. They grew nerve cells in petri dishes in the laboratory. Klotho was added to some of the dishes. When amyloid, like that which is found to accumulate in the neurons of Alzheimer’s disease, was added to all the dishes, the ones with the added Klotho showed a much higher survival rate of nerve cells than the untreated dishes. Carmela Abraham, Ph.D.is the principal investigator of this study and a professor of biochemistry and pharmacology at Boston University Medical Center. She says “We now have evidence that if more Klotho is present in the brain, it will protect the neurons from the oxidative stress induced by amyloid and glutamate. Finding a neuroprotective agent that will protect nerve cells from amyloid that accumulates as a function of age in the brain is novel and of major importance.”
However, it is not possible to introduce Klotho directly as a pill or an injection as it is a large molecule that cannot cross the blood-brain barrier. A compound of smaller molecules that can cross the blood-brain barrier and increase the levels of Klotho in the brain is presently under development. Dr. Abraham believes that “increasing Klotho levels with such compounds would improve the outcome for Alzheimer’s patients, and if started early enough would prevent further deterioration. This potential treatment has implications for other neurodegenerative disease such as PARKINSON’S, Huntington’s, ALS and brain trauma, as well.”
E. Zeldich, C.-D. Chen, T. A. Colvin, E. A. Bove-Fenderson, J. Liang, T. B. Tucker Zhou, D. A. Harris, C. R. Abraham. The Neuroprotective Effect of Klotho is Mediated via Regulation of Members of the Redox System. Journal of Biological Chemistry, 2014; DOI: 10.1074/jbc.M114.567321
Review by Marcia McCall
An Ambitious Study of World Wide Prevalence of PARKINSON’S DISEASE
In an effort to prepare public health systems to better serve future populations, a team of investigators from the University of Calgary in Alberta, Canada reviewed and analyzed over 4,000 epidemiological studies of PARKINSON’S DISEASE conducted throughout the world between the years of 1985 and 2006. This study was part of a larger study that actually looked at 15 different neurodegenerative diseases to ensure effective planning for medical services for populations that are increasing and now include larger numbers of elderly citizens who are most affected by diseases of aging such as Alzheimer’s disease and PARKINSON’S DISEASE. Many nations of the world will be facing health care costs for their people that will seriously strain, if not exhaust their available finances.
Although they found over 4,000 epidemiological studies from all over the world, there were many obstacles to distilling the information. Each study had unique differences in the demographics of the participants and the methodology of the study. Studies using only medical information did not count people who did not seek medical treatment; drug studies were also affected by cultural differences as well as the financial burdens of obtaining the medications. Slight differences in diagnostic criteria can increase or decrease the numbers of subjects included. Some subjects may have been misdiagnosed; others may not have had access to good medical care. Another impediment to research on medical records is government restrictions on access to the personal data contained in those records. Overcoming these disparities in information required detailed screening of eligibility requirements to meet the standards of this study. Ultimately, only 134 of the original 4,219 research reports met those standards. Those were reduced even further to allow for 47 studies that were considered to meet random population sample and diagnostic criteria
The results of this study found fascinating differences in geographic distribution, age and sex. Analysis of the data show that PARKINSON’S DISEASE is increasing worldwide, beginning with the 40 to 49 year old group, and increasing substantially in each age group. Interestingly, in the 70 to 79 year old group there was a significant decrease (646 per 100,000 individuals) compared to Europe, North America and Australia (1,602 per 100,000 individuals). This highest affected numbers were in the over 80 age group, with 1,903 individual per 100,000. One reason for the higher numbers in the over 80 group may be the improvements in treatment for PARKINSON’S DISEASE as well as higher quality general care has improved chances for survival to this age and decreased mortality rates for everyone.
Division by sex showed that in all the age groups, males had only a slight increase over females. But in the 50 to 59 age group, males had a much higher prevalence, more than three times higher than females in that same age group. It has been suggested that estrogen in females may increase the available dopamine in the striatum that may present as a milder version of PARKINSON’S DISEASE that progresses more slowly.
While the genetics and environmental factors that lead to PARKINSON’S DISEASE are beginning to be investigated, these new studies may also have a major impact on the type and quality of medical care available to this population. This study shows that while the world’s population is now living longer, there is also an increased prevalence in PARKINSON’S DISEASE that will require effective planning for public health care to implement resources and availability of quality care for the increased numbers of the aging population.
Review by Marcia McCall
The Potential Benefits of Coffee and Cinnamon for PARKINSON’S DISEASE
Two research articles published very recently could make you think that a breakfast of multiple cups of strong coffee and cinnamon rolls was deliciously beneficial for people with PARKINSON’S DISEASE. The first article is from a team of researchers at Linkoping University in Sweden. They very carefully looked at the relationship of coffee and a genetic variation specific to PARKINSON’S DISEASE. The second study came from Rush University Medical Center in Chicago, IL and looked at the potentially beneficial effects of cinnamon as a neuroprotective anti-oxidant for PARKINSON’S DISEASE. Alas and unfortunately, what makes for good research news is not necessarily good practical advice.
The Swedish coffee research studied 570 subjects from southeastern Sweden, 193 who had PARKINSON’S DISEASE AND 377 controls. PARKINSON’S DISEASE is thought to result from a complex interaction of genetic predisposition and environmental factors. While many of the genes involved in PARKINSON’S have been isolated, interactions of individual genes with environmental factors have been much more difficult to study. This group looked at one single nucleotide polymorphism (SNP), a specific genetic modifier that has been found in many people with PARKINSON’S DISEASE. They genotyped all the subjects to determine if they carried this SNP, then they interviewed them to establish their levels of coffee drinking or caffeine use, either high or low. They then studied the effects of heavy caffeine consumption or light consumption on this specific SNP and found that heavy caffeine consumption, especially on a particular form of the SNP did provide a protective benefit.
The study of cinnamon from Rush University looked at the benefits of this widely used cooking and baking spice on the brains of mice. They found that “after oral feeding, ground cinnamon is metabolized into sodium benzoate, which then enters into the brain, stops the loss of Parkin and DJ-1, protects neurons, normalizes neurotransmitter levels, and improves motor functions in mice with PD” Parkin and DJ-1 are proteins that are known to be compromised by oxidative stress in people with PARKINSON’S. In this way, sodium benzoate could act as an anti-oxidant, to preserve the cells. Dr. Kalipada Pahan, the principal investigator of this study enthusiastically states: “Now we need to translate this finding to the clinic and test ground cinnamon in patients with PD. If these results are replicated in PD patients, it would be a remarkable advance in the treatment of this devastating neurodegenerative disease”
But not so fast, here. Using anti-oxidants to preserve brain cells is an idea that has shown many good results in mice but has not proved definitively effective in humans. Cinnamon is just the newest candidate. More research on the benefit of cinnamon is in order. Cinnamon breaks down into sodium benzoate in the liver. Sodium benzoate does not have a great reputation, particularly as an additive to food. In small quantities, chemically produced sodium benzoate is added to commercial food products as an anti-microbial and a preservative to extend shelf life. It is also found in pickles, salsas, processed lunchmeats, sodas and juice drinks. When it combines with acids, such as vitamin C (ascorbic acid) it forms benzene, which is a known carcinogen. While the sodium benzoate added to food is of a manufactured nature, it is consumed in very small quantities and the Food and Drug Administration does not consider it dangerous although the cumulative effects have not been thoroughly studied. More research on the safety and effectiveness of cinnamon to protect people from Parkinson’s disease will be informative.
You can still enjoy a cinnamon roll and a good strong cup of coffee…just don’t expect them to deliver the neuroprotection needed to resolve your PARKINSON’S symptoms!
Naomi Yamada-Fowler, Mats Fredrikson, Peter Söderkvist. Caffeine Interaction with Glutamate Receptor Gene GRIN2A: Parkinson’s Disease in Swedish Population. PLoS ONE, 2014; 9 (6): e99294 DOI: 10.1371/journal.pone.0099294
Saurabh Khasnavis, Kalipada Pahan. Cinnamon Treatment Upregulates Neuroprotective Proteins Parkin and DJ-1 and Protects Dopaminergic Neurons in a Mouse Model of Parkinson’s Disease. Journal of Neuroimmune Pharmacology, 2014; DOI: 10.1007/s11481-014-9552-2
Review by Marcia McCall
Long Term Effectiveness of Three Types of PARKINSON’S Medications Compared
Treatment of newly diagnosed people with PARKINSON’S DISEASE can pose certain dilemmas for both the physician and the patient. While levodopa therapy is still considered the “gold standard” and most effective treatment, it may not be the best drug of choice for initial treatment. And PARKINSON’S patients have sometimes been compared to snowflakes, alike in general similarities, but each person has very unique qualities and symptoms. So there can be no “one size fits all” standard of treatment.
One ambitious study was undertaken in England to try to establish the long-term effectiveness of several categories of drugs standard in the treatment of PARKINSON’S DISEASE. They divided their study into three categories, levodopa, dopamine agonists and MAO-B (monoamine oxidase inhibitor type B) inhibitors. Sinemet is a popular levodopa replacement, ropinerole or pramipexole are dopamine agonists and rasagiline or selegiline are MAO-B inhibitors. This study was designed to see which class of drug provided the most effective long-term control of PARKINSON’S symptoms based on patient mobility scores and provided the best quality of life for the patient. Over 1,600 subjects were followed for a 9 year period during this study.
528 subjects were assigned to levodopa, 632 subjects received a dopamine agonist and 460 received an MAO-B inhibitor. After three years of observation, subjects in the levodopa category performed only slightly better in the mobility tests. Subjects in the dopamine agonist and MAO-B categories mobility scores were also similarly improved with the MAO-B group reporting a slightly better quality of life.
After seven years, levodopa was still effective, however it provided no increased improvement. Disease progression remained similar in all three groups, as measured by onset of dementia, institutional admissions or death. 28% of the subjects in the dopamine agonist group discontinued the use of the agonists due to side effects. 23% of the group of MAO-B subjects also experienced side effects that caused them to discontinue that medication. Only 11% of the levodopa group discontinued that treatment due to side effects.
The study authors report that MAO-B inhibitors are as effective as dopamine agonists, but levodopa has a slight edge in improving mobility scores.
PD MED Collaborative Group; Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson’s disease (PD MED): a large, open-label, pragmatic randomised trial; The Lancet, Early Online Publication, 11 June 2014, doi:10.1016/S0140-6736(14)60683-8
Review by Marcia McCall
Get Moving! Walking Helps!
An article published recently by the American Academy of Neurology stresses the benefits of walking for people with PARKINSON’S DISEASE. Actually, the advice is equally appropriate for people who do not have PARKINSON’S DISEASE! A small study conducted at the University of Iowa and the Veterans Affairs Medical Center in Iowa City suggested that a brisk walk was a simple, easy way to alleviate some of the symptoms of PARKINSON’S DISEASE.
The study observed 60 subjects who walked for 45 minutes three times a week over a period of six months while wearing heart rate monitors. The biggest changes were clinically significant improvements in motor symptoms and mood and the scores to tests measuring attention and control responses were also considerably improved. Walkers also reported that they felt less tired and more physically fit overall.
Lead author of this study, Dr. Ergun Y. Uc suggests “People with mild-moderate Parkinson’s who do not have dementia and are able to walk independently without a cane or walker can safely follow he recommended exercise guidelines for health adults, which includes 150 minutes per week of moderate intensity aerobic activity, and experience benefits.” People without PARKINSON’S DISEASE….take note!!!
E. Y. Uc, K. C. Doerschug, V. Magnotta, J. D. Dawson, T. R. Thomsen, J. N. Kline, M. Rizzo, S. R. Newman, S. Mehta, T. J. Grabowski, J. Bruss, D. R. Blanchette, S. W. Anderson, M. W. Voss, A. F. Kramer, W. G. Darling. Phase I/II randomized trial of aerobic exercise in Parkinson disease in a community setting. Neurology, 2014; DOI: 10.1212/WNL.0000000000000644
Two Studies of the Dynamics of Dopamine in PARKINSON’S DISEASE
Two new studies have been published recently that examine how the neurotransmitter dopamine affects the neurons involved in PARKINSON’S DISEASE. The first study, from the Medical University of Vienna compared brain tissue from deceased human to that of deceased non-Parkinsonian controls to find out why the brain cells of people with PARKINSON’S do not process dopamine effectively. This study was lead by Oleh Hornykiewicz, M.D. who was one of the early pioneers studying the role of neurotransmitters in the brain. He was the first to demonstrate the lack of dopamine as a cause of PARKINSON’S DISEASE and also in developing L-dopa for dopamine replacement therapy.
The second study comes from the Rollins School of Public Health at Emory University, in Atlanta. Gary W. Miller, Ph.D. is the principal investigator for a large team of researchers involved in this study. Dr. Miller’s team found a unique way that may help increase the function of dopamine and thereby help people with PARKINSON’S DISEASE.
To appreciate the scope of these studies, a basic understanding of neuroscience may help. Neurons communicate by means of the exchange of neurotransmitters such as dopamine, norepinephrine or serotonin (just to name a few) between their synapses. These neurotransmitters are constantly being created and then are pumped into storage vesicles to be used in the synapse as needed. A synapse can contain many different neurotransmitter vesicles and can fire them off extremely rapidly.
In Dr. Hornykiewicz’s study, they were able to image the dopamine storing vesicles and found that the pumps that load dopamine into those vesicles were not functioning efficiently. Dopamine is constantly being reformed or created at the contact points of the neurons, but if it is not loaded into the vesicles for storage, it can damage the surrounding neurons and actually destroy them. Dr. Christian Piff, one of the contributing researchers explains “This pump deficiency and the associated reduction in dopamine storage capacity of the Parkinson’s vesicles cold lead to dopamine collection in the nerve cells, developing its toxic effect and destroying nerve cells.”
Dr. Miller’s team used a novel mouse model to examine the dynamics of vesicular activities, how the neurotransmitters are loaded into the vesicle, their capacity and their release into the synapse of the neuron. These mice had a modification that increased the transporter’s ability to pump dopamine into the vesicle. They found that if the transporter pumping the dopamine into the vesicle was increased to double, then the storage capacity of the vesicle and its release into the synapse was also increased. The mice in this model showed improvement in their locomotor activity and improvement in anxiety and depressive-like behaviors. The increase in dopamine release from the vesicle into the synapse also provided protection from toxic effects and reduced cell loss in the substantia nigra. Dr. White says “Results of this study suggests that enhanced vesicular filling can be enhanced over time and may be a viable therapeutic approach for a variety of central nervous system disorders that involve the storage and release of dopamine, serotonin, or norepinephrine.”
1. C. Pifl, A. Rajput, H. Reither, J. Blesa, C. Cavada, J. A. Obeso, A. H. Rajput, O. Hornykiewicz. Is Parkinson’s Disease a Vesicular Dopamine Storage Disorder? Evidence from a Study in Isolated Synaptic Vesicles of Human and Nonhuman Primate Striatum. Journal of Neuroscience, 2014; 34 (24): 8210 DOI: 10.1523/JNEUROSCI.5456-13.2014
2. K. M. Lohr, A. I. Bernstein, K. A. Stout, A. R. Dunn, C. R. Lazo, S. P. Alter, M. Wang, Y. Li, X. Fan, E. J. Hess, H. Yi, L. M. Vecchio, D. S. Goldstein, T. S. Guillot, A. Salahpour, G. W. Miller. Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo. Proceedings of the National Academy of Sciences, 2014; DOI: 10.1073/pnas.1402134111
Review by Marcia McCall
New Technique for Dopamine Cell Replacement in PARKINSON’S DISEASE
Love those Italians…. they excel in fashion design and make the best designer shoes! Now they have taken design to the cellular level and are creating designer drugs for designer receptors on those cells. They call it DREADD (designer receptor exclusively activated by designer drug. But this is really serious science.
Cell transplantation in PARKINSON’S DISEASE, while in theory, sounds very plausible, in practice has yielded mixed results with the development of serious dyskinesias or even tumors being a major problem. Because it is a particular type of neuronal cell that is affected in PARKINSON’S DISEASE, cell therapy with dopamine producing cells could yield a potential therapeutic treatment. If dopamine producing cells could be developed, transplanted and become effective and efficient producers of dopamine, the troublesome motor symptoms that plague people with PARKINSON’S could be banished.
Embryonic stem cells or induced pluripotent stem cells have been developed from both mouse and human cells and have been somewhat effective in alleviating motor symptoms when transplanted into animal models of PARKINSON’S DISEASE. But if the differentiation from stem cell to dopamine producing cell is not well controlled, tumors can develop. Cells developed from human fibroblasts can be induced to become neurons, but are more difficult to produce, with more opportunity for potential error. Much stem cell technology exists only in petri dishes, and the degree to which these reprogrammed cells would be functional or stable when transplanted into living models is not yet known. For modified cells to be transplanted and become effective a system needs to be developed that will allow the transplanted cells to be monitored and modulated to serve the physiological environment into which they are introduced.
Previous studies have shown that only dopamine neurons from the mid brain region were successful in reversing motor function in lesioned rats. This team developed an induced dopaminergic neuron (iDA) from fibroblast, so the challenge was to see if it could be as effective as mid brain dopamine neurons. The grafted iDA neurons did improve the motor function of the animals, but not as well as native embryonic DA neurons. Stereological cell counting showed that there were as many surviving iDA cells as there were native DA cells and this lead to the idea that iDA neurons were less functional intrinsically. The team believes that an improved method for generating better quality induced pluripotent stem cells from the fibroblasts will result in more uniformly expressing iDA neurons.
To measure the integration of the iDA neurons into the host environment, they used the DREADD technology. This technology allows the addition of a uniquely designed receptor that permits a specific interaction with a pharmacological drug to manipulate the activity of the re-programmed neuron. It thus enforces a sort of “remote control” over the transplanted neuron to enhance its effects in living animals. This method may offer a better approach to cell replacement therapy by combining an external, pharmacological agent with the transplanted re-programmed neurons to respond to the physiological needs and requirements of the recipient.
This research study was done by a large team of researchers under the direction of Vania Broccoli, Ph.D. who is a developmental neurologist at the Hospital San Rafaele in Milan, Italy. It will be published in the Journal of Clinical Investigation on July 1, 2013.
Broccoli, V. et al; Remote control of induced dopaminergic neurons in parkinsonian rats; J Clin Invest. 2014;124(7):3215-3229. doi:10.1172/JCI74664
Review by Marcia McCall