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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
Improvement Seen in First Clinical Trial of Magnetic Stimulation for PARKINSON’S DISEASE
A double blind, randomized trial tested two targets of magnetic stimulation as well as a sham stimulation on 60 subjects that had moderate PARKINSON’S DISEASE. They received their usual Parkinson’s medications in addition to the stimulation. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive treatment that researchers hope will augment pharmaceutical treatments for PARKINSON’S DISEASE. This trial has safety and efficacy as its primary outcome measures as well as improving clinical results when the subjects were off their drugs. While other studies have reported mixed results from transcranial magnetic stimulation, this trial used a larger, unique coil with the ability to generate a larger field of stimulation that penetrated deeper into the brain.
Principal investigator of this trial was Mario FIchera, M.D. from the Institute of Experimental Neurology at the Scientific Institute Hospital San Raffaele in Milan, Italy who presented his findings at the 24th Meeting of the European Neurological Society on June 1, 2014. He stated that compared to the group receiving sham stimulation, both groups that received targeted stimulation improved significantly, with no serious adverse events. In addition to reported improvements as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) part III, subjects reported they experienced a better quality of life, but he cautioned that a further trial should be done to “validate the efficacy seen in this trial and to gauge the duration of the effects.”
Transcranial Magnetic Stimulation is a relatively new technique that changes neuronal function by using an electromagnetic field generated by a coil. Electricity passes in opposite directions through the shape of the coil and where the current crosses it generates an electrical field, whose intensity can be modified by regulating the amount of electrical current. Pulses can be applied singly or repetitively and at varying intensities. The strength and frequency of the pulses can determine excitability or inhibition of the target neurons. The coil is placed against the scalp and the magnetic field passes through the skull to change the electrical field of the underlying neurons. In this study TMS was applied in repetitive pulses, timed milliseconds apart. TMS treatment is usually done several times a week for several weeks.
In this study, all groups of subjects received treatment three times a week for four weeks. One group received treatment on the motor cortex region, contralateral to their affected side, and also to the prefrontal cortex. Group two received treatment to the motor cortex region, but sham treatment on the prefrontal cortex. Group three received sham treatments on both treatment sites. Both groups that received actual treatment showed reductions in the motor symptoms and tremors compared to the sham group.
Dr. Josep Valis-Solis, a neurologist and neurophysiologist at the Hospital Clinic in Barcelona, Spain said “I think that we have to promote a bit this kind of treatment that is noninvasive and nonpharmacological, so some hope that we are escaping from toxicity from drugs.” It is still early and there needs to be more investigation into the types and differences of effects from different coils. Cost and availability of the equipment and training and availability of personnel to administer treatment is another issue that needs to be studied together with the rate of retreatment necessary to maintain a positive effect over an as yet unknown, period of time.
Magnetic Stimulation Improves Parkinson’s Symptoms, Medscape Jun 17, 2014
Review by Marcia McCall.
New PARKINSON’S Gene Discovery Could Lead to New Treatment
The new molecular sciences continue to delve deeper into the mysteries of the cellular actions and interactions to unlock the keys to PARKINSON’S DISEASE. A team of genetic researchers at the University of California at Los Angeles headed by Dr. Ming Guo has found one more clue, a gene that mediates the interactions of two mutated genes and helps cells maintain their health to prevent neurodegeneration.
The genes PINK1and Parkin play important roles in protecting the energy producing mitochondria of cells. When these genes are mutated, they do not operate correctly and allow for accumulations of unhealthy cells with damaged mitochondria that leads to the early on-set of PARKINSON’S DISEASE. Working in fruit flies and mouse models of disease, Guo and her team found that a gene called MUL-1 mediated the interaction of PINK-1 and Parkin and contributed to the health of the mitochondria. When MUL-1 was removed from the interaction with PINK-1 and Parkin in the neurons in the mouse model, they found it caused deterioration of the mitochondria, but when an extra amount of MUL-1 was added, the mitochondrial damage was repaired.
The discovery of this new genetic interaction is exciting, showing a new mechanism for improving the function of mitochondria and maintaining the health of the cell, but also because it may lead to the development of a drug that could enhance its presence and prevent neurodegeneration. Such a new drug would be of immense benefit to people with PARKINSON’S DISEASE.
Further studies will test these findings in more complex biological organisms and will help to find more cellular interactions related to MUL-1. Testing for drugs that will enhance MUL-1 and become a basis for treatment is another a priority. The team will also be looking for mutations of the MUL-1 gene and to understand its heritability to see if it exists in all PARKINSON’S patients or if it is found only in the inherited forms of PARKINSON’S.
J. Yun, R. Puri, H. Yang, M. A. Lizzio, C. Wu, Z.-H. Sheng, M. Guo. MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin. eLife, 2014; 3 (0): e01958 DOI:10.7554/eLife.01958
Review by Marcia McCall
Hopeful New Drug Therapy Being Developed at University of Alabama
Alpha-synuclein is one of the most prevalent proteins found in human brains. It is also the one that when it fails to conform to its normal configuration, or mis-folds, contributes to the neurodegeneration seen in PARKINSON’S DISEASE. Researchers at the University of Alabama led by Andrew West, Ph.D. think they may have found a key to prevent alpha-synuclein from misfolding and aggregating.
The gene LRRK2 has been linked to PARKINSON’S DISEASE and West’s lab demonstrated that the known mutations of this gene all increase its activity. Other studies have shown that it is related to alpha-synuclein in several ways. This study has shown that blocking the expression of LRRK2 in mouse models that are genetically very similar to human models, blocked the over-expression of alpha-synuclein. Blocking alpha-synuclein may prevent the death of dopamine producing cells in the substantia nigra, thus offering a potential treatment to prevent or slow the progress of PARKINSON’S DISEASE. The search for a drug to inhibit the expression of LRRK2 is now underway.
LRRK2 is known to be significantly involved in the genetic forms of PARKINSONS, in populations of Ashkenazy Jews from Eastern Europe and from Mediterranean ethnic populations such as the Berbers of North Africa, but is not as highly involved in non inherited forms of the disease. Still, West’s team thinks LRRK2 has more than one method of action as seen in the genetic forms. It may interact with alpha-synuclein in other ways.
He asks, “What would happen if you simply remove all LRRK2 activity? Modern approaches allow us to approximate what a perfect drug would do in rats and mice. We think LRRK2 is plugging into PARKINSON’S DISEASE in more than one way. It is making the disease more likely to happen and making it progress faster when it does happen. So we think knocking out LRRK2 will do the opposite–slow the disease or make it much less likely to develop.”
Simply slowing the progress of the disease would be a major break through. It could extend the length of time that levodopa effectively alleviates the symptoms and could even reduce or eliminate some of the side effects that can sometimes be worse than the disease.
Southern Research Institute is pharmaceutical research company partnering with Dr. West’s lab to develop a drug to inhibit LRRK2. They hope to be able to test it in humans early next year.
J. P. L. Daher, L. A. Volpicelli-Daley, J. P. Blackburn, M. S. Moehle, A. B. West.Abrogation of -synuclein-mediated dopaminergic neurodegeneration in LRRK2-deficient rats. Proceedings of the National Academy of Sciences, 2014; DOI: 10.1073/pnas.1403215111
Review by Marcia McCall