Potential Parkinson treatment from Artificial Sweetener

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α-Synuclein has long been known to accumulate in the brains of people with Parkinson’s and cause cognitive changes.  Finding treatment to prevent clumping  of α-synuclein has been very complex and challenging.  But a substance used by surgeons during surgery to open the blood-brain barrier and allow necessary drugs to pass may hold the key.  Mannitol  is also  Federal Drug Administration (FDA) approved as a diuretic, to flush out excess fluids.  And it is a popular artificial sweetener in sugar free gum.

Researchers Ehud Gazit and Daniel Segal identified the structures of α-synuclein that cause it to form clumps and bind together.  Understanding how those structures worked lead them to look for various substances that might prevent the clumps from forming.  It was in that process that they identified Mannitol as being one of the most effective at preventing aggregation of α-synuclein in test tubes.  Making it an even more attractive candidate was the fact  that it was already FDA approved for other medical uses.

They began by testing Mannitol in the brains of very simple creatures: fruit flies that were genetically engineered to express human α-synuclein and ordinary fruit flies without any genetic changes.  Next, they measured the fruit flies ability to climb up the walls of a test tube, a so called “climbing assay”.  In the first trial, 72 percent of the “normal” fruit flies were able to complete the climb up the test tube, but only 38 per cent of the genetically modified fruit flies were able to successfully climb the test tube.

For 27 days they added Mannitol to the food of the genetically altered fruit flies, but not to the food of the control flies.  When the “climbing assay” was again administered, 70 per cent of the genetically altered fruit flies were able to climb the test tube walls.  On examining the brains of these flies, they found  a 70 per cent reduction in α-synuclein.

Dr. Eliezer Masliah of the University of San Diego repeated the experiment, this time using genetically modified mice.  The results showed a dramatic reduction in the aggregates of α-synuclein after four months of injections of Mannitol.

Fruit flies and mice are still a long way from human people with Parkinson’s disease!  The proven reduction of α-synuclein in the brain is exciting, but more studies of behavior in other animal models of Parkinson’s are needed. The researchers are presently searching for ways to modify the Mannitol compound in order to optimize its effectiveness and insure its safety.  Much more animal research will need to be performed before trials for humans can begin.

Dr. Segal does not advise people with Parkinson’s to begin chewing quantities of sugar free gum!  But he does hold hope that because Mannitol is useful in crossing the blood-brain barrier, it may prove useful as a transporter for other medications for Parkinson’s that are now very difficult to get into certain regions of the brain.

This research was done at Tel Aviv University, Depoartment of Molecular Microbiology and Biotechnology and the Sagol School of Neuroscience.  Collegue Ronit Shaltiel-Karyo and Ph.D. candidate Moran Frenkel-Pinter were also participants in this study.  The results were presented at the Drosophilia Conference in Washington, D.C. in April.



A Blood-Brain Barrier (BBB) Disrupter Is Also a Potent α-Synuclein (α-syn) Aggregation Inhibitor: A NOVEL DUAL MECHANISM OF MANNITOL FOR THE TREATMENT OF PARKINSON DISEASE (PD)J. Biol. Chem. 2013 288: 17579-17588. First Published on May 1, 2013,doi:10.1074/jbc.M112.434787

Improved Techniques for Deep Brain Stimulation

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Dr, Kim Burchiel, the head of Neurosurgery at Oregon Health and Science University was the first surgeon to use the techniques for Deep Brain Stimulation (DBS) surgery in the United States more than 10 years ago.  Now he has refined the techniques making them even more accurate and improving the safety of the surgery for patients.

“This surgery allows for extremely accurate placement of the electrodes and it’s safer.  Plus patients don’t need to be awake during this surgery – which will mean many more patients who can be helped by this surgery will now be willing to consider it:” said Dr. Burchiel.

The new technique uses advances in medical imaging to improve the accuracy of the placement of the electrodes in the brain.  An MRI of the patient’s brain is obtained prior to the surgery and during the surgery a CT scan provides improved clarity for surgeons to eliminate any errors of placement.

DBS has been used in the United States for the last twenty years to help relieve some of the symptoms of Parkinson’s, such as tremor.  It is also used to treat some other neurodegenerative disease, such as familial tremor and dystonias.

DBS surgery places very thin electrical wires and electrodes into specific regions of the patient’s brain and then connects them to a pacemaker-like device implanted under the skin of the chest.  Surgery can last between four and six hours, and the patient is required to be awake to make sure the placement is accurate.  Many patients who might benefit from this surgery cannot endure the thought of being awake for such a long surgery.

Dr. Burchiel tested the new technique in a FDA approved study on over 60 patients at the Oregon Health and Science University Hospital and followed them for 18 months..  He is reporting the results of that study in the Journal of Neurosurgery.  Since the study, over 140 more surgeries using the new technique have been successfully performed.  Dr. Burchiel says that although the length of the surgery during the studywas slightly longer than the previous technique, with time, these new surgical techniques should be able to be done in about half the time as before.  DBS surgery may eventually offer new ways of treating Alzheimer’s, depression and even obesity.


Kim J. Burchiel, Shirley McCartney, Albert Lee, Ahmed M. Raslan. Accuracy of deep brain stimulation electrode placement using intraoperative computed tomography without microelectrode recordingJournal of Neurosurgery, 2013; : 1 DOI: 10.3171/2013.4.JNS122324

Please Participate….An Interesting Study on Positive Coping in Parkinson’s

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Dr. Laurie Mischley at Bastyr University in Washington State wants to know what Parkinson’s patients who are living well are doing to maintain their state of well being in spite of Parkinson’s.  And she wants to hear from YOU!

This is your opportunity to participate in an on-line research study that wants to focus on wellness and not on sickness.  Every six months  for five years you will be asked to fill out an on-line questionnaire that will help researchers understand what people who are doing well are doing differently from those who are not.  Results of this study could lead to new clinical trials and to new interventions and therapies for the treatment of Parkinson’s.

It is a unique study in that it will be looking for what works rather than for what isn’t working in the lives of people with Parkinson’s.  People who do better than predicted with their disease are called “positive deviants”, a rather catchy way of thinking about what you are doing right, to help you live better.  So, this is YOUR opportunity to help researchers find out what REALLY works for YOU!!!


Higher Iron Levels in Blood May Protect Against Parkinson’s

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Causes of Parkinson’s disease remain unknown however a relationship between genetics and environmental elements has long been suspected.  One such environmental aspect has been that many people with Parkinson’s exhibit low levels of iron in their blood compared to normal controls.  In addition, higher iron levels are found in their brains… The value of these findings makes it difficult to interpret if there is a causal relationship between blood levels of iron and accumulations of iron in the brain.  Can iron be identified as a possible environmental risk that can be modified to possibly prevent the development of Parkinson’s?

A group of international researchers performed an analysis of  studies that had been done previously.  They employed a novel epidemiological study design, mendelian randomization, which uses genotype-disease associations.  They analyzed results of studies that included 22,000 people from Europe and Australia for the genetic effect on iron levels and then analyzed studies of the genetic effect on the risk of Parkinson’s disease that included 20,809 people with Parkinson’s and 88,892 controls from Europe and the United States. They then performed more analyses based on  three polymorphism in two genes to determine the effect of iron on Parkinson’s.

They found that high levels of iron in the blood are likely to be protective against developing Parkinson’s although it is not clearly understood how that happens.   Also, accumulations of iron in the brain may be the result of genetic abnormalities. They stress that there may be other factors involved that might influence this analysis. While higher levels of iron in the blood may confer some protection, it is not necessary to begin taking iron supplements until it is understood why iron accumulates in Parkinson’s brains.

This is an important first study for researchers working on the prevention of Parkinson’s.     Further studies on the mechanism of action will also be necessary before any recommendations for specific treatments can be made.



Citation: Pichler I, Del Greco M. F, Gögele M, Lill CM, Bertram L, et al. (2013) Serum Iron Levels and the Risk of Parkinson Disease: A Mendelian Randomization Study. PLoS Med 10(6): e1001462. doi:10.1371/journal.pmed.1001462

Unlocking the secrets of PARKIN

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Parkin is a protein that is associated with the PARK2 gene.  Mutations of the Parkin protein are associated with young on-set and familial forms of Parkinson’s.  The role of Parkin in cells is to regulate the function of the mitochondria, or the little energy furnace of the cell. Mutations in the Parkin gene lead to instability of the Parkin protein which can be very debilitating in nerve cells, a mechanism that is not yet fully understood.

One of the roles of Parkin is to remove damaged proteins in the mitochondrial outer membrane and eliminate them.  Research suggests that problems in this pathway may be the cause of Parkinson’s.   Parkin also has other roles in cell signaling as well as in suppressing tumors.  With so many biological roles, understanding how Parkin interacts in so many domains is essential.

In order to investigate some of these interactions, two young researchers at the MRC Laboratory of Molecular Biology in Cambridge, England, have crystallized a form of human Parkin into a three dimensional structure.  Using X-ray diffraction patterns to create the three dimensional structure they were able to see how the protein actually folds.  The Parkin protein structure is controlled by an internal regulation system, which is lost when it is affected by mutations that account for Parkinson’s disease.

When Parkin is functioning properly, it is may be able to protect the cells and lead to their longevity, and by its other roles, some of which are yet unknown, protect against the risk of Parkinson’s and other diseases.  The three dimensional crystal structure of this protein created by these young researchers is already unlocking some of the secrets of Parkin.


Tobias Wauer, Daid Kommander. Structure of the human Parkin ligase domain in an autoinhibited stateThe EMBO Journal, 2013: DOI: 10.1038/emboj.2013.125

Dreaming Your Way to Parkinson’s

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Does your bed mate complain that you fight in your sleep?  Do you dream of being chased by wild animals about to devour you?  Do you physically try to fend them off?  Sleep disturbances, especially when they feature trying to escape from wild animals, are a sign of impending neurodegeneration.  People with Parkinson’s often have dreams with physical aggression such as fighting with animals.   And people who act out the actions of their dreams have a very high risk of developing Parkinson’s within 10 to 15 years.  But the question now is which is the cause and which is the effect.  Does early stage neurodegeneration lead to sleep disturbance or is it the sleep disturbance that leads to neurodegeneration?

Rapid Eye Movement (REM) sleep and non REM (NREM) sleep are normal patterns of human sleep.  During REM sleep, rapid eye movements are accompanied by a paralysis of the muscles, except for the diaphragm to allow for breathing.  In REM sleep behavior disorder (RBD) the sleeper’s muscles are active and he acts out the disturbances of his sleep, sometimes with vocalizations.  Periods of RBD can range from mild movements to violent thrashing about, sometimes injuring the sleeper or harming his bed partner. This behavior can also change over time; it can be mild when young progressing to more violent over the years. While it is sometimes observed in younger patients, it affects mostly men over 50. Presently, there are medications to help alleviate some of the problems and permit the sleeper to get a good night’s rest.

Parkinson’s disease has a long period of slow development; it can take years for the symptoms to progress to the point of concern.  Symptoms such as depression, anxiety, anemia, constipation and loss of smell can seem to appear independently along with aging without anyone suspecting that they are strong predictors of neurodegeneration or Parkinson’s.  Studies of RBD have shown that the sleep disturbance is accompanied by synuclein inclusions in the brain, which are definite precursors to neurodegenerative diseases.

This scenario gives researchers plenty of areas to study–the relationship between RBD and the development of Parkinson’s holds much promise.  The first is the potential to test disease predictors i.e. does RBD predict Parkinson’s?  Secondly it presents the opportunity to study the long period of development of Parkinson’s with imaging techniques such as trans cranial ultrasound, Single Photon emission computed tomography (SPECT) and dopaminergic imaging.  And finally, the potential to develop neuroprotective therapies.

Given the already strong relationship between RBD and neurodegenerative disease, it is important for neurologists and other professionals to identify this as a pre-motor symptom and to use this information to provide serious counseling to the patients who are at risk.

*Postuma, R.B.;Gagnon, J-F.; Montplasir, J.Y. REM Sleep Behavior Disorder and Prodomal Neurodegeneration – Where Are We Headed?; Tremor Other Hyperkinet Mov (NY) 2013; 3 tre-03-134-2929-1

Risk of Parkinson’s Increases with Pesticide Use

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A group of researchers from the Research Center Hospital San Mateo in Pavia, Italy examined over 100 recent studies of toxic materials used as pesticides and solvents and found a high correlation with the risk of developing Parkinson’s disease by people who used them.  These are often the people who work on farms or in landscape or horticultural industries..

Pesticides are types of toxic chemicals or biological agents usually identified by the type of pest they are designed to control.  Herbicides are used to control unwanted plant materials in food crops, ornamental plants and lawns and meadows.  Controls for specific types of insect or rodent pests are also included in pesticides.  Some pesticides are applied as liquid, others as powders and still others are used a bait.

Specific chemicals or combinations of chemicals were not differentiated in this survey study, nor were the methods of application or strength of the agent reviewed.  The main criteria examined was the length of time workers had been using the products.  It was noted that the risk of developing Parkinson’s increased in a dose response manner as the length of exposure to the chemicals increased.  People utilizing these chemicals had between 30 and 80 per cent increased risk.

Also included in the review materials was exposure to the chemical solvent  used in the dry cleaning industry, trichloroethylene .  Previous studies of this solvent have noted a 5 times greater risk of developing Parkinson’s.

The analysis of over 100 studies does show a causative role for pesticides and solvents in neurodegenerative disorders in people who work with them.  However more studies are needed to understand how people who may be exposed to these chemicals in hobby gardening or in residential maintenance or people who wear clothing that has been dry cleaned may be affected by these agents.  Of even more importance, is the diet of people who consume the fruits, vegetables and grains that are grown in fields treated with these chemicals.

Supreme Court to Rule on Gene Patents

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The Supreme Court of the United States is presently considering a very interesting case with  serious consequences for Parkinson’s research.  They are expected to issue their ruling by the end of June.

This case involves a company based in Utah that has obtained patents on two specific genes and developed specialized tests based on these genes.  Presently, Myriad is the only company who is able to test for these genes and the cost of this testing, about $4,000 must be borne by the patient or, more likely, their  insurance company.  The two genes involved are BRCA1  and BRCA2 which are linked to hereditary breast cancer.  However, the tests originally developed actually missed about.10% of the cancer in the mutated genes.   So they developed another test, and added $650 to $700 more to the testing process.

There are several other diagnostic genetic testing companies that also hold patents on testing for specific genes – and the profits from these tests are not small.  One study by the United Health Group found that over $5 billion a year is spent on genetic testing for about 2,500 conditions in the U.S.   One such company is 23andMe, which has the only testing protocol for familial Parkinson’s gene in this country.  Anyone who wants to know if they carry this gene must use the kit from 23andMe.

The question the Supreme Court  is asking is “are genes patentable?”  And, like most cases, there are two sides to this debate.  Research is expensive and companies who develop specific tests on specific genes depend of the income generated during the 20 years of the patent’s life to recoup their initial expense and  pursue more avenues of research.   But if the gene itself is patented,  that places the gene out of the reach of other researchers by making it too expensive to obtain and forcing them to go through a complicated process of obtaining permissions. This stand in the way of further research or developing other ways of using it.  It interferes with doctors’ ability to conduct clinical research and treat patients. These researcher feel that a gene is a part of nature and nature is not patentable.  Patents are issued for inventions, but genes are part of our DNA.

The company holding the patents claims that once a gene is extracted from the chain of DNA, it has been manipulated and therefore is no  longer a simple part of nature, that the manipulation separates it from nature and makes it comparable to an invention.

This is a philosophical as well a practical dilemma, with  wide ranging implications for the future of medical research and development of tests and  treatments.  Patents may encourage investors to back certain types of research and protect their investments. On the other side is the question of human dignity:  is not human DNA intrinsic to one’s body and therefore part of one’s very nature?  Are patents even the right way to even think about developing  and financing research along these lines?

The United States Supreme Court is not alone in considering these issues.  Australia is also considering the same charges against this company.  It may take the Supreme Court longer than June 30th to clarify the issues and render its decision.  Whatever the decision, the companies working with genetic testing are probably going to have some changes in their future.

Peripheral Neuropathic Pain

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Peripheral neuropathic pain in Parkinson’s disease has been reported to be seven times higher than in a normal population.  It has variously been attributed to insufficient vitamin B-12, perhaps from long term used of levodopa replacement medications or even to levodopa itself causing demyelination of neurons that  transmit pain impulses. In another disease, Charcot-Marie-Tooth (CMT) disease it results from a genetic mutation.  The principle of the cause of this demyelination process  in CMT has been identified and it is hoped that it will lead to treatments to alleviate this pain not only in CMT but Parkinson’s and other diseases as well.

Lawrence Wrabetz, M.D. and colleagues at the Hunter James Kelly Research Institute in Buffalo, New York, along with other European researchers have identified the mechanism by which proteins in the myelin sheath are mis-produced and found  the gene that also interferes in this mis-production process. The sheath is composed of Schwann cells  which produce myelin in nerve cells.  When the proteins that produce those cells begin synthesizing  mutated proteins, a gene called Gadd34 turns on and causes them to reproduce those mutated proteins at a much higher level, thereby increasing the problems in the myelination process.

Dr. Wrabetz’s team has also identified a way to improve myelin production with the addition  of a small molecule drug.  When salubrinal, a small molecule drug is added in both laboratory cultures and animal models of CMT Gadd34 is effectively reduced.  It partially turns off the protein syntheses process and helps restore myelination.

While Dr. Wrabetz disease model has been Charcot-Marie-Tooth disease, his main research has involved understanding myelination disorders in general.  He thinks that there may be one unifying underlying mechanism and that what applies to one disease may also apply to others.  If they are successful in finding a safe and effective dose for humans of salubrinal, the suffering from painful neuropathies will hopefully become a thing of the past.

Depression and the Subsequent Risk of Parkinson’s Disease

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This study looks at the association between depression and Parkinson’s disease (PD) in a study group of 992 PD patients that were diagnosed after 2000. The diagnosis of depression and Parkinson’s Disease were self-reported. The conclusion drawn from this study is that a depression diagnosis before 2000 was in fact associated with higher levels of PD. However, it is important to note that this study does not explore other moderators such as poor health status. The authors conclude that depression may either share etiological factors with Parkinson’s Disease or that depression may in fact be an early symptom of PD. Further study into this topic is needed.

Full article: - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2914462/


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